Original Research

Unplanned hospital admissions and readmissions have become a major focus of efforts to improve the value of healthcare given that these potentially preventable events exert substantial burden on patients, caregivers, health systems, and the economy.¹ The percentage of patients who are rehospitalized within 30 days have decreased from 20%-21% at the start of the Accountable Care Act and readmission penalties to approximately 18%.^2-5 Rehospitalization rates are 33% at 90 days and approach 40% at six months.^6,7 Readmissions cost Medicare more than $26 billion annually,⁴ with one in five Medicare beneficiaries readmitted within 30 days of hospital discharge.⁸ Centers for Medicare and Medicaid Services and other payers use condition-specific and all-cause 30-day unplanned readmission rates and potentially preventable admissions among patients with complex or multiple comorbidities for public reporting, value-based purchasing, and performance-based reimbursement.^9,10 Consequently, medical groups and hospitals have begun to place an increasing emphasis on improving the transitions of care following hospitalization with the goal of reducing unplanned readmissions.¹¹ Care transitions programs have been shown to decrease readmission rates, mortality, and emergency department (ED) visits.¹²

Care transitions programs vary greatly in their scope of intervention and target groups, as well as in their efficacy in reducing readmissions.^13,14 The Mayo Clinic Care Transition Program, hereafter referred to as CTP, was launched in 2011. This program was modeled after other successful programs and involves home visits by a nurse practitioner (NP) and telephonic support and triage provided by a registered nurse (RN). It is offered to high-risk community-dwelling patients during their hospitalization and begins within a week of hospital discharge.

Although the CTP reduces 30-day readmissions from 20% to 17%,⁷ it is a highly resource-intensive, multimodal, multidisciplinary program. Moreover, whether some components of the CTP are more critical than others remains unknown. Prior studies that examined the individual components of successful CTPs have suggested that a multipronged approach that includes close patient and caregiver support is most predictive of program efficacy.¹³ Long-term program sustainability would benefit from optimization of the most critical components of the program while reducing or eliminating resource-intensive factors that have negligible effects on program success. We therefore examined our CTP to identify whether and which program components are most critical for preventing 30-day readmissions and whether any patient characteristics contribute risk within this complex population.

Study Design and Setting

This study is a retrospective cohort study of patients who were enrolled in the care transitions program of Mayo Clinic Rochester during the period January 1, 2010 to June 30, 2013. Patient demographic and clinical data were obtained from electronic health records (EHR), and information regarding CTP processes and interventions was obtained from a prospectively maintained program database. The study complied with the principles of the Declaration of Helsinki and was approved by the Mayo Clinic Institutional Review Board.

Objectives

The study aimed to describe the performance and utilization of a multidisciplinary care transitions program that has been successful in reducing readmissions for high-risk patients. The study also sought to identify patient and/or program factors associated with failure to prevent readmission within 30 days of program enrollment.

Population

Patients who were enrolled in the CTP following hospital discharge and seen for a posthospital in-home visit prior to hospital readmission (for those readmitted) were included. Patients discharged to a skilled nursing facility were excluded. Patients were eligible for CTP enrollment if they were hospitalized for any cause, community dwelling (including assisted living) prior to hospitalization, and ≥60 years old with an Elder Risk Assessment (ERA) score ≥16.⁷ The ERA incorporates information regarding previous hospital days, age, and comorbid health burden and has been shown to predict 30-day readmissions, mortality, and critical illness (

Intervention

Detailed descriptions of the CTP have been previously published.^7,17 Patients meeting enrollment criteria are enrolled into the CTP by a RN prior to or immediately after hospital discharge. The patient is then seen at home within one to five business days of discharge and again the following week by a NP who performs medication reconciliation; chronic illness management; and acute illness, mobility, safety, and cognition assessments. The NP also provides patient education on self-care and advance care planning. Patient and caregiver support and liaisons with community resources are provided. Home visits by an NP or MD are continued as needed for at least one month. A RN case manager performs weekly phone calls to assess changes in the patient’s clinical status and is available for phone triage of acute health issues. An interdisciplinary team composed of MDs, NPs, RNs, and pharmacists review patient management at weekly meetings. Although after-hours or weekend coverage for home visits are unavailable, an on-call primary care physician is available by phone at all times.

Primary Outcome

The primary outcome was all-cause hospital readmission within 30 days of the first CTP home visit, indicating successful program enrollment. Hospitalization was determined on the basis of billing codes from Mayo Clinic hospitals; this approach is 99% reliable in detecting readmissions for this population.¹⁸

Secondary Outcome Measures

Secondary outcome measures included six-month mortality and hospitalizations, as well as the number of hospital and ICU days and home, ED, primary care, and specialty office visits within 180 days after index hospitalizations as per the EHR. ED visits were counted only when they did not result in a hospital admission.

Independent Variables

Patient characteristics and clinical variables were retrieved from the EHR and included patient age, sex, and marital status. Comorbidities, ERA score,¹⁹ and Charlson comorbidity index (CCI)²⁰ within two years of program enrollment were determined by using ICD-9 billing codes. The frequencies of primary care and specialty visits within six months of the index hospitalization were also ascertained using the EHR. Mobility limitations and cognitive impairment were categorized as binary variables (yes/no) and were assessed at the first home visit by the NP. The presence of mobility limitations was defined as a Barthel’s score of <75^21,22 or Timed up and Go time of >20 seconds.²³ Cognitive impairment was established as Kokmen below the normal cutoff for patient’s age group,²⁴ Mini-Cog ≤2,²⁵or AD8 ≥2.²⁶ If these measures were not specifically documented during the first visit, clinical notes were queried for the description of pertinent cognitive and/or mobility limitations. Dementia diagnosis billing codes (ICD9 Code 290.*) were also included. High medication use was defined as >14 given the reported average medication number ranges from 8-13 in this population.²⁷

As previously published, fidelity measures were abstracted from clinical notes by a trained nurse abstractor within 30 days of program enrollment and prior to a readmission.⁷ The five program fidelity measures included medication reconciliation, home service evaluation, advanced directives discussion, action plan for acute and chronic disease, safety plan, and discussion of community resources. The presence of advanced care planning was determined on the basis of visit medical notes and/or change of code status within the EHR, the identification or scanning of written advanced directives or “provider order for life-sustaining treatment,” and documentation of the discussion of resuscitation status. It was abstracted in duplicate by a nurse abstractor with physician adjudication for disagreement. Moreover, whether the initial visit met the goal of being within five days of discharge was determined by using billing data.

Analysis

The contribution of each independent variable to 30-day readmission was first directly assessed by using a univariate logistic regression model. Five patients died within 30 days without being admitted. These deaths, however, were not censored given that home death (as opposed to hospital death) was considered a positive outcome of the CTP. Multivariable modeling was performed through log rank test with backwards elimination and included all independent variables with P < .05. Variables with P values between .05 and >.1 were tested for interaction with age and sex. Age was categorized as <80 or ≥80 years. The length of hospital stay was categorized as <3 days (not qualifying for a Medicare skilled nursing facility), 3-13 days, or ≥14 days.

