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Multifaceted Intervention Reduces Cost
Healthcare costs continue to increase and are estimated to be approximately $3.1 trillion per year in the United States.[1] Waste is a major contributor to this cost, accounting for an estimated $910 billion/year.[2] Laboratory tests are well documented to contribute to healthcare waste, with an estimated 30% to 50% of tests for hospitalized patients being unnecessary.[3, 4, 5] This issue has been highlighted by the American Board of Internal Medicine Foundation's Choosing Wisely campaign as an area to reduce waste.[6] Evaluating this concern locally, a University Health Systems Consortium 2011 analysis indicated that the University of Utah general internal medicine hospitalist service had a higher average direct lab cost per discharge compared to top performers, indicating an opportunity for improvement.
Multiple interventions have been described in the literature to address excessive laboratory utilization, including physician education, audit and feedback, cost information display, and administrative rules restricting certain types of ordering.[7, 8, 9, 10, 11] Despite these interventions, barriers remain common and not all interventions are sustained. For example, interventions focused mainly on education see a small improvement initially that is not sustained.[4, 12, 13] Additionally, although most studies focus on individual interventions, those that target multiple factors have been found to be more successful at producing and sustaining change.[14] Therefore, the opportunity existed to incorporate multiple etiologies into a single intervention and apply a checklist to laboratory ordering to see if combined modalities could be effective at reducing laboratory costs in a sustainable manner.
In addition to cost, there is potential patient harm resulting from unnecessary laboratory testing. For prolonged hospitalizations, anemia is a well‐recognized side effect of phlebotomy,[15, 16] and a recent evaluation of cardiac surgery patients found an average cumulative blood loss due to phlebotomy of 454 mL/hospital stay.[17] The sheer number of tests ordered can lead to false positive tests that result in additional testing and monitoring. Furthermore, patients subjected to laboratory blood draws are often awakened early in the morning, which is unpleasant and could adversely affect the patient experience.
Recognizing laboratory cost as a problem, the University of Utah general internal medicine hospitalist service implemented a multifaceted quality‐improvement initiative with a goal to reduce laboratory testing. At the time of this project, University of Utah Health Care (UUHC) developed a Value Driven Outcomes (VDO) tool to give direct data related to costs of care, including the actual cost paid by the hospital to the university‐owned laboratory vendor (ARUP Laboratories, Salt Lake City, UT) for testing.[18] The hospitalist group incorporated VDO into the initiative for routine cost feedback. This study evaluates the impact of this intervention on laboratory costs.
METHODS
Design
A retrospective, controlled, interrupted time series (ITS) study was performed to compare changes in lab costs between hospitalists (intervention study group) and other providers (control study group). The intervention initiation date was February 1, 2013. The baseline period was July 1, 2012 to January 31, 2013, as that was the period in which the VDO tool became available for cost analysis prior to intervention. The intervention period was February 1, 2013 to April 30, 2014, as there was a change in the electronic health record (EHR) in May 2014 that affected data flow and could act as a major confounder. The institutional review board classified this project as quality improvement and did not require review and oversight.
Setting
UUHC is a 500‐bed academic medical center in Salt Lake City, Utah. The hospitalist service is a teaching service composed of 4 teams with internal medicine residents and medical students. The nonhospitalist services include all surgical services, as well as pulmonary, cardiology, hematology, and oncology services on which internal medicine residents rotate. All services at UUHC are staffed by academic physicians affiliated with the University of Utah School of Medicine.
Population
All patients 18 years and older admitted to the hospital to a service other than obstetrics, rehabilitation, or psychiatry between July 1, 2012 and April 30, 2014 were evaluated. Patients with missing data for outcomes or covariates were excluded.
Intervention
Initial evaluation included an informal review of patient charts and discussion with hospitalist group members, both indicating laboratory overuse. A working group was then established including hospitalists and process engineers to evaluate the workflow by which laboratory tests were ordered. Concurrently, a literature review was performed to help identify the scope of the problem and evaluate methods that had been successful at other institutions. Through this review, it was noted that interns were the most frequent orderers of tests and the largest contributors to variation of testing for inpatients.[19] Two specific studies with direct applicability to this project demonstrated that discussion of costs with attendings in a trauma intensive care unit resulted in a 30% reduction of tests ordered,[20] and discussion of testing with a senior resident in an internal medicine inpatient setting demonstrated a 20% reduction in laboratory testing.[21]
Our laboratory reduction intervention expanded on the current literature to incorporate education, process change, cost feedback, and financial incentives. Specifically, starting February 1, 2013, the following interventions were performed:
- Education of all providers involved, including the hospitalist group and all internal medicine residents at the start of their rotation with the hospitalist service. Education included a 30‐minute discussion of laboratory overuse, costs associated with laboratory overuse, previous interventions and their success, and current intervention with goals. Each resident was provided a pocket card with the most common lab tests and associated charges. Charges were used instead of costs due to concerns regarding the possible public dissemination of institutional costs.
- Standardization of the rounding process including a checklist review (see Supporting Information, Appendix, in the online version of this article) for all patients that ensured discussion of labs, telemetry, pain, lines/tubes, nursing presence, and follow‐up needed. The expectation was that all plans for lab testing would be discussed during rounds. The third‐year medical student was responsible to ensure that all items were covered daily on each patient.
- Monthly feedback at the hospitalist group meeting regarding laboratory costs using the VDO tool. Data were presented as a monthly group average and compared to preintervention baseline costs. Individual performance could be viewed and compared to other providers within the group.
- Financial incentive through a program that shares 50% of cost savings realized by the hospital with the Division of General Internal Medicine. The incentive could be used to support future quality‐improvement projects, but there was no individual physician incentive.
Data Collection and Preparation
Clinical data were collected in the inpatient EHR (Cerner Corp., Kansas City, MO) and later imported into the enterprise data warehouse (EDW) as part of the normal data flow. Billing data were imported into the EDW from the billing system. Cost data were estimated using the VDO tool developed by the University of Utah to identify clinical costs to the UUHC system.[18]
Clinical and Cost Outcomes
We hypothesized that following the intervention, the number of tests and lab costs would decrease greater for patients in the intervention group than in the control group, with no adverse effect on length of stay (LOS) or 30‐day readmissions.
Lab cost per day was calculated as the total lab cost per visit divided by the LOS. We adjusted all lab costs to 2013 US dollars using Consumer Price Index inflation data.[22] To account for different LOS, we used LOS as a weight variable when estimating descriptive characteristics and P values for lab cost per day and the number of tests. Thirty‐day readmissions included inpatient encounters followed by another inpatient encounter within 30 days excluding obstetrics, rehabilitation, and psychiatry visits.
Descriptive Variables
We included information on age at admission in years and Charlson Comorbidity Index (CCI) to evaluate differences in control and intervention groups.[23]
Statistical Analysis
First, unadjusted descriptive statistics were calculated for study outcomes and visit characteristics. Descriptive statistics were expressed as n (%) and mean standard deviation. Simple comparisons were performed based on 2 tests of homogeneity for categorical variables and on t tests for continuous variables.
Second, an ITS analysis was conducted to evaluate the impact of the intervention while accounting for baseline trends.[24] In this analysis, the dependent variable (yt) was the difference in aggregated outcome measures between the intervention and control groups every 2 weeks (eg, difference in average lab costs in a given 2‐week period between the 2 groups). Intervention impact was then evaluated in terms of changes in the level of the outcome (b2) as well as in the trend over time (b3) compared to the initial difference in means (b0) and baseline trend (b1). The following difference‐in‐differences segmented regression model was fitted using the autoreg procedure in SAS: yt = b0 + b1*timet + b2*study periodt + b3*time after the interventiont + errort, where timet is biweekly intervals after the beginning of the study, time after the interventiont is biweekly intervals after the intervention date, and study periodt is 1 postintervention and 0 preintervention. The models were fitted using maximum likelihood and stepwise autoregression to test 24 lags.
P values <0.05 were considered significant. SAS (version 9.3; SAS Institute Inc., Cary, NC) was used for data analysis.
RESULTS
We analyzed 48,327 inpatient visits that met inclusion criteria. We excluded 15,659 obstetrics, rehabilitation, and psychiatry visits. Seven hundred seventy‐two (2.4%) of the remaining visits were excluded due to missing data. A total of 31,896 inpatient visits by 22,545 patients were included in the analysis. There were 10,136 visits before the intervention and 21,760 visits after. Characteristics of the study groups for the full study timeframe (July 1, 2012April 30, 2014) are summarized in Table 1.
| Characteristic | Study Group* | |||
|---|---|---|---|---|
| Overall, N = 31,896 | Control, N = 25,586 | Intervention, N = 6,310 | P Value | |
| ||||
| Patient characteristics | ||||
| Age, y | 55.47 17.61 | 55.27 17.13 | 56.30 19.39 | <0.001 |
| Female gender | 14,995 (47%) | 11,753 (46%) | 3,242 (51%) | <0.001 |
| CCI | 3.73 3.25 | 3.61 3.17 | 4.20 3.54 | <0.001 |
| Outcomes | ||||
| Cost per day, $ | 130.95 392.16 | 131.57 423.94 | 127.68 220.40 | 0.022 |
| Cost per visit, $ | 733.75 1,693.98 | 772.30 1,847.65 | 577.40 795.29 | <0.001 |
| BMP tests per day | 0.73 1.17 | 0.74 1.19 | 0.67 1.05 | <0.001 |
| CMP tests per day | 0.20 0.67 | 0.19 0.68 | 0.26 0.62 | <0.001 |
| CBC tests per day | 0.83 1.10 | 0.84 1.15 | 0.73 0.82 | <0.001 |
| PT/INR tests per day | 0.36 1.03 | 0.36 1.07 | 0.34 0.83 | <.001 |
| LOS, d | 5.60 7.12 | 5.87 7.55 | 4.52 4.82 | <0.001 |
| 30‐day readmissions | 4,374 (14%) | 3,603 (14%) | 771 (12%) | <0.001 |
During the study period, there were 25,586 visits in the control group and 6310 visits in the intervention group. Patients in the intervention group were on average older than patients in the control group. There were more female patients in the intervention group. Mean CCI was 4.2 in the intervention group and 3.6 in the control group. The intervention group had lower LOS and 30‐day readmissions than the control group.
Descriptive statistics and simple comparisons of covariates and outcomes before and after the intervention are shown in Table 2. Age and gender distributions remained unchanged in both groups. CCI increased in the control group by 0.24 (P < 0.001) and remained unchanged in the intervention group. In the intervention group, lab cost per day was reduced from $138 before the intervention to $123 after the intervention (P < 0.001). In contrast, among control patients, cost per day increased nonsignificantly from $130 preintervention to $132 postintervention (P = 0.37). Number of tests per day significantly decreased for all specific tests in the intervention group. Readmission rates decreased significantly from 14% to 11% in the intervention group (P = 0.01). LOS remained constant in both groups.
| Characteristic* | Control | Intervention | ||||
|---|---|---|---|---|---|---|
| Preintervention, N = 8,102 | Postintervention, N = 17,484 | P Value | Preintervention, N = 2,034 | Postintervention, N = 4,276 | P Value | |
| ||||||
| Patient characteristics | ||||||
| Age, yr | 55.17 17.46 | 55.31 16.98 | 0.55 | 55.90 19.47 | 56.50 19.35 | 0.25 |
| Female gender | 3,707 (46%) | 8,046 (46%) | 0.69 | 1,039 (51%) | 2,203 (52%) | 0.74 |
| CCI | 3.45 3.06 | 3.69 3.21 | <0.001 | 4.19 3.51 | 4.20 3.56 | 0.89 |
| Outcomes | ||||||
| Cost per day, $ | 130.1 431.8 | 132.2 420.3 | 0.37 | 137.9 232.9 | 122.9 213.5 | <0.001 |
| Cost per visit, $ | 760.4 1,813.6 | 777.8 1,863.3 | 0.48 | 617.8 844.1 | 558.2 770.3 | 0.005 |
| BMP tests per day | 0.74 1.21 | 0.74 1.18 | 0.67 | 0.75 1.03 | 0.63 1.05 | <0.001 |
| CMP tests per day | 0.19 0.68 | 0.19 0.68 | 0.85 | 0.32 0.68 | 0.23 0.58 | <0.001 |
| CBC tests per day | 0.85 1.14 | 0.84 1.15 | 0.045 | 0.92 0.79 | 0.64 0.76 | <0.001 |
| PT/INR tests per day | 0.34 1.04 | 0.37 1.08 | <0.001 | 0.35 0.82 | 0.33 0.84 | 0.020 |
| LOS, d | 5.84 7.66 | 5.88 7.50 | 0.71 | 4.48 5.12 | 4.54 4.67 | 0.63 |
| 30‐day readmissions | 1,173 (14%) | 2,430 (14%) | 0.22 | 280 (14%) | 491 (11%) | 0.010 |
ITS analysis results are shown in Table 3. After the intervention, the difference in monthly means between the 2 groups dropped by $16 for cost per day (P = 0.034) and by $128 for cost per visit (P = 0.02). The decreased cost in the intervention group amounts to approximately $251,427 (95% confidence interval [CI]: $20,370‐$482,484) savings over the first year. If the intervention was rolled out for the control group and had a similar impact, it could have led to an additional cost savings of $1,321,669 (95% CI: 107,081‐2,536,256). Moreover, the number of basic metabolic panel, comprehensive metabolic panel, and complete blood count test per day were reduced significantly more in the intervention group compared to the control group (<0.001, 0.004, and <0.001).
| Outcome | Parameter* | Parameter Estimate | Standard Error | t Value | Pr > |t| |
|---|---|---|---|---|---|
| |||||
| Lab cost per day ($) | Baseline difference level (b0) | 9.3450 | 6.5640 | 1.4237 | 0.16 |
| Baseline difference trend (b1) | 0.2150 | 0.7709 | 0.2789 | 0.78 | |
| Change in difference level after intervention(b2) | 16.1200 | 7.3297 | 2.1993 | 0.034 | |
| Change in difference trend after intervention (b3) | 0.2388 | 0.8090 | 0.2952 | 0.77 | |
| Lab cost per visit ($) | Baseline difference level (b0) | 166.081 | 48.3425 | 3.4355 | 0.001 |
| Baseline difference trend (b1) | 3.6663 | 5.8571 | 0.6260 | 0.53 | |
| Change in difference level after intervention(b2) | 128.527 | 53.0278 | 2.4238 | 0.020 | |
| Change in difference trend after intervention (b3) | 2.2586 | 5.8463 | 0.3863 | 0.70 | |
| BMP tests per day | Baseline difference level (b0) | 0.0061 | 0.0250 | 0.2439 | 0.81 |
| Baseline difference trend (b1) | 0.0004 | 0.0030 | 0.1449 | 0.89 | |
| Change in difference level after intervention(b2) | 0.1034 | 0.0276 | 3.7426 | <0.001 | |
| Change in difference trend after intervention (b3) | 0.0014 | 0.0030 | 0.4588 | 0.65 | |
| CMP tests per day | Baseline difference level (b0) | 0.1226 | 0.0226 | 5.4302 | <0.001 |
| Baseline difference trend (b1) | 0.0015 | 0.0028 | 0.5539 | 0.58 | |
| Change in difference level after intervention(b2) | 0.0754 | 0.0248 | 3.0397 | 0.004 | |
| Change in difference trend after intervention (b3) | 0.0030 | 0.0028 | 1.0937 | 0.28 | |
| CBC tests per day | Baseline difference level (b0) | 0.0539 | 0.0190 | 2.8338 | 0.007 |
| Baseline difference trend (b1) | 0.0013 | 0.0023 | 0.5594 | 0.58 | |
| Change in difference level after intervention(b2) | 0.2343 | 0.0213 | 10.997 | <0.001 | |
| Change in difference trend after intervention (b3) | 0.0036 | 0.0023 | 1.5539 | 0.13 | |
| PT/INR tests per day | Baseline difference level (b0) | 0.0413 | 0.0242 | 1.7063 | 0.096 |
| Baseline difference trend (b1) | 0.0040 | 0.0028 | 1.4095 | 0.17 | |
| Change in difference level after intervention(b2) | 0.0500 | 0.0270 | 1.8507 | 0.072 | |
| Change in difference trend after intervention (b3) | 0.0054 | 0.0030 | 1.7940 | 0.080 | |
| LOS, d | Baseline difference level (b0) | 1.4211 | 0.2746 | 5.1743 | <0.001 |
| Baseline difference trend (b1) | 0.0093 | 0.0333 | 0.2807 | 0.78 | |
| Change in difference level after intervention(b2) | 0.1007 | 0.2988 | 0.3368 | 0.74 | |
| Change in difference trend after intervention (b3) | 0.0053 | 0.0331 | 0.1588 | 0.87 | |
| 30‐day readmissions | Baseline difference level (b0) | 0.0057 | 0.0185 | 0.3084 | 0.76 |
| Baseline difference trend (b1) | 0.0017 | 0.0022 | 0.8016 | 0.43 | |
| Change in difference level after intervention(b2) | 0.0110 | 0.0206 | 0.5315 | 0.60 | |
| Change in difference trend after intervention (b3) | 0.0021 | 0.0023 | 0.9111 | 0.37 | |
Figure 1 shows a graphical representation of the biweekly means for the 2 primary outcomeslab cost per day and lab cost per visit. Figure 2 shows all other outcomes. To the right of each figure, P values are provided for the b2 coefficients from Table 3.
DISCUSSION
Through a multifaceted quality‐improvement initiative, the UUHC hospitalist group was able to reduce lab cost per day and per visit as well as commonly ordered routine labs as compared to an institutional control group. A multifaceted approach was selected given the literature supporting this approach as the most likely method to sustain improvement.[14] At the same time, the use of a multifaceted intervention makes it difficult to rigorously determine the relative impact of different components of the intervention. In discussing this issue, however, the hospitalist group felt that the driving factors for change were those related to process change, specifically, the use of a standardized rounding checklist to discuss lab testing and the routine review of lab costs at group meetings. The ultimate goal was to change the culture of routine test ordering into a thoughtful process of needed tests and thereby reduce costs. Prior to this intervention, the least experienced person on this team (the intern) ordered any test he or she wanted, usually without discussion. The intervention focused on this issue through standardized supervision and explicit discussion of laboratory tests. Importantly, although improvements from education initiatives typically decrease over time, the incorporation of process change in this intervention was felt to likely contribute to the sustained reduction seen at 15 months. Although use of the rounding checklist added another step to daily rounds, the routine cost feedback, including comparisons to peers, helped encourage use of the checklist. Thus, we feel that routine feedback was essential to sustaining the intervention and its impact.
Inappropriate and unnecessary testing has been recognized for decades, and multiple interventions have been attempted, including a recent article that demonstrated a 10% reduction in common laboratory ordering through an initiative mainly focused on education and ordering feedback.[25] Despite reported success of several interventions, none have combined multiple interventions and explicitly required discussion of laboratory tests on rounds. For example, although the UUHC intervention used Attali et al.[21] and Barie and Hydo's[20] work to develop the intervention, neither of these studies described how laboratory testing was discussed with the attending or supervising resident. The UUHC intervention thus builds on the current literature by combining other successful modalities with explicit discussion of laboratory testing via a rounding checklist and feedback with the novel VDO tool to reduce laboratory costs. A major strength of this intervention is the relatively low cost and the generalizability of implementing rounding checklists. Initial support from the hospital was needed to provide accurate VDO information to the hospitalist group. However, ongoing costs were minimal and related to any additional time spent during rounds to discuss laboratory tests. Thus, we feel that this intervention is feasible for wide replication.
Another strength of the study is the use of the VDO tool to measure actual costs. Whereas previous studies have relied on estimated costs with extrapolation to potential cost savings, this study used direct costs to the institution as a more accurate marker of cost savings. Additionally, most studies on lab utilization have used a before/after analysis without a control group. The presence of a control group for this analysis is important to help assess for institutional trends that may not be reflected in a before/after intervention. The reduction in cost in the intervention group despite a trend toward increased cost in the institutional control group supports the impact of this intervention.
Limitations of this study include that it was a single‐center, controlled ITS study and not a randomized controlled trial. Related to this limitation, the control group reflected a different patient population compared to the intervention group, with a longer LOS, lower CCI, and inclusion of nonmedical patients. However, these differences were relatively stable before and after the intervention. Also, ITS is considered one of the most robust research designs outside of randomized controlled trials, and it accounts for baseline differences in both levels and trends.[24] Nevertheless, it remains possible that secular trends existed that we did not capture and that affected the 2 populations differently.
A further limitation is that the baseline period was only 7 months and the intervention was 15 months. As the 7 months started in July, this could have reflected the time when interns were least experienced with ordering. Unfortunately, we did not have VDO availability for a full year prior to the intervention. We believe that any major effect due to this shortened baseline period should have been seen in the control group as well, and therefore accounted for in the analysis. Additionally, it is possible that there was spillover of the intervention to the control group, as internal medicine residents rotated throughout the hospital to other medical services (pulmonary, cardiology, hematology, and oncology). However, any effect of their rotation should have been to lower the control lab cost, thus making differences less profound.
CONCLUSIONS
A multifaceted approach to laboratory reduction through education, process change, cost feedback, and financial incentive resulted in a significant reduction in laboratory cost per day, laboratory cost per visit, and the ordering of common laboratory tests at a major academic medical center.
Acknowledgements
The authors thank Mr. Michael Swanicke for his assistance in process engineering, Mr. Tony Clawson for his routine provision of VDO data, and Ms. Selma Lopez for her editorial support.
Disclosures: K.K. is or has been a consultant on clinical decision support (CDS) or electronic clinical quality measurement to the US Office of the National Coordinator for Health IT, ARUP Laboratories, McKesson InterQual, ESAC, Inc., JBS International, Inc., Inflexxion, Inc., Intelligent Automation, Inc., Partners HealthCare, Mayo Clinic, and the RAND Corporation. K.K. receives royalties for a Duke University‐owned CDS technology for infectious disease management known as CustomID that he helped develop. K.K. was formerly a consultant for Religent, Inc. and a co‐owner and consultant for Clinica Software, Inc., both of which provide commercial CDS services, including through use of a CDS technology known as SEBASTIAN that K.K. developed. K.K. no longer has a financial relationship with either Religent or Clinica Software. K.K. has no competing interest with any specific product or intervention evaluated in this article. All other authors declare no competing interests.
- , , , et al. National health expenditure projections, 2014–24: spending growth faster than recent trends. Health Aff (Millwood). 2015;34(8):1407–1417.
- , . Eliminating waste in US health care. JAMA. 2012;307(14):1513–1516.
- , , , et al. Utilization of arterial blood gas measurements in a large tertiary care hospital. Am J Clin Pathol. 2007;127:604–609.
- , . Strategies to promote rational clinical chemistry test utilization. Clin Biochem. 1996;29:291–299.
- , , , , . The landscape of inappropriate laboratory testing: a 15‐year meta‐analysis. PLoS One. 2013;8:e78962.
- ABIM Choosing Wisely Society of Hospital Medicine–Adult Hospital Medicine. Five things physicians and patients should question. Available at: http://www.choosingwisely.org/societies/society‐of‐hospital‐medicine‐adult. Published February 21, 2013. Accessed September 2, 2015.
- , , , , , . Effect of daily charge feedback on inpatient charges and physician knowledge and behavior. Arch Intern Med. 1989;149:426–429.
- , , , et al. A utilization management intervention to reduce unnecessary testing in the coronary care unit. Arch Intern Med. 2002;162:1885–1890.
- , , , et al. The impact of peer management on test‐ordering behavior. Ann Intern Med. 2004;141:196–204.
- , , , , . An administrative intervention to improve the utilization of laboratory tests within a university hospital. Int J Qual Health Care. 2005;17:243–248.
- , , , et al. Impact of providing fee data on laboratory test ordering. JAMA Intern Med. 2013;173(10):903–908.
- , , , et al. The failure of physician education as a cost containment strategy. JAMA. 1984;252:225–230.
- . Is that lab test necessary? Am J Clin Pathol. 2006;126:335–336.
- , , , . Techniques to improve physicians' use of diagnostic tests. JAMA. 1998;280:2020–2027.
- , , . Laboratory testing in the intensive care unit. Crit Care Clin. 2007;23:435–465.
- . Complications of critical care: lab testing and iatrogenic anemia. MLO Med Lab Obs. 200;33(10):28–31.
- , , , et al. Contemporary bloodletting in cardiac surgical care. Ann Thorac Surg. 2015;99:779–785.
- , , , et al. Value Driven Outcomes (VDO): a pragmatic, modular, and extensible software framework for understanding and improving health care costs and outcomes. J Am Med Inform Assoc. 2015:22:223–235.
- , , . The impact of residents, interns, and attendings on inpatient laboratory ordering patterns: a report from one university's hospitalist service. Acad Med. 2011;86:139–145.
- , . Learning to not know: results of a program for ancillary cost reduction in surgical care. J Trauma. 1996;41:714–720.
- , , , et al. A cost‐effective method for reducing the volume of laboratory tests in a university‐associated teaching hospital. Mt Sinai J Med. 2006;73:787–794.
- US Bureau of Labor Statistics. CPI inflation calculator. Available at: http://www.bls.gov/data/inflation_calculator.htm. Accessed May 22, 2015.
- , , , et al. Coding algorithms for defining comorbidities in ICD‐9‐CM and ICD‐10 administrative data. Med Care. 2005;43:113–1139.
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- , , , et al. A multifaceted hospitalist quality improvement intervention: decreased frequency of common labs. J Hosp Med. 2015;10:390–395.
Healthcare costs continue to increase and are estimated to be approximately $3.1 trillion per year in the United States.[1] Waste is a major contributor to this cost, accounting for an estimated $910 billion/year.[2] Laboratory tests are well documented to contribute to healthcare waste, with an estimated 30% to 50% of tests for hospitalized patients being unnecessary.[3, 4, 5] This issue has been highlighted by the American Board of Internal Medicine Foundation's Choosing Wisely campaign as an area to reduce waste.[6] Evaluating this concern locally, a University Health Systems Consortium 2011 analysis indicated that the University of Utah general internal medicine hospitalist service had a higher average direct lab cost per discharge compared to top performers, indicating an opportunity for improvement.
Multiple interventions have been described in the literature to address excessive laboratory utilization, including physician education, audit and feedback, cost information display, and administrative rules restricting certain types of ordering.[7, 8, 9, 10, 11] Despite these interventions, barriers remain common and not all interventions are sustained. For example, interventions focused mainly on education see a small improvement initially that is not sustained.[4, 12, 13] Additionally, although most studies focus on individual interventions, those that target multiple factors have been found to be more successful at producing and sustaining change.[14] Therefore, the opportunity existed to incorporate multiple etiologies into a single intervention and apply a checklist to laboratory ordering to see if combined modalities could be effective at reducing laboratory costs in a sustainable manner.
In addition to cost, there is potential patient harm resulting from unnecessary laboratory testing. For prolonged hospitalizations, anemia is a well‐recognized side effect of phlebotomy,[15, 16] and a recent evaluation of cardiac surgery patients found an average cumulative blood loss due to phlebotomy of 454 mL/hospital stay.[17] The sheer number of tests ordered can lead to false positive tests that result in additional testing and monitoring. Furthermore, patients subjected to laboratory blood draws are often awakened early in the morning, which is unpleasant and could adversely affect the patient experience.
Recognizing laboratory cost as a problem, the University of Utah general internal medicine hospitalist service implemented a multifaceted quality‐improvement initiative with a goal to reduce laboratory testing. At the time of this project, University of Utah Health Care (UUHC) developed a Value Driven Outcomes (VDO) tool to give direct data related to costs of care, including the actual cost paid by the hospital to the university‐owned laboratory vendor (ARUP Laboratories, Salt Lake City, UT) for testing.[18] The hospitalist group incorporated VDO into the initiative for routine cost feedback. This study evaluates the impact of this intervention on laboratory costs.
METHODS
Design
A retrospective, controlled, interrupted time series (ITS) study was performed to compare changes in lab costs between hospitalists (intervention study group) and other providers (control study group). The intervention initiation date was February 1, 2013. The baseline period was July 1, 2012 to January 31, 2013, as that was the period in which the VDO tool became available for cost analysis prior to intervention. The intervention period was February 1, 2013 to April 30, 2014, as there was a change in the electronic health record (EHR) in May 2014 that affected data flow and could act as a major confounder. The institutional review board classified this project as quality improvement and did not require review and oversight.
Setting
UUHC is a 500‐bed academic medical center in Salt Lake City, Utah. The hospitalist service is a teaching service composed of 4 teams with internal medicine residents and medical students. The nonhospitalist services include all surgical services, as well as pulmonary, cardiology, hematology, and oncology services on which internal medicine residents rotate. All services at UUHC are staffed by academic physicians affiliated with the University of Utah School of Medicine.
Population
All patients 18 years and older admitted to the hospital to a service other than obstetrics, rehabilitation, or psychiatry between July 1, 2012 and April 30, 2014 were evaluated. Patients with missing data for outcomes or covariates were excluded.
Intervention
Initial evaluation included an informal review of patient charts and discussion with hospitalist group members, both indicating laboratory overuse. A working group was then established including hospitalists and process engineers to evaluate the workflow by which laboratory tests were ordered. Concurrently, a literature review was performed to help identify the scope of the problem and evaluate methods that had been successful at other institutions. Through this review, it was noted that interns were the most frequent orderers of tests and the largest contributors to variation of testing for inpatients.[19] Two specific studies with direct applicability to this project demonstrated that discussion of costs with attendings in a trauma intensive care unit resulted in a 30% reduction of tests ordered,[20] and discussion of testing with a senior resident in an internal medicine inpatient setting demonstrated a 20% reduction in laboratory testing.[21]
Our laboratory reduction intervention expanded on the current literature to incorporate education, process change, cost feedback, and financial incentives. Specifically, starting February 1, 2013, the following interventions were performed:
- Education of all providers involved, including the hospitalist group and all internal medicine residents at the start of their rotation with the hospitalist service. Education included a 30‐minute discussion of laboratory overuse, costs associated with laboratory overuse, previous interventions and their success, and current intervention with goals. Each resident was provided a pocket card with the most common lab tests and associated charges. Charges were used instead of costs due to concerns regarding the possible public dissemination of institutional costs.
- Standardization of the rounding process including a checklist review (see Supporting Information, Appendix, in the online version of this article) for all patients that ensured discussion of labs, telemetry, pain, lines/tubes, nursing presence, and follow‐up needed. The expectation was that all plans for lab testing would be discussed during rounds. The third‐year medical student was responsible to ensure that all items were covered daily on each patient.
- Monthly feedback at the hospitalist group meeting regarding laboratory costs using the VDO tool. Data were presented as a monthly group average and compared to preintervention baseline costs. Individual performance could be viewed and compared to other providers within the group.
- Financial incentive through a program that shares 50% of cost savings realized by the hospital with the Division of General Internal Medicine. The incentive could be used to support future quality‐improvement projects, but there was no individual physician incentive.
Data Collection and Preparation
Clinical data were collected in the inpatient EHR (Cerner Corp., Kansas City, MO) and later imported into the enterprise data warehouse (EDW) as part of the normal data flow. Billing data were imported into the EDW from the billing system. Cost data were estimated using the VDO tool developed by the University of Utah to identify clinical costs to the UUHC system.[18]
Clinical and Cost Outcomes
We hypothesized that following the intervention, the number of tests and lab costs would decrease greater for patients in the intervention group than in the control group, with no adverse effect on length of stay (LOS) or 30‐day readmissions.
Lab cost per day was calculated as the total lab cost per visit divided by the LOS. We adjusted all lab costs to 2013 US dollars using Consumer Price Index inflation data.[22] To account for different LOS, we used LOS as a weight variable when estimating descriptive characteristics and P values for lab cost per day and the number of tests. Thirty‐day readmissions included inpatient encounters followed by another inpatient encounter within 30 days excluding obstetrics, rehabilitation, and psychiatry visits.
Descriptive Variables
We included information on age at admission in years and Charlson Comorbidity Index (CCI) to evaluate differences in control and intervention groups.[23]
Statistical Analysis
First, unadjusted descriptive statistics were calculated for study outcomes and visit characteristics. Descriptive statistics were expressed as n (%) and mean standard deviation. Simple comparisons were performed based on 2 tests of homogeneity for categorical variables and on t tests for continuous variables.
Second, an ITS analysis was conducted to evaluate the impact of the intervention while accounting for baseline trends.[24] In this analysis, the dependent variable (yt) was the difference in aggregated outcome measures between the intervention and control groups every 2 weeks (eg, difference in average lab costs in a given 2‐week period between the 2 groups). Intervention impact was then evaluated in terms of changes in the level of the outcome (b2) as well as in the trend over time (b3) compared to the initial difference in means (b0) and baseline trend (b1). The following difference‐in‐differences segmented regression model was fitted using the autoreg procedure in SAS: yt = b0 + b1*timet + b2*study periodt + b3*time after the interventiont + errort, where timet is biweekly intervals after the beginning of the study, time after the interventiont is biweekly intervals after the intervention date, and study periodt is 1 postintervention and 0 preintervention. The models were fitted using maximum likelihood and stepwise autoregression to test 24 lags.
P values <0.05 were considered significant. SAS (version 9.3; SAS Institute Inc., Cary, NC) was used for data analysis.
RESULTS
We analyzed 48,327 inpatient visits that met inclusion criteria. We excluded 15,659 obstetrics, rehabilitation, and psychiatry visits. Seven hundred seventy‐two (2.4%) of the remaining visits were excluded due to missing data. A total of 31,896 inpatient visits by 22,545 patients were included in the analysis. There were 10,136 visits before the intervention and 21,760 visits after. Characteristics of the study groups for the full study timeframe (July 1, 2012April 30, 2014) are summarized in Table 1.
| Characteristic | Study Group* | |||
|---|---|---|---|---|
| Overall, N = 31,896 | Control, N = 25,586 | Intervention, N = 6,310 | P Value | |
| ||||
| Patient characteristics | ||||
| Age, y | 55.47 17.61 | 55.27 17.13 | 56.30 19.39 | <0.001 |
| Female gender | 14,995 (47%) | 11,753 (46%) | 3,242 (51%) | <0.001 |
| CCI | 3.73 3.25 | 3.61 3.17 | 4.20 3.54 | <0.001 |
| Outcomes | ||||
| Cost per day, $ | 130.95 392.16 | 131.57 423.94 | 127.68 220.40 | 0.022 |
| Cost per visit, $ | 733.75 1,693.98 | 772.30 1,847.65 | 577.40 795.29 | <0.001 |
| BMP tests per day | 0.73 1.17 | 0.74 1.19 | 0.67 1.05 | <0.001 |
| CMP tests per day | 0.20 0.67 | 0.19 0.68 | 0.26 0.62 | <0.001 |
| CBC tests per day | 0.83 1.10 | 0.84 1.15 | 0.73 0.82 | <0.001 |
| PT/INR tests per day | 0.36 1.03 | 0.36 1.07 | 0.34 0.83 | <.001 |
| LOS, d | 5.60 7.12 | 5.87 7.55 | 4.52 4.82 | <0.001 |
| 30‐day readmissions | 4,374 (14%) | 3,603 (14%) | 771 (12%) | <0.001 |
During the study period, there were 25,586 visits in the control group and 6310 visits in the intervention group. Patients in the intervention group were on average older than patients in the control group. There were more female patients in the intervention group. Mean CCI was 4.2 in the intervention group and 3.6 in the control group. The intervention group had lower LOS and 30‐day readmissions than the control group.
Descriptive statistics and simple comparisons of covariates and outcomes before and after the intervention are shown in Table 2. Age and gender distributions remained unchanged in both groups. CCI increased in the control group by 0.24 (P < 0.001) and remained unchanged in the intervention group. In the intervention group, lab cost per day was reduced from $138 before the intervention to $123 after the intervention (P < 0.001). In contrast, among control patients, cost per day increased nonsignificantly from $130 preintervention to $132 postintervention (P = 0.37). Number of tests per day significantly decreased for all specific tests in the intervention group. Readmission rates decreased significantly from 14% to 11% in the intervention group (P = 0.01). LOS remained constant in both groups.
| Characteristic* | Control | Intervention | ||||
|---|---|---|---|---|---|---|
| Preintervention, N = 8,102 | Postintervention, N = 17,484 | P Value | Preintervention, N = 2,034 | Postintervention, N = 4,276 | P Value | |
| ||||||
| Patient characteristics | ||||||
| Age, yr | 55.17 17.46 | 55.31 16.98 | 0.55 | 55.90 19.47 | 56.50 19.35 | 0.25 |
| Female gender | 3,707 (46%) | 8,046 (46%) | 0.69 | 1,039 (51%) | 2,203 (52%) | 0.74 |
| CCI | 3.45 3.06 | 3.69 3.21 | <0.001 | 4.19 3.51 | 4.20 3.56 | 0.89 |
| Outcomes | ||||||
| Cost per day, $ | 130.1 431.8 | 132.2 420.3 | 0.37 | 137.9 232.9 | 122.9 213.5 | <0.001 |
| Cost per visit, $ | 760.4 1,813.6 | 777.8 1,863.3 | 0.48 | 617.8 844.1 | 558.2 770.3 | 0.005 |
| BMP tests per day | 0.74 1.21 | 0.74 1.18 | 0.67 | 0.75 1.03 | 0.63 1.05 | <0.001 |
| CMP tests per day | 0.19 0.68 | 0.19 0.68 | 0.85 | 0.32 0.68 | 0.23 0.58 | <0.001 |
| CBC tests per day | 0.85 1.14 | 0.84 1.15 | 0.045 | 0.92 0.79 | 0.64 0.76 | <0.001 |
| PT/INR tests per day | 0.34 1.04 | 0.37 1.08 | <0.001 | 0.35 0.82 | 0.33 0.84 | 0.020 |
| LOS, d | 5.84 7.66 | 5.88 7.50 | 0.71 | 4.48 5.12 | 4.54 4.67 | 0.63 |
| 30‐day readmissions | 1,173 (14%) | 2,430 (14%) | 0.22 | 280 (14%) | 491 (11%) | 0.010 |
ITS analysis results are shown in Table 3. After the intervention, the difference in monthly means between the 2 groups dropped by $16 for cost per day (P = 0.034) and by $128 for cost per visit (P = 0.02). The decreased cost in the intervention group amounts to approximately $251,427 (95% confidence interval [CI]: $20,370‐$482,484) savings over the first year. If the intervention was rolled out for the control group and had a similar impact, it could have led to an additional cost savings of $1,321,669 (95% CI: 107,081‐2,536,256). Moreover, the number of basic metabolic panel, comprehensive metabolic panel, and complete blood count test per day were reduced significantly more in the intervention group compared to the control group (<0.001, 0.004, and <0.001).
| Outcome | Parameter* | Parameter Estimate | Standard Error | t Value | Pr > |t| |
|---|---|---|---|---|---|
| |||||
| Lab cost per day ($) | Baseline difference level (b0) | 9.3450 | 6.5640 | 1.4237 | 0.16 |
| Baseline difference trend (b1) | 0.2150 | 0.7709 | 0.2789 | 0.78 | |
| Change in difference level after intervention(b2) | 16.1200 | 7.3297 | 2.1993 | 0.034 | |
| Change in difference trend after intervention (b3) | 0.2388 | 0.8090 | 0.2952 | 0.77 | |
| Lab cost per visit ($) | Baseline difference level (b0) | 166.081 | 48.3425 | 3.4355 | 0.001 |
| Baseline difference trend (b1) | 3.6663 | 5.8571 | 0.6260 | 0.53 | |
| Change in difference level after intervention(b2) | 128.527 | 53.0278 | 2.4238 | 0.020 | |
| Change in difference trend after intervention (b3) | 2.2586 | 5.8463 | 0.3863 | 0.70 | |
| BMP tests per day | Baseline difference level (b0) | 0.0061 | 0.0250 | 0.2439 | 0.81 |
| Baseline difference trend (b1) | 0.0004 | 0.0030 | 0.1449 | 0.89 | |
| Change in difference level after intervention(b2) | 0.1034 | 0.0276 | 3.7426 | <0.001 | |
| Change in difference trend after intervention (b3) | 0.0014 | 0.0030 | 0.4588 | 0.65 | |
| CMP tests per day | Baseline difference level (b0) | 0.1226 | 0.0226 | 5.4302 | <0.001 |
| Baseline difference trend (b1) | 0.0015 | 0.0028 | 0.5539 | 0.58 | |
| Change in difference level after intervention(b2) | 0.0754 | 0.0248 | 3.0397 | 0.004 | |
| Change in difference trend after intervention (b3) | 0.0030 | 0.0028 | 1.0937 | 0.28 | |
| CBC tests per day | Baseline difference level (b0) | 0.0539 | 0.0190 | 2.8338 | 0.007 |
| Baseline difference trend (b1) | 0.0013 | 0.0023 | 0.5594 | 0.58 | |
| Change in difference level after intervention(b2) | 0.2343 | 0.0213 | 10.997 | <0.001 | |
| Change in difference trend after intervention (b3) | 0.0036 | 0.0023 | 1.5539 | 0.13 | |
| PT/INR tests per day | Baseline difference level (b0) | 0.0413 | 0.0242 | 1.7063 | 0.096 |
| Baseline difference trend (b1) | 0.0040 | 0.0028 | 1.4095 | 0.17 | |
| Change in difference level after intervention(b2) | 0.0500 | 0.0270 | 1.8507 | 0.072 | |
| Change in difference trend after intervention (b3) | 0.0054 | 0.0030 | 1.7940 | 0.080 | |
| LOS, d | Baseline difference level (b0) | 1.4211 | 0.2746 | 5.1743 | <0.001 |
| Baseline difference trend (b1) | 0.0093 | 0.0333 | 0.2807 | 0.78 | |
| Change in difference level after intervention(b2) | 0.1007 | 0.2988 | 0.3368 | 0.74 | |
| Change in difference trend after intervention (b3) | 0.0053 | 0.0331 | 0.1588 | 0.87 | |
| 30‐day readmissions | Baseline difference level (b0) | 0.0057 | 0.0185 | 0.3084 | 0.76 |
| Baseline difference trend (b1) | 0.0017 | 0.0022 | 0.8016 | 0.43 | |
| Change in difference level after intervention(b2) | 0.0110 | 0.0206 | 0.5315 | 0.60 | |
| Change in difference trend after intervention (b3) | 0.0021 | 0.0023 | 0.9111 | 0.37 | |
Figure 1 shows a graphical representation of the biweekly means for the 2 primary outcomeslab cost per day and lab cost per visit. Figure 2 shows all other outcomes. To the right of each figure, P values are provided for the b2 coefficients from Table 3.
DISCUSSION
Through a multifaceted quality‐improvement initiative, the UUHC hospitalist group was able to reduce lab cost per day and per visit as well as commonly ordered routine labs as compared to an institutional control group. A multifaceted approach was selected given the literature supporting this approach as the most likely method to sustain improvement.[14] At the same time, the use of a multifaceted intervention makes it difficult to rigorously determine the relative impact of different components of the intervention. In discussing this issue, however, the hospitalist group felt that the driving factors for change were those related to process change, specifically, the use of a standardized rounding checklist to discuss lab testing and the routine review of lab costs at group meetings. The ultimate goal was to change the culture of routine test ordering into a thoughtful process of needed tests and thereby reduce costs. Prior to this intervention, the least experienced person on this team (the intern) ordered any test he or she wanted, usually without discussion. The intervention focused on this issue through standardized supervision and explicit discussion of laboratory tests. Importantly, although improvements from education initiatives typically decrease over time, the incorporation of process change in this intervention was felt to likely contribute to the sustained reduction seen at 15 months. Although use of the rounding checklist added another step to daily rounds, the routine cost feedback, including comparisons to peers, helped encourage use of the checklist. Thus, we feel that routine feedback was essential to sustaining the intervention and its impact.
Inappropriate and unnecessary testing has been recognized for decades, and multiple interventions have been attempted, including a recent article that demonstrated a 10% reduction in common laboratory ordering through an initiative mainly focused on education and ordering feedback.[25] Despite reported success of several interventions, none have combined multiple interventions and explicitly required discussion of laboratory tests on rounds. For example, although the UUHC intervention used Attali et al.[21] and Barie and Hydo's[20] work to develop the intervention, neither of these studies described how laboratory testing was discussed with the attending or supervising resident. The UUHC intervention thus builds on the current literature by combining other successful modalities with explicit discussion of laboratory testing via a rounding checklist and feedback with the novel VDO tool to reduce laboratory costs. A major strength of this intervention is the relatively low cost and the generalizability of implementing rounding checklists. Initial support from the hospital was needed to provide accurate VDO information to the hospitalist group. However, ongoing costs were minimal and related to any additional time spent during rounds to discuss laboratory tests. Thus, we feel that this intervention is feasible for wide replication.
Another strength of the study is the use of the VDO tool to measure actual costs. Whereas previous studies have relied on estimated costs with extrapolation to potential cost savings, this study used direct costs to the institution as a more accurate marker of cost savings. Additionally, most studies on lab utilization have used a before/after analysis without a control group. The presence of a control group for this analysis is important to help assess for institutional trends that may not be reflected in a before/after intervention. The reduction in cost in the intervention group despite a trend toward increased cost in the institutional control group supports the impact of this intervention.
Limitations of this study include that it was a single‐center, controlled ITS study and not a randomized controlled trial. Related to this limitation, the control group reflected a different patient population compared to the intervention group, with a longer LOS, lower CCI, and inclusion of nonmedical patients. However, these differences were relatively stable before and after the intervention. Also, ITS is considered one of the most robust research designs outside of randomized controlled trials, and it accounts for baseline differences in both levels and trends.[24] Nevertheless, it remains possible that secular trends existed that we did not capture and that affected the 2 populations differently.
A further limitation is that the baseline period was only 7 months and the intervention was 15 months. As the 7 months started in July, this could have reflected the time when interns were least experienced with ordering. Unfortunately, we did not have VDO availability for a full year prior to the intervention. We believe that any major effect due to this shortened baseline period should have been seen in the control group as well, and therefore accounted for in the analysis. Additionally, it is possible that there was spillover of the intervention to the control group, as internal medicine residents rotated throughout the hospital to other medical services (pulmonary, cardiology, hematology, and oncology). However, any effect of their rotation should have been to lower the control lab cost, thus making differences less profound.
CONCLUSIONS
A multifaceted approach to laboratory reduction through education, process change, cost feedback, and financial incentive resulted in a significant reduction in laboratory cost per day, laboratory cost per visit, and the ordering of common laboratory tests at a major academic medical center.
Acknowledgements
The authors thank Mr. Michael Swanicke for his assistance in process engineering, Mr. Tony Clawson for his routine provision of VDO data, and Ms. Selma Lopez for her editorial support.
Disclosures: K.K. is or has been a consultant on clinical decision support (CDS) or electronic clinical quality measurement to the US Office of the National Coordinator for Health IT, ARUP Laboratories, McKesson InterQual, ESAC, Inc., JBS International, Inc., Inflexxion, Inc., Intelligent Automation, Inc., Partners HealthCare, Mayo Clinic, and the RAND Corporation. K.K. receives royalties for a Duke University‐owned CDS technology for infectious disease management known as CustomID that he helped develop. K.K. was formerly a consultant for Religent, Inc. and a co‐owner and consultant for Clinica Software, Inc., both of which provide commercial CDS services, including through use of a CDS technology known as SEBASTIAN that K.K. developed. K.K. no longer has a financial relationship with either Religent or Clinica Software. K.K. has no competing interest with any specific product or intervention evaluated in this article. All other authors declare no competing interests.
Healthcare costs continue to increase and are estimated to be approximately $3.1 trillion per year in the United States.[1] Waste is a major contributor to this cost, accounting for an estimated $910 billion/year.[2] Laboratory tests are well documented to contribute to healthcare waste, with an estimated 30% to 50% of tests for hospitalized patients being unnecessary.[3, 4, 5] This issue has been highlighted by the American Board of Internal Medicine Foundation's Choosing Wisely campaign as an area to reduce waste.[6] Evaluating this concern locally, a University Health Systems Consortium 2011 analysis indicated that the University of Utah general internal medicine hospitalist service had a higher average direct lab cost per discharge compared to top performers, indicating an opportunity for improvement.
Multiple interventions have been described in the literature to address excessive laboratory utilization, including physician education, audit and feedback, cost information display, and administrative rules restricting certain types of ordering.[7, 8, 9, 10, 11] Despite these interventions, barriers remain common and not all interventions are sustained. For example, interventions focused mainly on education see a small improvement initially that is not sustained.[4, 12, 13] Additionally, although most studies focus on individual interventions, those that target multiple factors have been found to be more successful at producing and sustaining change.[14] Therefore, the opportunity existed to incorporate multiple etiologies into a single intervention and apply a checklist to laboratory ordering to see if combined modalities could be effective at reducing laboratory costs in a sustainable manner.
In addition to cost, there is potential patient harm resulting from unnecessary laboratory testing. For prolonged hospitalizations, anemia is a well‐recognized side effect of phlebotomy,[15, 16] and a recent evaluation of cardiac surgery patients found an average cumulative blood loss due to phlebotomy of 454 mL/hospital stay.[17] The sheer number of tests ordered can lead to false positive tests that result in additional testing and monitoring. Furthermore, patients subjected to laboratory blood draws are often awakened early in the morning, which is unpleasant and could adversely affect the patient experience.
Recognizing laboratory cost as a problem, the University of Utah general internal medicine hospitalist service implemented a multifaceted quality‐improvement initiative with a goal to reduce laboratory testing. At the time of this project, University of Utah Health Care (UUHC) developed a Value Driven Outcomes (VDO) tool to give direct data related to costs of care, including the actual cost paid by the hospital to the university‐owned laboratory vendor (ARUP Laboratories, Salt Lake City, UT) for testing.[18] The hospitalist group incorporated VDO into the initiative for routine cost feedback. This study evaluates the impact of this intervention on laboratory costs.
METHODS
Design
A retrospective, controlled, interrupted time series (ITS) study was performed to compare changes in lab costs between hospitalists (intervention study group) and other providers (control study group). The intervention initiation date was February 1, 2013. The baseline period was July 1, 2012 to January 31, 2013, as that was the period in which the VDO tool became available for cost analysis prior to intervention. The intervention period was February 1, 2013 to April 30, 2014, as there was a change in the electronic health record (EHR) in May 2014 that affected data flow and could act as a major confounder. The institutional review board classified this project as quality improvement and did not require review and oversight.
Setting
UUHC is a 500‐bed academic medical center in Salt Lake City, Utah. The hospitalist service is a teaching service composed of 4 teams with internal medicine residents and medical students. The nonhospitalist services include all surgical services, as well as pulmonary, cardiology, hematology, and oncology services on which internal medicine residents rotate. All services at UUHC are staffed by academic physicians affiliated with the University of Utah School of Medicine.
Population
All patients 18 years and older admitted to the hospital to a service other than obstetrics, rehabilitation, or psychiatry between July 1, 2012 and April 30, 2014 were evaluated. Patients with missing data for outcomes or covariates were excluded.
Intervention
Initial evaluation included an informal review of patient charts and discussion with hospitalist group members, both indicating laboratory overuse. A working group was then established including hospitalists and process engineers to evaluate the workflow by which laboratory tests were ordered. Concurrently, a literature review was performed to help identify the scope of the problem and evaluate methods that had been successful at other institutions. Through this review, it was noted that interns were the most frequent orderers of tests and the largest contributors to variation of testing for inpatients.[19] Two specific studies with direct applicability to this project demonstrated that discussion of costs with attendings in a trauma intensive care unit resulted in a 30% reduction of tests ordered,[20] and discussion of testing with a senior resident in an internal medicine inpatient setting demonstrated a 20% reduction in laboratory testing.[21]
Our laboratory reduction intervention expanded on the current literature to incorporate education, process change, cost feedback, and financial incentives. Specifically, starting February 1, 2013, the following interventions were performed:
- Education of all providers involved, including the hospitalist group and all internal medicine residents at the start of their rotation with the hospitalist service. Education included a 30‐minute discussion of laboratory overuse, costs associated with laboratory overuse, previous interventions and their success, and current intervention with goals. Each resident was provided a pocket card with the most common lab tests and associated charges. Charges were used instead of costs due to concerns regarding the possible public dissemination of institutional costs.
- Standardization of the rounding process including a checklist review (see Supporting Information, Appendix, in the online version of this article) for all patients that ensured discussion of labs, telemetry, pain, lines/tubes, nursing presence, and follow‐up needed. The expectation was that all plans for lab testing would be discussed during rounds. The third‐year medical student was responsible to ensure that all items were covered daily on each patient.
- Monthly feedback at the hospitalist group meeting regarding laboratory costs using the VDO tool. Data were presented as a monthly group average and compared to preintervention baseline costs. Individual performance could be viewed and compared to other providers within the group.
- Financial incentive through a program that shares 50% of cost savings realized by the hospital with the Division of General Internal Medicine. The incentive could be used to support future quality‐improvement projects, but there was no individual physician incentive.
Data Collection and Preparation
Clinical data were collected in the inpatient EHR (Cerner Corp., Kansas City, MO) and later imported into the enterprise data warehouse (EDW) as part of the normal data flow. Billing data were imported into the EDW from the billing system. Cost data were estimated using the VDO tool developed by the University of Utah to identify clinical costs to the UUHC system.[18]
Clinical and Cost Outcomes
We hypothesized that following the intervention, the number of tests and lab costs would decrease greater for patients in the intervention group than in the control group, with no adverse effect on length of stay (LOS) or 30‐day readmissions.
Lab cost per day was calculated as the total lab cost per visit divided by the LOS. We adjusted all lab costs to 2013 US dollars using Consumer Price Index inflation data.[22] To account for different LOS, we used LOS as a weight variable when estimating descriptive characteristics and P values for lab cost per day and the number of tests. Thirty‐day readmissions included inpatient encounters followed by another inpatient encounter within 30 days excluding obstetrics, rehabilitation, and psychiatry visits.
Descriptive Variables
We included information on age at admission in years and Charlson Comorbidity Index (CCI) to evaluate differences in control and intervention groups.[23]
Statistical Analysis
First, unadjusted descriptive statistics were calculated for study outcomes and visit characteristics. Descriptive statistics were expressed as n (%) and mean standard deviation. Simple comparisons were performed based on 2 tests of homogeneity for categorical variables and on t tests for continuous variables.
Second, an ITS analysis was conducted to evaluate the impact of the intervention while accounting for baseline trends.[24] In this analysis, the dependent variable (yt) was the difference in aggregated outcome measures between the intervention and control groups every 2 weeks (eg, difference in average lab costs in a given 2‐week period between the 2 groups). Intervention impact was then evaluated in terms of changes in the level of the outcome (b2) as well as in the trend over time (b3) compared to the initial difference in means (b0) and baseline trend (b1). The following difference‐in‐differences segmented regression model was fitted using the autoreg procedure in SAS: yt = b0 + b1*timet + b2*study periodt + b3*time after the interventiont + errort, where timet is biweekly intervals after the beginning of the study, time after the interventiont is biweekly intervals after the intervention date, and study periodt is 1 postintervention and 0 preintervention. The models were fitted using maximum likelihood and stepwise autoregression to test 24 lags.
P values <0.05 were considered significant. SAS (version 9.3; SAS Institute Inc., Cary, NC) was used for data analysis.
RESULTS
We analyzed 48,327 inpatient visits that met inclusion criteria. We excluded 15,659 obstetrics, rehabilitation, and psychiatry visits. Seven hundred seventy‐two (2.4%) of the remaining visits were excluded due to missing data. A total of 31,896 inpatient visits by 22,545 patients were included in the analysis. There were 10,136 visits before the intervention and 21,760 visits after. Characteristics of the study groups for the full study timeframe (July 1, 2012April 30, 2014) are summarized in Table 1.
| Characteristic | Study Group* | |||
|---|---|---|---|---|
| Overall, N = 31,896 | Control, N = 25,586 | Intervention, N = 6,310 | P Value | |
| ||||
| Patient characteristics | ||||
| Age, y | 55.47 17.61 | 55.27 17.13 | 56.30 19.39 | <0.001 |
| Female gender | 14,995 (47%) | 11,753 (46%) | 3,242 (51%) | <0.001 |
| CCI | 3.73 3.25 | 3.61 3.17 | 4.20 3.54 | <0.001 |
| Outcomes | ||||
| Cost per day, $ | 130.95 392.16 | 131.57 423.94 | 127.68 220.40 | 0.022 |
| Cost per visit, $ | 733.75 1,693.98 | 772.30 1,847.65 | 577.40 795.29 | <0.001 |
| BMP tests per day | 0.73 1.17 | 0.74 1.19 | 0.67 1.05 | <0.001 |
| CMP tests per day | 0.20 0.67 | 0.19 0.68 | 0.26 0.62 | <0.001 |
| CBC tests per day | 0.83 1.10 | 0.84 1.15 | 0.73 0.82 | <0.001 |
| PT/INR tests per day | 0.36 1.03 | 0.36 1.07 | 0.34 0.83 | <.001 |
| LOS, d | 5.60 7.12 | 5.87 7.55 | 4.52 4.82 | <0.001 |
| 30‐day readmissions | 4,374 (14%) | 3,603 (14%) | 771 (12%) | <0.001 |
During the study period, there were 25,586 visits in the control group and 6310 visits in the intervention group. Patients in the intervention group were on average older than patients in the control group. There were more female patients in the intervention group. Mean CCI was 4.2 in the intervention group and 3.6 in the control group. The intervention group had lower LOS and 30‐day readmissions than the control group.
Descriptive statistics and simple comparisons of covariates and outcomes before and after the intervention are shown in Table 2. Age and gender distributions remained unchanged in both groups. CCI increased in the control group by 0.24 (P < 0.001) and remained unchanged in the intervention group. In the intervention group, lab cost per day was reduced from $138 before the intervention to $123 after the intervention (P < 0.001). In contrast, among control patients, cost per day increased nonsignificantly from $130 preintervention to $132 postintervention (P = 0.37). Number of tests per day significantly decreased for all specific tests in the intervention group. Readmission rates decreased significantly from 14% to 11% in the intervention group (P = 0.01). LOS remained constant in both groups.
| Characteristic* | Control | Intervention | ||||
|---|---|---|---|---|---|---|
| Preintervention, N = 8,102 | Postintervention, N = 17,484 | P Value | Preintervention, N = 2,034 | Postintervention, N = 4,276 | P Value | |
| ||||||
| Patient characteristics | ||||||
| Age, yr | 55.17 17.46 | 55.31 16.98 | 0.55 | 55.90 19.47 | 56.50 19.35 | 0.25 |
| Female gender | 3,707 (46%) | 8,046 (46%) | 0.69 | 1,039 (51%) | 2,203 (52%) | 0.74 |
| CCI | 3.45 3.06 | 3.69 3.21 | <0.001 | 4.19 3.51 | 4.20 3.56 | 0.89 |
| Outcomes | ||||||
| Cost per day, $ | 130.1 431.8 | 132.2 420.3 | 0.37 | 137.9 232.9 | 122.9 213.5 | <0.001 |
| Cost per visit, $ | 760.4 1,813.6 | 777.8 1,863.3 | 0.48 | 617.8 844.1 | 558.2 770.3 | 0.005 |
| BMP tests per day | 0.74 1.21 | 0.74 1.18 | 0.67 | 0.75 1.03 | 0.63 1.05 | <0.001 |
| CMP tests per day | 0.19 0.68 | 0.19 0.68 | 0.85 | 0.32 0.68 | 0.23 0.58 | <0.001 |
| CBC tests per day | 0.85 1.14 | 0.84 1.15 | 0.045 | 0.92 0.79 | 0.64 0.76 | <0.001 |
| PT/INR tests per day | 0.34 1.04 | 0.37 1.08 | <0.001 | 0.35 0.82 | 0.33 0.84 | 0.020 |
| LOS, d | 5.84 7.66 | 5.88 7.50 | 0.71 | 4.48 5.12 | 4.54 4.67 | 0.63 |
| 30‐day readmissions | 1,173 (14%) | 2,430 (14%) | 0.22 | 280 (14%) | 491 (11%) | 0.010 |
ITS analysis results are shown in Table 3. After the intervention, the difference in monthly means between the 2 groups dropped by $16 for cost per day (P = 0.034) and by $128 for cost per visit (P = 0.02). The decreased cost in the intervention group amounts to approximately $251,427 (95% confidence interval [CI]: $20,370‐$482,484) savings over the first year. If the intervention was rolled out for the control group and had a similar impact, it could have led to an additional cost savings of $1,321,669 (95% CI: 107,081‐2,536,256). Moreover, the number of basic metabolic panel, comprehensive metabolic panel, and complete blood count test per day were reduced significantly more in the intervention group compared to the control group (<0.001, 0.004, and <0.001).
| Outcome | Parameter* | Parameter Estimate | Standard Error | t Value | Pr > |t| |
|---|---|---|---|---|---|
| |||||
| Lab cost per day ($) | Baseline difference level (b0) | 9.3450 | 6.5640 | 1.4237 | 0.16 |
| Baseline difference trend (b1) | 0.2150 | 0.7709 | 0.2789 | 0.78 | |
| Change in difference level after intervention(b2) | 16.1200 | 7.3297 | 2.1993 | 0.034 | |
| Change in difference trend after intervention (b3) | 0.2388 | 0.8090 | 0.2952 | 0.77 | |
| Lab cost per visit ($) | Baseline difference level (b0) | 166.081 | 48.3425 | 3.4355 | 0.001 |
| Baseline difference trend (b1) | 3.6663 | 5.8571 | 0.6260 | 0.53 | |
| Change in difference level after intervention(b2) | 128.527 | 53.0278 | 2.4238 | 0.020 | |
| Change in difference trend after intervention (b3) | 2.2586 | 5.8463 | 0.3863 | 0.70 | |
| BMP tests per day | Baseline difference level (b0) | 0.0061 | 0.0250 | 0.2439 | 0.81 |
| Baseline difference trend (b1) | 0.0004 | 0.0030 | 0.1449 | 0.89 | |
| Change in difference level after intervention(b2) | 0.1034 | 0.0276 | 3.7426 | <0.001 | |
| Change in difference trend after intervention (b3) | 0.0014 | 0.0030 | 0.4588 | 0.65 | |
| CMP tests per day | Baseline difference level (b0) | 0.1226 | 0.0226 | 5.4302 | <0.001 |
| Baseline difference trend (b1) | 0.0015 | 0.0028 | 0.5539 | 0.58 | |
| Change in difference level after intervention(b2) | 0.0754 | 0.0248 | 3.0397 | 0.004 | |
| Change in difference trend after intervention (b3) | 0.0030 | 0.0028 | 1.0937 | 0.28 | |
| CBC tests per day | Baseline difference level (b0) | 0.0539 | 0.0190 | 2.8338 | 0.007 |
| Baseline difference trend (b1) | 0.0013 | 0.0023 | 0.5594 | 0.58 | |
| Change in difference level after intervention(b2) | 0.2343 | 0.0213 | 10.997 | <0.001 | |
| Change in difference trend after intervention (b3) | 0.0036 | 0.0023 | 1.5539 | 0.13 | |
| PT/INR tests per day | Baseline difference level (b0) | 0.0413 | 0.0242 | 1.7063 | 0.096 |
| Baseline difference trend (b1) | 0.0040 | 0.0028 | 1.4095 | 0.17 | |
| Change in difference level after intervention(b2) | 0.0500 | 0.0270 | 1.8507 | 0.072 | |
| Change in difference trend after intervention (b3) | 0.0054 | 0.0030 | 1.7940 | 0.080 | |
| LOS, d | Baseline difference level (b0) | 1.4211 | 0.2746 | 5.1743 | <0.001 |
| Baseline difference trend (b1) | 0.0093 | 0.0333 | 0.2807 | 0.78 | |
| Change in difference level after intervention(b2) | 0.1007 | 0.2988 | 0.3368 | 0.74 | |
| Change in difference trend after intervention (b3) | 0.0053 | 0.0331 | 0.1588 | 0.87 | |
| 30‐day readmissions | Baseline difference level (b0) | 0.0057 | 0.0185 | 0.3084 | 0.76 |
| Baseline difference trend (b1) | 0.0017 | 0.0022 | 0.8016 | 0.43 | |
| Change in difference level after intervention(b2) | 0.0110 | 0.0206 | 0.5315 | 0.60 | |
| Change in difference trend after intervention (b3) | 0.0021 | 0.0023 | 0.9111 | 0.37 | |
Figure 1 shows a graphical representation of the biweekly means for the 2 primary outcomeslab cost per day and lab cost per visit. Figure 2 shows all other outcomes. To the right of each figure, P values are provided for the b2 coefficients from Table 3.
DISCUSSION
Through a multifaceted quality‐improvement initiative, the UUHC hospitalist group was able to reduce lab cost per day and per visit as well as commonly ordered routine labs as compared to an institutional control group. A multifaceted approach was selected given the literature supporting this approach as the most likely method to sustain improvement.[14] At the same time, the use of a multifaceted intervention makes it difficult to rigorously determine the relative impact of different components of the intervention. In discussing this issue, however, the hospitalist group felt that the driving factors for change were those related to process change, specifically, the use of a standardized rounding checklist to discuss lab testing and the routine review of lab costs at group meetings. The ultimate goal was to change the culture of routine test ordering into a thoughtful process of needed tests and thereby reduce costs. Prior to this intervention, the least experienced person on this team (the intern) ordered any test he or she wanted, usually without discussion. The intervention focused on this issue through standardized supervision and explicit discussion of laboratory tests. Importantly, although improvements from education initiatives typically decrease over time, the incorporation of process change in this intervention was felt to likely contribute to the sustained reduction seen at 15 months. Although use of the rounding checklist added another step to daily rounds, the routine cost feedback, including comparisons to peers, helped encourage use of the checklist. Thus, we feel that routine feedback was essential to sustaining the intervention and its impact.
Inappropriate and unnecessary testing has been recognized for decades, and multiple interventions have been attempted, including a recent article that demonstrated a 10% reduction in common laboratory ordering through an initiative mainly focused on education and ordering feedback.[25] Despite reported success of several interventions, none have combined multiple interventions and explicitly required discussion of laboratory tests on rounds. For example, although the UUHC intervention used Attali et al.[21] and Barie and Hydo's[20] work to develop the intervention, neither of these studies described how laboratory testing was discussed with the attending or supervising resident. The UUHC intervention thus builds on the current literature by combining other successful modalities with explicit discussion of laboratory testing via a rounding checklist and feedback with the novel VDO tool to reduce laboratory costs. A major strength of this intervention is the relatively low cost and the generalizability of implementing rounding checklists. Initial support from the hospital was needed to provide accurate VDO information to the hospitalist group. However, ongoing costs were minimal and related to any additional time spent during rounds to discuss laboratory tests. Thus, we feel that this intervention is feasible for wide replication.
Another strength of the study is the use of the VDO tool to measure actual costs. Whereas previous studies have relied on estimated costs with extrapolation to potential cost savings, this study used direct costs to the institution as a more accurate marker of cost savings. Additionally, most studies on lab utilization have used a before/after analysis without a control group. The presence of a control group for this analysis is important to help assess for institutional trends that may not be reflected in a before/after intervention. The reduction in cost in the intervention group despite a trend toward increased cost in the institutional control group supports the impact of this intervention.
Limitations of this study include that it was a single‐center, controlled ITS study and not a randomized controlled trial. Related to this limitation, the control group reflected a different patient population compared to the intervention group, with a longer LOS, lower CCI, and inclusion of nonmedical patients. However, these differences were relatively stable before and after the intervention. Also, ITS is considered one of the most robust research designs outside of randomized controlled trials, and it accounts for baseline differences in both levels and trends.[24] Nevertheless, it remains possible that secular trends existed that we did not capture and that affected the 2 populations differently.
A further limitation is that the baseline period was only 7 months and the intervention was 15 months. As the 7 months started in July, this could have reflected the time when interns were least experienced with ordering. Unfortunately, we did not have VDO availability for a full year prior to the intervention. We believe that any major effect due to this shortened baseline period should have been seen in the control group as well, and therefore accounted for in the analysis. Additionally, it is possible that there was spillover of the intervention to the control group, as internal medicine residents rotated throughout the hospital to other medical services (pulmonary, cardiology, hematology, and oncology). However, any effect of their rotation should have been to lower the control lab cost, thus making differences less profound.
CONCLUSIONS
A multifaceted approach to laboratory reduction through education, process change, cost feedback, and financial incentive resulted in a significant reduction in laboratory cost per day, laboratory cost per visit, and the ordering of common laboratory tests at a major academic medical center.
Acknowledgements
The authors thank Mr. Michael Swanicke for his assistance in process engineering, Mr. Tony Clawson for his routine provision of VDO data, and Ms. Selma Lopez for her editorial support.
Disclosures: K.K. is or has been a consultant on clinical decision support (CDS) or electronic clinical quality measurement to the US Office of the National Coordinator for Health IT, ARUP Laboratories, McKesson InterQual, ESAC, Inc., JBS International, Inc., Inflexxion, Inc., Intelligent Automation, Inc., Partners HealthCare, Mayo Clinic, and the RAND Corporation. K.K. receives royalties for a Duke University‐owned CDS technology for infectious disease management known as CustomID that he helped develop. K.K. was formerly a consultant for Religent, Inc. and a co‐owner and consultant for Clinica Software, Inc., both of which provide commercial CDS services, including through use of a CDS technology known as SEBASTIAN that K.K. developed. K.K. no longer has a financial relationship with either Religent or Clinica Software. K.K. has no competing interest with any specific product or intervention evaluated in this article. All other authors declare no competing interests.
- , , , et al. National health expenditure projections, 2014–24: spending growth faster than recent trends. Health Aff (Millwood). 2015;34(8):1407–1417.
- , . Eliminating waste in US health care. JAMA. 2012;307(14):1513–1516.
- , , , et al. Utilization of arterial blood gas measurements in a large tertiary care hospital. Am J Clin Pathol. 2007;127:604–609.
- , . Strategies to promote rational clinical chemistry test utilization. Clin Biochem. 1996;29:291–299.
- , , , , . The landscape of inappropriate laboratory testing: a 15‐year meta‐analysis. PLoS One. 2013;8:e78962.
- ABIM Choosing Wisely Society of Hospital Medicine–Adult Hospital Medicine. Five things physicians and patients should question. Available at: http://www.choosingwisely.org/societies/society‐of‐hospital‐medicine‐adult. Published February 21, 2013. Accessed September 2, 2015.
- , , , , , . Effect of daily charge feedback on inpatient charges and physician knowledge and behavior. Arch Intern Med. 1989;149:426–429.
- , , , et al. A utilization management intervention to reduce unnecessary testing in the coronary care unit. Arch Intern Med. 2002;162:1885–1890.
- , , , et al. The impact of peer management on test‐ordering behavior. Ann Intern Med. 2004;141:196–204.
- , , , , . An administrative intervention to improve the utilization of laboratory tests within a university hospital. Int J Qual Health Care. 2005;17:243–248.
- , , , et al. Impact of providing fee data on laboratory test ordering. JAMA Intern Med. 2013;173(10):903–908.
- , , , et al. The failure of physician education as a cost containment strategy. JAMA. 1984;252:225–230.
- . Is that lab test necessary? Am J Clin Pathol. 2006;126:335–336.
- , , , . Techniques to improve physicians' use of diagnostic tests. JAMA. 1998;280:2020–2027.
- , , . Laboratory testing in the intensive care unit. Crit Care Clin. 2007;23:435–465.
- . Complications of critical care: lab testing and iatrogenic anemia. MLO Med Lab Obs. 200;33(10):28–31.
- , , , et al. Contemporary bloodletting in cardiac surgical care. Ann Thorac Surg. 2015;99:779–785.
- , , , et al. Value Driven Outcomes (VDO): a pragmatic, modular, and extensible software framework for understanding and improving health care costs and outcomes. J Am Med Inform Assoc. 2015:22:223–235.
- , , . The impact of residents, interns, and attendings on inpatient laboratory ordering patterns: a report from one university's hospitalist service. Acad Med. 2011;86:139–145.
- , . Learning to not know: results of a program for ancillary cost reduction in surgical care. J Trauma. 1996;41:714–720.
- , , , et al. A cost‐effective method for reducing the volume of laboratory tests in a university‐associated teaching hospital. Mt Sinai J Med. 2006;73:787–794.
- US Bureau of Labor Statistics. CPI inflation calculator. Available at: http://www.bls.gov/data/inflation_calculator.htm. Accessed May 22, 2015.
- , , , et al. Coding algorithms for defining comorbidities in ICD‐9‐CM and ICD‐10 administrative data. Med Care. 2005;43:113–1139.
- , , , . Segmented regression analysis of interrupted time series studies in medication use research. J Clin Pharm Ther. 2002;27(4):299–309.
- , , , et al. A multifaceted hospitalist quality improvement intervention: decreased frequency of common labs. J Hosp Med. 2015;10:390–395.
- , , , et al. National health expenditure projections, 2014–24: spending growth faster than recent trends. Health Aff (Millwood). 2015;34(8):1407–1417.
- , . Eliminating waste in US health care. JAMA. 2012;307(14):1513–1516.
- , , , et al. Utilization of arterial blood gas measurements in a large tertiary care hospital. Am J Clin Pathol. 2007;127:604–609.
- , . Strategies to promote rational clinical chemistry test utilization. Clin Biochem. 1996;29:291–299.
- , , , , . The landscape of inappropriate laboratory testing: a 15‐year meta‐analysis. PLoS One. 2013;8:e78962.
- ABIM Choosing Wisely Society of Hospital Medicine–Adult Hospital Medicine. Five things physicians and patients should question. Available at: http://www.choosingwisely.org/societies/society‐of‐hospital‐medicine‐adult. Published February 21, 2013. Accessed September 2, 2015.