This study had 30% power to detect a reduction of 5% in the rates of hospital admissions; 5% is the median absolute risk reduction reported by previous randomized studies on care transitions programs previously reported.¹⁰ All analyses were performed using SAS 6.01 (SAS Inc., Cary, North Carolina).

Study Population

The study cohort included 315 patients who met the inclusion criteria (Fig 1). The demographic and clinical characteristics of the participants were ascertained at the time of CTP enrollment and are shown in Table 1. Patients were, on average, 82.5 (SD, 8.2) years old and had multiple comorbidities with a mean CCI score of 6.2 and ERA score of 18.5. Almost half of the patients (43.2%) exhibited cognitive impairment and more than half (51.7%) had mobility limitations. Among the patients, 42.9% had been hospitalized at least once in the 180 days prior to their CTP-qualifying hospitalization and 14.2% had ≥2 hospitalizations prior to their CTP-qualifying hospitalization. Similarly, 32.4% had at least one emergency department (ED) visit, and 3.5% had ≥3 ED visits. The majority of patients had frequent outpatient visits, with 30.8% having ≥4 office visits in primary care and 32.4% having ≥4 specialty office visits in the preceding six months.

Readmissions, Mortality, ED, and Outpatient Visits

Of the 315 patients, 54 (17.1%) had a readmission within 30 days and seven (2%) had >1 readmission. Among the patients, 126 (40.0%) were readmitted at least once within 180 days with 55 (17.5%) having more than one readmission. A total of 41 patients (13.1%) died during the six-month follow-up period. The need for both office and ED visits was reduced compared to the 180 days prior to admission with the biggest difference in ED visits: 72 (22.9%) of patients needed visits within 180 days of enrollment, as opposed to 102 (32.4%) before enrollment.

Impact of Patient Clinical Variables on Readmission Risk

Readmitted patients were less likely to exhibit cognitive impairment (29.6% vs 46.0%; P = .03) and were more likely to have high medication use (59.3% vs 44.4%; P = .047) than patients without readmission (Table 1). Readmitted patients had a higher frequency of visits to primary care (4.0 vs 3.0; P =.02) in the six months prior to admission and more hospital days in the prior year (4.6 vs 2.5; P = .04) than those without readmission.

Multivariable analysis, which included the cognitive status of the patient; the high use of medication; and the number of ED visits, primary care visits, and hospital days in the previous six months, provided a C statistic of 0.665. After backwards elimination, only the cognitive status of the patient and number of ED visits remained predictive of readmission risk.

Impact of Program Interventions on Readmission Risk

The completion of the CTP fidelity measures drastically varied with completion rates between 29.5% (community resource evaluation) and 87.0% (home visit within five days of hospital discharge; Table 2). Only 12.1% of patients received all components of the CTP at the first home visit. Readmission rates among patients who received all program components (13.2%) were lower than those among patients who did not receive all program components. This difference, however, failed to reach statistical significance. No single program component significantly reduced readmission risk. The completion rate of program fidelity measures increased with time (Figure 2). The present findings did not change even after performing sensitivity analysis that excluded the first program year. The overall agreement between chart abstractors on determining whether advance care planning occurred was 69.5% but the Cohens Kappa was only 18.4. This result was largely ascribed to the following: One abstractor counted the presence of a shorthand template used to document the delivery of an advance care planning document as discussion, whereas the other abstractor required further documentation or corroborating evidence (ie, change of code status). The majority of patients required multiple home visits to address ongoing medical needs (mean 2.7; SD = 1.3) over the first 30 days. Among these patients, only 17.1% received one visit, and 54.6% of patients received ≥3 visits. Eleven (3.5%) patients transitioned to a palliative homebound program that we began offering toward the end of this study to meet patient needs.²⁸

The present study met our objective of identifying individual patient factors that are predictive of the success of our CTP. Cognitively impaired patients were less likely to be readmitted than cognitively intact patients. This finding is particularly important because patients with dementia constitute a subgroup that is at an increased risk of readmission after hospitalization²⁹ and often suffer burdensome transitions at the end of life.^30,31 High medication use and high number of visits to primary care and number of hospital days in the six months leading up to enrollment increase the likelihood of readmission and are plausible measures of disease severity or multi-morbidity that have been identified in previous studies.^32,33 No one program intervention was found to be significantly associated with readmission. This result is consistent with prior works that demonstrated the need for multifaceted and intensive interventions to reduce readmission risk among highly complex and multimorbid patients.^13,14

Our findings suggest that the provision of an alternative to stressful hospitalization to cognitively impaired patients and their caregivers may be an important benefit of care transitions programs. Having a trusted team to consult in acute situations may have enabled early intervention and crisis avoidance. Avoiding hospitalizations and ED visits may also have been in line with their goals of care.^34,35 Given that program intensity varied on the basis of the discretion of the clinical team, patients with cognitive impairment and their caregivers may also have received more intensive support than cognitively intact patients.

In contrast to recent systematic reviews, our study did not find that advance directive discussion had significant effects on reductions in readmission.^36,37 The lack of discussion surrounding the goals of care for patients with serious illnesses was also listed as one of four factors that are strongly associated with preventability in a national cohort of readmitted general medicine patients.³⁸ The lack of power and incomplete documentation may have contributed to our null findings. Trust building must also occur before any meaningful discussion of the goals of care could be achieved, and follow-up time may have to be extended. Toward the end of this study, we developed an extension of our program for patients with limited life expectancy and conservative goals of care. In this extension, reductions in hospitalizations were observed among patients who had multiple goals of care discussions.²⁸

Previous studies have shown that readmissions reduced with timely follow up among patients with heart failure.³⁹ Our results showed no difference in readmission rate based on whether or not our patients were visited within five days from discharge, but we may have been underpowered to detect this difference. In addition, we may have missed readmissions that occurred before the enrollment visit.

The elements of the CTP were evidence based. Fidelity to program goals improved over time and reached high levels with program maturity. Only 12% of the patients received all program components at the first home visit. Patients that had all pillars addressed and documented showed a nonsignificant trend toward reduced readmission rates. NPs were given discretion as to how many visits were required to stabilize a patient and achieve program objectives. Heart failure management was driven by protocol with input from cardiology. Medication reconciliation and clinical assessment with action plan were prioritized at the first visit and thus allowed for the completion of other goals at a subsequent visit if time was insufficient. These decisions were deliberated at weekly physician-led multidisciplinary meetings. This variability allowed the team to meet chronic and urgent needs but further confounded the interpretation of our results. One possible way to interpret the lack of significant predictors of success is that through clinical assessment and flexibility, we were able to tailor our program to meet the needs of this complex multi-morbid population.

This study has important limitations. Given that it is a retrospective cohort study, we were unable to include patients who were enrolled but were either readmitted or dropped out before the first program visit. In addition, because of our study’s limited sample size and readmission rate, we had limited power to detect other potential predictor variables and test for confounding and interaction. While we included numerous variables in our analyses, we lacked information on mental health and the social determinants of health, which are known to influence readmission risk.^40,41 Similarly, we lacked patient self-reported measures of health and information regarding caregiver support, which are important.^42,43 Several of our predictive measures (cognitive impairment, mobility limitations, and program objective completion) were dependent on supplementing billing codes with heterogeneous data abstracted from usual clinical care as opposed to standardized research protocols. Neither method is completely accurate, nor can the combination of the two be assumed to be without inaccuracies. Failure to adequately document the clinical interventions performed by the clinical team is possibly a major confounder as evidenced by the considerable lack of agreement by our trained abstractors in determining whether advance care planning took place. The generalizability of our results is also a concern because the local population is largely white and highly educated, although our experience tells us that many of our program patients have limited means and thus may more closely resemble the general US population.⁴⁴ The strength of our study is that it uses real, practice-based data that can be directly translated to practice.

This study focused on a successful high-intensity CTP. Results showed that compared with patients without dementia, patients with dementia were more likely to avoid hospitalizations as a result of enrollment in the investigated CTP. This study, however, failed to identify specific programmatic components critical for the success of the CTP. These findings support the current hypothesis that multidisciplinary, multimodal, and highly intensive interventions are necessary to care for complex and multi-morbid patients. They also suggest that compared with cognitively functional patients, cognitively impaired patients with conservative goals of care may be more likely to avoid burdensome hospitalizations when provided with early intervention in their home.

Acknowledgments

B.T. conceived and designed the study, interpreted the data, drafted and provided final revisions to the manuscript. P.Y.T, N.D.S., and J.M.N obtained funding, contributed to the conception and design of the study, analysis, and interpretation of the data, and provided critical revisions to the manuscript. P.A.R., R.G.M, and G.J.H., contributed to the conception and design of the study, analysis, and interpretation of the data, and provided critical revisions to the manuscript. S.M.P. Assisted with data acquisition and interpretation, performed the data analysis, and drafted parts of the manuscript. C.Y.Y.C, L.J.H., A.L, A.C., L.B., and R.H. helped with methodologic questions and data interpretation, and provided critical revisions to the manuscript.

All authors read and approved the final manuscript and the decision to submit the manuscript for publication.

We thank Donna Lawson, RN for her help with data abstraction and Annika Beck and Anna Jones in Mayo Clinic Biomedical Ethics Research Program for her help in preparing this manuscript for publication.

Disclosures

The authors declare no conflicts of interest.

Funding

This publication was supported by the Mayo Clinic, Robert D and Patricia E. Center for the Science of Health Care Delivery (B.T., R.H., R.G.M, L.J.H), by the Extramural Grant Program by Satellite Healthcare, a not-for-profit renal care provider (L.J.H., B.T.), and by the National Institute of Health (NIH) National Institute Of Diabetes And Digestive And Kidney Diseases grant K23 DK109134 (L.J.H.) K23DK114497 (RGM) and National Institute on Aging grant K23 AG051679 (B.T.). Additional support was provided by the National Center for Advancing Translational Sciences grant UL1 TR000135. Study contents are the sole responsibility of the authors and do not necessarily represent the official views of NIH.

The sponsors had no role in the design, execution, or reporting of this study.

Prior Presentations

Part of this data was presented in poster format at the American Geriatrics Society meeting in Washington DC 2015.

Unplanned hospital admissions and readmissions have become a major focus of efforts to improve the value of healthcare given that these potentially preventable events exert substantial burden on patients, caregivers, health systems, and the economy.¹ The percentage of patients who are rehospitalized within 30 days have decreased from 20%-21% at the start of the Accountable Care Act and readmission penalties to approximately 18%.^2-5 Rehospitalization rates are 33% at 90 days and approach 40% at six months.^6,7 Readmissions cost Medicare more than $26 billion annually,⁴ with one in five Medicare beneficiaries readmitted within 30 days of hospital discharge.⁸ Centers for Medicare and Medicaid Services and other payers use condition-specific and all-cause 30-day unplanned readmission rates and potentially preventable admissions among patients with complex or multiple comorbidities for public reporting, value-based purchasing, and performance-based reimbursement.^9,10 Consequently, medical groups and hospitals have begun to place an increasing emphasis on improving the transitions of care following hospitalization with the goal of reducing unplanned readmissions.¹¹ Care transitions programs have been shown to decrease readmission rates, mortality, and emergency department (ED) visits.¹²

Care transitions programs vary greatly in their scope of intervention and target groups, as well as in their efficacy in reducing readmissions.^13,14 The Mayo Clinic Care Transition Program, hereafter referred to as CTP, was launched in 2011. This program was modeled after other successful programs and involves home visits by a nurse practitioner (NP) and telephonic support and triage provided by a registered nurse (RN). It is offered to high-risk community-dwelling patients during their hospitalization and begins within a week of hospital discharge.

Although the CTP reduces 30-day readmissions from 20% to 17%,⁷ it is a highly resource-intensive, multimodal, multidisciplinary program. Moreover, whether some components of the CTP are more critical than others remains unknown. Prior studies that examined the individual components of successful CTPs have suggested that a multipronged approach that includes close patient and caregiver support is most predictive of program efficacy.¹³ Long-term program sustainability would benefit from optimization of the most critical components of the program while reducing or eliminating resource-intensive factors that have negligible effects on program success. We therefore examined our CTP to identify whether and which program components are most critical for preventing 30-day readmissions and whether any patient characteristics contribute risk within this complex population.

Study Design and Setting

This study is a retrospective cohort study of patients who were enrolled in the care transitions program of Mayo Clinic Rochester during the period January 1, 2010 to June 30, 2013. Patient demographic and clinical data were obtained from electronic health records (EHR), and information regarding CTP processes and interventions was obtained from a prospectively maintained program database. The study complied with the principles of the Declaration of Helsinki and was approved by the Mayo Clinic Institutional Review Board.

Objectives

The study aimed to describe the performance and utilization of a multidisciplinary care transitions program that has been successful in reducing readmissions for high-risk patients. The study also sought to identify patient and/or program factors associated with failure to prevent readmission within 30 days of program enrollment.

Population

Patients who were enrolled in the CTP following hospital discharge and seen for a posthospital in-home visit prior to hospital readmission (for those readmitted) were included. Patients discharged to a skilled nursing facility were excluded. Patients were eligible for CTP enrollment if they were hospitalized for any cause, community dwelling (including assisted living) prior to hospitalization, and ≥60 years old with an Elder Risk Assessment (ERA) score ≥16.⁷ The ERA incorporates information regarding previous hospital days, age, and comorbid health burden and has been shown to predict 30-day readmissions, mortality, and critical illness (

Intervention

Detailed descriptions of the CTP have been previously published.^7,17 Patients meeting enrollment criteria are enrolled into the CTP by a RN prior to or immediately after hospital discharge. The patient is then seen at home within one to five business days of discharge and again the following week by a NP who performs medication reconciliation; chronic illness management; and acute illness, mobility, safety, and cognition assessments. The NP also provides patient education on self-care and advance care planning. Patient and caregiver support and liaisons with community resources are provided. Home visits by an NP or MD are continued as needed for at least one month. A RN case manager performs weekly phone calls to assess changes in the patient’s clinical status and is available for phone triage of acute health issues. An interdisciplinary team composed of MDs, NPs, RNs, and pharmacists review patient management at weekly meetings. Although after-hours or weekend coverage for home visits are unavailable, an on-call primary care physician is available by phone at all times.