- , , , , , . Effect of daily charge feedback on inpatient charges and physician knowledge and behavior. Arch Intern Med. 1989;149:426–429.
- , , , et al. A utilization management intervention to reduce unnecessary testing in the coronary care unit. Arch Intern Med. 2002;162:1885–1890.
- , , , et al. The impact of peer management on test‐ordering behavior. Ann Intern Med. 2004;141:196–204.
- , , , , . An administrative intervention to improve the utilization of laboratory tests within a university hospital. Int J Qual Health Care. 2005;17:243–248.
- , , , et al. Impact of providing fee data on laboratory test ordering. JAMA Intern Med. 2013;173(10):903–908.
- , , , et al. The failure of physician education as a cost containment strategy. JAMA. 1984;252:225–230.
- . Is that lab test necessary? Am J Clin Pathol. 2006;126:335–336.
- , , , . Techniques to improve physicians' use of diagnostic tests. JAMA. 1998;280:2020–2027.
- , , . Laboratory testing in the intensive care unit. Crit Care Clin. 2007;23:435–465.
- . Complications of critical care: lab testing and iatrogenic anemia. MLO Med Lab Obs. 200;33(10):28–31.
- , , , et al. Contemporary bloodletting in cardiac surgical care. Ann Thorac Surg. 2015;99:779–785.
- , , , et al. Value Driven Outcomes (VDO): a pragmatic, modular, and extensible software framework for understanding and improving health care costs and outcomes. J Am Med Inform Assoc. 2015:22:223–235.
- , , . The impact of residents, interns, and attendings on inpatient laboratory ordering patterns: a report from one university's hospitalist service. Acad Med. 2011;86:139–145.
- , . Learning to not know: results of a program for ancillary cost reduction in surgical care. J Trauma. 1996;41:714–720.
- , , , et al. A cost‐effective method for reducing the volume of laboratory tests in a university‐associated teaching hospital. Mt Sinai J Med. 2006;73:787–794.
- US Bureau of Labor Statistics. CPI inflation calculator. Available at: http://www.bls.gov/data/inflation_calculator.htm. Accessed May 22, 2015.
- , , , et al. Coding algorithms for defining comorbidities in ICD‐9‐CM and ICD‐10 administrative data. Med Care. 2005;43:113–1139.
- , , , . Segmented regression analysis of interrupted time series studies in medication use research. J Clin Pharm Ther. 2002;27(4):299–309.
- , , , et al. A multifaceted hospitalist quality improvement intervention: decreased frequency of common labs. J Hosp Med. 2015;10:390–395.
© 2016 Society of Hospital Medicine
Readmission Analysis Using Fault Tree
As physicians strive to increase the value of healthcare delivery, there has been increased focus on improving the quality of care that patients receive while lowering per capita costs. A provision of the Affordable Care Act implemented in 2012 identified all‐cause 30‐day readmission rates as a measure of hospital quality, and as part of the Act's Hospital Readmission and Reduction Program, Medicare now penalizes hospitals with higher than expected all‐cause readmissions rates for adult patients with certain conditions by lowering reimbursements.[1] Although readmissions are not yet commonly used to determine reimbursements for pediatric hospitals, several states are penalizing higher than expected readmission rates for Medicaid enrollees,[2, 3] using an imprecise algorithm to determine which readmissions resulted from low‐quality care during the index admission.[4, 5, 6]
There is growing concern, however, that readmission rates are not an accurate gauge of the quality of care patients receive while in the hospital or during the discharge process to prepare them for their transition home.[7, 8, 9, 10] This is especially true in pediatric settings, where overall readmission rates are much lower than in adult settings, many readmissions are expected as part of a patient's planned course of care, and variation in readmission rates between hospitals is correlated with the percentage of patients with certain complex chronic conditions.[1, 7, 11] Thus, there is increasing agreement that hospitals and external evaluators need to shift the focus from all‐cause readmissions to a reliable, consistent, and fair measure of potentially preventable readmissions.[12, 13] In addition to being a more useful quality metric, analyzing preventable readmissions will help hospitals focus resources on patients with potentially modifiable risk factors and develop meaningful quality‐improvement initiatives to improve inpatient care as well as the discharge process to prepare families for their transition to home.[14]
Although previous studies have attempted to distinguish preventable from nonpreventable readmissions, many reported significant challenges in completing reviews efficiently, achieving consistency in how readmissions were classified, and attaining consensus on final determinations.[12, 13, 14] Studies have also demonstrated that the algorithms some states are using to streamline preventability reviews and determine reimbursements overestimate the rate of potentially preventable readmissions.[4, 5, 6]
To increase the efficiency of preventability reviews and reduce the subjectivity involved in reaching final determinations, while still accounting for the nuances necessary to conduct a fair review, a quality‐improvement team from the Division of General Pediatrics at The Children's Hospital of Philadelphia (CHOP) implemented a fault tree analysis tool based on a framework developed by Howard Parker at Intermountain Primary Children's Hospital. The CHOP team coded this framework into a secure Web‐based data‐collection tool in the form of a decision tree to guide reviewers through a logical progression of questions that result in 1 of 18 root causes of readmissions, 8 of which are considered potentially preventable. We hypothesized that this method would help reviewers efficiently reach consensus on the root causes of hospital readmissions, and thus help the division and the hospital focus efforts on developing relevant quality‐improvement initiatives.
METHODS
Inclusion Criteria and Study Design
This study was conducted at CHOP, a 535‐bed urban, tertiary‐care, freestanding children's hospital with approximately 29,000 annual discharges. Of those discharges, 7000 to 8000 are from the general pediatrics service, meaning that the attending of record was a general pediatrician. Patients were included in the study if (1) they were discharged from the general pediatrics service between January 2014 and December 2014, and (2) they were readmitted to the hospital, for any reason, within 15 days of discharge. Because this analysis was done as part of a quality‐improvement initiative, it focuses on 15‐day, early readmissions to target cases with a higher probability of being potentially preventable from the perspective of the hospital care team.[10, 12, 13] Patients under observation status during the index admission or the readmission were included. However, patients who returned to the emergency department but were not admitted to an inpatient unit were excluded. Objective details about each case, including the patient's name, demographics, chart number, and diagnosis code, were pre‐loaded from EPIC (Epic Systems Corp., Verona, WI) into REDCap (Research Electronic Data Capture;
A panel of 10 general pediatricians divided up the cases to perform retrospective chart reviews. For each case, REDCap guided reviewers through the fault tree analysis. Reviewers met monthly to discuss difficult cases and reach consensus on any identified ambiguities in the process. After all cases were reviewed once, 3 panel members independently reviewed a random selection of cases to measure inter‐rater reliability and confirm reproducibility of final determinations. The inter‐rater reliability statistic was calculated using Stata 12.1 (StataCorp LP, College Station, TX). During chart reviews, panel members were not blinded to the identity of physicians and other staff members caring for the patients under review. CHOP's institutional review board determined this study to be exempt from ongoing review.
Fault Tree Analysis
Using the decision tree framework for analyzing readmissions that was developed at Intermountain Primary Children's Hospital, the REDCap tool prompted reviewers with a series of sequential questions, each with mutually exclusive options. Using imbedded branching logic to select follow‐up questions, the tool guided reviewers to 1 of 18 terminal nodes, each representing a potential root cause of the readmission. Of those 18 potential causes, 8 were considered potentially preventable. A diagram of the fault tree framework, color coded to indicate which nodes were considered potentially preventable, is shown in Figure 1.
RESULTS
In 2014, 7252 patients were discharged from the general pediatrics service at CHOP. Of those patients, 248 were readmitted within 15 days for an overall general pediatrics 15‐day readmission rate of 3.4%.
Preventability Analysis
Of the 248 readmissions, 233 (94.0%) were considered not preventable. The most common cause for readmission, which accounted for 145 cases (58.5%), was a patient developing an unpredictable problem related to the index diagnosis or a natural progression of the disease that required readmission. The second most common cause, which accounted for 53 cases (21.4%), was a patient developing a new condition unrelated to the index diagnosis or a readmission unrelated to the quality of care received during the index stay. The third most frequent cause, which accounted for 11 cases (4.4%), was a legitimate nonclinical readmission due to lack of alternative resources, psychosocial or economic factors, or case‐specific factors. Other nonpreventable causes of readmission, including scheduled readmissions, each accounted for 7 or fewer cases and <3% of total readmissions.
The 15 readmissions considered potentially preventable accounted for 6.0% of total readmissions and 0.2% of total discharges from the general pediatrics service in 2014. The most common cause of preventable readmissions, which accounted for 6 cases, was premature discharge. The second most common cause, which accounted for 4 cases, was a problem resulting from nosocomial or iatrogenic factors. Other potentially preventable causes included delayed detection of problem (3 cases), inappropriate readmission (1 case), and inadequate postdischarge care planning (1 case).
A breakdown of fault tree results, including examples of cases associated with each terminal node, is shown in Table 1. Information about general pediatrics patients and readmitted patients is included in Tables 2 and 3. A breakdown of determinations for each reviewer is included in Supporting Table 1 in the online version of this article.
| Fault Tree Terminal Node | Root Cause of Readmission | No. of Cases | % of Total Readmissions | % Within Preventability Category | % of Total Discharges |
|---|---|---|---|---|---|
| |||||
| 2 (Potentially Preventable) | Problematic condition on discharge. Example:* Index admission: Infant with history of prematurity admitted with RSV and rhinovirus bronchiolitis. Had some waxing and waning symptoms. Just prior to discharge, noted to have increased work of breathing related to feeds. Readmission: 12 hours later with tachypnea, retractions, and hypoxia. | 6 | 2.4% | 40.0% | 0.08% |
| 3 (Potentially Preventable) | Nosocomial/Iatrogenic factors. Example*: Index admission: Toddler admitted with fever and neutropenia. Treated with antibiotics 24 hours. Diagnosed with viral illness and discharged home. Readmission: symptomatic Clostridum difficile infection. | 4 | 1.6% | 26.7% | 0.06% |
| 8 (Potentially Preventable) | Detection/treatment of problem was delayed and not appropriately facilitated. Example:* Index admission: Preteen admitted with abdominal pain, concern for appendicitis. Ultrasound and abdominal MRI negative for appendicitis. Symptoms improved. Tolerated PO. Readmission: 3 days later with similar abdominal pain. Diagnosed with constipation with significant improvement following clean‐out. | 3 | 1.2% | 20.0% | 0.04% |
| 1 (Potentially Preventable) | Inappropriate readmission. Example:* Index admission: Infant with laryngomalacia admitted with bronchiolitis. Readmission: Continued mild bronchiolitis symptoms but did not require oxygen or suctioning, normal CXR. | 1 | 0.4% | 6.7% | 0.01% |
| 5 (Potentially Preventable) | Resulted from inadequate postdischarge care planning. Example:* Index diagnosis: Infant with vomiting, prior admissions, and extensive evaluation, diagnosed with milk protein allergy and GERD. PPI increased. Readmission: Persistent symptoms, required NGT feeds supplementation. | 1 | 0.4% | 6.7% | 0.01% |
| 4 (Potentially Preventable) | Resulted from a preventable complication and hospital/physician did not take the appropriate steps to minimize likelihood of complication. | ||||
| 6 (Potentially Preventable) | Resulted from improper care by patient/family and effort by hospital/physician to ensure correct postdischarge care was inadequate. | ||||
| 7 (Potentially Preventable) | Resulted from inadequate care by community services and effort by hospital/physician to ensure correct postdischarge care was inadequate. | ||||
| 15 | 6.0% | 100% | 0.2% | ||
| 12 (Not Preventable) | Problem was unpredictable. Example:* Index admission: Infant admitted with gastroenteritis and dehydration with an anion gap metabolic acidosis. Vomiting and diarrhea improved, rehydrated, acidosis improved. Readmission: 1 day later, presented with emesis and fussiness. Readmitted for metabolic acidosis. | 145 | 58.5% | 62.2% | 2.00% |
| 10 (Not Preventable) | Patient developed new condition unrelated to index diagnosis or quality of care. Example:* Index admission: Toddler admitted with cellulitis. Readmission: Bronchiolitis (did not meet CDC guidelines for nosocomial infection). | 53 | 21.4% | 22.7% | 0.73% |
| 9 (Not Preventable) | Legitimate nonclinical readmission. Example:* Index admission: Infant admitted with second episode of bronchiolitis. Readmission: 4 days later with mild diarrhea. Tolerated PO challenge in emergency department. Admitted due to parental anxiety. | 11 | 4.4% | 4.7% | 0.15% |
| 17 (Not Preventable) | Problem resulted from improper care by patient/family but effort by hospital/physician to ensure correct postdischarge care was appropriate. Example:* Index admission: Infant admitted with diarrhea, diagnosed with milk protein allergy. Discharged on soy formula. Readmission: Developed vomiting and diarrhea with cow milk formula. | 7 | 2.8% | 3.0% | 0.10% |
| 11 (Not Preventable) | Scheduled readmission. Example:* Index admission: Infant with conjunctivitis and preseptal cellulitis with nasolacrimal duct obstruction. Readmission: Postoperatively following scheduled nasolacrimal duct repair. | 7 | 2.8% | 3.0% | 0.10% |
| 14 (Not Preventable) | Detection/treatment of problem was delayed, but earlier detection was not feasible. Example:* Index admission: Preteen admitted with fever, abdominal pain, and elevated inflammatory markers. Fever resolved and symptoms improved. Diagnosed with unspecified viral infection. Readmission: 4 days later with lower extremity pyomyositis and possible osteomyelitis. | 4 | 1.6% | 1.7% | 0.06% |
| 15 (Not Preventable) | Detection/treatment of problem was delayed, earlier detection was feasible, but detection was appropriately facilitated. Example:* Index admission: Infant with history of laryngomalacia and GER admitted with an ALTE. No events during hospitalization. Appropriate workup and cleared by consultants for discharge. Zantac increased. Readmission: Infant had similar ALTE events within a week after discharge. Ultimately underwent supraglottoplasty. | 2 | 0.8% | 0.9% | 0.03% |
| 13 (Not Preventable) | Resulted from preventable complication but efforts to minimize likelihood were appropriate. Example:* Index admission: Patient on GJ feeds admitted for dislodged GJ. Extensive conversations between primary team and multiple consulting services regarding best type of tube. Determined that no other tube options were appropriate. Temporizing measures were initiated. Readmission: GJ tube dislodged again. | 2 | 0.8% | 0.9% | 0.03% |
| 18 (Not Preventable) | Resulted from medication side effect (after watch period). Example:* Index admission: Preteen with MSSA bacteremia spread to other organs. Sent home on appropriate IV antibiotics. Readmission: Fever, rash, increased LFTs. Blood cultures negative. Presumed drug reaction. Fevers resolved with alternate medication. | 2 | 0.8% | 0.9% | 0.03% |
| 16 (Not Preventable) | Resulted from inadequate care by community services, but effort by hospital/physician to ensure correct postdischarge care was appropriate. | ||||
| 233 | 94.0% | 100% | 3.2% | ||
| Fault Tree Terminal Node | Root Cause of Potentially Preventable Readmission with Case Descriptions* |
|---|---|
| |
| 2 (Potentially Preventable) | Problematic condition on discharge |
| Case 1: Index admission: Infant with history of prematurity admitted with RSV and rhinovirus bronchiolitis. Had some waxing and waning symptoms. Just prior to discharge, noted to have increased work of breathing related to feeds. Readmission: 12 hours later with tachypnea, retractions, and hypoxia. | |
| Case 2: Index admission: Toddler admitted with febrile seizure in setting of gastroenteritis. Poor PO intake during hospitalization. Readmission: 1 day later with dehydration. | |
| Case 3: Index admission: Infant admitted with a prolonged complex febrile seizure. Workup included an unremarkable lumbar puncture. No additional seizures. No inpatient imaging obtained. Readmission: Abnormal outpatient MRI requiring intervention. | |
| Case 4: Index admission: Teenager with wheezing and history of chronic daily symptoms. Discharged <24 hours later on albuterol every 4 hours and prednisone. Readmission: 1 day later, seen by primary care physician with persistent asthma flare. | |
| Case 5: Index admission: Exfull‐term infant admitted with bronchiolitis, early in course. At time of discharge, had been off oxygen for 24 hours, but last recorded respiratory rate was >70. Readmission: 1 day later due to continued tachypnea and increased work of breathing. No hypoxia. CXR normal. | |
| Case 6: Exfull‐term infant admitted with bilious emesis, diarrhea, and dehydration. Ultrasound of pylorus, UGI, and BMP all normal. Tolerated oral intake but had emesis and loose stools prior to discharge. Readmission: <48 hours later with severe metabolic acidosis. | |
| 3 (Potentially Preventable) | Nosocomial/ematrogenic factors |
| Case 1: Index admission: Toddler admitted with fever and neutropenia. Treated with antibiotics 24 hours. Diagnosed with viral illness and discharged home. Readmission: Symptomatic Clostridum difficile infection. | |
| Case 2: Index admission: Patient with autism admitted with viral gastroenteritis. Readmission: Presumed nosocominal upper respiratory infection. | |
| Case 3: Index admission: Infant admitted with bronchiolitis. Recovered from initial infection. Readmission: New upper respiratory infection and presumed nosocomial infection. | |
| Case 4: Index admission: <28‐day‐old full‐term neonate presenting with neonatal fever and rash. Full septic workup performed and all cultures negative at 24 hours. Readmission: CSF culture positive at 36 hours and readmitted while awaiting speciation. Discharged once culture grew out a contaminant. | |
| 8 (Potentially Preventable) | Detection/treatment of problem was delayed and/or not appropriately facilitated |
| Case 1: Index admission: Preteen admitted with abdominal pain, concern for appendicitis. Ultrasound and MRI abdomen negative for appendicitis. Symptoms improved. Tolerated PO. Readmission: 3 days later with similar abdominal pain. Diagnosed with constipation with significant improvement following clean‐out. | |
| Case 2: Index admission: Infant with history of macrocephaly presented with fever and full fontanelle. Head CT showed mild prominence of the extra‐axial space, and lumbar puncture was normal. Readmission: Patient developed torticollis. MRI demonstrated a malignant lesion. | |
| Case 3: Index admission: School‐age child with RLQ abdominal pain, fever, leukocytosis, and indeterminate RLQ abdominal ultrasound. Twelve‐hour observation with no further fevers. Pain and appetite improved. Readmission: 1 day later with fever, anorexia, and abdominal pain. RLQ ultrasound unchanged. Appendectomy performed with inflamed appendix. | |
| 1 (Potentially Preventable) | Inappropriate readmission |
| Case 1: Index admission: Infant with laryngomalacia admitted with bronchiolitis. Readmission: Continued mild bronchiolitis symptoms but did not require oxygen or suctioning. Normal CXR. | |
| 5 (Potentially Preventable) | Resulted from inadequate postdischarge care planning |
| Case 1: Index diagnosis: Infant with vomiting, prior admissions, and extensive evaluation, diagnosed with milk protein allergy and GERD. PPI increased. Readmission: Persistent symptoms, required NGT feeds supplementation. | |
| All General Pediatrics Patients in 2014 | General Pediatric Readmitted Patients in 2014 | ||||
|---|---|---|---|---|---|
| Major Diagnosis Category at Index Admission | No. | % | Major Diagnosis Category at Index Admission | No. | % |
| |||||
| Respiratory | 2,723 | 37.5% | Respiratory | 79 | 31.9% |
| Digestive | 748 | 10.3% | Digestive | 41 | 16.5% |
| Ear, nose, mouth, throat | 675 | 9.3% | Ear, nose, mouth, throat | 24 | 9.7% |
| Skin, subcutaneous tissue | 480 | 6.6% | Musculoskeletal and connective tissue | 14 | 5.6% |
| Infectious, parasitic, systemic | 455 | 6.3% | Nervous | 13 | 5.2% |
| Factors influencing health status | 359 | 5.0% | Endocrine, nutritional, metabolic | 13 | 5.2% |
| Endocrine, nutritional, metabolic | 339 | 4.7% | Infectious, parasitic, systemic | 12 | 4.8% |
| Nervous | 239 | 3.3% | Newborn, neonate, perinatal period | 11 | 4.4% |
| Musculoskeletal and connective tissue | 228 | 3.1% | Hepatobiliary system and pancreas | 8 | 3.2% |
| Newborn, neonate, perinatal period | 206 | 2.8% | Skin, subcutaneous tissue | 8 | 3.2% |
| Other* | 800 | 11.0% | Other | 25 | 10.1% |
| Total | 7,252 | 100% | Total | 248 | 100% |
Inter‐Rater Reliability Analysis
A random selection of 50 cases (20% of total readmissions) was selected for a second review to test the tool's inter‐rater reliability. The second review resulted in the same terminal node for 44 (86%) of the cross‐checked files ( = 0.79; 95% confidence interval: 0.60‐0.98). Of the 6 cross‐checked files that ended at different nodes, 5 resulted in the same final determination about preventability. Only 1 of the cross‐checks (2% of total cross‐checked files) resulted in a different conclusion about preventability.
Efficiency Analysis
Reviewers reported that using the tool to reach a determination about preventability took approximately 20 minutes per case. Thus, initial reviews on the 248 cases required approximately 82.6 reviewer hours. Divided across 10 reviewers, this resulted in 8 to 9 hours of review time per reviewer over the year.
DISCUSSION
As part of an effort to direct quality‐improvement initiatives, this project used a Web‐based fault tree tool to identify root causes of general pediatrics readmissions at a freestanding children's hospital and classify them as either preventable or not preventable. The project also investigated the efficiency and inter‐rater reliability of the tool, which was designed to systematically guide physicians through the chart review process to a final determination about preventability. The project confirmed that using the tool helped reviewers reach final determinations about preventability efficiently with a high degree of consistency. It also confirmed that only a very small percentage of general pediatrics 15‐day readmissions are potentially preventable. Specifically, potentially preventable readmissions accounted for only 6.0% of total readmissions and 0.2% of general pediatrics discharges in 2014. Although our analysis focused on 15‐day readmissions, the fault tree methodology can be applied to any timeframe.
Previous studies attempting to distinguish preventable from nonpreventable readmissions, which used a range of methodologies to reach final determinations, reported that their review process was both time intensive and highly subjective. One study, which had 4 reviewers independently review charts and assign each case a preventability score on a 5‐point Likert scale, reported that reviewers disagreed on the final determination in 62.5% of cases.[12] Another study had 2 physicians independently review a selection of cases and assign a preventability score on a scale from 0 to 3. Scores for the 2 reviewers were added together, and cases above a certain composite threshold were classified as preventable. Despite being time‐intensive, this method resulted in only moderate agreement among physicians about the likelihood of preventability (weighted statistic of 0.44).[14] A more recent study, in which 2 physicians independently classified readmissions into 1 of 4 predefined categories, also reported only moderate agreement between reviewers ( = 0.44).[13] Other methods that have been reported include classifying readmissions as preventable only if multiple reviewers independently agreed, and using a third reviewer as a tie‐breaker.[14]
In an attempt to identify potentially preventable readmissions without using chart reviews, 3M (St. Paul, MN) developed its Potentially Preventable Readmissions software (3M‐PPR), which uses administrative data to identify which readmissions were potentially preventable. Although this automated approach is less time intensive, evidence suggests that due to a lack of nuance, the algorithm significantly overestimates the percentage of readmissions that are potentially preventable.[4, 5] A study that used 3M‐PPR to assess 1.7 million hospitalizations across 58 children's hospitals found that the algorithm classified 81% of sickle cell crisis and asthma readmissions, and 83% of bronchiolitis readmissions as potentially preventable.[10, 11] However, many readmissions for asthma and bronchiolitis are due to social factors that are outside of a hospital's direct control,[4, 5] and at many hospitals, readmissions for sickle cell crisis are part of a high‐value care model that weighs length of stay against potential readmissions. In addition, when assessing readmissions 7, 15, and 30 days after discharge, the algorithm classified almost the same percentage as potentially preventable, which is inconsistent with the notion that readmissions are more likely to have been preventable if they occurred closer to the initial discharge.[4, 13] Another study that assessed the performance of the software in the adult population reported that the algorithm performed with 85% sensitivity, but only 28% specificity.[5, 6]
The results of this quality‐improvement project indicate that using the fault tree tool to guide physicians through the chart review process helped address some of the shortcomings of methods reported in previous studies, by increasing the efficiency and reducing the subjectivity of final determinations, while still accounting for the nuances necessary to conduct a fair review. Because the tool provided a systematic framework for reviews, each case was completed in approximately 20 minutes, and because the process was the same for all reviewers, inter‐rater reliability was extremely high. In 86% of cross‐checked cases, the second reviewer ended at the same terminal node in the decision tree as the original reviewer, and in 98% of cross‐checked cases the second reviewer reached the same conclusion about preventability, even if they did not end at the same terminal node. Even accounting for agreement due to chance, the statistic of 0.79 confirmed that there was substantial agreement among reviewers about final determinations. Because the tool is easily adaptable, other hospitals can adopt this framework for their own preventability reviews and quality‐improvement initiatives.
Using the fault tree tool to access root causes of all 15‐day general pediatric readmissions helped the division focus quality‐improvement efforts on the most common causes of potentially preventable readmissions. Because 40% of potentially preventable readmissions were due to premature discharges, this prompted quality‐improvement teams to focus efforts on improving and clarifying the division's discharge criteria and clinical pathways. The division also initiated processes to improve discharge planning, including improved teaching of discharge instructions and having families pick up prescriptions prior to discharge.
Although these results did help the division identify a few areas of focus to potentially reduce readmissions, the fact that the overall 15‐day readmission rate for general pediatrics, as well as the percentage of readmissions and total discharges that were deemed potentially preventable, were so low (3.4%, 6.0%, and 0.2%, respectively), supports those who question whether prioritizing pediatric readmissions is the best place for hospitals to focus quality‐improvement efforts.[10, 12, 15, 16] As these results indicate, most pediatric readmissions are not preventable, and thus consistent with an efficient, effective, timely, patient‐centered, and equitable health system. Other studies have also shown that because overall and condition‐specific readmissions at pediatric hospitals are low, few pediatric hospitals are high or low performing for readmissions, and thus readmission rates are likely not a good measure of hospital quality.[8]
However, other condition‐specific studies of readmissions in pediatrics have indicated that there are some areas of opportunity to identify populations at high risk for readmission. One study found that although pneumonia‐specific 30‐day readmission rates in a national cohort of children hospitalized with pneumonia was only 3.1%, the chances of readmission were higher for children <1 year old, children with chronic comorbidities or complicated pneumonia, and children cared for in hospitals with lower volumes of pneumonia admissions.[17] Another study found that 17.1% of adolescents in a statewide database were readmitted post‐tonsillectomy for pain, nausea, and dehydration.[18] Thus, adapting the tool to identify root causes of condition‐specific or procedure‐specific readmissions, especially for surgical patients, may be an area of opportunity for future quality‐improvement efforts.[5] However, for general pediatrics, shifting the focus from reducing readmissions to improving the quality of care patients receive in the hospital, improving the discharge process, and adopting a population health approach to mitigate external risk factors, may be appropriate.
This project was subject to limitations. First, because it was conducted at a single site and only on general pediatrics patients, results may not be generalizable to other hospitals or other pediatric divisions. Thus, future studies might use the fault tree framework to assess preventability of pediatric readmissions in other divisions or specialties. Second, because readmissions to other hospitals were not included in the sample, the overall readmissions rate is likely underestimated.[19] However, it is unclear how this would affect the rate of potentially preventable readmissions. Third, although the fault tree framework reduced the subjectivity of the review process, there is still a degree of subjectivity inherent at each decision node. To minimize this, reviewers should try to discuss and come to consensus on how they are making determinations at each juncture in the decision tree. Similarly, because reviewers' answers to decision‐tree questions rely heavily on chart documentation, reviews may be compromised by unclear or incomplete documentation. For example, if information about steps the hospital team took to prepare a family for discharge were not properly documented, it would be difficult to determine whether appropriate steps were taken to minimize the likelihood of a complication. In the case of insufficient documentation of relevant social concerns, cases may be incorrectly classified as preventable, because addressing social issues is often not within a hospital's direct control. Finally, because reviewers were not blinded to the original discharging physician, there may have been some unconscious bias of unknown direction in the reviews.
CONCLUSION
Using the Web‐based fault tree tool helped physicians to identify the root causes of hospital readmissions and classify them as preventable or not preventable in a standardized, efficient, and consistent way, while still accounting for the nuances necessary to conduct a fair review. Thus, other hospitals should consider adopting this framework for their own preventability reviews and quality‐improvement initiatives. However, this project also confirmed that only a very small percentage of general pediatrics 15‐day readmissions are potentially preventable, suggesting that general pediatrics readmissions are not an appropriate measure of hospital quality. Instead, adapting the tool to identify root causes of condition‐specific or procedure‐specific readmission rates may be an area of opportunity for future quality‐improvement efforts.
Disclosures: This work was supported through internal funds from The Children's Hospital of Philadelphia. The authors have no financial interests, relationships or affiliations relevant to the subject matter or materials discussed in the article to disclose. The authors have no potential conflicts of interest relevant to the subject matter or materials discussed in the article to disclose.
- , . Pediatric readmissions as a hospital quality measure. JAMA. 2013;309(4):396–398.
- Texas Health and Human Services Commission. Potentially preventable readmissions in the Texas Medicaid population, state fiscal year 2012. Available at: http://www.hhsc.state.tx.us/reports/2013/ppr‐report.pdf. Published November 2013. Accessed August 16, 2015.
- Illinois Department of Healthcare and Family Services. Quality initiative to reduce hospital potentially preventable readmissions (PPR): Status update. Available at: http://www.illinois.gov/hfs/SiteCollectionDocuments/PPRPolicyStatusUpdate.pdf. Published September 3, 2014. Accessed August 16, 2015.
- , , , et al. Rates and impact of potentially preventable readmissions at children's hospitals. J Pediatr. 2015;166(3):613–619.e615.
- , . Preventing pediatric readmissions: which ones and how? J Pediatr. 2015;166(3):519–520.
- , , , , , . Manual and automated methods for identifying potentially preventable readmissions: a comparison in a large healthcare system. BMC Med Inform Decis Mak. 2014;14:28.
- , . Section on hospital medicine leadership and staff. Hosp Pediatr. 2013;3(4):390–393.
- , , , et al. Measuring hospital quality using pediatric readmission and revisit rates. Pediatrics. 2013;132(3):429–436.
- , . Hospital readmissions—not just a measure of quality. JAMA. 2011;306(16):1796–1797.
- , . Preventing readmissions in children: how do we do that? Hosp Pediatr. 2015;5(11):602–604.
- , , , et al. Pediatric readmission prevalence and variability across hospitals. JAMA. 2013;309(4):372–380.
- , , , , , . Preventability of early readmissions at a children's hospital. Pediatrics. 2013;131(1):e171–e181.
- , , , et al. An examination of physician‐, caregiver‐, and disease‐related factors associated with readmission from a pediatric hospital medicine service. Hosp Pediatr. 2015;5(11):566–573.
- , , , et al. Clinical preventability of 30‐day readmission after percutaneous coronary intervention. J Am Heart Assoc. 2014;3(5):e001290.
- . 3M algorithm overestimates preventable pediatric readmissions. Hospitalist News website. Available at: http://www.ehospitalistnews.com/specialty‐focus/pediatrics/single‐article‐page/3m‐algorithm‐overestimates‐preventable‐pediatric‐readmissions.html. Published August 16, 2013. Accessed August 16, 2015.
- . The 30‐day readmission rate: not a quality measure but an accountability measure. An Ounce of Evidence: Health Policy blog. Available at: https://blogs.sph.harvard.edu/ashish‐jha/?s=30‐day+readmission+rate. Published February 14, 2013. Accessed August 16, 2015.
- , , , et al. Readmissions among children previously hospitalized with pneumonia. Pediatrics. 2014;134(1):100–109.
- , , . A population‐based study of acute care revisits following tonsillectomy. J Pediatr. 2015;166(3):607–612.e605.
- , , , et al. Same‐hospital readmission rates as a measure of pediatric quality of care. JAMA Pediatr. 2015;169(10):905–912.
As physicians strive to increase the value of healthcare delivery, there has been increased focus on improving the quality of care that patients receive while lowering per capita costs. A provision of the Affordable Care Act implemented in 2012 identified all‐cause 30‐day readmission rates as a measure of hospital quality, and as part of the Act's Hospital Readmission and Reduction Program, Medicare now penalizes hospitals with higher than expected all‐cause readmissions rates for adult patients with certain conditions by lowering reimbursements.[1] Although readmissions are not yet commonly used to determine reimbursements for pediatric hospitals, several states are penalizing higher than expected readmission rates for Medicaid enrollees,[2, 3] using an imprecise algorithm to determine which readmissions resulted from low‐quality care during the index admission.[4, 5, 6]
There is growing concern, however, that readmission rates are not an accurate gauge of the quality of care patients receive while in the hospital or during the discharge process to prepare them for their transition home.[7, 8, 9, 10] This is especially true in pediatric settings, where overall readmission rates are much lower than in adult settings, many readmissions are expected as part of a patient's planned course of care, and variation in readmission rates between hospitals is correlated with the percentage of patients with certain complex chronic conditions.[1, 7, 11] Thus, there is increasing agreement that hospitals and external evaluators need to shift the focus from all‐cause readmissions to a reliable, consistent, and fair measure of potentially preventable readmissions.[12, 13] In addition to being a more useful quality metric, analyzing preventable readmissions will help hospitals focus resources on patients with potentially modifiable risk factors and develop meaningful quality‐improvement initiatives to improve inpatient care as well as the discharge process to prepare families for their transition to home.[14]
Although previous studies have attempted to distinguish preventable from nonpreventable readmissions, many reported significant challenges in completing reviews efficiently, achieving consistency in how readmissions were classified, and attaining consensus on final determinations.[12, 13, 14] Studies have also demonstrated that the algorithms some states are using to streamline preventability reviews and determine reimbursements overestimate the rate of potentially preventable readmissions.[4, 5, 6]
To increase the efficiency of preventability reviews and reduce the subjectivity involved in reaching final determinations, while still accounting for the nuances necessary to conduct a fair review, a quality‐improvement team from the Division of General Pediatrics at The Children's Hospital of Philadelphia (CHOP) implemented a fault tree analysis tool based on a framework developed by Howard Parker at Intermountain Primary Children's Hospital. The CHOP team coded this framework into a secure Web‐based data‐collection tool in the form of a decision tree to guide reviewers through a logical progression of questions that result in 1 of 18 root causes of readmissions, 8 of which are considered potentially preventable. We hypothesized that this method would help reviewers efficiently reach consensus on the root causes of hospital readmissions, and thus help the division and the hospital focus efforts on developing relevant quality‐improvement initiatives.
METHODS
Inclusion Criteria and Study Design
This study was conducted at CHOP, a 535‐bed urban, tertiary‐care, freestanding children's hospital with approximately 29,000 annual discharges. Of those discharges, 7000 to 8000 are from the general pediatrics service, meaning that the attending of record was a general pediatrician. Patients were included in the study if (1) they were discharged from the general pediatrics service between January 2014 and December 2014, and (2) they were readmitted to the hospital, for any reason, within 15 days of discharge. Because this analysis was done as part of a quality‐improvement initiative, it focuses on 15‐day, early readmissions to target cases with a higher probability of being potentially preventable from the perspective of the hospital care team.[10, 12, 13] Patients under observation status during the index admission or the readmission were included. However, patients who returned to the emergency department but were not admitted to an inpatient unit were excluded. Objective details about each case, including the patient's name, demographics, chart number, and diagnosis code, were pre‐loaded from EPIC (Epic Systems Corp., Verona, WI) into REDCap (Research Electronic Data Capture;
A panel of 10 general pediatricians divided up the cases to perform retrospective chart reviews. For each case, REDCap guided reviewers through the fault tree analysis. Reviewers met monthly to discuss difficult cases and reach consensus on any identified ambiguities in the process. After all cases were reviewed once, 3 panel members independently reviewed a random selection of cases to measure inter‐rater reliability and confirm reproducibility of final determinations. The inter‐rater reliability statistic was calculated using Stata 12.1 (StataCorp LP, College Station, TX). During chart reviews, panel members were not blinded to the identity of physicians and other staff members caring for the patients under review. CHOP's institutional review board determined this study to be exempt from ongoing review.
Fault Tree Analysis
Using the decision tree framework for analyzing readmissions that was developed at Intermountain Primary Children's Hospital, the REDCap tool prompted reviewers with a series of sequential questions, each with mutually exclusive options. Using imbedded branching logic to select follow‐up questions, the tool guided reviewers to 1 of 18 terminal nodes, each representing a potential root cause of the readmission. Of those 18 potential causes, 8 were considered potentially preventable. A diagram of the fault tree framework, color coded to indicate which nodes were considered potentially preventable, is shown in Figure 1.
RESULTS
In 2014, 7252 patients were discharged from the general pediatrics service at CHOP. Of those patients, 248 were readmitted within 15 days for an overall general pediatrics 15‐day readmission rate of 3.4%.
Preventability Analysis
Of the 248 readmissions, 233 (94.0%) were considered not preventable. The most common cause for readmission, which accounted for 145 cases (58.5%), was a patient developing an unpredictable problem related to the index diagnosis or a natural progression of the disease that required readmission. The second most common cause, which accounted for 53 cases (21.4%), was a patient developing a new condition unrelated to the index diagnosis or a readmission unrelated to the quality of care received during the index stay. The third most frequent cause, which accounted for 11 cases (4.4%), was a legitimate nonclinical readmission due to lack of alternative resources, psychosocial or economic factors, or case‐specific factors. Other nonpreventable causes of readmission, including scheduled readmissions, each accounted for 7 or fewer cases and <3% of total readmissions.
The 15 readmissions considered potentially preventable accounted for 6.0% of total readmissions and 0.2% of total discharges from the general pediatrics service in 2014. The most common cause of preventable readmissions, which accounted for 6 cases, was premature discharge. The second most common cause, which accounted for 4 cases, was a problem resulting from nosocomial or iatrogenic factors. Other potentially preventable causes included delayed detection of problem (3 cases), inappropriate readmission (1 case), and inadequate postdischarge care planning (1 case).
A breakdown of fault tree results, including examples of cases associated with each terminal node, is shown in Table 1. Information about general pediatrics patients and readmitted patients is included in Tables 2 and 3. A breakdown of determinations for each reviewer is included in Supporting Table 1 in the online version of this article.
| Fault Tree Terminal Node | Root Cause of Readmission | No. of Cases | % of Total Readmissions | % Within Preventability Category | % of Total Discharges |
|---|---|---|---|---|---|
| |||||
| 2 (Potentially Preventable) | Problematic condition on discharge. Example:* Index admission: Infant with history of prematurity admitted with RSV and rhinovirus bronchiolitis. Had some waxing and waning symptoms. Just prior to discharge, noted to have increased work of breathing related to feeds. Readmission: 12 hours later with tachypnea, retractions, and hypoxia. | 6 | 2.4% | 40.0% | 0.08% |
| 3 (Potentially Preventable) | Nosocomial/Iatrogenic factors. Example*: Index admission: Toddler admitted with fever and neutropenia. Treated with antibiotics 24 hours. Diagnosed with viral illness and discharged home. Readmission: symptomatic Clostridum difficile infection. | 4 | 1.6% | 26.7% | 0.06% |
| 8 (Potentially Preventable) | Detection/treatment of problem was delayed and not appropriately facilitated. Example:* Index admission: Preteen admitted with abdominal pain, concern for appendicitis. Ultrasound and abdominal MRI negative for appendicitis. Symptoms improved. Tolerated PO. Readmission: 3 days later with similar abdominal pain. Diagnosed with constipation with significant improvement following clean‐out. | 3 | 1.2% | 20.0% | 0.04% |
| 1 (Potentially Preventable) | Inappropriate readmission. Example:* Index admission: Infant with laryngomalacia admitted with bronchiolitis. Readmission: Continued mild bronchiolitis symptoms but did not require oxygen or suctioning, normal CXR. | 1 | 0.4% | 6.7% | 0.01% |
| 5 (Potentially Preventable) | Resulted from inadequate postdischarge care planning. Example:* Index diagnosis: Infant with vomiting, prior admissions, and extensive evaluation, diagnosed with milk protein allergy and GERD. PPI increased. Readmission: Persistent symptoms, required NGT feeds supplementation. | 1 | 0.4% | 6.7% | 0.01% |
| 4 (Potentially Preventable) | Resulted from a preventable complication and hospital/physician did not take the appropriate steps to minimize likelihood of complication. | ||||
| 6 (Potentially Preventable) | Resulted from improper care by patient/family and effort by hospital/physician to ensure correct postdischarge care was inadequate. | ||||
| 7 (Potentially Preventable) | Resulted from inadequate care by community services and effort by hospital/physician to ensure correct postdischarge care was inadequate. | ||||
| 15 | 6.0% | 100% | 0.2% | ||
| 12 (Not Preventable) | Problem was unpredictable. Example:* Index admission: Infant admitted with gastroenteritis and dehydration with an anion gap metabolic acidosis. Vomiting and diarrhea improved, rehydrated, acidosis improved. Readmission: 1 day later, presented with emesis and fussiness. Readmitted for metabolic acidosis. | 145 | 58.5% | 62.2% | 2.00% |
| 10 (Not Preventable) | Patient developed new condition unrelated to index diagnosis or quality of care. Example:* Index admission: Toddler admitted with cellulitis. Readmission: Bronchiolitis (did not meet CDC guidelines for nosocomial infection). | 53 | 21.4% | 22.7% | 0.73% |
| 9 (Not Preventable) | Legitimate nonclinical readmission. Example:* Index admission: Infant admitted with second episode of bronchiolitis. Readmission: 4 days later with mild diarrhea. Tolerated PO challenge in emergency department. Admitted due to parental anxiety. | 11 | 4.4% | 4.7% | 0.15% |
| 17 (Not Preventable) | Problem resulted from improper care by patient/family but effort by hospital/physician to ensure correct postdischarge care was appropriate. Example:* Index admission: Infant admitted with diarrhea, diagnosed with milk protein allergy. Discharged on soy formula. Readmission: Developed vomiting and diarrhea with cow milk formula. | 7 | 2.8% | 3.0% | 0.10% |
| 11 (Not Preventable) | Scheduled readmission. Example:* Index admission: Infant with conjunctivitis and preseptal cellulitis with nasolacrimal duct obstruction. Readmission: Postoperatively following scheduled nasolacrimal duct repair. | 7 | 2.8% | 3.0% | 0.10% |
| 14 (Not Preventable) | Detection/treatment of problem was delayed, but earlier detection was not feasible. Example:* Index admission: Preteen admitted with fever, abdominal pain, and elevated inflammatory markers. Fever resolved and symptoms improved. Diagnosed with unspecified viral infection. Readmission: 4 days later with lower extremity pyomyositis and possible osteomyelitis. | 4 | 1.6% | 1.7% | 0.06% |
| 15 (Not Preventable) | Detection/treatment of problem was delayed, earlier detection was feasible, but detection was appropriately facilitated. Example:* Index admission: Infant with history of laryngomalacia and GER admitted with an ALTE. No events during hospitalization. Appropriate workup and cleared by consultants for discharge. Zantac increased. Readmission: Infant had similar ALTE events within a week after discharge. Ultimately underwent supraglottoplasty. | 2 | 0.8% | 0.9% | 0.03% |
| 13 (Not Preventable) | Resulted from preventable complication but efforts to minimize likelihood were appropriate. Example:* Index admission: Patient on GJ feeds admitted for dislodged GJ. Extensive conversations between primary team and multiple consulting services regarding best type of tube. Determined that no other tube options were appropriate. Temporizing measures were initiated. Readmission: GJ tube dislodged again. | 2 | 0.8% | 0.9% | 0.03% |
| 18 (Not Preventable) | Resulted from medication side effect (after watch period). Example:* Index admission: Preteen with MSSA bacteremia spread to other organs. Sent home on appropriate IV antibiotics. Readmission: Fever, rash, increased LFTs. Blood cultures negative. Presumed drug reaction. Fevers resolved with alternate medication. | 2 | 0.8% | 0.9% | 0.03% |
| 16 (Not Preventable) | Resulted from inadequate care by community services, but effort by hospital/physician to ensure correct postdischarge care was appropriate. | ||||
| 233 | 94.0% | 100% | 3.2% | ||
| Fault Tree Terminal Node | Root Cause of Potentially Preventable Readmission with Case Descriptions* |
|---|---|
| |
| 2 (Potentially Preventable) | Problematic condition on discharge |
| Case 1: Index admission: Infant with history of prematurity admitted with RSV and rhinovirus bronchiolitis. Had some waxing and waning symptoms. Just prior to discharge, noted to have increased work of breathing related to feeds. Readmission: 12 hours later with tachypnea, retractions, and hypoxia. | |
| Case 2: Index admission: Toddler admitted with febrile seizure in setting of gastroenteritis. Poor PO intake during hospitalization. Readmission: 1 day later with dehydration. | |
| Case 3: Index admission: Infant admitted with a prolonged complex febrile seizure. Workup included an unremarkable lumbar puncture. No additional seizures. No inpatient imaging obtained. Readmission: Abnormal outpatient MRI requiring intervention. | |
| Case 4: Index admission: Teenager with wheezing and history of chronic daily symptoms. Discharged <24 hours later on albuterol every 4 hours and prednisone. Readmission: 1 day later, seen by primary care physician with persistent asthma flare. | |
| Case 5: Index admission: Exfull‐term infant admitted with bronchiolitis, early in course. At time of discharge, had been off oxygen for 24 hours, but last recorded respiratory rate was >70. Readmission: 1 day later due to continued tachypnea and increased work of breathing. No hypoxia. CXR normal. | |
| Case 6: Exfull‐term infant admitted with bilious emesis, diarrhea, and dehydration. Ultrasound of pylorus, UGI, and BMP all normal. Tolerated oral intake but had emesis and loose stools prior to discharge. Readmission: <48 hours later with severe metabolic acidosis. | |
| 3 (Potentially Preventable) | Nosocomial/ematrogenic factors |
| Case 1: Index admission: Toddler admitted with fever and neutropenia. Treated with antibiotics 24 hours. Diagnosed with viral illness and discharged home. Readmission: Symptomatic Clostridum difficile infection. | |
| Case 2: Index admission: Patient with autism admitted with viral gastroenteritis. Readmission: Presumed nosocominal upper respiratory infection. | |
| Case 3: Index admission: Infant admitted with bronchiolitis. Recovered from initial infection. Readmission: New upper respiratory infection and presumed nosocomial infection. | |
| Case 4: Index admission: <28‐day‐old full‐term neonate presenting with neonatal fever and rash. Full septic workup performed and all cultures negative at 24 hours. Readmission: CSF culture positive at 36 hours and readmitted while awaiting speciation. Discharged once culture grew out a contaminant. | |
| 8 (Potentially Preventable) | Detection/treatment of problem was delayed and/or not appropriately facilitated |
| Case 1: Index admission: Preteen admitted with abdominal pain, concern for appendicitis. Ultrasound and MRI abdomen negative for appendicitis. Symptoms improved. Tolerated PO. Readmission: 3 days later with similar abdominal pain. Diagnosed with constipation with significant improvement following clean‐out. | |
| Case 2: Index admission: Infant with history of macrocephaly presented with fever and full fontanelle. Head CT showed mild prominence of the extra‐axial space, and lumbar puncture was normal. Readmission: Patient developed torticollis. MRI demonstrated a malignant lesion. | |
| Case 3: Index admission: School‐age child with RLQ abdominal pain, fever, leukocytosis, and indeterminate RLQ abdominal ultrasound. Twelve‐hour observation with no further fevers. Pain and appetite improved. Readmission: 1 day later with fever, anorexia, and abdominal pain. RLQ ultrasound unchanged. Appendectomy performed with inflamed appendix. | |
| 1 (Potentially Preventable) | Inappropriate readmission |
| Case 1: Index admission: Infant with laryngomalacia admitted with bronchiolitis. Readmission: Continued mild bronchiolitis symptoms but did not require oxygen or suctioning. Normal CXR. | |
| 5 (Potentially Preventable) | Resulted from inadequate postdischarge care planning |
| Case 1: Index diagnosis: Infant with vomiting, prior admissions, and extensive evaluation, diagnosed with milk protein allergy and GERD. PPI increased. Readmission: Persistent symptoms, required NGT feeds supplementation. | |
| All General Pediatrics Patients in 2014 | General Pediatric Readmitted Patients in 2014 | ||||
|---|---|---|---|---|---|
| Major Diagnosis Category at Index Admission | No. | % | Major Diagnosis Category at Index Admission | No. | % |
| |||||
| Respiratory | 2,723 | 37.5% | Respiratory | 79 | 31.9% |
| Digestive | 748 | 10.3% | Digestive | 41 | 16.5% |
| Ear, nose, mouth, throat | 675 | 9.3% | Ear, nose, mouth, throat | 24 | 9.7% |
| Skin, subcutaneous tissue | 480 | 6.6% | Musculoskeletal and connective tissue | 14 | 5.6% |
| Infectious, parasitic, systemic | 455 | 6.3% | Nervous | 13 | 5.2% |
| Factors influencing health status | 359 | 5.0% | Endocrine, nutritional, metabolic | 13 | 5.2% |
| Endocrine, nutritional, metabolic | 339 | 4.7% | Infectious, parasitic, systemic | 12 | 4.8% |
| Nervous | 239 | 3.3% | Newborn, neonate, perinatal period | 11 | 4.4% |
| Musculoskeletal and connective tissue | 228 | 3.1% | Hepatobiliary system and pancreas | 8 | 3.2% |
| Newborn, neonate, perinatal period | 206 | 2.8% | Skin, subcutaneous tissue | 8 | 3.2% |
| Other* | 800 | 11.0% | Other | 25 | 10.1% |
| Total | 7,252 | 100% | Total | 248 | 100% |
Inter‐Rater Reliability Analysis
A random selection of 50 cases (20% of total readmissions) was selected for a second review to test the tool's inter‐rater reliability. The second review resulted in the same terminal node for 44 (86%) of the cross‐checked files ( = 0.79; 95% confidence interval: 0.60‐0.98). Of the 6 cross‐checked files that ended at different nodes, 5 resulted in the same final determination about preventability. Only 1 of the cross‐checks (2% of total cross‐checked files) resulted in a different conclusion about preventability.
Efficiency Analysis
Reviewers reported that using the tool to reach a determination about preventability took approximately 20 minutes per case. Thus, initial reviews on the 248 cases required approximately 82.6 reviewer hours. Divided across 10 reviewers, this resulted in 8 to 9 hours of review time per reviewer over the year.
DISCUSSION
As part of an effort to direct quality‐improvement initiatives, this project used a Web‐based fault tree tool to identify root causes of general pediatrics readmissions at a freestanding children's hospital and classify them as either preventable or not preventable. The project also investigated the efficiency and inter‐rater reliability of the tool, which was designed to systematically guide physicians through the chart review process to a final determination about preventability. The project confirmed that using the tool helped reviewers reach final determinations about preventability efficiently with a high degree of consistency. It also confirmed that only a very small percentage of general pediatrics 15‐day readmissions are potentially preventable. Specifically, potentially preventable readmissions accounted for only 6.0% of total readmissions and 0.2% of general pediatrics discharges in 2014. Although our analysis focused on 15‐day readmissions, the fault tree methodology can be applied to any timeframe.
Previous studies attempting to distinguish preventable from nonpreventable readmissions, which used a range of methodologies to reach final determinations, reported that their review process was both time intensive and highly subjective. One study, which had 4 reviewers independently review charts and assign each case a preventability score on a 5‐point Likert scale, reported that reviewers disagreed on the final determination in 62.5% of cases.[12] Another study had 2 physicians independently review a selection of cases and assign a preventability score on a scale from 0 to 3. Scores for the 2 reviewers were added together, and cases above a certain composite threshold were classified as preventable. Despite being time‐intensive, this method resulted in only moderate agreement among physicians about the likelihood of preventability (weighted statistic of 0.44).[14] A more recent study, in which 2 physicians independently classified readmissions into 1 of 4 predefined categories, also reported only moderate agreement between reviewers ( = 0.44).[13] Other methods that have been reported include classifying readmissions as preventable only if multiple reviewers independently agreed, and using a third reviewer as a tie‐breaker.[14]
In an attempt to identify potentially preventable readmissions without using chart reviews, 3M (St. Paul, MN) developed its Potentially Preventable Readmissions software (3M‐PPR), which uses administrative data to identify which readmissions were potentially preventable. Although this automated approach is less time intensive, evidence suggests that due to a lack of nuance, the algorithm significantly overestimates the percentage of readmissions that are potentially preventable.[4, 5] A study that used 3M‐PPR to assess 1.7 million hospitalizations across 58 children's hospitals found that the algorithm classified 81% of sickle cell crisis and asthma readmissions, and 83% of bronchiolitis readmissions as potentially preventable.[10, 11] However, many readmissions for asthma and bronchiolitis are due to social factors that are outside of a hospital's direct control,[4, 5] and at many hospitals, readmissions for sickle cell crisis are part of a high‐value care model that weighs length of stay against potential readmissions. In addition, when assessing readmissions 7, 15, and 30 days after discharge, the algorithm classified almost the same percentage as potentially preventable, which is inconsistent with the notion that readmissions are more likely to have been preventable if they occurred closer to the initial discharge.[4, 13] Another study that assessed the performance of the software in the adult population reported that the algorithm performed with 85% sensitivity, but only 28% specificity.[5, 6]
The results of this quality‐improvement project indicate that using the fault tree tool to guide physicians through the chart review process helped address some of the shortcomings of methods reported in previous studies, by increasing the efficiency and reducing the subjectivity of final determinations, while still accounting for the nuances necessary to conduct a fair review. Because the tool provided a systematic framework for reviews, each case was completed in approximately 20 minutes, and because the process was the same for all reviewers, inter‐rater reliability was extremely high. In 86% of cross‐checked cases, the second reviewer ended at the same terminal node in the decision tree as the original reviewer, and in 98% of cross‐checked cases the second reviewer reached the same conclusion about preventability, even if they did not end at the same terminal node. Even accounting for agreement due to chance, the statistic of 0.79 confirmed that there was substantial agreement among reviewers about final determinations. Because the tool is easily adaptable, other hospitals can adopt this framework for their own preventability reviews and quality‐improvement initiatives.
Using the fault tree tool to access root causes of all 15‐day general pediatric readmissions helped the division focus quality‐improvement efforts on the most common causes of potentially preventable readmissions. Because 40% of potentially preventable readmissions were due to premature discharges, this prompted quality‐improvement teams to focus efforts on improving and clarifying the division's discharge criteria and clinical pathways. The division also initiated processes to improve discharge planning, including improved teaching of discharge instructions and having families pick up prescriptions prior to discharge.
Although these results did help the division identify a few areas of focus to potentially reduce readmissions, the fact that the overall 15‐day readmission rate for general pediatrics, as well as the percentage of readmissions and total discharges that were deemed potentially preventable, were so low (3.4%, 6.0%, and 0.2%, respectively), supports those who question whether prioritizing pediatric readmissions is the best place for hospitals to focus quality‐improvement efforts.[10, 12, 15, 16] As these results indicate, most pediatric readmissions are not preventable, and thus consistent with an efficient, effective, timely, patient‐centered, and equitable health system. Other studies have also shown that because overall and condition‐specific readmissions at pediatric hospitals are low, few pediatric hospitals are high or low performing for readmissions, and thus readmission rates are likely not a good measure of hospital quality.[8]
However, other condition‐specific studies of readmissions in pediatrics have indicated that there are some areas of opportunity to identify populations at high risk for readmission. One study found that although pneumonia‐specific 30‐day readmission rates in a national cohort of children hospitalized with pneumonia was only 3.1%, the chances of readmission were higher for children <1 year old, children with chronic comorbidities or complicated pneumonia, and children cared for in hospitals with lower volumes of pneumonia admissions.[17] Another study found that 17.1% of adolescents in a statewide database were readmitted post‐tonsillectomy for pain, nausea, and dehydration.[18] Thus, adapting the tool to identify root causes of condition‐specific or procedure‐specific readmissions, especially for surgical patients, may be an area of opportunity for future quality‐improvement efforts.[5] However, for general pediatrics, shifting the focus from reducing readmissions to improving the quality of care patients receive in the hospital, improving the discharge process, and adopting a population health approach to mitigate external risk factors, may be appropriate.
This project was subject to limitations. First, because it was conducted at a single site and only on general pediatrics patients, results may not be generalizable to other hospitals or other pediatric divisions. Thus, future studies might use the fault tree framework to assess preventability of pediatric readmissions in other divisions or specialties. Second, because readmissions to other hospitals were not included in the sample, the overall readmissions rate is likely underestimated.[19] However, it is unclear how this would affect the rate of potentially preventable readmissions. Third, although the fault tree framework reduced the subjectivity of the review process, there is still a degree of subjectivity inherent at each decision node. To minimize this, reviewers should try to discuss and come to consensus on how they are making determinations at each juncture in the decision tree. Similarly, because reviewers' answers to decision‐tree questions rely heavily on chart documentation, reviews may be compromised by unclear or incomplete documentation. For example, if information about steps the hospital team took to prepare a family for discharge were not properly documented, it would be difficult to determine whether appropriate steps were taken to minimize the likelihood of a complication. In the case of insufficient documentation of relevant social concerns, cases may be incorrectly classified as preventable, because addressing social issues is often not within a hospital's direct control. Finally, because reviewers were not blinded to the original discharging physician, there may have been some unconscious bias of unknown direction in the reviews.
CONCLUSION
Using the Web‐based fault tree tool helped physicians to identify the root causes of hospital readmissions and classify them as preventable or not preventable in a standardized, efficient, and consistent way, while still accounting for the nuances necessary to conduct a fair review. Thus, other hospitals should consider adopting this framework for their own preventability reviews and quality‐improvement initiatives. However, this project also confirmed that only a very small percentage of general pediatrics 15‐day readmissions are potentially preventable, suggesting that general pediatrics readmissions are not an appropriate measure of hospital quality. Instead, adapting the tool to identify root causes of condition‐specific or procedure‐specific readmission rates may be an area of opportunity for future quality‐improvement efforts.
Disclosures: This work was supported through internal funds from The Children's Hospital of Philadelphia. The authors have no financial interests, relationships or affiliations relevant to the subject matter or materials discussed in the article to disclose. The authors have no potential conflicts of interest relevant to the subject matter or materials discussed in the article to disclose.
As physicians strive to increase the value of healthcare delivery, there has been increased focus on improving the quality of care that patients receive while lowering per capita costs. A provision of the Affordable Care Act implemented in 2012 identified all‐cause 30‐day readmission rates as a measure of hospital quality, and as part of the Act's Hospital Readmission and Reduction Program, Medicare now penalizes hospitals with higher than expected all‐cause readmissions rates for adult patients with certain conditions by lowering reimbursements.[1] Although readmissions are not yet commonly used to determine reimbursements for pediatric hospitals, several states are penalizing higher than expected readmission rates for Medicaid enrollees,[2, 3] using an imprecise algorithm to determine which readmissions resulted from low‐quality care during the index admission.[4, 5, 6]
There is growing concern, however, that readmission rates are not an accurate gauge of the quality of care patients receive while in the hospital or during the discharge process to prepare them for their transition home.[7, 8, 9, 10] This is especially true in pediatric settings, where overall readmission rates are much lower than in adult settings, many readmissions are expected as part of a patient's planned course of care, and variation in readmission rates between hospitals is correlated with the percentage of patients with certain complex chronic conditions.[1, 7, 11] Thus, there is increasing agreement that hospitals and external evaluators need to shift the focus from all‐cause readmissions to a reliable, consistent, and fair measure of potentially preventable readmissions.[12, 13] In addition to being a more useful quality metric, analyzing preventable readmissions will help hospitals focus resources on patients with potentially modifiable risk factors and develop meaningful quality‐improvement initiatives to improve inpatient care as well as the discharge process to prepare families for their transition to home.[14]
Although previous studies have attempted to distinguish preventable from nonpreventable readmissions, many reported significant challenges in completing reviews efficiently, achieving consistency in how readmissions were classified, and attaining consensus on final determinations.[12, 13, 14] Studies have also demonstrated that the algorithms some states are using to streamline preventability reviews and determine reimbursements overestimate the rate of potentially preventable readmissions.[4, 5, 6]
To increase the efficiency of preventability reviews and reduce the subjectivity involved in reaching final determinations, while still accounting for the nuances necessary to conduct a fair review, a quality‐improvement team from the Division of General Pediatrics at The Children's Hospital of Philadelphia (CHOP) implemented a fault tree analysis tool based on a framework developed by Howard Parker at Intermountain Primary Children's Hospital. The CHOP team coded this framework into a secure Web‐based data‐collection tool in the form of a decision tree to guide reviewers through a logical progression of questions that result in 1 of 18 root causes of readmissions, 8 of which are considered potentially preventable. We hypothesized that this method would help reviewers efficiently reach consensus on the root causes of hospital readmissions, and thus help the division and the hospital focus efforts on developing relevant quality‐improvement initiatives.
METHODS
Inclusion Criteria and Study Design
This study was conducted at CHOP, a 535‐bed urban, tertiary‐care, freestanding children's hospital with approximately 29,000 annual discharges. Of those discharges, 7000 to 8000 are from the general pediatrics service, meaning that the attending of record was a general pediatrician. Patients were included in the study if (1) they were discharged from the general pediatrics service between January 2014 and December 2014, and (2) they were readmitted to the hospital, for any reason, within 15 days of discharge. Because this analysis was done as part of a quality‐improvement initiative, it focuses on 15‐day, early readmissions to target cases with a higher probability of being potentially preventable from the perspective of the hospital care team.[10, 12, 13] Patients under observation status during the index admission or the readmission were included. However, patients who returned to the emergency department but were not admitted to an inpatient unit were excluded. Objective details about each case, including the patient's name, demographics, chart number, and diagnosis code, were pre‐loaded from EPIC (Epic Systems Corp., Verona, WI) into REDCap (Research Electronic Data Capture;
A panel of 10 general pediatricians divided up the cases to perform retrospective chart reviews. For each case, REDCap guided reviewers through the fault tree analysis. Reviewers met monthly to discuss difficult cases and reach consensus on any identified ambiguities in the process. After all cases were reviewed once, 3 panel members independently reviewed a random selection of cases to measure inter‐rater reliability and confirm reproducibility of final determinations. The inter‐rater reliability statistic was calculated using Stata 12.1 (StataCorp LP, College Station, TX). During chart reviews, panel members were not blinded to the identity of physicians and other staff members caring for the patients under review. CHOP's institutional review board determined this study to be exempt from ongoing review.
Fault Tree Analysis
Using the decision tree framework for analyzing readmissions that was developed at Intermountain Primary Children's Hospital, the REDCap tool prompted reviewers with a series of sequential questions, each with mutually exclusive options. Using imbedded branching logic to select follow‐up questions, the tool guided reviewers to 1 of 18 terminal nodes, each representing a potential root cause of the readmission. Of those 18 potential causes, 8 were considered potentially preventable. A diagram of the fault tree framework, color coded to indicate which nodes were considered potentially preventable, is shown in Figure 1.
RESULTS
In 2014, 7252 patients were discharged from the general pediatrics service at CHOP. Of those patients, 248 were readmitted within 15 days for an overall general pediatrics 15‐day readmission rate of 3.4%.
Preventability Analysis
Of the 248 readmissions, 233 (94.0%) were considered not preventable. The most common cause for readmission, which accounted for 145 cases (58.5%), was a patient developing an unpredictable problem related to the index diagnosis or a natural progression of the disease that required readmission. The second most common cause, which accounted for 53 cases (21.4%), was a patient developing a new condition unrelated to the index diagnosis or a readmission unrelated to the quality of care received during the index stay. The third most frequent cause, which accounted for 11 cases (4.4%), was a legitimate nonclinical readmission due to lack of alternative resources, psychosocial or economic factors, or case‐specific factors. Other nonpreventable causes of readmission, including scheduled readmissions, each accounted for 7 or fewer cases and <3% of total readmissions.
The 15 readmissions considered potentially preventable accounted for 6.0% of total readmissions and 0.2% of total discharges from the general pediatrics service in 2014. The most common cause of preventable readmissions, which accounted for 6 cases, was premature discharge. The second most common cause, which accounted for 4 cases, was a problem resulting from nosocomial or iatrogenic factors. Other potentially preventable causes included delayed detection of problem (3 cases), inappropriate readmission (1 case), and inadequate postdischarge care planning (1 case).
A breakdown of fault tree results, including examples of cases associated with each terminal node, is shown in Table 1. Information about general pediatrics patients and readmitted patients is included in Tables 2 and 3. A breakdown of determinations for each reviewer is included in Supporting Table 1 in the online version of this article.
| Fault Tree Terminal Node | Root Cause of Readmission | No. of Cases | % of Total Readmissions | % Within Preventability Category | % of Total Discharges |
|---|---|---|---|---|---|
| |||||
| 2 (Potentially Preventable) | Problematic condition on discharge. Example:* Index admission: Infant with history of prematurity admitted with RSV and rhinovirus bronchiolitis. Had some waxing and waning symptoms. Just prior to discharge, noted to have increased work of breathing related to feeds. Readmission: 12 hours later with tachypnea, retractions, and hypoxia. | 6 | 2.4% | 40.0% | 0.08% |
| 3 (Potentially Preventable) | Nosocomial/Iatrogenic factors. Example*: Index admission: Toddler admitted with fever and neutropenia. Treated with antibiotics 24 hours. Diagnosed with viral illness and discharged home. Readmission: symptomatic Clostridum difficile infection. | 4 | 1.6% | 26.7% | 0.06% |
| 8 (Potentially Preventable) | Detection/treatment of problem was delayed and not appropriately facilitated. Example:* Index admission: Preteen admitted with abdominal pain, concern for appendicitis. Ultrasound and abdominal MRI negative for appendicitis. Symptoms improved. Tolerated PO. Readmission: 3 days later with similar abdominal pain. Diagnosed with constipation with significant improvement following clean‐out. | 3 | 1.2% | 20.0% | 0.04% |
| 1 (Potentially Preventable) | Inappropriate readmission. Example:* Index admission: Infant with laryngomalacia admitted with bronchiolitis. Readmission: Continued mild bronchiolitis symptoms but did not require oxygen or suctioning, normal CXR. | 1 | 0.4% | 6.7% | 0.01% |
| 5 (Potentially Preventable) | Resulted from inadequate postdischarge care planning. Example:* Index diagnosis: Infant with vomiting, prior admissions, and extensive evaluation, diagnosed with milk protein allergy and GERD. PPI increased. Readmission: Persistent symptoms, required NGT feeds supplementation. | 1 | 0.4% | 6.7% | 0.01% |
| 4 (Potentially Preventable) | Resulted from a preventable complication and hospital/physician did not take the appropriate steps to minimize likelihood of complication. | ||||
| 6 (Potentially Preventable) | Resulted from improper care by patient/family and effort by hospital/physician to ensure correct postdischarge care was inadequate. | ||||
| 7 (Potentially Preventable) | Resulted from inadequate care by community services and effort by hospital/physician to ensure correct postdischarge care was inadequate. | ||||
| 15 | 6.0% | 100% | 0.2% | ||
| 12 (Not Preventable) | Problem was unpredictable. Example:* Index admission: Infant admitted with gastroenteritis and dehydration with an anion gap metabolic acidosis. Vomiting and diarrhea improved, rehydrated, acidosis improved. Readmission: 1 day later, presented with emesis and fussiness. Readmitted for metabolic acidosis. | 145 | 58.5% | 62.2% | 2.00% |
| 10 (Not Preventable) | Patient developed new condition unrelated to index diagnosis or quality of care. Example:* Index admission: Toddler admitted with cellulitis. Readmission: Bronchiolitis (did not meet CDC guidelines for nosocomial infection). | 53 | 21.4% | 22.7% | 0.73% |
| 9 (Not Preventable) | Legitimate nonclinical readmission. Example:* Index admission: Infant admitted with second episode of bronchiolitis. Readmission: 4 days later with mild diarrhea. Tolerated PO challenge in emergency department. Admitted due to parental anxiety. | 11 | 4.4% | 4.7% | 0.15% |
| 17 (Not Preventable) | Problem resulted from improper care by patient/family but effort by hospital/physician to ensure correct postdischarge care was appropriate. Example:* Index admission: Infant admitted with diarrhea, diagnosed with milk protein allergy. Discharged on soy formula. Readmission: Developed vomiting and diarrhea with cow milk formula. | 7 | 2.8% | 3.0% | 0.10% |
| 11 (Not Preventable) | Scheduled readmission. Example:* Index admission: Infant with conjunctivitis and preseptal cellulitis with nasolacrimal duct obstruction. Readmission: Postoperatively following scheduled nasolacrimal duct repair. | 7 | 2.8% | 3.0% | 0.10% |
| 14 (Not Preventable) | Detection/treatment of problem was delayed, but earlier detection was not feasible. Example:* Index admission: Preteen admitted with fever, abdominal pain, and elevated inflammatory markers. Fever resolved and symptoms improved. Diagnosed with unspecified viral infection. Readmission: 4 days later with lower extremity pyomyositis and possible osteomyelitis. | 4 | 1.6% | 1.7% | 0.06% |
| 15 (Not Preventable) | Detection/treatment of problem was delayed, earlier detection was feasible, but detection was appropriately facilitated. Example:* Index admission: Infant with history of laryngomalacia and GER admitted with an ALTE. No events during hospitalization. Appropriate workup and cleared by consultants for discharge. Zantac increased. Readmission: Infant had similar ALTE events within a week after discharge. Ultimately underwent supraglottoplasty. | 2 | 0.8% | 0.9% | 0.03% |
| 13 (Not Preventable) | Resulted from preventable complication but efforts to minimize likelihood were appropriate. Example:* Index admission: Patient on GJ feeds admitted for dislodged GJ. Extensive conversations between primary team and multiple consulting services regarding best type of tube. Determined that no other tube options were appropriate. Temporizing measures were initiated. Readmission: GJ tube dislodged again. | 2 | 0.8% | 0.9% | 0.03% |
| 18 (Not Preventable) | Resulted from medication side effect (after watch period). Example:* Index admission: Preteen with MSSA bacteremia spread to other organs. Sent home on appropriate IV antibiotics. Readmission: Fever, rash, increased LFTs. Blood cultures negative. Presumed drug reaction. Fevers resolved with alternate medication. | 2 | 0.8% | 0.9% | 0.03% |
| 16 (Not Preventable) | Resulted from inadequate care by community services, but effort by hospital/physician to ensure correct postdischarge care was appropriate. | ||||
| 233 | 94.0% | 100% | 3.2% | ||
| Fault Tree Terminal Node | Root Cause of Potentially Preventable Readmission with Case Descriptions* |
|---|---|
| |
| 2 (Potentially Preventable) | Problematic condition on discharge |
| Case 1: Index admission: Infant with history of prematurity admitted with RSV and rhinovirus bronchiolitis. Had some waxing and waning symptoms. Just prior to discharge, noted to have increased work of breathing related to feeds. Readmission: 12 hours later with tachypnea, retractions, and hypoxia. | |
| Case 2: Index admission: Toddler admitted with febrile seizure in setting of gastroenteritis. Poor PO intake during hospitalization. Readmission: 1 day later with dehydration. | |
| Case 3: Index admission: Infant admitted with a prolonged complex febrile seizure. Workup included an unremarkable lumbar puncture. No additional seizures. No inpatient imaging obtained. Readmission: Abnormal outpatient MRI requiring intervention. | |
| Case 4: Index admission: Teenager with wheezing and history of chronic daily symptoms. Discharged <24 hours later on albuterol every 4 hours and prednisone. Readmission: 1 day later, seen by primary care physician with persistent asthma flare. | |
| Case 5: Index admission: Exfull‐term infant admitted with bronchiolitis, early in course. At time of discharge, had been off oxygen for 24 hours, but last recorded respiratory rate was >70. Readmission: 1 day later due to continued tachypnea and increased work of breathing. No hypoxia. CXR normal. | |
| Case 6: Exfull‐term infant admitted with bilious emesis, diarrhea, and dehydration. Ultrasound of pylorus, UGI, and BMP all normal. Tolerated oral intake but had emesis and loose stools prior to discharge. Readmission: <48 hours later with severe metabolic acidosis. | |
| 3 (Potentially Preventable) | Nosocomial/ematrogenic factors |
| Case 1: Index admission: Toddler admitted with fever and neutropenia. Treated with antibiotics 24 hours. Diagnosed with viral illness and discharged home. Readmission: Symptomatic Clostridum difficile infection. | |
| Case 2: Index admission: Patient with autism admitted with viral gastroenteritis. Readmission: Presumed nosocominal upper respiratory infection. | |
| Case 3: Index admission: Infant admitted with bronchiolitis. Recovered from initial infection. Readmission: New upper respiratory infection and presumed nosocomial infection. | |
| Case 4: Index admission: <28‐day‐old full‐term neonate presenting with neonatal fever and rash. Full septic workup performed and all cultures negative at 24 hours. Readmission: CSF culture positive at 36 hours and readmitted while awaiting speciation. Discharged once culture grew out a contaminant. | |
| 8 (Potentially Preventable) | Detection/treatment of problem was delayed and/or not appropriately facilitated |
| Case 1: Index admission: Preteen admitted with abdominal pain, concern for appendicitis. Ultrasound and MRI abdomen negative for appendicitis. Symptoms improved. Tolerated PO. Readmission: 3 days later with similar abdominal pain. Diagnosed with constipation with significant improvement following clean‐out. | |
| Case 2: Index admission: Infant with history of macrocephaly presented with fever and full fontanelle. Head CT showed mild prominence of the extra‐axial space, and lumbar puncture was normal. Readmission: Patient developed torticollis. MRI demonstrated a malignant lesion. | |
| Case 3: Index admission: School‐age child with RLQ abdominal pain, fever, leukocytosis, and indeterminate RLQ abdominal ultrasound. Twelve‐hour observation with no further fevers. Pain and appetite improved. Readmission: 1 day later with fever, anorexia, and abdominal pain. RLQ ultrasound unchanged. Appendectomy performed with inflamed appendix. | |
| 1 (Potentially Preventable) | Inappropriate readmission |
| Case 1: Index admission: Infant with laryngomalacia admitted with bronchiolitis. Readmission: Continued mild bronchiolitis symptoms but did not require oxygen or suctioning. Normal CXR. | |
| 5 (Potentially Preventable) | Resulted from inadequate postdischarge care planning |
| Case 1: Index diagnosis: Infant with vomiting, prior admissions, and extensive evaluation, diagnosed with milk protein allergy and GERD. PPI increased. Readmission: Persistent symptoms, required NGT feeds supplementation. | |
| All General Pediatrics Patients in 2014 | General Pediatric Readmitted Patients in 2014 | ||||
|---|---|---|---|---|---|
| Major Diagnosis Category at Index Admission | No. | % | Major Diagnosis Category at Index Admission | No. | % |
| |||||
| Respiratory | 2,723 | 37.5% | Respiratory | 79 | 31.9% |
| Digestive | 748 | 10.3% | Digestive | 41 | 16.5% |
| Ear, nose, mouth, throat | 675 | 9.3% | Ear, nose, mouth, throat | 24 | 9.7% |
| Skin, subcutaneous tissue | 480 | 6.6% | Musculoskeletal and connective tissue | 14 | 5.6% |
| Infectious, parasitic, systemic | 455 | 6.3% | Nervous | 13 | 5.2% |
| Factors influencing health status | 359 | 5.0% | Endocrine, nutritional, metabolic | 13 | 5.2% |
| Endocrine, nutritional, metabolic | 339 | 4.7% | Infectious, parasitic, systemic | 12 | 4.8% |
| Nervous | 239 | 3.3% | Newborn, neonate, perinatal period | 11 | 4.4% |
| Musculoskeletal and connective tissue | 228 | 3.1% | Hepatobiliary system and pancreas | 8 | 3.2% |
| Newborn, neonate, perinatal period | 206 | 2.8% | Skin, subcutaneous tissue | 8 | 3.2% |
| Other* | 800 | 11.0% | Other | 25 | 10.1% |
| Total | 7,252 | 100% | Total | 248 | 100% |
Inter‐Rater Reliability Analysis
A random selection of 50 cases (20% of total readmissions) was selected for a second review to test the tool's inter‐rater reliability. The second review resulted in the same terminal node for 44 (86%) of the cross‐checked files ( = 0.79; 95% confidence interval: 0.60‐0.98). Of the 6 cross‐checked files that ended at different nodes, 5 resulted in the same final determination about preventability. Only 1 of the cross‐checks (2% of total cross‐checked files) resulted in a different conclusion about preventability.