Primary Outcome

The primary outcome was all-cause hospital readmission within 30 days of the first CTP home visit, indicating successful program enrollment. Hospitalization was determined on the basis of billing codes from Mayo Clinic hospitals; this approach is 99% reliable in detecting readmissions for this population.¹⁸

Secondary Outcome Measures

Secondary outcome measures included six-month mortality and hospitalizations, as well as the number of hospital and ICU days and home, ED, primary care, and specialty office visits within 180 days after index hospitalizations as per the EHR. ED visits were counted only when they did not result in a hospital admission.

Independent Variables

Patient characteristics and clinical variables were retrieved from the EHR and included patient age, sex, and marital status. Comorbidities, ERA score,¹⁹ and Charlson comorbidity index (CCI)²⁰ within two years of program enrollment were determined by using ICD-9 billing codes. The frequencies of primary care and specialty visits within six months of the index hospitalization were also ascertained using the EHR. Mobility limitations and cognitive impairment were categorized as binary variables (yes/no) and were assessed at the first home visit by the NP. The presence of mobility limitations was defined as a Barthel’s score of <75^21,22 or Timed up and Go time of >20 seconds.²³ Cognitive impairment was established as Kokmen below the normal cutoff for patient’s age group,²⁴ Mini-Cog ≤2,²⁵or AD8 ≥2.²⁶ If these measures were not specifically documented during the first visit, clinical notes were queried for the description of pertinent cognitive and/or mobility limitations. Dementia diagnosis billing codes (ICD9 Code 290.*) were also included. High medication use was defined as >14 given the reported average medication number ranges from 8-13 in this population.²⁷

As previously published, fidelity measures were abstracted from clinical notes by a trained nurse abstractor within 30 days of program enrollment and prior to a readmission.⁷ The five program fidelity measures included medication reconciliation, home service evaluation, advanced directives discussion, action plan for acute and chronic disease, safety plan, and discussion of community resources. The presence of advanced care planning was determined on the basis of visit medical notes and/or change of code status within the EHR, the identification or scanning of written advanced directives or “provider order for life-sustaining treatment,” and documentation of the discussion of resuscitation status. It was abstracted in duplicate by a nurse abstractor with physician adjudication for disagreement. Moreover, whether the initial visit met the goal of being within five days of discharge was determined by using billing data.

Analysis

The contribution of each independent variable to 30-day readmission was first directly assessed by using a univariate logistic regression model. Five patients died within 30 days without being admitted. These deaths, however, were not censored given that home death (as opposed to hospital death) was considered a positive outcome of the CTP. Multivariable modeling was performed through log rank test with backwards elimination and included all independent variables with P < .05. Variables with P values between .05 and >.1 were tested for interaction with age and sex. Age was categorized as <80 or ≥80 years. The length of hospital stay was categorized as <3 days (not qualifying for a Medicare skilled nursing facility), 3-13 days, or ≥14 days.

This study had 30% power to detect a reduction of 5% in the rates of hospital admissions; 5% is the median absolute risk reduction reported by previous randomized studies on care transitions programs previously reported.¹⁰ All analyses were performed using SAS 6.01 (SAS Inc., Cary, North Carolina).

Study Population

The study cohort included 315 patients who met the inclusion criteria (Fig 1). The demographic and clinical characteristics of the participants were ascertained at the time of CTP enrollment and are shown in Table 1. Patients were, on average, 82.5 (SD, 8.2) years old and had multiple comorbidities with a mean CCI score of 6.2 and ERA score of 18.5. Almost half of the patients (43.2%) exhibited cognitive impairment and more than half (51.7%) had mobility limitations. Among the patients, 42.9% had been hospitalized at least once in the 180 days prior to their CTP-qualifying hospitalization and 14.2% had ≥2 hospitalizations prior to their CTP-qualifying hospitalization. Similarly, 32.4% had at least one emergency department (ED) visit, and 3.5% had ≥3 ED visits. The majority of patients had frequent outpatient visits, with 30.8% having ≥4 office visits in primary care and 32.4% having ≥4 specialty office visits in the preceding six months.

Readmissions, Mortality, ED, and Outpatient Visits

Of the 315 patients, 54 (17.1%) had a readmission within 30 days and seven (2%) had >1 readmission. Among the patients, 126 (40.0%) were readmitted at least once within 180 days with 55 (17.5%) having more than one readmission. A total of 41 patients (13.1%) died during the six-month follow-up period. The need for both office and ED visits was reduced compared to the 180 days prior to admission with the biggest difference in ED visits: 72 (22.9%) of patients needed visits within 180 days of enrollment, as opposed to 102 (32.4%) before enrollment.

Impact of Patient Clinical Variables on Readmission Risk

Readmitted patients were less likely to exhibit cognitive impairment (29.6% vs 46.0%; P = .03) and were more likely to have high medication use (59.3% vs 44.4%; P = .047) than patients without readmission (Table 1). Readmitted patients had a higher frequency of visits to primary care (4.0 vs 3.0; P =.02) in the six months prior to admission and more hospital days in the prior year (4.6 vs 2.5; P = .04) than those without readmission.

Multivariable analysis, which included the cognitive status of the patient; the high use of medication; and the number of ED visits, primary care visits, and hospital days in the previous six months, provided a C statistic of 0.665. After backwards elimination, only the cognitive status of the patient and number of ED visits remained predictive of readmission risk.

Impact of Program Interventions on Readmission Risk

The completion of the CTP fidelity measures drastically varied with completion rates between 29.5% (community resource evaluation) and 87.0% (home visit within five days of hospital discharge; Table 2). Only 12.1% of patients received all components of the CTP at the first home visit. Readmission rates among patients who received all program components (13.2%) were lower than those among patients who did not receive all program components. This difference, however, failed to reach statistical significance. No single program component significantly reduced readmission risk. The completion rate of program fidelity measures increased with time (Figure 2). The present findings did not change even after performing sensitivity analysis that excluded the first program year. The overall agreement between chart abstractors on determining whether advance care planning occurred was 69.5% but the Cohens Kappa was only 18.4. This result was largely ascribed to the following: One abstractor counted the presence of a shorthand template used to document the delivery of an advance care planning document as discussion, whereas the other abstractor required further documentation or corroborating evidence (ie, change of code status). The majority of patients required multiple home visits to address ongoing medical needs (mean 2.7; SD = 1.3) over the first 30 days. Among these patients, only 17.1% received one visit, and 54.6% of patients received ≥3 visits. Eleven (3.5%) patients transitioned to a palliative homebound program that we began offering toward the end of this study to meet patient needs.²⁸

The present study met our objective of identifying individual patient factors that are predictive of the success of our CTP. Cognitively impaired patients were less likely to be readmitted than cognitively intact patients. This finding is particularly important because patients with dementia constitute a subgroup that is at an increased risk of readmission after hospitalization²⁹ and often suffer burdensome transitions at the end of life.^30,31 High medication use and high number of visits to primary care and number of hospital days in the six months leading up to enrollment increase the likelihood of readmission and are plausible measures of disease severity or multi-morbidity that have been identified in previous studies.^32,33 No one program intervention was found to be significantly associated with readmission. This result is consistent with prior works that demonstrated the need for multifaceted and intensive interventions to reduce readmission risk among highly complex and multimorbid patients.^13,14

Our findings suggest that the provision of an alternative to stressful hospitalization to cognitively impaired patients and their caregivers may be an important benefit of care transitions programs. Having a trusted team to consult in acute situations may have enabled early intervention and crisis avoidance. Avoiding hospitalizations and ED visits may also have been in line with their goals of care.^34,35 Given that program intensity varied on the basis of the discretion of the clinical team, patients with cognitive impairment and their caregivers may also have received more intensive support than cognitively intact patients.

In contrast to recent systematic reviews, our study did not find that advance directive discussion had significant effects on reductions in readmission.^36,37 The lack of discussion surrounding the goals of care for patients with serious illnesses was also listed as one of four factors that are strongly associated with preventability in a national cohort of readmitted general medicine patients.³⁸ The lack of power and incomplete documentation may have contributed to our null findings. Trust building must also occur before any meaningful discussion of the goals of care could be achieved, and follow-up time may have to be extended. Toward the end of this study, we developed an extension of our program for patients with limited life expectancy and conservative goals of care. In this extension, reductions in hospitalizations were observed among patients who had multiple goals of care discussions.²⁸

Previous studies have shown that readmissions reduced with timely follow up among patients with heart failure.³⁹ Our results showed no difference in readmission rate based on whether or not our patients were visited within five days from discharge, but we may have been underpowered to detect this difference. In addition, we may have missed readmissions that occurred before the enrollment visit.

The elements of the CTP were evidence based. Fidelity to program goals improved over time and reached high levels with program maturity. Only 12% of the patients received all program components at the first home visit. Patients that had all pillars addressed and documented showed a nonsignificant trend toward reduced readmission rates. NPs were given discretion as to how many visits were required to stabilize a patient and achieve program objectives. Heart failure management was driven by protocol with input from cardiology. Medication reconciliation and clinical assessment with action plan were prioritized at the first visit and thus allowed for the completion of other goals at a subsequent visit if time was insufficient. These decisions were deliberated at weekly physician-led multidisciplinary meetings. This variability allowed the team to meet chronic and urgent needs but further confounded the interpretation of our results. One possible way to interpret the lack of significant predictors of success is that through clinical assessment and flexibility, we were able to tailor our program to meet the needs of this complex multi-morbid population.

This study has important limitations. Given that it is a retrospective cohort study, we were unable to include patients who were enrolled but were either readmitted or dropped out before the first program visit. In addition, because of our study’s limited sample size and readmission rate, we had limited power to detect other potential predictor variables and test for confounding and interaction. While we included numerous variables in our analyses, we lacked information on mental health and the social determinants of health, which are known to influence readmission risk.^40,41 Similarly, we lacked patient self-reported measures of health and information regarding caregiver support, which are important.^42,43 Several of our predictive measures (cognitive impairment, mobility limitations, and program objective completion) were dependent on supplementing billing codes with heterogeneous data abstracted from usual clinical care as opposed to standardized research protocols. Neither method is completely accurate, nor can the combination of the two be assumed to be without inaccuracies. Failure to adequately document the clinical interventions performed by the clinical team is possibly a major confounder as evidenced by the considerable lack of agreement by our trained abstractors in determining whether advance care planning took place. The generalizability of our results is also a concern because the local population is largely white and highly educated, although our experience tells us that many of our program patients have limited means and thus may more closely resemble the general US population.⁴⁴ The strength of our study is that it uses real, practice-based data that can be directly translated to practice.

This study focused on a successful high-intensity CTP. Results showed that compared with patients without dementia, patients with dementia were more likely to avoid hospitalizations as a result of enrollment in the investigated CTP. This study, however, failed to identify specific programmatic components critical for the success of the CTP. These findings support the current hypothesis that multidisciplinary, multimodal, and highly intensive interventions are necessary to care for complex and multi-morbid patients. They also suggest that compared with cognitively functional patients, cognitively impaired patients with conservative goals of care may be more likely to avoid burdensome hospitalizations when provided with early intervention in their home.

Acknowledgments

B.T. conceived and designed the study, interpreted the data, drafted and provided final revisions to the manuscript. P.Y.T, N.D.S., and J.M.N obtained funding, contributed to the conception and design of the study, analysis, and interpretation of the data, and provided critical revisions to the manuscript. P.A.R., R.G.M, and G.J.H., contributed to the conception and design of the study, analysis, and interpretation of the data, and provided critical revisions to the manuscript. S.M.P. Assisted with data acquisition and interpretation, performed the data analysis, and drafted parts of the manuscript. C.Y.Y.C, L.J.H., A.L, A.C., L.B., and R.H. helped with methodologic questions and data interpretation, and provided critical revisions to the manuscript.

All authors read and approved the final manuscript and the decision to submit the manuscript for publication.

We thank Donna Lawson, RN for her help with data abstraction and Annika Beck and Anna Jones in Mayo Clinic Biomedical Ethics Research Program for her help in preparing this manuscript for publication.

Disclosures

The authors declare no conflicts of interest.

Funding

This publication was supported by the Mayo Clinic, Robert D and Patricia E. Center for the Science of Health Care Delivery (B.T., R.H., R.G.M, L.J.H), by the Extramural Grant Program by Satellite Healthcare, a not-for-profit renal care provider (L.J.H., B.T.), and by the National Institute of Health (NIH) National Institute Of Diabetes And Digestive And Kidney Diseases grant K23 DK109134 (L.J.H.) K23DK114497 (RGM) and National Institute on Aging grant K23 AG051679 (B.T.). Additional support was provided by the National Center for Advancing Translational Sciences grant UL1 TR000135. Study contents are the sole responsibility of the authors and do not necessarily represent the official views of NIH.

The sponsors had no role in the design, execution, or reporting of this study.

Prior Presentations

Part of this data was presented in poster format at the American Geriatrics Society meeting in Washington DC 2015.

Unplanned hospital admissions and readmissions have become a major focus of efforts to improve the value of healthcare given that these potentially preventable events exert substantial burden on patients, caregivers, health systems, and the economy.¹ The percentage of patients who are rehospitalized within 30 days have decreased from 20%-21% at the start of the Accountable Care Act and readmission penalties to approximately 18%.^2-5 Rehospitalization rates are 33% at 90 days and approach 40% at six months.^6,7 Readmissions cost Medicare more than $26 billion annually,⁴ with one in five Medicare beneficiaries readmitted within 30 days of hospital discharge.⁸ Centers for Medicare and Medicaid Services and other payers use condition-specific and all-cause 30-day unplanned readmission rates and potentially preventable admissions among patients with complex or multiple comorbidities for public reporting, value-based purchasing, and performance-based reimbursement.^9,10 Consequently, medical groups and hospitals have begun to place an increasing emphasis on improving the transitions of care following hospitalization with the goal of reducing unplanned readmissions.¹¹ Care transitions programs have been shown to decrease readmission rates, mortality, and emergency department (ED) visits.¹²

Care transitions programs vary greatly in their scope of intervention and target groups, as well as in their efficacy in reducing readmissions.^13,14 The Mayo Clinic Care Transition Program, hereafter referred to as CTP, was launched in 2011. This program was modeled after other successful programs and involves home visits by a nurse practitioner (NP) and telephonic support and triage provided by a registered nurse (RN). It is offered to high-risk community-dwelling patients during their hospitalization and begins within a week of hospital discharge.