Efficiency Analysis
Reviewers reported that using the tool to reach a determination about preventability took approximately 20 minutes per case. Thus, initial reviews on the 248 cases required approximately 82.6 reviewer hours. Divided across 10 reviewers, this resulted in 8 to 9 hours of review time per reviewer over the year.
DISCUSSION
As part of an effort to direct quality‐improvement initiatives, this project used a Web‐based fault tree tool to identify root causes of general pediatrics readmissions at a freestanding children's hospital and classify them as either preventable or not preventable. The project also investigated the efficiency and inter‐rater reliability of the tool, which was designed to systematically guide physicians through the chart review process to a final determination about preventability. The project confirmed that using the tool helped reviewers reach final determinations about preventability efficiently with a high degree of consistency. It also confirmed that only a very small percentage of general pediatrics 15‐day readmissions are potentially preventable. Specifically, potentially preventable readmissions accounted for only 6.0% of total readmissions and 0.2% of general pediatrics discharges in 2014. Although our analysis focused on 15‐day readmissions, the fault tree methodology can be applied to any timeframe.
Previous studies attempting to distinguish preventable from nonpreventable readmissions, which used a range of methodologies to reach final determinations, reported that their review process was both time intensive and highly subjective. One study, which had 4 reviewers independently review charts and assign each case a preventability score on a 5‐point Likert scale, reported that reviewers disagreed on the final determination in 62.5% of cases.[12] Another study had 2 physicians independently review a selection of cases and assign a preventability score on a scale from 0 to 3. Scores for the 2 reviewers were added together, and cases above a certain composite threshold were classified as preventable. Despite being time‐intensive, this method resulted in only moderate agreement among physicians about the likelihood of preventability (weighted statistic of 0.44).[14] A more recent study, in which 2 physicians independently classified readmissions into 1 of 4 predefined categories, also reported only moderate agreement between reviewers ( = 0.44).[13] Other methods that have been reported include classifying readmissions as preventable only if multiple reviewers independently agreed, and using a third reviewer as a tie‐breaker.[14]
In an attempt to identify potentially preventable readmissions without using chart reviews, 3M (St. Paul, MN) developed its Potentially Preventable Readmissions software (3M‐PPR), which uses administrative data to identify which readmissions were potentially preventable. Although this automated approach is less time intensive, evidence suggests that due to a lack of nuance, the algorithm significantly overestimates the percentage of readmissions that are potentially preventable.[4, 5] A study that used 3M‐PPR to assess 1.7 million hospitalizations across 58 children's hospitals found that the algorithm classified 81% of sickle cell crisis and asthma readmissions, and 83% of bronchiolitis readmissions as potentially preventable.[10, 11] However, many readmissions for asthma and bronchiolitis are due to social factors that are outside of a hospital's direct control,[4, 5] and at many hospitals, readmissions for sickle cell crisis are part of a high‐value care model that weighs length of stay against potential readmissions. In addition, when assessing readmissions 7, 15, and 30 days after discharge, the algorithm classified almost the same percentage as potentially preventable, which is inconsistent with the notion that readmissions are more likely to have been preventable if they occurred closer to the initial discharge.[4, 13] Another study that assessed the performance of the software in the adult population reported that the algorithm performed with 85% sensitivity, but only 28% specificity.[5, 6]
The results of this quality‐improvement project indicate that using the fault tree tool to guide physicians through the chart review process helped address some of the shortcomings of methods reported in previous studies, by increasing the efficiency and reducing the subjectivity of final determinations, while still accounting for the nuances necessary to conduct a fair review. Because the tool provided a systematic framework for reviews, each case was completed in approximately 20 minutes, and because the process was the same for all reviewers, inter‐rater reliability was extremely high. In 86% of cross‐checked cases, the second reviewer ended at the same terminal node in the decision tree as the original reviewer, and in 98% of cross‐checked cases the second reviewer reached the same conclusion about preventability, even if they did not end at the same terminal node. Even accounting for agreement due to chance, the statistic of 0.79 confirmed that there was substantial agreement among reviewers about final determinations. Because the tool is easily adaptable, other hospitals can adopt this framework for their own preventability reviews and quality‐improvement initiatives.
Using the fault tree tool to access root causes of all 15‐day general pediatric readmissions helped the division focus quality‐improvement efforts on the most common causes of potentially preventable readmissions. Because 40% of potentially preventable readmissions were due to premature discharges, this prompted quality‐improvement teams to focus efforts on improving and clarifying the division's discharge criteria and clinical pathways. The division also initiated processes to improve discharge planning, including improved teaching of discharge instructions and having families pick up prescriptions prior to discharge.
Although these results did help the division identify a few areas of focus to potentially reduce readmissions, the fact that the overall 15‐day readmission rate for general pediatrics, as well as the percentage of readmissions and total discharges that were deemed potentially preventable, were so low (3.4%, 6.0%, and 0.2%, respectively), supports those who question whether prioritizing pediatric readmissions is the best place for hospitals to focus quality‐improvement efforts.[10, 12, 15, 16] As these results indicate, most pediatric readmissions are not preventable, and thus consistent with an efficient, effective, timely, patient‐centered, and equitable health system. Other studies have also shown that because overall and condition‐specific readmissions at pediatric hospitals are low, few pediatric hospitals are high or low performing for readmissions, and thus readmission rates are likely not a good measure of hospital quality.[8]
However, other condition‐specific studies of readmissions in pediatrics have indicated that there are some areas of opportunity to identify populations at high risk for readmission. One study found that although pneumonia‐specific 30‐day readmission rates in a national cohort of children hospitalized with pneumonia was only 3.1%, the chances of readmission were higher for children <1 year old, children with chronic comorbidities or complicated pneumonia, and children cared for in hospitals with lower volumes of pneumonia admissions.[17] Another study found that 17.1% of adolescents in a statewide database were readmitted post‐tonsillectomy for pain, nausea, and dehydration.[18] Thus, adapting the tool to identify root causes of condition‐specific or procedure‐specific readmissions, especially for surgical patients, may be an area of opportunity for future quality‐improvement efforts.[5] However, for general pediatrics, shifting the focus from reducing readmissions to improving the quality of care patients receive in the hospital, improving the discharge process, and adopting a population health approach to mitigate external risk factors, may be appropriate.
This project was subject to limitations. First, because it was conducted at a single site and only on general pediatrics patients, results may not be generalizable to other hospitals or other pediatric divisions. Thus, future studies might use the fault tree framework to assess preventability of pediatric readmissions in other divisions or specialties. Second, because readmissions to other hospitals were not included in the sample, the overall readmissions rate is likely underestimated.[19] However, it is unclear how this would affect the rate of potentially preventable readmissions. Third, although the fault tree framework reduced the subjectivity of the review process, there is still a degree of subjectivity inherent at each decision node. To minimize this, reviewers should try to discuss and come to consensus on how they are making determinations at each juncture in the decision tree. Similarly, because reviewers' answers to decision‐tree questions rely heavily on chart documentation, reviews may be compromised by unclear or incomplete documentation. For example, if information about steps the hospital team took to prepare a family for discharge were not properly documented, it would be difficult to determine whether appropriate steps were taken to minimize the likelihood of a complication. In the case of insufficient documentation of relevant social concerns, cases may be incorrectly classified as preventable, because addressing social issues is often not within a hospital's direct control. Finally, because reviewers were not blinded to the original discharging physician, there may have been some unconscious bias of unknown direction in the reviews.
CONCLUSION
Using the Web‐based fault tree tool helped physicians to identify the root causes of hospital readmissions and classify them as preventable or not preventable in a standardized, efficient, and consistent way, while still accounting for the nuances necessary to conduct a fair review. Thus, other hospitals should consider adopting this framework for their own preventability reviews and quality‐improvement initiatives. However, this project also confirmed that only a very small percentage of general pediatrics 15‐day readmissions are potentially preventable, suggesting that general pediatrics readmissions are not an appropriate measure of hospital quality. Instead, adapting the tool to identify root causes of condition‐specific or procedure‐specific readmission rates may be an area of opportunity for future quality‐improvement efforts.
Disclosures: This work was supported through internal funds from The Children's Hospital of Philadelphia. The authors have no financial interests, relationships or affiliations relevant to the subject matter or materials discussed in the article to disclose. The authors have no potential conflicts of interest relevant to the subject matter or materials discussed in the article to disclose.
- , . Pediatric readmissions as a hospital quality measure. JAMA. 2013;309(4):396–398.
- Texas Health and Human Services Commission. Potentially preventable readmissions in the Texas Medicaid population, state fiscal year 2012. Available at: http://www.hhsc.state.tx.us/reports/2013/ppr‐report.pdf. Published November 2013. Accessed August 16, 2015.
- Illinois Department of Healthcare and Family Services. Quality initiative to reduce hospital potentially preventable readmissions (PPR): Status update. Available at: http://www.illinois.gov/hfs/SiteCollectionDocuments/PPRPolicyStatusUpdate.pdf. Published September 3, 2014. Accessed August 16, 2015.
- , , , et al. Rates and impact of potentially preventable readmissions at children's hospitals. J Pediatr. 2015;166(3):613–619.e615.
- , . Preventing pediatric readmissions: which ones and how? J Pediatr. 2015;166(3):519–520.
- , , , , , . Manual and automated methods for identifying potentially preventable readmissions: a comparison in a large healthcare system. BMC Med Inform Decis Mak. 2014;14:28.
- , . Section on hospital medicine leadership and staff. Hosp Pediatr. 2013;3(4):390–393.
- , , , et al. Measuring hospital quality using pediatric readmission and revisit rates. Pediatrics. 2013;132(3):429–436.
- , . Hospital readmissions—not just a measure of quality. JAMA. 2011;306(16):1796–1797.
- , . Preventing readmissions in children: how do we do that? Hosp Pediatr. 2015;5(11):602–604.
- , , , et al. Pediatric readmission prevalence and variability across hospitals. JAMA. 2013;309(4):372–380.
- , , , , , . Preventability of early readmissions at a children's hospital. Pediatrics. 2013;131(1):e171–e181.
- , , , et al. An examination of physician‐, caregiver‐, and disease‐related factors associated with readmission from a pediatric hospital medicine service. Hosp Pediatr. 2015;5(11):566–573.
- , , , et al. Clinical preventability of 30‐day readmission after percutaneous coronary intervention. J Am Heart Assoc. 2014;3(5):e001290.
- . 3M algorithm overestimates preventable pediatric readmissions. Hospitalist News website. Available at: http://www.ehospitalistnews.com/specialty‐focus/pediatrics/single‐article‐page/3m‐algorithm‐overestimates‐preventable‐pediatric‐readmissions.html. Published August 16, 2013. Accessed August 16, 2015.
- . The 30‐day readmission rate: not a quality measure but an accountability measure. An Ounce of Evidence: Health Policy blog. Available at: https://blogs.sph.harvard.edu/ashish‐jha/?s=30‐day+readmission+rate. Published February 14, 2013. Accessed August 16, 2015.
- , , , et al. Readmissions among children previously hospitalized with pneumonia. Pediatrics. 2014;134(1):100–109.
- , , . A population‐based study of acute care revisits following tonsillectomy. J Pediatr. 2015;166(3):607–612.e605.
- , , , et al. Same‐hospital readmission rates as a measure of pediatric quality of care. JAMA Pediatr. 2015;169(10):905–912.
- , . Pediatric readmissions as a hospital quality measure. JAMA. 2013;309(4):396–398.
- Texas Health and Human Services Commission. Potentially preventable readmissions in the Texas Medicaid population, state fiscal year 2012. Available at: http://www.hhsc.state.tx.us/reports/2013/ppr‐report.pdf. Published November 2013. Accessed August 16, 2015.
- Illinois Department of Healthcare and Family Services. Quality initiative to reduce hospital potentially preventable readmissions (PPR): Status update. Available at: http://www.illinois.gov/hfs/SiteCollectionDocuments/PPRPolicyStatusUpdate.pdf. Published September 3, 2014. Accessed August 16, 2015.
- , , , et al. Rates and impact of potentially preventable readmissions at children's hospitals. J Pediatr. 2015;166(3):613–619.e615.
- , . Preventing pediatric readmissions: which ones and how? J Pediatr. 2015;166(3):519–520.
- , , , , , . Manual and automated methods for identifying potentially preventable readmissions: a comparison in a large healthcare system. BMC Med Inform Decis Mak. 2014;14:28.
- , . Section on hospital medicine leadership and staff. Hosp Pediatr. 2013;3(4):390–393.
- , , , et al. Measuring hospital quality using pediatric readmission and revisit rates. Pediatrics. 2013;132(3):429–436.
- , . Hospital readmissions—not just a measure of quality. JAMA. 2011;306(16):1796–1797.
- , . Preventing readmissions in children: how do we do that? Hosp Pediatr. 2015;5(11):602–604.
- , , , et al. Pediatric readmission prevalence and variability across hospitals. JAMA. 2013;309(4):372–380.
- , , , , , . Preventability of early readmissions at a children's hospital. Pediatrics. 2013;131(1):e171–e181.
- , , , et al. An examination of physician‐, caregiver‐, and disease‐related factors associated with readmission from a pediatric hospital medicine service. Hosp Pediatr. 2015;5(11):566–573.
- , , , et al. Clinical preventability of 30‐day readmission after percutaneous coronary intervention. J Am Heart Assoc. 2014;3(5):e001290.
- . 3M algorithm overestimates preventable pediatric readmissions. Hospitalist News website. Available at: http://www.ehospitalistnews.com/specialty‐focus/pediatrics/single‐article‐page/3m‐algorithm‐overestimates‐preventable‐pediatric‐readmissions.html. Published August 16, 2013. Accessed August 16, 2015.
- . The 30‐day readmission rate: not a quality measure but an accountability measure. An Ounce of Evidence: Health Policy blog. Available at: https://blogs.sph.harvard.edu/ashish‐jha/?s=30‐day+readmission+rate. Published February 14, 2013. Accessed August 16, 2015.
- , , , et al. Readmissions among children previously hospitalized with pneumonia. Pediatrics. 2014;134(1):100–109.
- , , . A population‐based study of acute care revisits following tonsillectomy. J Pediatr. 2015;166(3):607–612.e605.
- , , , et al. Same‐hospital readmission rates as a measure of pediatric quality of care. JAMA Pediatr. 2015;169(10):905–912.
© 2016 Society of Hospital Medicine
Novel Intraoperative Technique to Visualize the Lower Cervical Spine: A Case Series
Two adequate views of the lower cervical vertebrae are necessary to confirm the 3-dimensional location of any hardware placed during cervical spine fusion. Visualizing the lower cervical vertebrae in 2 planes intraoperatively is often a challenge because the shoulders obstruct the lateral view.1 Techniques have been described to improve lateral visualization, including gentle traction of the arms via wrist restraints or taping the shoulders down inferiorly.2,3 These techniques have their inadequacies, including an association with peripheral nerve injury and brachial plexopathy.4 In patients with stout necks, these methods may still be insufficient to achieve adequate visualization of the lower cervical vertebrae.
Invasive techniques to improve visualization have also been described. In 1 study, exposure had to be extended cephalad to allow for manual counting of cervical vertebrae when the mid- to lower cervical vertebrae had to be identified in a morbidly obese patient.5 More invasive spine procedures are associated with higher rates of complications, increased blood loss, more soft-tissue trauma, and longer hospital stays.6 We present a view 30º oblique from horizontal and 30º cephalad from neutral as a variation of the lateral radiograph that improves visualization of the mid- to lower cervical vertebrae. The authors have obtained the patients’ informed written consent for print and electronic publication of these case reports.
Technique
We used either the Smith-Robinson or Cloward approach to the anterior spine. Both techniques use the avascular plane between the medially located esophagus and trachea and the lateral sternocleidomastoid and carotid sheath to approach the anterior cervical spine. Once adequate exposure was achieved, standard anteroposterior and lateral radiographs were obtained to confirm the correct vertebral level. Gentle caudal traction was applied to the patient’s wrist straps, and when visualization continued to be compromised, a view 30º oblique from horizontal and 30º cephalad from neutral was obtained (Figure 1).
Case Series
Case 1
A 54-year-old man with a body mass index (BMI) of 50 presented with neck and bilateral arm pain, with left greater than right radicular symptoms in the C6 and C7 distribution. Magnetic resonance imaging (MRI) showed disc herniations at C5-C6 and C6-C7 with spinal cord signal changes, and he underwent a C5-C6 and C6-C7 anterior cervical discectomy and fusion. Initial localization was determined using a lateral radiograph and vertebral needle. During hardware placement, anteroposterior and lateral fluoroscopic radiographs confirmed adequate placement of the superior screw, but visualization of the inferior portion of the plate and inferior screw was challenging (Figure 2). Our oblique 30º–30º view provided better visualization of the plate and screws in the lower cervical vertebrae than lateral imaging, and allowed confirmation that the hardware was positioned correctly (Figure 3). It took 1 attempt to achieve adequate visualization with the 30º–30º view.
Postoperatively, the patient’s radiculopathy and motor weakness improved. Radiographs confirmed adequate hardware placement, and he was discharged on postoperative day 1 (Figure 4). Imaging at the patient’s 6-week follow-up confirmed adequate fusion from C5-C7, anatomically aligned facet joints, and no hardware failure. The patient’s Neck Disability Index was 31/50 preoperatively and 26/50 at this visit.
Case 2
A 51-year-old man with a BMI of 29 presented with a long-standing history of neck pain and bilateral arm pain left greater than right in the C6 and C7 dermomyotome. MRI showed a broad-based disc herniation with foraminal narrowing at C5-C6 and C6-C7, and the patient underwent a 2-level anterior cervical discectomy and fusion. This patient had pronounced neck musculature, and a deeper than normal incision was required.
Intraoperative lateral fluoroscopy was obtained to confirm the C5-C6 and C6-C7 level prior to discectomy. The musculature of the patient’s neck and shoulder made visualization of the C6-C7 disc space difficult on the lateral radiograph (Figure 5). One attempt was required to obtain the 30º–30º oblique view, which was used to ensure correct placement of the screws and plate (Figure 6).
Postoperatively, the patient’s pain had improved, and radiographs confirmed adequate hardware placement. He was discharged 1 day after surgery (Figure 7). Imaging at the patient’s 6-week follow-up confirmed adequate fusion from C5-C7, stable disc spaces, and anatomically aligned facet joints. His Neck Disability Index was 34/50 preoperatively and 32/50 at 2-week follow-up.
Discussion
The aim of this study was to describe an alternative to the lateral radiograph for imaging the cervical spine in patients with challenging anatomy or in procedures involving hardware placement at the lower cervical vertebrae. Techniques have been developed to assist with improved lateral visualization, including gentle traction of the arms via wrist restraints or taping the shoulders down inferiorly.2,3 However, visualization in 2 planes continues to be a challenge in a subset of patients. It is particularly difficult to obtain adequate lateral radiographs of the cervical spine in patients with stout necks.3 In patients with stout necks, there is more obstruction of the radiography path through the cervical spine. This leads to imaging that is unclear or may fail to show the mid- to lower cervical spine. The extent to which one should rely on the 30º–30º oblique technique for adequate visualization of the cervical spine depends on the anatomy of a particular patient. Historically, it is more challenging to obtain satisfactory lateral radiographs in patients with stout necks,3 and these patients have benefited the most from using the 30º–30º degree oblique view.
Lack of visualization can lead to aborted surgeries or, potentially, surgery at the wrong level.3 A 2008 American Academy of Neurological Surgeons survey indicated that 50% of spine surgeons had performed a wrong-level surgery at least once in their career, and the cervical spine accounted for 21% of all incorrect-level spine surgeries.7 Intraoperative factors reported during cases of wrong-level spinal surgeries included misinterpretation of intraoperative imaging, no intraoperative imaging, and unusual anatomy or physical characteristics.8 Such complications can lead to revision surgery and other significant morbidities for the patient.
In most patients, fluoroscopy allows confirmation of the correct level before disc incision.3 However, operating at a lower cervical level in a patient with a short neck or prominent shoulders poses a significant problem.3 A case report from Singh and colleagues9 described a modified intraoperative fluoroscopic view for spinal level localization at cervicothoracic levels. Their method focuses on identifying the bony lamina and using them as landmarks to count spinal levels, whereas our 30º–30º oblique image is useful for confirmation of adequate hardware placement during anterior cervical spinal fusions. Often, the initial localization of cervical vertebral levels can be achieved with a standard lateral radiograph. We recognized the utility of the 30º–30º oblique view when we were attempting to visualize the inferior aspect of the plate and inferior screw placement.
In patients with stout necks, a lateral radiograph may show only visualization down to C4 or C5.3 Even with applying traction to the arms or taping the shoulders down, it can be impossible to visualize C6, C7, or T1 because the shoulder bones and muscles obstruct the image.3 Using a 30º–30º oblique view, we were able to obtain adequate visualization and assess the accurate placement of hardware.
Conclusion
A 30º oblique view from horizontal and 30º cephalad from neutral radiograph can be used intraoperatively in patients with challenging anatomy to identify placement of hardware at the correct vertebral level in the lower cervical spine. It is a noninvasive technique that can help reduce the risk of wrong-site surgeries without prolonging operation time. This technique describes an alternative to the lateral radiograph and provides a solution to the difficult problem of intraoperative imaging of the mid- to lower cervical spine in 2 adequate planes.
1. Bebawy JF, Koht A, Mirkovic S. Anterior cervical spine surgery. In: Khot A, Sloan TB, Toleikis JR, eds. Monitoring the Nervous System for Anesthesiologists and Other Health Care Professionals. New York, NY: Springer; 2012:539-554.
2. Abumi K, Shono Y, Ito M, Taneichi H, Kotani Y, Kaneda K. Complications of pedicle screw fixation in reconstructive surgery of the cervical spine. Spine. 2000;25(8):962-969.
3. Irace C. Intraoperative imaging for verification of the correct level during spinal surgery. In: Fountas KN, ed. Novel Frontiers of Advanced Neuroimaging. Rijeka, Croatia: Intech; 2013:175-188.
4. Schwartz DM, Sestokas AK, Hilibrand AS, et al. Neurophysiological identification of position-induced neurologic injury during anterior cervical spine surgery. J Clin Monit Comput. 2006;20(6):437-444.
5. Telfeian AE, Reiter GT, Durham SR, Marcotte P. Spine surgery in morbidly obese patients. J Neurosurg Spine. 2002;97(1):20-24.
6. Oppenheimer JH, DeCastro I, McDonnell DE. Minimally invasive spine technology and minimally invasive spine surgery: a historical review. Neurosurg Focus. 2009;27(3):E9.
7. Mody MG, Nourbakhsh A, Stahl DL, Gibbs M, Alfawareh M, Garges KJ. The prevalence of wrong level surgery among spine surgeons. Spine. 2008;33(2):194.
8. Jhawar BS, Mitsis D, Duggal N. Wrong-sided and wrong-level neurosurgery: A national survey. J Neurosurg Spine. 2007;7(5):467-472.
9. Singh H, Meyer SA, Hecht AC, Jenkins AL 3rd. Novel fluoroscopic technique for localization at cervicothoracic levels. J Spinal Disord Tech. 2009;22(8):615-618.
Two adequate views of the lower cervical vertebrae are necessary to confirm the 3-dimensional location of any hardware placed during cervical spine fusion. Visualizing the lower cervical vertebrae in 2 planes intraoperatively is often a challenge because the shoulders obstruct the lateral view.1 Techniques have been described to improve lateral visualization, including gentle traction of the arms via wrist restraints or taping the shoulders down inferiorly.2,3 These techniques have their inadequacies, including an association with peripheral nerve injury and brachial plexopathy.4 In patients with stout necks, these methods may still be insufficient to achieve adequate visualization of the lower cervical vertebrae.
Invasive techniques to improve visualization have also been described. In 1 study, exposure had to be extended cephalad to allow for manual counting of cervical vertebrae when the mid- to lower cervical vertebrae had to be identified in a morbidly obese patient.5 More invasive spine procedures are associated with higher rates of complications, increased blood loss, more soft-tissue trauma, and longer hospital stays.6 We present a view 30º oblique from horizontal and 30º cephalad from neutral as a variation of the lateral radiograph that improves visualization of the mid- to lower cervical vertebrae. The authors have obtained the patients’ informed written consent for print and electronic publication of these case reports.
Technique
We used either the Smith-Robinson or Cloward approach to the anterior spine. Both techniques use the avascular plane between the medially located esophagus and trachea and the lateral sternocleidomastoid and carotid sheath to approach the anterior cervical spine. Once adequate exposure was achieved, standard anteroposterior and lateral radiographs were obtained to confirm the correct vertebral level. Gentle caudal traction was applied to the patient’s wrist straps, and when visualization continued to be compromised, a view 30º oblique from horizontal and 30º cephalad from neutral was obtained (Figure 1).
Case Series
Case 1
A 54-year-old man with a body mass index (BMI) of 50 presented with neck and bilateral arm pain, with left greater than right radicular symptoms in the C6 and C7 distribution. Magnetic resonance imaging (MRI) showed disc herniations at C5-C6 and C6-C7 with spinal cord signal changes, and he underwent a C5-C6 and C6-C7 anterior cervical discectomy and fusion. Initial localization was determined using a lateral radiograph and vertebral needle. During hardware placement, anteroposterior and lateral fluoroscopic radiographs confirmed adequate placement of the superior screw, but visualization of the inferior portion of the plate and inferior screw was challenging (Figure 2). Our oblique 30º–30º view provided better visualization of the plate and screws in the lower cervical vertebrae than lateral imaging, and allowed confirmation that the hardware was positioned correctly (Figure 3). It took 1 attempt to achieve adequate visualization with the 30º–30º view.
Postoperatively, the patient’s radiculopathy and motor weakness improved. Radiographs confirmed adequate hardware placement, and he was discharged on postoperative day 1 (Figure 4). Imaging at the patient’s 6-week follow-up confirmed adequate fusion from C5-C7, anatomically aligned facet joints, and no hardware failure. The patient’s Neck Disability Index was 31/50 preoperatively and 26/50 at this visit.
Case 2
A 51-year-old man with a BMI of 29 presented with a long-standing history of neck pain and bilateral arm pain left greater than right in the C6 and C7 dermomyotome. MRI showed a broad-based disc herniation with foraminal narrowing at C5-C6 and C6-C7, and the patient underwent a 2-level anterior cervical discectomy and fusion. This patient had pronounced neck musculature, and a deeper than normal incision was required.
Intraoperative lateral fluoroscopy was obtained to confirm the C5-C6 and C6-C7 level prior to discectomy. The musculature of the patient’s neck and shoulder made visualization of the C6-C7 disc space difficult on the lateral radiograph (Figure 5). One attempt was required to obtain the 30º–30º oblique view, which was used to ensure correct placement of the screws and plate (Figure 6).
Postoperatively, the patient’s pain had improved, and radiographs confirmed adequate hardware placement. He was discharged 1 day after surgery (Figure 7). Imaging at the patient’s 6-week follow-up confirmed adequate fusion from C5-C7, stable disc spaces, and anatomically aligned facet joints. His Neck Disability Index was 34/50 preoperatively and 32/50 at 2-week follow-up.
Discussion
The aim of this study was to describe an alternative to the lateral radiograph for imaging the cervical spine in patients with challenging anatomy or in procedures involving hardware placement at the lower cervical vertebrae. Techniques have been developed to assist with improved lateral visualization, including gentle traction of the arms via wrist restraints or taping the shoulders down inferiorly.2,3 However, visualization in 2 planes continues to be a challenge in a subset of patients. It is particularly difficult to obtain adequate lateral radiographs of the cervical spine in patients with stout necks.3 In patients with stout necks, there is more obstruction of the radiography path through the cervical spine. This leads to imaging that is unclear or may fail to show the mid- to lower cervical spine. The extent to which one should rely on the 30º–30º oblique technique for adequate visualization of the cervical spine depends on the anatomy of a particular patient. Historically, it is more challenging to obtain satisfactory lateral radiographs in patients with stout necks,3 and these patients have benefited the most from using the 30º–30º degree oblique view.
Lack of visualization can lead to aborted surgeries or, potentially, surgery at the wrong level.3 A 2008 American Academy of Neurological Surgeons survey indicated that 50% of spine surgeons had performed a wrong-level surgery at least once in their career, and the cervical spine accounted for 21% of all incorrect-level spine surgeries.7 Intraoperative factors reported during cases of wrong-level spinal surgeries included misinterpretation of intraoperative imaging, no intraoperative imaging, and unusual anatomy or physical characteristics.8 Such complications can lead to revision surgery and other significant morbidities for the patient.
In most patients, fluoroscopy allows confirmation of the correct level before disc incision.3 However, operating at a lower cervical level in a patient with a short neck or prominent shoulders poses a significant problem.3 A case report from Singh and colleagues9 described a modified intraoperative fluoroscopic view for spinal level localization at cervicothoracic levels. Their method focuses on identifying the bony lamina and using them as landmarks to count spinal levels, whereas our 30º–30º oblique image is useful for confirmation of adequate hardware placement during anterior cervical spinal fusions. Often, the initial localization of cervical vertebral levels can be achieved with a standard lateral radiograph. We recognized the utility of the 30º–30º oblique view when we were attempting to visualize the inferior aspect of the plate and inferior screw placement.
In patients with stout necks, a lateral radiograph may show only visualization down to C4 or C5.3 Even with applying traction to the arms or taping the shoulders down, it can be impossible to visualize C6, C7, or T1 because the shoulder bones and muscles obstruct the image.3 Using a 30º–30º oblique view, we were able to obtain adequate visualization and assess the accurate placement of hardware.
Conclusion
A 30º oblique view from horizontal and 30º cephalad from neutral radiograph can be used intraoperatively in patients with challenging anatomy to identify placement of hardware at the correct vertebral level in the lower cervical spine. It is a noninvasive technique that can help reduce the risk of wrong-site surgeries without prolonging operation time. This technique describes an alternative to the lateral radiograph and provides a solution to the difficult problem of intraoperative imaging of the mid- to lower cervical spine in 2 adequate planes.
Two adequate views of the lower cervical vertebrae are necessary to confirm the 3-dimensional location of any hardware placed during cervical spine fusion. Visualizing the lower cervical vertebrae in 2 planes intraoperatively is often a challenge because the shoulders obstruct the lateral view.1 Techniques have been described to improve lateral visualization, including gentle traction of the arms via wrist restraints or taping the shoulders down inferiorly.2,3 These techniques have their inadequacies, including an association with peripheral nerve injury and brachial plexopathy.4 In patients with stout necks, these methods may still be insufficient to achieve adequate visualization of the lower cervical vertebrae.
Invasive techniques to improve visualization have also been described. In 1 study, exposure had to be extended cephalad to allow for manual counting of cervical vertebrae when the mid- to lower cervical vertebrae had to be identified in a morbidly obese patient.5 More invasive spine procedures are associated with higher rates of complications, increased blood loss, more soft-tissue trauma, and longer hospital stays.6 We present a view 30º oblique from horizontal and 30º cephalad from neutral as a variation of the lateral radiograph that improves visualization of the mid- to lower cervical vertebrae. The authors have obtained the patients’ informed written consent for print and electronic publication of these case reports.
Technique
We used either the Smith-Robinson or Cloward approach to the anterior spine. Both techniques use the avascular plane between the medially located esophagus and trachea and the lateral sternocleidomastoid and carotid sheath to approach the anterior cervical spine. Once adequate exposure was achieved, standard anteroposterior and lateral radiographs were obtained to confirm the correct vertebral level. Gentle caudal traction was applied to the patient’s wrist straps, and when visualization continued to be compromised, a view 30º oblique from horizontal and 30º cephalad from neutral was obtained (Figure 1).
Case Series
Case 1
A 54-year-old man with a body mass index (BMI) of 50 presented with neck and bilateral arm pain, with left greater than right radicular symptoms in the C6 and C7 distribution. Magnetic resonance imaging (MRI) showed disc herniations at C5-C6 and C6-C7 with spinal cord signal changes, and he underwent a C5-C6 and C6-C7 anterior cervical discectomy and fusion. Initial localization was determined using a lateral radiograph and vertebral needle. During hardware placement, anteroposterior and lateral fluoroscopic radiographs confirmed adequate placement of the superior screw, but visualization of the inferior portion of the plate and inferior screw was challenging (Figure 2). Our oblique 30º–30º view provided better visualization of the plate and screws in the lower cervical vertebrae than lateral imaging, and allowed confirmation that the hardware was positioned correctly (Figure 3). It took 1 attempt to achieve adequate visualization with the 30º–30º view.
Postoperatively, the patient’s radiculopathy and motor weakness improved. Radiographs confirmed adequate hardware placement, and he was discharged on postoperative day 1 (Figure 4). Imaging at the patient’s 6-week follow-up confirmed adequate fusion from C5-C7, anatomically aligned facet joints, and no hardware failure. The patient’s Neck Disability Index was 31/50 preoperatively and 26/50 at this visit.
Case 2
A 51-year-old man with a BMI of 29 presented with a long-standing history of neck pain and bilateral arm pain left greater than right in the C6 and C7 dermomyotome. MRI showed a broad-based disc herniation with foraminal narrowing at C5-C6 and C6-C7, and the patient underwent a 2-level anterior cervical discectomy and fusion. This patient had pronounced neck musculature, and a deeper than normal incision was required.
Intraoperative lateral fluoroscopy was obtained to confirm the C5-C6 and C6-C7 level prior to discectomy. The musculature of the patient’s neck and shoulder made visualization of the C6-C7 disc space difficult on the lateral radiograph (Figure 5). One attempt was required to obtain the 30º–30º oblique view, which was used to ensure correct placement of the screws and plate (Figure 6).
Postoperatively, the patient’s pain had improved, and radiographs confirmed adequate hardware placement. He was discharged 1 day after surgery (Figure 7). Imaging at the patient’s 6-week follow-up confirmed adequate fusion from C5-C7, stable disc spaces, and anatomically aligned facet joints. His Neck Disability Index was 34/50 preoperatively and 32/50 at 2-week follow-up.
Discussion
The aim of this study was to describe an alternative to the lateral radiograph for imaging the cervical spine in patients with challenging anatomy or in procedures involving hardware placement at the lower cervical vertebrae. Techniques have been developed to assist with improved lateral visualization, including gentle traction of the arms via wrist restraints or taping the shoulders down inferiorly.2,3 However, visualization in 2 planes continues to be a challenge in a subset of patients. It is particularly difficult to obtain adequate lateral radiographs of the cervical spine in patients with stout necks.3 In patients with stout necks, there is more obstruction of the radiography path through the cervical spine. This leads to imaging that is unclear or may fail to show the mid- to lower cervical spine. The extent to which one should rely on the 30º–30º oblique technique for adequate visualization of the cervical spine depends on the anatomy of a particular patient. Historically, it is more challenging to obtain satisfactory lateral radiographs in patients with stout necks,3 and these patients have benefited the most from using the 30º–30º degree oblique view.
Lack of visualization can lead to aborted surgeries or, potentially, surgery at the wrong level.3 A 2008 American Academy of Neurological Surgeons survey indicated that 50% of spine surgeons had performed a wrong-level surgery at least once in their career, and the cervical spine accounted for 21% of all incorrect-level spine surgeries.7 Intraoperative factors reported during cases of wrong-level spinal surgeries included misinterpretation of intraoperative imaging, no intraoperative imaging, and unusual anatomy or physical characteristics.8 Such complications can lead to revision surgery and other significant morbidities for the patient.
In most patients, fluoroscopy allows confirmation of the correct level before disc incision.3 However, operating at a lower cervical level in a patient with a short neck or prominent shoulders poses a significant problem.3 A case report from Singh and colleagues9 described a modified intraoperative fluoroscopic view for spinal level localization at cervicothoracic levels. Their method focuses on identifying the bony lamina and using them as landmarks to count spinal levels, whereas our 30º–30º oblique image is useful for confirmation of adequate hardware placement during anterior cervical spinal fusions. Often, the initial localization of cervical vertebral levels can be achieved with a standard lateral radiograph. We recognized the utility of the 30º–30º oblique view when we were attempting to visualize the inferior aspect of the plate and inferior screw placement.
In patients with stout necks, a lateral radiograph may show only visualization down to C4 or C5.3 Even with applying traction to the arms or taping the shoulders down, it can be impossible to visualize C6, C7, or T1 because the shoulder bones and muscles obstruct the image.3 Using a 30º–30º oblique view, we were able to obtain adequate visualization and assess the accurate placement of hardware.
Conclusion
A 30º oblique view from horizontal and 30º cephalad from neutral radiograph can be used intraoperatively in patients with challenging anatomy to identify placement of hardware at the correct vertebral level in the lower cervical spine. It is a noninvasive technique that can help reduce the risk of wrong-site surgeries without prolonging operation time. This technique describes an alternative to the lateral radiograph and provides a solution to the difficult problem of intraoperative imaging of the mid- to lower cervical spine in 2 adequate planes.
1. Bebawy JF, Koht A, Mirkovic S. Anterior cervical spine surgery. In: Khot A, Sloan TB, Toleikis JR, eds. Monitoring the Nervous System for Anesthesiologists and Other Health Care Professionals. New York, NY: Springer; 2012:539-554.
2. Abumi K, Shono Y, Ito M, Taneichi H, Kotani Y, Kaneda K. Complications of pedicle screw fixation in reconstructive surgery of the cervical spine. Spine. 2000;25(8):962-969.
3. Irace C. Intraoperative imaging for verification of the correct level during spinal surgery. In: Fountas KN, ed. Novel Frontiers of Advanced Neuroimaging. Rijeka, Croatia: Intech; 2013:175-188.
4. Schwartz DM, Sestokas AK, Hilibrand AS, et al. Neurophysiological identification of position-induced neurologic injury during anterior cervical spine surgery. J Clin Monit Comput. 2006;20(6):437-444.
5. Telfeian AE, Reiter GT, Durham SR, Marcotte P. Spine surgery in morbidly obese patients. J Neurosurg Spine. 2002;97(1):20-24.
6. Oppenheimer JH, DeCastro I, McDonnell DE. Minimally invasive spine technology and minimally invasive spine surgery: a historical review. Neurosurg Focus. 2009;27(3):E9.
7. Mody MG, Nourbakhsh A, Stahl DL, Gibbs M, Alfawareh M, Garges KJ. The prevalence of wrong level surgery among spine surgeons. Spine. 2008;33(2):194.
8. Jhawar BS, Mitsis D, Duggal N. Wrong-sided and wrong-level neurosurgery: A national survey. J Neurosurg Spine. 2007;7(5):467-472.
9. Singh H, Meyer SA, Hecht AC, Jenkins AL 3rd. Novel fluoroscopic technique for localization at cervicothoracic levels. J Spinal Disord Tech. 2009;22(8):615-618.
1. Bebawy JF, Koht A, Mirkovic S. Anterior cervical spine surgery. In: Khot A, Sloan TB, Toleikis JR, eds. Monitoring the Nervous System for Anesthesiologists and Other Health Care Professionals. New York, NY: Springer; 2012:539-554.
2. Abumi K, Shono Y, Ito M, Taneichi H, Kotani Y, Kaneda K. Complications of pedicle screw fixation in reconstructive surgery of the cervical spine. Spine. 2000;25(8):962-969.
3. Irace C. Intraoperative imaging for verification of the correct level during spinal surgery. In: Fountas KN, ed. Novel Frontiers of Advanced Neuroimaging. Rijeka, Croatia: Intech; 2013:175-188.
4. Schwartz DM, Sestokas AK, Hilibrand AS, et al. Neurophysiological identification of position-induced neurologic injury during anterior cervical spine surgery. J Clin Monit Comput. 2006;20(6):437-444.
5. Telfeian AE, Reiter GT, Durham SR, Marcotte P. Spine surgery in morbidly obese patients. J Neurosurg Spine. 2002;97(1):20-24.
6. Oppenheimer JH, DeCastro I, McDonnell DE. Minimally invasive spine technology and minimally invasive spine surgery: a historical review. Neurosurg Focus. 2009;27(3):E9.
7. Mody MG, Nourbakhsh A, Stahl DL, Gibbs M, Alfawareh M, Garges KJ. The prevalence of wrong level surgery among spine surgeons. Spine. 2008;33(2):194.
8. Jhawar BS, Mitsis D, Duggal N. Wrong-sided and wrong-level neurosurgery: A national survey. J Neurosurg Spine. 2007;7(5):467-472.
9. Singh H, Meyer SA, Hecht AC, Jenkins AL 3rd. Novel fluoroscopic technique for localization at cervicothoracic levels. J Spinal Disord Tech. 2009;22(8):615-618.
Improving Spanning-Knee External Fixator Stiffness: A Biomechanical Study
External fixators are commonly used as a temporizing treatment for periarticular fractures about the knee. Since its inception with a claw used for patellar fractures by Malgaigne in 1853,1 external fixation has evolved to include pin–crossbar constructs. The stiffness of the construct directly affects the rate at which the frames are likely to fail.2 Most external fixation systems have the option for 2 types of pin–bar connectors, pin-to-bar clamps or multipin clamps. The multipin clamps rely on a cluster of multiple pins to connect the longitudinal supports. These clamps use the “bull horn” extensions to connect the pins to bars (Figure 1). The implant manufacturers recommend the use of 2 longitudinal bars when using these clamps. Conversely, single pin-to-bar clamps permit widely spaced pins but multipin clamps do not. Pin-to-bar clamps also tend to allow the longitudinal cross-bars to be placed closer to bone, improving frame stability.1
In the experience of Dr. Reisman, utilization of pin-to-bar clamps has resulted in improved external fixator construct stiffness compared with those using multipin clamps. He has recognized that, in his own practice, a busy level I trauma center where 4 to 5 spanning knee frames are applied daily, fracture stability is improved with the use of pin-to-bar clamps and often with only a single crossbar, resulting in a simpler, low-cost construct. Despite external fixators used for temporary fixation, frames need to be strong enough to maintain fracture length and stabilize the soft-tissue envelope for days to weeks. It is critical that the frame’s stability allows for patient transfers but controls fracture motion until definitive fixation. Despite having both options available in the external fixator set, there are no biomechanical studies that compare the effect of using pin-to-bar clamps or multipin clamps and bull horns on external fixator stiffness.
In this study, we compared the stiffness of 3 different types of spanning knee external fixator configurations, using multi-pin clamps and 2 crossbars, or pin-to-bar clamps with 1 or 2 crossbars. We compared constructs using 2 systems, 1 with 8-mm–diameter and another with 11-mm–diameter crossbars. We hypothesized that constructs assembled with pin-to-bar clamps would have improved bending stiffness compared with constructs using multipin clamps.
Materials and Methods
Three constructs were made under the supervision of Dr. Reisman, a trauma fellowship–trained orthopedic surgeon. The first construct (construct 1) used two 200-mm bars attached to pin-to-bar clamps with a single 450-mm–long spanning bar connecting the 2 segments (Figure 2). The second construct (construct 2) used 2 spanning bars with pin-to-bar clamps. The third construct (construct 3) used multipin clamps proximally and distally with two 450-mm–long spanning bars. Therefore, we tested 2 types of constructs using pin-to-bar clamps and 1 construct with multipin clamps. Four of each construct type were assembled with both 8-mm (Stryker) and 11-mm bars (Synthes), providing 24 testable constructs. For this study, we tested previously used and cleaned external fixation pins, bars, and clamps obtained from our trauma center. All equipment was examined thoroughly for any potential damaged parts.
To simulate the femoral and tibial attachments, two 5-mm–diameter pins were drilled into each of 2 steel cylinders and welded in place. The femoral cylinder (8.3×2.5 cm) had a pin distance of 55 mm, and the tibial cylinder (6.4×2.5 cm) had a pin distance of 32 mm (Figure 3). The pins were welded intosteel cylinders to help prevent any loosening or failure at the pin (ie, metal interface isolating stress to the components). Dr. Desai assembled the constructs and placed them on the cylinders with a distance of 25 mm between the fixator construct and the cylinder, with 306 mm between the femoral and tibial cylinders. The pin diameters, pin spread, pin number, and bar-to-cylinder distance were constant throughout testing with these specifications.
The assembled constructs were tested on a materials testing machine (MTS 858 Mini-Bionix Test System). A compressive force was applied, through a roller, to a flat plate (Figures 4, 5). This allowed the constructs to flex and bend freely without overly stressing the simulated pin-to-bone interface. Using this loading method, we could compare the stiffness of the different assembled constructs. Each assembled construct was tested 4 times sequentially on the MTS machine. There was no pin deformation when the load was applied through the roller to the flat plate, to the cylinder, to the pins, and onto the construct. It was possible to observe that the construct flexed when the load was applied. Load-displacement curves were produced for each test, and the stiffness was calculated from the slope of this curve. Each test was repeated 4 times, and the stiffness was measured from the load-displacement curve each time. The 4 stiffness measurements were averaged for each construct and compared across all constructs, using a Wilcoxon rank sum test for statistical analysis.
Results
Construct Design
Three different construct designs were evaluated using our testing protocol. The mean stiffness differed across all constructs as seen in Figure 6. Of the constructs using the 11-mm–diameter bars, construct 2 had the highest mean stiffness (32.1 +/- 3.7 N/mm), and this stiffness was significantly greater than the mean stiffness for construct 1 (15.3 +/- 1.5 N/mm; P < .05) and construct 3 (18.4 +/- 2.9 N/mm; P< .05). There was no statistically significant difference in stiffness between construct 1 and construct 3.
Of the constructs using 8-mm–diameter bars, construct 2 had the highest mean stiffness (11.5 +/- 2.4 N/mm), and this stiffness was significantly greater than the mean stiffness for construct 1 (5.0 +/- 0.9 N/mm; P < .05). There was no statistically significant difference in stiffness between construct 2 and construct 3 (7.8 +/- 1.9 N/mm) or between construct 1 and construct 3.
Discussion
Although numerous investigators have examined the biomechanical properties of external fixator systems, the effect of pin-to-bar clamps on frame stiffness is unknown. Biomechanical studies have found that uniplanar constructs with multiple bars can provide adequate strength for temporary fixation.3-9 With multiple options within a particular external fixator set, it is ideal to understand the benefit of using one component instead of another.
The main results from this experiment are: (1) constructs with pin-to-bar clamps and 2 crossbars are stiffer than those using multipin clamps and 2 crossbars; (2) constructs with a single crossbar and pin-to-bar clamps are as stiff as constructs using 2 crossbars and multipin clamps.
Figure 6 shows the average stiffness differences between the 8-mm and 11-mm–diameter bar constructs tested in this study. As expected, each 11-mm diameter–bar construct had a higher average stiffness compared with the 8-mm–diameter bar constructs. Across both the 8-mm and 11-mm–diameter bar constructs, construct 2 had a higher stiffness than that of constructs 1 and 3. Furthermore, there was no difference in the stiffness between constructs 1 and 3.
To improve external fixator stiffness, number of pins and optimization of pin spread can improve the strength of the construct.7 When using pin-to-bar clamps, 1 pin should be as close to the fracture as possible, with the second pin as far from the fracture as possible. 7 Multipin clamps, by design, prevent any optimization of pin spread and require a clustered-pin arrangement.
Bar configuration also plays a critical role in construct stiffness. Bar-to-bone distance should be approximately 2 fingerbreadths from the skin to maximize the stiffness of the construct.4,10-14 Multipin clamps use “bull horn” extensions that tend to elevate the bar away from the skin, increasing the distance between the bar and the bone.
A temporary spanning knee external fixator is commonly used for treating high-energy periarticular tibial or femoral fractures. To hold the fracture in an adequately reduced position, the frame must resist the deforming forces inherent with all fractures. A frame that is not adequately stiff will not hold the fracture in the reduced position, even at the time of initial surgery, which negates one of the benefits of placing the patient in the frame. Hence, adequate stiffness of the spanning-knee fixator is critical to the effectiveness of temporary stabilization before permanent fixation.
The results of this study provide evidence for the superiority of pin-to-bar clamps over multipin clamps in optimizing external fixator construct stiffness. At our institution, we almost exclusively use the single pin-to-bar clamps for spanning-knee external fixation. Based on the results of this study, we often use only a single crossbar. The ability to use a single bar greatly reduces the cost of the construct because crossbars can cost from $100 to $150, depending on the manufacturer.
A recent cost analysis of spanning-knee external fixators showed that construct costs can range from $8,000 to $19,000.15 The lower-cost constructs included 2 crossbars while the more expensive constructs had additional bars and multipin clamps. The authors noted that constructs with larger diameter bars and higher overall stiffness resulted in an improved cost per stiffness ratio. The results of this study support our conclusions regarding bar diameter. Additionally, our results show improved stiffness of constructs with pin-to-bar clamps instead of multipin clamps. By limiting the need for an additional bar, using pin-to-bar clamps and a single large diameter crossbar can create a very cost-efficient and rigidly stable construct.
One criticism of this study is the testing of used equipment. All external fixator manufacturers must evaluate and carefully examine any used equipment prior to the resterilization process and potential release to the practitioner for re-use. Our rationale for using used equipment is based on the assumption that the vast majority of patients do not have their external fixators removed because of failure but because of definitive surgical treatment, and the timing of removal does not necessarily follow a predetermined protocol. For example, timing of definitive surgery is usually set by the patient’s general health status, status of the soft tissues, and surgeon availability. Therefore, this equipment was tested with the presumption that the equipment was in the same state as if the patient continued to wear the frame 1 more day. A study testing unused equipment would be the next step in evaluating external fixators.
Another potential criticism of this study is the use of the same pin spread for constructs using pin-to-bar clamps and those using multipin clamps. We established that, to minimize confounding variables, a constant pin spread was necessary. This also mirrors our more common pin configurations for external fixators with pins placed outside the zone of injury. However, a key determinant of external fixator stability is pin spread, and this is a potential benefit to using pin-to-bar clamps over the multipin clamps that require an exact pin spread. Indeed, our results may have shown a larger difference between constructs using the pin-to-bar clamps compared with the multipin clamps had we maximized the pin spread. Future studies may be able to use a fracture model to compare the pin-to-bar clamps and multipin clamps using pin spread to maximize stability.
Conclusion
This study has shown that using pin-to-bar clamps can create strong, stable constructs for temporary external fixation. In particular, constructs made with a single bar and pin-to-bar clamps can produce easily implantable and less expensive constructs that are stiff enough to withstand deformation and allow patient transfers without excessive displacement of the fracture.
1. Behrens F. A primer of fixator devices and configurations. Clin Orthop Relat Res. 1989;241:5-14.
2. Chao EY, Aro HT, Lewallen DG, Kelly PJ. The effect of rigidity on fracture healing in external fixation. Clin Orthop Relat Res. 1989;241:24-35.
3. Schrøder HA, Weeth RE, Madsen T. Experimental analysis of Hoffman external fixation in various mountings. Arch Orthop Trauma Surg. 1985;104(4):197-200.
4. Kempson GE, Campbell D. The comparative stiffness of external fixation frames. Injury. 1981;12(4):297-304.
5. Giotakis N, Narayan B. Stability with unilateral external fixation in the tibia. Strategies Trauma Limb Reconstr. 2007;2(1):13-20.
6. Briggs BT, Chao EY. The mechanical performance of the standard Hoffmann-Vidal external fixation apparatus. J Bone Joint Surg Am. 1982;64(4):566-573.
7. Hipp JA, Edgerton BC, An KN, Hayes WC. Structural consequences of transcortical holes in long bones loaded in torsion. J Biomech. 1990;23(12):1261-1268.
8. Edgerton BC, An KN, Morrey BF. Torsional strength reduction due to cortical defects in bone. J Orthop Res. 1990;8(6):851-855.
9. Huiskes R, Chao E. Guidelines for external fixation frame rigidity and stresses. J Orthop Res. 1986;4(1):68-75.
10. Pettine KA, Chao EY, Kelly PJ. Analysis of the external fixator pin-bone interface. Clin Orthop Relat Res. 1993;(293):18-27.
11. Halsey D, Fleming B, Pope MH, Krag M, Kristiansen T. External fixator pin design. Clin Orthop Relat Res. 1992;(278):305-312.
12. Huiskes R, Chao EY, Crippen TE. Parametric analyses of pin-bone stresses in external fracture fixation devices. J Orthop Res. 1985;3(3):341-349.
13. Behrens F, Johnson W. Unilateral external fixation methods to increase and reduce frame stiffness. Clin Orthop Relat Res.1989;(241):48-56.
14. Mercer D, Firoozbakhsh K, Prevost M, Mulkey P, DeCoster TA, Schenck R. Stiffness of knee spanning external fixation systems for traumatic knee dislocations: a biomechanical study. J Orthop Trauma. 2010;24(11):693-696.
15. Kim H, Russell JP, Hsieh AH, O’Toole RV. Bar diameter is an important component of knee-spanning external fixator stiffness and cost. Orthopedics. 2014;37(7):e671-e677.
External fixators are commonly used as a temporizing treatment for periarticular fractures about the knee. Since its inception with a claw used for patellar fractures by Malgaigne in 1853,1 external fixation has evolved to include pin–crossbar constructs. The stiffness of the construct directly affects the rate at which the frames are likely to fail.2 Most external fixation systems have the option for 2 types of pin–bar connectors, pin-to-bar clamps or multipin clamps. The multipin clamps rely on a cluster of multiple pins to connect the longitudinal supports. These clamps use the “bull horn” extensions to connect the pins to bars (Figure 1). The implant manufacturers recommend the use of 2 longitudinal bars when using these clamps. Conversely, single pin-to-bar clamps permit widely spaced pins but multipin clamps do not. Pin-to-bar clamps also tend to allow the longitudinal cross-bars to be placed closer to bone, improving frame stability.1
In the experience of Dr. Reisman, utilization of pin-to-bar clamps has resulted in improved external fixator construct stiffness compared with those using multipin clamps. He has recognized that, in his own practice, a busy level I trauma center where 4 to 5 spanning knee frames are applied daily, fracture stability is improved with the use of pin-to-bar clamps and often with only a single crossbar, resulting in a simpler, low-cost construct. Despite external fixators used for temporary fixation, frames need to be strong enough to maintain fracture length and stabilize the soft-tissue envelope for days to weeks. It is critical that the frame’s stability allows for patient transfers but controls fracture motion until definitive fixation. Despite having both options available in the external fixator set, there are no biomechanical studies that compare the effect of using pin-to-bar clamps or multipin clamps and bull horns on external fixator stiffness.
In this study, we compared the stiffness of 3 different types of spanning knee external fixator configurations, using multi-pin clamps and 2 crossbars, or pin-to-bar clamps with 1 or 2 crossbars. We compared constructs using 2 systems, 1 with 8-mm–diameter and another with 11-mm–diameter crossbars. We hypothesized that constructs assembled with pin-to-bar clamps would have improved bending stiffness compared with constructs using multipin clamps.
Materials and Methods
Three constructs were made under the supervision of Dr. Reisman, a trauma fellowship–trained orthopedic surgeon. The first construct (construct 1) used two 200-mm bars attached to pin-to-bar clamps with a single 450-mm–long spanning bar connecting the 2 segments (Figure 2). The second construct (construct 2) used 2 spanning bars with pin-to-bar clamps. The third construct (construct 3) used multipin clamps proximally and distally with two 450-mm–long spanning bars. Therefore, we tested 2 types of constructs using pin-to-bar clamps and 1 construct with multipin clamps. Four of each construct type were assembled with both 8-mm (Stryker) and 11-mm bars (Synthes), providing 24 testable constructs. For this study, we tested previously used and cleaned external fixation pins, bars, and clamps obtained from our trauma center. All equipment was examined thoroughly for any potential damaged parts.
To simulate the femoral and tibial attachments, two 5-mm–diameter pins were drilled into each of 2 steel cylinders and welded in place. The femoral cylinder (8.3×2.5 cm) had a pin distance of 55 mm, and the tibial cylinder (6.4×2.5 cm) had a pin distance of 32 mm (Figure 3). The pins were welded intosteel cylinders to help prevent any loosening or failure at the pin (ie, metal interface isolating stress to the components). Dr. Desai assembled the constructs and placed them on the cylinders with a distance of 25 mm between the fixator construct and the cylinder, with 306 mm between the femoral and tibial cylinders. The pin diameters, pin spread, pin number, and bar-to-cylinder distance were constant throughout testing with these specifications.
The assembled constructs were tested on a materials testing machine (MTS 858 Mini-Bionix Test System). A compressive force was applied, through a roller, to a flat plate (Figures 4, 5). This allowed the constructs to flex and bend freely without overly stressing the simulated pin-to-bone interface. Using this loading method, we could compare the stiffness of the different assembled constructs. Each assembled construct was tested 4 times sequentially on the MTS machine. There was no pin deformation when the load was applied through the roller to the flat plate, to the cylinder, to the pins, and onto the construct. It was possible to observe that the construct flexed when the load was applied. Load-displacement curves were produced for each test, and the stiffness was calculated from the slope of this curve. Each test was repeated 4 times, and the stiffness was measured from the load-displacement curve each time. The 4 stiffness measurements were averaged for each construct and compared across all constructs, using a Wilcoxon rank sum test for statistical analysis.
Results
Construct Design
Three different construct designs were evaluated using our testing protocol. The mean stiffness differed across all constructs as seen in Figure 6. Of the constructs using the 11-mm–diameter bars, construct 2 had the highest mean stiffness (32.1 +/- 3.7 N/mm), and this stiffness was significantly greater than the mean stiffness for construct 1 (15.3 +/- 1.5 N/mm; P < .05) and construct 3 (18.4 +/- 2.9 N/mm; P< .05). There was no statistically significant difference in stiffness between construct 1 and construct 3.
Of the constructs using 8-mm–diameter bars, construct 2 had the highest mean stiffness (11.5 +/- 2.4 N/mm), and this stiffness was significantly greater than the mean stiffness for construct 1 (5.0 +/- 0.9 N/mm; P < .05). There was no statistically significant difference in stiffness between construct 2 and construct 3 (7.8 +/- 1.9 N/mm) or between construct 1 and construct 3.
Discussion
Although numerous investigators have examined the biomechanical properties of external fixator systems, the effect of pin-to-bar clamps on frame stiffness is unknown. Biomechanical studies have found that uniplanar constructs with multiple bars can provide adequate strength for temporary fixation.3-9 With multiple options within a particular external fixator set, it is ideal to understand the benefit of using one component instead of another.
The main results from this experiment are: (1) constructs with pin-to-bar clamps and 2 crossbars are stiffer than those using multipin clamps and 2 crossbars; (2) constructs with a single crossbar and pin-to-bar clamps are as stiff as constructs using 2 crossbars and multipin clamps.
Figure 6 shows the average stiffness differences between the 8-mm and 11-mm–diameter bar constructs tested in this study. As expected, each 11-mm diameter–bar construct had a higher average stiffness compared with the 8-mm–diameter bar constructs. Across both the 8-mm and 11-mm–diameter bar constructs, construct 2 had a higher stiffness than that of constructs 1 and 3. Furthermore, there was no difference in the stiffness between constructs 1 and 3.
To improve external fixator stiffness, number of pins and optimization of pin spread can improve the strength of the construct.7 When using pin-to-bar clamps, 1 pin should be as close to the fracture as possible, with the second pin as far from the fracture as possible. 7 Multipin clamps, by design, prevent any optimization of pin spread and require a clustered-pin arrangement.
Bar configuration also plays a critical role in construct stiffness. Bar-to-bone distance should be approximately 2 fingerbreadths from the skin to maximize the stiffness of the construct.4,10-14 Multipin clamps use “bull horn” extensions that tend to elevate the bar away from the skin, increasing the distance between the bar and the bone.
A temporary spanning knee external fixator is commonly used for treating high-energy periarticular tibial or femoral fractures. To hold the fracture in an adequately reduced position, the frame must resist the deforming forces inherent with all fractures. A frame that is not adequately stiff will not hold the fracture in the reduced position, even at the time of initial surgery, which negates one of the benefits of placing the patient in the frame. Hence, adequate stiffness of the spanning-knee fixator is critical to the effectiveness of temporary stabilization before permanent fixation.
The results of this study provide evidence for the superiority of pin-to-bar clamps over multipin clamps in optimizing external fixator construct stiffness. At our institution, we almost exclusively use the single pin-to-bar clamps for spanning-knee external fixation. Based on the results of this study, we often use only a single crossbar. The ability to use a single bar greatly reduces the cost of the construct because crossbars can cost from $100 to $150, depending on the manufacturer.
A recent cost analysis of spanning-knee external fixators showed that construct costs can range from $8,000 to $19,000.15 The lower-cost constructs included 2 crossbars while the more expensive constructs had additional bars and multipin clamps. The authors noted that constructs with larger diameter bars and higher overall stiffness resulted in an improved cost per stiffness ratio. The results of this study support our conclusions regarding bar diameter. Additionally, our results show improved stiffness of constructs with pin-to-bar clamps instead of multipin clamps. By limiting the need for an additional bar, using pin-to-bar clamps and a single large diameter crossbar can create a very cost-efficient and rigidly stable construct.
One criticism of this study is the testing of used equipment. All external fixator manufacturers must evaluate and carefully examine any used equipment prior to the resterilization process and potential release to the practitioner for re-use. Our rationale for using used equipment is based on the assumption that the vast majority of patients do not have their external fixators removed because of failure but because of definitive surgical treatment, and the timing of removal does not necessarily follow a predetermined protocol. For example, timing of definitive surgery is usually set by the patient’s general health status, status of the soft tissues, and surgeon availability. Therefore, this equipment was tested with the presumption that the equipment was in the same state as if the patient continued to wear the frame 1 more day. A study testing unused equipment would be the next step in evaluating external fixators.
Another potential criticism of this study is the use of the same pin spread for constructs using pin-to-bar clamps and those using multipin clamps. We established that, to minimize confounding variables, a constant pin spread was necessary. This also mirrors our more common pin configurations for external fixators with pins placed outside the zone of injury. However, a key determinant of external fixator stability is pin spread, and this is a potential benefit to using pin-to-bar clamps over the multipin clamps that require an exact pin spread. Indeed, our results may have shown a larger difference between constructs using the pin-to-bar clamps compared with the multipin clamps had we maximized the pin spread. Future studies may be able to use a fracture model to compare the pin-to-bar clamps and multipin clamps using pin spread to maximize stability.
Conclusion
This study has shown that using pin-to-bar clamps can create strong, stable constructs for temporary external fixation. In particular, constructs made with a single bar and pin-to-bar clamps can produce easily implantable and less expensive constructs that are stiff enough to withstand deformation and allow patient transfers without excessive displacement of the fracture.
External fixators are commonly used as a temporizing treatment for periarticular fractures about the knee. Since its inception with a claw used for patellar fractures by Malgaigne in 1853,1 external fixation has evolved to include pin–crossbar constructs. The stiffness of the construct directly affects the rate at which the frames are likely to fail.2 Most external fixation systems have the option for 2 types of pin–bar connectors, pin-to-bar clamps or multipin clamps. The multipin clamps rely on a cluster of multiple pins to connect the longitudinal supports. These clamps use the “bull horn” extensions to connect the pins to bars (Figure 1). The implant manufacturers recommend the use of 2 longitudinal bars when using these clamps. Conversely, single pin-to-bar clamps permit widely spaced pins but multipin clamps do not. Pin-to-bar clamps also tend to allow the longitudinal cross-bars to be placed closer to bone, improving frame stability.1
In the experience of Dr. Reisman, utilization of pin-to-bar clamps has resulted in improved external fixator construct stiffness compared with those using multipin clamps. He has recognized that, in his own practice, a busy level I trauma center where 4 to 5 spanning knee frames are applied daily, fracture stability is improved with the use of pin-to-bar clamps and often with only a single crossbar, resulting in a simpler, low-cost construct. Despite external fixators used for temporary fixation, frames need to be strong enough to maintain fracture length and stabilize the soft-tissue envelope for days to weeks. It is critical that the frame’s stability allows for patient transfers but controls fracture motion until definitive fixation. Despite having both options available in the external fixator set, there are no biomechanical studies that compare the effect of using pin-to-bar clamps or multipin clamps and bull horns on external fixator stiffness.
In this study, we compared the stiffness of 3 different types of spanning knee external fixator configurations, using multi-pin clamps and 2 crossbars, or pin-to-bar clamps with 1 or 2 crossbars. We compared constructs using 2 systems, 1 with 8-mm–diameter and another with 11-mm–diameter crossbars. We hypothesized that constructs assembled with pin-to-bar clamps would have improved bending stiffness compared with constructs using multipin clamps.
Materials and Methods
Three constructs were made under the supervision of Dr. Reisman, a trauma fellowship–trained orthopedic surgeon. The first construct (construct 1) used two 200-mm bars attached to pin-to-bar clamps with a single 450-mm–long spanning bar connecting the 2 segments (Figure 2). The second construct (construct 2) used 2 spanning bars with pin-to-bar clamps. The third construct (construct 3) used multipin clamps proximally and distally with two 450-mm–long spanning bars. Therefore, we tested 2 types of constructs using pin-to-bar clamps and 1 construct with multipin clamps. Four of each construct type were assembled with both 8-mm (Stryker) and 11-mm bars (Synthes), providing 24 testable constructs. For this study, we tested previously used and cleaned external fixation pins, bars, and clamps obtained from our trauma center. All equipment was examined thoroughly for any potential damaged parts.
To simulate the femoral and tibial attachments, two 5-mm–diameter pins were drilled into each of 2 steel cylinders and welded in place. The femoral cylinder (8.3×2.5 cm) had a pin distance of 55 mm, and the tibial cylinder (6.4×2.5 cm) had a pin distance of 32 mm (Figure 3). The pins were welded intosteel cylinders to help prevent any loosening or failure at the pin (ie, metal interface isolating stress to the components). Dr. Desai assembled the constructs and placed them on the cylinders with a distance of 25 mm between the fixator construct and the cylinder, with 306 mm between the femoral and tibial cylinders. The pin diameters, pin spread, pin number, and bar-to-cylinder distance were constant throughout testing with these specifications.
The assembled constructs were tested on a materials testing machine (MTS 858 Mini-Bionix Test System). A compressive force was applied, through a roller, to a flat plate (Figures 4, 5). This allowed the constructs to flex and bend freely without overly stressing the simulated pin-to-bone interface. Using this loading method, we could compare the stiffness of the different assembled constructs. Each assembled construct was tested 4 times sequentially on the MTS machine. There was no pin deformation when the load was applied through the roller to the flat plate, to the cylinder, to the pins, and onto the construct. It was possible to observe that the construct flexed when the load was applied. Load-displacement curves were produced for each test, and the stiffness was calculated from the slope of this curve. Each test was repeated 4 times, and the stiffness was measured from the load-displacement curve each time. The 4 stiffness measurements were averaged for each construct and compared across all constructs, using a Wilcoxon rank sum test for statistical analysis.
Results
Construct Design
Three different construct designs were evaluated using our testing protocol. The mean stiffness differed across all constructs as seen in Figure 6. Of the constructs using the 11-mm–diameter bars, construct 2 had the highest mean stiffness (32.1 +/- 3.7 N/mm), and this stiffness was significantly greater than the mean stiffness for construct 1 (15.3 +/- 1.5 N/mm; P < .05) and construct 3 (18.4 +/- 2.9 N/mm; P< .05). There was no statistically significant difference in stiffness between construct 1 and construct 3.
Of the constructs using 8-mm–diameter bars, construct 2 had the highest mean stiffness (11.5 +/- 2.4 N/mm), and this stiffness was significantly greater than the mean stiffness for construct 1 (5.0 +/- 0.9 N/mm; P < .05). There was no statistically significant difference in stiffness between construct 2 and construct 3 (7.8 +/- 1.9 N/mm) or between construct 1 and construct 3.
Discussion
Although numerous investigators have examined the biomechanical properties of external fixator systems, the effect of pin-to-bar clamps on frame stiffness is unknown. Biomechanical studies have found that uniplanar constructs with multiple bars can provide adequate strength for temporary fixation.3-9 With multiple options within a particular external fixator set, it is ideal to understand the benefit of using one component instead of another.
The main results from this experiment are: (1) constructs with pin-to-bar clamps and 2 crossbars are stiffer than those using multipin clamps and 2 crossbars; (2) constructs with a single crossbar and pin-to-bar clamps are as stiff as constructs using 2 crossbars and multipin clamps.
Figure 6 shows the average stiffness differences between the 8-mm and 11-mm–diameter bar constructs tested in this study. As expected, each 11-mm diameter–bar construct had a higher average stiffness compared with the 8-mm–diameter bar constructs. Across both the 8-mm and 11-mm–diameter bar constructs, construct 2 had a higher stiffness than that of constructs 1 and 3. Furthermore, there was no difference in the stiffness between constructs 1 and 3.
To improve external fixator stiffness, number of pins and optimization of pin spread can improve the strength of the construct.7 When using pin-to-bar clamps, 1 pin should be as close to the fracture as possible, with the second pin as far from the fracture as possible. 7 Multipin clamps, by design, prevent any optimization of pin spread and require a clustered-pin arrangement.
Bar configuration also plays a critical role in construct stiffness. Bar-to-bone distance should be approximately 2 fingerbreadths from the skin to maximize the stiffness of the construct.4,10-14 Multipin clamps use “bull horn” extensions that tend to elevate the bar away from the skin, increasing the distance between the bar and the bone.
A temporary spanning knee external fixator is commonly used for treating high-energy periarticular tibial or femoral fractures. To hold the fracture in an adequately reduced position, the frame must resist the deforming forces inherent with all fractures. A frame that is not adequately stiff will not hold the fracture in the reduced position, even at the time of initial surgery, which negates one of the benefits of placing the patient in the frame. Hence, adequate stiffness of the spanning-knee fixator is critical to the effectiveness of temporary stabilization before permanent fixation.
The results of this study provide evidence for the superiority of pin-to-bar clamps over multipin clamps in optimizing external fixator construct stiffness. At our institution, we almost exclusively use the single pin-to-bar clamps for spanning-knee external fixation. Based on the results of this study, we often use only a single crossbar. The ability to use a single bar greatly reduces the cost of the construct because crossbars can cost from $100 to $150, depending on the manufacturer.
A recent cost analysis of spanning-knee external fixators showed that construct costs can range from $8,000 to $19,000.15 The lower-cost constructs included 2 crossbars while the more expensive constructs had additional bars and multipin clamps. The authors noted that constructs with larger diameter bars and higher overall stiffness resulted in an improved cost per stiffness ratio. The results of this study support our conclusions regarding bar diameter. Additionally, our results show improved stiffness of constructs with pin-to-bar clamps instead of multipin clamps. By limiting the need for an additional bar, using pin-to-bar clamps and a single large diameter crossbar can create a very cost-efficient and rigidly stable construct.
One criticism of this study is the testing of used equipment. All external fixator manufacturers must evaluate and carefully examine any used equipment prior to the resterilization process and potential release to the practitioner for re-use. Our rationale for using used equipment is based on the assumption that the vast majority of patients do not have their external fixators removed because of failure but because of definitive surgical treatment, and the timing of removal does not necessarily follow a predetermined protocol. For example, timing of definitive surgery is usually set by the patient’s general health status, status of the soft tissues, and surgeon availability. Therefore, this equipment was tested with the presumption that the equipment was in the same state as if the patient continued to wear the frame 1 more day. A study testing unused equipment would be the next step in evaluating external fixators.
Another potential criticism of this study is the use of the same pin spread for constructs using pin-to-bar clamps and those using multipin clamps. We established that, to minimize confounding variables, a constant pin spread was necessary. This also mirrors our more common pin configurations for external fixators with pins placed outside the zone of injury. However, a key determinant of external fixator stability is pin spread, and this is a potential benefit to using pin-to-bar clamps over the multipin clamps that require an exact pin spread. Indeed, our results may have shown a larger difference between constructs using the pin-to-bar clamps compared with the multipin clamps had we maximized the pin spread. Future studies may be able to use a fracture model to compare the pin-to-bar clamps and multipin clamps using pin spread to maximize stability.
Conclusion
This study has shown that using pin-to-bar clamps can create strong, stable constructs for temporary external fixation. In particular, constructs made with a single bar and pin-to-bar clamps can produce easily implantable and less expensive constructs that are stiff enough to withstand deformation and allow patient transfers without excessive displacement of the fracture.
1. Behrens F. A primer of fixator devices and configurations. Clin Orthop Relat Res. 1989;241:5-14.
2. Chao EY, Aro HT, Lewallen DG, Kelly PJ. The effect of rigidity on fracture healing in external fixation. Clin Orthop Relat Res. 1989;241:24-35.
3. Schrøder HA, Weeth RE, Madsen T. Experimental analysis of Hoffman external fixation in various mountings. Arch Orthop Trauma Surg. 1985;104(4):197-200.
4. Kempson GE, Campbell D. The comparative stiffness of external fixation frames. Injury. 1981;12(4):297-304.
5. Giotakis N, Narayan B. Stability with unilateral external fixation in the tibia. Strategies Trauma Limb Reconstr. 2007;2(1):13-20.
6. Briggs BT, Chao EY. The mechanical performance of the standard Hoffmann-Vidal external fixation apparatus. J Bone Joint Surg Am. 1982;64(4):566-573.
7. Hipp JA, Edgerton BC, An KN, Hayes WC. Structural consequences of transcortical holes in long bones loaded in torsion. J Biomech. 1990;23(12):1261-1268.
8. Edgerton BC, An KN, Morrey BF. Torsional strength reduction due to cortical defects in bone. J Orthop Res. 1990;8(6):851-855.
9. Huiskes R, Chao E. Guidelines for external fixation frame rigidity and stresses. J Orthop Res. 1986;4(1):68-75.
10. Pettine KA, Chao EY, Kelly PJ. Analysis of the external fixator pin-bone interface. Clin Orthop Relat Res. 1993;(293):18-27.
11. Halsey D, Fleming B, Pope MH, Krag M, Kristiansen T. External fixator pin design. Clin Orthop Relat Res. 1992;(278):305-312.
12. Huiskes R, Chao EY, Crippen TE. Parametric analyses of pin-bone stresses in external fracture fixation devices. J Orthop Res. 1985;3(3):341-349.
13. Behrens F, Johnson W. Unilateral external fixation methods to increase and reduce frame stiffness. Clin Orthop Relat Res.1989;(241):48-56.
14. Mercer D, Firoozbakhsh K, Prevost M, Mulkey P, DeCoster TA, Schenck R. Stiffness of knee spanning external fixation systems for traumatic knee dislocations: a biomechanical study. J Orthop Trauma. 2010;24(11):693-696.
15. Kim H, Russell JP, Hsieh AH, O’Toole RV. Bar diameter is an important component of knee-spanning external fixator stiffness and cost. Orthopedics. 2014;37(7):e671-e677.
1. Behrens F. A primer of fixator devices and configurations. Clin Orthop Relat Res. 1989;241:5-14.
2. Chao EY, Aro HT, Lewallen DG, Kelly PJ. The effect of rigidity on fracture healing in external fixation. Clin Orthop Relat Res. 1989;241:24-35.
3. Schrøder HA, Weeth RE, Madsen T. Experimental analysis of Hoffman external fixation in various mountings. Arch Orthop Trauma Surg. 1985;104(4):197-200.
4. Kempson GE, Campbell D. The comparative stiffness of external fixation frames. Injury. 1981;12(4):297-304.
5. Giotakis N, Narayan B. Stability with unilateral external fixation in the tibia. Strategies Trauma Limb Reconstr. 2007;2(1):13-20.
6. Briggs BT, Chao EY. The mechanical performance of the standard Hoffmann-Vidal external fixation apparatus. J Bone Joint Surg Am. 1982;64(4):566-573.
7. Hipp JA, Edgerton BC, An KN, Hayes WC. Structural consequences of transcortical holes in long bones loaded in torsion. J Biomech. 1990;23(12):1261-1268.
8. Edgerton BC, An KN, Morrey BF. Torsional strength reduction due to cortical defects in bone. J Orthop Res. 1990;8(6):851-855.
9. Huiskes R, Chao E. Guidelines for external fixation frame rigidity and stresses. J Orthop Res. 1986;4(1):68-75.
10. Pettine KA, Chao EY, Kelly PJ. Analysis of the external fixator pin-bone interface. Clin Orthop Relat Res. 1993;(293):18-27.
11. Halsey D, Fleming B, Pope MH, Krag M, Kristiansen T. External fixator pin design. Clin Orthop Relat Res. 1992;(278):305-312.
12. Huiskes R, Chao EY, Crippen TE. Parametric analyses of pin-bone stresses in external fracture fixation devices. J Orthop Res. 1985;3(3):341-349.
13. Behrens F, Johnson W. Unilateral external fixation methods to increase and reduce frame stiffness. Clin Orthop Relat Res.1989;(241):48-56.
14. Mercer D, Firoozbakhsh K, Prevost M, Mulkey P, DeCoster TA, Schenck R. Stiffness of knee spanning external fixation systems for traumatic knee dislocations: a biomechanical study. J Orthop Trauma. 2010;24(11):693-696.
15. Kim H, Russell JP, Hsieh AH, O’Toole RV. Bar diameter is an important component of knee-spanning external fixator stiffness and cost. Orthopedics. 2014;37(7):e671-e677.
Outcomes and Aseptic Survivorship of Revision Total Knee Arthroplasty
Over the past 3 decades, total knee arthroplasty (TKA) has been considered a safe and effective treatment for end-stage knee arthritis.1 However, as the population, the incidence of obesity, and life expectancy continue to increase, the number of TKAs will rise as well.2,3 It is expected that over the next 16 years, the number of TKAs performed annually will exceed 3 million in the United States alone.4 This projection represents an over 600% increase from 2005 figures.5 Given the demographic shift expected over the next 2 decades, patients are anticipated to undergo these procedures at younger ages compared with previous generations, such that those age 65 years or younger will account for more than 55% of primary TKAs.6 More important, given this exponential growth in primary TKAs, there will be a concordant rise in revision procedures. It is expected that, the annual number has roughly doubled from that recorded for 2005.4
Compared with primary TKAs, however, revision TKAs have had less promising results, with survivorship as low as 60% over shorter periods.7,8 In addition, recent studies have found an even higher degree of dissatisfaction and functional limitations among revision TKA patients than among primary TKA patients, 15% to 30% of whom are unhappy with their procedures.9-11 These shortcomings of revision TKAs are thought to result from several factors, including poor bone quality, insufficient bone stock, ligamentous instability, soft-tissue incompetence, infection, malalignment, problems with extensor mechanisms, and substantial pain of uncertain etiology.
Despite there being several complex factors that can lead to worse outcomes with revision TKAs, surgeons are expected to produce results equivalent to those of primary TKAs. It is therefore imperative to delineate the objective and subjective outcomes of revision techniques to identify areas in need of improvement. In this article, we provide a concise overview of revision TKA outcomes in order to stimulate manufacturers, surgeons, and hospitals to improve on implant designs, surgical techniques, and care guidelines for revision TKA. We review the evidence on 5 points: aseptic survivorship, functional outcomes, patient satisfaction, quality of life (QOL), and economic impact. In addition, we compare available outcome data for revision and primary TKAs.
1. Aseptic survivorship
Fehring and colleagues12 in 2001 and Sharkey and colleagues13 in 2002 evaluated mechanisms of failure for revision TKA and reported many failures resulted from infection or were associated with the implant, and occurred within 2 years after the primary procedure. More recently, Dy and colleagues14 found the most common reason for revision was aseptic loosening, followed by infection. The present review focuses on aseptic femoral and tibial revision.
The failure rate for revision TKA is substantially higher than for primary TKA with the same type of prosthesis because of the complexity of the revision procedure, the increasing constraint of the implant design, and the higher degree of bone loss. (Appendix 1 lists risk factors for revision surgery. Appendix 2 is a complete list of survivorship outcomes of revision TKA.)
Sheng and colleagues15 in 2006 and Koskinen and colleagues16 in 2008 analyzed Finnish Arthroplasty Register data to determine failure rates for revision and primary TKA. Sheng and colleagues15 examined survivorship of 2637 revision TKAs (performed between 1990 and 2002) for all-cause endpoints after first revision procedure. Survivorship rates were 89% (5 years) and 79% (10 years), while Koskinen and colleagues16 noted all-cause survival rates of 80% at 15 years. More recently, in 2013, the New Zealand Orthopaedic Association17 analyzed New Zealand Joint Registry data for revision and re-revision rates (rates of revision per 100 component years) for 64,556 primary TKAs performed between 1999 and 2012. During the period studied, 1684 revisions were performed, reflecting a 2.6% revision rate, a 0.50% rate of revision per 100 component years, and a 13-year Kaplan-Meier survivorship of 94.5%. The most common reasons for revision were pain, deep infection, and tibial component loosening (Table 1).
Posterior stabilized implants
Laskin and Ohnsorge18 retrospectively reviewed the cases of 58 patients who underwent unilateral revision TKA (with a posterior stabilized implant), of which 42% were for coronal instability and 44% for a loose tibial component. At minimum 4-year follow-up, 52 of the 58 patients had anteroposterior instability of less than 5 mm. In addition, 5 years after surgery, aseptic survivorship was 96%. Meijer and colleagues19 conducted a retrospective comparative study of 69 revision TKAs (65 patients) in which 9 knees received a primary implant and 60 received a revision implant with stems and augmentation (60 = 37 posterior stabilized, 20 constrained, 3 rotating hinge). Survival rates for the primary implants were 100% (1 year), 73% (2 years), and 44% (5 years), and survival rates for the revision implants were significantly better: 95% (1 year), 92% (2 years), and 92% (5 years) (hazard ratio, 5.87; P = .008). The authors therefore indicated that it was unclear whether using a primary implant should still be an option in revision TKA and, if it is used, whether it should be limited to less complex situations in which bone loss and ligament damage are minimal (Table 2).
Constrained and semiconstrained implants
In a study of 234 knees (209 patients) with soft-tissue deficiency, Wilke and colleagues20 evaluated the long-term survivorship of revision TKA with use of a semiconstrained modular fixed-bearing implant system. Overall Kaplan-Meier survival rates were 91% (5 years) and 81% (10 years) at a mean follow-up of 9 years. When aseptic revision was evaluated, however, the survival rates increased to 95% (5 years) and 90% (10 years). The authors noted that male sex was the only variable that significantly increased the risk for re-revision (hazard ratio, 2.07; P = .02), which they attributed to potentially higher activity levels. In 2006 and 2011, Lachiewicz and Soileau21,22 evaluated the survival of first- and second-generation constrained condylar prostheses in primary TKA cases with severe valgus deformities, incompetent collateral ligaments, or severe flexion contractures. Of the 54 knees (44 patients) with first-generation prostheses, 42 (34 patients) had a mean follow-up of 9 years (range, 5-16 years). Ten-year survival with failure, defined as component revision for loosening, was 96%. The 27 TKAs using second-generation prostheses had a mean follow-up of about 5 years (range, 2-12 years). At final follow-up, there were no revisions for loosening or patellar problems, but 6 knees (22%) required lateral retinacular release of the patella (Table 3).
Rotating hinge implants
Neumann and colleagues23 evaluated the clinical and radiographic outcomes of 24 rotating hinge prostheses used for aseptic loosening with substantial bone loss and collateral ligament instability. At a mean follow-up of 56 months (range, 3-5 years), there was no evidence of loosening of any implants, and nonprogressive radiolucent lines were found in only 2 tibial components. Kowalczewski and colleagues24 evaluated the clinical and radiologic outcomes of 12 primary TKAs using a rotating hinge knee prosthesis at a minimum follow-up of 10 years. By most recent follow-up, no implants had been revised for loosening, and only 3 had nonprogressive radiolucent lines (Table 4).
Endoprostheses (modular segmental implants)
In a systematic review of 9 studies, Korim and colleagues25 evaluated 241 endoprostheses used for limb salvage under nononcologic conditions. Mean follow-up was about 3 years (range, 1-5 years). The devices were used to treat various conditions, including periprosthetic fracture, bone loss with aseptic loosening, and ligament insufficiency. The overall reoperation rate was 17% (41/241 cases). Mechanical failures were less frequent (6%-19%) (Table 5).
2. Functional outcomes
The goal in both primary and revision TKA is to restore the function and mobility of the knee and to alleviate pain. Whereas primary TKAs are realistically predictable and reproducible in their outcomes, revision TKAs are vastly more complicated, which can result in worse postoperative outcomes and function. In addition, revision TKAs may require extensive surgical exposure, which causes more tissue and muscle damage, prolonging rehabilitation. (Appendix 3 is a complete list of studies of functional outcomes of revision TKA.)
This discrepancy in functional outcomes between primary and revision TKA begins as early as the postoperative inpatient rehabilitation period. Using the functional independence measurement (FIM), which estimates performance of activities of daily living, mobility, and cognition, Vincent and colleagues26 evaluated the functional improvement produced by revision versus primary TKA during inpatient rehabilitation. They compared 424 consecutive primary TKAs with 138 revision TKAs. For both groups, FIM scores increased significantly (P = .015) between admission and discharge. On discharge, however, FIM scores were significantly (P = .01) higher for the primary group than the revision group (29 and 27 points, respectively). Furthermore, in the evaluation of mechanisms of failure, patients who had revision TKA for mechanical or pain-related problems did markedly better than those who had revision TKA for infection.
Compared with primary knee implants, revision implants require increasing constraint. We assume increasing constraint affects knee biomechanics, leading to worsening functional outcomes. In a study of 60 revision TKAs (57 patients) using posterior stabilized, condylar constrained, or rotating hinge prostheses, Vasso and colleagues27 examined functional outcomes at a median follow-up of 9 years (range, 4-12 years). At most recent follow-up, mean International Knee Society (IKS) Knee and Function scores were 81 (range, 48-97) and 79 (range, 56-92), mean Hospital for Special Surgery (HSS) score was 84 (range, 62-98), and mean range of motion (ROM) was 121° (range, 98°-132°) (P < .001). Although there were no significant differences in IKS and HSS scores between prosthesis types, ROM was significantly (P < .01) wider in the posterior stabilized group than in the condylar constrained and rotating hinge groups (127° vs 112° and 108°), suggesting increasing constraint resulted in decreased ROM. Several studies have found increasing constraint might lead to reduced function.28-30
However, Hwang and colleagues31 evaluated functional outcomes in 36 revision TKAs and noted that the cemented posterior stabilized (n = 8), condylar constrained (n = 25), and rotating hinge (n = 13) prostheses used did not differ in their mean Knee Society scores (78, 81, and 83, respectively).
There remains a marked disparity in patient limitations seen after revision versus primary TKA. Given the positive results being obtained with newer implants, studies might suggest recent generations of prostheses have allowed designs to be comparable. As design development continues, we may come closer to achieving outcomes comparable to those of primary TKA.
3. Patient satisfaction
Several recent reports have shown that 10% to 25% of patients who underwent primary TKA were dissatisfied with their surgery30,32; other studies have found patient satisfaction often correlating to function and pain.33-35 Given the worse outcomes for revision TKA (outlined in the preceding section), the substantial pain accompanying a second, more complex procedure, and the extensive rehabilitation expected, we suspect patients who undergo revision TKA are even less satisfied with their surgery than their primary counterparts are. (See Appendix 4 for a complete list of studies of patient satisfaction after revision TKA.)
Barrack and colleagues32 evaluated a consecutive series of 238 patients followed up for at least 1 year after revision TKA. Patients were asked to rate their degree of satisfaction with both their primary procedure and the revision and to indicate their expectations regarding their revision prosthesis. Mean satisfaction score was 7.4 (maximum = 10), with 13% of patients dissatisfied, 18% somewhat satisfied, and 69% satisfied. Seventy-four percent of patients expected their revision prosthesis to last longer than the primary prosthesis.
Greidanus and colleagues36 evaluated patient satisfaction in 60 revision TKA cases and 199 primary TKA cases at 2-year follow-up. The primary TKA group had significantly (P < .01) higher satisfaction scores in a comparison with the revision TKA group: Global (86 vs 73), Pain Relief (88 vs 70), Function (83 vs 67), and Recreation (77 vs 62). These findings support the satisfaction rates reported by Dahm and colleagues33,34: 91% for primary TKA patients and 77% for revision TKA patients.
4. Quality of life
Procedure complexity leads to reduced survivorship, function, and mobility, longer rehabilitation, and decreased QOL for revision TKA patients relative to primary TKA patients.37 (See Appendix 5 for a complete list of studies of QOL outcomes of revision TKA.)
Greidanus and colleagues36 evaluated joint-specific QOL (using the 12-item Oxford Knee Score; OKS) and generic QOL (using the 12-Item Short Form Health Survey; SF-12) in 60 revision TKA cases and 199 primary TKA cases at a mean follow-up of 2 years. (The OKS survey is used to evaluate patient perspectives on TKA outcomes,38 and the multipurpose SF-12 questionnaire is used to assess mental and physical function and general health-related QOL.39) Compared with the revision TKA group, the primary TKA group had significantly higher OKS after surgery (78 vs 68; P = .01) as well as significantly higher SF-12 scores: Global (84 vs 72; P = .01), Mental (54 vs 50; P = .03), and Physical (43 vs 37; P = .01). Similarly, Ghomrawi and colleagues40 evaluated patterns of improvement in 308 patients (318 knees) who had revision TKA. At 24-month follow-up, mean SF-36 Physical and Mental scores were 35 and 52, respectively.
Deehan and colleagues41 used the Nottingham Health Profile (NHP) to compare 94 patients’ health-related QOL scores before revision TKA with their scores 3 months, 1 year, and 5 years after revision. NHP Pain subscale scores were significantly lower 3 and 12 months after surgery than before surgery, but this difference was no longer seen at the 5-year follow-up. There was no significant improvement in scores on the other 5 NHP subscales (Sleep, Energy, Emotion, Mobility, Social Isolation) at any time points.
As shown in the literature, patients’ QOL outcomes improve after revision TKA, but these gains are not at the level of patients who undergo primary TKA.36,41 Given that revision surgery is more extensive, and that perhaps revision patients have poorer muscle function, they usually do not return to the level they attained after their index procedure.
5. Economic impact
Consistent with the outcomes already described, the economic impact of revision TKAs is excess expenditures and costs to patients and health care institutions.42 The sources of this impact are higher implant costs, extra operative trays and times, longer hospital stays, more rehabilitation, and increased medication use.43 Revision TKA costs range from $49,000 to more than $100,000—a tremendous increase over primary TKA costs ($25,000-$30,000).43-45 Furthermore, the annual economic burden associated with revision TKA, now $2.7 billion, is expected to exceed $13 billion by 2030.46 In the United States, about $23.2 billion will be spent on 926,527 primary TKAs in 2015; significantly, the costs associated with revising just 10% of these cases account for almost 50% of the total cost of the primary procedures.46
In a retrospective cost-identification multicenter cohort study, Bozic and colleagues47 found that both-component and single-component revisions, compared with primary procedures, were associated with significantly increased operative time (~265 and 221 minutes vs 200 minutes), use of allograft bone (23% and 14% vs 1%), length of stay (5.4 and 5.7 days vs 5.0 days), and percentage of patients discharged to extended-care facilities (26% and 26% vs 25%) (P < .0001). Hospital costs for both- and single-component revisions were 138% and 114% higher than costs for primary procedures (P < .0001). More recently, Kallala and colleagues44 analyzed UK National Health Service data and compared the costs of revision for infection with revision for other causes (pain, instability, aseptic loosening, fracture). Mean length of stay associated with revision for infection (21.5 days) was more than double that associated with revision for aseptic loosening (9.5 days; P < .0001), and mean cost of revision for septic causes (£30,011) was more than 3 times that of revision for other causes (£9655; P < .0001). The authors concluded that the higher costs of revision knee surgery have a considerable economic impact, especially in infection cases.
With more extensive procedures, long-stem or more constrained prostheses are often needed to obtain adequate fixation and stability. The resulting increased, substantial economic burden is felt by patients and the health care system. Given that health care reimbursements are declining, hospitals that perform revision TKAs can sustain marked financial losses. Some centers are asking whether it is cost-effective to continue to perform these types of procedures. We must find new ways to provide revision procedures using less costly implants and tools so that centers will continue to make these procedures available to patients.
Conclusion
Given the exponential growth in primary TKAs, there will be a concordant increase in revision TKAs in the decades to come. This review provides a concise overview of revision TKA outcomes. Given the low level of evidence regarding revision TKAs, we need further higher quality studies of their prostheses and outcomes. Specifically, we need systematic reviews and meta-analyses to provide higher quality evidence regarding outcomes of using individual prosthetic designs.
1. Cram P, Lu X, Kates SL, Singh JA, Li Y, Wolf BR. Total knee arthroplasty volume, utilization, and outcomes among Medicare beneficiaries, 1991–2010. JAMA. 2012;308(12):1227-1236.
2. Crowninshield RD, Rosenberg AG, Sporer SM. Changing demographics of patients with total joint replacement. Clin Orthop Relat Res. 2006;443:266-272.
3. Ravi B, Croxford R, Reichmann WM, Losina E, Katz JN, Hawker GA. The changing demographics of total joint arthroplasty recipients in the United States and Ontario from 2001 to 2007. Best Pract Res Clin Rheumatol. 2012;26(5):637-647.
4. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am. 2007;89(4):780-785.
5. Kurtz SM, Ong KL, Schmier J, Zhao K, Mowat F, Lau E. Primary and revision arthroplasty surgery caseloads in the United States from 1990 to 2004. J Arthroplasty. 2009;24(2):195-203.
6. Kurtz SM, Lau E, Ong K, Zhao K, Kelly M, Bozic KJ. Future young patient demand for primary and revision joint replacement: national projections from 2010 to 2030. Clin Orthop Relat Res. 2009;467(10):2606-2612.
7. Bryan RS, Rand JA. Revision total knee arthroplasty. Clin Orthop Relat Res. 1982;170:116-122.
8. Rand JA, Bryan RS. Revision after total knee arthroplasty. Orthop Clin North Am. 1982;13(1):201-212.
9. Bozic KJ, Kurtz SM, Lau E, et al. The epidemiology of revision total knee arthroplasty in the United States. Clin Orthop Relat Res. 2010;468(1):45-51.
10. Parvizi J, Nunley RM, Berend KR, et al. High level of residual symptoms in young patients after total knee arthroplasty. Clin Orthop Relat Res. 2014;472(1):133-137.
11. Ali A, Sundberg M, Robertsson O, et al. Dissatisfied patients after total knee arthroplasty: a registry study involving 114 patients with 8-13 years of followup. Acta Orthop. 2014;85(3):229-233.
12. Fehring TK, Odum S, Griffin WL, Mason JB, Nadaud M. Early failures in total knee arthroplasty. Clin Orthop Relat Res. 2001;392:315-318.
13. Sharkey PF, Hozack WJ, Rothman RH, Shastri S, Jacoby SM. Insall Award paper. Why are total knee arthroplasties failing today? Clin Orthop Relat Res. 2002;404:7-13.
14. Dy CJ, Marx RG, Bozic KJ, Pan TJ, Padgett DE, Lyman S. Risk factors for revision within 10 years of total knee arthroplasty. Clin Orthop Relat Res. 2014;472(4):1198-1207.
15. Sheng PY, Konttinen L, Lehto M, et al. Revision total knee arthroplasty: 1990 through 2002. A review of the Finnish Arthroplasty Registry. J Bone Joint Surg Am. 2006;88(7):1425-1430.
16. Koskinen E, Eskelinen A, Paavolainen P, Pulkkinen P, Remes V. Comparison of survival and cost-effectiveness between unicondylar arthroplasty and total knee arthroplasty in patients with primary osteoarthritis: a follow-up study of 50,493 knee replacements from the Finnish Arthroplasty Register. Acta Orthop. 2008;79(4):499-507.
17. New Zealand Orthopaedic Association. The New Zealand Joint Registry Fourteen Year Report (January 1999 to December 2012). http://www.nzoa.org.nz/system/files/NJR%2014%20Year%20Report.pdf. Published November 2013. Accessed December 16, 2015.
18. Laskin RS, Ohnsorge J. The use of standard posterior stabilized implants in revision total knee arthroplasty. Clin Orthop Relat Res. 2005;(440):122-125.
19. Meijer MF, Reininga IH, Boerboom AL, Stevens M, Bulstra SK. Poorer survival after a primary implant during revision total knee arthroplasty. Int Orthop. 2013;37(3):415-419.
20. Wilke BK, Wagner ER, Trousdale RT. Long-term survival of semi-constrained total knee arthroplasty for revision surgery. J Arthroplasty. 2014;29(5):1005-1008.
21. Lachiewicz PF, Soileau ES. Ten-year survival and clinical results of constrained components in primary total knee arthroplasty. J Arthroplasty. 2006;21(6):803-808.
22. Lachiewicz PF, Soileau ES. Results of a second-generation constrained condylar prosthesis in primary total knee arthroplasty. J Arthroplasty. 2011;26(8):1228-1231.
23. Neumann DR, Hofstaedter T, Dorn U. Follow-up of a modular rotating hinge knee system in salvage revision total knee arthroplasty. J Arthroplasty. 2012;27(5):814-819.
24. Kowalczewski J, Marczak D, Synder M, Sibinski M. Primary rotating-hinge total knee arthroplasty: good outcomes at mid-term follow-up. J Arthroplasty. 2014;29(6):1202-1206.
25. Korim MT, Esler CN, Reddy VR, Ashford RU. A systematic review of endoprosthetic replacement for non-tumour indications around the knee joint. Knee. 2013;20(6):367-375.
26. Vincent KR, Vincent HK, Lee LW, Alfano AP. Inpatient rehabilitation outcomes in primary and revision total knee arthroplasty patients. Clin Orthop Relat Res. 2006;(446):201-207.
27. Vasso M, Beaufils P, Schiavone Panni A. Constraint choice in revision knee arthroplasty. Int Orthop. 2013;37(7):1279-1284.
28. Baier C, Luring C, Schaumburger J, et al. Assessing patient-oriented results after revision total knee arthroplasty. J Orthop Sci. 2013;18(6):955-961.
29. Hartford JM, Goodman SB, Schurman DJ, Knoblick G. Complex primary and revision total knee arthroplasty using the condylar constrained prosthesis: an average 5-year follow-up. J Arthroplasty. 1998;13(4):380-387.
30. Haidukewych GJ, Jacofsky DJ, Pagnano MW, Trousdale RT. Functional results after revision of well-fixed components for stiffness after primary total knee arthroplasty. J Arthroplasty. 2005;20(2):133-138.
31. Hwang SC, Kong JY, Nam DC, et al. Revision total knee arthroplasty with a cemented posterior stabilized, condylar constrained or fully constrained prosthesis: a minimum 2-year follow-up analysis. Clin Orthop Surg. 2010;2(2):112-120.
32. Barrack RL, McClure JT, Burak CF, Clohisy JC, Parvizi J, Sharkey P. Revision total knee arthroplasty: the patient’s perspective. Clin Orthop Relat Res. 2007;464:146-150.
33. Dahm DL, Barnes SA, Harrington JR, Berry DJ. Patient reported activity after revision total knee arthroplasty. J Arthroplasty. 2007;22(6 suppl 2):106-110.
34. Dahm DL, Barnes SA, Harrington JR, Sayeed SA, Berry DJ. Patient-reported activity level after total knee arthroplasty. J Arthroplasty. 2008;23(3):401-407.
35. Richards CJ, Garbuz DS, Pugh L, Masri BA. Revision total knee arthroplasty: clinical outcome comparison with and without the use of femoral head structural allograft. J Arthroplasty. 2011;26(8):1299-1304.
36. Greidanus NV, Peterson RC, Masri BA, Garbuz DS. Quality of life outcomes in revision versus primary total knee arthroplasty. J Arthroplasty. 2011;26(4):615-620.
37. Ethgen O, Bruyere O, Richy F, Dardennes C, Reginster JY. Health-related quality of life in total hip and total knee arthroplasty. A qualitative and systematic review of the literature. J Bone Joint Surg Am. 2004;86(5):963-974.
38. Murray DW, Fitzpatrick R, Rogers K, et al. The use of the Oxford hip and knee scores. J Bone Joint Surg Br. 2007;89(8):1010-1014.
39. Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220-233.
40. Ghomrawi HM, Kane RL, Eberly LE, Bershadsky B, Saleh KJ; North American Knee Arthroplasty Revision Study Group. Patterns of functional improvement after revision knee arthroplasty. J Bone Joint Surg Am. 2009;91(12):2838-2845.
41. Deehan DJ, Murray JD, Birdsall PD, Pinder IM. Quality of life after knee revision arthroplasty. Acta Orthop. 2006;77(5):761-766.
42. Kapadia BH, McElroy MJ, Issa K, Johnson AJ, Bozic KJ, Mont MA. The economic impact of periprosthetic infections following total knee arthroplasty at a specialized tertiary-care center. J Arthroplasty. 2014;29(5):929-932.
43. Bhandari M, Smith J, Miller LE, Block JE. Clinical and economic burden of revision knee arthroplasty. Clin Med Insights Arthritis Musculoskelet Disord. 2012;5:89-94.
44. Kallala RF, Vanhegan IS, Ibrahim MS, Sarmah S, Haddad FS. Financial analysis of revision knee surgery based on NHS tariffs and hospital costs: does it pay to provide a revision service? Bone Joint J Br. 2015;97(2):197-201.
45. Ong KL, Mowat FS, Chan N, Lau E, Halpern MT, Kurtz SM. Economic burden of revision hip and knee arthroplasty in Medicare enrollees. Clin Orthop Relat Res. 2006;446:22-28.
46. Kurtz SM, Ong KL, Lau E, Bozic KJ. Impact of the economic downturn on total joint replacement demand in the United States: updated projections to 2021. J Bone Joint Surg Am. 2014;96(8):624-630.
47. Bozic KJ, Durbhakula S, Berry DJ, et al. Differences in patient and procedure characteristics and hospital resource use in primary and revision total joint arthroplasty: a multicenter study. J Arthroplasty. 2005;20(7 suppl 3):17-25.
48. Lee KJ, Moon JY, Song EK, Lim HA, Seon JK. Minimum Two-year Results of Revision Total Knee Arthroplasty Following Infectious or Non-infectious Causes. Knee Surg Relat Res. 2012;24(4):227-234.
49. Bae DK, Song SJ, Heo DB, Lee SH, Song WJ. Long-term survival rate of implants and modes of failure after revision total knee arthroplasty by a single surgeon. J Arthroplasty. 2013;28(7):1130-1134.
50. Sheng PY, Jämsen E, Lehto MU, Konttinen YT, Pajamäki J, Halonen P. Revision total knee arthroplasty with the Total Condylar III system in inflammatory arthritis. J Bone Joint Surg Br. 2005;87(9):1222-1224.
51. Lachiewicz PF, Soileau ES. Ten-year survival and clinical results of constrained components in primary total knee arthroplasty. J Arthroplasty. 2006;21(6):803-808.
52. Haas SB, Insall JN, Montgomery W 3rd, Windsor RE. Revision total knee arthroplasty with use of modular components with stems inserted without cement. J Bone Joint Surg Am. 1995;77(11):1700-1707.
53. Mabry TM, Vessely MB, Schleck CD, Harmsen WS, Berry DJ. Revision total knee arthroplasty with modular cemented stems: long-term follow-up. J Arthroplasty. 2007;22(6 Suppl 2):100-105.
54. Gudnason A, Milbrink J, Hailer NP. Implant survival and outcome after rotating-hinge total knee revision arthroplasty: a minimum 6-year follow-up. Arch Orthop Trauma Surg. 2011;131(11):1601-1607.
55. Hofmann AA, Goldberg T, Tanner AM, Kurtin SM. Treatment of infected total knee arthroplasty using an articulating spacer: 2- to 12-year experience. Clin Orthop Relat Res. 2005;430:125-131.
56. Greene JW, Reynolds SM, Stimac JD, Malkani AL, Massini MA. Midterm results of hybrid cement technique in revision total knee arthroplasty. J Arthroplasty. 2013;28(4):570-574.
57. Dalury DF, Adams MJ. Minimum 6-year follow-up of revision total knee arthroplasty without patella reimplantation. Journal Arthroplasty. 2012;27(8 Suppl):91-94.
58. Whaley AL, Trousdale RT, Rand JA, Hanssen AD. Cemented long-stem revision total knee arthroplasty. J Arthroplasty. 2003;18(5):592-599.
59. Friedman RJ, Hirst P, Poss R, Kelley K, Sledge CB. Results of revision total knee arthroplasty performed for aseptic loosening. Clinical Orthop Relat Res. 1990;255:235-241.
60. Barrack RL, Rorabeck C, Partington P, Sawhney J, Engh G. The results of retaining a well-fixed patellar component in revision total knee arthroplasty. J Arthroplasty. 2000;15(4):413-417.
61. Christensen CP, Crawford JJ, Olin MD, Vail TP. Revision of the stiff total knee arthroplasty. J Arthroplasty. 2002;17(4):409-415.
62. Garcia RM, Hardy BT, Kraay MJ, Goldberg VM. Revision total knee arthroplasty for aseptic and septic causes in patients with rheumatoid arthritis. Clin Orthop Relat Res. 2010;468(1):82-89.
63. Patil N, Lee K, Huddleston JI, Harris AH, Goodman SB. Aseptic versus septic revision total knee arthroplasty: patient satisfaction, outcome and quality of life improvement. Knee. 2010;17(3):200-203.
64. Luque R, Rizo B, Urda A, et al. Predictive factors for failure after total knee replacement revision. Int Orthop. 2014;38(2):429-435.
65. Bistolfi A, Massazza G, Rosso F, Crova M. Rotating-hinge total knee for revision total knee arthroplasty. Orthopedics. 2012;35(3):e325-e330.
66. Bottner F, Laskin R, Windsor RE, Haas SB. Hybrid component fixation in revision total knee arthroplasty. Clin Orthop Relat Res. 2006;446:127-131.
67. Jensen CL, Winther N, Schroder HM, Petersen MM. Outcome of revision total knee arthroplasty with the use of trabecular metal cone for reconstruction of severe bone loss at the proximal tibia. Knee. 2014;21(6):1233-1237.
68. Howard JL, Kudera J, Lewallen DG, Hanssen AD. Early results of the use of tantalum femoral cones for revision total knee arthroplasty. J Bone Joint Surg Am. 2011;93(5):478-484.
69. Yang JH, Yoon JR, Oh CH, Kim TS. Hybrid component fixation in total knee arthroplasty: minimum of 10-year follow-up study. J Arthroplasty. 2012;27(6):1111-1118.
70. Peters CL, Erickson JA, Gililland JM. Clinical and radiographic results of 184 consecutive revision total knee arthroplasties placed with modular cementless stems. J Arthroplasty. 2009;24(6 Suppl):48-53.
71. Registry AOANJR. Hip and Knee Arthroplasty. Annual Report 2014. 2014.
72. Registry AOANJR. Hip and Knee Arthroplasty. Annual Report 2013. 2013.
Over the past 3 decades, total knee arthroplasty (TKA) has been considered a safe and effective treatment for end-stage knee arthritis.1 However, as the population, the incidence of obesity, and life expectancy continue to increase, the number of TKAs will rise as well.2,3 It is expected that over the next 16 years, the number of TKAs performed annually will exceed 3 million in the United States alone.4 This projection represents an over 600% increase from 2005 figures.5 Given the demographic shift expected over the next 2 decades, patients are anticipated to undergo these procedures at younger ages compared with previous generations, such that those age 65 years or younger will account for more than 55% of primary TKAs.6 More important, given this exponential growth in primary TKAs, there will be a concordant rise in revision procedures. It is expected that, the annual number has roughly doubled from that recorded for 2005.4
Compared with primary TKAs, however, revision TKAs have had less promising results, with survivorship as low as 60% over shorter periods.7,8 In addition, recent studies have found an even higher degree of dissatisfaction and functional limitations among revision TKA patients than among primary TKA patients, 15% to 30% of whom are unhappy with their procedures.9-11 These shortcomings of revision TKAs are thought to result from several factors, including poor bone quality, insufficient bone stock, ligamentous instability, soft-tissue incompetence, infection, malalignment, problems with extensor mechanisms, and substantial pain of uncertain etiology.
Despite there being several complex factors that can lead to worse outcomes with revision TKAs, surgeons are expected to produce results equivalent to those of primary TKAs. It is therefore imperative to delineate the objective and subjective outcomes of revision techniques to identify areas in need of improvement. In this article, we provide a concise overview of revision TKA outcomes in order to stimulate manufacturers, surgeons, and hospitals to improve on implant designs, surgical techniques, and care guidelines for revision TKA. We review the evidence on 5 points: aseptic survivorship, functional outcomes, patient satisfaction, quality of life (QOL), and economic impact. In addition, we compare available outcome data for revision and primary TKAs.
1. Aseptic survivorship
Fehring and colleagues12 in 2001 and Sharkey and colleagues13 in 2002 evaluated mechanisms of failure for revision TKA and reported many failures resulted from infection or were associated with the implant, and occurred within 2 years after the primary procedure. More recently, Dy and colleagues14 found the most common reason for revision was aseptic loosening, followed by infection. The present review focuses on aseptic femoral and tibial revision.
The failure rate for revision TKA is substantially higher than for primary TKA with the same type of prosthesis because of the complexity of the revision procedure, the increasing constraint of the implant design, and the higher degree of bone loss. (Appendix 1 lists risk factors for revision surgery. Appendix 2 is a complete list of survivorship outcomes of revision TKA.)
Sheng and colleagues15 in 2006 and Koskinen and colleagues16 in 2008 analyzed Finnish Arthroplasty Register data to determine failure rates for revision and primary TKA. Sheng and colleagues15 examined survivorship of 2637 revision TKAs (performed between 1990 and 2002) for all-cause endpoints after first revision procedure. Survivorship rates were 89% (5 years) and 79% (10 years), while Koskinen and colleagues16 noted all-cause survival rates of 80% at 15 years. More recently, in 2013, the New Zealand Orthopaedic Association17 analyzed New Zealand Joint Registry data for revision and re-revision rates (rates of revision per 100 component years) for 64,556 primary TKAs performed between 1999 and 2012. During the period studied, 1684 revisions were performed, reflecting a 2.6% revision rate, a 0.50% rate of revision per 100 component years, and a 13-year Kaplan-Meier survivorship of 94.5%. The most common reasons for revision were pain, deep infection, and tibial component loosening (Table 1).
Posterior stabilized implants
Laskin and Ohnsorge18 retrospectively reviewed the cases of 58 patients who underwent unilateral revision TKA (with a posterior stabilized implant), of which 42% were for coronal instability and 44% for a loose tibial component. At minimum 4-year follow-up, 52 of the 58 patients had anteroposterior instability of less than 5 mm. In addition, 5 years after surgery, aseptic survivorship was 96%. Meijer and colleagues19 conducted a retrospective comparative study of 69 revision TKAs (65 patients) in which 9 knees received a primary implant and 60 received a revision implant with stems and augmentation (60 = 37 posterior stabilized, 20 constrained, 3 rotating hinge). Survival rates for the primary implants were 100% (1 year), 73% (2 years), and 44% (5 years), and survival rates for the revision implants were significantly better: 95% (1 year), 92% (2 years), and 92% (5 years) (hazard ratio, 5.87; P = .008). The authors therefore indicated that it was unclear whether using a primary implant should still be an option in revision TKA and, if it is used, whether it should be limited to less complex situations in which bone loss and ligament damage are minimal (Table 2).
Constrained and semiconstrained implants
In a study of 234 knees (209 patients) with soft-tissue deficiency, Wilke and colleagues20 evaluated the long-term survivorship of revision TKA with use of a semiconstrained modular fixed-bearing implant system. Overall Kaplan-Meier survival rates were 91% (5 years) and 81% (10 years) at a mean follow-up of 9 years. When aseptic revision was evaluated, however, the survival rates increased to 95% (5 years) and 90% (10 years). The authors noted that male sex was the only variable that significantly increased the risk for re-revision (hazard ratio, 2.07; P = .02), which they attributed to potentially higher activity levels. In 2006 and 2011, Lachiewicz and Soileau21,22 evaluated the survival of first- and second-generation constrained condylar prostheses in primary TKA cases with severe valgus deformities, incompetent collateral ligaments, or severe flexion contractures. Of the 54 knees (44 patients) with first-generation prostheses, 42 (34 patients) had a mean follow-up of 9 years (range, 5-16 years). Ten-year survival with failure, defined as component revision for loosening, was 96%. The 27 TKAs using second-generation prostheses had a mean follow-up of about 5 years (range, 2-12 years). At final follow-up, there were no revisions for loosening or patellar problems, but 6 knees (22%) required lateral retinacular release of the patella (Table 3).
Rotating hinge implants
Neumann and colleagues23 evaluated the clinical and radiographic outcomes of 24 rotating hinge prostheses used for aseptic loosening with substantial bone loss and collateral ligament instability. At a mean follow-up of 56 months (range, 3-5 years), there was no evidence of loosening of any implants, and nonprogressive radiolucent lines were found in only 2 tibial components. Kowalczewski and colleagues24 evaluated the clinical and radiologic outcomes of 12 primary TKAs using a rotating hinge knee prosthesis at a minimum follow-up of 10 years. By most recent follow-up, no implants had been revised for loosening, and only 3 had nonprogressive radiolucent lines (Table 4).
Endoprostheses (modular segmental implants)
In a systematic review of 9 studies, Korim and colleagues25 evaluated 241 endoprostheses used for limb salvage under nononcologic conditions. Mean follow-up was about 3 years (range, 1-5 years). The devices were used to treat various conditions, including periprosthetic fracture, bone loss with aseptic loosening, and ligament insufficiency. The overall reoperation rate was 17% (41/241 cases). Mechanical failures were less frequent (6%-19%) (Table 5).
2. Functional outcomes
The goal in both primary and revision TKA is to restore the function and mobility of the knee and to alleviate pain. Whereas primary TKAs are realistically predictable and reproducible in their outcomes, revision TKAs are vastly more complicated, which can result in worse postoperative outcomes and function. In addition, revision TKAs may require extensive surgical exposure, which causes more tissue and muscle damage, prolonging rehabilitation. (Appendix 3 is a complete list of studies of functional outcomes of revision TKA.)
This discrepancy in functional outcomes between primary and revision TKA begins as early as the postoperative inpatient rehabilitation period. Using the functional independence measurement (FIM), which estimates performance of activities of daily living, mobility, and cognition, Vincent and colleagues26 evaluated the functional improvement produced by revision versus primary TKA during inpatient rehabilitation. They compared 424 consecutive primary TKAs with 138 revision TKAs. For both groups, FIM scores increased significantly (P = .015) between admission and discharge. On discharge, however, FIM scores were significantly (P = .01) higher for the primary group than the revision group (29 and 27 points, respectively). Furthermore, in the evaluation of mechanisms of failure, patients who had revision TKA for mechanical or pain-related problems did markedly better than those who had revision TKA for infection.
Compared with primary knee implants, revision implants require increasing constraint. We assume increasing constraint affects knee biomechanics, leading to worsening functional outcomes. In a study of 60 revision TKAs (57 patients) using posterior stabilized, condylar constrained, or rotating hinge prostheses, Vasso and colleagues27 examined functional outcomes at a median follow-up of 9 years (range, 4-12 years). At most recent follow-up, mean International Knee Society (IKS) Knee and Function scores were 81 (range, 48-97) and 79 (range, 56-92), mean Hospital for Special Surgery (HSS) score was 84 (range, 62-98), and mean range of motion (ROM) was 121° (range, 98°-132°) (P < .001). Although there were no significant differences in IKS and HSS scores between prosthesis types, ROM was significantly (P < .01) wider in the posterior stabilized group than in the condylar constrained and rotating hinge groups (127° vs 112° and 108°), suggesting increasing constraint resulted in decreased ROM. Several studies have found increasing constraint might lead to reduced function.28-30
However, Hwang and colleagues31 evaluated functional outcomes in 36 revision TKAs and noted that the cemented posterior stabilized (n = 8), condylar constrained (n = 25), and rotating hinge (n = 13) prostheses used did not differ in their mean Knee Society scores (78, 81, and 83, respectively).
There remains a marked disparity in patient limitations seen after revision versus primary TKA. Given the positive results being obtained with newer implants, studies might suggest recent generations of prostheses have allowed designs to be comparable. As design development continues, we may come closer to achieving outcomes comparable to those of primary TKA.
3. Patient satisfaction
Several recent reports have shown that 10% to 25% of patients who underwent primary TKA were dissatisfied with their surgery30,32; other studies have found patient satisfaction often correlating to function and pain.33-35 Given the worse outcomes for revision TKA (outlined in the preceding section), the substantial pain accompanying a second, more complex procedure, and the extensive rehabilitation expected, we suspect patients who undergo revision TKA are even less satisfied with their surgery than their primary counterparts are. (See Appendix 4 for a complete list of studies of patient satisfaction after revision TKA.)
Barrack and colleagues32 evaluated a consecutive series of 238 patients followed up for at least 1 year after revision TKA. Patients were asked to rate their degree of satisfaction with both their primary procedure and the revision and to indicate their expectations regarding their revision prosthesis. Mean satisfaction score was 7.4 (maximum = 10), with 13% of patients dissatisfied, 18% somewhat satisfied, and 69% satisfied. Seventy-four percent of patients expected their revision prosthesis to last longer than the primary prosthesis.
Greidanus and colleagues36 evaluated patient satisfaction in 60 revision TKA cases and 199 primary TKA cases at 2-year follow-up. The primary TKA group had significantly (P < .01) higher satisfaction scores in a comparison with the revision TKA group: Global (86 vs 73), Pain Relief (88 vs 70), Function (83 vs 67), and Recreation (77 vs 62). These findings support the satisfaction rates reported by Dahm and colleagues33,34: 91% for primary TKA patients and 77% for revision TKA patients.
4. Quality of life
Procedure complexity leads to reduced survivorship, function, and mobility, longer rehabilitation, and decreased QOL for revision TKA patients relative to primary TKA patients.37 (See Appendix 5 for a complete list of studies of QOL outcomes of revision TKA.)
Greidanus and colleagues36 evaluated joint-specific QOL (using the 12-item Oxford Knee Score; OKS) and generic QOL (using the 12-Item Short Form Health Survey; SF-12) in 60 revision TKA cases and 199 primary TKA cases at a mean follow-up of 2 years. (The OKS survey is used to evaluate patient perspectives on TKA outcomes,38 and the multipurpose SF-12 questionnaire is used to assess mental and physical function and general health-related QOL.39) Compared with the revision TKA group, the primary TKA group had significantly higher OKS after surgery (78 vs 68; P = .01) as well as significantly higher SF-12 scores: Global (84 vs 72; P = .01), Mental (54 vs 50; P = .03), and Physical (43 vs 37; P = .01). Similarly, Ghomrawi and colleagues40 evaluated patterns of improvement in 308 patients (318 knees) who had revision TKA. At 24-month follow-up, mean SF-36 Physical and Mental scores were 35 and 52, respectively.
Deehan and colleagues41 used the Nottingham Health Profile (NHP) to compare 94 patients’ health-related QOL scores before revision TKA with their scores 3 months, 1 year, and 5 years after revision. NHP Pain subscale scores were significantly lower 3 and 12 months after surgery than before surgery, but this difference was no longer seen at the 5-year follow-up. There was no significant improvement in scores on the other 5 NHP subscales (Sleep, Energy, Emotion, Mobility, Social Isolation) at any time points.
As shown in the literature, patients’ QOL outcomes improve after revision TKA, but these gains are not at the level of patients who undergo primary TKA.36,41 Given that revision surgery is more extensive, and that perhaps revision patients have poorer muscle function, they usually do not return to the level they attained after their index procedure.
5. Economic impact
Consistent with the outcomes already described, the economic impact of revision TKAs is excess expenditures and costs to patients and health care institutions.42 The sources of this impact are higher implant costs, extra operative trays and times, longer hospital stays, more rehabilitation, and increased medication use.43 Revision TKA costs range from $49,000 to more than $100,000—a tremendous increase over primary TKA costs ($25,000-$30,000).43-45 Furthermore, the annual economic burden associated with revision TKA, now $2.7 billion, is expected to exceed $13 billion by 2030.46 In the United States, about $23.2 billion will be spent on 926,527 primary TKAs in 2015; significantly, the costs associated with revising just 10% of these cases account for almost 50% of the total cost of the primary procedures.46
In a retrospective cost-identification multicenter cohort study, Bozic and colleagues47 found that both-component and single-component revisions, compared with primary procedures, were associated with significantly increased operative time (~265 and 221 minutes vs 200 minutes), use of allograft bone (23% and 14% vs 1%), length of stay (5.4 and 5.7 days vs 5.0 days), and percentage of patients discharged to extended-care facilities (26% and 26% vs 25%) (P < .0001). Hospital costs for both- and single-component revisions were 138% and 114% higher than costs for primary procedures (P < .0001). More recently, Kallala and colleagues44 analyzed UK National Health Service data and compared the costs of revision for infection with revision for other causes (pain, instability, aseptic loosening, fracture). Mean length of stay associated with revision for infection (21.5 days) was more than double that associated with revision for aseptic loosening (9.5 days; P < .0001), and mean cost of revision for septic causes (£30,011) was more than 3 times that of revision for other causes (£9655; P < .0001). The authors concluded that the higher costs of revision knee surgery have a considerable economic impact, especially in infection cases.
With more extensive procedures, long-stem or more constrained prostheses are often needed to obtain adequate fixation and stability. The resulting increased, substantial economic burden is felt by patients and the health care system. Given that health care reimbursements are declining, hospitals that perform revision TKAs can sustain marked financial losses. Some centers are asking whether it is cost-effective to continue to perform these types of procedures. We must find new ways to provide revision procedures using less costly implants and tools so that centers will continue to make these procedures available to patients.
Conclusion
Given the exponential growth in primary TKAs, there will be a concordant increase in revision TKAs in the decades to come. This review provides a concise overview of revision TKA outcomes. Given the low level of evidence regarding revision TKAs, we need further higher quality studies of their prostheses and outcomes. Specifically, we need systematic reviews and meta-analyses to provide higher quality evidence regarding outcomes of using individual prosthetic designs.
Over the past 3 decades, total knee arthroplasty (TKA) has been considered a safe and effective treatment for end-stage knee arthritis.1 However, as the population, the incidence of obesity, and life expectancy continue to increase, the number of TKAs will rise as well.2,3 It is expected that over the next 16 years, the number of TKAs performed annually will exceed 3 million in the United States alone.4 This projection represents an over 600% increase from 2005 figures.5 Given the demographic shift expected over the next 2 decades, patients are anticipated to undergo these procedures at younger ages compared with previous generations, such that those age 65 years or younger will account for more than 55% of primary TKAs.6 More important, given this exponential growth in primary TKAs, there will be a concordant rise in revision procedures. It is expected that, the annual number has roughly doubled from that recorded for 2005.4
Compared with primary TKAs, however, revision TKAs have had less promising results, with survivorship as low as 60% over shorter periods.7,8 In addition, recent studies have found an even higher degree of dissatisfaction and functional limitations among revision TKA patients than among primary TKA patients, 15% to 30% of whom are unhappy with their procedures.9-11 These shortcomings of revision TKAs are thought to result from several factors, including poor bone quality, insufficient bone stock, ligamentous instability, soft-tissue incompetence, infection, malalignment, problems with extensor mechanisms, and substantial pain of uncertain etiology.
Despite there being several complex factors that can lead to worse outcomes with revision TKAs, surgeons are expected to produce results equivalent to those of primary TKAs. It is therefore imperative to delineate the objective and subjective outcomes of revision techniques to identify areas in need of improvement. In this article, we provide a concise overview of revision TKA outcomes in order to stimulate manufacturers, surgeons, and hospitals to improve on implant designs, surgical techniques, and care guidelines for revision TKA. We review the evidence on 5 points: aseptic survivorship, functional outcomes, patient satisfaction, quality of life (QOL), and economic impact. In addition, we compare available outcome data for revision and primary TKAs.
1. Aseptic survivorship
Fehring and colleagues12 in 2001 and Sharkey and colleagues13 in 2002 evaluated mechanisms of failure for revision TKA and reported many failures resulted from infection or were associated with the implant, and occurred within 2 years after the primary procedure. More recently, Dy and colleagues14 found the most common reason for revision was aseptic loosening, followed by infection. The present review focuses on aseptic femoral and tibial revision.
The failure rate for revision TKA is substantially higher than for primary TKA with the same type of prosthesis because of the complexity of the revision procedure, the increasing constraint of the implant design, and the higher degree of bone loss. (Appendix 1 lists risk factors for revision surgery. Appendix 2 is a complete list of survivorship outcomes of revision TKA.)
Sheng and colleagues15 in 2006 and Koskinen and colleagues16 in 2008 analyzed Finnish Arthroplasty Register data to determine failure rates for revision and primary TKA. Sheng and colleagues15 examined survivorship of 2637 revision TKAs (performed between 1990 and 2002) for all-cause endpoints after first revision procedure. Survivorship rates were 89% (5 years) and 79% (10 years), while Koskinen and colleagues16 noted all-cause survival rates of 80% at 15 years. More recently, in 2013, the New Zealand Orthopaedic Association17 analyzed New Zealand Joint Registry data for revision and re-revision rates (rates of revision per 100 component years) for 64,556 primary TKAs performed between 1999 and 2012. During the period studied, 1684 revisions were performed, reflecting a 2.6% revision rate, a 0.50% rate of revision per 100 component years, and a 13-year Kaplan-Meier survivorship of 94.5%. The most common reasons for revision were pain, deep infection, and tibial component loosening (Table 1).
Posterior stabilized implants
Laskin and Ohnsorge18 retrospectively reviewed the cases of 58 patients who underwent unilateral revision TKA (with a posterior stabilized implant), of which 42% were for coronal instability and 44% for a loose tibial component. At minimum 4-year follow-up, 52 of the 58 patients had anteroposterior instability of less than 5 mm. In addition, 5 years after surgery, aseptic survivorship was 96%. Meijer and colleagues19 conducted a retrospective comparative study of 69 revision TKAs (65 patients) in which 9 knees received a primary implant and 60 received a revision implant with stems and augmentation (60 = 37 posterior stabilized, 20 constrained, 3 rotating hinge). Survival rates for the primary implants were 100% (1 year), 73% (2 years), and 44% (5 years), and survival rates for the revision implants were significantly better: 95% (1 year), 92% (2 years), and 92% (5 years) (hazard ratio, 5.87; P = .008). The authors therefore indicated that it was unclear whether using a primary implant should still be an option in revision TKA and, if it is used, whether it should be limited to less complex situations in which bone loss and ligament damage are minimal (Table 2).
Constrained and semiconstrained implants
In a study of 234 knees (209 patients) with soft-tissue deficiency, Wilke and colleagues20 evaluated the long-term survivorship of revision TKA with use of a semiconstrained modular fixed-bearing implant system. Overall Kaplan-Meier survival rates were 91% (5 years) and 81% (10 years) at a mean follow-up of 9 years. When aseptic revision was evaluated, however, the survival rates increased to 95% (5 years) and 90% (10 years). The authors noted that male sex was the only variable that significantly increased the risk for re-revision (hazard ratio, 2.07; P = .02), which they attributed to potentially higher activity levels. In 2006 and 2011, Lachiewicz and Soileau21,22 evaluated the survival of first- and second-generation constrained condylar prostheses in primary TKA cases with severe valgus deformities, incompetent collateral ligaments, or severe flexion contractures. Of the 54 knees (44 patients) with first-generation prostheses, 42 (34 patients) had a mean follow-up of 9 years (range, 5-16 years). Ten-year survival with failure, defined as component revision for loosening, was 96%. The 27 TKAs using second-generation prostheses had a mean follow-up of about 5 years (range, 2-12 years). At final follow-up, there were no revisions for loosening or patellar problems, but 6 knees (22%) required lateral retinacular release of the patella (Table 3).
Rotating hinge implants
Neumann and colleagues23 evaluated the clinical and radiographic outcomes of 24 rotating hinge prostheses used for aseptic loosening with substantial bone loss and collateral ligament instability. At a mean follow-up of 56 months (range, 3-5 years), there was no evidence of loosening of any implants, and nonprogressive radiolucent lines were found in only 2 tibial components. Kowalczewski and colleagues24 evaluated the clinical and radiologic outcomes of 12 primary TKAs using a rotating hinge knee prosthesis at a minimum follow-up of 10 years. By most recent follow-up, no implants had been revised for loosening, and only 3 had nonprogressive radiolucent lines (Table 4).
Endoprostheses (modular segmental implants)
In a systematic review of 9 studies, Korim and colleagues25 evaluated 241 endoprostheses used for limb salvage under nononcologic conditions. Mean follow-up was about 3 years (range, 1-5 years). The devices were used to treat various conditions, including periprosthetic fracture, bone loss with aseptic loosening, and ligament insufficiency. The overall reoperation rate was 17% (41/241 cases). Mechanical failures were less frequent (6%-19%) (Table 5).
2. Functional outcomes
The goal in both primary and revision TKA is to restore the function and mobility of the knee and to alleviate pain. Whereas primary TKAs are realistically predictable and reproducible in their outcomes, revision TKAs are vastly more complicated, which can result in worse postoperative outcomes and function. In addition, revision TKAs may require extensive surgical exposure, which causes more tissue and muscle damage, prolonging rehabilitation. (Appendix 3 is a complete list of studies of functional outcomes of revision TKA.)
This discrepancy in functional outcomes between primary and revision TKA begins as early as the postoperative inpatient rehabilitation period. Using the functional independence measurement (FIM), which estimates performance of activities of daily living, mobility, and cognition, Vincent and colleagues26 evaluated the functional improvement produced by revision versus primary TKA during inpatient rehabilitation. They compared 424 consecutive primary TKAs with 138 revision TKAs. For both groups, FIM scores increased significantly (P = .015) between admission and discharge. On discharge, however, FIM scores were significantly (P = .01) higher for the primary group than the revision group (29 and 27 points, respectively). Furthermore, in the evaluation of mechanisms of failure, patients who had revision TKA for mechanical or pain-related problems did markedly better than those who had revision TKA for infection.
Compared with primary knee implants, revision implants require increasing constraint. We assume increasing constraint affects knee biomechanics, leading to worsening functional outcomes. In a study of 60 revision TKAs (57 patients) using posterior stabilized, condylar constrained, or rotating hinge prostheses, Vasso and colleagues27 examined functional outcomes at a median follow-up of 9 years (range, 4-12 years). At most recent follow-up, mean International Knee Society (IKS) Knee and Function scores were 81 (range, 48-97) and 79 (range, 56-92), mean Hospital for Special Surgery (HSS) score was 84 (range, 62-98), and mean range of motion (ROM) was 121° (range, 98°-132°) (P < .001). Although there were no significant differences in IKS and HSS scores between prosthesis types, ROM was significantly (P < .01) wider in the posterior stabilized group than in the condylar constrained and rotating hinge groups (127° vs 112° and 108°), suggesting increasing constraint resulted in decreased ROM. Several studies have found increasing constraint might lead to reduced function.28-30
However, Hwang and colleagues31 evaluated functional outcomes in 36 revision TKAs and noted that the cemented posterior stabilized (n = 8), condylar constrained (n = 25), and rotating hinge (n = 13) prostheses used did not differ in their mean Knee Society scores (78, 81, and 83, respectively).
There remains a marked disparity in patient limitations seen after revision versus primary TKA. Given the positive results being obtained with newer implants, studies might suggest recent generations of prostheses have allowed designs to be comparable. As design development continues, we may come closer to achieving outcomes comparable to those of primary TKA.
3. Patient satisfaction
Several recent reports have shown that 10% to 25% of patients who underwent primary TKA were dissatisfied with their surgery30,32; other studies have found patient satisfaction often correlating to function and pain.33-35 Given the worse outcomes for revision TKA (outlined in the preceding section), the substantial pain accompanying a second, more complex procedure, and the extensive rehabilitation expected, we suspect patients who undergo revision TKA are even less satisfied with their surgery than their primary counterparts are. (See Appendix 4 for a complete list of studies of patient satisfaction after revision TKA.)
Barrack and colleagues32 evaluated a consecutive series of 238 patients followed up for at least 1 year after revision TKA. Patients were asked to rate their degree of satisfaction with both their primary procedure and the revision and to indicate their expectations regarding their revision prosthesis. Mean satisfaction score was 7.4 (maximum = 10), with 13% of patients dissatisfied, 18% somewhat satisfied, and 69% satisfied. Seventy-four percent of patients expected their revision prosthesis to last longer than the primary prosthesis.
Greidanus and colleagues36 evaluated patient satisfaction in 60 revision TKA cases and 199 primary TKA cases at 2-year follow-up. The primary TKA group had significantly (P < .01) higher satisfaction scores in a comparison with the revision TKA group: Global (86 vs 73), Pain Relief (88 vs 70), Function (83 vs 67), and Recreation (77 vs 62). These findings support the satisfaction rates reported by Dahm and colleagues33,34: 91% for primary TKA patients and 77% for revision TKA patients.
4. Quality of life
Procedure complexity leads to reduced survivorship, function, and mobility, longer rehabilitation, and decreased QOL for revision TKA patients relative to primary TKA patients.37 (See Appendix 5 for a complete list of studies of QOL outcomes of revision TKA.)
Greidanus and colleagues36 evaluated joint-specific QOL (using the 12-item Oxford Knee Score; OKS) and generic QOL (using the 12-Item Short Form Health Survey; SF-12) in 60 revision TKA cases and 199 primary TKA cases at a mean follow-up of 2 years. (The OKS survey is used to evaluate patient perspectives on TKA outcomes,38 and the multipurpose SF-12 questionnaire is used to assess mental and physical function and general health-related QOL.39) Compared with the revision TKA group, the primary TKA group had significantly higher OKS after surgery (78 vs 68; P = .01) as well as significantly higher SF-12 scores: Global (84 vs 72; P = .01), Mental (54 vs 50; P = .03), and Physical (43 vs 37; P = .01). Similarly, Ghomrawi and colleagues40 evaluated patterns of improvement in 308 patients (318 knees) who had revision TKA. At 24-month follow-up, mean SF-36 Physical and Mental scores were 35 and 52, respectively.
Deehan and colleagues41 used the Nottingham Health Profile (NHP) to compare 94 patients’ health-related QOL scores before revision TKA with their scores 3 months, 1 year, and 5 years after revision. NHP Pain subscale scores were significantly lower 3 and 12 months after surgery than before surgery, but this difference was no longer seen at the 5-year follow-up. There was no significant improvement in scores on the other 5 NHP subscales (Sleep, Energy, Emotion, Mobility, Social Isolation) at any time points.
As shown in the literature, patients’ QOL outcomes improve after revision TKA, but these gains are not at the level of patients who undergo primary TKA.36,41 Given that revision surgery is more extensive, and that perhaps revision patients have poorer muscle function, they usually do not return to the level they attained after their index procedure.
5. Economic impact
Consistent with the outcomes already described, the economic impact of revision TKAs is excess expenditures and costs to patients and health care institutions.42 The sources of this impact are higher implant costs, extra operative trays and times, longer hospital stays, more rehabilitation, and increased medication use.43 Revision TKA costs range from $49,000 to more than $100,000—a tremendous increase over primary TKA costs ($25,000-$30,000).43-45 Furthermore, the annual economic burden associated with revision TKA, now $2.7 billion, is expected to exceed $13 billion by 2030.46 In the United States, about $23.2 billion will be spent on 926,527 primary TKAs in 2015; significantly, the costs associated with revising just 10% of these cases account for almost 50% of the total cost of the primary procedures.46
In a retrospective cost-identification multicenter cohort study, Bozic and colleagues47 found that both-component and single-component revisions, compared with primary procedures, were associated with significantly increased operative time (~265 and 221 minutes vs 200 minutes), use of allograft bone (23% and 14% vs 1%), length of stay (5.4 and 5.7 days vs 5.0 days), and percentage of patients discharged to extended-care facilities (26% and 26% vs 25%) (P < .0001). Hospital costs for both- and single-component revisions were 138% and 114% higher than costs for primary procedures (P < .0001). More recently, Kallala and colleagues44 analyzed UK National Health Service data and compared the costs of revision for infection with revision for other causes (pain, instability, aseptic loosening, fracture). Mean length of stay associated with revision for infection (21.5 days) was more than double that associated with revision for aseptic loosening (9.5 days; P < .0001), and mean cost of revision for septic causes (£30,011) was more than 3 times that of revision for other causes (£9655; P < .0001). The authors concluded that the higher costs of revision knee surgery have a considerable economic impact, especially in infection cases.
With more extensive procedures, long-stem or more constrained prostheses are often needed to obtain adequate fixation and stability. The resulting increased, substantial economic burden is felt by patients and the health care system. Given that health care reimbursements are declining, hospitals that perform revision TKAs can sustain marked financial losses. Some centers are asking whether it is cost-effective to continue to perform these types of procedures. We must find new ways to provide revision procedures using less costly implants and tools so that centers will continue to make these procedures available to patients.
Conclusion
Given the exponential growth in primary TKAs, there will be a concordant increase in revision TKAs in the decades to come. This review provides a concise overview of revision TKA outcomes. Given the low level of evidence regarding revision TKAs, we need further higher quality studies of their prostheses and outcomes. Specifically, we need systematic reviews and meta-analyses to provide higher quality evidence regarding outcomes of using individual prosthetic designs.
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9. Bozic KJ, Kurtz SM, Lau E, et al. The epidemiology of revision total knee arthroplasty in the United States. Clin Orthop Relat Res. 2010;468(1):45-51.
10. Parvizi J, Nunley RM, Berend KR, et al. High level of residual symptoms in young patients after total knee arthroplasty. Clin Orthop Relat Res. 2014;472(1):133-137.
11. Ali A, Sundberg M, Robertsson O, et al. Dissatisfied patients after total knee arthroplasty: a registry study involving 114 patients with 8-13 years of followup. Acta Orthop. 2014;85(3):229-233.
12. Fehring TK, Odum S, Griffin WL, Mason JB, Nadaud M. Early failures in total knee arthroplasty. Clin Orthop Relat Res. 2001;392:315-318.
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1. Cram P, Lu X, Kates SL, Singh JA, Li Y, Wolf BR. Total knee arthroplasty volume, utilization, and outcomes among Medicare beneficiaries, 1991–2010. JAMA. 2012;308(12):1227-1236.
2. Crowninshield RD, Rosenberg AG, Sporer SM. Changing demographics of patients with total joint replacement. Clin Orthop Relat Res. 2006;443:266-272.
3. Ravi B, Croxford R, Reichmann WM, Losina E, Katz JN, Hawker GA. The changing demographics of total joint arthroplasty recipients in the United States and Ontario from 2001 to 2007. Best Pract Res Clin Rheumatol. 2012;26(5):637-647.
4. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am. 2007;89(4):780-785.
5. Kurtz SM, Ong KL, Schmier J, Zhao K, Mowat F, Lau E. Primary and revision arthroplasty surgery caseloads in the United States from 1990 to 2004. J Arthroplasty. 2009;24(2):195-203.
6. Kurtz SM, Lau E, Ong K, Zhao K, Kelly M, Bozic KJ. Future young patient demand for primary and revision joint replacement: national projections from 2010 to 2030. Clin Orthop Relat Res. 2009;467(10):2606-2612.
7. Bryan RS, Rand JA. Revision total knee arthroplasty. Clin Orthop Relat Res. 1982;170:116-122.
8. Rand JA, Bryan RS. Revision after total knee arthroplasty. Orthop Clin North Am. 1982;13(1):201-212.
9. Bozic KJ, Kurtz SM, Lau E, et al. The epidemiology of revision total knee arthroplasty in the United States. Clin Orthop Relat Res. 2010;468(1):45-51.
10. Parvizi J, Nunley RM, Berend KR, et al. High level of residual symptoms in young patients after total knee arthroplasty. Clin Orthop Relat Res. 2014;472(1):133-137.
11. Ali A, Sundberg M, Robertsson O, et al. Dissatisfied patients after total knee arthroplasty: a registry study involving 114 patients with 8-13 years of followup. Acta Orthop. 2014;85(3):229-233.
12. Fehring TK, Odum S, Griffin WL, Mason JB, Nadaud M. Early failures in total knee arthroplasty. Clin Orthop Relat Res. 2001;392:315-318.
13. Sharkey PF, Hozack WJ, Rothman RH, Shastri S, Jacoby SM. Insall Award paper. Why are total knee arthroplasties failing today? Clin Orthop Relat Res. 2002;404:7-13.
14. Dy CJ, Marx RG, Bozic KJ, Pan TJ, Padgett DE, Lyman S. Risk factors for revision within 10 years of total knee arthroplasty. Clin Orthop Relat Res. 2014;472(4):1198-1207.
15. Sheng PY, Konttinen L, Lehto M, et al. Revision total knee arthroplasty: 1990 through 2002. A review of the Finnish Arthroplasty Registry. J Bone Joint Surg Am. 2006;88(7):1425-1430.
16. Koskinen E, Eskelinen A, Paavolainen P, Pulkkinen P, Remes V. Comparison of survival and cost-effectiveness between unicondylar arthroplasty and total knee arthroplasty in patients with primary osteoarthritis: a follow-up study of 50,493 knee replacements from the Finnish Arthroplasty Register. Acta Orthop. 2008;79(4):499-507.
17. New Zealand Orthopaedic Association. The New Zealand Joint Registry Fourteen Year Report (January 1999 to December 2012). http://www.nzoa.org.nz/system/files/NJR%2014%20Year%20Report.pdf. Published November 2013. Accessed December 16, 2015.
18. Laskin RS, Ohnsorge J. The use of standard posterior stabilized implants in revision total knee arthroplasty. Clin Orthop Relat Res. 2005;(440):122-125.
19. Meijer MF, Reininga IH, Boerboom AL, Stevens M, Bulstra SK. Poorer survival after a primary implant during revision total knee arthroplasty. Int Orthop. 2013;37(3):415-419.
20. Wilke BK, Wagner ER, Trousdale RT. Long-term survival of semi-constrained total knee arthroplasty for revision surgery. J Arthroplasty. 2014;29(5):1005-1008.
21. Lachiewicz PF, Soileau ES. Ten-year survival and clinical results of constrained components in primary total knee arthroplasty. J Arthroplasty. 2006;21(6):803-808.
22. Lachiewicz PF, Soileau ES. Results of a second-generation constrained condylar prosthesis in primary total knee arthroplasty. J Arthroplasty. 2011;26(8):1228-1231.
23. Neumann DR, Hofstaedter T, Dorn U. Follow-up of a modular rotating hinge knee system in salvage revision total knee arthroplasty. J Arthroplasty. 2012;27(5):814-819.
24. Kowalczewski J, Marczak D, Synder M, Sibinski M. Primary rotating-hinge total knee arthroplasty: good outcomes at mid-term follow-up. J Arthroplasty. 2014;29(6):1202-1206.
25. Korim MT, Esler CN, Reddy VR, Ashford RU. A systematic review of endoprosthetic replacement for non-tumour indications around the knee joint. Knee. 2013;20(6):367-375.
26. Vincent KR, Vincent HK, Lee LW, Alfano AP. Inpatient rehabilitation outcomes in primary and revision total knee arthroplasty patients. Clin Orthop Relat Res. 2006;(446):201-207.
27. Vasso M, Beaufils P, Schiavone Panni A. Constraint choice in revision knee arthroplasty. Int Orthop. 2013;37(7):1279-1284.
28. Baier C, Luring C, Schaumburger J, et al. Assessing patient-oriented results after revision total knee arthroplasty. J Orthop Sci. 2013;18(6):955-961.
29. Hartford JM, Goodman SB, Schurman DJ, Knoblick G. Complex primary and revision total knee arthroplasty using the condylar constrained prosthesis: an average 5-year follow-up. J Arthroplasty. 1998;13(4):380-387.
30. Haidukewych GJ, Jacofsky DJ, Pagnano MW, Trousdale RT. Functional results after revision of well-fixed components for stiffness after primary total knee arthroplasty. J Arthroplasty. 2005;20(2):133-138.
31. Hwang SC, Kong JY, Nam DC, et al. Revision total knee arthroplasty with a cemented posterior stabilized, condylar constrained or fully constrained prosthesis: a minimum 2-year follow-up analysis. Clin Orthop Surg. 2010;2(2):112-120.