Although the CTP reduces 30-day readmissions from 20% to 17%,⁷ it is a highly resource-intensive, multimodal, multidisciplinary program. Moreover, whether some components of the CTP are more critical than others remains unknown. Prior studies that examined the individual components of successful CTPs have suggested that a multipronged approach that includes close patient and caregiver support is most predictive of program efficacy.¹³ Long-term program sustainability would benefit from optimization of the most critical components of the program while reducing or eliminating resource-intensive factors that have negligible effects on program success. We therefore examined our CTP to identify whether and which program components are most critical for preventing 30-day readmissions and whether any patient characteristics contribute risk within this complex population.

Study Design and Setting

This study is a retrospective cohort study of patients who were enrolled in the care transitions program of Mayo Clinic Rochester during the period January 1, 2010 to June 30, 2013. Patient demographic and clinical data were obtained from electronic health records (EHR), and information regarding CTP processes and interventions was obtained from a prospectively maintained program database. The study complied with the principles of the Declaration of Helsinki and was approved by the Mayo Clinic Institutional Review Board.

Objectives

The study aimed to describe the performance and utilization of a multidisciplinary care transitions program that has been successful in reducing readmissions for high-risk patients. The study also sought to identify patient and/or program factors associated with failure to prevent readmission within 30 days of program enrollment.

Population

Patients who were enrolled in the CTP following hospital discharge and seen for a posthospital in-home visit prior to hospital readmission (for those readmitted) were included. Patients discharged to a skilled nursing facility were excluded. Patients were eligible for CTP enrollment if they were hospitalized for any cause, community dwelling (including assisted living) prior to hospitalization, and ≥60 years old with an Elder Risk Assessment (ERA) score ≥16.⁷ The ERA incorporates information regarding previous hospital days, age, and comorbid health burden and has been shown to predict 30-day readmissions, mortality, and critical illness (

Intervention

Detailed descriptions of the CTP have been previously published.^7,17 Patients meeting enrollment criteria are enrolled into the CTP by a RN prior to or immediately after hospital discharge. The patient is then seen at home within one to five business days of discharge and again the following week by a NP who performs medication reconciliation; chronic illness management; and acute illness, mobility, safety, and cognition assessments. The NP also provides patient education on self-care and advance care planning. Patient and caregiver support and liaisons with community resources are provided. Home visits by an NP or MD are continued as needed for at least one month. A RN case manager performs weekly phone calls to assess changes in the patient’s clinical status and is available for phone triage of acute health issues. An interdisciplinary team composed of MDs, NPs, RNs, and pharmacists review patient management at weekly meetings. Although after-hours or weekend coverage for home visits are unavailable, an on-call primary care physician is available by phone at all times.

Primary Outcome

The primary outcome was all-cause hospital readmission within 30 days of the first CTP home visit, indicating successful program enrollment. Hospitalization was determined on the basis of billing codes from Mayo Clinic hospitals; this approach is 99% reliable in detecting readmissions for this population.¹⁸

Secondary Outcome Measures

Secondary outcome measures included six-month mortality and hospitalizations, as well as the number of hospital and ICU days and home, ED, primary care, and specialty office visits within 180 days after index hospitalizations as per the EHR. ED visits were counted only when they did not result in a hospital admission.

Independent Variables

Patient characteristics and clinical variables were retrieved from the EHR and included patient age, sex, and marital status. Comorbidities, ERA score,¹⁹ and Charlson comorbidity index (CCI)²⁰ within two years of program enrollment were determined by using ICD-9 billing codes. The frequencies of primary care and specialty visits within six months of the index hospitalization were also ascertained using the EHR. Mobility limitations and cognitive impairment were categorized as binary variables (yes/no) and were assessed at the first home visit by the NP. The presence of mobility limitations was defined as a Barthel’s score of <75^21,22 or Timed up and Go time of >20 seconds.²³ Cognitive impairment was established as Kokmen below the normal cutoff for patient’s age group,²⁴ Mini-Cog ≤2,²⁵or AD8 ≥2.²⁶ If these measures were not specifically documented during the first visit, clinical notes were queried for the description of pertinent cognitive and/or mobility limitations. Dementia diagnosis billing codes (ICD9 Code 290.*) were also included. High medication use was defined as >14 given the reported average medication number ranges from 8-13 in this population.²⁷

As previously published, fidelity measures were abstracted from clinical notes by a trained nurse abstractor within 30 days of program enrollment and prior to a readmission.⁷ The five program fidelity measures included medication reconciliation, home service evaluation, advanced directives discussion, action plan for acute and chronic disease, safety plan, and discussion of community resources. The presence of advanced care planning was determined on the basis of visit medical notes and/or change of code status within the EHR, the identification or scanning of written advanced directives or “provider order for life-sustaining treatment,” and documentation of the discussion of resuscitation status. It was abstracted in duplicate by a nurse abstractor with physician adjudication for disagreement. Moreover, whether the initial visit met the goal of being within five days of discharge was determined by using billing data.

Analysis

The contribution of each independent variable to 30-day readmission was first directly assessed by using a univariate logistic regression model. Five patients died within 30 days without being admitted. These deaths, however, were not censored given that home death (as opposed to hospital death) was considered a positive outcome of the CTP. Multivariable modeling was performed through log rank test with backwards elimination and included all independent variables with P < .05. Variables with P values between .05 and >.1 were tested for interaction with age and sex. Age was categorized as <80 or ≥80 years. The length of hospital stay was categorized as <3 days (not qualifying for a Medicare skilled nursing facility), 3-13 days, or ≥14 days.

This study had 30% power to detect a reduction of 5% in the rates of hospital admissions; 5% is the median absolute risk reduction reported by previous randomized studies on care transitions programs previously reported.¹⁰ All analyses were performed using SAS 6.01 (SAS Inc., Cary, North Carolina).

Study Population

The study cohort included 315 patients who met the inclusion criteria (Fig 1). The demographic and clinical characteristics of the participants were ascertained at the time of CTP enrollment and are shown in Table 1. Patients were, on average, 82.5 (SD, 8.2) years old and had multiple comorbidities with a mean CCI score of 6.2 and ERA score of 18.5. Almost half of the patients (43.2%) exhibited cognitive impairment and more than half (51.7%) had mobility limitations. Among the patients, 42.9% had been hospitalized at least once in the 180 days prior to their CTP-qualifying hospitalization and 14.2% had ≥2 hospitalizations prior to their CTP-qualifying hospitalization. Similarly, 32.4% had at least one emergency department (ED) visit, and 3.5% had ≥3 ED visits. The majority of patients had frequent outpatient visits, with 30.8% having ≥4 office visits in primary care and 32.4% having ≥4 specialty office visits in the preceding six months.