32. Barrack RL, McClure JT, Burak CF, Clohisy JC, Parvizi J, Sharkey P. Revision total knee arthroplasty: the patient’s perspective. Clin Orthop Relat Res. 2007;464:146-150.
33. Dahm DL, Barnes SA, Harrington JR, Berry DJ. Patient reported activity after revision total knee arthroplasty. J Arthroplasty. 2007;22(6 suppl 2):106-110.
34. Dahm DL, Barnes SA, Harrington JR, Sayeed SA, Berry DJ. Patient-reported activity level after total knee arthroplasty. J Arthroplasty. 2008;23(3):401-407.
35. Richards CJ, Garbuz DS, Pugh L, Masri BA. Revision total knee arthroplasty: clinical outcome comparison with and without the use of femoral head structural allograft. J Arthroplasty. 2011;26(8):1299-1304.
36. Greidanus NV, Peterson RC, Masri BA, Garbuz DS. Quality of life outcomes in revision versus primary total knee arthroplasty. J Arthroplasty. 2011;26(4):615-620.
37. Ethgen O, Bruyere O, Richy F, Dardennes C, Reginster JY. Health-related quality of life in total hip and total knee arthroplasty. A qualitative and systematic review of the literature. J Bone Joint Surg Am. 2004;86(5):963-974.
38. Murray DW, Fitzpatrick R, Rogers K, et al. The use of the Oxford hip and knee scores. J Bone Joint Surg Br. 2007;89(8):1010-1014.
39. Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220-233.
40. Ghomrawi HM, Kane RL, Eberly LE, Bershadsky B, Saleh KJ; North American Knee Arthroplasty Revision Study Group. Patterns of functional improvement after revision knee arthroplasty. J Bone Joint Surg Am. 2009;91(12):2838-2845.
41. Deehan DJ, Murray JD, Birdsall PD, Pinder IM. Quality of life after knee revision arthroplasty. Acta Orthop. 2006;77(5):761-766.
42. Kapadia BH, McElroy MJ, Issa K, Johnson AJ, Bozic KJ, Mont MA. The economic impact of periprosthetic infections following total knee arthroplasty at a specialized tertiary-care center. J Arthroplasty. 2014;29(5):929-932.
43. Bhandari M, Smith J, Miller LE, Block JE. Clinical and economic burden of revision knee arthroplasty. Clin Med Insights Arthritis Musculoskelet Disord. 2012;5:89-94.
44. Kallala RF, Vanhegan IS, Ibrahim MS, Sarmah S, Haddad FS. Financial analysis of revision knee surgery based on NHS tariffs and hospital costs: does it pay to provide a revision service? Bone Joint J Br. 2015;97(2):197-201.
45. Ong KL, Mowat FS, Chan N, Lau E, Halpern MT, Kurtz SM. Economic burden of revision hip and knee arthroplasty in Medicare enrollees. Clin Orthop Relat Res. 2006;446:22-28.
46. Kurtz SM, Ong KL, Lau E, Bozic KJ. Impact of the economic downturn on total joint replacement demand in the United States: updated projections to 2021. J Bone Joint Surg Am. 2014;96(8):624-630.
47. Bozic KJ, Durbhakula S, Berry DJ, et al. Differences in patient and procedure characteristics and hospital resource use in primary and revision total joint arthroplasty: a multicenter study. J Arthroplasty. 2005;20(7 suppl 3):17-25.
48. Lee KJ, Moon JY, Song EK, Lim HA, Seon JK. Minimum Two-year Results of Revision Total Knee Arthroplasty Following Infectious or Non-infectious Causes. Knee Surg Relat Res. 2012;24(4):227-234.
49. Bae DK, Song SJ, Heo DB, Lee SH, Song WJ. Long-term survival rate of implants and modes of failure after revision total knee arthroplasty by a single surgeon. J Arthroplasty. 2013;28(7):1130-1134.
50. Sheng PY, Jämsen E, Lehto MU, Konttinen YT, Pajamäki J, Halonen P. Revision total knee arthroplasty with the Total Condylar III system in inflammatory arthritis. J Bone Joint Surg Br. 2005;87(9):1222-1224.
51. Lachiewicz PF, Soileau ES. Ten-year survival and clinical results of constrained components in primary total knee arthroplasty. J Arthroplasty. 2006;21(6):803-808.
52. Haas SB, Insall JN, Montgomery W 3rd, Windsor RE. Revision total knee arthroplasty with use of modular components with stems inserted without cement. J Bone Joint Surg Am. 1995;77(11):1700-1707.
53. Mabry TM, Vessely MB, Schleck CD, Harmsen WS, Berry DJ. Revision total knee arthroplasty with modular cemented stems: long-term follow-up. J Arthroplasty. 2007;22(6 Suppl 2):100-105.
54. Gudnason A, Milbrink J, Hailer NP. Implant survival and outcome after rotating-hinge total knee revision arthroplasty: a minimum 6-year follow-up. Arch Orthop Trauma Surg. 2011;131(11):1601-1607.
55. Hofmann AA, Goldberg T, Tanner AM, Kurtin SM. Treatment of infected total knee arthroplasty using an articulating spacer: 2- to 12-year experience. Clin Orthop Relat Res. 2005;430:125-131.
56. Greene JW, Reynolds SM, Stimac JD, Malkani AL, Massini MA. Midterm results of hybrid cement technique in revision total knee arthroplasty. J Arthroplasty. 2013;28(4):570-574.
57. Dalury DF, Adams MJ. Minimum 6-year follow-up of revision total knee arthroplasty without patella reimplantation. Journal Arthroplasty. 2012;27(8 Suppl):91-94.
58. Whaley AL, Trousdale RT, Rand JA, Hanssen AD. Cemented long-stem revision total knee arthroplasty. J Arthroplasty. 2003;18(5):592-599.
59. Friedman RJ, Hirst P, Poss R, Kelley K, Sledge CB. Results of revision total knee arthroplasty performed for aseptic loosening. Clinical Orthop Relat Res. 1990;255:235-241.
60. Barrack RL, Rorabeck C, Partington P, Sawhney J, Engh G. The results of retaining a well-fixed patellar component in revision total knee arthroplasty. J Arthroplasty. 2000;15(4):413-417.
61. Christensen CP, Crawford JJ, Olin MD, Vail TP. Revision of the stiff total knee arthroplasty. J Arthroplasty. 2002;17(4):409-415.
62. Garcia RM, Hardy BT, Kraay MJ, Goldberg VM. Revision total knee arthroplasty for aseptic and septic causes in patients with rheumatoid arthritis. Clin Orthop Relat Res. 2010;468(1):82-89.
63. Patil N, Lee K, Huddleston JI, Harris AH, Goodman SB. Aseptic versus septic revision total knee arthroplasty: patient satisfaction, outcome and quality of life improvement. Knee. 2010;17(3):200-203.
64. Luque R, Rizo B, Urda A, et al. Predictive factors for failure after total knee replacement revision. Int Orthop. 2014;38(2):429-435.
65. Bistolfi A, Massazza G, Rosso F, Crova M. Rotating-hinge total knee for revision total knee arthroplasty. Orthopedics. 2012;35(3):e325-e330.
66. Bottner F, Laskin R, Windsor RE, Haas SB. Hybrid component fixation in revision total knee arthroplasty. Clin Orthop Relat Res. 2006;446:127-131.
67. Jensen CL, Winther N, Schroder HM, Petersen MM. Outcome of revision total knee arthroplasty with the use of trabecular metal cone for reconstruction of severe bone loss at the proximal tibia. Knee. 2014;21(6):1233-1237.
68. Howard JL, Kudera J, Lewallen DG, Hanssen AD. Early results of the use of tantalum femoral cones for revision total knee arthroplasty. J Bone Joint Surg Am. 2011;93(5):478-484.
69. Yang JH, Yoon JR, Oh CH, Kim TS. Hybrid component fixation in total knee arthroplasty: minimum of 10-year follow-up study. J Arthroplasty. 2012;27(6):1111-1118.
70. Peters CL, Erickson JA, Gililland JM. Clinical and radiographic results of 184 consecutive revision total knee arthroplasties placed with modular cementless stems. J Arthroplasty. 2009;24(6 Suppl):48-53.
71. Registry AOANJR. Hip and Knee Arthroplasty. Annual Report 2014. 2014.
72. Registry AOANJR. Hip and Knee Arthroplasty. Annual Report 2013. 2013.
Implant Designs in Revision Total Knee Arthroplasty
Before 1990, a considerable number of revisions were performed, largely for implant-associated failures, in the first few years after index primary knee arthroplasties.1,2 Since then, surgeons, manufacturers, and hospitals have collaborated to improve implant designs, techniques, and care guidelines.3,4 Despite the substantial improvements in designs, which led to implant longevity of more than 15 years in many cases, these devices still have limited life spans. Large studies have estimated that the risk for revision required after primary knee arthroplasty ranges from as low as 5% at 15 years to up to 9% at 10 years.4,5
The surgical goals of revision total knee arthroplasty (TKA) are to obtain stable fixation of the prosthesis to host bone, to obtain a stable range of motion compatible with the patient’s activities of daily living, and to achieve these goals while using the smallest amount of prosthetic augments and constraint so that the soft tissues may share in load transfer.6 As prosthetic constraint increases, the soft tissues participate less in load sharing, and increasing stresses are put on the implant–bone interface, which further increases the risk for early implant loosening.7 Hence, as characteristics of a revision implant become more constrained, there is often a higher rate of aseptic loosening expected.8
Controversy remains regarding the ideal implant type for revision TKA. To ensure the success of revision surgery and to reduce the risks for postoperative dissatisfaction, complications, and re-revision, orthopedists must understand the types of revision implant designs available, particularly as each has its own indications and potential complications.
In this article, we review the classification systems used for revision TKA as well as the types of prosthetic designs that can be used: posterior stabilized, nonlinked constrained, rotating hinge, and modular segmental.
1. Classification of bone loss and soft-tissue integrity
To further understand revision TKA, we must consider the complexity level of these cases, particularly by evaluating degree of bone loss and soft-tissue deficiency. The most accepted way to assess bone loss both before and during surgery is to use the AORI (Anderson Orthopaedic Research Institute) classification system.9 Bone loss can be classified into 3 types: I, in which metaphyseal bone is intact and small bone defects do not compromise component stability; II, in which metaphyseal bone is damaged and cancellous bone loss requires cement fill, augments, or bone graft; and III, in which metaphyseal bone is deficient, and lost bone comprises a major portion of condyle or plateau and occasionally requires bone grafts or custom implants (Table 1). These patterns of bone loss are occasionally associated with detachment of the collateral ligament or patellar tendon.
In addition to understanding bone loss in revision TKA, surgeons must be aware of soft-tissue deficiencies (eg, collateral ligaments, extensor mechanism), which also influence type and amount of prosthesis constraint. Specifically, constraint choice depends on amount of bone loss and on the condition of stabilizing tissues, such as the collateral ligaments. Under conditions of minimal bone loss and intact peripheral ligaments, a less constrained device, such as a primary posterior stabilized system, can be considered. When ligaments are present but insufficient, a semiconstrained device is recommended. In the presence of medial collateral ligament attenuation or complete medial or lateral collateral ligament dysfunction, a fully constrained prosthesis is required.8 Therefore, amount of bone loss or soft-tissue deficiency often dictates which prosthesis to use.
For radiographic classification, the Knee Society roentgenographic evaluation and scoring system10 has been implemented to allow for uniform reporting of radiographic results and to ensure adequate preoperative planning and postoperative assessment of component alignment. This system incorporates the evaluation of alignment in the coronal, sagittal, and patellofemoral planes and assesses radiolucency using zones dividing the implant–bone interface into segments to allow for easier classification of areas of lucency. More recently, a modified version of the Knee Society system was constructed.11 This modification simplifies zone classifications and accommodates more complex revision knee designs and stem extensions.
2. Posterior stabilized designs
Cruciate-retaining prostheses are seldom applicable in the revision TKA setting because of frequent damage to the posterior cruciate ligament, except in the case of simple polyethylene exchanges or, potentially, revisions of failed unicompartmental TKAs. Thus, posterior stabilized designs are the first-line choice for revision TKA (Figure 1). These prostheses are indicated only when the posterior cruciate ligament is incompetent and in the setting of adequate flexion and extension and medial and lateral collateral ligament balancing.
However, studies have shown that posterior stabilized TKAs have a limited role in revision TKAs, as the amount of ligamentous and bony damage is often underestimated in these patients, and use of a primary implant in a revision setting often requires additional augments, all of which may have contributed to the high failure rate. Thus, this design should be used only when the patient has adequate bone stock (AORI type I) and collateral ligament tension. This situation further emphasizes the importance of performing intraoperative testing for ligamentous balance and bone deficit evaluation in order to determine the most appropriate implant (Table 2).
3. Nonlinked constrained designs
Nonlinked constrained (condylar constrained) designs are the devices most commonly used for revision TKAs (>50% of revision knees). These prostheses provide increased articular constraint, which is required in patients with persistent instability, despite appropriate soft-tissue balancing. Increased articular constraint allows for more knee stability by providing progressive varus-valgus, coronal, and rotational stability with the aid of taller and wider tibial posts.12 Specifically, these implants incorporate a tibial post that fits closely between the femoral condyles, allowing for less motion compared with a standard posterior stabilized design.12
In addition, these designs may be used with augments, stems, and allografts when bone loss is more substantial. In particular, stem extensions allow for load distribution to the diaphyseal regions of the tibia and femur and thereby aid in reducing the increased stress at the bone–implant interface, which is a common concern with these implants. However, these extensions cost more, require intramedullary invasion, and are associated with higher rates of leg and thigh pain.12
These prostheses are often implicated in cases involving a high degree of bone loss (eg, AORI type II or III). They are ideally used in cases in which complete revision of both tibial and femoral components is needed and are indicated in cases of incompetent posterior cruciate ligament, partial functional loss of medial or lateral collateral ligaments, or flexion-extension mismatch.13 Furthermore, use of a constrained prosthesis is recommended in the setting of varus or valgus instability, or repeated dislocations of a posterior stabilized design (Table 2).
Ten-year survivorship ranges from 85% to 96%, but this is substantially lower than the 95% to 96% for condylar constrained prostheses used in primary TKAs.14-17 Moreover, the large discrepancy between survivorship of primary TKA and revision TKA with a constrained prosthesis further affirms that the complexity of revision surgery, rather than the prosthesis used, may have more deleterious effects on outcomes. However, surgeons must be aware that increased constraint leads to increased stress on the prosthetic interfaces with associated aseptic loosening and early failure, and this continues to be a legitimate concern.
4. Rotating hinge designs
Many patients who undergo revision TKA can be managed with a posterior stabilizing or nonlinked constrained design. However, in patients who present with severe ligamentous instability and bone loss (AORI type II or III), a rotating hinge prostheses, or highly constrained device, is often recommended (Figure 2).18 By using a rotating mobile-bearing platform, this prosthesis permits axial rotation through a metal-reinforced polyethylene-post articulation in the tibial tray. In addition, it involves use of modular diaphyseal-engaging stems and diaphyseal sleeves, which allow for the bypass of bony defects and areas of bone loss (Table 2).
However, the rigid biomechanics of hinged prostheses is associated with increased risk for aseptic loosening (aseptic 10-year survival, 60%-80%), imparted by the transfer of stresses across the bone. The higher risk for early loosening, osteolysis, and excessive wear—caused by the highly restricted biomechanics of early generations of fixed hinged designs—has led to the development of new devices with mobile mechanics. Prosthetic designs have been improved with an added rotational axis to reduce torsional stress, a patellar resurfacing option, and better stem fixation and patellofemoral kinematics. Overall, these are aimed to improve rates of instability and aseptic loosening, with promising results demonstrated in the literature.
5. Modular segmental arthroplasty designs
Segmental arthroplasty prostheses, which typically are end-of-the-line revision TKA options, are applicable only in cases of extensive bone loss (more than can be treated with allografts or augments; AORI type 3), complete ligamentous disruption/absence, loss of periprosthetic soft tissue, and multiple previous revision procedures (Figure 3). Despite the limited indications for these prostheses, they yield quick return to function without graft nonunion or resorption, and they augment ingrowth/ongrowth. Furthermore, the next surgical option could be fusion or amputation. When failures were specifically evaluated for aseptic loosening across 4 studies, the survival rate ranged from 83% to 99.5%, with the most frequent complication being infection (up to 33% in one series).6,19-21
The major roles for segmental arthroplasty prostheses in primary TKAs are in the setting of oncologic conditions that require bony excision, or unreconstuctable fractures about the knee. Used after ancillary metastatic disease, these prostheses demonstrate positive results, according to several reports.22,23 In the setting of revision TKA, however, these prostheses should be used only when other surgical options are unfeasible, given the high risk for infection and the re-revision rates. Currently, revision TKAs with tumor prostheses have a high failure rate (up to 50%) because of the extensive surgery and the lack of bony and soft-tissue support (Table 2).
Conclusion
Orthopedists performing revision TKAs must consider bone stock and remaining ligament stability. In particular, they should choose implants for least constraint and adequate knee stability, as these are essential in minimizing the stresses on the implant–bone interface. Ultimately, functional outcomes, survivorship, and postoperative satisfaction determine the success of these designs. However, predictors of outcomes of revision surgery are often multifactorial, and surgeons must also consider procedure complexity and patient-specific characteristics.
1. Fehring TK, Odum S, Griffin WL, Mason JB, Nadaud M. Early failures in total knee arthroplasty. Clin Orthop Relat Res. 2001;392:315-318.
2. Sharkey PF, Hozack WJ, Rothman RH, Shastri S, Jacoby SM. Insall Award paper. Why are total knee arthroplasties failing today? Clin Orthop Relat Res. 2002;404:7-13.
3. Schroer WC, Berend KR, Lombardi AV, et al. Why are total knees failing today? Etiology of total knee revision in 2010 and 2011. J Arthroplasty. 2013;28(8 suppl):116-119.
4. Kim TK. CORR Insights(®): risk factors for revision within 10 years of total knee arthroplasty. Clin Orthop Relat Res. 2014;472(4):1208-1209.
5. Sheng PY, Jämsen E, Lehto MU, Konttinen YT, Pajamäki J, Halonen P. Revision total knee arthroplasty with the Total Condylar III system in inflammatory arthritis. J Bone Joint Surg Br. 2005;87(9):1222-1224.
6. Haas SB, Insall JN, Montgomery W 3rd, Windsor RE. Revision total knee arthroplasty with use of modular components with stems inserted without cement. J Bone Joint Surg Am. 1995;77(11):1700-1707.
7. Dennis DA. A stepwise approach to revision total knee arthroplasty. J Arthroplasty. 2007;22(4 suppl 1):32-38.
8. Vasso M, Beaufils P, Schiavone Panni A. Constraint choice in revision knee arthroplasty. Int Orthop. 2013;37(7):1279-1284.
9. Engh GA, Ammeen DJ. Bone loss with revision total knee arthroplasty: defect classification and alternatives for reconstruction. Instr Course Lect. 1999;48:167-175.
10. Ewald FC. The Knee Society total knee arthroplasty roentgenographic evaluation and scoring system. Clin Orthop Relat Res. 1989;248:9-12.
11. Meneghini RM, Mont MA, Backstein DB, Bourne RB, Dennis DA, Scuderi GR. Development of a modern Knee Society radiographic evaluation system and methodology for total knee arthroplasty. J Arthroplasty. 2015;30(12):2311-2314.
12. Nam D, Umunna BP, Cross MB, Reinhardt KR, Duggal S, Cornell CN. Clinical results and failure mechanisms of a nonmodular constrained knee without stem extensions. HSS J. 2012;8(2):96-102.
13. Lombardi AV Jr, Berend KR. The role of implant constraint in revision TKA: striking the balance. Orthopedics. 2006;29(9):847-849.
14. Lachiewicz PF, Soileau ES. Results of a second-generation constrained condylar prosthesis in primary total knee arthroplasty. J Arthroplasty. 2011;26(8):1228-1231.
15. Bae DK, Song SJ, Heo DB, Lee SH, Song WJ. Long-term survival rate of implants and modes of failure after revision total knee arthroplasty by a single surgeon. J Arthroplasty. 2013;28(7):1130-1134.
16. Wilke BK, Wagner ER, Trousdale RT. Long-term survival of semi-constrained total knee arthroplasty for revision surgery. J Arthroplasty. 2014;29(5):1005-1008.
17. Lachiewicz PF, Soileau ES. Ten-year survival and clinical results of constrained components in primary total knee arthroplasty. J Arthroplasty. 2006;21(6):803-808.
18. Jones RE. Total knee arthroplasty with modular rotating-platform hinge. Orthopedics. 2006;29(9 suppl):S80-S82.
19. Korim MT, Esler CN, Reddy VR, Ashford RU. A systematic review of endoprosthetic replacement for non-tumour indications around the knee joint. The Knee. 2013;20:367-375.
20. Hofmann AA, Goldberg T, Tanner AM, Kurtin SM. Treatment of infected total knee arthroplasty using an articulating spacer: 2- to 12-year experience. Clin Orthop Relat Res. 2005;(430):125-131.
21. Peters CL, Erickson J, Kloepper RG, Mohr RA. Revision total knee arthroplasty with modular components inserted with metaphyseal cement and stems without cement. J Arthroplasty. 2005;20:302-308.
22. Pala E, Trovarelli G, Calabro T, Angelini A, Abati CN, Ruggieri P. Survival of modern knee tumor megaprostheses: failures, functional results, and a comparative statistical analysis. Clinical Orthop Relat Res. 2015;473:891-899.
23. Angelini A, Henderson E, Trovarelli G, Ruggieri P. Is there a role for knee arthrodesis with modular endoprostheses for tumor and revision of failed endoprostheses? Clin Orthop Relat Res. 2013;471(10):3326-3335.
Before 1990, a considerable number of revisions were performed, largely for implant-associated failures, in the first few years after index primary knee arthroplasties.1,2 Since then, surgeons, manufacturers, and hospitals have collaborated to improve implant designs, techniques, and care guidelines.3,4 Despite the substantial improvements in designs, which led to implant longevity of more than 15 years in many cases, these devices still have limited life spans. Large studies have estimated that the risk for revision required after primary knee arthroplasty ranges from as low as 5% at 15 years to up to 9% at 10 years.4,5
The surgical goals of revision total knee arthroplasty (TKA) are to obtain stable fixation of the prosthesis to host bone, to obtain a stable range of motion compatible with the patient’s activities of daily living, and to achieve these goals while using the smallest amount of prosthetic augments and constraint so that the soft tissues may share in load transfer.6 As prosthetic constraint increases, the soft tissues participate less in load sharing, and increasing stresses are put on the implant–bone interface, which further increases the risk for early implant loosening.7 Hence, as characteristics of a revision implant become more constrained, there is often a higher rate of aseptic loosening expected.8
Controversy remains regarding the ideal implant type for revision TKA. To ensure the success of revision surgery and to reduce the risks for postoperative dissatisfaction, complications, and re-revision, orthopedists must understand the types of revision implant designs available, particularly as each has its own indications and potential complications.
In this article, we review the classification systems used for revision TKA as well as the types of prosthetic designs that can be used: posterior stabilized, nonlinked constrained, rotating hinge, and modular segmental.
1. Classification of bone loss and soft-tissue integrity
To further understand revision TKA, we must consider the complexity level of these cases, particularly by evaluating degree of bone loss and soft-tissue deficiency. The most accepted way to assess bone loss both before and during surgery is to use the AORI (Anderson Orthopaedic Research Institute) classification system.9 Bone loss can be classified into 3 types: I, in which metaphyseal bone is intact and small bone defects do not compromise component stability; II, in which metaphyseal bone is damaged and cancellous bone loss requires cement fill, augments, or bone graft; and III, in which metaphyseal bone is deficient, and lost bone comprises a major portion of condyle or plateau and occasionally requires bone grafts or custom implants (Table 1). These patterns of bone loss are occasionally associated with detachment of the collateral ligament or patellar tendon.
In addition to understanding bone loss in revision TKA, surgeons must be aware of soft-tissue deficiencies (eg, collateral ligaments, extensor mechanism), which also influence type and amount of prosthesis constraint. Specifically, constraint choice depends on amount of bone loss and on the condition of stabilizing tissues, such as the collateral ligaments. Under conditions of minimal bone loss and intact peripheral ligaments, a less constrained device, such as a primary posterior stabilized system, can be considered. When ligaments are present but insufficient, a semiconstrained device is recommended. In the presence of medial collateral ligament attenuation or complete medial or lateral collateral ligament dysfunction, a fully constrained prosthesis is required.8 Therefore, amount of bone loss or soft-tissue deficiency often dictates which prosthesis to use.
For radiographic classification, the Knee Society roentgenographic evaluation and scoring system10 has been implemented to allow for uniform reporting of radiographic results and to ensure adequate preoperative planning and postoperative assessment of component alignment. This system incorporates the evaluation of alignment in the coronal, sagittal, and patellofemoral planes and assesses radiolucency using zones dividing the implant–bone interface into segments to allow for easier classification of areas of lucency. More recently, a modified version of the Knee Society system was constructed.11 This modification simplifies zone classifications and accommodates more complex revision knee designs and stem extensions.
2. Posterior stabilized designs
Cruciate-retaining prostheses are seldom applicable in the revision TKA setting because of frequent damage to the posterior cruciate ligament, except in the case of simple polyethylene exchanges or, potentially, revisions of failed unicompartmental TKAs. Thus, posterior stabilized designs are the first-line choice for revision TKA (Figure 1). These prostheses are indicated only when the posterior cruciate ligament is incompetent and in the setting of adequate flexion and extension and medial and lateral collateral ligament balancing.
However, studies have shown that posterior stabilized TKAs have a limited role in revision TKAs, as the amount of ligamentous and bony damage is often underestimated in these patients, and use of a primary implant in a revision setting often requires additional augments, all of which may have contributed to the high failure rate. Thus, this design should be used only when the patient has adequate bone stock (AORI type I) and collateral ligament tension. This situation further emphasizes the importance of performing intraoperative testing for ligamentous balance and bone deficit evaluation in order to determine the most appropriate implant (Table 2).
3. Nonlinked constrained designs
Nonlinked constrained (condylar constrained) designs are the devices most commonly used for revision TKAs (>50% of revision knees). These prostheses provide increased articular constraint, which is required in patients with persistent instability, despite appropriate soft-tissue balancing. Increased articular constraint allows for more knee stability by providing progressive varus-valgus, coronal, and rotational stability with the aid of taller and wider tibial posts.12 Specifically, these implants incorporate a tibial post that fits closely between the femoral condyles, allowing for less motion compared with a standard posterior stabilized design.12
In addition, these designs may be used with augments, stems, and allografts when bone loss is more substantial. In particular, stem extensions allow for load distribution to the diaphyseal regions of the tibia and femur and thereby aid in reducing the increased stress at the bone–implant interface, which is a common concern with these implants. However, these extensions cost more, require intramedullary invasion, and are associated with higher rates of leg and thigh pain.12
These prostheses are often implicated in cases involving a high degree of bone loss (eg, AORI type II or III). They are ideally used in cases in which complete revision of both tibial and femoral components is needed and are indicated in cases of incompetent posterior cruciate ligament, partial functional loss of medial or lateral collateral ligaments, or flexion-extension mismatch.13 Furthermore, use of a constrained prosthesis is recommended in the setting of varus or valgus instability, or repeated dislocations of a posterior stabilized design (Table 2).
Ten-year survivorship ranges from 85% to 96%, but this is substantially lower than the 95% to 96% for condylar constrained prostheses used in primary TKAs.14-17 Moreover, the large discrepancy between survivorship of primary TKA and revision TKA with a constrained prosthesis further affirms that the complexity of revision surgery, rather than the prosthesis used, may have more deleterious effects on outcomes. However, surgeons must be aware that increased constraint leads to increased stress on the prosthetic interfaces with associated aseptic loosening and early failure, and this continues to be a legitimate concern.
4. Rotating hinge designs
Many patients who undergo revision TKA can be managed with a posterior stabilizing or nonlinked constrained design. However, in patients who present with severe ligamentous instability and bone loss (AORI type II or III), a rotating hinge prostheses, or highly constrained device, is often recommended (Figure 2).18 By using a rotating mobile-bearing platform, this prosthesis permits axial rotation through a metal-reinforced polyethylene-post articulation in the tibial tray. In addition, it involves use of modular diaphyseal-engaging stems and diaphyseal sleeves, which allow for the bypass of bony defects and areas of bone loss (Table 2).
However, the rigid biomechanics of hinged prostheses is associated with increased risk for aseptic loosening (aseptic 10-year survival, 60%-80%), imparted by the transfer of stresses across the bone. The higher risk for early loosening, osteolysis, and excessive wear—caused by the highly restricted biomechanics of early generations of fixed hinged designs—has led to the development of new devices with mobile mechanics. Prosthetic designs have been improved with an added rotational axis to reduce torsional stress, a patellar resurfacing option, and better stem fixation and patellofemoral kinematics. Overall, these are aimed to improve rates of instability and aseptic loosening, with promising results demonstrated in the literature.
5. Modular segmental arthroplasty designs
Segmental arthroplasty prostheses, which typically are end-of-the-line revision TKA options, are applicable only in cases of extensive bone loss (more than can be treated with allografts or augments; AORI type 3), complete ligamentous disruption/absence, loss of periprosthetic soft tissue, and multiple previous revision procedures (Figure 3). Despite the limited indications for these prostheses, they yield quick return to function without graft nonunion or resorption, and they augment ingrowth/ongrowth. Furthermore, the next surgical option could be fusion or amputation. When failures were specifically evaluated for aseptic loosening across 4 studies, the survival rate ranged from 83% to 99.5%, with the most frequent complication being infection (up to 33% in one series).6,19-21
The major roles for segmental arthroplasty prostheses in primary TKAs are in the setting of oncologic conditions that require bony excision, or unreconstuctable fractures about the knee. Used after ancillary metastatic disease, these prostheses demonstrate positive results, according to several reports.22,23 In the setting of revision TKA, however, these prostheses should be used only when other surgical options are unfeasible, given the high risk for infection and the re-revision rates. Currently, revision TKAs with tumor prostheses have a high failure rate (up to 50%) because of the extensive surgery and the lack of bony and soft-tissue support (Table 2).
Conclusion
Orthopedists performing revision TKAs must consider bone stock and remaining ligament stability. In particular, they should choose implants for least constraint and adequate knee stability, as these are essential in minimizing the stresses on the implant–bone interface. Ultimately, functional outcomes, survivorship, and postoperative satisfaction determine the success of these designs. However, predictors of outcomes of revision surgery are often multifactorial, and surgeons must also consider procedure complexity and patient-specific characteristics.
Before 1990, a considerable number of revisions were performed, largely for implant-associated failures, in the first few years after index primary knee arthroplasties.1,2 Since then, surgeons, manufacturers, and hospitals have collaborated to improve implant designs, techniques, and care guidelines.3,4 Despite the substantial improvements in designs, which led to implant longevity of more than 15 years in many cases, these devices still have limited life spans. Large studies have estimated that the risk for revision required after primary knee arthroplasty ranges from as low as 5% at 15 years to up to 9% at 10 years.4,5
The surgical goals of revision total knee arthroplasty (TKA) are to obtain stable fixation of the prosthesis to host bone, to obtain a stable range of motion compatible with the patient’s activities of daily living, and to achieve these goals while using the smallest amount of prosthetic augments and constraint so that the soft tissues may share in load transfer.6 As prosthetic constraint increases, the soft tissues participate less in load sharing, and increasing stresses are put on the implant–bone interface, which further increases the risk for early implant loosening.7 Hence, as characteristics of a revision implant become more constrained, there is often a higher rate of aseptic loosening expected.8
Controversy remains regarding the ideal implant type for revision TKA. To ensure the success of revision surgery and to reduce the risks for postoperative dissatisfaction, complications, and re-revision, orthopedists must understand the types of revision implant designs available, particularly as each has its own indications and potential complications.
In this article, we review the classification systems used for revision TKA as well as the types of prosthetic designs that can be used: posterior stabilized, nonlinked constrained, rotating hinge, and modular segmental.
1. Classification of bone loss and soft-tissue integrity
To further understand revision TKA, we must consider the complexity level of these cases, particularly by evaluating degree of bone loss and soft-tissue deficiency. The most accepted way to assess bone loss both before and during surgery is to use the AORI (Anderson Orthopaedic Research Institute) classification system.9 Bone loss can be classified into 3 types: I, in which metaphyseal bone is intact and small bone defects do not compromise component stability; II, in which metaphyseal bone is damaged and cancellous bone loss requires cement fill, augments, or bone graft; and III, in which metaphyseal bone is deficient, and lost bone comprises a major portion of condyle or plateau and occasionally requires bone grafts or custom implants (Table 1). These patterns of bone loss are occasionally associated with detachment of the collateral ligament or patellar tendon.
In addition to understanding bone loss in revision TKA, surgeons must be aware of soft-tissue deficiencies (eg, collateral ligaments, extensor mechanism), which also influence type and amount of prosthesis constraint. Specifically, constraint choice depends on amount of bone loss and on the condition of stabilizing tissues, such as the collateral ligaments. Under conditions of minimal bone loss and intact peripheral ligaments, a less constrained device, such as a primary posterior stabilized system, can be considered. When ligaments are present but insufficient, a semiconstrained device is recommended. In the presence of medial collateral ligament attenuation or complete medial or lateral collateral ligament dysfunction, a fully constrained prosthesis is required.8 Therefore, amount of bone loss or soft-tissue deficiency often dictates which prosthesis to use.
For radiographic classification, the Knee Society roentgenographic evaluation and scoring system10 has been implemented to allow for uniform reporting of radiographic results and to ensure adequate preoperative planning and postoperative assessment of component alignment. This system incorporates the evaluation of alignment in the coronal, sagittal, and patellofemoral planes and assesses radiolucency using zones dividing the implant–bone interface into segments to allow for easier classification of areas of lucency. More recently, a modified version of the Knee Society system was constructed.11 This modification simplifies zone classifications and accommodates more complex revision knee designs and stem extensions.
2. Posterior stabilized designs
Cruciate-retaining prostheses are seldom applicable in the revision TKA setting because of frequent damage to the posterior cruciate ligament, except in the case of simple polyethylene exchanges or, potentially, revisions of failed unicompartmental TKAs. Thus, posterior stabilized designs are the first-line choice for revision TKA (Figure 1). These prostheses are indicated only when the posterior cruciate ligament is incompetent and in the setting of adequate flexion and extension and medial and lateral collateral ligament balancing.
However, studies have shown that posterior stabilized TKAs have a limited role in revision TKAs, as the amount of ligamentous and bony damage is often underestimated in these patients, and use of a primary implant in a revision setting often requires additional augments, all of which may have contributed to the high failure rate. Thus, this design should be used only when the patient has adequate bone stock (AORI type I) and collateral ligament tension. This situation further emphasizes the importance of performing intraoperative testing for ligamentous balance and bone deficit evaluation in order to determine the most appropriate implant (Table 2).
3. Nonlinked constrained designs
Nonlinked constrained (condylar constrained) designs are the devices most commonly used for revision TKAs (>50% of revision knees). These prostheses provide increased articular constraint, which is required in patients with persistent instability, despite appropriate soft-tissue balancing. Increased articular constraint allows for more knee stability by providing progressive varus-valgus, coronal, and rotational stability with the aid of taller and wider tibial posts.12 Specifically, these implants incorporate a tibial post that fits closely between the femoral condyles, allowing for less motion compared with a standard posterior stabilized design.12
In addition, these designs may be used with augments, stems, and allografts when bone loss is more substantial. In particular, stem extensions allow for load distribution to the diaphyseal regions of the tibia and femur and thereby aid in reducing the increased stress at the bone–implant interface, which is a common concern with these implants. However, these extensions cost more, require intramedullary invasion, and are associated with higher rates of leg and thigh pain.12
These prostheses are often implicated in cases involving a high degree of bone loss (eg, AORI type II or III). They are ideally used in cases in which complete revision of both tibial and femoral components is needed and are indicated in cases of incompetent posterior cruciate ligament, partial functional loss of medial or lateral collateral ligaments, or flexion-extension mismatch.13 Furthermore, use of a constrained prosthesis is recommended in the setting of varus or valgus instability, or repeated dislocations of a posterior stabilized design (Table 2).
Ten-year survivorship ranges from 85% to 96%, but this is substantially lower than the 95% to 96% for condylar constrained prostheses used in primary TKAs.14-17 Moreover, the large discrepancy between survivorship of primary TKA and revision TKA with a constrained prosthesis further affirms that the complexity of revision surgery, rather than the prosthesis used, may have more deleterious effects on outcomes. However, surgeons must be aware that increased constraint leads to increased stress on the prosthetic interfaces with associated aseptic loosening and early failure, and this continues to be a legitimate concern.
4. Rotating hinge designs
Many patients who undergo revision TKA can be managed with a posterior stabilizing or nonlinked constrained design. However, in patients who present with severe ligamentous instability and bone loss (AORI type II or III), a rotating hinge prostheses, or highly constrained device, is often recommended (Figure 2).18 By using a rotating mobile-bearing platform, this prosthesis permits axial rotation through a metal-reinforced polyethylene-post articulation in the tibial tray. In addition, it involves use of modular diaphyseal-engaging stems and diaphyseal sleeves, which allow for the bypass of bony defects and areas of bone loss (Table 2).
However, the rigid biomechanics of hinged prostheses is associated with increased risk for aseptic loosening (aseptic 10-year survival, 60%-80%), imparted by the transfer of stresses across the bone. The higher risk for early loosening, osteolysis, and excessive wear—caused by the highly restricted biomechanics of early generations of fixed hinged designs—has led to the development of new devices with mobile mechanics. Prosthetic designs have been improved with an added rotational axis to reduce torsional stress, a patellar resurfacing option, and better stem fixation and patellofemoral kinematics. Overall, these are aimed to improve rates of instability and aseptic loosening, with promising results demonstrated in the literature.
5. Modular segmental arthroplasty designs
Segmental arthroplasty prostheses, which typically are end-of-the-line revision TKA options, are applicable only in cases of extensive bone loss (more than can be treated with allografts or augments; AORI type 3), complete ligamentous disruption/absence, loss of periprosthetic soft tissue, and multiple previous revision procedures (Figure 3). Despite the limited indications for these prostheses, they yield quick return to function without graft nonunion or resorption, and they augment ingrowth/ongrowth. Furthermore, the next surgical option could be fusion or amputation. When failures were specifically evaluated for aseptic loosening across 4 studies, the survival rate ranged from 83% to 99.5%, with the most frequent complication being infection (up to 33% in one series).6,19-21
The major roles for segmental arthroplasty prostheses in primary TKAs are in the setting of oncologic conditions that require bony excision, or unreconstuctable fractures about the knee. Used after ancillary metastatic disease, these prostheses demonstrate positive results, according to several reports.22,23 In the setting of revision TKA, however, these prostheses should be used only when other surgical options are unfeasible, given the high risk for infection and the re-revision rates. Currently, revision TKAs with tumor prostheses have a high failure rate (up to 50%) because of the extensive surgery and the lack of bony and soft-tissue support (Table 2).
Conclusion
Orthopedists performing revision TKAs must consider bone stock and remaining ligament stability. In particular, they should choose implants for least constraint and adequate knee stability, as these are essential in minimizing the stresses on the implant–bone interface. Ultimately, functional outcomes, survivorship, and postoperative satisfaction determine the success of these designs. However, predictors of outcomes of revision surgery are often multifactorial, and surgeons must also consider procedure complexity and patient-specific characteristics.
1. Fehring TK, Odum S, Griffin WL, Mason JB, Nadaud M. Early failures in total knee arthroplasty. Clin Orthop Relat Res. 2001;392:315-318.
2. Sharkey PF, Hozack WJ, Rothman RH, Shastri S, Jacoby SM. Insall Award paper. Why are total knee arthroplasties failing today? Clin Orthop Relat Res. 2002;404:7-13.
3. Schroer WC, Berend KR, Lombardi AV, et al. Why are total knees failing today? Etiology of total knee revision in 2010 and 2011. J Arthroplasty. 2013;28(8 suppl):116-119.
4. Kim TK. CORR Insights(®): risk factors for revision within 10 years of total knee arthroplasty. Clin Orthop Relat Res. 2014;472(4):1208-1209.
5. Sheng PY, Jämsen E, Lehto MU, Konttinen YT, Pajamäki J, Halonen P. Revision total knee arthroplasty with the Total Condylar III system in inflammatory arthritis. J Bone Joint Surg Br. 2005;87(9):1222-1224.
6. Haas SB, Insall JN, Montgomery W 3rd, Windsor RE. Revision total knee arthroplasty with use of modular components with stems inserted without cement. J Bone Joint Surg Am. 1995;77(11):1700-1707.
7. Dennis DA. A stepwise approach to revision total knee arthroplasty. J Arthroplasty. 2007;22(4 suppl 1):32-38.
8. Vasso M, Beaufils P, Schiavone Panni A. Constraint choice in revision knee arthroplasty. Int Orthop. 2013;37(7):1279-1284.
9. Engh GA, Ammeen DJ. Bone loss with revision total knee arthroplasty: defect classification and alternatives for reconstruction. Instr Course Lect. 1999;48:167-175.
10. Ewald FC. The Knee Society total knee arthroplasty roentgenographic evaluation and scoring system. Clin Orthop Relat Res. 1989;248:9-12.
11. Meneghini RM, Mont MA, Backstein DB, Bourne RB, Dennis DA, Scuderi GR. Development of a modern Knee Society radiographic evaluation system and methodology for total knee arthroplasty. J Arthroplasty. 2015;30(12):2311-2314.
12. Nam D, Umunna BP, Cross MB, Reinhardt KR, Duggal S, Cornell CN. Clinical results and failure mechanisms of a nonmodular constrained knee without stem extensions. HSS J. 2012;8(2):96-102.
13. Lombardi AV Jr, Berend KR. The role of implant constraint in revision TKA: striking the balance. Orthopedics. 2006;29(9):847-849.
14. Lachiewicz PF, Soileau ES. Results of a second-generation constrained condylar prosthesis in primary total knee arthroplasty. J Arthroplasty. 2011;26(8):1228-1231.
15. Bae DK, Song SJ, Heo DB, Lee SH, Song WJ. Long-term survival rate of implants and modes of failure after revision total knee arthroplasty by a single surgeon. J Arthroplasty. 2013;28(7):1130-1134.
16. Wilke BK, Wagner ER, Trousdale RT. Long-term survival of semi-constrained total knee arthroplasty for revision surgery. J Arthroplasty. 2014;29(5):1005-1008.
17. Lachiewicz PF, Soileau ES. Ten-year survival and clinical results of constrained components in primary total knee arthroplasty. J Arthroplasty. 2006;21(6):803-808.
18. Jones RE. Total knee arthroplasty with modular rotating-platform hinge. Orthopedics. 2006;29(9 suppl):S80-S82.
19. Korim MT, Esler CN, Reddy VR, Ashford RU. A systematic review of endoprosthetic replacement for non-tumour indications around the knee joint. The Knee. 2013;20:367-375.
20. Hofmann AA, Goldberg T, Tanner AM, Kurtin SM. Treatment of infected total knee arthroplasty using an articulating spacer: 2- to 12-year experience. Clin Orthop Relat Res. 2005;(430):125-131.
21. Peters CL, Erickson J, Kloepper RG, Mohr RA. Revision total knee arthroplasty with modular components inserted with metaphyseal cement and stems without cement. J Arthroplasty. 2005;20:302-308.
22. Pala E, Trovarelli G, Calabro T, Angelini A, Abati CN, Ruggieri P. Survival of modern knee tumor megaprostheses: failures, functional results, and a comparative statistical analysis. Clinical Orthop Relat Res. 2015;473:891-899.
23. Angelini A, Henderson E, Trovarelli G, Ruggieri P. Is there a role for knee arthrodesis with modular endoprostheses for tumor and revision of failed endoprostheses? Clin Orthop Relat Res. 2013;471(10):3326-3335.
1. Fehring TK, Odum S, Griffin WL, Mason JB, Nadaud M. Early failures in total knee arthroplasty. Clin Orthop Relat Res. 2001;392:315-318.
2. Sharkey PF, Hozack WJ, Rothman RH, Shastri S, Jacoby SM. Insall Award paper. Why are total knee arthroplasties failing today? Clin Orthop Relat Res. 2002;404:7-13.
3. Schroer WC, Berend KR, Lombardi AV, et al. Why are total knees failing today? Etiology of total knee revision in 2010 and 2011. J Arthroplasty. 2013;28(8 suppl):116-119.
4. Kim TK. CORR Insights(®): risk factors for revision within 10 years of total knee arthroplasty. Clin Orthop Relat Res. 2014;472(4):1208-1209.
5. Sheng PY, Jämsen E, Lehto MU, Konttinen YT, Pajamäki J, Halonen P. Revision total knee arthroplasty with the Total Condylar III system in inflammatory arthritis. J Bone Joint Surg Br. 2005;87(9):1222-1224.
6. Haas SB, Insall JN, Montgomery W 3rd, Windsor RE. Revision total knee arthroplasty with use of modular components with stems inserted without cement. J Bone Joint Surg Am. 1995;77(11):1700-1707.
7. Dennis DA. A stepwise approach to revision total knee arthroplasty. J Arthroplasty. 2007;22(4 suppl 1):32-38.
8. Vasso M, Beaufils P, Schiavone Panni A. Constraint choice in revision knee arthroplasty. Int Orthop. 2013;37(7):1279-1284.
9. Engh GA, Ammeen DJ. Bone loss with revision total knee arthroplasty: defect classification and alternatives for reconstruction. Instr Course Lect. 1999;48:167-175.
10. Ewald FC. The Knee Society total knee arthroplasty roentgenographic evaluation and scoring system. Clin Orthop Relat Res. 1989;248:9-12.
11. Meneghini RM, Mont MA, Backstein DB, Bourne RB, Dennis DA, Scuderi GR. Development of a modern Knee Society radiographic evaluation system and methodology for total knee arthroplasty. J Arthroplasty. 2015;30(12):2311-2314.
12. Nam D, Umunna BP, Cross MB, Reinhardt KR, Duggal S, Cornell CN. Clinical results and failure mechanisms of a nonmodular constrained knee without stem extensions. HSS J. 2012;8(2):96-102.
13. Lombardi AV Jr, Berend KR. The role of implant constraint in revision TKA: striking the balance. Orthopedics. 2006;29(9):847-849.
14. Lachiewicz PF, Soileau ES. Results of a second-generation constrained condylar prosthesis in primary total knee arthroplasty. J Arthroplasty. 2011;26(8):1228-1231.
15. Bae DK, Song SJ, Heo DB, Lee SH, Song WJ. Long-term survival rate of implants and modes of failure after revision total knee arthroplasty by a single surgeon. J Arthroplasty. 2013;28(7):1130-1134.
16. Wilke BK, Wagner ER, Trousdale RT. Long-term survival of semi-constrained total knee arthroplasty for revision surgery. J Arthroplasty. 2014;29(5):1005-1008.
17. Lachiewicz PF, Soileau ES. Ten-year survival and clinical results of constrained components in primary total knee arthroplasty. J Arthroplasty. 2006;21(6):803-808.
18. Jones RE. Total knee arthroplasty with modular rotating-platform hinge. Orthopedics. 2006;29(9 suppl):S80-S82.
19. Korim MT, Esler CN, Reddy VR, Ashford RU. A systematic review of endoprosthetic replacement for non-tumour indications around the knee joint. The Knee. 2013;20:367-375.
20. Hofmann AA, Goldberg T, Tanner AM, Kurtin SM. Treatment of infected total knee arthroplasty using an articulating spacer: 2- to 12-year experience. Clin Orthop Relat Res. 2005;(430):125-131.
21. Peters CL, Erickson J, Kloepper RG, Mohr RA. Revision total knee arthroplasty with modular components inserted with metaphyseal cement and stems without cement. J Arthroplasty. 2005;20:302-308.
22. Pala E, Trovarelli G, Calabro T, Angelini A, Abati CN, Ruggieri P. Survival of modern knee tumor megaprostheses: failures, functional results, and a comparative statistical analysis. Clinical Orthop Relat Res. 2015;473:891-899.
23. Angelini A, Henderson E, Trovarelli G, Ruggieri P. Is there a role for knee arthrodesis with modular endoprostheses for tumor and revision of failed endoprostheses? Clin Orthop Relat Res. 2013;471(10):3326-3335.
Nonoperative Treatment of Rotator Cuff Tears
Rotator cuff disease is extremely common, yet indications for surgery are not well established. Unfortunately, data on the natural history of patients with rotator cuff disease are lacking, as are high-level studies evaluating the effectiveness of rotator cuff repair. This deficit is highlighted by the recent American Academy of Orthopaedic Surgeons clinical practice guideline on optimizing the management of rotator cuff problems,1 in which none of the position statements were based on high-level evidence, and 22 of 25 statements were inconclusive or based on weak evidence or represented the panel’s consensus opinion. Although the traditional teaching is that rotator cuff tears (RCTs) should be surgically repaired, the present article reviews the evidence supporting physical therapy as a treatment for atraumatic full-thickness RCTs.
1. Less than 5% of people with RCTs undergo surgery
Studies on symptomatic and asymptomatic patients have found a high incidence of RCTs in the population at large.2,3 By conservative estimate, 10% of people older than 65 years have full-thickness RCTs. Therefore, the 2010 US Census4 finding of 57 million people over age 65 years translates to 5.7 million with full-thickness RCTs. In the United States, about 275,000 rotator cuff surgeries are performed annually.5 That is, less than 5% of people with RCTs undergo surgery each year.
2. Symptoms do not correlate well with RCT severity
Pain is statistically more likely in patients who experience RCT progression than in those who do not.6-8 However, RCTs may progress without pain, or there may be pain without progression, making pain a poor sign of RCT progression.9 The Multicenter Orthopaedic Outcome Network (MOON) Shoulder Group, studying a cohort of patients with atraumatic full-thickness RCTs, found no relationship between RCT severity and pain,10 symptom duration,11 or activity level,12 suggesting the relationship between RCTs and symptoms is not robust.
3. The high failure rates of surgical repairs do not affect patient-reported outcomes
Postoperative imaging has demonstrated high failure rates for rotator cuff repairs, yet patient-reported outcome scores do not differ between cases of intact and failed repairs.13,14 Strength is better, however, in intact repairs.14
4. Physical therapy is effective in treating atraumatic RCTs
The MOON Shoulder Group conducted a prospective cohort study to determine the predictors of failed physical therapy for atraumatic full-thickness RCTs and to help define the indications for rotator cuff surgery.15 All enrolled patients started with a well-defined physical therapy program, and they could opt out and have surgery at any time. The physical therapy program, derived from a systematic review of the literature, was found to be effective in more than 80% of patients with follow-up of 2 years or longer.15 The most important predictor of failed nonoperative treatment was patient expectations: For a patient who thought physical therapy would work, it worked; for a patient who thought it would not work, surgery was the more likely choice. No measure of pain or RCT severity predicted the need for surgery.16 For 2 randomized trials that compared surgery and physical therapy, the success of nonoperative treatment was similar: 76% (Moosmayer and colleagues17) and 92% (Kukkonen and colleagues18).
5. What are the indications for surgery?
These data suggest that physical therapy is reasonable for patients with atraumatic RCTs. Some data suggest that traumatic RCTs should be treated with surgery and that it should be performed early.19 Other data suggest strength is better after rotator cuff repair.13,14 What, then, are the indications for surgery? Patients with acute tears probably should have surgery; patients concerned about weakness should consider surgery but should keep in mind that its benefit depends on an intact rotator cuff repair; and patients with low expectations about the effectiveness of physical therapy probably should consider surgery.
When discussing options with a patient, you might approach informed consent as follows:
“Mr. Smith, you have a rotator cuff tear. So do at least 6 million other Americans over age 60 years. Only 5% of those undergo surgery. If your problem is weakness or functional loss, you should have surgery, though there is about a 30% chance the repair will fail. I don’t know how to predict the outcome of repair yet, but I worry your atraumatic tear is at risk for repair failure.
“If your problem is pain, you have an 80% chance of improving with physical therapy, and pain relief seems to last at least 2 years. If you go with physical therapy, however, there is a risk your tear could progress and start causing symptoms. I don’t yet know how likely it is your tear will progress or, if it does progress, how likely it is the tear will cause symptoms. I wish we had better information to help you make your decision.”
1. Pedowitz RA, Yamaguchi K, Ahmad CS, et al. American Academy of Orthopaedic Surgeons clinical practice guideline on: optimizing the management of rotator cuff problems. J Bone Joint Surg Am. 2012;94(2):163-167.
2. Reilly P, Macleod I, Macfarlane R, Windley J, Emery RJ. Dead men and radiologists don’t lie: a review of cadaveric and radiological studies of rotator cuff tear prevalence. Ann R Coll Surg Engl. 2006;88(2):116-121.
3. Teunis, T, Lubberts B, Reilly BT, Ring D. A systematic review and pooled analysis of the prevalence of rotator cuff pathology with increasing age. J Shoulder Elbow Surg. 2014;23(12):1913-1921.
4. Werner CA. The older population: 2010 (2010 Census briefs). US Census Bureau website. http://www.census.gov/prod/cen2010/briefs/c2010br-09.pdf. Published November 2011. Accessed December 13, 2015.
5. Colvin AC, Egorova N, Harrison AK, Moskowitz A, Flatow EL. National trends in rotator cuff repair. J Bone Joint Surg Am. 2012;94(3):227-233.
6. Mall NA, Kim HM, Keener JD, et al. Symptomatic progression of asymptomatic rotator cuff tears: a prospective study of clinical and sonographic variables. J Bone Joint Surg Am. 2010;92(16):2623-2633.
7. Moosmayer S, Tariq R, Stiris M, Smith HJ. The natural history of asymptomatic rotator cuff tears: a three-year follow-up of fifty cases. J Bone Joint Surg Am. 2013;95(14):1249-1255.
8. Safran O, Schroeder J, Bloom R, Weil Y, Milgrom C. Natural history of nonoperatively treated symptomatic rotator cuff tears in patients 60 years old or younger. Am J Sports Med. 2011;39(4):710-714.
9. Kuhn JE. Are atraumatic rotator cuff tears painful? A model to describe the relationship between pain and rotator cuff tears. Minerva Orthop Traumatol. 2015;66:51-61.
10. Dunn WR, Kuhn JE, Sanders R, et al. Symptoms of pain do not correlate with rotator cuff tear severity: a cross-sectional study of 393 patients with a symptomatic atraumatic full-thickness rotator cuff tear. J Bone Joint Surg Am. 2014;96(10):793-800.
11. MOON Shoulder Group: Unruh KP, Kuhn JE, Sanders R, et al. The duration of symptoms does not correlate with rotator cuff tear severity or other patient-related features: a cross-sectional study of patients with atraumatic, full-thickness rotator cuff tears. J Shoulder Elbow Surg. 2014;23(7):1052-1058.
12. Brophy RH, Dunn WR, Kuhn JE; MOON Shoulder Group. Shoulder activity level is not associated with the severity of symptomatic, atraumatic rotator cuff tears in patients electing nonoperative treatment. Am J Sports Med. 2014;42(5):1150-1154.
13. Slabaugh MA, Nho SJ, Grumet RC, et al. Does the literature confirm superior clinical results in radiographically healed rotator cuffs after rotator cuff repair? Arthroscopy. 2010;26(3):393-403.
14. Russell RD, Knight JR, Mulligan E, Khazzam MS. Structural integrity after rotator cuff repair does not correlate with patient function and pain: a meta-analysis. J Bone Joint Surg Am. 2014;96(4):265-271.
15. Kuhn JE, Dunn WR, Sanders R, et al; MOON Shoulder Group. Effectiveness of physical therapy in treating atraumatic full-thickness rotator cuff tears: a multicenter prospective cohort study. J Shoulder Elbow Surg. 2013;22(10):1371-1379.
16. Dunn WR, Kuhn JE, Sanders R, et al. Defining indications for rotator cuff repair: predictors of failure of nonoperative treatment of chronic, symptomatic full-thickness rotator cuff tears. Paper presented at: Open Meeting of the American Shoulder and Elbow Surgeons; March 23, 2013; Chicago, IL.
17. Moosmayer S, Lund G, Seljom US, et al. Tendon repair compared with physiotherapy in the treatment of rotator cuff tears: a randomized controlled study in 103 cases with a five-year follow-up. J Bone Joint Surg Am. 2014;96(18):1504-1514.
18. Kukkonen J, Joukainen A, Lehtinen J, et al. Treatment of non-traumatic rotator cuff tears: a randomised controlled trial with one-year clinical results. Bone Joint J Br. 2014;96(1):75-81.
19. Oh LS, Wolf BR, Hall MP, Levy BA, Marx RG. Indications for rotator cuff repair: a systematic review. Clin Orthop Relat Res. 2007;(455):52-63.
Rotator cuff disease is extremely common, yet indications for surgery are not well established. Unfortunately, data on the natural history of patients with rotator cuff disease are lacking, as are high-level studies evaluating the effectiveness of rotator cuff repair. This deficit is highlighted by the recent American Academy of Orthopaedic Surgeons clinical practice guideline on optimizing the management of rotator cuff problems,1 in which none of the position statements were based on high-level evidence, and 22 of 25 statements were inconclusive or based on weak evidence or represented the panel’s consensus opinion. Although the traditional teaching is that rotator cuff tears (RCTs) should be surgically repaired, the present article reviews the evidence supporting physical therapy as a treatment for atraumatic full-thickness RCTs.
1. Less than 5% of people with RCTs undergo surgery
Studies on symptomatic and asymptomatic patients have found a high incidence of RCTs in the population at large.2,3 By conservative estimate, 10% of people older than 65 years have full-thickness RCTs. Therefore, the 2010 US Census4 finding of 57 million people over age 65 years translates to 5.7 million with full-thickness RCTs. In the United States, about 275,000 rotator cuff surgeries are performed annually.5 That is, less than 5% of people with RCTs undergo surgery each year.
2. Symptoms do not correlate well with RCT severity
Pain is statistically more likely in patients who experience RCT progression than in those who do not.6-8 However, RCTs may progress without pain, or there may be pain without progression, making pain a poor sign of RCT progression.9 The Multicenter Orthopaedic Outcome Network (MOON) Shoulder Group, studying a cohort of patients with atraumatic full-thickness RCTs, found no relationship between RCT severity and pain,10 symptom duration,11 or activity level,12 suggesting the relationship between RCTs and symptoms is not robust.
3. The high failure rates of surgical repairs do not affect patient-reported outcomes
Postoperative imaging has demonstrated high failure rates for rotator cuff repairs, yet patient-reported outcome scores do not differ between cases of intact and failed repairs.13,14 Strength is better, however, in intact repairs.14
4. Physical therapy is effective in treating atraumatic RCTs
The MOON Shoulder Group conducted a prospective cohort study to determine the predictors of failed physical therapy for atraumatic full-thickness RCTs and to help define the indications for rotator cuff surgery.15 All enrolled patients started with a well-defined physical therapy program, and they could opt out and have surgery at any time. The physical therapy program, derived from a systematic review of the literature, was found to be effective in more than 80% of patients with follow-up of 2 years or longer.15 The most important predictor of failed nonoperative treatment was patient expectations: For a patient who thought physical therapy would work, it worked; for a patient who thought it would not work, surgery was the more likely choice. No measure of pain or RCT severity predicted the need for surgery.16 For 2 randomized trials that compared surgery and physical therapy, the success of nonoperative treatment was similar: 76% (Moosmayer and colleagues17) and 92% (Kukkonen and colleagues18).
5. What are the indications for surgery?
These data suggest that physical therapy is reasonable for patients with atraumatic RCTs. Some data suggest that traumatic RCTs should be treated with surgery and that it should be performed early.19 Other data suggest strength is better after rotator cuff repair.13,14 What, then, are the indications for surgery? Patients with acute tears probably should have surgery; patients concerned about weakness should consider surgery but should keep in mind that its benefit depends on an intact rotator cuff repair; and patients with low expectations about the effectiveness of physical therapy probably should consider surgery.
When discussing options with a patient, you might approach informed consent as follows:
“Mr. Smith, you have a rotator cuff tear. So do at least 6 million other Americans over age 60 years. Only 5% of those undergo surgery. If your problem is weakness or functional loss, you should have surgery, though there is about a 30% chance the repair will fail. I don’t know how to predict the outcome of repair yet, but I worry your atraumatic tear is at risk for repair failure.
“If your problem is pain, you have an 80% chance of improving with physical therapy, and pain relief seems to last at least 2 years. If you go with physical therapy, however, there is a risk your tear could progress and start causing symptoms. I don’t yet know how likely it is your tear will progress or, if it does progress, how likely it is the tear will cause symptoms. I wish we had better information to help you make your decision.”
Rotator cuff disease is extremely common, yet indications for surgery are not well established. Unfortunately, data on the natural history of patients with rotator cuff disease are lacking, as are high-level studies evaluating the effectiveness of rotator cuff repair. This deficit is highlighted by the recent American Academy of Orthopaedic Surgeons clinical practice guideline on optimizing the management of rotator cuff problems,1 in which none of the position statements were based on high-level evidence, and 22 of 25 statements were inconclusive or based on weak evidence or represented the panel’s consensus opinion. Although the traditional teaching is that rotator cuff tears (RCTs) should be surgically repaired, the present article reviews the evidence supporting physical therapy as a treatment for atraumatic full-thickness RCTs.
1. Less than 5% of people with RCTs undergo surgery
Studies on symptomatic and asymptomatic patients have found a high incidence of RCTs in the population at large.2,3 By conservative estimate, 10% of people older than 65 years have full-thickness RCTs. Therefore, the 2010 US Census4 finding of 57 million people over age 65 years translates to 5.7 million with full-thickness RCTs. In the United States, about 275,000 rotator cuff surgeries are performed annually.5 That is, less than 5% of people with RCTs undergo surgery each year.
2. Symptoms do not correlate well with RCT severity
Pain is statistically more likely in patients who experience RCT progression than in those who do not.6-8 However, RCTs may progress without pain, or there may be pain without progression, making pain a poor sign of RCT progression.9 The Multicenter Orthopaedic Outcome Network (MOON) Shoulder Group, studying a cohort of patients with atraumatic full-thickness RCTs, found no relationship between RCT severity and pain,10 symptom duration,11 or activity level,12 suggesting the relationship between RCTs and symptoms is not robust.
3. The high failure rates of surgical repairs do not affect patient-reported outcomes
Postoperative imaging has demonstrated high failure rates for rotator cuff repairs, yet patient-reported outcome scores do not differ between cases of intact and failed repairs.13,14 Strength is better, however, in intact repairs.14
4. Physical therapy is effective in treating atraumatic RCTs
The MOON Shoulder Group conducted a prospective cohort study to determine the predictors of failed physical therapy for atraumatic full-thickness RCTs and to help define the indications for rotator cuff surgery.15 All enrolled patients started with a well-defined physical therapy program, and they could opt out and have surgery at any time. The physical therapy program, derived from a systematic review of the literature, was found to be effective in more than 80% of patients with follow-up of 2 years or longer.15 The most important predictor of failed nonoperative treatment was patient expectations: For a patient who thought physical therapy would work, it worked; for a patient who thought it would not work, surgery was the more likely choice. No measure of pain or RCT severity predicted the need for surgery.16 For 2 randomized trials that compared surgery and physical therapy, the success of nonoperative treatment was similar: 76% (Moosmayer and colleagues17) and 92% (Kukkonen and colleagues18).
5. What are the indications for surgery?
These data suggest that physical therapy is reasonable for patients with atraumatic RCTs. Some data suggest that traumatic RCTs should be treated with surgery and that it should be performed early.19 Other data suggest strength is better after rotator cuff repair.13,14 What, then, are the indications for surgery? Patients with acute tears probably should have surgery; patients concerned about weakness should consider surgery but should keep in mind that its benefit depends on an intact rotator cuff repair; and patients with low expectations about the effectiveness of physical therapy probably should consider surgery.
When discussing options with a patient, you might approach informed consent as follows:
“Mr. Smith, you have a rotator cuff tear. So do at least 6 million other Americans over age 60 years. Only 5% of those undergo surgery. If your problem is weakness or functional loss, you should have surgery, though there is about a 30% chance the repair will fail. I don’t know how to predict the outcome of repair yet, but I worry your atraumatic tear is at risk for repair failure.
“If your problem is pain, you have an 80% chance of improving with physical therapy, and pain relief seems to last at least 2 years. If you go with physical therapy, however, there is a risk your tear could progress and start causing symptoms. I don’t yet know how likely it is your tear will progress or, if it does progress, how likely it is the tear will cause symptoms. I wish we had better information to help you make your decision.”
1. Pedowitz RA, Yamaguchi K, Ahmad CS, et al. American Academy of Orthopaedic Surgeons clinical practice guideline on: optimizing the management of rotator cuff problems. J Bone Joint Surg Am. 2012;94(2):163-167.
2. Reilly P, Macleod I, Macfarlane R, Windley J, Emery RJ. Dead men and radiologists don’t lie: a review of cadaveric and radiological studies of rotator cuff tear prevalence. Ann R Coll Surg Engl. 2006;88(2):116-121.
3. Teunis, T, Lubberts B, Reilly BT, Ring D. A systematic review and pooled analysis of the prevalence of rotator cuff pathology with increasing age. J Shoulder Elbow Surg. 2014;23(12):1913-1921.
4. Werner CA. The older population: 2010 (2010 Census briefs). US Census Bureau website. http://www.census.gov/prod/cen2010/briefs/c2010br-09.pdf. Published November 2011. Accessed December 13, 2015.
5. Colvin AC, Egorova N, Harrison AK, Moskowitz A, Flatow EL. National trends in rotator cuff repair. J Bone Joint Surg Am. 2012;94(3):227-233.
6. Mall NA, Kim HM, Keener JD, et al. Symptomatic progression of asymptomatic rotator cuff tears: a prospective study of clinical and sonographic variables. J Bone Joint Surg Am. 2010;92(16):2623-2633.
7. Moosmayer S, Tariq R, Stiris M, Smith HJ. The natural history of asymptomatic rotator cuff tears: a three-year follow-up of fifty cases. J Bone Joint Surg Am. 2013;95(14):1249-1255.
8. Safran O, Schroeder J, Bloom R, Weil Y, Milgrom C. Natural history of nonoperatively treated symptomatic rotator cuff tears in patients 60 years old or younger. Am J Sports Med. 2011;39(4):710-714.
9. Kuhn JE. Are atraumatic rotator cuff tears painful? A model to describe the relationship between pain and rotator cuff tears. Minerva Orthop Traumatol. 2015;66:51-61.
10. Dunn WR, Kuhn JE, Sanders R, et al. Symptoms of pain do not correlate with rotator cuff tear severity: a cross-sectional study of 393 patients with a symptomatic atraumatic full-thickness rotator cuff tear. J Bone Joint Surg Am. 2014;96(10):793-800.
11. MOON Shoulder Group: Unruh KP, Kuhn JE, Sanders R, et al. The duration of symptoms does not correlate with rotator cuff tear severity or other patient-related features: a cross-sectional study of patients with atraumatic, full-thickness rotator cuff tears. J Shoulder Elbow Surg. 2014;23(7):1052-1058.
12. Brophy RH, Dunn WR, Kuhn JE; MOON Shoulder Group. Shoulder activity level is not associated with the severity of symptomatic, atraumatic rotator cuff tears in patients electing nonoperative treatment. Am J Sports Med. 2014;42(5):1150-1154.
13. Slabaugh MA, Nho SJ, Grumet RC, et al. Does the literature confirm superior clinical results in radiographically healed rotator cuffs after rotator cuff repair? Arthroscopy. 2010;26(3):393-403.
14. Russell RD, Knight JR, Mulligan E, Khazzam MS. Structural integrity after rotator cuff repair does not correlate with patient function and pain: a meta-analysis. J Bone Joint Surg Am. 2014;96(4):265-271.
15. Kuhn JE, Dunn WR, Sanders R, et al; MOON Shoulder Group. Effectiveness of physical therapy in treating atraumatic full-thickness rotator cuff tears: a multicenter prospective cohort study. J Shoulder Elbow Surg. 2013;22(10):1371-1379.
16. Dunn WR, Kuhn JE, Sanders R, et al. Defining indications for rotator cuff repair: predictors of failure of nonoperative treatment of chronic, symptomatic full-thickness rotator cuff tears. Paper presented at: Open Meeting of the American Shoulder and Elbow Surgeons; March 23, 2013; Chicago, IL.
17. Moosmayer S, Lund G, Seljom US, et al. Tendon repair compared with physiotherapy in the treatment of rotator cuff tears: a randomized controlled study in 103 cases with a five-year follow-up. J Bone Joint Surg Am. 2014;96(18):1504-1514.
18. Kukkonen J, Joukainen A, Lehtinen J, et al. Treatment of non-traumatic rotator cuff tears: a randomised controlled trial with one-year clinical results. Bone Joint J Br. 2014;96(1):75-81.
19. Oh LS, Wolf BR, Hall MP, Levy BA, Marx RG. Indications for rotator cuff repair: a systematic review. Clin Orthop Relat Res. 2007;(455):52-63.
1. Pedowitz RA, Yamaguchi K, Ahmad CS, et al. American Academy of Orthopaedic Surgeons clinical practice guideline on: optimizing the management of rotator cuff problems. J Bone Joint Surg Am. 2012;94(2):163-167.
2. Reilly P, Macleod I, Macfarlane R, Windley J, Emery RJ. Dead men and radiologists don’t lie: a review of cadaveric and radiological studies of rotator cuff tear prevalence. Ann R Coll Surg Engl. 2006;88(2):116-121.
3. Teunis, T, Lubberts B, Reilly BT, Ring D. A systematic review and pooled analysis of the prevalence of rotator cuff pathology with increasing age. J Shoulder Elbow Surg. 2014;23(12):1913-1921.
4. Werner CA. The older population: 2010 (2010 Census briefs). US Census Bureau website. http://www.census.gov/prod/cen2010/briefs/c2010br-09.pdf. Published November 2011. Accessed December 13, 2015.
5. Colvin AC, Egorova N, Harrison AK, Moskowitz A, Flatow EL. National trends in rotator cuff repair. J Bone Joint Surg Am. 2012;94(3):227-233.
6. Mall NA, Kim HM, Keener JD, et al. Symptomatic progression of asymptomatic rotator cuff tears: a prospective study of clinical and sonographic variables. J Bone Joint Surg Am. 2010;92(16):2623-2633.
7. Moosmayer S, Tariq R, Stiris M, Smith HJ. The natural history of asymptomatic rotator cuff tears: a three-year follow-up of fifty cases. J Bone Joint Surg Am. 2013;95(14):1249-1255.
8. Safran O, Schroeder J, Bloom R, Weil Y, Milgrom C. Natural history of nonoperatively treated symptomatic rotator cuff tears in patients 60 years old or younger. Am J Sports Med. 2011;39(4):710-714.
9. Kuhn JE. Are atraumatic rotator cuff tears painful? A model to describe the relationship between pain and rotator cuff tears. Minerva Orthop Traumatol. 2015;66:51-61.
10. Dunn WR, Kuhn JE, Sanders R, et al. Symptoms of pain do not correlate with rotator cuff tear severity: a cross-sectional study of 393 patients with a symptomatic atraumatic full-thickness rotator cuff tear. J Bone Joint Surg Am. 2014;96(10):793-800.
11. MOON Shoulder Group: Unruh KP, Kuhn JE, Sanders R, et al. The duration of symptoms does not correlate with rotator cuff tear severity or other patient-related features: a cross-sectional study of patients with atraumatic, full-thickness rotator cuff tears. J Shoulder Elbow Surg. 2014;23(7):1052-1058.
12. Brophy RH, Dunn WR, Kuhn JE; MOON Shoulder Group. Shoulder activity level is not associated with the severity of symptomatic, atraumatic rotator cuff tears in patients electing nonoperative treatment. Am J Sports Med. 2014;42(5):1150-1154.
13. Slabaugh MA, Nho SJ, Grumet RC, et al. Does the literature confirm superior clinical results in radiographically healed rotator cuffs after rotator cuff repair? Arthroscopy. 2010;26(3):393-403.
14. Russell RD, Knight JR, Mulligan E, Khazzam MS. Structural integrity after rotator cuff repair does not correlate with patient function and pain: a meta-analysis. J Bone Joint Surg Am. 2014;96(4):265-271.
15. Kuhn JE, Dunn WR, Sanders R, et al; MOON Shoulder Group. Effectiveness of physical therapy in treating atraumatic full-thickness rotator cuff tears: a multicenter prospective cohort study. J Shoulder Elbow Surg. 2013;22(10):1371-1379.
16. Dunn WR, Kuhn JE, Sanders R, et al. Defining indications for rotator cuff repair: predictors of failure of nonoperative treatment of chronic, symptomatic full-thickness rotator cuff tears. Paper presented at: Open Meeting of the American Shoulder and Elbow Surgeons; March 23, 2013; Chicago, IL.
17. Moosmayer S, Lund G, Seljom US, et al. Tendon repair compared with physiotherapy in the treatment of rotator cuff tears: a randomized controlled study in 103 cases with a five-year follow-up. J Bone Joint Surg Am. 2014;96(18):1504-1514.
18. Kukkonen J, Joukainen A, Lehtinen J, et al. Treatment of non-traumatic rotator cuff tears: a randomised controlled trial with one-year clinical results. Bone Joint J Br. 2014;96(1):75-81.
19. Oh LS, Wolf BR, Hall MP, Levy BA, Marx RG. Indications for rotator cuff repair: a systematic review. Clin Orthop Relat Res. 2007;(455):52-63.
Adipose Flap Versus Fascial Sling for Anterior Subcutaneous Transposition of the Ulnar Nerve
Compression of the ulnar nerve at the elbow, also referred to as cubital tunnel syndrome (CuTS), is the second most common peripheral nerve compression syndrome in the upper extremity.1,2 Although the ulnar nerve can be compressed at 5 different sites, including arcade of Struthers, medial intermuscular septum, medial epicondyle, and deep flexor aponeurosis, the cubital tunnel is most commonly affected.3 Patients typically present with paresthesias in the fourth and fifth digits and weakness of hand muscle intrinsics. Activity-related pain or pain at the medial elbow can also occur in more advanced pathology.4 It is estimated that conservative therapy fails and surgical intervention is required in up to 30% of patients with CuTS.1 Surgical approaches range from in situ decompression to transposition techniques, but there is no consensus in the orthopedic community as to which technique offers the best results. In a 2008 meta-analysis, Macadam and colleagues5 found no statistical differences in outcomes among the various surgical approaches. Nevertheless, subcutaneous transposition of the ulnar nerve at the elbow is a popular option.6
Despite the widespread success of surgical intervention for CuTS, persistent or recurrent pain occurs in 9.9% to 21.0% of cases.7-10 In addition, several investigators have cited perineural scarring as a major cause of recurrent symptoms after primary surgery.11-14 Filippi and colleagues11 noted that patients who required reoperation after primary anterior transposition had “serious epineural fibrosis and fibrosis around the transposed ulnar nerve.” At our institution, we have similarly found that scarring of the fascial sling around the ulnar nerve led to recurrence of CuTS within 4 months after initial surgery (Figure 1).
We therefore prefer to use a vascularized adipose flap to secure the anteriorly transposed ulnar nerve. This flap provides a pliable, vascularized adipose environment for the nerve, which helps reduce nerve adherence and may enhance nerve recovery.15 In the study reported here, we retrospectively reviewed the long-term outcomes of ulnar nerve anterior subcutaneous transposition secured with either an adipose flap or a fascial sling. We hypothesized that patients in the 2 groups (adipose flap, fascial sling) would have equivalent outcomes.
Materials and Methods
After obtaining institutional review board approval, we reviewed the medical and surgical records of 104 patients (107 limbs) who underwent transposition of the ulnar nerve secured with either an adipose flap (27 limbs) or a fascial sling (80 limbs) over a 14-year period. The fascial sling cohort was used as a comparison group, matched to the adipose flap cohort by sex, age at time of surgery, hand dominance, symptom duration, and length of follow-up (Table 1). Patients were indicated for surgery and were included in the study if they had a history and physical examination consistent with primary CuTS, symptom duration longer than 1 year, and failed conservative management, including activity modification, night splinting, elbow pads, occupational therapy, and home exercise regimen. Electrodiagnostic testing was used at the discretion of the attending surgeon when the diagnosis was not clear from the history and physical examination. All fascial sling procedures were performed at our institution by 1 of 3 fellowship-trained hand surgeons, including Dr. Rosenwasser. The adipose flap modification was performed only by Dr. Rosenwasser. Of the 27 patients in the adipose flap group, 23 underwent surgery for primary CuTS and were included in the study; the other 4 (revision cases) were excluded; 1 patient subsequently died of a cause unrelated to the surgical procedure, and 6 were lost to follow-up. Of the 80 patients in the fascial sling group, 30 underwent surgery for primary CuTS; 5 died before follow-up, and 8 declined to participate.
Thirty-three patients (16 adipose flap, 17 fascial sling) met the inclusion criteria. Of the 16 adipose flap patients, 15 underwent the physical examination and completed the questionnaire, and 1 was interviewed by telephone. Similarly, of the 17 fascial sling patients, 15 underwent the physical examination and completed the questionnaire, and 2 were interviewed by telephone. There were no bilateral cases. Conservative management (activity modification, night splinting, elbow pads, occupational therapy, home exercise) failed in all cases.
A trained study team member who was not part of the surgical team performed follow-up evaluations using objective outcome measures and subjective questionnaires. Patients were assessed at a mean follow-up of 5.6 years (range, 1.6-15.9 years). Patients completed the DASH (Disabilities of the Arm, Shoulder, and Hand) questionnaire16 and visual analog scales (VASs) for pain, numbness, tingling, and weakness in the ulnar nerve distribution. They also rated the presence of night symptoms that were interfering with sleep. The Modified Bishop Rating Scale (MBRS) was used to quantify patient self-reported data17,18 (Figure 2). The MBRS measures overall satisfaction, symptom improvement, presence of residual symptoms, ability to engage in activities, work capability, and subjective changes in strength and sensibility.
In the physical examinations, we tested for Tinel, Wartenberg, and Froment signs; performed an elbow flexion test; and measured elbow range of motion for flexion and extension as well as forearm pronation and supination. We also evaluated lateral pinch strength and grip strength, using a Jamar hydraulic pinch gauge and a Jamar dynamometer (Therapeutic Equipment Corp) and taking the average of 3 assessments. Fifth-digit abduction strength was graded on a standard muscle strength scale. Two-point discrimination was measured at the middle, ring, and small digits of the operated and contralateral hands.19
Surgical Technique
Standard ulnar nerve decompression with anterior subcutaneous transposition and the following modifications were performed on all patients.20 A posteromedial incision parallel to the intermuscular septum was developed and the ulnar nerve identified. Minimizing stripping of the vascular mesentery, the dissection continued along the course of the nerve, and the medial intermuscular septum was excised to prevent secondary compression after transposition. The ulnar nerve was mobilized and transposed anterior to the medial epicondyle (Figure 3). For patients who received the fascial sling, a fascial sleeve was elevated from the flexor-pronator mass and sutured to the edge of the retinaculum securing the nerve. For patients who received the adipose flap, the flap with its vascular pedicle intact was elevated from the subcutaneous tissue of the anterior skin overlying the transposed nerve. The adipose tissue was sharply dissected in half while sufficient subcutaneous tissue was kept between the skin and the flap. A plane was developed based on an anterior adipose pedicle, which included a cutaneous artery and a vein that would supply the vascularized adipose flap. The flap was elevated and wrapped around the nerve without tension while the ulnar nerve was protected from being kinked by the construct. The flap was sutured to the anterior subcutaneous tissue to create a tunnel of adipose tissue surrounding the nerve along its length (Figure 4). The elbow was then flexed and extended to ensure free nerve gliding before wound closure.
The patient was allowed to move the elbow within the bulky dressings immediately after surgery. After 2 weeks, sutures were removed. Formal occupational therapy is not needed for these patients, except in the presence of significant weakness.
Results
As mentioned, the 2 groups were matched on demographics: age at time of surgery, sex, symptom duration, and length of follow-up (Table 1).
For the 16 adipose flap patients (Table 2), mean DASH score was 19.9 (range, 0-71.7). Seven of these patients reported upper extremity pain with a mean VAS score of 1.7 (range, 0-8); 4 patients reported pain in the wrist and fourth and fifth digits; only 1 patient reported pain that occasionally woke the patient from sleep. Constant numbness was present in 6 patients. Four patients reported constant mild tingling in the hand, and 11 reported intermittent tingling. Eleven patients (68.7%) reported operated-arm weakness with a mean VAS score of 3.4 (range, 0-8). In patients who had a physical examination, mean elbow flexion–extension arc of motion was 134° (range, 95°-150°), representing 99% of the motion of the contralateral arm. Mean pronation–supination arc was 174° (range, 150°-180°), accounting for 104% of the contralateral arm. Mean lateral pinch strength was 73% of the contralateral arm, and mean grip strength was 114% of the contralateral arm. The Tinel sign was present in 2 patients, the Froment sign was present in 3 patients, and the elbow flexion test was positive in 2 patients. No patient had a positive Wartenberg sign. On the MBRS, 10 patients had an excellent score, and 6 had a good score.
For the 17 fascial sling patients (Table 2), mean DASH score was 22.7 (range, 0-63.3). Three patients reported upper extremity pain with a mean VAS score of 1.4 (range, 0-7); 3 patients reported pain that occasionally woke them from sleep. Seven patients had constant numbness in the distribution of the ulnar nerve. Two patients had constant paresthesias, and 7 had intermittent paresthesias. Nine patients (52.9%) reported arm weakness with a mean VAS score of 2.5 (range, 0-8). Mean elbow flexion–extension arc of motion was 136° (range, 100°-150°), representing 100% of the contralateral arm. Mean pronation–supination arc was 187° (range, 155°-225°), accounting for 102% of the contralateral arm. Mean lateral pinch strength was 93% of the contralateral arm, and mean grip strength was 80% of the contralateral arm. The Tinel sign was present in 6 patients, the Froment sign in 3 patients, and the Wartenberg sign in 2 patients. The elbow flexion test was positive in 4 patients. On the MBRS, 10 patients had an excellent score, and 7 had a good score.
There was no recurrence of CuTS in either group. One adipose flap patient developed a wound infection that required reoperation.
Discussion
Ulnar neuropathy was described by Magee and Phalen21 in 1949 and termed cubital tunnel syndrome by Feindel and Stratford22 in 1958. Since then, numerous procedures, including in situ decompression, medial epicondylectomy, and endoscopic decompression,23,24 have been advocated for the treatment of this condition. In addition, anterior transposition, which involves securing the ulnar nerve in a submuscular, intramuscular, or subcutaneous sleeve,6 remains a popular option. Despite more than half a century of surgical treatment for this condition, there is no consensus about which procedure offers the best outcomes. Bartels and colleagues8 retrospectively reviewed surgical treatments for CuTS, examining 3148 arms over a 27-year period. They found simple decompression and anterior intramuscular transposition had the best results, followed by medial epicondylectomy and anterior subcutaneous transposition, with anterior submuscular transposition yielding the poorest outcomes. Despite these findings, the operative groups’ recurrence rates remained significant. These results were challenged in a 2008 meta-analysis5 that found no significant difference among simple decompression, subcutaneous transposition, and submuscular transposition and instead demonstrated trends toward better outcomes with anterior transposition. Osterman and Davis7 reported a 5% to 15% rate of unsatisfactory outcomes with anterior subcutaneous transposition, a popular technique used by surgeons at our institution.
The causes for failure or recurrence of ulnar neuropathy after surgical intervention are multifactorial and include preexisting medical conditions and improper operative technique. It is well established that failure to excise all 5 anatomical points of entrapment, or creation of new points of tension during surgery, leads to poor outcomes.12 Nevertheless, the contribution of perineural scarring to postoperative recurrent ulnar neuropathy is currently being recognized: Gabel and Amadio13 described postoperative fibrosis in one-third of their patients with surgically treated recurrent CuTS, Rogers and colleagues14 noted dense perineural fibrosis after intramuscular and subcutaneous transposition procedures, Filippi and colleagues11 cited serious epineural fibrosis and fibrosis around the ulnar nerve as the main findings in their study of 22 patients with recurrent ulnar neuropathy, and Vogel and colleagues12 found that 88% of their patients with persistent CuTS after surgery exhibited perineural scarring.
We think that use of a scar tissue barrier during ulnar nerve transposition reduces the incidence of cicatrix and produces better outcomes—a position largely echoed by the orthopedic community, as fascial, fasciocutaneous, free, and venous flaps have all been used for such purposes.25,26 Vein wrapping has demonstrated good recovery of a nerve after perineural scarring.27 Advocates of intramuscular transposition argue that their technique provides the nerve with a vascularized tunnel, as segmental vascular stripping is an inevitability in transposition. However, this technique increases the incidence of scarring and potential muscle damage.28,29 We think the pedicled adipofascial flap benefits the peripheral nerve by providing a scar tissue barrier and an optimal milieu for vascular regeneration. Kilic and colleagues15 demonstrated the regenerative effects of adipose tissue flaps on peripheral nerves after crush injuries in a rat model, and Strickland and colleagues30 retrospectively examined the effects of hypothenar fat flaps on recalcitrant carpal tunnel syndrome, showing excellent results for this procedure. It is hypothesized that adipose tissue provides not only adipose-derived stem cells but also a rich vascular bed on which nerves will regenerate.
For all patients in the present study, symptoms improved, though the adipose flap and fascial sling groups were not significantly different in their outcomes. We used the MBRS to quantify and compare the groups’ patient-rated outcomes. No statistically significant difference was found between the adipose flap and fascial sling groups. On the MBRS, excellent and good outcomes were reported by 62.5% and 37.5% of the adipose flap patients, respectively, and 59% and 41% of the fascial sling patients (Table 3). Likewise, objective measurements did not show a significant difference between the 2 interventions—indicating that, compared with the current standard of care, adipose flaps are more efficacious in securing the anteriorly transposed nerve.
Complications of the adipose flap technique are consistent with those reported for other techniques for anterior transposition of the ulnar nerve. The most common complication is hematoma, which can be avoided with meticulous hemostasis. Damage of the medial antebrachial cutaneous nerve or motor branches to the flexor carpi ulnaris has been reported for the fascial technique (we have not had such outcomes at our institution). Contraindications to the adipofascial technique include insufficient subcutaneous adipose tissue for covering the ulnar nerve.
This study was limited by its retrospective setup, which reduced access to preoperative objective and subjective data. The small sample size also limited our ability to demonstrate the advantageous effects of an adipofascial flap in preventing postoperative perineural scarring.
The adipose flap technique is a viable option for securing the anteriorly transposed ulnar nerve. Outcomes in this study demonstrated an efficacy comparable to that of the fascial sling technique. Symptoms resolve or improve, and the majority of patients are satisfied with long-term surgical outcomes. The adipofascial flap may have additional advantages, as it provides a pliable, vascular fat envelope mimicking the natural fatty environment of peripheral nerves.
1. Latinovic R, Gulliford MC, Hughes RA. Incidence of common compressive neuropathies in primary care. J Neurol Neurosurg Psychiatry. 2006;77(2):263-265.
2. Robertson C, Saratsiotis J. A review of compression ulnar neuropathy at the elbow. J Manipulative Physiol Ther. 2005;28(5):345.
3. Posner MA. Compressive ulnar neuropathies at the elbow: I. Etiology and diagnosis. J Am Acad Orthop Surg. 1998;6(5):282-288.
4. Piligian G, Herbert R, Hearns M, Dropkin J, Landsbergis P, Cherniack M. Evaluation and management of chronic work-related musculoskeletal disorders of the distal upper extremity. Am J Ind Med. 2000;37(1):75-93.
5. Macadam SA, Gandhi R, Bezuhly M, Lefaivre KA. Simple decompression versus anterior subcutaneous and submuscular transposition of the ulnar nerve for cubital tunnel syndrome: a meta-analysis. J Hand Surg Am. 2008;33(8):1314.e1-e12.
6. Soltani AM, Best MJ, Francis CS, Allan BJ, Panthaki ZJ. Trends in the surgical treatment of cubital tunnel syndrome: an analysis of the National Survey of Ambulatory Surgery database. J Hand Surg Am. 2013;38(8):1551-1556.
7. Osterman AL, Davis CA. Subcutaneous transposition of the ulnar nerve for treatment of cubital tunnel syndrome. Hand Clin. 1996;12(2):421-433.
8. Bartels RH, Menovsky T, Van Overbeeke JJ, Verhagen WI. Surgical management of ulnar nerve compression at the elbow: an analysis of the literature. J Neurosurg. 1998;89(5):722-727.
9. Seradge H, Owen W. Cubital tunnel release with medial epicondylectomy factors influencing the outcome. J Hand Surg Am. 1998;23(3):483-491.
10. Schnabl SM, Kisslinger F, Schramm A, et al. Subjective outcome, neurophysiological investigations, postoperative complications and recurrence rate of partial medial epicondylectomy in cubital tunnel syndrome. Arch Orthop Trauma Surg. 2011;131(8):1027-1033.
11. Filippi R, Charalampaki P, Reisch R, Koch D, Grunert P. Recurrent cubital tunnel syndrome. Etiology and treatment. Minim Invasive Neurosurg. 2001;44(4):197-201.
12. Vogel RB, Nossaman BC, Rayan GM. Revision anterior submuscular transposition of the ulnar nerve for failed subcutaneous transposition. Br J Plast Surg. 2004;57(4):311-316.
13. Gabel GT, Amadio PC. Reoperation for failed decompression of the ulnar nerve in the region of the elbow. J Bone Joint Surg Am. 1990;72(2):213-219.
14. Rogers MR, Bergfield TG, Aulicino PL. The failed ulnar nerve transposition. Etiology and treatment. Clin Orthop. 1991;269:193-200.
15. Kilic A, Ojo B, Rajfer RA, et al. Effect of white adipose tissue flap and insulin-like growth factor-1 on nerve regeneration in rats. Microsurgery. 2013;33(5):367-375.
16. Ebersole GC, Davidge K, Damiano M, Mackinnon SE. Validity and responsiveness of the DASH questionnaire as an outcome measure following ulnar nerve transposition for cubital tunnel syndrome. Plast Reconstr Surg. 2013;132(1):81e-90e.
17. Kleinman WB, Bishop AT. Anterior intramuscular transposition of the ulnar nerve. J Hand Surg Am. 1989;14(6):972-979.
18. Dützmann S, Martin KD, Sobottka S, et al. Open vs retractor-endoscopic in situ decompression of the ulnar nerve in cubital tunnel syndrome: a retrospective cohort study. Neurosurgery. 2013;72(4):605-616.
19. Dellon AL, Mackinnon SE, Crosby PM. Reliability of two-point discrimination measurements. J Hand Surg Am. 1987;12(5 pt 1):693-696.
20. Danoff JR, Lombardi JM, Rosenwasser MP. Use of a pedicled adipose flap as a sling for anterior subcutaneous transposition of the ulnar nerve. J Hand Surg Am. 2014;39(3):552-555.
21. Magee RB, Phalen GS. Tardy ulnar palsy. Am J Surg. 1949;78(4):470-474.
22. Feindel W, Stratford J. Cubital tunnel compression in tardy ulnar palsy. Can Med Assoc J. 1958;78(5):351-353.
23. Tsai TM, Bonczar M, Tsuruta T, Syed SA. A new operative technique: cubital tunnel decompression with endoscopic assistance. Hand Clin. 1995;11(1):71-80.
24. Hoffmann R, Siemionow M. The endoscopic management of cubital tunnel syndrome. J Hand Surg Br. 2006;31(1):23-29.
25. Luchetti R, Riccio M, Papini Zorli I, Fairplay T. Protective coverage of the median nerve using fascial, fasciocutaneous or island flaps. Handchir Mikrochir Plast Chir. 2006;38(5):317-330.
26. Kokkalis ZT, Jain S, Sotereanos DG. Vein wrapping at cubital tunnel for ulnar nerve problems. J Shoulder Elbow Surg. 2010;19(2):91-97.
27. Masear VR, Colgin S. The treatment of epineural scarring with allograft vein wrapping. Hand Clin. 1996;12(4):773-779.
28. Kleinman WB, Bishop AT. Anterior intramuscular transposition of the ulnar nerve. J Hand Surg Am. 1989;14(6):972-979.
29. Lundborg G. Surgical treatment for ulnar nerve entrapment at the elbow. J Hand Surg Br. 1992;17(3):245-247.
30. Strickland JW, Idler RS, Lourie GM, Plancher KD. The hypothenar fat pad flap for management of recalcitrant carpal tunnel syndrome. J Hand Surg Am. 1996;21(5):840-848.
Compression of the ulnar nerve at the elbow, also referred to as cubital tunnel syndrome (CuTS), is the second most common peripheral nerve compression syndrome in the upper extremity.1,2 Although the ulnar nerve can be compressed at 5 different sites, including arcade of Struthers, medial intermuscular septum, medial epicondyle, and deep flexor aponeurosis, the cubital tunnel is most commonly affected.3 Patients typically present with paresthesias in the fourth and fifth digits and weakness of hand muscle intrinsics. Activity-related pain or pain at the medial elbow can also occur in more advanced pathology.4 It is estimated that conservative therapy fails and surgical intervention is required in up to 30% of patients with CuTS.1 Surgical approaches range from in situ decompression to transposition techniques, but there is no consensus in the orthopedic community as to which technique offers the best results. In a 2008 meta-analysis, Macadam and colleagues5 found no statistical differences in outcomes among the various surgical approaches. Nevertheless, subcutaneous transposition of the ulnar nerve at the elbow is a popular option.6
Despite the widespread success of surgical intervention for CuTS, persistent or recurrent pain occurs in 9.9% to 21.0% of cases.7-10 In addition, several investigators have cited perineural scarring as a major cause of recurrent symptoms after primary surgery.11-14 Filippi and colleagues11 noted that patients who required reoperation after primary anterior transposition had “serious epineural fibrosis and fibrosis around the transposed ulnar nerve.” At our institution, we have similarly found that scarring of the fascial sling around the ulnar nerve led to recurrence of CuTS within 4 months after initial surgery (Figure 1).
We therefore prefer to use a vascularized adipose flap to secure the anteriorly transposed ulnar nerve. This flap provides a pliable, vascularized adipose environment for the nerve, which helps reduce nerve adherence and may enhance nerve recovery.15 In the study reported here, we retrospectively reviewed the long-term outcomes of ulnar nerve anterior subcutaneous transposition secured with either an adipose flap or a fascial sling. We hypothesized that patients in the 2 groups (adipose flap, fascial sling) would have equivalent outcomes.
Materials and Methods
After obtaining institutional review board approval, we reviewed the medical and surgical records of 104 patients (107 limbs) who underwent transposition of the ulnar nerve secured with either an adipose flap (27 limbs) or a fascial sling (80 limbs) over a 14-year period. The fascial sling cohort was used as a comparison group, matched to the adipose flap cohort by sex, age at time of surgery, hand dominance, symptom duration, and length of follow-up (Table 1). Patients were indicated for surgery and were included in the study if they had a history and physical examination consistent with primary CuTS, symptom duration longer than 1 year, and failed conservative management, including activity modification, night splinting, elbow pads, occupational therapy, and home exercise regimen. Electrodiagnostic testing was used at the discretion of the attending surgeon when the diagnosis was not clear from the history and physical examination. All fascial sling procedures were performed at our institution by 1 of 3 fellowship-trained hand surgeons, including Dr. Rosenwasser. The adipose flap modification was performed only by Dr. Rosenwasser. Of the 27 patients in the adipose flap group, 23 underwent surgery for primary CuTS and were included in the study; the other 4 (revision cases) were excluded; 1 patient subsequently died of a cause unrelated to the surgical procedure, and 6 were lost to follow-up. Of the 80 patients in the fascial sling group, 30 underwent surgery for primary CuTS; 5 died before follow-up, and 8 declined to participate.
Thirty-three patients (16 adipose flap, 17 fascial sling) met the inclusion criteria. Of the 16 adipose flap patients, 15 underwent the physical examination and completed the questionnaire, and 1 was interviewed by telephone. Similarly, of the 17 fascial sling patients, 15 underwent the physical examination and completed the questionnaire, and 2 were interviewed by telephone. There were no bilateral cases. Conservative management (activity modification, night splinting, elbow pads, occupational therapy, home exercise) failed in all cases.
A trained study team member who was not part of the surgical team performed follow-up evaluations using objective outcome measures and subjective questionnaires. Patients were assessed at a mean follow-up of 5.6 years (range, 1.6-15.9 years). Patients completed the DASH (Disabilities of the Arm, Shoulder, and Hand) questionnaire16 and visual analog scales (VASs) for pain, numbness, tingling, and weakness in the ulnar nerve distribution. They also rated the presence of night symptoms that were interfering with sleep. The Modified Bishop Rating Scale (MBRS) was used to quantify patient self-reported data17,18 (Figure 2). The MBRS measures overall satisfaction, symptom improvement, presence of residual symptoms, ability to engage in activities, work capability, and subjective changes in strength and sensibility.
In the physical examinations, we tested for Tinel, Wartenberg, and Froment signs; performed an elbow flexion test; and measured elbow range of motion for flexion and extension as well as forearm pronation and supination. We also evaluated lateral pinch strength and grip strength, using a Jamar hydraulic pinch gauge and a Jamar dynamometer (Therapeutic Equipment Corp) and taking the average of 3 assessments. Fifth-digit abduction strength was graded on a standard muscle strength scale. Two-point discrimination was measured at the middle, ring, and small digits of the operated and contralateral hands.19
Surgical Technique
Standard ulnar nerve decompression with anterior subcutaneous transposition and the following modifications were performed on all patients.20 A posteromedial incision parallel to the intermuscular septum was developed and the ulnar nerve identified. Minimizing stripping of the vascular mesentery, the dissection continued along the course of the nerve, and the medial intermuscular septum was excised to prevent secondary compression after transposition. The ulnar nerve was mobilized and transposed anterior to the medial epicondyle (Figure 3). For patients who received the fascial sling, a fascial sleeve was elevated from the flexor-pronator mass and sutured to the edge of the retinaculum securing the nerve. For patients who received the adipose flap, the flap with its vascular pedicle intact was elevated from the subcutaneous tissue of the anterior skin overlying the transposed nerve. The adipose tissue was sharply dissected in half while sufficient subcutaneous tissue was kept between the skin and the flap. A plane was developed based on an anterior adipose pedicle, which included a cutaneous artery and a vein that would supply the vascularized adipose flap. The flap was elevated and wrapped around the nerve without tension while the ulnar nerve was protected from being kinked by the construct. The flap was sutured to the anterior subcutaneous tissue to create a tunnel of adipose tissue surrounding the nerve along its length (Figure 4). The elbow was then flexed and extended to ensure free nerve gliding before wound closure.
The patient was allowed to move the elbow within the bulky dressings immediately after surgery. After 2 weeks, sutures were removed. Formal occupational therapy is not needed for these patients, except in the presence of significant weakness.
Results
As mentioned, the 2 groups were matched on demographics: age at time of surgery, sex, symptom duration, and length of follow-up (Table 1).
For the 16 adipose flap patients (Table 2), mean DASH score was 19.9 (range, 0-71.7). Seven of these patients reported upper extremity pain with a mean VAS score of 1.7 (range, 0-8); 4 patients reported pain in the wrist and fourth and fifth digits; only 1 patient reported pain that occasionally woke the patient from sleep. Constant numbness was present in 6 patients. Four patients reported constant mild tingling in the hand, and 11 reported intermittent tingling. Eleven patients (68.7%) reported operated-arm weakness with a mean VAS score of 3.4 (range, 0-8). In patients who had a physical examination, mean elbow flexion–extension arc of motion was 134° (range, 95°-150°), representing 99% of the motion of the contralateral arm. Mean pronation–supination arc was 174° (range, 150°-180°), accounting for 104% of the contralateral arm. Mean lateral pinch strength was 73% of the contralateral arm, and mean grip strength was 114% of the contralateral arm. The Tinel sign was present in 2 patients, the Froment sign was present in 3 patients, and the elbow flexion test was positive in 2 patients. No patient had a positive Wartenberg sign. On the MBRS, 10 patients had an excellent score, and 6 had a good score.
For the 17 fascial sling patients (Table 2), mean DASH score was 22.7 (range, 0-63.3). Three patients reported upper extremity pain with a mean VAS score of 1.4 (range, 0-7); 3 patients reported pain that occasionally woke them from sleep. Seven patients had constant numbness in the distribution of the ulnar nerve. Two patients had constant paresthesias, and 7 had intermittent paresthesias. Nine patients (52.9%) reported arm weakness with a mean VAS score of 2.5 (range, 0-8). Mean elbow flexion–extension arc of motion was 136° (range, 100°-150°), representing 100% of the contralateral arm. Mean pronation–supination arc was 187° (range, 155°-225°), accounting for 102% of the contralateral arm. Mean lateral pinch strength was 93% of the contralateral arm, and mean grip strength was 80% of the contralateral arm. The Tinel sign was present in 6 patients, the Froment sign in 3 patients, and the Wartenberg sign in 2 patients. The elbow flexion test was positive in 4 patients. On the MBRS, 10 patients had an excellent score, and 7 had a good score.
There was no recurrence of CuTS in either group. One adipose flap patient developed a wound infection that required reoperation.
Discussion
Ulnar neuropathy was described by Magee and Phalen21 in 1949 and termed cubital tunnel syndrome by Feindel and Stratford22 in 1958. Since then, numerous procedures, including in situ decompression, medial epicondylectomy, and endoscopic decompression,23,24 have been advocated for the treatment of this condition. In addition, anterior transposition, which involves securing the ulnar nerve in a submuscular, intramuscular, or subcutaneous sleeve,6 remains a popular option. Despite more than half a century of surgical treatment for this condition, there is no consensus about which procedure offers the best outcomes. Bartels and colleagues8 retrospectively reviewed surgical treatments for CuTS, examining 3148 arms over a 27-year period. They found simple decompression and anterior intramuscular transposition had the best results, followed by medial epicondylectomy and anterior subcutaneous transposition, with anterior submuscular transposition yielding the poorest outcomes. Despite these findings, the operative groups’ recurrence rates remained significant. These results were challenged in a 2008 meta-analysis5 that found no significant difference among simple decompression, subcutaneous transposition, and submuscular transposition and instead demonstrated trends toward better outcomes with anterior transposition. Osterman and Davis7 reported a 5% to 15% rate of unsatisfactory outcomes with anterior subcutaneous transposition, a popular technique used by surgeons at our institution.
The causes for failure or recurrence of ulnar neuropathy after surgical intervention are multifactorial and include preexisting medical conditions and improper operative technique. It is well established that failure to excise all 5 anatomical points of entrapment, or creation of new points of tension during surgery, leads to poor outcomes.12 Nevertheless, the contribution of perineural scarring to postoperative recurrent ulnar neuropathy is currently being recognized: Gabel and Amadio13 described postoperative fibrosis in one-third of their patients with surgically treated recurrent CuTS, Rogers and colleagues14 noted dense perineural fibrosis after intramuscular and subcutaneous transposition procedures, Filippi and colleagues11 cited serious epineural fibrosis and fibrosis around the ulnar nerve as the main findings in their study of 22 patients with recurrent ulnar neuropathy, and Vogel and colleagues12 found that 88% of their patients with persistent CuTS after surgery exhibited perineural scarring.
We think that use of a scar tissue barrier during ulnar nerve transposition reduces the incidence of cicatrix and produces better outcomes—a position largely echoed by the orthopedic community, as fascial, fasciocutaneous, free, and venous flaps have all been used for such purposes.25,26 Vein wrapping has demonstrated good recovery of a nerve after perineural scarring.27 Advocates of intramuscular transposition argue that their technique provides the nerve with a vascularized tunnel, as segmental vascular stripping is an inevitability in transposition. However, this technique increases the incidence of scarring and potential muscle damage.28,29 We think the pedicled adipofascial flap benefits the peripheral nerve by providing a scar tissue barrier and an optimal milieu for vascular regeneration. Kilic and colleagues15 demonstrated the regenerative effects of adipose tissue flaps on peripheral nerves after crush injuries in a rat model, and Strickland and colleagues30 retrospectively examined the effects of hypothenar fat flaps on recalcitrant carpal tunnel syndrome, showing excellent results for this procedure. It is hypothesized that adipose tissue provides not only adipose-derived stem cells but also a rich vascular bed on which nerves will regenerate.
For all patients in the present study, symptoms improved, though the adipose flap and fascial sling groups were not significantly different in their outcomes. We used the MBRS to quantify and compare the groups’ patient-rated outcomes. No statistically significant difference was found between the adipose flap and fascial sling groups. On the MBRS, excellent and good outcomes were reported by 62.5% and 37.5% of the adipose flap patients, respectively, and 59% and 41% of the fascial sling patients (Table 3). Likewise, objective measurements did not show a significant difference between the 2 interventions—indicating that, compared with the current standard of care, adipose flaps are more efficacious in securing the anteriorly transposed nerve.
Complications of the adipose flap technique are consistent with those reported for other techniques for anterior transposition of the ulnar nerve. The most common complication is hematoma, which can be avoided with meticulous hemostasis. Damage of the medial antebrachial cutaneous nerve or motor branches to the flexor carpi ulnaris has been reported for the fascial technique (we have not had such outcomes at our institution). Contraindications to the adipofascial technique include insufficient subcutaneous adipose tissue for covering the ulnar nerve.
This study was limited by its retrospective setup, which reduced access to preoperative objective and subjective data. The small sample size also limited our ability to demonstrate the advantageous effects of an adipofascial flap in preventing postoperative perineural scarring.
The adipose flap technique is a viable option for securing the anteriorly transposed ulnar nerve. Outcomes in this study demonstrated an efficacy comparable to that of the fascial sling technique. Symptoms resolve or improve, and the majority of patients are satisfied with long-term surgical outcomes. The adipofascial flap may have additional advantages, as it provides a pliable, vascular fat envelope mimicking the natural fatty environment of peripheral nerves.
Compression of the ulnar nerve at the elbow, also referred to as cubital tunnel syndrome (CuTS), is the second most common peripheral nerve compression syndrome in the upper extremity.1,2 Although the ulnar nerve can be compressed at 5 different sites, including arcade of Struthers, medial intermuscular septum, medial epicondyle, and deep flexor aponeurosis, the cubital tunnel is most commonly affected.3 Patients typically present with paresthesias in the fourth and fifth digits and weakness of hand muscle intrinsics. Activity-related pain or pain at the medial elbow can also occur in more advanced pathology.4 It is estimated that conservative therapy fails and surgical intervention is required in up to 30% of patients with CuTS.1 Surgical approaches range from in situ decompression to transposition techniques, but there is no consensus in the orthopedic community as to which technique offers the best results. In a 2008 meta-analysis, Macadam and colleagues5 found no statistical differences in outcomes among the various surgical approaches. Nevertheless, subcutaneous transposition of the ulnar nerve at the elbow is a popular option.6
Despite the widespread success of surgical intervention for CuTS, persistent or recurrent pain occurs in 9.9% to 21.0% of cases.7-10 In addition, several investigators have cited perineural scarring as a major cause of recurrent symptoms after primary surgery.11-14 Filippi and colleagues11 noted that patients who required reoperation after primary anterior transposition had “serious epineural fibrosis and fibrosis around the transposed ulnar nerve.” At our institution, we have similarly found that scarring of the fascial sling around the ulnar nerve led to recurrence of CuTS within 4 months after initial surgery (Figure 1).
We therefore prefer to use a vascularized adipose flap to secure the anteriorly transposed ulnar nerve. This flap provides a pliable, vascularized adipose environment for the nerve, which helps reduce nerve adherence and may enhance nerve recovery.15 In the study reported here, we retrospectively reviewed the long-term outcomes of ulnar nerve anterior subcutaneous transposition secured with either an adipose flap or a fascial sling. We hypothesized that patients in the 2 groups (adipose flap, fascial sling) would have equivalent outcomes.
Materials and Methods
After obtaining institutional review board approval, we reviewed the medical and surgical records of 104 patients (107 limbs) who underwent transposition of the ulnar nerve secured with either an adipose flap (27 limbs) or a fascial sling (80 limbs) over a 14-year period. The fascial sling cohort was used as a comparison group, matched to the adipose flap cohort by sex, age at time of surgery, hand dominance, symptom duration, and length of follow-up (Table 1). Patients were indicated for surgery and were included in the study if they had a history and physical examination consistent with primary CuTS, symptom duration longer than 1 year, and failed conservative management, including activity modification, night splinting, elbow pads, occupational therapy, and home exercise regimen. Electrodiagnostic testing was used at the discretion of the attending surgeon when the diagnosis was not clear from the history and physical examination. All fascial sling procedures were performed at our institution by 1 of 3 fellowship-trained hand surgeons, including Dr. Rosenwasser. The adipose flap modification was performed only by Dr. Rosenwasser. Of the 27 patients in the adipose flap group, 23 underwent surgery for primary CuTS and were included in the study; the other 4 (revision cases) were excluded; 1 patient subsequently died of a cause unrelated to the surgical procedure, and 6 were lost to follow-up. Of the 80 patients in the fascial sling group, 30 underwent surgery for primary CuTS; 5 died before follow-up, and 8 declined to participate.
Thirty-three patients (16 adipose flap, 17 fascial sling) met the inclusion criteria. Of the 16 adipose flap patients, 15 underwent the physical examination and completed the questionnaire, and 1 was interviewed by telephone. Similarly, of the 17 fascial sling patients, 15 underwent the physical examination and completed the questionnaire, and 2 were interviewed by telephone. There were no bilateral cases. Conservative management (activity modification, night splinting, elbow pads, occupational therapy, home exercise) failed in all cases.
A trained study team member who was not part of the surgical team performed follow-up evaluations using objective outcome measures and subjective questionnaires. Patients were assessed at a mean follow-up of 5.6 years (range, 1.6-15.9 years). Patients completed the DASH (Disabilities of the Arm, Shoulder, and Hand) questionnaire16 and visual analog scales (VASs) for pain, numbness, tingling, and weakness in the ulnar nerve distribution. They also rated the presence of night symptoms that were interfering with sleep. The Modified Bishop Rating Scale (MBRS) was used to quantify patient self-reported data17,18 (Figure 2). The MBRS measures overall satisfaction, symptom improvement, presence of residual symptoms, ability to engage in activities, work capability, and subjective changes in strength and sensibility.
In the physical examinations, we tested for Tinel, Wartenberg, and Froment signs; performed an elbow flexion test; and measured elbow range of motion for flexion and extension as well as forearm pronation and supination. We also evaluated lateral pinch strength and grip strength, using a Jamar hydraulic pinch gauge and a Jamar dynamometer (Therapeutic Equipment Corp) and taking the average of 3 assessments. Fifth-digit abduction strength was graded on a standard muscle strength scale. Two-point discrimination was measured at the middle, ring, and small digits of the operated and contralateral hands.19
Surgical Technique
Standard ulnar nerve decompression with anterior subcutaneous transposition and the following modifications were performed on all patients.20 A posteromedial incision parallel to the intermuscular septum was developed and the ulnar nerve identified. Minimizing stripping of the vascular mesentery, the dissection continued along the course of the nerve, and the medial intermuscular septum was excised to prevent secondary compression after transposition. The ulnar nerve was mobilized and transposed anterior to the medial epicondyle (Figure 3). For patients who received the fascial sling, a fascial sleeve was elevated from the flexor-pronator mass and sutured to the edge of the retinaculum securing the nerve. For patients who received the adipose flap, the flap with its vascular pedicle intact was elevated from the subcutaneous tissue of the anterior skin overlying the transposed nerve. The adipose tissue was sharply dissected in half while sufficient subcutaneous tissue was kept between the skin and the flap. A plane was developed based on an anterior adipose pedicle, which included a cutaneous artery and a vein that would supply the vascularized adipose flap. The flap was elevated and wrapped around the nerve without tension while the ulnar nerve was protected from being kinked by the construct. The flap was sutured to the anterior subcutaneous tissue to create a tunnel of adipose tissue surrounding the nerve along its length (Figure 4). The elbow was then flexed and extended to ensure free nerve gliding before wound closure.
The patient was allowed to move the elbow within the bulky dressings immediately after surgery. After 2 weeks, sutures were removed. Formal occupational therapy is not needed for these patients, except in the presence of significant weakness.
Results
As mentioned, the 2 groups were matched on demographics: age at time of surgery, sex, symptom duration, and length of follow-up (Table 1).
For the 16 adipose flap patients (Table 2), mean DASH score was 19.9 (range, 0-71.7). Seven of these patients reported upper extremity pain with a mean VAS score of 1.7 (range, 0-8); 4 patients reported pain in the wrist and fourth and fifth digits; only 1 patient reported pain that occasionally woke the patient from sleep. Constant numbness was present in 6 patients. Four patients reported constant mild tingling in the hand, and 11 reported intermittent tingling. Eleven patients (68.7%) reported operated-arm weakness with a mean VAS score of 3.4 (range, 0-8). In patients who had a physical examination, mean elbow flexion–extension arc of motion was 134° (range, 95°-150°), representing 99% of the motion of the contralateral arm. Mean pronation–supination arc was 174° (range, 150°-180°), accounting for 104% of the contralateral arm. Mean lateral pinch strength was 73% of the contralateral arm, and mean grip strength was 114% of the contralateral arm. The Tinel sign was present in 2 patients, the Froment sign was present in 3 patients, and the elbow flexion test was positive in 2 patients. No patient had a positive Wartenberg sign. On the MBRS, 10 patients had an excellent score, and 6 had a good score.
For the 17 fascial sling patients (Table 2), mean DASH score was 22.7 (range, 0-63.3). Three patients reported upper extremity pain with a mean VAS score of 1.4 (range, 0-7); 3 patients reported pain that occasionally woke them from sleep. Seven patients had constant numbness in the distribution of the ulnar nerve. Two patients had constant paresthesias, and 7 had intermittent paresthesias. Nine patients (52.9%) reported arm weakness with a mean VAS score of 2.5 (range, 0-8). Mean elbow flexion–extension arc of motion was 136° (range, 100°-150°), representing 100% of the contralateral arm. Mean pronation–supination arc was 187° (range, 155°-225°), accounting for 102% of the contralateral arm. Mean lateral pinch strength was 93% of the contralateral arm, and mean grip strength was 80% of the contralateral arm. The Tinel sign was present in 6 patients, the Froment sign in 3 patients, and the Wartenberg sign in 2 patients. The elbow flexion test was positive in 4 patients. On the MBRS, 10 patients had an excellent score, and 7 had a good score.
There was no recurrence of CuTS in either group. One adipose flap patient developed a wound infection that required reoperation.
Discussion
Ulnar neuropathy was described by Magee and Phalen21 in 1949 and termed cubital tunnel syndrome by Feindel and Stratford22 in 1958. Since then, numerous procedures, including in situ decompression, medial epicondylectomy, and endoscopic decompression,23,24 have been advocated for the treatment of this condition. In addition, anterior transposition, which involves securing the ulnar nerve in a submuscular, intramuscular, or subcutaneous sleeve,6 remains a popular option. Despite more than half a century of surgical treatment for this condition, there is no consensus about which procedure offers the best outcomes. Bartels and colleagues8 retrospectively reviewed surgical treatments for CuTS, examining 3148 arms over a 27-year period. They found simple decompression and anterior intramuscular transposition had the best results, followed by medial epicondylectomy and anterior subcutaneous transposition, with anterior submuscular transposition yielding the poorest outcomes. Despite these findings, the operative groups’ recurrence rates remained significant. These results were challenged in a 2008 meta-analysis5 that found no significant difference among simple decompression, subcutaneous transposition, and submuscular transposition and instead demonstrated trends toward better outcomes with anterior transposition. Osterman and Davis7 reported a 5% to 15% rate of unsatisfactory outcomes with anterior subcutaneous transposition, a popular technique used by surgeons at our institution.
The causes for failure or recurrence of ulnar neuropathy after surgical intervention are multifactorial and include preexisting medical conditions and improper operative technique. It is well established that failure to excise all 5 anatomical points of entrapment, or creation of new points of tension during surgery, leads to poor outcomes.12 Nevertheless, the contribution of perineural scarring to postoperative recurrent ulnar neuropathy is currently being recognized: Gabel and Amadio13 described postoperative fibrosis in one-third of their patients with surgically treated recurrent CuTS, Rogers and colleagues14 noted dense perineural fibrosis after intramuscular and subcutaneous transposition procedures, Filippi and colleagues11 cited serious epineural fibrosis and fibrosis around the ulnar nerve as the main findings in their study of 22 patients with recurrent ulnar neuropathy, and Vogel and colleagues12 found that 88% of their patients with persistent CuTS after surgery exhibited perineural scarring.
We think that use of a scar tissue barrier during ulnar nerve transposition reduces the incidence of cicatrix and produces better outcomes—a position largely echoed by the orthopedic community, as fascial, fasciocutaneous, free, and venous flaps have all been used for such purposes.25,26 Vein wrapping has demonstrated good recovery of a nerve after perineural scarring.27 Advocates of intramuscular transposition argue that their technique provides the nerve with a vascularized tunnel, as segmental vascular stripping is an inevitability in transposition. However, this technique increases the incidence of scarring and potential muscle damage.28,29 We think the pedicled adipofascial flap benefits the peripheral nerve by providing a scar tissue barrier and an optimal milieu for vascular regeneration. Kilic and colleagues15 demonstrated the regenerative effects of adipose tissue flaps on peripheral nerves after crush injuries in a rat model, and Strickland and colleagues30 retrospectively examined the effects of hypothenar fat flaps on recalcitrant carpal tunnel syndrome, showing excellent results for this procedure. It is hypothesized that adipose tissue provides not only adipose-derived stem cells but also a rich vascular bed on which nerves will regenerate.
For all patients in the present study, symptoms improved, though the adipose flap and fascial sling groups were not significantly different in their outcomes. We used the MBRS to quantify and compare the groups’ patient-rated outcomes. No statistically significant difference was found between the adipose flap and fascial sling groups. On the MBRS, excellent and good outcomes were reported by 62.5% and 37.5% of the adipose flap patients, respectively, and 59% and 41% of the fascial sling patients (Table 3). Likewise, objective measurements did not show a significant difference between the 2 interventions—indicating that, compared with the current standard of care, adipose flaps are more efficacious in securing the anteriorly transposed nerve.
Complications of the adipose flap technique are consistent with those reported for other techniques for anterior transposition of the ulnar nerve. The most common complication is hematoma, which can be avoided with meticulous hemostasis. Damage of the medial antebrachial cutaneous nerve or motor branches to the flexor carpi ulnaris has been reported for the fascial technique (we have not had such outcomes at our institution). Contraindications to the adipofascial technique include insufficient subcutaneous adipose tissue for covering the ulnar nerve.
This study was limited by its retrospective setup, which reduced access to preoperative objective and subjective data. The small sample size also limited our ability to demonstrate the advantageous effects of an adipofascial flap in preventing postoperative perineural scarring.
The adipose flap technique is a viable option for securing the anteriorly transposed ulnar nerve. Outcomes in this study demonstrated an efficacy comparable to that of the fascial sling technique. Symptoms resolve or improve, and the majority of patients are satisfied with long-term surgical outcomes. The adipofascial flap may have additional advantages, as it provides a pliable, vascular fat envelope mimicking the natural fatty environment of peripheral nerves.
1. Latinovic R, Gulliford MC, Hughes RA. Incidence of common compressive neuropathies in primary care. J Neurol Neurosurg Psychiatry. 2006;77(2):263-265.
2. Robertson C, Saratsiotis J. A review of compression ulnar neuropathy at the elbow. J Manipulative Physiol Ther. 2005;28(5):345.
3. Posner MA. Compressive ulnar neuropathies at the elbow: I. Etiology and diagnosis. J Am Acad Orthop Surg. 1998;6(5):282-288.
4. Piligian G, Herbert R, Hearns M, Dropkin J, Landsbergis P, Cherniack M. Evaluation and management of chronic work-related musculoskeletal disorders of the distal upper extremity. Am J Ind Med. 2000;37(1):75-93.
5. Macadam SA, Gandhi R, Bezuhly M, Lefaivre KA. Simple decompression versus anterior subcutaneous and submuscular transposition of the ulnar nerve for cubital tunnel syndrome: a meta-analysis. J Hand Surg Am. 2008;33(8):1314.e1-e12.
6. Soltani AM, Best MJ, Francis CS, Allan BJ, Panthaki ZJ. Trends in the surgical treatment of cubital tunnel syndrome: an analysis of the National Survey of Ambulatory Surgery database. J Hand Surg Am. 2013;38(8):1551-1556.
7. Osterman AL, Davis CA. Subcutaneous transposition of the ulnar nerve for treatment of cubital tunnel syndrome. Hand Clin. 1996;12(2):421-433.
8. Bartels RH, Menovsky T, Van Overbeeke JJ, Verhagen WI. Surgical management of ulnar nerve compression at the elbow: an analysis of the literature. J Neurosurg. 1998;89(5):722-727.
9. Seradge H, Owen W. Cubital tunnel release with medial epicondylectomy factors influencing the outcome. J Hand Surg Am. 1998;23(3):483-491.
10. Schnabl SM, Kisslinger F, Schramm A, et al. Subjective outcome, neurophysiological investigations, postoperative complications and recurrence rate of partial medial epicondylectomy in cubital tunnel syndrome. Arch Orthop Trauma Surg. 2011;131(8):1027-1033.
11. Filippi R, Charalampaki P, Reisch R, Koch D, Grunert P. Recurrent cubital tunnel syndrome. Etiology and treatment. Minim Invasive Neurosurg. 2001;44(4):197-201.
12. Vogel RB, Nossaman BC, Rayan GM. Revision anterior submuscular transposition of the ulnar nerve for failed subcutaneous transposition. Br J Plast Surg. 2004;57(4):311-316.
13. Gabel GT, Amadio PC. Reoperation for failed decompression of the ulnar nerve in the region of the elbow. J Bone Joint Surg Am. 1990;72(2):213-219.
14. Rogers MR, Bergfield TG, Aulicino PL. The failed ulnar nerve transposition. Etiology and treatment. Clin Orthop. 1991;269:193-200.
15. Kilic A, Ojo B, Rajfer RA, et al. Effect of white adipose tissue flap and insulin-like growth factor-1 on nerve regeneration in rats. Microsurgery. 2013;33(5):367-375.
16. Ebersole GC, Davidge K, Damiano M, Mackinnon SE. Validity and responsiveness of the DASH questionnaire as an outcome measure following ulnar nerve transposition for cubital tunnel syndrome. Plast Reconstr Surg. 2013;132(1):81e-90e.
17. Kleinman WB, Bishop AT. Anterior intramuscular transposition of the ulnar nerve. J Hand Surg Am. 1989;14(6):972-979.
18. Dützmann S, Martin KD, Sobottka S, et al. Open vs retractor-endoscopic in situ decompression of the ulnar nerve in cubital tunnel syndrome: a retrospective cohort study. Neurosurgery. 2013;72(4):605-616.
19. Dellon AL, Mackinnon SE, Crosby PM. Reliability of two-point discrimination measurements. J Hand Surg Am. 1987;12(5 pt 1):693-696.
20. Danoff JR, Lombardi JM, Rosenwasser MP. Use of a pedicled adipose flap as a sling for anterior subcutaneous transposition of the ulnar nerve. J Hand Surg Am. 2014;39(3):552-555.
21. Magee RB, Phalen GS. Tardy ulnar palsy. Am J Surg. 1949;78(4):470-474.
22. Feindel W, Stratford J. Cubital tunnel compression in tardy ulnar palsy. Can Med Assoc J. 1958;78(5):351-353.
23. Tsai TM, Bonczar M, Tsuruta T, Syed SA. A new operative technique: cubital tunnel decompression with endoscopic assistance. Hand Clin. 1995;11(1):71-80.
24. Hoffmann R, Siemionow M. The endoscopic management of cubital tunnel syndrome. J Hand Surg Br. 2006;31(1):23-29.
25. Luchetti R, Riccio M, Papini Zorli I, Fairplay T. Protective coverage of the median nerve using fascial, fasciocutaneous or island flaps. Handchir Mikrochir Plast Chir. 2006;38(5):317-330.
26. Kokkalis ZT, Jain S, Sotereanos DG. Vein wrapping at cubital tunnel for ulnar nerve problems. J Shoulder Elbow Surg. 2010;19(2):91-97.
27. Masear VR, Colgin S. The treatment of epineural scarring with allograft vein wrapping. Hand Clin. 1996;12(4):773-779.
28. Kleinman WB, Bishop AT. Anterior intramuscular transposition of the ulnar nerve. J Hand Surg Am. 1989;14(6):972-979.
29. Lundborg G. Surgical treatment for ulnar nerve entrapment at the elbow. J Hand Surg Br. 1992;17(3):245-247.
30. Strickland JW, Idler RS, Lourie GM, Plancher KD. The hypothenar fat pad flap for management of recalcitrant carpal tunnel syndrome. J Hand Surg Am. 1996;21(5):840-848.
1. Latinovic R, Gulliford MC, Hughes RA. Incidence of common compressive neuropathies in primary care. J Neurol Neurosurg Psychiatry. 2006;77(2):263-265.
2. Robertson C, Saratsiotis J. A review of compression ulnar neuropathy at the elbow. J Manipulative Physiol Ther. 2005;28(5):345.
3. Posner MA. Compressive ulnar neuropathies at the elbow: I. Etiology and diagnosis. J Am Acad Orthop Surg. 1998;6(5):282-288.
4. Piligian G, Herbert R, Hearns M, Dropkin J, Landsbergis P, Cherniack M. Evaluation and management of chronic work-related musculoskeletal disorders of the distal upper extremity. Am J Ind Med. 2000;37(1):75-93.
5. Macadam SA, Gandhi R, Bezuhly M, Lefaivre KA. Simple decompression versus anterior subcutaneous and submuscular transposition of the ulnar nerve for cubital tunnel syndrome: a meta-analysis. J Hand Surg Am. 2008;33(8):1314.e1-e12.
6. Soltani AM, Best MJ, Francis CS, Allan BJ, Panthaki ZJ. Trends in the surgical treatment of cubital tunnel syndrome: an analysis of the National Survey of Ambulatory Surgery database. J Hand Surg Am. 2013;38(8):1551-1556.
7. Osterman AL, Davis CA. Subcutaneous transposition of the ulnar nerve for treatment of cubital tunnel syndrome. Hand Clin. 1996;12(2):421-433.
8. Bartels RH, Menovsky T, Van Overbeeke JJ, Verhagen WI. Surgical management of ulnar nerve compression at the elbow: an analysis of the literature. J Neurosurg. 1998;89(5):722-727.
9. Seradge H, Owen W. Cubital tunnel release with medial epicondylectomy factors influencing the outcome. J Hand Surg Am. 1998;23(3):483-491.
10. Schnabl SM, Kisslinger F, Schramm A, et al. Subjective outcome, neurophysiological investigations, postoperative complications and recurrence rate of partial medial epicondylectomy in cubital tunnel syndrome. Arch Orthop Trauma Surg. 2011;131(8):1027-1033.
11. Filippi R, Charalampaki P, Reisch R, Koch D, Grunert P. Recurrent cubital tunnel syndrome. Etiology and treatment. Minim Invasive Neurosurg. 2001;44(4):197-201.
12. Vogel RB, Nossaman BC, Rayan GM. Revision anterior submuscular transposition of the ulnar nerve for failed subcutaneous transposition. Br J Plast Surg. 2004;57(4):311-316.
13. Gabel GT, Amadio PC. Reoperation for failed decompression of the ulnar nerve in the region of the elbow. J Bone Joint Surg Am. 1990;72(2):213-219.
14. Rogers MR, Bergfield TG, Aulicino PL. The failed ulnar nerve transposition. Etiology and treatment. Clin Orthop. 1991;269:193-200.
15. Kilic A, Ojo B, Rajfer RA, et al. Effect of white adipose tissue flap and insulin-like growth factor-1 on nerve regeneration in rats. Microsurgery. 2013;33(5):367-375.
16. Ebersole GC, Davidge K, Damiano M, Mackinnon SE. Validity and responsiveness of the DASH questionnaire as an outcome measure following ulnar nerve transposition for cubital tunnel syndrome. Plast Reconstr Surg. 2013;132(1):81e-90e.
17. Kleinman WB, Bishop AT. Anterior intramuscular transposition of the ulnar nerve. J Hand Surg Am. 1989;14(6):972-979.
18. Dützmann S, Martin KD, Sobottka S, et al. Open vs retractor-endoscopic in situ decompression of the ulnar nerve in cubital tunnel syndrome: a retrospective cohort study. Neurosurgery. 2013;72(4):605-616.
19. Dellon AL, Mackinnon SE, Crosby PM. Reliability of two-point discrimination measurements. J Hand Surg Am. 1987;12(5 pt 1):693-696.
20. Danoff JR, Lombardi JM, Rosenwasser MP. Use of a pedicled adipose flap as a sling for anterior subcutaneous transposition of the ulnar nerve. J Hand Surg Am. 2014;39(3):552-555.
21. Magee RB, Phalen GS. Tardy ulnar palsy. Am J Surg. 1949;78(4):470-474.
22. Feindel W, Stratford J. Cubital tunnel compression in tardy ulnar palsy. Can Med Assoc J. 1958;78(5):351-353.
23. Tsai TM, Bonczar M, Tsuruta T, Syed SA. A new operative technique: cubital tunnel decompression with endoscopic assistance. Hand Clin. 1995;11(1):71-80.
24. Hoffmann R, Siemionow M. The endoscopic management of cubital tunnel syndrome. J Hand Surg Br. 2006;31(1):23-29.
25. Luchetti R, Riccio M, Papini Zorli I, Fairplay T. Protective coverage of the median nerve using fascial, fasciocutaneous or island flaps. Handchir Mikrochir Plast Chir. 2006;38(5):317-330.
26. Kokkalis ZT, Jain S, Sotereanos DG. Vein wrapping at cubital tunnel for ulnar nerve problems. J Shoulder Elbow Surg. 2010;19(2):91-97.
27. Masear VR, Colgin S. The treatment of epineural scarring with allograft vein wrapping. Hand Clin. 1996;12(4):773-779.
28. Kleinman WB, Bishop AT. Anterior intramuscular transposition of the ulnar nerve. J Hand Surg Am. 1989;14(6):972-979.
29. Lundborg G. Surgical treatment for ulnar nerve entrapment at the elbow. J Hand Surg Br. 1992;17(3):245-247.
30. Strickland JW, Idler RS, Lourie GM, Plancher KD. The hypothenar fat pad flap for management of recalcitrant carpal tunnel syndrome. J Hand Surg Am. 1996;21(5):840-848.
Obesity Management: Clinical Review and Update of the Pharmacologic Treatment Options
Over the past decade the prevalence of obesity as defined by a body mass index (BMI) ≥ 30 kg/m2 has significantly increased. In the U.S. more than 78 million adults are estimated to be obese.1 The World Health Organization projects that by 2025 up to half the U.S. population will be obese. Cardiovascular disease (CVD) and diabetes mellitus (DM) are the main comorbid conditions that are complicated by obesity. Initial weight loss of 5% to 10% of total body weight reduces CVD risk factors, prevents or delays the development of type 2 DM (T2DM) and improves the health consequences of obesity.2
To date, public health initiatives that have focused on obesity prevention and lifestyle intervention have had marginal success. In recent years, anti-obesity drug therapies have had a limited role in clinical treatment algorithms. In 2013, the American Medical Association acknowledged obesity as a disease. In turn, this acknowledgement allowed the recognition of anti-obesity drugs as acceptable therapeutic adjuncts to intensive lifestyle intervention that could address the growing obesity endemic.
In the past, medications for weight reduction were limited. Several that were FDA approved had to be removed from the market due to safety concerns. With few approved options, clinicians often had to resort to off-label use of medications. However, the landscape has changed with 4 new medications gaining recent FDA approval. This review covers older available medications and the newer medications that are now available.
Sympathomimetics
Sympathomimetic drugs have been approved for use as a pharmacological method to lose weight since 1960. Of the many versions of this drug class that have been available since then, there are 4 major versions available today. These include diethylpropion3 and benzphetamine,4 both approved in 1960; phendimetrazine, approved in 1976;5 phentermine, approved in 1980;6 and phentermine hydrochloride, approved in 2012.7 Despite the existence of several other classes of drugs to treat obesity, phentermine remains the most often prescribed weight loss drug in the U.S.8
Although the mechanism of action (MOA) of sympathomimetic drugs is not particularly clear, weight loss from these medications is believed to be due to the increase in the release of biogenic amines (mainly norepinephrine, but also possibly dopamine), from storage sites in nerve terminals. It is possible that these drugs slow catecholamine metabolism by inhibiting the actions of monoamine oxidase. The resulting increase in amine availability, particularly in the lateral hypothalamic feeding center, is associated with reduced food intake. Interestingly, injection of these drugs into the ventromedial satiety center dooes not seem to suppress food intake, and the effects of biogenic amines on increasing metabolism does not seem to play a significant role in weight loss in patients on these medications.9
Each of these drugs is rapidly absorbed from the gastrointestinal (GI) tract except for phentermine hydrochloride, the newest of the medications in this class. Phentermine hydrochloride is a sublingual tablet that is readily absorbed through the buccal mucosa.5 All of the drugs in this class are excreted through the kidneys, with varying rates. Each drug’s excretion is highly dependent on the pH of the urine—more alkaline conditions result in less excretion and more acidic conditions result in more excretion. As a result, these drugs should be used with caution in patients with renal impairment; however, there are no specific contraindications listed for patients with poor renal function.
The adverse effects (AEs) for this drug class are to be expected from an increase in the release of biogenic amines in the central nervous system (CNS). The most common AEs include palpitations, tremors, restlessness, insomnia, dry mouth, constipation, diaphoresis, changes in libido, and irritability. The more dangerous AEs that have been observed include arrhythmias, hypertension, dependency/abuse, convulsions, acute transient ischemic colitis, and acute urinary retention secondary to increased bladder sphincter tone, transient hyperthyroxemia, and paranoia.10
Several contraindications exist for sympathomimetics, including the presence of advanced arteriosclerosis, symptomatic CVD, moderate to severe hypertension, hyperthyroidism, glaucoma, patients in an agitated state, or those with a history of amphetamine abuse. The warnings for prescribers include pulmonary hypertension and cardiomyopathy secondary to chronic use of sympathomimetics, and valvular heart disease secondary to use of sympathomimetics with additional anorectic agents.
Additional precautions should be considered in those with a history of anxiety/psychosis, those who operate machinery and motor vehicles, and even those with mild hypertension. The data surrounding the effects of sympathomimetics on blood pressure (BP) appears to be conflicting and the relationship does not seem to have been significantly studied in depth to warrant any definitive conclusions. The MOA of this drug class itself is enough to urge caution to prescribers.11 Special attention should be given to patients with diabetes when using sympathomimetics. A reduction of insulin dose or oral hypoglycemic dose may be necessary in some people with diabetes.
Only diethylpropion is pregnancy category B, whereas the others drugs in this class are pregnancy category X. It has been demonstrated that diethylpropion and benzphetamine are secreted into breastmilk; insufficient data exist to suggest whether or not phentermine and phendimetrazine are present in breastmilk. All drugs in this class should be used in caution with breastfeeding mothers.
Although all 4 drugs are registered as controlled substances, benzphetamine and phendimetrazine are schedule III and phentermine and diethylpropion are schedule IV, despite evidence suggesting the potential for abuse to be extremely low.12,13 Phentermine has been approved for adults aged > 18 years, phendimetrazine has been approved for those aged > 17 years, diethylpropion has been approved for those aged > 16 years, and benzphetamine has been approved for those aged > 12 years.
There is a wealth of literature surrounding the effectiveness of this drug class for weight loss. One of the longest trials of phentermine was recently conducted as part of the initial component of a FDA study for the newly approved topiramate-phentermine combination. Weight loss at 6 months in the phentermine-only group was significantly higher at -5.8% compared with -1.5% with the placebo group in the last observation carried forward-Intent to treat (LOCF-ITT) analysis.14 Similarly, a long-term study looking at diethylpropion examined the use of diethylpropion for up to a year vs placebo. Participants administered diethylpropion lost a mean 9.8% of original weight vs 3.7% in the placebo group in the first 6 months alone.15
Several meta-analyses and review papers have been authored that examine and analyze the published data on this drug class overall and comparatively within this class. Haddock and colleagues in 2002 reviewed the numerous clinical trials associated with each drug in this class, in addition to several other classes, and found that although each drug demonstrated a significant advantage vs placebo in weight loss, there was not a specific drug that was significantly superior to any of the others.16
These results seem to be in relative agreement with additional studies like that published by Suplicy and colleagues, which demonstrated that several sympathomimetics were better than placebo in weight loss, and that there was little difference between the specific drugs in the class.17 However, it should be noted that as highlighted in a review by Ioannides-Demos and colleagues in 2005, the vast majority of studies that had been performed on this drug class focused on short-term use (< 16 weeks) and none of the sympathomimetics listed here have been approved for long-term use.18
Orlistat
Orlistat 120 mg was approved in 1999 as a reversible inhibitor of GI lipases that specifically reduced the absorption of dietary fat due to the inhibition of triglyceride hydrolysis.19 Orlistat was later approved in 2007 for release in a reduced dosage form (60 mg) for over-the-counter sales.20
Orlistat forms a covalent bond with the active serine residue site of gastric and pancreatic lipases in the lumen of the stomach and small intestine. The inhibition of these enzymes causes dietary fat to remain undigested as triglycerides, which cannot be converted to absorbable free fatty acids and monoglycerides, leading to decreased calorie absorption. Orlistat is not systemically absorbed and is eliminated mainly through feces. Some metabolism occurs in the GI wall.21Orlistat is most known for its GI AEs. Because it is most active in the lumen of the GI system and reduces the absorption of triglycerides, many AEs are related to malabsorption. The most common issues 1 year after starting the drug were oily spotting (26.6% vs 1.3% placebo); flatus with discharge (23.9% vs 1.4% placebo); fecal urgency (22.1% vs 6.7% placebo); fatty/oily stool (20% vs 2.9% placebo); increased defecation (10.8% vs 4.1% placebo); and fecal incontinence (7.7% vs 0.9% placebo) (Table 1). Most of these AEs were greatly reduced after taking the drug for 2 years. Orlistat also has more serious AEs noted, including abdominal pain/discomfort; nausea; infectious diarrhea; rectal pain/discomfort; tooth disorder; gingival disorder; vomiting; upper respiratory infection; lower respiratory infection; ear, nose and throat symptoms; back pain; arthritis; myalgia; joint disorders; tendonitis; headache; dizziness; fatigue; sleep disorders; rash; dry skin; menstrual irregularity; vaginitis; urinary tract infection; and psychiatric disorders, although these did not differ markedly from placebo.
One of the most serious AEs reported was fulminate hepatic failure, though this AE is rare. Thirteen cases of liver injury were reported with the 120-mg prescription dose of orlistat and 1 case report in the U.S. involved the 60-mg over-the-counter dosage of orlistat.21,22 The FDA suggests that patients talk to their physicians about risks of liver failure, and that physicians should educate their patients about signs and symptoms of liver failure so that patients can stop taking orlistat and seek immediate medical help if symptoms occur.
One of the first published trials was the European Multicentre Orlistat Study Group, which included 743 participants with BMI between 28 kg/m2 and 47 kg/m2 from 15 different European centers. To test adherence, a 4-week single blind placebo lead-in was started with a hypocaloric diet. The first stage was completed by 688 patients who then proceeded to the double blind randomized control trial portion with a hypocaloric diet. From the start of lead-in to the end of year 1, the orlistat group weight decreased 10.2% (10.3 kg) vs 6.1% (6.1 kg) in the placebo group. The placebo subtracted difference between the groups was 3.9 kg (P < .001).23
A U.S.-based randomized double-blind placebo-controlled multicenter study included 796 obese patients with BMI between 30 kg/m2 and 44 kg/m2. Patients were assigned to 1 of 3 groups: placebo, orlistat 60 mg 3 times daily, or orlistat 120 mg 3 times daily. All groups were given a reduced energy diet. Patients in the orlistat 120 mg group lost significantly more weight than did the placebo group, -8.78% vs -4.26% respectively in year 1 in the completer analysis (P = .001). More participants who were treated with orlistat 120 mg lost 5% or more of their initial weight in year 1 compared with placebo, 50.5% vs 30.7% respectively (P < .001).24
In the XENDOS study the primary outcome measurement was time to onset of T2DM. Eligible participants were aged 30 to 60 years, with a BMI > 30 kg/m2. All patients had a 75-g oral glucose tolerance test and were required to have normal glucose tolerance or impaired glucose tolerance, but not T2DM. The double-blind randomized controlled trial included 3,305 subjects and compared a group taking 120 mg orlistat 3 times daily vs placebo. All patients were prescribed a reduced-calorie diet (800 kcal/d deficit) containing 30% of calories from fat. Patients were also encouraged to walk at least 1 kilometer daily in addition to their usual physical activity. Incidence of T2DM after 4 years was 6.2% in the orlistat group and 9.0% in the placebo group, reflecting a 37.3% risk reduction in the orlistat group (P = .0032).25,26
Lorcaserin
In 2012, lorcaserin HCl was FDA approved as a schedule IV drug for use as a weight loss medication as an adjunct to a reduced-calorie diet and increased physical activity. Lorcaserin is thought to act on 5-hydroxytryptamine-2c (5HT2c) receptors on the pro-opiomelanocortin (POMC) neurons in the arcuate nucleus, causing release of alpha-melanocortin-stimulating hormone (alpha-MSH), which in turn acts on melanocortin-4 receptors in the paraventricular nucleus to suppress appetite. At the maximum suggested dose of 10 mg twice daily, lorcaserin binds with 15 to 100 times greater affinity to 5HT2c receptors compared with 5HT2a and 5HT2b receptors respectively.
Indications for lorcaserin include patients with BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 or greater with a weight-related comorbid condition such as hypertension, dyslipidemia, cardiovascular disease, impaired glucose tolerance, or sleep apnea.
The efficacy of lorcaserin for weight loss has been evaluated in 3 separate trials. The trials were randomized, double blinded and placebo controlled. The BLOOM trial, which included 3,182 patients with a mean BMI of 36.2 kg/m2, evaluated the efficacy of lorcaserin as a weight loss adjunct.27 Patients with pre-existing valvular disease, uncontrolled hypertension, or a major psychiatric condition were excluded. After initial randomization, patients were assigned to receive either lorcaserin 10 mg twice daily or a placebo. The primary endpoint was a 5% weight reduction from baseline by the end of 2 years. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost ≥ 5% of their body weight (P <.001). The average loss for the lorcaserin group was 5.8 ± 0.2 kg and 2.2 ± 0.1 kg for the placebo group at 1 year (P < .001).
The BLOSSOM trial was a 1-year study of 4,008 patients aged 18 to 65 years. The trial evaluated the effects of lorcaserin on body weight, CVD risk factors, and safety in obese and overweight patients.28 Patients were randomized in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily, lorcaserin 10 mg once daily, or placebo. The primary endpoint was the proportion of patients achieving at least 5% reduction in body weight. Completer analysis showed weight reduction in the placebo group was 4.0% and 7.9% in the lorcaserin group (P < .001). In the modified intent-to-treat/last observation carried forward analysis (MITT/LOCF), a statistically significant 47.2% of patients receiving lorcaserin 10 mg twice daily and 40.2% of patients receiving lorcaserin 10 mg once daily lost at least 5% of baseline body weight; compared with 25% of patients receiving placebo (P < .001). Weight loss of at least 10% was achieved by 22.6% of patients receiving lorcaserin 10 mg twice daily, and 17.4% of patients receiving 10 mg daily compared with 9.7% of patients in the placebo group (P < .001).
The most common AEs noted were headache, nausea, and dizziness. Echocardiographic evidence of valvulopathy occurred in 2% of patients taking lorcaserin 10 mg twice daily and those taking the placebo. Lorcaserin administered in conjunction with a diet and exercise program was associated with an overall reduction in baseline BMI when compared with placebo over the year.
The BLOOM-DM study evaluated efficacy and safety of lorcaserin for weight loss in 604 patients with T2DM over the course of 1 year.29 Patients had a hemoglobin A1c (A1c) of 7% to 10% and were treated with metformin, a sulfonylurea, or both. The primary endpoint was a 5% weight reduction from baseline at the end of 1 year. Patients were randomized into 3 groups: 1 group received lorcaserin 10 mg twice daily, 1 group took lorcaserin 10 mg daily, and 1 group received the placebo. A statistically significant 37.5% of patients taking lorcaserin 10 mg twice daily achieved > 5% body weight reduction, compared with 44.7% in the lorcaserin 10 mg daily group, and 16.1% in the placebo group. Overall reductions in A1c and fasting glucose were observed in both lorcaserin groups taking as compared with placebo. Patient A1c decreased 0.9 ± 0.06 with lorcaserin 10 mg bid, 1.0 ± 0.09 with lorcaserin 10 mg qd, and 0.4 ± 0.06 with the placebo (P < .001). Fasting glucose in the lorcaserin bid, lorcaserin qd, and placebo groups decreased 27.4 ± 2.5 mg/dL, 28.4 ± 3.8 mg/dL, and 11.9 ± 2.5 mg/dL, respectively (P < .001). Symptomatic hypoglycemia occurred in 7.4% of patients on lorcaserin bid, 10.5% on lorcaserin qd, and 6.3% on placebo. Headache, back pain, nasopharyngitis, and nausea were among the most commonly reported AEs.
As lorcaserin is a serotonergic agonist, potential interactions exist when used with other medications affecting serotonin. Most notably, serotonin syndrome and neuroleptic malignant syndrome-like reactions may occur. Because of this, it is recommended to avoid selective serotonin re-uptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors, tricyclic antidepressants, bupropion, triptans, monoamine oxidase inhibitors, lithium, dextromethorphan, and dopamine agonists. Lorcaserin seems to be safe in those patient populations with mild hepatic as well as mild renal impairment; however, it is not recommended for those with severe renal impairment. Given the multiple enzymatic pathways used to metabolize lorcaserin, there is a low probability for cytochrome drug interactions. Safety has not been well evaluated in patients aged < 18 years and those that are pregnant (pregnancy category X).
Adverse events include headache, dizziness, fatigue, nausea, and dry mouth. Other notable AEs include nasopharyngitis and URI. Hypoglycemia appeared to be more common in patients with DM taking lorcaserin. Cognitive impairment and psychiatric disorders including euphoria and hallucinations were also reported. Notably, valvular heart disease has been reported in patients who take medications with 5HT2b activity. In a 1-year clinical trial, a small number of patients were found to develop valvular regurgitation. Furthermore, bradycardia, priapism, leucopenia, elevated prolactin, and pulmonary hypertension have also been observed. Caution is recommended if symptoms of any of the aforementioned conditions are noticed.