Readmissions, Mortality, ED, and Outpatient Visits

Of the 315 patients, 54 (17.1%) had a readmission within 30 days and seven (2%) had >1 readmission. Among the patients, 126 (40.0%) were readmitted at least once within 180 days with 55 (17.5%) having more than one readmission. A total of 41 patients (13.1%) died during the six-month follow-up period. The need for both office and ED visits was reduced compared to the 180 days prior to admission with the biggest difference in ED visits: 72 (22.9%) of patients needed visits within 180 days of enrollment, as opposed to 102 (32.4%) before enrollment.

Impact of Patient Clinical Variables on Readmission Risk

Readmitted patients were less likely to exhibit cognitive impairment (29.6% vs 46.0%; P = .03) and were more likely to have high medication use (59.3% vs 44.4%; P = .047) than patients without readmission (Table 1). Readmitted patients had a higher frequency of visits to primary care (4.0 vs 3.0; P =.02) in the six months prior to admission and more hospital days in the prior year (4.6 vs 2.5; P = .04) than those without readmission.

Multivariable analysis, which included the cognitive status of the patient; the high use of medication; and the number of ED visits, primary care visits, and hospital days in the previous six months, provided a C statistic of 0.665. After backwards elimination, only the cognitive status of the patient and number of ED visits remained predictive of readmission risk.

Impact of Program Interventions on Readmission Risk

The completion of the CTP fidelity measures drastically varied with completion rates between 29.5% (community resource evaluation) and 87.0% (home visit within five days of hospital discharge; Table 2). Only 12.1% of patients received all components of the CTP at the first home visit. Readmission rates among patients who received all program components (13.2%) were lower than those among patients who did not receive all program components. This difference, however, failed to reach statistical significance. No single program component significantly reduced readmission risk. The completion rate of program fidelity measures increased with time (Figure 2). The present findings did not change even after performing sensitivity analysis that excluded the first program year. The overall agreement between chart abstractors on determining whether advance care planning occurred was 69.5% but the Cohens Kappa was only 18.4. This result was largely ascribed to the following: One abstractor counted the presence of a shorthand template used to document the delivery of an advance care planning document as discussion, whereas the other abstractor required further documentation or corroborating evidence (ie, change of code status). The majority of patients required multiple home visits to address ongoing medical needs (mean 2.7; SD = 1.3) over the first 30 days. Among these patients, only 17.1% received one visit, and 54.6% of patients received ≥3 visits. Eleven (3.5%) patients transitioned to a palliative homebound program that we began offering toward the end of this study to meet patient needs.²⁸

The present study met our objective of identifying individual patient factors that are predictive of the success of our CTP. Cognitively impaired patients were less likely to be readmitted than cognitively intact patients. This finding is particularly important because patients with dementia constitute a subgroup that is at an increased risk of readmission after hospitalization²⁹ and often suffer burdensome transitions at the end of life.^30,31 High medication use and high number of visits to primary care and number of hospital days in the six months leading up to enrollment increase the likelihood of readmission and are plausible measures of disease severity or multi-morbidity that have been identified in previous studies.^32,33 No one program intervention was found to be significantly associated with readmission. This result is consistent with prior works that demonstrated the need for multifaceted and intensive interventions to reduce readmission risk among highly complex and multimorbid patients.^13,14

Our findings suggest that the provision of an alternative to stressful hospitalization to cognitively impaired patients and their caregivers may be an important benefit of care transitions programs. Having a trusted team to consult in acute situations may have enabled early intervention and crisis avoidance. Avoiding hospitalizations and ED visits may also have been in line with their goals of care.^34,35 Given that program intensity varied on the basis of the discretion of the clinical team, patients with cognitive impairment and their caregivers may also have received more intensive support than cognitively intact patients.

In contrast to recent systematic reviews, our study did not find that advance directive discussion had significant effects on reductions in readmission.^36,37 The lack of discussion surrounding the goals of care for patients with serious illnesses was also listed as one of four factors that are strongly associated with preventability in a national cohort of readmitted general medicine patients.³⁸ The lack of power and incomplete documentation may have contributed to our null findings. Trust building must also occur before any meaningful discussion of the goals of care could be achieved, and follow-up time may have to be extended. Toward the end of this study, we developed an extension of our program for patients with limited life expectancy and conservative goals of care. In this extension, reductions in hospitalizations were observed among patients who had multiple goals of care discussions.²⁸

Previous studies have shown that readmissions reduced with timely follow up among patients with heart failure.³⁹ Our results showed no difference in readmission rate based on whether or not our patients were visited within five days from discharge, but we may have been underpowered to detect this difference. In addition, we may have missed readmissions that occurred before the enrollment visit.

The elements of the CTP were evidence based. Fidelity to program goals improved over time and reached high levels with program maturity. Only 12% of the patients received all program components at the first home visit. Patients that had all pillars addressed and documented showed a nonsignificant trend toward reduced readmission rates. NPs were given discretion as to how many visits were required to stabilize a patient and achieve program objectives. Heart failure management was driven by protocol with input from cardiology. Medication reconciliation and clinical assessment with action plan were prioritized at the first visit and thus allowed for the completion of other goals at a subsequent visit if time was insufficient. These decisions were deliberated at weekly physician-led multidisciplinary meetings. This variability allowed the team to meet chronic and urgent needs but further confounded the interpretation of our results. One possible way to interpret the lack of significant predictors of success is that through clinical assessment and flexibility, we were able to tailor our program to meet the needs of this complex multi-morbid population.

This study has important limitations. Given that it is a retrospective cohort study, we were unable to include patients who were enrolled but were either readmitted or dropped out before the first program visit. In addition, because of our study’s limited sample size and readmission rate, we had limited power to detect other potential predictor variables and test for confounding and interaction. While we included numerous variables in our analyses, we lacked information on mental health and the social determinants of health, which are known to influence readmission risk.^40,41 Similarly, we lacked patient self-reported measures of health and information regarding caregiver support, which are important.^42,43 Several of our predictive measures (cognitive impairment, mobility limitations, and program objective completion) were dependent on supplementing billing codes with heterogeneous data abstracted from usual clinical care as opposed to standardized research protocols. Neither method is completely accurate, nor can the combination of the two be assumed to be without inaccuracies. Failure to adequately document the clinical interventions performed by the clinical team is possibly a major confounder as evidenced by the considerable lack of agreement by our trained abstractors in determining whether advance care planning took place. The generalizability of our results is also a concern because the local population is largely white and highly educated, although our experience tells us that many of our program patients have limited means and thus may more closely resemble the general US population.⁴⁴ The strength of our study is that it uses real, practice-based data that can be directly translated to practice.

This study focused on a successful high-intensity CTP. Results showed that compared with patients without dementia, patients with dementia were more likely to avoid hospitalizations as a result of enrollment in the investigated CTP. This study, however, failed to identify specific programmatic components critical for the success of the CTP. These findings support the current hypothesis that multidisciplinary, multimodal, and highly intensive interventions are necessary to care for complex and multi-morbid patients. They also suggest that compared with cognitively functional patients, cognitively impaired patients with conservative goals of care may be more likely to avoid burdensome hospitalizations when provided with early intervention in their home.