Qsymia
The schedule IV controlled substance Qsymia (Vivus, Mountain View, CA) is a combination of phentermine, an anorexigenic agent, and topiramate extended-release, an antiepileptic drug. In July of 2012 it was approved for chronic weight management as an addition to a reduced-calorie diet and exercise. The drug is approved for adults with a BMI ≥ 30 kg/m2 or adults with a BMI ≥ 27 kg/m2 who have at least 1 weight-related condition such as hypertension, T2DM, or dyslipidemia.30
In 1996 topiramate was approved by the FDA for the treatment of seizure disorders and was also approved for migraine prophylaxis in 2004. In patients who were treated with topiramate for seizure disorders and migraines, weight loss and a reduction in visceral body fat has been observed.31 The precise MOA of topiramate in regards to weight loss is not fully understood. It may be due to its effects on both appetite suppression and satiety enhancement. Topiramate exhibits a combination of properties including modulatory effects on sodium channels, enhancement of GABA-activated chloride channels, inhibition of excitatory neurotransmission through actions on kainite and AMPA receptors, and inhibition of carbonic anhydrase (CA) isoenzymes in particular CA II and IV.14
The combination of phentermine and topiramate is a once-daily formulation that is designed to provide an immediate release of phentermine and a delayed release of topiramate, allowing a peak exposure of the phentermine in the morning and a peak concentration of topiramate in the evening. It should be taken in the morning in order to avoid the possibility of insomnia that can occur if taken in the evening. It can be taken with or without food. The recommended dose is as follows: Start treatment with Qsymia 3.75 mg/23 mg extended-release daily for 14 days; after 14 days increase to the recommended dose of Qsymia 7.5 mg/46 mg once daily.
Weight loss should be evaluated after 12 weeks at the higher dose. If at least 3% of baseline body weight has not been lost at that time, discontinue or escalate the dose. To escalate the dose: Increase to Qsymia 11.25 mg/69 mg daily for 14 days; followed by Qsymia 15 mg/92 mg daily. Evaluate weight loss following dose escalation to Qsymia 15 mg/92 mg after an additional 12 weeks of treatment. If at least 5% of baseline body weight has not been lost on Qsymia 15 mg/92 mg, discontinue as directed. It is important not to suddenly discontinue, as this may cause seizures. Patients should be slowly titrated off the medication.
In vitro studies of phentermine and topiramate indicate that these drugs are not likely to cause clinically significant interactions with drugs using the cytochrome P450 enzyme pathways, or those involved in plasma protein binding displacement; however there is evidence suggesting that ethinyl estradiol levels may be decreased by 16%, thus raising a concern about the possibility of decreased contraceptive efficacy.31 In patients with moderate (creatine clearance ≥ 30 mL/min to < 50 mL/min) and severe renal dysfunction (< 30 mL/min), the maximum dose of should not exceed 7.5 mg/46 mg.
Qsymia was evaluated in 3 phase 3 trials for its long-term efficacy and safety. In all trials, diet and lifestyle counseling were provided for all patients. The first of these studies was OB-301, a 28-week confirmatory trial with a factorial design involving 7 treatment arms, tested 2 fixed-dose Qsymia combinations—regular dose (7.5 mg/46 mg) and maximum dose (15 mg/92 mg)—as well as regular and maximum doses of the individual constituent drugs vs placebo.32 The study randomized 756 obese patients with a BMI range of 30 kg/m2 to 45 kg/m2 to 1 of the 7 treatment arms for 28 weeks. Patients treated with maximum-dose Qsymia achieved an average weight change of -9.0%, vs -1.5% with placebo (P < .0001). Weight change with regular-dose Qsymia was -8.2%. Weight changes with monotherapies were: -6.1% with topiramate 92 mg, -4.9% with topiramate 46 mg, -5.8% with phentermine 15 mg, and -5.2% with phentermine 7.5 mg.
OB-302 was a 56-week trial that randomized 1,267 morbidly obese patients with a BMI ≥ 35 kg/m2 without significant comorbidities to low-dose Qsymia (3.7 mg/23 mg), maximum-dose Qsymia (15 mg/92 mg), or placebo.33 At baseline, the mean BMI for the entire study cohort was 42 kg/m2. Mean weight changes were -1.6% with placebo, -5.1% with low-dose Qsymia, and -10.9% with maximum-dose Qsymia. The proportions of patients achieving ≥ 5% weight loss were: 17% with placebo, 45% with low-dose Qsymia, and 67% with maximum-dose Qsymia.
CONQUER was the largest of the phase 3 trials. It randomized 2,487 overweight or obese patients with a BMI of 27 kg/m2 to 45 kg/m2 and ≥ 2 obesity-related comorbidities (hypertension, dyslipidemia, T2DM, prediabetes or abdominal obesity) to receive a placebo, regular-dose Qsymia, or maximum-dose Qsymia for 56 weeks.34 In the completer population, mean weight changes in the placebo, regular dose Qsymia, and maximum-dose Qsymia groups were -1.6%, -9.6% (P <.0001), and -12.4% (P < .0001); and weight loss of ≥ 5% was achieved by 21%, 62%, and 70%, respectively. Relative to placebo, there were greater reductions in systolic BP, triglycerides, and fasting insulin with both doses of Qsymia.
Patients should not take Qsymia if they are pregnant, planning to become pregnant, or become pregnant during Qsymia treatment as there is an increased risk of birth defects, namely cleft lip and cleft palate. Women who can become pregnant should have a negative pregnancy test before taking Qsymia and every month while on the medication. They should use effective birth control consistently while taking Qsymia.
Qsymia is contraindicated in patients with glaucoma and patients who have hyperthyroidism. Qsymia can cause an increase in resting heart rate and regular monitoring of resting heart rate is recommended, especially in patients with cardiac or cerebrovascular disease. It has not been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended.
Qsymia can cause mood disorders such as anxiety and depression and can increase the risk of suicidal thoughts. Patients should be monitored for worsening depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. It is not recommended in patients with a history of suicidal attempts or active suicidal ideation. Qsymia can cause cognitive dysfunction. It can cause confusion, problems with concentration, attention, memory, or speech. Patients should be cautioned about operating automobiles and hazardous machinery.
Normal anion gap hyperchloremic metabolic acidosis has been reported in patients treated with Qsymia. If this does develop and persists, consideration should be given to either reduce the dose or discontinue Qsymia.
Weight loss may increase the risk of hypoglycemia in patients with T2DM treated with insulin and/or insulin secretagogues (eg, sulfonylureas). Qsymia has not been studied in combination with insulin. A reduction in the dose of antidiabetic medications, which are nonglucose dependent, should be considered to reduce the risk of hypoglycemia.
The most common AEs in controlled clinical studies (≥ 5% and at least 1.5 times placebo) included paraesthesia in the hands, arms, feet or face, dizziness, dysgeusia, insomnia, constipation, and dry mouth.
Contrave
In 2014, the FDA approved Contrave (Takeda, Deerfield, IL) as treatment option for chronic weight management in addition to reduced-calorie diet and physical activity. The combination of naltrexone hydrochloride and bupropion hydrochloride was originally introduced for the treatment of opioid addiction and later expanded to include the treatment of alcoholism. The antidepressant bupropion was approved in the U.S. in 1989. It is structurally different from all other marketed antidepressants (ie, tricyclics, tetracyclics, and SSRIs), but closely resembles the structure of diethylpropion, an appetite depressant with minimal CNS effects.35
This drug is approved for adults with BMI ≥ 30 kg/m2 and for adults with BMI ≥ 27 kg/m2 with at least 1 weight-related risk factors such as hypertension, T2DM, or dyslipidemia. It should be used as an adjunct to diet and exercise and is not approved for use for depression even though it contains bupropion.
Naltrexone is a pure opioid antagonist with high affinity to μ-opioid receptor, which is implicated in eating behavior. Naltrexone is rapidly and nearly completely absorbed from the GI tract after oral administration. The time to peak plasma concentration is about 1 hour. Naltrexone is well absorbed but first pass extraction and metabolism by the liver decreases oral bioavailability to between 5% to 40%. Primary elimination of naltrexone and its metabolites is renal excretion.
Bupropion is a weak inhibitor of neuronal reuptake of dopamine and norepinephrine. This drug is used to treat depression and seasonal affective disorder, and aid in smoking cessation. Bupropion is absorbed rapidly after oral administration, but the absolute oral bioavailability of bupropion is not known because an IV preparation is not available. The time to peak plasma concentrations of bupropion is within 2 hours of oral administration. Bupropion is extensively metabolized by the liver to multiple metabolites. Primary elimination of bupropion is urinary excretion. However, hepatic and renal impairment may affect the elimination of bupropion and its metabolites. Patients with hepatic or renal impairment should use a reduced dosage.
Combination therapy has been found to have complementary actions on CNS to reduce food intake. They are believed to dampen CNS reward pathways, taking away the compulsive feeding behavior and pleasure of feeding, ultimately leading to weight loss. Bupropion stimulates hypothalamic pro-opiomelanocortin neurons (POMC), which results in reduced food intake and increased energy expenditure. Naltrexone blocks opioid-receptor mediated POMC auto-inhibition, blocks the increase in dopamine in nucleus accumbens that occurs when eating, and acting synergistically with bupropion in augmenting POMC firing.
The COR-I and COR-II trials compared Contrave to diet and exercise in patients who did not have DM. The COR-Diabetes trial included the same study design but focused on patients with DM. In all the studies the participants had a 4-week titration to Contrave (naltrexone 8 mg/bupropion 90 mg) to decrease nausea. The first week dosing was 1 tablet in the morning. Week 2 was 1 tablet in morning and 1 tablet in the evening. In week 3, patients took 2 tablets in the morning and 1 tablet in the evening. The final titration step was 2 tablets in the morning and 2 tablets in the evening.
The COR-1 study was a 56-week randomized, double-blind, placebo-controlled study. It compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.36 To be included adults must be aged 18 to 65 years with a BMI 30 kg/m2 to 45 kg/m2 or a BMI 27 kg/m2 to 45 kg/m2 with dyslipidemia or hypertension. Patients were instructed on a hypocaloric diet that was a 500 kcal per day deficit based on World Health Organization algorithm for calculating metabolic rate and they were urged to increase physical activity.
The completer population results showed 8.0% weight loss in the NB32/360 group and 1.9% weight loss in the placebo group (P < .001). For the NB32/360 and placebo groups, weight loss of ≥ 5% was achieved by 48% and 16% (P <.001), respectively; and weight loss of ≥ 10% by 25% and 7% (P < .001), respectively. The most common AE was nausea—29.8% with NB32/360 vs 5.3% with placebo. Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (6.3%) then the overall reported nausea rates.
Contrave was also studied in patients with T2DM. The COR-Diabetes Trial was a 56-week randomized, double blind, placebo-controlled study. The trial compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.37 Inclusion criteria for the trial were patients aged 18 to 70 years with T2DM and a BMI from 27 kg/m2 to 45 kg/m2, A1c between 7% and 10%, and fasting blood glucose < 270 mg/dL. Participants either were not taking a DM medication or were on stable doses of oral antidiabetes drugs ≥ 3 months prior to randomization. Patients were placed on a 500 kcal hypocaloric diet and advised to increase physical activity.
The results showed 5.0% weight loss in the NB32/360 group and 1.8% weight loss in the placebo group (P < .001). Weight loss of ≥ 5% and ≥ 10% was achieved by 44.5% and 18.5% of the NB32/360 group, respectively, and 18.9% and 5.7%, respectively (P < .001) of the placebo group. The NB32/360 and placebo showed a reduction of A1c of 0.6% and 0.1% respectively (P < .001). The most common AE was nausea (42.3% with NB32/360 vs 7.1% with placebo). Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (9.6%) then the overall reported nausea rates.37
Due to potential nausea caused by naltrexone, Contrave should be titrated over 4 weeks as described earlier. At maintenance dose, patients should be evaluated after 12 weeks to determine treatment benefits. If a patient has not lost at least 5% of baseline body weight, Contrave should be discontinued, because it would be unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. Contrave should not be taken with high-fat meals that may result in significant increase in bupropion and naltrexone systemic exposure.
Since Contrave contains the antidepressant bupropion, it has a boxed warning similar to other antidepressants in its class of increased risk of suicidal thoughts and behaviors, especially in children, adolescents, and young adults.38Contrave can lower the seizure threshold; therefore it should not be used in people with a seizure disorder. It can also raise BP and heart rate; however the clinical significance of hypertension and elevated heart rate observed with Contrave treatment is unclear. Blood pressure rose on average by 1 point during the first 8 weeks of treatment and then returned to baseline.38 The heart rate also increased by about 1.7 beats per minute.38 Patients with uncontrolled hypertension should avoid Contrave.
Contrave should not be taken with products contain bupropion or naltrexone. It should not be taken by patient who are regularly taking opioids or who are opioid dependent, or who are experiencing opiate withdrawal. Pregnant women should also avoid Contrave. In patients with renal impairment the maximum dose is 1 tablet twice a day and in patients with hepatic impairment the maximum dose is 1 tablet a day.
Liraglutide
Liraglutide is the newest weight loss medication to be approved by the FDA for chronic weight management as an adjunct to a reduced calorie diet and increased physical activity in adult patients with BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with hypertension, diabetes, or dyslipidemia. The recommended dose of liraglutide is 3 mg daily. The initial dose is 0.6 mg daily for the first week, then titrated up by 0.6 each week for 4 weeks, until reaching 3 mg daily.
Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) receptor agonist, which are expressed in the brain and is involved in the control of appetite. It is also found in the beta cells of the pancreas, where GLP-1 receptors stimulate insulin release in response to elevated blood glucose concentrations and suppress glucagon secretion. Endogenous GLP-1 has a half-life of 1.5 to 2 minutes due to degradation by the DDP-4 enzyme, but liraglutide is stable against degradation by peptidases and has a half- life of 13 hours.
Liraglutide was studied in a 56-week randomized, double-blind, placebo-controlled trial, which compared liraglutide 3 mg with an active placebo of diet and physical activity.39 Inclusion criteria were adults aged ≥ 18 years old with a BMI 30 kg/m2 to 45 kg/m2 or BMI 27 kg/m2 to 45 kg/m2 with dyslipidemia and/or hypertension. Both groups received lifestyle modification counseling. Patients were excluded if they had DM.
In the trial, 3,731 participants enrolled, 2,487 in the liraglutide group and 1,244 in the placebo group; 78.7% of the participants were female and the average age was 45 years. Subjects in the liraglutide group had a weekly titration regimen. The starting dose at week 1 was 0.6 mg, week 2 was 1.2 mg, week 3 was 1.8 mg, week 4 was 2.4 mg, and week 5 was 3.0 kg.
The completer population showed 9.2% weight loss in the liraglutide group and 3.0% weight loss in the control group.39 Weight loss of ≥ 5% was seen in 63.2% and 27.1% of the liraglutide and placebo groups, respectively. Weight loss rates of ≥ 10% was seen by 33.1% and 10.6%, respectively. The most common AEs were nausea, diarrhea, and constipation. Nausea generally occurred early during the titration period and then diminished.
A second clinically relevant study was performed with liraglutide. Often patients are able to lose weight with diet and exercise and then plateau. This study examined participants who lost 5% percent of their initial body weight and then were randomized to liraglutide or placebo.40 Key inclusion criteria were people aged ≥ 18 years old with a BMI 30 kg/m2 to 45 kg/m2 or BMI 27 kg/m2 to 45 kg/m2 with dyslipidemia and/or hypertension. In order to be randomized, participants were required to lose at least 5% of their initial body weight on a 1,200 kcal to 1,400 kcal diet with increased physical activity during a 4 to 12 week run-in period.
Four hundred twenty-two participants were enrolled, 212 in the liraglutide group and 210 in the placebo group. Most of the participants were female (81%). The average BMI in the study was 35.6 kg/m2. Subjects in the liraglutide group had a weekly titration regimen.
After an average weight loss of 6% using a low calorie diet and increased physical activity the participants were randomized to continue diet and increased activity alone (placebo) or with liraglutide. At week 56 the results showed an additional 6.2% weight loss in the liraglutide group and 0.2% weight gain in the placebo group. The liraglutide group had a greater number of participants with ≥ 5% weight loss compared to placebo, 50.5% vs 21.8% (P < .0001).40 In the pooled data set from the registration trials the 3 most common GI AEs were nausea, diarrhea, and constipation occurring in 39.3%, 20.9%, and 19.4% of participants respectively. Discontinuation due to nausea for liraglutide was 2.9%.41
Clinicians should be aware that medications that can cause hypoglycemia such as sulfonylureas and insulin must be tapered as patients lose weight with liraglutide. Documented symptomatic hypoglycemia in patients with T2DM and with sulfonylurea background therapy was 43.6% with liraglutide vs 27.3% with placebo.
In the setting of renal impairment, patients treated with GLP-1 receptor agonists, including liraglutide, have had reports of acute renal failure and worsening of chronic renal failure usually associated with nausea, vomiting, diarrhea, or dehydration. Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. As the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2.
Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide in postmarketing reports. After initiation of liraglutide, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, liraglutide should promptly be discontinued.
Conclusion
The treatment of obesity and overweight with comorbidities has always been a challenge. In the past there were few FDA-approved drugs and many drugs had to be used off-label. The toolbox of medications available for medical weight management is more robust than ever. The medications have different MOAs and can be used in a variety of patients. There are differences in the classes and some are controlled substances. Phentermine, lorcaserin, and Qsymia (phentermine/topiramate) are controlled substances whereas orlistat, naltrexone/bupropion and liraglutide are not. Other differences exist including duration of use. The sympathomimetic drugs have a limited window of use whereas orlistat, Qsymia (phentermine/topiramate), lorcaserin, naltrexone/bupropion, and liraglutide do not.
The medications that are available have a wide variety of MOAs. Therefore, if a patient fails one medication, then it is very reasonable to try a medication with a different MOA. In addition, there is the potential for weight regain when weight reduction medications are discontinued. As people lose weight their metabolic rate decreases about 15 kcal per pound of weight reduction.42
Another challenge of using these medications is managing patient expectations. The current metric used for FDA approval is a 5% weight loss that is greater in the study group compared with the diet and physical activity active control. However, many clinicians and patients do not find this weight reduction amount consistent with their expectations. In addition weight loss trajectory may also be too slow for patients and cause early discontinuation. Therefore, patient education and a discussion of reasonable expectations for weight reduction medications are necessary.
Clinicians must acknowledge that there are limitations to the use of these medications. Newer agents do have a higher cost and insurance reimbursement is somewhat limited. However, they offer the opportunity to prevent more expensive, protracted conditions such as diabetes and cardiovascular disease. In summary, clinicians now have a wider variety of medication options to be used with dietary and lifestyle changes in order to improve health and prevent chronic diseases.
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3. U.S. Food and Drug Administration. Drugs@FDA: diethylpropion hydrochloride. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=012546&DrugName=TENUATE%20DOSPAN&ActiveIngred=DIETHYLPROPION%20HYDROCHLORIDE&SponsorApplicant=ACTAVIS%20LABS%20UT%20INC&ProductMktStatus=1&goto=Search.DrugDetails. Accessed December 28, 2015.
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5. U.S. Food and Drug Administration. Drugs@ FDA: phendimetrazine tartrate. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=088021&DrugName=BONTRIL&ActiveIngred=PHENDIMETRAZINE%20TARTRATE&SponsorApplicant=VALEANT&ProductMktStatus=3&goto=Search.DrugDetails. Accessed December 28, 2015.
6. U.S. Food and Drug Administration. Drugs@FDA: phentermine. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=085128&DrugName=ADIPEX%2DP&ActiveIngred=PHENTERMINE%20HYDROCHLORIDE&SponsorApplicant=TEVA&ProductMktStatus=1&goto=Search.DrugDetails. Accessed December 28, 2015.
7. U.S. Food and Drug Administration. Drugs @ FDA: phentermine hydrochloride. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=202088&DrugName=SUPRENZA&ActiveIngred=PHENTERMINE%20HYDROCHLORIDE&SponsorApplicant=CITIUS%20PHARMS&ProductMktStatus=1&goto=Search.DrugDetails. Accessed December 28, 2015.
8. Hendricks EJ, Rothman RB, Greenway FL. How Physician Obesity Specialists use drugs to treat obesity. Obesity (Silver Spring). 2009;17(9):1730-1735.
9. Gilman AG, Gilman A, Goodman LS, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th ed. New York: Pergamon Press; 1990: 211.
10. Gilman AG, Gilman A, Goodman LS, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th ed. New York: Pergamon Press; 1990:217.
11. Addy C, Jumes P, Rosko K, et al. Pharmacokinetics, safety, and tolerability of phentermine in health participants receiving taranabant, a novel cannabinoid-1 receptor (CB1R) inverse agonist. J Clin Pharmacol. 2009;49(10):1228-1232.
12. U.S. Department of Justice, Drug Enforcement Administration, Office of Diversion Control. Controlled substances. U.S. Department of Justice Website. http://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf. Updated November 12, 2015. Accessed December 16, 2015.
13. Bray GA, Greenway FL. Pharmacological treatment of the overweight patient. Pharmacol Rev. 2007;59(2):151-184.
14. V1-0521 (QNEXA) Advisory committee briefing document. NDA 022580. Endocrinologic and Metabolic Drugs Advisory Committee meeting; June 17, 2010.
15. Cercato C, Roizenblatt VA, Leanca CC, et al. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of diethylpropion in the treatment of obese subjects. Int J Obes (Lond). 2009;33(8):857-865.
16. Haddock CK, Poston WS, Dill PL, Foreyt JP, Ericsson M. Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Int J Obes (Lond). 2002;26(2):262-273.
17. Suplicy H, Boquszewski CL, dos Santos CM, do Desterro de Fiqueiredo M, Cunha DR, Radominski R. A comparative study of five centrally acting drugs on pharmacological treatment of obesity. Int J Obes (Lond). 2014;38(8):1097-1103.
18. Ioannides-Demos LL, Proietto J, McNeill JJ. 2005. Pharmacotherapy for obesity. Drugs. 2005;65(10): 1391-1418.
19. Drent ML, van der Veen EA. Lipase inhibition: a novel concept in the treatment of obesity. Int J Obes Relat Metab Disord. 1993;17(4):241-244.
20. Xenical [package insert]. Nutley, NJ: Roche Laboratories Inc.; 1999.
21. U.S. Food and Drug Administration. FDA Drug Safety Communication: Completed safety review of Xenical/Alli and severe liver injury. U.S. Food and Drug Administration Website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213038.htm. Updated August 2, 2010. Accessed December 16, 2015.
22. Sall D, Wang J, Rashkin M, Welch M, Droege C, Schauer D. Orlistat-induced fulminant hepatic failure. Clin Obes. 2014;4(6):342-347.
23. Sjöström L, Rissanen A, Andersen T, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet. 1998;352(9123):167-172.
24. Hauptman J, Lucas C, Boldrin MN, Collins H, Segal KR. Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med. 2000;9(2):160-167.
25. Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27(1):155-161.
26. Torgerson JS, Arlinger K, Käppi M, Sjöström L. Principles for enhanced recruitment of subjects in a large clinical trial. the XENDOS (XENical in the prevention of Diabetes in Obese Subjects) study experience. Control Clin Trials. 2001;22(5):515-525.
27.Smith SR, Weissman NJ, Anderson CM, et al; Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363(3):245-256.
28. Fidler MC, Sanchez M, Raether B, et al; BLOSSOM Clinical Trial Group. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96(10):3067-3077.
29. O’Neil PM, Smith SR, Weisserman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM Study. Obesity (Silver Spring). 2012;20(7):1426-1436.
30. U.S. Food and Drug Administration. FDA approves weight-management drug Qsymia. U.S. Food and Drug Administration Website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm. Published July 17, 2012. Accessed December 16, 2015.
31. Shin J, Gadde KM. Clinical utility of phentermine/topiramate (Qsymia™) combination for the treatment of obesity. Diabetes Metab Syndr Obes. 2013;6:131-139.
32. Qsymia [package insert] Mountain View, CA: Vivus, Inc; 2012.
33. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20(2):330-342.
34. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9774):1341-1352.
35. Plodkowski RA, Nguyen Q, Sundaram U, Nguyen L, Chau DL, St Jeor S. Bupropion and naltrexone: a review of their use individually and in combination for the treatment of obesity. Expert Opin Pharmacother. 2009;10(6):1069-1081.
36. Greenway FL, Fujioka K, Plodkowski RA, et al; COR-I Study Group. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2010;376(9741):595-605.
37. Hollander P, Gupta AK, Plodkowski R, et al; COR-Diabetes Study Group. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care. 2013;36(12):4022-4029.
38. Contrave [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2014.
39. Pi-Sunyer X, Astrup A, Fujioka K, et al; SCALE Obesity and Prediabetes NN8022-1839 Study Group. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Eng J Med. 2015;373(1):11-22.
40. Wadden TA, Hollander P, Klein S, et al; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013;37(11):1443-1451
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Over the past decade the prevalence of obesity as defined by a body mass index (BMI) ≥ 30 kg/m2 has significantly increased. In the U.S. more than 78 million adults are estimated to be obese.1 The World Health Organization projects that by 2025 up to half the U.S. population will be obese. Cardiovascular disease (CVD) and diabetes mellitus (DM) are the main comorbid conditions that are complicated by obesity. Initial weight loss of 5% to 10% of total body weight reduces CVD risk factors, prevents or delays the development of type 2 DM (T2DM) and improves the health consequences of obesity.2
To date, public health initiatives that have focused on obesity prevention and lifestyle intervention have had marginal success. In recent years, anti-obesity drug therapies have had a limited role in clinical treatment algorithms. In 2013, the American Medical Association acknowledged obesity as a disease. In turn, this acknowledgement allowed the recognition of anti-obesity drugs as acceptable therapeutic adjuncts to intensive lifestyle intervention that could address the growing obesity endemic.
In the past, medications for weight reduction were limited. Several that were FDA approved had to be removed from the market due to safety concerns. With few approved options, clinicians often had to resort to off-label use of medications. However, the landscape has changed with 4 new medications gaining recent FDA approval. This review covers older available medications and the newer medications that are now available.
Sympathomimetics
Sympathomimetic drugs have been approved for use as a pharmacological method to lose weight since 1960. Of the many versions of this drug class that have been available since then, there are 4 major versions available today. These include diethylpropion3 and benzphetamine,4 both approved in 1960; phendimetrazine, approved in 1976;5 phentermine, approved in 1980;6 and phentermine hydrochloride, approved in 2012.7 Despite the existence of several other classes of drugs to treat obesity, phentermine remains the most often prescribed weight loss drug in the U.S.8
Although the mechanism of action (MOA) of sympathomimetic drugs is not particularly clear, weight loss from these medications is believed to be due to the increase in the release of biogenic amines (mainly norepinephrine, but also possibly dopamine), from storage sites in nerve terminals. It is possible that these drugs slow catecholamine metabolism by inhibiting the actions of monoamine oxidase. The resulting increase in amine availability, particularly in the lateral hypothalamic feeding center, is associated with reduced food intake. Interestingly, injection of these drugs into the ventromedial satiety center dooes not seem to suppress food intake, and the effects of biogenic amines on increasing metabolism does not seem to play a significant role in weight loss in patients on these medications.9
Each of these drugs is rapidly absorbed from the gastrointestinal (GI) tract except for phentermine hydrochloride, the newest of the medications in this class. Phentermine hydrochloride is a sublingual tablet that is readily absorbed through the buccal mucosa.5 All of the drugs in this class are excreted through the kidneys, with varying rates. Each drug’s excretion is highly dependent on the pH of the urine—more alkaline conditions result in less excretion and more acidic conditions result in more excretion. As a result, these drugs should be used with caution in patients with renal impairment; however, there are no specific contraindications listed for patients with poor renal function.
The adverse effects (AEs) for this drug class are to be expected from an increase in the release of biogenic amines in the central nervous system (CNS). The most common AEs include palpitations, tremors, restlessness, insomnia, dry mouth, constipation, diaphoresis, changes in libido, and irritability. The more dangerous AEs that have been observed include arrhythmias, hypertension, dependency/abuse, convulsions, acute transient ischemic colitis, and acute urinary retention secondary to increased bladder sphincter tone, transient hyperthyroxemia, and paranoia.10
Several contraindications exist for sympathomimetics, including the presence of advanced arteriosclerosis, symptomatic CVD, moderate to severe hypertension, hyperthyroidism, glaucoma, patients in an agitated state, or those with a history of amphetamine abuse. The warnings for prescribers include pulmonary hypertension and cardiomyopathy secondary to chronic use of sympathomimetics, and valvular heart disease secondary to use of sympathomimetics with additional anorectic agents.
Additional precautions should be considered in those with a history of anxiety/psychosis, those who operate machinery and motor vehicles, and even those with mild hypertension. The data surrounding the effects of sympathomimetics on blood pressure (BP) appears to be conflicting and the relationship does not seem to have been significantly studied in depth to warrant any definitive conclusions. The MOA of this drug class itself is enough to urge caution to prescribers.11 Special attention should be given to patients with diabetes when using sympathomimetics. A reduction of insulin dose or oral hypoglycemic dose may be necessary in some people with diabetes.
Only diethylpropion is pregnancy category B, whereas the others drugs in this class are pregnancy category X. It has been demonstrated that diethylpropion and benzphetamine are secreted into breastmilk; insufficient data exist to suggest whether or not phentermine and phendimetrazine are present in breastmilk. All drugs in this class should be used in caution with breastfeeding mothers.
Although all 4 drugs are registered as controlled substances, benzphetamine and phendimetrazine are schedule III and phentermine and diethylpropion are schedule IV, despite evidence suggesting the potential for abuse to be extremely low.12,13 Phentermine has been approved for adults aged > 18 years, phendimetrazine has been approved for those aged > 17 years, diethylpropion has been approved for those aged > 16 years, and benzphetamine has been approved for those aged > 12 years.
There is a wealth of literature surrounding the effectiveness of this drug class for weight loss. One of the longest trials of phentermine was recently conducted as part of the initial component of a FDA study for the newly approved topiramate-phentermine combination. Weight loss at 6 months in the phentermine-only group was significantly higher at -5.8% compared with -1.5% with the placebo group in the last observation carried forward-Intent to treat (LOCF-ITT) analysis.14 Similarly, a long-term study looking at diethylpropion examined the use of diethylpropion for up to a year vs placebo. Participants administered diethylpropion lost a mean 9.8% of original weight vs 3.7% in the placebo group in the first 6 months alone.15
Several meta-analyses and review papers have been authored that examine and analyze the published data on this drug class overall and comparatively within this class. Haddock and colleagues in 2002 reviewed the numerous clinical trials associated with each drug in this class, in addition to several other classes, and found that although each drug demonstrated a significant advantage vs placebo in weight loss, there was not a specific drug that was significantly superior to any of the others.16
These results seem to be in relative agreement with additional studies like that published by Suplicy and colleagues, which demonstrated that several sympathomimetics were better than placebo in weight loss, and that there was little difference between the specific drugs in the class.17 However, it should be noted that as highlighted in a review by Ioannides-Demos and colleagues in 2005, the vast majority of studies that had been performed on this drug class focused on short-term use (< 16 weeks) and none of the sympathomimetics listed here have been approved for long-term use.18
Orlistat
Orlistat 120 mg was approved in 1999 as a reversible inhibitor of GI lipases that specifically reduced the absorption of dietary fat due to the inhibition of triglyceride hydrolysis.19 Orlistat was later approved in 2007 for release in a reduced dosage form (60 mg) for over-the-counter sales.20
Orlistat forms a covalent bond with the active serine residue site of gastric and pancreatic lipases in the lumen of the stomach and small intestine. The inhibition of these enzymes causes dietary fat to remain undigested as triglycerides, which cannot be converted to absorbable free fatty acids and monoglycerides, leading to decreased calorie absorption. Orlistat is not systemically absorbed and is eliminated mainly through feces. Some metabolism occurs in the GI wall.21Orlistat is most known for its GI AEs. Because it is most active in the lumen of the GI system and reduces the absorption of triglycerides, many AEs are related to malabsorption. The most common issues 1 year after starting the drug were oily spotting (26.6% vs 1.3% placebo); flatus with discharge (23.9% vs 1.4% placebo); fecal urgency (22.1% vs 6.7% placebo); fatty/oily stool (20% vs 2.9% placebo); increased defecation (10.8% vs 4.1% placebo); and fecal incontinence (7.7% vs 0.9% placebo) (Table 1). Most of these AEs were greatly reduced after taking the drug for 2 years. Orlistat also has more serious AEs noted, including abdominal pain/discomfort; nausea; infectious diarrhea; rectal pain/discomfort; tooth disorder; gingival disorder; vomiting; upper respiratory infection; lower respiratory infection; ear, nose and throat symptoms; back pain; arthritis; myalgia; joint disorders; tendonitis; headache; dizziness; fatigue; sleep disorders; rash; dry skin; menstrual irregularity; vaginitis; urinary tract infection; and psychiatric disorders, although these did not differ markedly from placebo.
One of the most serious AEs reported was fulminate hepatic failure, though this AE is rare. Thirteen cases of liver injury were reported with the 120-mg prescription dose of orlistat and 1 case report in the U.S. involved the 60-mg over-the-counter dosage of orlistat.21,22 The FDA suggests that patients talk to their physicians about risks of liver failure, and that physicians should educate their patients about signs and symptoms of liver failure so that patients can stop taking orlistat and seek immediate medical help if symptoms occur.
One of the first published trials was the European Multicentre Orlistat Study Group, which included 743 participants with BMI between 28 kg/m2 and 47 kg/m2 from 15 different European centers. To test adherence, a 4-week single blind placebo lead-in was started with a hypocaloric diet. The first stage was completed by 688 patients who then proceeded to the double blind randomized control trial portion with a hypocaloric diet. From the start of lead-in to the end of year 1, the orlistat group weight decreased 10.2% (10.3 kg) vs 6.1% (6.1 kg) in the placebo group. The placebo subtracted difference between the groups was 3.9 kg (P < .001).23
A U.S.-based randomized double-blind placebo-controlled multicenter study included 796 obese patients with BMI between 30 kg/m2 and 44 kg/m2. Patients were assigned to 1 of 3 groups: placebo, orlistat 60 mg 3 times daily, or orlistat 120 mg 3 times daily. All groups were given a reduced energy diet. Patients in the orlistat 120 mg group lost significantly more weight than did the placebo group, -8.78% vs -4.26% respectively in year 1 in the completer analysis (P = .001). More participants who were treated with orlistat 120 mg lost 5% or more of their initial weight in year 1 compared with placebo, 50.5% vs 30.7% respectively (P < .001).24
In the XENDOS study the primary outcome measurement was time to onset of T2DM. Eligible participants were aged 30 to 60 years, with a BMI > 30 kg/m2. All patients had a 75-g oral glucose tolerance test and were required to have normal glucose tolerance or impaired glucose tolerance, but not T2DM. The double-blind randomized controlled trial included 3,305 subjects and compared a group taking 120 mg orlistat 3 times daily vs placebo. All patients were prescribed a reduced-calorie diet (800 kcal/d deficit) containing 30% of calories from fat. Patients were also encouraged to walk at least 1 kilometer daily in addition to their usual physical activity. Incidence of T2DM after 4 years was 6.2% in the orlistat group and 9.0% in the placebo group, reflecting a 37.3% risk reduction in the orlistat group (P = .0032).25,26
Lorcaserin
In 2012, lorcaserin HCl was FDA approved as a schedule IV drug for use as a weight loss medication as an adjunct to a reduced-calorie diet and increased physical activity. Lorcaserin is thought to act on 5-hydroxytryptamine-2c (5HT2c) receptors on the pro-opiomelanocortin (POMC) neurons in the arcuate nucleus, causing release of alpha-melanocortin-stimulating hormone (alpha-MSH), which in turn acts on melanocortin-4 receptors in the paraventricular nucleus to suppress appetite. At the maximum suggested dose of 10 mg twice daily, lorcaserin binds with 15 to 100 times greater affinity to 5HT2c receptors compared with 5HT2a and 5HT2b receptors respectively.
Indications for lorcaserin include patients with BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 or greater with a weight-related comorbid condition such as hypertension, dyslipidemia, cardiovascular disease, impaired glucose tolerance, or sleep apnea.
The efficacy of lorcaserin for weight loss has been evaluated in 3 separate trials. The trials were randomized, double blinded and placebo controlled. The BLOOM trial, which included 3,182 patients with a mean BMI of 36.2 kg/m2, evaluated the efficacy of lorcaserin as a weight loss adjunct.27 Patients with pre-existing valvular disease, uncontrolled hypertension, or a major psychiatric condition were excluded. After initial randomization, patients were assigned to receive either lorcaserin 10 mg twice daily or a placebo. The primary endpoint was a 5% weight reduction from baseline by the end of 2 years. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost ≥ 5% of their body weight (P <.001). The average loss for the lorcaserin group was 5.8 ± 0.2 kg and 2.2 ± 0.1 kg for the placebo group at 1 year (P < .001).
The BLOSSOM trial was a 1-year study of 4,008 patients aged 18 to 65 years. The trial evaluated the effects of lorcaserin on body weight, CVD risk factors, and safety in obese and overweight patients.28 Patients were randomized in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily, lorcaserin 10 mg once daily, or placebo. The primary endpoint was the proportion of patients achieving at least 5% reduction in body weight. Completer analysis showed weight reduction in the placebo group was 4.0% and 7.9% in the lorcaserin group (P < .001). In the modified intent-to-treat/last observation carried forward analysis (MITT/LOCF), a statistically significant 47.2% of patients receiving lorcaserin 10 mg twice daily and 40.2% of patients receiving lorcaserin 10 mg once daily lost at least 5% of baseline body weight; compared with 25% of patients receiving placebo (P < .001). Weight loss of at least 10% was achieved by 22.6% of patients receiving lorcaserin 10 mg twice daily, and 17.4% of patients receiving 10 mg daily compared with 9.7% of patients in the placebo group (P < .001).
The most common AEs noted were headache, nausea, and dizziness. Echocardiographic evidence of valvulopathy occurred in 2% of patients taking lorcaserin 10 mg twice daily and those taking the placebo. Lorcaserin administered in conjunction with a diet and exercise program was associated with an overall reduction in baseline BMI when compared with placebo over the year.
The BLOOM-DM study evaluated efficacy and safety of lorcaserin for weight loss in 604 patients with T2DM over the course of 1 year.29 Patients had a hemoglobin A1c (A1c) of 7% to 10% and were treated with metformin, a sulfonylurea, or both. The primary endpoint was a 5% weight reduction from baseline at the end of 1 year. Patients were randomized into 3 groups: 1 group received lorcaserin 10 mg twice daily, 1 group took lorcaserin 10 mg daily, and 1 group received the placebo. A statistically significant 37.5% of patients taking lorcaserin 10 mg twice daily achieved > 5% body weight reduction, compared with 44.7% in the lorcaserin 10 mg daily group, and 16.1% in the placebo group. Overall reductions in A1c and fasting glucose were observed in both lorcaserin groups taking as compared with placebo. Patient A1c decreased 0.9 ± 0.06 with lorcaserin 10 mg bid, 1.0 ± 0.09 with lorcaserin 10 mg qd, and 0.4 ± 0.06 with the placebo (P < .001). Fasting glucose in the lorcaserin bid, lorcaserin qd, and placebo groups decreased 27.4 ± 2.5 mg/dL, 28.4 ± 3.8 mg/dL, and 11.9 ± 2.5 mg/dL, respectively (P < .001). Symptomatic hypoglycemia occurred in 7.4% of patients on lorcaserin bid, 10.5% on lorcaserin qd, and 6.3% on placebo. Headache, back pain, nasopharyngitis, and nausea were among the most commonly reported AEs.
As lorcaserin is a serotonergic agonist, potential interactions exist when used with other medications affecting serotonin. Most notably, serotonin syndrome and neuroleptic malignant syndrome-like reactions may occur. Because of this, it is recommended to avoid selective serotonin re-uptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors, tricyclic antidepressants, bupropion, triptans, monoamine oxidase inhibitors, lithium, dextromethorphan, and dopamine agonists. Lorcaserin seems to be safe in those patient populations with mild hepatic as well as mild renal impairment; however, it is not recommended for those with severe renal impairment. Given the multiple enzymatic pathways used to metabolize lorcaserin, there is a low probability for cytochrome drug interactions. Safety has not been well evaluated in patients aged < 18 years and those that are pregnant (pregnancy category X).
Adverse events include headache, dizziness, fatigue, nausea, and dry mouth. Other notable AEs include nasopharyngitis and URI. Hypoglycemia appeared to be more common in patients with DM taking lorcaserin. Cognitive impairment and psychiatric disorders including euphoria and hallucinations were also reported. Notably, valvular heart disease has been reported in patients who take medications with 5HT2b activity. In a 1-year clinical trial, a small number of patients were found to develop valvular regurgitation. Furthermore, bradycardia, priapism, leucopenia, elevated prolactin, and pulmonary hypertension have also been observed. Caution is recommended if symptoms of any of the aforementioned conditions are noticed.
Qsymia
The schedule IV controlled substance Qsymia (Vivus, Mountain View, CA) is a combination of phentermine, an anorexigenic agent, and topiramate extended-release, an antiepileptic drug. In July of 2012 it was approved for chronic weight management as an addition to a reduced-calorie diet and exercise. The drug is approved for adults with a BMI ≥ 30 kg/m2 or adults with a BMI ≥ 27 kg/m2 who have at least 1 weight-related condition such as hypertension, T2DM, or dyslipidemia.30
In 1996 topiramate was approved by the FDA for the treatment of seizure disorders and was also approved for migraine prophylaxis in 2004. In patients who were treated with topiramate for seizure disorders and migraines, weight loss and a reduction in visceral body fat has been observed.31 The precise MOA of topiramate in regards to weight loss is not fully understood. It may be due to its effects on both appetite suppression and satiety enhancement. Topiramate exhibits a combination of properties including modulatory effects on sodium channels, enhancement of GABA-activated chloride channels, inhibition of excitatory neurotransmission through actions on kainite and AMPA receptors, and inhibition of carbonic anhydrase (CA) isoenzymes in particular CA II and IV.14
The combination of phentermine and topiramate is a once-daily formulation that is designed to provide an immediate release of phentermine and a delayed release of topiramate, allowing a peak exposure of the phentermine in the morning and a peak concentration of topiramate in the evening. It should be taken in the morning in order to avoid the possibility of insomnia that can occur if taken in the evening. It can be taken with or without food. The recommended dose is as follows: Start treatment with Qsymia 3.75 mg/23 mg extended-release daily for 14 days; after 14 days increase to the recommended dose of Qsymia 7.5 mg/46 mg once daily.
Weight loss should be evaluated after 12 weeks at the higher dose. If at least 3% of baseline body weight has not been lost at that time, discontinue or escalate the dose. To escalate the dose: Increase to Qsymia 11.25 mg/69 mg daily for 14 days; followed by Qsymia 15 mg/92 mg daily. Evaluate weight loss following dose escalation to Qsymia 15 mg/92 mg after an additional 12 weeks of treatment. If at least 5% of baseline body weight has not been lost on Qsymia 15 mg/92 mg, discontinue as directed. It is important not to suddenly discontinue, as this may cause seizures. Patients should be slowly titrated off the medication.
In vitro studies of phentermine and topiramate indicate that these drugs are not likely to cause clinically significant interactions with drugs using the cytochrome P450 enzyme pathways, or those involved in plasma protein binding displacement; however there is evidence suggesting that ethinyl estradiol levels may be decreased by 16%, thus raising a concern about the possibility of decreased contraceptive efficacy.31 In patients with moderate (creatine clearance ≥ 30 mL/min to < 50 mL/min) and severe renal dysfunction (< 30 mL/min), the maximum dose of should not exceed 7.5 mg/46 mg.
Qsymia was evaluated in 3 phase 3 trials for its long-term efficacy and safety. In all trials, diet and lifestyle counseling were provided for all patients. The first of these studies was OB-301, a 28-week confirmatory trial with a factorial design involving 7 treatment arms, tested 2 fixed-dose Qsymia combinations—regular dose (7.5 mg/46 mg) and maximum dose (15 mg/92 mg)—as well as regular and maximum doses of the individual constituent drugs vs placebo.32 The study randomized 756 obese patients with a BMI range of 30 kg/m2 to 45 kg/m2 to 1 of the 7 treatment arms for 28 weeks. Patients treated with maximum-dose Qsymia achieved an average weight change of -9.0%, vs -1.5% with placebo (P < .0001). Weight change with regular-dose Qsymia was -8.2%. Weight changes with monotherapies were: -6.1% with topiramate 92 mg, -4.9% with topiramate 46 mg, -5.8% with phentermine 15 mg, and -5.2% with phentermine 7.5 mg.
OB-302 was a 56-week trial that randomized 1,267 morbidly obese patients with a BMI ≥ 35 kg/m2 without significant comorbidities to low-dose Qsymia (3.7 mg/23 mg), maximum-dose Qsymia (15 mg/92 mg), or placebo.33 At baseline, the mean BMI for the entire study cohort was 42 kg/m2. Mean weight changes were -1.6% with placebo, -5.1% with low-dose Qsymia, and -10.9% with maximum-dose Qsymia. The proportions of patients achieving ≥ 5% weight loss were: 17% with placebo, 45% with low-dose Qsymia, and 67% with maximum-dose Qsymia.
CONQUER was the largest of the phase 3 trials. It randomized 2,487 overweight or obese patients with a BMI of 27 kg/m2 to 45 kg/m2 and ≥ 2 obesity-related comorbidities (hypertension, dyslipidemia, T2DM, prediabetes or abdominal obesity) to receive a placebo, regular-dose Qsymia, or maximum-dose Qsymia for 56 weeks.34 In the completer population, mean weight changes in the placebo, regular dose Qsymia, and maximum-dose Qsymia groups were -1.6%, -9.6% (P <.0001), and -12.4% (P < .0001); and weight loss of ≥ 5% was achieved by 21%, 62%, and 70%, respectively. Relative to placebo, there were greater reductions in systolic BP, triglycerides, and fasting insulin with both doses of Qsymia.
Patients should not take Qsymia if they are pregnant, planning to become pregnant, or become pregnant during Qsymia treatment as there is an increased risk of birth defects, namely cleft lip and cleft palate. Women who can become pregnant should have a negative pregnancy test before taking Qsymia and every month while on the medication. They should use effective birth control consistently while taking Qsymia.
Qsymia is contraindicated in patients with glaucoma and patients who have hyperthyroidism. Qsymia can cause an increase in resting heart rate and regular monitoring of resting heart rate is recommended, especially in patients with cardiac or cerebrovascular disease. It has not been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended.
Qsymia can cause mood disorders such as anxiety and depression and can increase the risk of suicidal thoughts. Patients should be monitored for worsening depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. It is not recommended in patients with a history of suicidal attempts or active suicidal ideation. Qsymia can cause cognitive dysfunction. It can cause confusion, problems with concentration, attention, memory, or speech. Patients should be cautioned about operating automobiles and hazardous machinery.
Normal anion gap hyperchloremic metabolic acidosis has been reported in patients treated with Qsymia. If this does develop and persists, consideration should be given to either reduce the dose or discontinue Qsymia.
Weight loss may increase the risk of hypoglycemia in patients with T2DM treated with insulin and/or insulin secretagogues (eg, sulfonylureas). Qsymia has not been studied in combination with insulin. A reduction in the dose of antidiabetic medications, which are nonglucose dependent, should be considered to reduce the risk of hypoglycemia.
The most common AEs in controlled clinical studies (≥ 5% and at least 1.5 times placebo) included paraesthesia in the hands, arms, feet or face, dizziness, dysgeusia, insomnia, constipation, and dry mouth.
Contrave
In 2014, the FDA approved Contrave (Takeda, Deerfield, IL) as treatment option for chronic weight management in addition to reduced-calorie diet and physical activity. The combination of naltrexone hydrochloride and bupropion hydrochloride was originally introduced for the treatment of opioid addiction and later expanded to include the treatment of alcoholism. The antidepressant bupropion was approved in the U.S. in 1989. It is structurally different from all other marketed antidepressants (ie, tricyclics, tetracyclics, and SSRIs), but closely resembles the structure of diethylpropion, an appetite depressant with minimal CNS effects.35
This drug is approved for adults with BMI ≥ 30 kg/m2 and for adults with BMI ≥ 27 kg/m2 with at least 1 weight-related risk factors such as hypertension, T2DM, or dyslipidemia. It should be used as an adjunct to diet and exercise and is not approved for use for depression even though it contains bupropion.
Naltrexone is a pure opioid antagonist with high affinity to μ-opioid receptor, which is implicated in eating behavior. Naltrexone is rapidly and nearly completely absorbed from the GI tract after oral administration. The time to peak plasma concentration is about 1 hour. Naltrexone is well absorbed but first pass extraction and metabolism by the liver decreases oral bioavailability to between 5% to 40%. Primary elimination of naltrexone and its metabolites is renal excretion.
Bupropion is a weak inhibitor of neuronal reuptake of dopamine and norepinephrine. This drug is used to treat depression and seasonal affective disorder, and aid in smoking cessation. Bupropion is absorbed rapidly after oral administration, but the absolute oral bioavailability of bupropion is not known because an IV preparation is not available. The time to peak plasma concentrations of bupropion is within 2 hours of oral administration. Bupropion is extensively metabolized by the liver to multiple metabolites. Primary elimination of bupropion is urinary excretion. However, hepatic and renal impairment may affect the elimination of bupropion and its metabolites. Patients with hepatic or renal impairment should use a reduced dosage.
Combination therapy has been found to have complementary actions on CNS to reduce food intake. They are believed to dampen CNS reward pathways, taking away the compulsive feeding behavior and pleasure of feeding, ultimately leading to weight loss. Bupropion stimulates hypothalamic pro-opiomelanocortin neurons (POMC), which results in reduced food intake and increased energy expenditure. Naltrexone blocks opioid-receptor mediated POMC auto-inhibition, blocks the increase in dopamine in nucleus accumbens that occurs when eating, and acting synergistically with bupropion in augmenting POMC firing.
The COR-I and COR-II trials compared Contrave to diet and exercise in patients who did not have DM. The COR-Diabetes trial included the same study design but focused on patients with DM. In all the studies the participants had a 4-week titration to Contrave (naltrexone 8 mg/bupropion 90 mg) to decrease nausea. The first week dosing was 1 tablet in the morning. Week 2 was 1 tablet in morning and 1 tablet in the evening. In week 3, patients took 2 tablets in the morning and 1 tablet in the evening. The final titration step was 2 tablets in the morning and 2 tablets in the evening.
The COR-1 study was a 56-week randomized, double-blind, placebo-controlled study. It compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.36 To be included adults must be aged 18 to 65 years with a BMI 30 kg/m2 to 45 kg/m2 or a BMI 27 kg/m2 to 45 kg/m2 with dyslipidemia or hypertension. Patients were instructed on a hypocaloric diet that was a 500 kcal per day deficit based on World Health Organization algorithm for calculating metabolic rate and they were urged to increase physical activity.
The completer population results showed 8.0% weight loss in the NB32/360 group and 1.9% weight loss in the placebo group (P < .001). For the NB32/360 and placebo groups, weight loss of ≥ 5% was achieved by 48% and 16% (P <.001), respectively; and weight loss of ≥ 10% by 25% and 7% (P < .001), respectively. The most common AE was nausea—29.8% with NB32/360 vs 5.3% with placebo. Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (6.3%) then the overall reported nausea rates.
Contrave was also studied in patients with T2DM. The COR-Diabetes Trial was a 56-week randomized, double blind, placebo-controlled study. The trial compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.37 Inclusion criteria for the trial were patients aged 18 to 70 years with T2DM and a BMI from 27 kg/m2 to 45 kg/m2, A1c between 7% and 10%, and fasting blood glucose < 270 mg/dL. Participants either were not taking a DM medication or were on stable doses of oral antidiabetes drugs ≥ 3 months prior to randomization. Patients were placed on a 500 kcal hypocaloric diet and advised to increase physical activity.
The results showed 5.0% weight loss in the NB32/360 group and 1.8% weight loss in the placebo group (P < .001). Weight loss of ≥ 5% and ≥ 10% was achieved by 44.5% and 18.5% of the NB32/360 group, respectively, and 18.9% and 5.7%, respectively (P < .001) of the placebo group. The NB32/360 and placebo showed a reduction of A1c of 0.6% and 0.1% respectively (P < .001). The most common AE was nausea (42.3% with NB32/360 vs 7.1% with placebo). Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (9.6%) then the overall reported nausea rates.37
Due to potential nausea caused by naltrexone, Contrave should be titrated over 4 weeks as described earlier. At maintenance dose, patients should be evaluated after 12 weeks to determine treatment benefits. If a patient has not lost at least 5% of baseline body weight, Contrave should be discontinued, because it would be unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. Contrave should not be taken with high-fat meals that may result in significant increase in bupropion and naltrexone systemic exposure.
Since Contrave contains the antidepressant bupropion, it has a boxed warning similar to other antidepressants in its class of increased risk of suicidal thoughts and behaviors, especially in children, adolescents, and young adults.38Contrave can lower the seizure threshold; therefore it should not be used in people with a seizure disorder. It can also raise BP and heart rate; however the clinical significance of hypertension and elevated heart rate observed with Contrave treatment is unclear. Blood pressure rose on average by 1 point during the first 8 weeks of treatment and then returned to baseline.38 The heart rate also increased by about 1.7 beats per minute.38 Patients with uncontrolled hypertension should avoid Contrave.
Contrave should not be taken with products contain bupropion or naltrexone. It should not be taken by patient who are regularly taking opioids or who are opioid dependent, or who are experiencing opiate withdrawal. Pregnant women should also avoid Contrave. In patients with renal impairment the maximum dose is 1 tablet twice a day and in patients with hepatic impairment the maximum dose is 1 tablet a day.
Liraglutide
Liraglutide is the newest weight loss medication to be approved by the FDA for chronic weight management as an adjunct to a reduced calorie diet and increased physical activity in adult patients with BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with hypertension, diabetes, or dyslipidemia. The recommended dose of liraglutide is 3 mg daily. The initial dose is 0.6 mg daily for the first week, then titrated up by 0.6 each week for 4 weeks, until reaching 3 mg daily.
Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) receptor agonist, which are expressed in the brain and is involved in the control of appetite. It is also found in the beta cells of the pancreas, where GLP-1 receptors stimulate insulin release in response to elevated blood glucose concentrations and suppress glucagon secretion. Endogenous GLP-1 has a half-life of 1.5 to 2 minutes due to degradation by the DDP-4 enzyme, but liraglutide is stable against degradation by peptidases and has a half- life of 13 hours.
Liraglutide was studied in a 56-week randomized, double-blind, placebo-controlled trial, which compared liraglutide 3 mg with an active placebo of diet and physical activity.39 Inclusion criteria were adults aged ≥ 18 years old with a BMI 30 kg/m2 to 45 kg/m2 or BMI 27 kg/m2 to 45 kg/m2 with dyslipidemia and/or hypertension. Both groups received lifestyle modification counseling. Patients were excluded if they had DM.
In the trial, 3,731 participants enrolled, 2,487 in the liraglutide group and 1,244 in the placebo group; 78.7% of the participants were female and the average age was 45 years. Subjects in the liraglutide group had a weekly titration regimen. The starting dose at week 1 was 0.6 mg, week 2 was 1.2 mg, week 3 was 1.8 mg, week 4 was 2.4 mg, and week 5 was 3.0 kg.
The completer population showed 9.2% weight loss in the liraglutide group and 3.0% weight loss in the control group.39 Weight loss of ≥ 5% was seen in 63.2% and 27.1% of the liraglutide and placebo groups, respectively. Weight loss rates of ≥ 10% was seen by 33.1% and 10.6%, respectively. The most common AEs were nausea, diarrhea, and constipation. Nausea generally occurred early during the titration period and then diminished.
A second clinically relevant study was performed with liraglutide. Often patients are able to lose weight with diet and exercise and then plateau. This study examined participants who lost 5% percent of their initial body weight and then were randomized to liraglutide or placebo.40 Key inclusion criteria were people aged ≥ 18 years old with a BMI 30 kg/m2 to 45 kg/m2 or BMI 27 kg/m2 to 45 kg/m2 with dyslipidemia and/or hypertension. In order to be randomized, participants were required to lose at least 5% of their initial body weight on a 1,200 kcal to 1,400 kcal diet with increased physical activity during a 4 to 12 week run-in period.
Four hundred twenty-two participants were enrolled, 212 in the liraglutide group and 210 in the placebo group. Most of the participants were female (81%). The average BMI in the study was 35.6 kg/m2. Subjects in the liraglutide group had a weekly titration regimen.
After an average weight loss of 6% using a low calorie diet and increased physical activity the participants were randomized to continue diet and increased activity alone (placebo) or with liraglutide. At week 56 the results showed an additional 6.2% weight loss in the liraglutide group and 0.2% weight gain in the placebo group. The liraglutide group had a greater number of participants with ≥ 5% weight loss compared to placebo, 50.5% vs 21.8% (P < .0001).40 In the pooled data set from the registration trials the 3 most common GI AEs were nausea, diarrhea, and constipation occurring in 39.3%, 20.9%, and 19.4% of participants respectively. Discontinuation due to nausea for liraglutide was 2.9%.41
Clinicians should be aware that medications that can cause hypoglycemia such as sulfonylureas and insulin must be tapered as patients lose weight with liraglutide. Documented symptomatic hypoglycemia in patients with T2DM and with sulfonylurea background therapy was 43.6% with liraglutide vs 27.3% with placebo.
In the setting of renal impairment, patients treated with GLP-1 receptor agonists, including liraglutide, have had reports of acute renal failure and worsening of chronic renal failure usually associated with nausea, vomiting, diarrhea, or dehydration. Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. As the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2.
Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide in postmarketing reports. After initiation of liraglutide, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, liraglutide should promptly be discontinued.
Conclusion
The treatment of obesity and overweight with comorbidities has always been a challenge. In the past there were few FDA-approved drugs and many drugs had to be used off-label. The toolbox of medications available for medical weight management is more robust than ever. The medications have different MOAs and can be used in a variety of patients. There are differences in the classes and some are controlled substances. Phentermine, lorcaserin, and Qsymia (phentermine/topiramate) are controlled substances whereas orlistat, naltrexone/bupropion and liraglutide are not. Other differences exist including duration of use. The sympathomimetic drugs have a limited window of use whereas orlistat, Qsymia (phentermine/topiramate), lorcaserin, naltrexone/bupropion, and liraglutide do not.
The medications that are available have a wide variety of MOAs. Therefore, if a patient fails one medication, then it is very reasonable to try a medication with a different MOA. In addition, there is the potential for weight regain when weight reduction medications are discontinued. As people lose weight their metabolic rate decreases about 15 kcal per pound of weight reduction.42
Another challenge of using these medications is managing patient expectations. The current metric used for FDA approval is a 5% weight loss that is greater in the study group compared with the diet and physical activity active control. However, many clinicians and patients do not find this weight reduction amount consistent with their expectations. In addition weight loss trajectory may also be too slow for patients and cause early discontinuation. Therefore, patient education and a discussion of reasonable expectations for weight reduction medications are necessary.
Clinicians must acknowledge that there are limitations to the use of these medications. Newer agents do have a higher cost and insurance reimbursement is somewhat limited. However, they offer the opportunity to prevent more expensive, protracted conditions such as diabetes and cardiovascular disease. In summary, clinicians now have a wider variety of medication options to be used with dietary and lifestyle changes in order to improve health and prevent chronic diseases.
Over the past decade the prevalence of obesity as defined by a body mass index (BMI) ≥ 30 kg/m2 has significantly increased. In the U.S. more than 78 million adults are estimated to be obese.1 The World Health Organization projects that by 2025 up to half the U.S. population will be obese. Cardiovascular disease (CVD) and diabetes mellitus (DM) are the main comorbid conditions that are complicated by obesity. Initial weight loss of 5% to 10% of total body weight reduces CVD risk factors, prevents or delays the development of type 2 DM (T2DM) and improves the health consequences of obesity.2
To date, public health initiatives that have focused on obesity prevention and lifestyle intervention have had marginal success. In recent years, anti-obesity drug therapies have had a limited role in clinical treatment algorithms. In 2013, the American Medical Association acknowledged obesity as a disease. In turn, this acknowledgement allowed the recognition of anti-obesity drugs as acceptable therapeutic adjuncts to intensive lifestyle intervention that could address the growing obesity endemic.
In the past, medications for weight reduction were limited. Several that were FDA approved had to be removed from the market due to safety concerns. With few approved options, clinicians often had to resort to off-label use of medications. However, the landscape has changed with 4 new medications gaining recent FDA approval. This review covers older available medications and the newer medications that are now available.
Sympathomimetics
Sympathomimetic drugs have been approved for use as a pharmacological method to lose weight since 1960. Of the many versions of this drug class that have been available since then, there are 4 major versions available today. These include diethylpropion3 and benzphetamine,4 both approved in 1960; phendimetrazine, approved in 1976;5 phentermine, approved in 1980;6 and phentermine hydrochloride, approved in 2012.7 Despite the existence of several other classes of drugs to treat obesity, phentermine remains the most often prescribed weight loss drug in the U.S.8
Although the mechanism of action (MOA) of sympathomimetic drugs is not particularly clear, weight loss from these medications is believed to be due to the increase in the release of biogenic amines (mainly norepinephrine, but also possibly dopamine), from storage sites in nerve terminals. It is possible that these drugs slow catecholamine metabolism by inhibiting the actions of monoamine oxidase. The resulting increase in amine availability, particularly in the lateral hypothalamic feeding center, is associated with reduced food intake. Interestingly, injection of these drugs into the ventromedial satiety center dooes not seem to suppress food intake, and the effects of biogenic amines on increasing metabolism does not seem to play a significant role in weight loss in patients on these medications.9
Each of these drugs is rapidly absorbed from the gastrointestinal (GI) tract except for phentermine hydrochloride, the newest of the medications in this class. Phentermine hydrochloride is a sublingual tablet that is readily absorbed through the buccal mucosa.5 All of the drugs in this class are excreted through the kidneys, with varying rates. Each drug’s excretion is highly dependent on the pH of the urine—more alkaline conditions result in less excretion and more acidic conditions result in more excretion. As a result, these drugs should be used with caution in patients with renal impairment; however, there are no specific contraindications listed for patients with poor renal function.
The adverse effects (AEs) for this drug class are to be expected from an increase in the release of biogenic amines in the central nervous system (CNS). The most common AEs include palpitations, tremors, restlessness, insomnia, dry mouth, constipation, diaphoresis, changes in libido, and irritability. The more dangerous AEs that have been observed include arrhythmias, hypertension, dependency/abuse, convulsions, acute transient ischemic colitis, and acute urinary retention secondary to increased bladder sphincter tone, transient hyperthyroxemia, and paranoia.10
Several contraindications exist for sympathomimetics, including the presence of advanced arteriosclerosis, symptomatic CVD, moderate to severe hypertension, hyperthyroidism, glaucoma, patients in an agitated state, or those with a history of amphetamine abuse. The warnings for prescribers include pulmonary hypertension and cardiomyopathy secondary to chronic use of sympathomimetics, and valvular heart disease secondary to use of sympathomimetics with additional anorectic agents.
Additional precautions should be considered in those with a history of anxiety/psychosis, those who operate machinery and motor vehicles, and even those with mild hypertension. The data surrounding the effects of sympathomimetics on blood pressure (BP) appears to be conflicting and the relationship does not seem to have been significantly studied in depth to warrant any definitive conclusions. The MOA of this drug class itself is enough to urge caution to prescribers.11 Special attention should be given to patients with diabetes when using sympathomimetics. A reduction of insulin dose or oral hypoglycemic dose may be necessary in some people with diabetes.
Only diethylpropion is pregnancy category B, whereas the others drugs in this class are pregnancy category X. It has been demonstrated that diethylpropion and benzphetamine are secreted into breastmilk; insufficient data exist to suggest whether or not phentermine and phendimetrazine are present in breastmilk. All drugs in this class should be used in caution with breastfeeding mothers.
Although all 4 drugs are registered as controlled substances, benzphetamine and phendimetrazine are schedule III and phentermine and diethylpropion are schedule IV, despite evidence suggesting the potential for abuse to be extremely low.12,13 Phentermine has been approved for adults aged > 18 years, phendimetrazine has been approved for those aged > 17 years, diethylpropion has been approved for those aged > 16 years, and benzphetamine has been approved for those aged > 12 years.
There is a wealth of literature surrounding the effectiveness of this drug class for weight loss. One of the longest trials of phentermine was recently conducted as part of the initial component of a FDA study for the newly approved topiramate-phentermine combination. Weight loss at 6 months in the phentermine-only group was significantly higher at -5.8% compared with -1.5% with the placebo group in the last observation carried forward-Intent to treat (LOCF-ITT) analysis.14 Similarly, a long-term study looking at diethylpropion examined the use of diethylpropion for up to a year vs placebo. Participants administered diethylpropion lost a mean 9.8% of original weight vs 3.7% in the placebo group in the first 6 months alone.15
Several meta-analyses and review papers have been authored that examine and analyze the published data on this drug class overall and comparatively within this class. Haddock and colleagues in 2002 reviewed the numerous clinical trials associated with each drug in this class, in addition to several other classes, and found that although each drug demonstrated a significant advantage vs placebo in weight loss, there was not a specific drug that was significantly superior to any of the others.16
These results seem to be in relative agreement with additional studies like that published by Suplicy and colleagues, which demonstrated that several sympathomimetics were better than placebo in weight loss, and that there was little difference between the specific drugs in the class.17 However, it should be noted that as highlighted in a review by Ioannides-Demos and colleagues in 2005, the vast majority of studies that had been performed on this drug class focused on short-term use (< 16 weeks) and none of the sympathomimetics listed here have been approved for long-term use.18
Orlistat
Orlistat 120 mg was approved in 1999 as a reversible inhibitor of GI lipases that specifically reduced the absorption of dietary fat due to the inhibition of triglyceride hydrolysis.19 Orlistat was later approved in 2007 for release in a reduced dosage form (60 mg) for over-the-counter sales.20
Orlistat forms a covalent bond with the active serine residue site of gastric and pancreatic lipases in the lumen of the stomach and small intestine. The inhibition of these enzymes causes dietary fat to remain undigested as triglycerides, which cannot be converted to absorbable free fatty acids and monoglycerides, leading to decreased calorie absorption. Orlistat is not systemically absorbed and is eliminated mainly through feces. Some metabolism occurs in the GI wall.21Orlistat is most known for its GI AEs. Because it is most active in the lumen of the GI system and reduces the absorption of triglycerides, many AEs are related to malabsorption. The most common issues 1 year after starting the drug were oily spotting (26.6% vs 1.3% placebo); flatus with discharge (23.9% vs 1.4% placebo); fecal urgency (22.1% vs 6.7% placebo); fatty/oily stool (20% vs 2.9% placebo); increased defecation (10.8% vs 4.1% placebo); and fecal incontinence (7.7% vs 0.9% placebo) (Table 1). Most of these AEs were greatly reduced after taking the drug for 2 years. Orlistat also has more serious AEs noted, including abdominal pain/discomfort; nausea; infectious diarrhea; rectal pain/discomfort; tooth disorder; gingival disorder; vomiting; upper respiratory infection; lower respiratory infection; ear, nose and throat symptoms; back pain; arthritis; myalgia; joint disorders; tendonitis; headache; dizziness; fatigue; sleep disorders; rash; dry skin; menstrual irregularity; vaginitis; urinary tract infection; and psychiatric disorders, although these did not differ markedly from placebo.
One of the most serious AEs reported was fulminate hepatic failure, though this AE is rare. Thirteen cases of liver injury were reported with the 120-mg prescription dose of orlistat and 1 case report in the U.S. involved the 60-mg over-the-counter dosage of orlistat.21,22 The FDA suggests that patients talk to their physicians about risks of liver failure, and that physicians should educate their patients about signs and symptoms of liver failure so that patients can stop taking orlistat and seek immediate medical help if symptoms occur.
One of the first published trials was the European Multicentre Orlistat Study Group, which included 743 participants with BMI between 28 kg/m2 and 47 kg/m2 from 15 different European centers. To test adherence, a 4-week single blind placebo lead-in was started with a hypocaloric diet. The first stage was completed by 688 patients who then proceeded to the double blind randomized control trial portion with a hypocaloric diet. From the start of lead-in to the end of year 1, the orlistat group weight decreased 10.2% (10.3 kg) vs 6.1% (6.1 kg) in the placebo group. The placebo subtracted difference between the groups was 3.9 kg (P < .001).23
A U.S.-based randomized double-blind placebo-controlled multicenter study included 796 obese patients with BMI between 30 kg/m2 and 44 kg/m2. Patients were assigned to 1 of 3 groups: placebo, orlistat 60 mg 3 times daily, or orlistat 120 mg 3 times daily. All groups were given a reduced energy diet. Patients in the orlistat 120 mg group lost significantly more weight than did the placebo group, -8.78% vs -4.26% respectively in year 1 in the completer analysis (P = .001). More participants who were treated with orlistat 120 mg lost 5% or more of their initial weight in year 1 compared with placebo, 50.5% vs 30.7% respectively (P < .001).24
In the XENDOS study the primary outcome measurement was time to onset of T2DM. Eligible participants were aged 30 to 60 years, with a BMI > 30 kg/m2. All patients had a 75-g oral glucose tolerance test and were required to have normal glucose tolerance or impaired glucose tolerance, but not T2DM. The double-blind randomized controlled trial included 3,305 subjects and compared a group taking 120 mg orlistat 3 times daily vs placebo. All patients were prescribed a reduced-calorie diet (800 kcal/d deficit) containing 30% of calories from fat. Patients were also encouraged to walk at least 1 kilometer daily in addition to their usual physical activity. Incidence of T2DM after 4 years was 6.2% in the orlistat group and 9.0% in the placebo group, reflecting a 37.3% risk reduction in the orlistat group (P = .0032).25,26
Lorcaserin
In 2012, lorcaserin HCl was FDA approved as a schedule IV drug for use as a weight loss medication as an adjunct to a reduced-calorie diet and increased physical activity. Lorcaserin is thought to act on 5-hydroxytryptamine-2c (5HT2c) receptors on the pro-opiomelanocortin (POMC) neurons in the arcuate nucleus, causing release of alpha-melanocortin-stimulating hormone (alpha-MSH), which in turn acts on melanocortin-4 receptors in the paraventricular nucleus to suppress appetite. At the maximum suggested dose of 10 mg twice daily, lorcaserin binds with 15 to 100 times greater affinity to 5HT2c receptors compared with 5HT2a and 5HT2b receptors respectively.
Indications for lorcaserin include patients with BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 or greater with a weight-related comorbid condition such as hypertension, dyslipidemia, cardiovascular disease, impaired glucose tolerance, or sleep apnea.
The efficacy of lorcaserin for weight loss has been evaluated in 3 separate trials. The trials were randomized, double blinded and placebo controlled. The BLOOM trial, which included 3,182 patients with a mean BMI of 36.2 kg/m2, evaluated the efficacy of lorcaserin as a weight loss adjunct.27 Patients with pre-existing valvular disease, uncontrolled hypertension, or a major psychiatric condition were excluded. After initial randomization, patients were assigned to receive either lorcaserin 10 mg twice daily or a placebo. The primary endpoint was a 5% weight reduction from baseline by the end of 2 years. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost ≥ 5% of their body weight (P <.001). The average loss for the lorcaserin group was 5.8 ± 0.2 kg and 2.2 ± 0.1 kg for the placebo group at 1 year (P < .001).
The BLOSSOM trial was a 1-year study of 4,008 patients aged 18 to 65 years. The trial evaluated the effects of lorcaserin on body weight, CVD risk factors, and safety in obese and overweight patients.28 Patients were randomized in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily, lorcaserin 10 mg once daily, or placebo. The primary endpoint was the proportion of patients achieving at least 5% reduction in body weight. Completer analysis showed weight reduction in the placebo group was 4.0% and 7.9% in the lorcaserin group (P < .001). In the modified intent-to-treat/last observation carried forward analysis (MITT/LOCF), a statistically significant 47.2% of patients receiving lorcaserin 10 mg twice daily and 40.2% of patients receiving lorcaserin 10 mg once daily lost at least 5% of baseline body weight; compared with 25% of patients receiving placebo (P < .001). Weight loss of at least 10% was achieved by 22.6% of patients receiving lorcaserin 10 mg twice daily, and 17.4% of patients receiving 10 mg daily compared with 9.7% of patients in the placebo group (P < .001).
The most common AEs noted were headache, nausea, and dizziness. Echocardiographic evidence of valvulopathy occurred in 2% of patients taking lorcaserin 10 mg twice daily and those taking the placebo. Lorcaserin administered in conjunction with a diet and exercise program was associated with an overall reduction in baseline BMI when compared with placebo over the year.
The BLOOM-DM study evaluated efficacy and safety of lorcaserin for weight loss in 604 patients with T2DM over the course of 1 year.29 Patients had a hemoglobin A1c (A1c) of 7% to 10% and were treated with metformin, a sulfonylurea, or both. The primary endpoint was a 5% weight reduction from baseline at the end of 1 year. Patients were randomized into 3 groups: 1 group received lorcaserin 10 mg twice daily, 1 group took lorcaserin 10 mg daily, and 1 group received the placebo. A statistically significant 37.5% of patients taking lorcaserin 10 mg twice daily achieved > 5% body weight reduction, compared with 44.7% in the lorcaserin 10 mg daily group, and 16.1% in the placebo group. Overall reductions in A1c and fasting glucose were observed in both lorcaserin groups taking as compared with placebo. Patient A1c decreased 0.9 ± 0.06 with lorcaserin 10 mg bid, 1.0 ± 0.09 with lorcaserin 10 mg qd, and 0.4 ± 0.06 with the placebo (P < .001). Fasting glucose in the lorcaserin bid, lorcaserin qd, and placebo groups decreased 27.4 ± 2.5 mg/dL, 28.4 ± 3.8 mg/dL, and 11.9 ± 2.5 mg/dL, respectively (P < .001). Symptomatic hypoglycemia occurred in 7.4% of patients on lorcaserin bid, 10.5% on lorcaserin qd, and 6.3% on placebo. Headache, back pain, nasopharyngitis, and nausea were among the most commonly reported AEs.
As lorcaserin is a serotonergic agonist, potential interactions exist when used with other medications affecting serotonin. Most notably, serotonin syndrome and neuroleptic malignant syndrome-like reactions may occur. Because of this, it is recommended to avoid selective serotonin re-uptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors, tricyclic antidepressants, bupropion, triptans, monoamine oxidase inhibitors, lithium, dextromethorphan, and dopamine agonists. Lorcaserin seems to be safe in those patient populations with mild hepatic as well as mild renal impairment; however, it is not recommended for those with severe renal impairment. Given the multiple enzymatic pathways used to metabolize lorcaserin, there is a low probability for cytochrome drug interactions. Safety has not been well evaluated in patients aged < 18 years and those that are pregnant (pregnancy category X).
Adverse events include headache, dizziness, fatigue, nausea, and dry mouth. Other notable AEs include nasopharyngitis and URI. Hypoglycemia appeared to be more common in patients with DM taking lorcaserin. Cognitive impairment and psychiatric disorders including euphoria and hallucinations were also reported. Notably, valvular heart disease has been reported in patients who take medications with 5HT2b activity. In a 1-year clinical trial, a small number of patients were found to develop valvular regurgitation. Furthermore, bradycardia, priapism, leucopenia, elevated prolactin, and pulmonary hypertension have also been observed. Caution is recommended if symptoms of any of the aforementioned conditions are noticed.
Qsymia
The schedule IV controlled substance Qsymia (Vivus, Mountain View, CA) is a combination of phentermine, an anorexigenic agent, and topiramate extended-release, an antiepileptic drug. In July of 2012 it was approved for chronic weight management as an addition to a reduced-calorie diet and exercise. The drug is approved for adults with a BMI ≥ 30 kg/m2 or adults with a BMI ≥ 27 kg/m2 who have at least 1 weight-related condition such as hypertension, T2DM, or dyslipidemia.30
In 1996 topiramate was approved by the FDA for the treatment of seizure disorders and was also approved for migraine prophylaxis in 2004. In patients who were treated with topiramate for seizure disorders and migraines, weight loss and a reduction in visceral body fat has been observed.31 The precise MOA of topiramate in regards to weight loss is not fully understood. It may be due to its effects on both appetite suppression and satiety enhancement. Topiramate exhibits a combination of properties including modulatory effects on sodium channels, enhancement of GABA-activated chloride channels, inhibition of excitatory neurotransmission through actions on kainite and AMPA receptors, and inhibition of carbonic anhydrase (CA) isoenzymes in particular CA II and IV.14
The combination of phentermine and topiramate is a once-daily formulation that is designed to provide an immediate release of phentermine and a delayed release of topiramate, allowing a peak exposure of the phentermine in the morning and a peak concentration of topiramate in the evening. It should be taken in the morning in order to avoid the possibility of insomnia that can occur if taken in the evening. It can be taken with or without food. The recommended dose is as follows: Start treatment with Qsymia 3.75 mg/23 mg extended-release daily for 14 days; after 14 days increase to the recommended dose of Qsymia 7.5 mg/46 mg once daily.
Weight loss should be evaluated after 12 weeks at the higher dose. If at least 3% of baseline body weight has not been lost at that time, discontinue or escalate the dose. To escalate the dose: Increase to Qsymia 11.25 mg/69 mg daily for 14 days; followed by Qsymia 15 mg/92 mg daily. Evaluate weight loss following dose escalation to Qsymia 15 mg/92 mg after an additional 12 weeks of treatment. If at least 5% of baseline body weight has not been lost on Qsymia 15 mg/92 mg, discontinue as directed. It is important not to suddenly discontinue, as this may cause seizures. Patients should be slowly titrated off the medication.
In vitro studies of phentermine and topiramate indicate that these drugs are not likely to cause clinically significant interactions with drugs using the cytochrome P450 enzyme pathways, or those involved in plasma protein binding displacement; however there is evidence suggesting that ethinyl estradiol levels may be decreased by 16%, thus raising a concern about the possibility of decreased contraceptive efficacy.31 In patients with moderate (creatine clearance ≥ 30 mL/min to < 50 mL/min) and severe renal dysfunction (< 30 mL/min), the maximum dose of should not exceed 7.5 mg/46 mg.
Qsymia was evaluated in 3 phase 3 trials for its long-term efficacy and safety. In all trials, diet and lifestyle counseling were provided for all patients. The first of these studies was OB-301, a 28-week confirmatory trial with a factorial design involving 7 treatment arms, tested 2 fixed-dose Qsymia combinations—regular dose (7.5 mg/46 mg) and maximum dose (15 mg/92 mg)—as well as regular and maximum doses of the individual constituent drugs vs placebo.32 The study randomized 756 obese patients with a BMI range of 30 kg/m2 to 45 kg/m2 to 1 of the 7 treatment arms for 28 weeks. Patients treated with maximum-dose Qsymia achieved an average weight change of -9.0%, vs -1.5% with placebo (P < .0001). Weight change with regular-dose Qsymia was -8.2%. Weight changes with monotherapies were: -6.1% with topiramate 92 mg, -4.9% with topiramate 46 mg, -5.8% with phentermine 15 mg, and -5.2% with phentermine 7.5 mg.
OB-302 was a 56-week trial that randomized 1,267 morbidly obese patients with a BMI ≥ 35 kg/m2 without significant comorbidities to low-dose Qsymia (3.7 mg/23 mg), maximum-dose Qsymia (15 mg/92 mg), or placebo.33 At baseline, the mean BMI for the entire study cohort was 42 kg/m2. Mean weight changes were -1.6% with placebo, -5.1% with low-dose Qsymia, and -10.9% with maximum-dose Qsymia. The proportions of patients achieving ≥ 5% weight loss were: 17% with placebo, 45% with low-dose Qsymia, and 67% with maximum-dose Qsymia.
CONQUER was the largest of the phase 3 trials. It randomized 2,487 overweight or obese patients with a BMI of 27 kg/m2 to 45 kg/m2 and ≥ 2 obesity-related comorbidities (hypertension, dyslipidemia, T2DM, prediabetes or abdominal obesity) to receive a placebo, regular-dose Qsymia, or maximum-dose Qsymia for 56 weeks.34 In the completer population, mean weight changes in the placebo, regular dose Qsymia, and maximum-dose Qsymia groups were -1.6%, -9.6% (P <.0001), and -12.4% (P < .0001); and weight loss of ≥ 5% was achieved by 21%, 62%, and 70%, respectively. Relative to placebo, there were greater reductions in systolic BP, triglycerides, and fasting insulin with both doses of Qsymia.
Patients should not take Qsymia if they are pregnant, planning to become pregnant, or become pregnant during Qsymia treatment as there is an increased risk of birth defects, namely cleft lip and cleft palate. Women who can become pregnant should have a negative pregnancy test before taking Qsymia and every month while on the medication. They should use effective birth control consistently while taking Qsymia.
Qsymia is contraindicated in patients with glaucoma and patients who have hyperthyroidism. Qsymia can cause an increase in resting heart rate and regular monitoring of resting heart rate is recommended, especially in patients with cardiac or cerebrovascular disease. It has not been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended.
Qsymia can cause mood disorders such as anxiety and depression and can increase the risk of suicidal thoughts. Patients should be monitored for worsening depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. It is not recommended in patients with a history of suicidal attempts or active suicidal ideation. Qsymia can cause cognitive dysfunction. It can cause confusion, problems with concentration, attention, memory, or speech. Patients should be cautioned about operating automobiles and hazardous machinery.
Normal anion gap hyperchloremic metabolic acidosis has been reported in patients treated with Qsymia. If this does develop and persists, consideration should be given to either reduce the dose or discontinue Qsymia.
Weight loss may increase the risk of hypoglycemia in patients with T2DM treated with insulin and/or insulin secretagogues (eg, sulfonylureas). Qsymia has not been studied in combination with insulin. A reduction in the dose of antidiabetic medications, which are nonglucose dependent, should be considered to reduce the risk of hypoglycemia.
The most common AEs in controlled clinical studies (≥ 5% and at least 1.5 times placebo) included paraesthesia in the hands, arms, feet or face, dizziness, dysgeusia, insomnia, constipation, and dry mouth.
Contrave
In 2014, the FDA approved Contrave (Takeda, Deerfield, IL) as treatment option for chronic weight management in addition to reduced-calorie diet and physical activity. The combination of naltrexone hydrochloride and bupropion hydrochloride was originally introduced for the treatment of opioid addiction and later expanded to include the treatment of alcoholism. The antidepressant bupropion was approved in the U.S. in 1989. It is structurally different from all other marketed antidepressants (ie, tricyclics, tetracyclics, and SSRIs), but closely resembles the structure of diethylpropion, an appetite depressant with minimal CNS effects.35
This drug is approved for adults with BMI ≥ 30 kg/m2 and for adults with BMI ≥ 27 kg/m2 with at least 1 weight-related risk factors such as hypertension, T2DM, or dyslipidemia. It should be used as an adjunct to diet and exercise and is not approved for use for depression even though it contains bupropion.
Naltrexone is a pure opioid antagonist with high affinity to μ-opioid receptor, which is implicated in eating behavior. Naltrexone is rapidly and nearly completely absorbed from the GI tract after oral administration. The time to peak plasma concentration is about 1 hour. Naltrexone is well absorbed but first pass extraction and metabolism by the liver decreases oral bioavailability to between 5% to 40%. Primary elimination of naltrexone and its metabolites is renal excretion.
Bupropion is a weak inhibitor of neuronal reuptake of dopamine and norepinephrine. This drug is used to treat depression and seasonal affective disorder, and aid in smoking cessation. Bupropion is absorbed rapidly after oral administration, but the absolute oral bioavailability of bupropion is not known because an IV preparation is not available. The time to peak plasma concentrations of bupropion is within 2 hours of oral administration. Bupropion is extensively metabolized by the liver to multiple metabolites. Primary elimination of bupropion is urinary excretion. However, hepatic and renal impairment may affect the elimination of bupropion and its metabolites. Patients with hepatic or renal impairment should use a reduced dosage.
Combination therapy has been found to have complementary actions on CNS to reduce food intake. They are believed to dampen CNS reward pathways, taking away the compulsive feeding behavior and pleasure of feeding, ultimately leading to weight loss. Bupropion stimulates hypothalamic pro-opiomelanocortin neurons (POMC), which results in reduced food intake and increased energy expenditure. Naltrexone blocks opioid-receptor mediated POMC auto-inhibition, blocks the increase in dopamine in nucleus accumbens that occurs when eating, and acting synergistically with bupropion in augmenting POMC firing.
The COR-I and COR-II trials compared Contrave to diet and exercise in patients who did not have DM. The COR-Diabetes trial included the same study design but focused on patients with DM. In all the studies the participants had a 4-week titration to Contrave (naltrexone 8 mg/bupropion 90 mg) to decrease nausea. The first week dosing was 1 tablet in the morning. Week 2 was 1 tablet in morning and 1 tablet in the evening. In week 3, patients took 2 tablets in the morning and 1 tablet in the evening. The final titration step was 2 tablets in the morning and 2 tablets in the evening.
The COR-1 study was a 56-week randomized, double-blind, placebo-controlled study. It compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.36 To be included adults must be aged 18 to 65 years with a BMI 30 kg/m2 to 45 kg/m2 or a BMI 27 kg/m2 to 45 kg/m2 with dyslipidemia or hypertension. Patients were instructed on a hypocaloric diet that was a 500 kcal per day deficit based on World Health Organization algorithm for calculating metabolic rate and they were urged to increase physical activity.
The completer population results showed 8.0% weight loss in the NB32/360 group and 1.9% weight loss in the placebo group (P < .001). For the NB32/360 and placebo groups, weight loss of ≥ 5% was achieved by 48% and 16% (P <.001), respectively; and weight loss of ≥ 10% by 25% and 7% (P < .001), respectively. The most common AE was nausea—29.8% with NB32/360 vs 5.3% with placebo. Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (6.3%) then the overall reported nausea rates.
Contrave was also studied in patients with T2DM. The COR-Diabetes Trial was a 56-week randomized, double blind, placebo-controlled study. The trial compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.37 Inclusion criteria for the trial were patients aged 18 to 70 years with T2DM and a BMI from 27 kg/m2 to 45 kg/m2, A1c between 7% and 10%, and fasting blood glucose < 270 mg/dL. Participants either were not taking a DM medication or were on stable doses of oral antidiabetes drugs ≥ 3 months prior to randomization. Patients were placed on a 500 kcal hypocaloric diet and advised to increase physical activity.
The results showed 5.0% weight loss in the NB32/360 group and 1.8% weight loss in the placebo group (P < .001). Weight loss of ≥ 5% and ≥ 10% was achieved by 44.5% and 18.5% of the NB32/360 group, respectively, and 18.9% and 5.7%, respectively (P < .001) of the placebo group. The NB32/360 and placebo showed a reduction of A1c of 0.6% and 0.1% respectively (P < .001). The most common AE was nausea (42.3% with NB32/360 vs 7.1% with placebo). Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (9.6%) then the overall reported nausea rates.37
Due to potential nausea caused by naltrexone, Contrave should be titrated over 4 weeks as described earlier. At maintenance dose, patients should be evaluated after 12 weeks to determine treatment benefits. If a patient has not lost at least 5% of baseline body weight, Contrave should be discontinued, because it would be unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. Contrave should not be taken with high-fat meals that may result in significant increase in bupropion and naltrexone systemic exposure.
Since Contrave contains the antidepressant bupropion, it has a boxed warning similar to other antidepressants in its class of increased risk of suicidal thoughts and behaviors, especially in children, adolescents, and young adults.38Contrave can lower the seizure threshold; therefore it should not be used in people with a seizure disorder. It can also raise BP and heart rate; however the clinical significance of hypertension and elevated heart rate observed with Contrave treatment is unclear. Blood pressure rose on average by 1 point during the first 8 weeks of treatment and then returned to baseline.38 The heart rate also increased by about 1.7 beats per minute.38 Patients with uncontrolled hypertension should avoid Contrave.
Contrave should not be taken with products contain bupropion or naltrexone. It should not be taken by patient who are regularly taking opioids or who are opioid dependent, or who are experiencing opiate withdrawal. Pregnant women should also avoid Contrave. In patients with renal impairment the maximum dose is 1 tablet twice a day and in patients with hepatic impairment the maximum dose is 1 tablet a day.
Liraglutide
Liraglutide is the newest weight loss medication to be approved by the FDA for chronic weight management as an adjunct to a reduced calorie diet and increased physical activity in adult patients with BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with hypertension, diabetes, or dyslipidemia. The recommended dose of liraglutide is 3 mg daily. The initial dose is 0.6 mg daily for the first week, then titrated up by 0.6 each week for 4 weeks, until reaching 3 mg daily.
Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) receptor agonist, which are expressed in the brain and is involved in the control of appetite. It is also found in the beta cells of the pancreas, where GLP-1 receptors stimulate insulin release in response to elevated blood glucose concentrations and suppress glucagon secretion. Endogenous GLP-1 has a half-life of 1.5 to 2 minutes due to degradation by the DDP-4 enzyme, but liraglutide is stable against degradation by peptidases and has a half- life of 13 hours.
Liraglutide was studied in a 56-week randomized, double-blind, placebo-controlled trial, which compared liraglutide 3 mg with an active placebo of diet and physical activity.39 Inclusion criteria were adults aged ≥ 18 years old with a BMI 30 kg/m2 to 45 kg/m2 or BMI 27 kg/m2 to 45 kg/m2 with dyslipidemia and/or hypertension. Both groups received lifestyle modification counseling. Patients were excluded if they had DM.
In the trial, 3,731 participants enrolled, 2,487 in the liraglutide group and 1,244 in the placebo group; 78.7% of the participants were female and the average age was 45 years. Subjects in the liraglutide group had a weekly titration regimen. The starting dose at week 1 was 0.6 mg, week 2 was 1.2 mg, week 3 was 1.8 mg, week 4 was 2.4 mg, and week 5 was 3.0 kg.
The completer population showed 9.2% weight loss in the liraglutide group and 3.0% weight loss in the control group.39 Weight loss of ≥ 5% was seen in 63.2% and 27.1% of the liraglutide and placebo groups, respectively. Weight loss rates of ≥ 10% was seen by 33.1% and 10.6%, respectively. The most common AEs were nausea, diarrhea, and constipation. Nausea generally occurred early during the titration period and then diminished.
A second clinically relevant study was performed with liraglutide. Often patients are able to lose weight with diet and exercise and then plateau. This study examined participants who lost 5% percent of their initial body weight and then were randomized to liraglutide or placebo.40 Key inclusion criteria were people aged ≥ 18 years old with a BMI 30 kg/m2 to 45 kg/m2 or BMI 27 kg/m2 to 45 kg/m2 with dyslipidemia and/or hypertension. In order to be randomized, participants were required to lose at least 5% of their initial body weight on a 1,200 kcal to 1,400 kcal diet with increased physical activity during a 4 to 12 week run-in period.
Four hundred twenty-two participants were enrolled, 212 in the liraglutide group and 210 in the placebo group. Most of the participants were female (81%). The average BMI in the study was 35.6 kg/m2. Subjects in the liraglutide group had a weekly titration regimen.
After an average weight loss of 6% using a low calorie diet and increased physical activity the participants were randomized to continue diet and increased activity alone (placebo) or with liraglutide. At week 56 the results showed an additional 6.2% weight loss in the liraglutide group and 0.2% weight gain in the placebo group. The liraglutide group had a greater number of participants with ≥ 5% weight loss compared to placebo, 50.5% vs 21.8% (P < .0001).40 In the pooled data set from the registration trials the 3 most common GI AEs were nausea, diarrhea, and constipation occurring in 39.3%, 20.9%, and 19.4% of participants respectively. Discontinuation due to nausea for liraglutide was 2.9%.41
Clinicians should be aware that medications that can cause hypoglycemia such as sulfonylureas and insulin must be tapered as patients lose weight with liraglutide. Documented symptomatic hypoglycemia in patients with T2DM and with sulfonylurea background therapy was 43.6% with liraglutide vs 27.3% with placebo.
In the setting of renal impairment, patients treated with GLP-1 receptor agonists, including liraglutide, have had reports of acute renal failure and worsening of chronic renal failure usually associated with nausea, vomiting, diarrhea, or dehydration. Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. As the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2.
Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide in postmarketing reports. After initiation of liraglutide, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, liraglutide should promptly be discontinued.
Conclusion
The treatment of obesity and overweight with comorbidities has always been a challenge. In the past there were few FDA-approved drugs and many drugs had to be used off-label. The toolbox of medications available for medical weight management is more robust than ever. The medications have different MOAs and can be used in a variety of patients. There are differences in the classes and some are controlled substances. Phentermine, lorcaserin, and Qsymia (phentermine/topiramate) are controlled substances whereas orlistat, naltrexone/bupropion and liraglutide are not. Other differences exist including duration of use. The sympathomimetic drugs have a limited window of use whereas orlistat, Qsymia (phentermine/topiramate), lorcaserin, naltrexone/bupropion, and liraglutide do not.
The medications that are available have a wide variety of MOAs. Therefore, if a patient fails one medication, then it is very reasonable to try a medication with a different MOA. In addition, there is the potential for weight regain when weight reduction medications are discontinued. As people lose weight their metabolic rate decreases about 15 kcal per pound of weight reduction.42
Another challenge of using these medications is managing patient expectations. The current metric used for FDA approval is a 5% weight loss that is greater in the study group compared with the diet and physical activity active control. However, many clinicians and patients do not find this weight reduction amount consistent with their expectations. In addition weight loss trajectory may also be too slow for patients and cause early discontinuation. Therefore, patient education and a discussion of reasonable expectations for weight reduction medications are necessary.
Clinicians must acknowledge that there are limitations to the use of these medications. Newer agents do have a higher cost and insurance reimbursement is somewhat limited. However, they offer the opportunity to prevent more expensive, protracted conditions such as diabetes and cardiovascular disease. In summary, clinicians now have a wider variety of medication options to be used with dietary and lifestyle changes in order to improve health and prevent chronic diseases.
1. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief. 2012(82):1-8.
2. Jensen MD, Ryan DH, Apovian CM, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129(25 suppl 2):S102-S138.
3. U.S. Food and Drug Administration. Drugs@FDA: diethylpropion hydrochloride. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=012546&DrugName=TENUATE%20DOSPAN&ActiveIngred=DIETHYLPROPION%20HYDROCHLORIDE&SponsorApplicant=ACTAVIS%20LABS%20UT%20INC&ProductMktStatus=1&goto=Search.DrugDetails. Accessed December 28, 2015.
4. U.S. Food and Drug Administration. Drugs@FDA: benzphetamine hydrochloride. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=012427&DrugName=DIDREX&ActiveIngred=BENZPHETAMINE%20HYDROCHLORIDE&SponsorApplicant=PHARMACIA%20AND%20UPJOHN&ProductMktStatus=3&goto=Search.DrugDetails. Accessed December 28, 2015.
5. U.S. Food and Drug Administration. Drugs@ FDA: phendimetrazine tartrate. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=088021&DrugName=BONTRIL&ActiveIngred=PHENDIMETRAZINE%20TARTRATE&SponsorApplicant=VALEANT&ProductMktStatus=3&goto=Search.DrugDetails. Accessed December 28, 2015.
6. U.S. Food and Drug Administration. Drugs@FDA: phentermine. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=085128&DrugName=ADIPEX%2DP&ActiveIngred=PHENTERMINE%20HYDROCHLORIDE&SponsorApplicant=TEVA&ProductMktStatus=1&goto=Search.DrugDetails. Accessed December 28, 2015.
7. U.S. Food and Drug Administration. Drugs @ FDA: phentermine hydrochloride. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=202088&DrugName=SUPRENZA&ActiveIngred=PHENTERMINE%20HYDROCHLORIDE&SponsorApplicant=CITIUS%20PHARMS&ProductMktStatus=1&goto=Search.DrugDetails. Accessed December 28, 2015.
8. Hendricks EJ, Rothman RB, Greenway FL. How Physician Obesity Specialists use drugs to treat obesity. Obesity (Silver Spring). 2009;17(9):1730-1735.
9. Gilman AG, Gilman A, Goodman LS, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th ed. New York: Pergamon Press; 1990: 211.
10. Gilman AG, Gilman A, Goodman LS, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th ed. New York: Pergamon Press; 1990:217.
11. Addy C, Jumes P, Rosko K, et al. Pharmacokinetics, safety, and tolerability of phentermine in health participants receiving taranabant, a novel cannabinoid-1 receptor (CB1R) inverse agonist. J Clin Pharmacol. 2009;49(10):1228-1232.
12. U.S. Department of Justice, Drug Enforcement Administration, Office of Diversion Control. Controlled substances. U.S. Department of Justice Website. http://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf. Updated November 12, 2015. Accessed December 16, 2015.
13. Bray GA, Greenway FL. Pharmacological treatment of the overweight patient. Pharmacol Rev. 2007;59(2):151-184.
14. V1-0521 (QNEXA) Advisory committee briefing document. NDA 022580. Endocrinologic and Metabolic Drugs Advisory Committee meeting; June 17, 2010.
15. Cercato C, Roizenblatt VA, Leanca CC, et al. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of diethylpropion in the treatment of obese subjects. Int J Obes (Lond). 2009;33(8):857-865.
16. Haddock CK, Poston WS, Dill PL, Foreyt JP, Ericsson M. Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Int J Obes (Lond). 2002;26(2):262-273.
17. Suplicy H, Boquszewski CL, dos Santos CM, do Desterro de Fiqueiredo M, Cunha DR, Radominski R. A comparative study of five centrally acting drugs on pharmacological treatment of obesity. Int J Obes (Lond). 2014;38(8):1097-1103.
18. Ioannides-Demos LL, Proietto J, McNeill JJ. 2005. Pharmacotherapy for obesity. Drugs. 2005;65(10): 1391-1418.
19. Drent ML, van der Veen EA. Lipase inhibition: a novel concept in the treatment of obesity. Int J Obes Relat Metab Disord. 1993;17(4):241-244.
20. Xenical [package insert]. Nutley, NJ: Roche Laboratories Inc.; 1999.
21. U.S. Food and Drug Administration. FDA Drug Safety Communication: Completed safety review of Xenical/Alli and severe liver injury. U.S. Food and Drug Administration Website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213038.htm. Updated August 2, 2010. Accessed December 16, 2015.
22. Sall D, Wang J, Rashkin M, Welch M, Droege C, Schauer D. Orlistat-induced fulminant hepatic failure. Clin Obes. 2014;4(6):342-347.
23. Sjöström L, Rissanen A, Andersen T, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet. 1998;352(9123):167-172.
24. Hauptman J, Lucas C, Boldrin MN, Collins H, Segal KR. Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med. 2000;9(2):160-167.
25. Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27(1):155-161.
26. Torgerson JS, Arlinger K, Käppi M, Sjöström L. Principles for enhanced recruitment of subjects in a large clinical trial. the XENDOS (XENical in the prevention of Diabetes in Obese Subjects) study experience. Control Clin Trials. 2001;22(5):515-525.
27.Smith SR, Weissman NJ, Anderson CM, et al; Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363(3):245-256.
28. Fidler MC, Sanchez M, Raether B, et al; BLOSSOM Clinical Trial Group. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96(10):3067-3077.
29. O’Neil PM, Smith SR, Weisserman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM Study. Obesity (Silver Spring). 2012;20(7):1426-1436.
30. U.S. Food and Drug Administration. FDA approves weight-management drug Qsymia. U.S. Food and Drug Administration Website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm. Published July 17, 2012. Accessed December 16, 2015.
31. Shin J, Gadde KM. Clinical utility of phentermine/topiramate (Qsymia™) combination for the treatment of obesity. Diabetes Metab Syndr Obes. 2013;6:131-139.
32. Qsymia [package insert] Mountain View, CA: Vivus, Inc; 2012.
33. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20(2):330-342.
34. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9774):1341-1352.
35. Plodkowski RA, Nguyen Q, Sundaram U, Nguyen L, Chau DL, St Jeor S. Bupropion and naltrexone: a review of their use individually and in combination for the treatment of obesity. Expert Opin Pharmacother. 2009;10(6):1069-1081.
36. Greenway FL, Fujioka K, Plodkowski RA, et al; COR-I Study Group. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2010;376(9741):595-605.
37. Hollander P, Gupta AK, Plodkowski R, et al; COR-Diabetes Study Group. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care. 2013;36(12):4022-4029.
38. Contrave [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2014.
39. Pi-Sunyer X, Astrup A, Fujioka K, et al; SCALE Obesity and Prediabetes NN8022-1839 Study Group. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Eng J Med. 2015;373(1):11-22.
40. Wadden TA, Hollander P, Klein S, et al; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013;37(11):1443-1451
41. Saxenda [package insert]. Novo Nordisk: Plainsboro, NJ; 2015.
42.Schwartz A, Doucet E. Relative changes in resting energy expenditure during weight loss: a systemic review. Obes Rev. 2010;11(7): 531-547. ```````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````
1. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief. 2012(82):1-8.
2. Jensen MD, Ryan DH, Apovian CM, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129(25 suppl 2):S102-S138.
3. U.S. Food and Drug Administration. Drugs@FDA: diethylpropion hydrochloride. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=012546&DrugName=TENUATE%20DOSPAN&ActiveIngred=DIETHYLPROPION%20HYDROCHLORIDE&SponsorApplicant=ACTAVIS%20LABS%20UT%20INC&ProductMktStatus=1&goto=Search.DrugDetails. Accessed December 28, 2015.
4. U.S. Food and Drug Administration. Drugs@FDA: benzphetamine hydrochloride. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=012427&DrugName=DIDREX&ActiveIngred=BENZPHETAMINE%20HYDROCHLORIDE&SponsorApplicant=PHARMACIA%20AND%20UPJOHN&ProductMktStatus=3&goto=Search.DrugDetails. Accessed December 28, 2015.
5. U.S. Food and Drug Administration. Drugs@ FDA: phendimetrazine tartrate. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=088021&DrugName=BONTRIL&ActiveIngred=PHENDIMETRAZINE%20TARTRATE&SponsorApplicant=VALEANT&ProductMktStatus=3&goto=Search.DrugDetails. Accessed December 28, 2015.
6. U.S. Food and Drug Administration. Drugs@FDA: phentermine. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=085128&DrugName=ADIPEX%2DP&ActiveIngred=PHENTERMINE%20HYDROCHLORIDE&SponsorApplicant=TEVA&ProductMktStatus=1&goto=Search.DrugDetails. Accessed December 28, 2015.
7. U.S. Food and Drug Administration. Drugs @ FDA: phentermine hydrochloride. U.S. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=202088&DrugName=SUPRENZA&ActiveIngred=PHENTERMINE%20HYDROCHLORIDE&SponsorApplicant=CITIUS%20PHARMS&ProductMktStatus=1&goto=Search.DrugDetails. Accessed December 28, 2015.
8. Hendricks EJ, Rothman RB, Greenway FL. How Physician Obesity Specialists use drugs to treat obesity. Obesity (Silver Spring). 2009;17(9):1730-1735.
9. Gilman AG, Gilman A, Goodman LS, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th ed. New York: Pergamon Press; 1990: 211.
10. Gilman AG, Gilman A, Goodman LS, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th ed. New York: Pergamon Press; 1990:217.
11. Addy C, Jumes P, Rosko K, et al. Pharmacokinetics, safety, and tolerability of phentermine in health participants receiving taranabant, a novel cannabinoid-1 receptor (CB1R) inverse agonist. J Clin Pharmacol. 2009;49(10):1228-1232.
12. U.S. Department of Justice, Drug Enforcement Administration, Office of Diversion Control. Controlled substances. U.S. Department of Justice Website. http://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf. Updated November 12, 2015. Accessed December 16, 2015.
13. Bray GA, Greenway FL. Pharmacological treatment of the overweight patient. Pharmacol Rev. 2007;59(2):151-184.
14. V1-0521 (QNEXA) Advisory committee briefing document. NDA 022580. Endocrinologic and Metabolic Drugs Advisory Committee meeting; June 17, 2010.
15. Cercato C, Roizenblatt VA, Leanca CC, et al. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of diethylpropion in the treatment of obese subjects. Int J Obes (Lond). 2009;33(8):857-865.
16. Haddock CK, Poston WS, Dill PL, Foreyt JP, Ericsson M. Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Int J Obes (Lond). 2002;26(2):262-273.
17. Suplicy H, Boquszewski CL, dos Santos CM, do Desterro de Fiqueiredo M, Cunha DR, Radominski R. A comparative study of five centrally acting drugs on pharmacological treatment of obesity. Int J Obes (Lond). 2014;38(8):1097-1103.
18. Ioannides-Demos LL, Proietto J, McNeill JJ. 2005. Pharmacotherapy for obesity. Drugs. 2005;65(10): 1391-1418.
19. Drent ML, van der Veen EA. Lipase inhibition: a novel concept in the treatment of obesity. Int J Obes Relat Metab Disord. 1993;17(4):241-244.
20. Xenical [package insert]. Nutley, NJ: Roche Laboratories Inc.; 1999.
21. U.S. Food and Drug Administration. FDA Drug Safety Communication: Completed safety review of Xenical/Alli and severe liver injury. U.S. Food and Drug Administration Website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213038.htm. Updated August 2, 2010. Accessed December 16, 2015.
22. Sall D, Wang J, Rashkin M, Welch M, Droege C, Schauer D. Orlistat-induced fulminant hepatic failure. Clin Obes. 2014;4(6):342-347.
23. Sjöström L, Rissanen A, Andersen T, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet. 1998;352(9123):167-172.
24. Hauptman J, Lucas C, Boldrin MN, Collins H, Segal KR. Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med. 2000;9(2):160-167.
25. Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27(1):155-161.
26. Torgerson JS, Arlinger K, Käppi M, Sjöström L. Principles for enhanced recruitment of subjects in a large clinical trial. the XENDOS (XENical in the prevention of Diabetes in Obese Subjects) study experience. Control Clin Trials. 2001;22(5):515-525.
27.Smith SR, Weissman NJ, Anderson CM, et al; Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363(3):245-256.
28. Fidler MC, Sanchez M, Raether B, et al; BLOSSOM Clinical Trial Group. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96(10):3067-3077.
29. O’Neil PM, Smith SR, Weisserman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM Study. Obesity (Silver Spring). 2012;20(7):1426-1436.
30. U.S. Food and Drug Administration. FDA approves weight-management drug Qsymia. U.S. Food and Drug Administration Website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm. Published July 17, 2012. Accessed December 16, 2015.
31. Shin J, Gadde KM. Clinical utility of phentermine/topiramate (Qsymia™) combination for the treatment of obesity. Diabetes Metab Syndr Obes. 2013;6:131-139.
32. Qsymia [package insert] Mountain View, CA: Vivus, Inc; 2012.
33. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20(2):330-342.
34. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9774):1341-1352.
35. Plodkowski RA, Nguyen Q, Sundaram U, Nguyen L, Chau DL, St Jeor S. Bupropion and naltrexone: a review of their use individually and in combination for the treatment of obesity. Expert Opin Pharmacother. 2009;10(6):1069-1081.
36. Greenway FL, Fujioka K, Plodkowski RA, et al; COR-I Study Group. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2010;376(9741):595-605.
37. Hollander P, Gupta AK, Plodkowski R, et al; COR-Diabetes Study Group. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care. 2013;36(12):4022-4029.
38. Contrave [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2014.
39. Pi-Sunyer X, Astrup A, Fujioka K, et al; SCALE Obesity and Prediabetes NN8022-1839 Study Group. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Eng J Med. 2015;373(1):11-22.
40. Wadden TA, Hollander P, Klein S, et al; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013;37(11):1443-1451
41. Saxenda [package insert]. Novo Nordisk: Plainsboro, NJ; 2015.
42.Schwartz A, Doucet E. Relative changes in resting energy expenditure during weight loss: a systemic review. Obes Rev. 2010;11(7): 531-547. ```````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````
Lessons Learned From the RACAT Trial: A Comparison of Rheumatoid Arthritis Therapies
Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints, leading to joint destruction, with significant long-term morbidity and mortality. Over the past quarter century, multiple new therapies and approaches have been introduced, so patients newly diagnosed with RA can realistically expect to be in remission while taking their medications. However, many of the most commonly used medications are costly, making RA care one of the most expensive per patient.1 Early treatment with disease-modifying antirheumatic drugs (DMARDs) and treating all patients to the target of low-disease activity are critical keys to optimal outcomes.
Methotrexate (MTX) is a highly effective and economical first-line DMARD that is recommended as the initial therapy for most patients.2,3 Unfortunately, one-half to two-thirds of patients will not have complete responses and, therefore, require additional therapy. Fortunately, there are more than a dozen therapies that, when added to MTX, have been shown to be better than MTX alone. However, since some of these options use conventional DMARDs and others require biologics, there exist very different economic as well as potential toxicity implications. Understanding how best to treat patients with RA with active disease while on an appropriate dose of MTX is important for both medical and economic reasons.
Despite this being a seminal question for the past 15 years, no blinded trial had addressed this issue before the VA Cooperative Studies Program (CSP) Rheumatoid Arthritis: Comparison of Active Therapies (RACAT) trial. This was true for several reasons, likely including the considerable cost of conducting such a trial and the low priority of this research question for the pharmaceutical industry. Industry-funded trials in RA often focus on new indications, and these studies often fail to address the questions most relevant to the day-to-day care of patients.
For example, it is often not particularly helpful to the clinician that patients placed on “therapy A” are doing better or worse than those placed on “therapy B” after 1 year of the same treatment. Such rigid protocols do not mimic what is done in the clinic: A patient’s treatment program is often changed much earlier than 1 year when it is not working. Therefore, RACAT was designed to more closely mirror clinical practice and to test the strategy of starting conventional therapy before biologic therapy, with the option of changing therapy for nonresponders—similar to what most clinicians would do in practice. This article explores the lessons learned from this landmark trial and highlights the critical role that the VA CSP played.
Trial Background
The RACAT trial, a comparative effectiveness, randomized, double-blind, noninferiority trial, originated as a joint effort of investigators from the VA and the Rheumatology and Arthritis Investigational Network (RAIN) and subsequently involved Canadian enrollment sites. The RACAT results were published in the New England Journal of Medicine in 2013, and its investigative team was awarded the 2014 Lee C. Howley Sr. Prize by the Arthritis Foundation for conducting the most important arthritis research worldwide from the previous year.4
The RACAT originated with a letter of intent to the VA CSP in 2003. The central question to be addressed was whether biologic therapy should be added first in patients with active RA despite MTX or whether clinicians should first add the much less expensive but very effective combination of conventional therapies, including sulfasalazine (SSZ) and hydroxychloroquine to MTX.5,6 This led to the 48-week, binational, multicenter, randomized, double-blind, noninferiority trial comparing the strategy of initially adding hydroxychloroquine and SSZ to MTX (triple therapy group) in patients with active disease despite MTX compared with the strategy of first adding etanercept to MTX.4 Etanercept is among the most commonly used biologic agents approved for RA. Etanercept works by targeting tumor necrosis factor, a pro-inflammatory cytokine central in disease pathogenesis. Both RACAT treatment groups were switched in a blinded fashion to the other therapy at 24 weeks if they did not have a clinically significant improvement. The primary endpoint was a change in the disease activity score (DAS28) from baseline to 48 weeks. An important secondary endpoint was the comparison of radiographic progression of disease at 48 weeks as measured by the validated modified Sharp scoring method. Additionally, and very importantly, economic and functional outcomes were assessed. To conduct the trial, investigators and patients participated from 16 VA sites in addition to 8 Canadian and 12 RAIN sites. The study was sponsored and primarily funded by the VA CSP, VA Office of Research and Development with additional funding coming from the Canadian Institutes of Health Research (CIHR) and from the National Institutes of Health.
Trial Design
To understand the RACAT trial design, one must appreciate the landscape of RA trials conducted in the early-to-mid 2000s. At that time, there had been an explosion of new biologic therapies for RA. Most of the trials were placebo-controlled studies with nonresponders to MTX being placed on placebo vs active drug.7 For ethical and legal reasons, however, clinicians do not treat patients with placebo, especially when highly effective therapies exist, thus limiting the relevance of the classic placebo-controlled trial in RA.8 One of the main tenets of RA therapy in this century has been to use effective therapies to treat patients with active RA with the goal of achieving (and maintaining) either low-disease activity or remission as measured by a composite scoring system, most commonly the DAS28. In order to do this in the framework of a designed research trial, therapies commonly need to be escalated when patients are not doing well, similar to what is done in clinical practice.
The RACAT trial was a comparative effectiveness trial. Comparative effectiveness is not a new idea; in fact, it is precisely how many clinicians practice medicine. It is simply comparing 2 or more treatments to determine which is more effective. Since the inception of the RACAT trial, the American Recovery and Reinvestment Act of 2009 provided $1.1 billion for major expansion of comparative effectiveness research. This changing landscape of federally funded research has highlighted the growing national interest in this type of trial.
This trial design posed several barriers as it applies to the study medications. Methotrexate, hydroxychloroquine, and SSZ are generic medications most often taken orally (MTX is available for parenteral administration). In contrast, etanercept is most often given as a subcutaneous injection and currently is not available in a biosimilar (generic) form in the U.S.; thus, the medication and its delivery device are proprietary. Because this was a double-blind, noninferiority trial, the study required both etanercept-active medication and placebo in identical delivery devices. The makers of etanercept donated placebo etanercept to make blinding possible. The VA, along with CIHR, purchased active etanercept for all trial participants, including those from Canada and the RAIN network. The VA research pharmacy in Albuquerque, New Mexico, was responsible for blinding all active and placebo drugs used in the trial and made these drugs available to all patients, even those not eligible for VA care.In a precedent-setting effort for rheumatology research, RACAT culminated from the collaborations among the private sector, the Canadian health system, and VA. The VA CSP was responsible for the collection of the clinical data, data analyses (Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System [VABHS]); the collection of economic data (VA Palo Alto Health Care System); the provision of and payment for the study medications; and the preparation and distribution of active etanercept and placebos (New Mexico VA Health Care System [NMVAHCS]). Through this organizational structure, the trial was successfully completed. In addition to placebo etanercept provided by Amgen (Thousand Oaks, CA), Pharmascience (Montreal, Quebec) provided blinded SSZ and blinded placebo. Neither company was involved in the study design nor did they have an active role in the trial. Hydroxychoroquine and matched placebo were provided by the central pharmacy of the NMVAHCS.
Safety Monitoring
As with any treatment study, patient safety was of paramount importance. Through the aforementioned organizational structure, each participating site had administrative team members who were responsible to the VABHS CSP to ensure research adherence and compliance with best practices. Additionally, an independent data and safety monitoring committee (DSMC) monitored the trial for safety and scientific integrity. At the time that the trial began in 2007, there were questions about the relative efficacy of triple therapy vs MTX plus biologic therapy. Because of this question, the DSMC raised concerns that patients may be placed at a higher risk of joint damage if not placed sooner on biologic therapy. As a response to this concern, the blinded radiographic reviewers were asked to read the hand and feet X-rays as the study progressed, allowing the DSMC to watch for any emerging safety signals. There were none, and in fact, the therapies were essentially identical radiographically.
The consequence of this request was multifold. First, patient safety was maintained; second, the study team was forced to navigate the logistic and technologic challenges posed by the reading and interpretation of the radiographs at an earlier time point than was originally planned; and last, as a result, results became available and were disseminated in a relatively narrow time frame. This third point was very important. One of the major concerns of foregoing biologic therapy was the potential for joint damage. Without the radiographic information, the manuscript could not have been completed in a timely fashion.
Trial Results
The trial was a 48-week, double-blind, noninferiority trial in which 353 patients with RA who had active disease despite MTX therapy were randomized to a triple therapy regimen of DMARDs (baseline MTX, plus SSZ and hydroxychloroquine) or baseline MTX plus etanercept (Figure 1). Patients who did not have a clinically significant improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy.
The primary endpoint, the change between baseline and 48 weeks in the DAS28, was similar; thus the strategy of first starting triple therapy was not inferior to first starting etanercept (the change in DAS28 was -2.12 and -2.29 respectively, P < .0001, supporting noninferiority, Figure 2). Both groups had significant improvement over the course of the first 24 weeks (P = .001). A total of 27% of participants in each group switched at 24 weeks (Figure 3). Patients in both groups who switched therapies had improvement after switching (P < .001), and the response after switching did not differ significantly between the 2 groups. Importantly, there were no significant between-group differences in radiographic progression (P = .43), pain and health-related quality of life (QOL), or in medication-associated major adverse events (AEs), although there were numerically more serious infections with etanercept-MTX therapy (12 vs 4). Gastrointestinal AEs were numerically more frequent with triple therapy; whereas infections and skin and subcutaneous AEs were more frequent with etanercept-MTX therapy.
The cost-effectiveness of adding SSZ and hydroxychloroquine to MTX vs adding etanercept to MTX, using a predetermined measurement of QOL, was assessed in this trial.9 These data were initially presented in abstract form at the 2014 American College of Rheumatology national meeting. Considered was the ratio of all the incremental costs between the 2 treatment strategies to the benefits, as measured in quality-adjusted life-years (QALYs), where QOL is measured as an index with 1 being equivalent to full health and 0 being equivalent to death. This incremental cost-effectiveness ratio produces a monetary cost for each QALY, which is an indication of cost-effectiveness and value. Most health care systems currently consider anything that costs < $50,000/QALY to be cost-effective. To be conservative, the trial researchers considered anything up to $100,000 for an additional QALY acceptable.
In the 48-week trial analysis, the use of etanercept first, instead of triple therapy, would incur about $1 million of cost per QALY, far more than the $50,000 to $100,000 deemed to be reasonable value. Biologic therapy use first, had a near-zero chance of being cost-effective and would be cost-effective only after failure of triple therapy; results that were robust to all plausible scenarios.
Economic Implications
As noted in the trial design, economic data were prospectively collected for later analysis. The availability and cost of biologic treatments have become a critical issue. In 2005, it was reported that the U.S. biologics market reached $52 billion and was noted to have an annual growth of 17%.10 In 2011, 8 of the top 20 drugs sold in the U.S. were biologics, and year-to-year biologics spending has grown by 6.6%. In 2013, the top 100 biologics in the U.S. had combined sales of $66.3 billion.11 The researchers analysis demonstrated that using a strategy of triple therapy first could result in health care cost savings in the tens of billions of dollars. Importantly, these savings would occur at the same time as patients were receiving optimal care.
Summary
The major conclusions from the RACAT trial in RA patients with active disease despite MTX are the following: 1. The strategy of first starting the conventional DMARD triple therapy combination is noninferior to first starting etanercept, based on both clinical and radiographic outcomes. 2. The triple therapy group had more minor gastrointestinal events, whereas the etanercept group had more infections. Patients in either group who did not respond well to the initial treatment and switched (27% in both groups) improved significantly after the switch. 3. The economic implications of these findings are significant. The incremental cost differences approached $1 million per QALY.
The VA CSP should be congratulated for supporting and funding this trial, which will inform therapeutic decisions in RA for years to come. These results allow clinicians to provide not only optimal health care for their RA patients, but also maximize the value of their health care.
1. Gavan S, Harrison M, Iglesias C, Barton A, Manca A, Payne K. Economics of stratified medicine in rheumatoid arthritis. Curr Rheumatol Rep. 2014;16(12):468.
2. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying anti-rheumatic drugs and biologics in the treatment of rheumatoid arthritis (RA). Arthritis Care Res (Hoboken). 2012;64(5):625-639.
3. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492-509.
4. O'Dell JR, Mikuls TR, Taylor TH, et al; CSP 551 RACAT Investigators. Therapies for active rheumatoid arthritis after methotrexate failure. N Eng J Med. 2013;369(4):307-318.
5. Moreland LW, O'Dell JR, Paulus HE, et al; TEAR Investigators. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the Treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012;64(9):2824-2835.
6. O'Dell JR, Leff R, Paulsen G, et al. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002;46(5):1164-1170.
7. Singh JA, Cameron DR. Summary of AHRQ's comparative effectiveness review of drug therapy for rheumatoid arthritis in adults-an update. J Manag Care Pharm. 2012;18(4)(suppl C):S1-S18.
8. Chan TE. Regulating the placebo effect in clinical practice. Med Law Rev. 2014;23(1):1-26.
9. Bansback N, Phibb S, Sun H, et al. Cost effectiveness of adding etanercept to methotrexate therapy versus first adding sulfasalazine and hydroxychloroquine: a randomized noninferiority trial [American College of Rheumatology abstract 2781]. Arthritis Rheum. 2014;66(suppl 11):S1214.
10. Ernst and Young. Beyond borders: global biotechnology report 2005. Ernst and Young Website. https://www2.eycom.ch/publications/items/biotech-report/2005/2005_EY_Global_Biotech_Report.pdf. Accessed December 3, 2015.
11. Mulcahy AW, Predmore Z, Mattke S. The cost savings potential of biosimilar drugs in the United States. Rand Corporation Website. http://www.rand.org/pubs/perspectives/PE127.html. Accessed December 3, 2015.
Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints, leading to joint destruction, with significant long-term morbidity and mortality. Over the past quarter century, multiple new therapies and approaches have been introduced, so patients newly diagnosed with RA can realistically expect to be in remission while taking their medications. However, many of the most commonly used medications are costly, making RA care one of the most expensive per patient.1 Early treatment with disease-modifying antirheumatic drugs (DMARDs) and treating all patients to the target of low-disease activity are critical keys to optimal outcomes.
Methotrexate (MTX) is a highly effective and economical first-line DMARD that is recommended as the initial therapy for most patients.2,3 Unfortunately, one-half to two-thirds of patients will not have complete responses and, therefore, require additional therapy. Fortunately, there are more than a dozen therapies that, when added to MTX, have been shown to be better than MTX alone. However, since some of these options use conventional DMARDs and others require biologics, there exist very different economic as well as potential toxicity implications. Understanding how best to treat patients with RA with active disease while on an appropriate dose of MTX is important for both medical and economic reasons.
Despite this being a seminal question for the past 15 years, no blinded trial had addressed this issue before the VA Cooperative Studies Program (CSP) Rheumatoid Arthritis: Comparison of Active Therapies (RACAT) trial. This was true for several reasons, likely including the considerable cost of conducting such a trial and the low priority of this research question for the pharmaceutical industry. Industry-funded trials in RA often focus on new indications, and these studies often fail to address the questions most relevant to the day-to-day care of patients.
For example, it is often not particularly helpful to the clinician that patients placed on “therapy A” are doing better or worse than those placed on “therapy B” after 1 year of the same treatment. Such rigid protocols do not mimic what is done in the clinic: A patient’s treatment program is often changed much earlier than 1 year when it is not working. Therefore, RACAT was designed to more closely mirror clinical practice and to test the strategy of starting conventional therapy before biologic therapy, with the option of changing therapy for nonresponders—similar to what most clinicians would do in practice. This article explores the lessons learned from this landmark trial and highlights the critical role that the VA CSP played.
Trial Background
The RACAT trial, a comparative effectiveness, randomized, double-blind, noninferiority trial, originated as a joint effort of investigators from the VA and the Rheumatology and Arthritis Investigational Network (RAIN) and subsequently involved Canadian enrollment sites. The RACAT results were published in the New England Journal of Medicine in 2013, and its investigative team was awarded the 2014 Lee C. Howley Sr. Prize by the Arthritis Foundation for conducting the most important arthritis research worldwide from the previous year.4
The RACAT originated with a letter of intent to the VA CSP in 2003. The central question to be addressed was whether biologic therapy should be added first in patients with active RA despite MTX or whether clinicians should first add the much less expensive but very effective combination of conventional therapies, including sulfasalazine (SSZ) and hydroxychloroquine to MTX.5,6 This led to the 48-week, binational, multicenter, randomized, double-blind, noninferiority trial comparing the strategy of initially adding hydroxychloroquine and SSZ to MTX (triple therapy group) in patients with active disease despite MTX compared with the strategy of first adding etanercept to MTX.4 Etanercept is among the most commonly used biologic agents approved for RA. Etanercept works by targeting tumor necrosis factor, a pro-inflammatory cytokine central in disease pathogenesis. Both RACAT treatment groups were switched in a blinded fashion to the other therapy at 24 weeks if they did not have a clinically significant improvement. The primary endpoint was a change in the disease activity score (DAS28) from baseline to 48 weeks. An important secondary endpoint was the comparison of radiographic progression of disease at 48 weeks as measured by the validated modified Sharp scoring method. Additionally, and very importantly, economic and functional outcomes were assessed. To conduct the trial, investigators and patients participated from 16 VA sites in addition to 8 Canadian and 12 RAIN sites. The study was sponsored and primarily funded by the VA CSP, VA Office of Research and Development with additional funding coming from the Canadian Institutes of Health Research (CIHR) and from the National Institutes of Health.
Trial Design
To understand the RACAT trial design, one must appreciate the landscape of RA trials conducted in the early-to-mid 2000s. At that time, there had been an explosion of new biologic therapies for RA. Most of the trials were placebo-controlled studies with nonresponders to MTX being placed on placebo vs active drug.7 For ethical and legal reasons, however, clinicians do not treat patients with placebo, especially when highly effective therapies exist, thus limiting the relevance of the classic placebo-controlled trial in RA.8 One of the main tenets of RA therapy in this century has been to use effective therapies to treat patients with active RA with the goal of achieving (and maintaining) either low-disease activity or remission as measured by a composite scoring system, most commonly the DAS28. In order to do this in the framework of a designed research trial, therapies commonly need to be escalated when patients are not doing well, similar to what is done in clinical practice.
The RACAT trial was a comparative effectiveness trial. Comparative effectiveness is not a new idea; in fact, it is precisely how many clinicians practice medicine. It is simply comparing 2 or more treatments to determine which is more effective. Since the inception of the RACAT trial, the American Recovery and Reinvestment Act of 2009 provided $1.1 billion for major expansion of comparative effectiveness research. This changing landscape of federally funded research has highlighted the growing national interest in this type of trial.
This trial design posed several barriers as it applies to the study medications. Methotrexate, hydroxychloroquine, and SSZ are generic medications most often taken orally (MTX is available for parenteral administration). In contrast, etanercept is most often given as a subcutaneous injection and currently is not available in a biosimilar (generic) form in the U.S.; thus, the medication and its delivery device are proprietary. Because this was a double-blind, noninferiority trial, the study required both etanercept-active medication and placebo in identical delivery devices. The makers of etanercept donated placebo etanercept to make blinding possible. The VA, along with CIHR, purchased active etanercept for all trial participants, including those from Canada and the RAIN network. The VA research pharmacy in Albuquerque, New Mexico, was responsible for blinding all active and placebo drugs used in the trial and made these drugs available to all patients, even those not eligible for VA care.In a precedent-setting effort for rheumatology research, RACAT culminated from the collaborations among the private sector, the Canadian health system, and VA. The VA CSP was responsible for the collection of the clinical data, data analyses (Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System [VABHS]); the collection of economic data (VA Palo Alto Health Care System); the provision of and payment for the study medications; and the preparation and distribution of active etanercept and placebos (New Mexico VA Health Care System [NMVAHCS]). Through this organizational structure, the trial was successfully completed. In addition to placebo etanercept provided by Amgen (Thousand Oaks, CA), Pharmascience (Montreal, Quebec) provided blinded SSZ and blinded placebo. Neither company was involved in the study design nor did they have an active role in the trial. Hydroxychoroquine and matched placebo were provided by the central pharmacy of the NMVAHCS.
Safety Monitoring
As with any treatment study, patient safety was of paramount importance. Through the aforementioned organizational structure, each participating site had administrative team members who were responsible to the VABHS CSP to ensure research adherence and compliance with best practices. Additionally, an independent data and safety monitoring committee (DSMC) monitored the trial for safety and scientific integrity. At the time that the trial began in 2007, there were questions about the relative efficacy of triple therapy vs MTX plus biologic therapy. Because of this question, the DSMC raised concerns that patients may be placed at a higher risk of joint damage if not placed sooner on biologic therapy. As a response to this concern, the blinded radiographic reviewers were asked to read the hand and feet X-rays as the study progressed, allowing the DSMC to watch for any emerging safety signals. There were none, and in fact, the therapies were essentially identical radiographically.
The consequence of this request was multifold. First, patient safety was maintained; second, the study team was forced to navigate the logistic and technologic challenges posed by the reading and interpretation of the radiographs at an earlier time point than was originally planned; and last, as a result, results became available and were disseminated in a relatively narrow time frame. This third point was very important. One of the major concerns of foregoing biologic therapy was the potential for joint damage. Without the radiographic information, the manuscript could not have been completed in a timely fashion.
Trial Results
The trial was a 48-week, double-blind, noninferiority trial in which 353 patients with RA who had active disease despite MTX therapy were randomized to a triple therapy regimen of DMARDs (baseline MTX, plus SSZ and hydroxychloroquine) or baseline MTX plus etanercept (Figure 1). Patients who did not have a clinically significant improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy.
The primary endpoint, the change between baseline and 48 weeks in the DAS28, was similar; thus the strategy of first starting triple therapy was not inferior to first starting etanercept (the change in DAS28 was -2.12 and -2.29 respectively, P < .0001, supporting noninferiority, Figure 2). Both groups had significant improvement over the course of the first 24 weeks (P = .001). A total of 27% of participants in each group switched at 24 weeks (Figure 3). Patients in both groups who switched therapies had improvement after switching (P < .001), and the response after switching did not differ significantly between the 2 groups. Importantly, there were no significant between-group differences in radiographic progression (P = .43), pain and health-related quality of life (QOL), or in medication-associated major adverse events (AEs), although there were numerically more serious infections with etanercept-MTX therapy (12 vs 4). Gastrointestinal AEs were numerically more frequent with triple therapy; whereas infections and skin and subcutaneous AEs were more frequent with etanercept-MTX therapy.
The cost-effectiveness of adding SSZ and hydroxychloroquine to MTX vs adding etanercept to MTX, using a predetermined measurement of QOL, was assessed in this trial.9 These data were initially presented in abstract form at the 2014 American College of Rheumatology national meeting. Considered was the ratio of all the incremental costs between the 2 treatment strategies to the benefits, as measured in quality-adjusted life-years (QALYs), where QOL is measured as an index with 1 being equivalent to full health and 0 being equivalent to death. This incremental cost-effectiveness ratio produces a monetary cost for each QALY, which is an indication of cost-effectiveness and value. Most health care systems currently consider anything that costs < $50,000/QALY to be cost-effective. To be conservative, the trial researchers considered anything up to $100,000 for an additional QALY acceptable.
In the 48-week trial analysis, the use of etanercept first, instead of triple therapy, would incur about $1 million of cost per QALY, far more than the $50,000 to $100,000 deemed to be reasonable value. Biologic therapy use first, had a near-zero chance of being cost-effective and would be cost-effective only after failure of triple therapy; results that were robust to all plausible scenarios.
Economic Implications
As noted in the trial design, economic data were prospectively collected for later analysis. The availability and cost of biologic treatments have become a critical issue. In 2005, it was reported that the U.S. biologics market reached $52 billion and was noted to have an annual growth of 17%.10 In 2011, 8 of the top 20 drugs sold in the U.S. were biologics, and year-to-year biologics spending has grown by 6.6%. In 2013, the top 100 biologics in the U.S. had combined sales of $66.3 billion.11 The researchers analysis demonstrated that using a strategy of triple therapy first could result in health care cost savings in the tens of billions of dollars. Importantly, these savings would occur at the same time as patients were receiving optimal care.
Summary
The major conclusions from the RACAT trial in RA patients with active disease despite MTX are the following: 1. The strategy of first starting the conventional DMARD triple therapy combination is noninferior to first starting etanercept, based on both clinical and radiographic outcomes. 2. The triple therapy group had more minor gastrointestinal events, whereas the etanercept group had more infections. Patients in either group who did not respond well to the initial treatment and switched (27% in both groups) improved significantly after the switch. 3. The economic implications of these findings are significant. The incremental cost differences approached $1 million per QALY.
The VA CSP should be congratulated for supporting and funding this trial, which will inform therapeutic decisions in RA for years to come. These results allow clinicians to provide not only optimal health care for their RA patients, but also maximize the value of their health care.
Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints, leading to joint destruction, with significant long-term morbidity and mortality. Over the past quarter century, multiple new therapies and approaches have been introduced, so patients newly diagnosed with RA can realistically expect to be in remission while taking their medications. However, many of the most commonly used medications are costly, making RA care one of the most expensive per patient.1 Early treatment with disease-modifying antirheumatic drugs (DMARDs) and treating all patients to the target of low-disease activity are critical keys to optimal outcomes.
Methotrexate (MTX) is a highly effective and economical first-line DMARD that is recommended as the initial therapy for most patients.2,3 Unfortunately, one-half to two-thirds of patients will not have complete responses and, therefore, require additional therapy. Fortunately, there are more than a dozen therapies that, when added to MTX, have been shown to be better than MTX alone. However, since some of these options use conventional DMARDs and others require biologics, there exist very different economic as well as potential toxicity implications. Understanding how best to treat patients with RA with active disease while on an appropriate dose of MTX is important for both medical and economic reasons.
Despite this being a seminal question for the past 15 years, no blinded trial had addressed this issue before the VA Cooperative Studies Program (CSP) Rheumatoid Arthritis: Comparison of Active Therapies (RACAT) trial. This was true for several reasons, likely including the considerable cost of conducting such a trial and the low priority of this research question for the pharmaceutical industry. Industry-funded trials in RA often focus on new indications, and these studies often fail to address the questions most relevant to the day-to-day care of patients.
For example, it is often not particularly helpful to the clinician that patients placed on “therapy A” are doing better or worse than those placed on “therapy B” after 1 year of the same treatment. Such rigid protocols do not mimic what is done in the clinic: A patient’s treatment program is often changed much earlier than 1 year when it is not working. Therefore, RACAT was designed to more closely mirror clinical practice and to test the strategy of starting conventional therapy before biologic therapy, with the option of changing therapy for nonresponders—similar to what most clinicians would do in practice. This article explores the lessons learned from this landmark trial and highlights the critical role that the VA CSP played.
Trial Background
The RACAT trial, a comparative effectiveness, randomized, double-blind, noninferiority trial, originated as a joint effort of investigators from the VA and the Rheumatology and Arthritis Investigational Network (RAIN) and subsequently involved Canadian enrollment sites. The RACAT results were published in the New England Journal of Medicine in 2013, and its investigative team was awarded the 2014 Lee C. Howley Sr. Prize by the Arthritis Foundation for conducting the most important arthritis research worldwide from the previous year.4
The RACAT originated with a letter of intent to the VA CSP in 2003. The central question to be addressed was whether biologic therapy should be added first in patients with active RA despite MTX or whether clinicians should first add the much less expensive but very effective combination of conventional therapies, including sulfasalazine (SSZ) and hydroxychloroquine to MTX.5,6 This led to the 48-week, binational, multicenter, randomized, double-blind, noninferiority trial comparing the strategy of initially adding hydroxychloroquine and SSZ to MTX (triple therapy group) in patients with active disease despite MTX compared with the strategy of first adding etanercept to MTX.4 Etanercept is among the most commonly used biologic agents approved for RA. Etanercept works by targeting tumor necrosis factor, a pro-inflammatory cytokine central in disease pathogenesis. Both RACAT treatment groups were switched in a blinded fashion to the other therapy at 24 weeks if they did not have a clinically significant improvement. The primary endpoint was a change in the disease activity score (DAS28) from baseline to 48 weeks. An important secondary endpoint was the comparison of radiographic progression of disease at 48 weeks as measured by the validated modified Sharp scoring method. Additionally, and very importantly, economic and functional outcomes were assessed. To conduct the trial, investigators and patients participated from 16 VA sites in addition to 8 Canadian and 12 RAIN sites. The study was sponsored and primarily funded by the VA CSP, VA Office of Research and Development with additional funding coming from the Canadian Institutes of Health Research (CIHR) and from the National Institutes of Health.
Trial Design
To understand the RACAT trial design, one must appreciate the landscape of RA trials conducted in the early-to-mid 2000s. At that time, there had been an explosion of new biologic therapies for RA. Most of the trials were placebo-controlled studies with nonresponders to MTX being placed on placebo vs active drug.7 For ethical and legal reasons, however, clinicians do not treat patients with placebo, especially when highly effective therapies exist, thus limiting the relevance of the classic placebo-controlled trial in RA.8 One of the main tenets of RA therapy in this century has been to use effective therapies to treat patients with active RA with the goal of achieving (and maintaining) either low-disease activity or remission as measured by a composite scoring system, most commonly the DAS28. In order to do this in the framework of a designed research trial, therapies commonly need to be escalated when patients are not doing well, similar to what is done in clinical practice.
The RACAT trial was a comparative effectiveness trial. Comparative effectiveness is not a new idea; in fact, it is precisely how many clinicians practice medicine. It is simply comparing 2 or more treatments to determine which is more effective. Since the inception of the RACAT trial, the American Recovery and Reinvestment Act of 2009 provided $1.1 billion for major expansion of comparative effectiveness research. This changing landscape of federally funded research has highlighted the growing national interest in this type of trial.
This trial design posed several barriers as it applies to the study medications. Methotrexate, hydroxychloroquine, and SSZ are generic medications most often taken orally (MTX is available for parenteral administration). In contrast, etanercept is most often given as a subcutaneous injection and currently is not available in a biosimilar (generic) form in the U.S.; thus, the medication and its delivery device are proprietary. Because this was a double-blind, noninferiority trial, the study required both etanercept-active medication and placebo in identical delivery devices. The makers of etanercept donated placebo etanercept to make blinding possible. The VA, along with CIHR, purchased active etanercept for all trial participants, including those from Canada and the RAIN network. The VA research pharmacy in Albuquerque, New Mexico, was responsible for blinding all active and placebo drugs used in the trial and made these drugs available to all patients, even those not eligible for VA care.In a precedent-setting effort for rheumatology research, RACAT culminated from the collaborations among the private sector, the Canadian health system, and VA. The VA CSP was responsible for the collection of the clinical data, data analyses (Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System [VABHS]); the collection of economic data (VA Palo Alto Health Care System); the provision of and payment for the study medications; and the preparation and distribution of active etanercept and placebos (New Mexico VA Health Care System [NMVAHCS]). Through this organizational structure, the trial was successfully completed. In addition to placebo etanercept provided by Amgen (Thousand Oaks, CA), Pharmascience (Montreal, Quebec) provided blinded SSZ and blinded placebo. Neither company was involved in the study design nor did they have an active role in the trial. Hydroxychoroquine and matched placebo were provided by the central pharmacy of the NMVAHCS.
Safety Monitoring
As with any treatment study, patient safety was of paramount importance. Through the aforementioned organizational structure, each participating site had administrative team members who were responsible to the VABHS CSP to ensure research adherence and compliance with best practices. Additionally, an independent data and safety monitoring committee (DSMC) monitored the trial for safety and scientific integrity. At the time that the trial began in 2007, there were questions about the relative efficacy of triple therapy vs MTX plus biologic therapy. Because of this question, the DSMC raised concerns that patients may be placed at a higher risk of joint damage if not placed sooner on biologic therapy. As a response to this concern, the blinded radiographic reviewers were asked to read the hand and feet X-rays as the study progressed, allowing the DSMC to watch for any emerging safety signals. There were none, and in fact, the therapies were essentially identical radiographically.
The consequence of this request was multifold. First, patient safety was maintained; second, the study team was forced to navigate the logistic and technologic challenges posed by the reading and interpretation of the radiographs at an earlier time point than was originally planned; and last, as a result, results became available and were disseminated in a relatively narrow time frame. This third point was very important. One of the major concerns of foregoing biologic therapy was the potential for joint damage. Without the radiographic information, the manuscript could not have been completed in a timely fashion.
Trial Results
The trial was a 48-week, double-blind, noninferiority trial in which 353 patients with RA who had active disease despite MTX therapy were randomized to a triple therapy regimen of DMARDs (baseline MTX, plus SSZ and hydroxychloroquine) or baseline MTX plus etanercept (Figure 1). Patients who did not have a clinically significant improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy.
The primary endpoint, the change between baseline and 48 weeks in the DAS28, was similar; thus the strategy of first starting triple therapy was not inferior to first starting etanercept (the change in DAS28 was -2.12 and -2.29 respectively, P < .0001, supporting noninferiority, Figure 2). Both groups had significant improvement over the course of the first 24 weeks (P = .001). A total of 27% of participants in each group switched at 24 weeks (Figure 3). Patients in both groups who switched therapies had improvement after switching (P < .001), and the response after switching did not differ significantly between the 2 groups. Importantly, there were no significant between-group differences in radiographic progression (P = .43), pain and health-related quality of life (QOL), or in medication-associated major adverse events (AEs), although there were numerically more serious infections with etanercept-MTX therapy (12 vs 4). Gastrointestinal AEs were numerically more frequent with triple therapy; whereas infections and skin and subcutaneous AEs were more frequent with etanercept-MTX therapy.
The cost-effectiveness of adding SSZ and hydroxychloroquine to MTX vs adding etanercept to MTX, using a predetermined measurement of QOL, was assessed in this trial.9 These data were initially presented in abstract form at the 2014 American College of Rheumatology national meeting. Considered was the ratio of all the incremental costs between the 2 treatment strategies to the benefits, as measured in quality-adjusted life-years (QALYs), where QOL is measured as an index with 1 being equivalent to full health and 0 being equivalent to death. This incremental cost-effectiveness ratio produces a monetary cost for each QALY, which is an indication of cost-effectiveness and value. Most health care systems currently consider anything that costs < $50,000/QALY to be cost-effective. To be conservative, the trial researchers considered anything up to $100,000 for an additional QALY acceptable.
In the 48-week trial analysis, the use of etanercept first, instead of triple therapy, would incur about $1 million of cost per QALY, far more than the $50,000 to $100,000 deemed to be reasonable value. Biologic therapy use first, had a near-zero chance of being cost-effective and would be cost-effective only after failure of triple therapy; results that were robust to all plausible scenarios.
Economic Implications
As noted in the trial design, economic data were prospectively collected for later analysis. The availability and cost of biologic treatments have become a critical issue. In 2005, it was reported that the U.S. biologics market reached $52 billion and was noted to have an annual growth of 17%.10 In 2011, 8 of the top 20 drugs sold in the U.S. were biologics, and year-to-year biologics spending has grown by 6.6%. In 2013, the top 100 biologics in the U.S. had combined sales of $66.3 billion.11 The researchers analysis demonstrated that using a strategy of triple therapy first could result in health care cost savings in the tens of billions of dollars. Importantly, these savings would occur at the same time as patients were receiving optimal care.
Summary
The major conclusions from the RACAT trial in RA patients with active disease despite MTX are the following: 1. The strategy of first starting the conventional DMARD triple therapy combination is noninferior to first starting etanercept, based on both clinical and radiographic outcomes. 2. The triple therapy group had more minor gastrointestinal events, whereas the etanercept group had more infections. Patients in either group who did not respond well to the initial treatment and switched (27% in both groups) improved significantly after the switch. 3. The economic implications of these findings are significant. The incremental cost differences approached $1 million per QALY.
The VA CSP should be congratulated for supporting and funding this trial, which will inform therapeutic decisions in RA for years to come. These results allow clinicians to provide not only optimal health care for their RA patients, but also maximize the value of their health care.
1. Gavan S, Harrison M, Iglesias C, Barton A, Manca A, Payne K. Economics of stratified medicine in rheumatoid arthritis. Curr Rheumatol Rep. 2014;16(12):468.
2. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying anti-rheumatic drugs and biologics in the treatment of rheumatoid arthritis (RA). Arthritis Care Res (Hoboken). 2012;64(5):625-639.
3. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492-509.
4. O'Dell JR, Mikuls TR, Taylor TH, et al; CSP 551 RACAT Investigators. Therapies for active rheumatoid arthritis after methotrexate failure. N Eng J Med. 2013;369(4):307-318.
5. Moreland LW, O'Dell JR, Paulus HE, et al; TEAR Investigators. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the Treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012;64(9):2824-2835.
6. O'Dell JR, Leff R, Paulsen G, et al. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002;46(5):1164-1170.
7. Singh JA, Cameron DR. Summary of AHRQ's comparative effectiveness review of drug therapy for rheumatoid arthritis in adults-an update. J Manag Care Pharm. 2012;18(4)(suppl C):S1-S18.
8. Chan TE. Regulating the placebo effect in clinical practice. Med Law Rev. 2014;23(1):1-26.
9. Bansback N, Phibb S, Sun H, et al. Cost effectiveness of adding etanercept to methotrexate therapy versus first adding sulfasalazine and hydroxychloroquine: a randomized noninferiority trial [American College of Rheumatology abstract 2781]. Arthritis Rheum. 2014;66(suppl 11):S1214.
10. Ernst and Young. Beyond borders: global biotechnology report 2005. Ernst and Young Website. https://www2.eycom.ch/publications/items/biotech-report/2005/2005_EY_Global_Biotech_Report.pdf. Accessed December 3, 2015.
11. Mulcahy AW, Predmore Z, Mattke S. The cost savings potential of biosimilar drugs in the United States. Rand Corporation Website. http://www.rand.org/pubs/perspectives/PE127.html. Accessed December 3, 2015.
1. Gavan S, Harrison M, Iglesias C, Barton A, Manca A, Payne K. Economics of stratified medicine in rheumatoid arthritis. Curr Rheumatol Rep. 2014;16(12):468.
2. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying anti-rheumatic drugs and biologics in the treatment of rheumatoid arthritis (RA). Arthritis Care Res (Hoboken). 2012;64(5):625-639.
3. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492-509.
4. O'Dell JR, Mikuls TR, Taylor TH, et al; CSP 551 RACAT Investigators. Therapies for active rheumatoid arthritis after methotrexate failure. N Eng J Med. 2013;369(4):307-318.
5. Moreland LW, O'Dell JR, Paulus HE, et al; TEAR Investigators. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the Treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012;64(9):2824-2835.
6. O'Dell JR, Leff R, Paulsen G, et al. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002;46(5):1164-1170.
7. Singh JA, Cameron DR. Summary of AHRQ's comparative effectiveness review of drug therapy for rheumatoid arthritis in adults-an update. J Manag Care Pharm. 2012;18(4)(suppl C):S1-S18.
8. Chan TE. Regulating the placebo effect in clinical practice. Med Law Rev. 2014;23(1):1-26.
9. Bansback N, Phibb S, Sun H, et al. Cost effectiveness of adding etanercept to methotrexate therapy versus first adding sulfasalazine and hydroxychloroquine: a randomized noninferiority trial [American College of Rheumatology abstract 2781]. Arthritis Rheum. 2014;66(suppl 11):S1214.
10. Ernst and Young. Beyond borders: global biotechnology report 2005. Ernst and Young Website. https://www2.eycom.ch/publications/items/biotech-report/2005/2005_EY_Global_Biotech_Report.pdf. Accessed December 3, 2015.
11. Mulcahy AW, Predmore Z, Mattke S. The cost savings potential of biosimilar drugs in the United States. Rand Corporation Website. http://www.rand.org/pubs/perspectives/PE127.html. Accessed December 3, 2015.