Acknowledgments

B.T. conceived and designed the study, interpreted the data, drafted and provided final revisions to the manuscript. P.Y.T, N.D.S., and J.M.N obtained funding, contributed to the conception and design of the study, analysis, and interpretation of the data, and provided critical revisions to the manuscript. P.A.R., R.G.M, and G.J.H., contributed to the conception and design of the study, analysis, and interpretation of the data, and provided critical revisions to the manuscript. S.M.P. Assisted with data acquisition and interpretation, performed the data analysis, and drafted parts of the manuscript. C.Y.Y.C, L.J.H., A.L, A.C., L.B., and R.H. helped with methodologic questions and data interpretation, and provided critical revisions to the manuscript.

All authors read and approved the final manuscript and the decision to submit the manuscript for publication.

We thank Donna Lawson, RN for her help with data abstraction and Annika Beck and Anna Jones in Mayo Clinic Biomedical Ethics Research Program for her help in preparing this manuscript for publication.

Disclosures

The authors declare no conflicts of interest.

Funding

This publication was supported by the Mayo Clinic, Robert D and Patricia E. Center for the Science of Health Care Delivery (B.T., R.H., R.G.M, L.J.H), by the Extramural Grant Program by Satellite Healthcare, a not-for-profit renal care provider (L.J.H., B.T.), and by the National Institute of Health (NIH) National Institute Of Diabetes And Digestive And Kidney Diseases grant K23 DK109134 (L.J.H.) K23DK114497 (RGM) and National Institute on Aging grant K23 AG051679 (B.T.). Additional support was provided by the National Center for Advancing Translational Sciences grant UL1 TR000135. Study contents are the sole responsibility of the authors and do not necessarily represent the official views of NIH.

The sponsors had no role in the design, execution, or reporting of this study.

Prior Presentations

Part of this data was presented in poster format at the American Geriatrics Society meeting in Washington DC 2015.

Computed tomography pulmonary angiography (CTPA) is often used in the evaluation of suspected pulmonary embolism (PE). The detection of incidental findings that require follow-up is common; in just over 50% of cases, those incidental findings are pulmonary nodules.¹ Although the majority of these nodules are benign, Fleischner Society guidelines² recommend that patients with nodules at high risk for malignancy should undergo follow-up CT imaging within 3-12 months, with patients who smoke and have large nodules requiring closer follow up.

The failure to follow-up on abnormal test results is known to contribute to diagnostic error and can lead to patient harm.³ We sought to determine the proportion of high-risk pulmonary nodules on CTPA which did not undergo the recommended follow-up imaging.

Study Setting and Design

This retrospective cohort study included all patients who underwent CTPA in the emergency department (ED) and inpatient settings at three academic health centers (Mount Sinai Hospital, Toronto General Hospital, and Toronto Western Hospital) in Toronto, Canada between September 1, 2014, and August 31, 2015.

We examined the proportion of patients with pulmonary nodules requiring follow up who received repeat CT imaging within six weeks of the time frame recommended by the radiologist. Since we were interested in measuring the rate of an important test result that is missed (rather than accuracy of the test itself), we defined “requiring follow up” as the inclusion of explicit recommendations for follow up in the radiology report.

Montage (Philadelphia, Pennsylvania), a natural language processing software, was applied to a linked radiology information system (RIS) to identify all CTPAs that contained pulmonary nodules. We conducted manual chart review to confirm software accuracy. We initially searched the RIS for all CTPAs that were completed within the study period, resulting in the identification of 1932 imaging studies. Following a review of these 1,932 studies, we excluded 22 as they were not CTPAs. We then applied the search term, “nodule-” to 1,910 confirmed CTPAs, resulting in the identification of 836 imaging studies. Following a review of these 836 studies, we excluded 10 as they were duplicate studies. We also excluded 152 studies where the term “nodule-” did not identify a pulmonary nodule but instead referred to a radiologist reporting the absence of pulmonary nodules (eg “there were no pulmonary nodules found”) or the presence of non-lung nodules (eg thyroid nodules). This resulted in the identification of 674 CTPAs containing pulmonary nodules (Figure 1).

Thereafter, we generated a cohort with possible new lung malignancy eligible for follow-up imaging by reviewing available health records and applying the following prespecified exclusion criteria: (1) patients who died, (2) left against medical advice, (3) were critically ill during the follow-up period, (4) lived outside the hospital catchment area (Greater Toronto Area), (5) were seen in the outpatient setting, (6) identified as palliative, (7) had an active malignancy, (8) had nodules that were already being followed, or (9) had nodules with characteristics suggestive of alternate diagnoses to lung malignancy (such as infection or inflammation) with no follow up recommended as reported by the radiologist. For patients with multiple CTPAs, we included only the first study. For each eligible patient, we determined whether follow-up imaging was completed by manually reviewing the linked RIS. We reviewed available health records to determine whether the pulmonary nodule findings had been discussed with the patient and whether the patient had attended an outpatient follow-up visit. In patients for whom recommended follow-up imaging was not confirmed, we notified the ordering physician by e-mail.

Each radiology department followed the same protocol adherent to the 2005 Fleischner guidelines for identifying nodules requiring follow up.² Virtually all CTPAs at the three study institutions are read and reported within 72 hours. The ordering physician is sometimes called at the discretion of the reading radiologist when the findings are judged to be urgent and time-sensitive in nature. For example, the ordering physician may be contacted if a CTPA is positive for segmental PE but is not typically called for incidental pulmonary nodules. It is not common practice for ordering physicians to be notified of incidental findings above and beyond the radiology report. Primary care physicians are not typically copied on radiology reports and usually do not use the same electronic health record.

Statistical Analysis

We calculated simple descriptive statistics for all results. Mean values were compared using two-tailed t-tests, categorical groups using chi-square tests, and median values using Mann-Whitney U tests. We performed all analyses using Microsoft Excel version 16.14.1 (Redmond, Washington).

Ethics Approval

This study was approved by each institution’s research ethics board.

Follow Up of Incidental High-Risk Pulmonary Nodules

Of the 1910 CTPAs performed over the study period (Figure), 674 (35.3%) contained pulmonary nodules. Of the 259 patients with new pulmonary nodules eligible for follow-up imaging, 194 (74.9%) did not have an explicit suggestion for follow up by the radiologist. Ninety-five percent of radiologists (184 out of 194) provided an explanation for not recommending follow up in the radiology report; the two most common reasons were small nodule size (often described as “tiny”) and no interval change compared with the prior imaging study.² Of the 65 patients who did receive an explicit suggestion for follow up by radiology, 35 (53.8%) did not receive repeat imaging within the recommended time frame, allowing for a six-week grace period. Of these 35 patients, 10 eventually went on to receive delayed repeat imaging. The median follow-up time for the 30 patients who received timely repeat imaging was four months (IQR 2-6 months); in contrast, the median follow-up time for the 10 patients who received delayed repeat imaging was seven months (IQR 6-8 months), P = .01.

Of the 65 patients for whom follow up was recommended, the medical record showed evidence that there was a discussion between the medical team and the patient regarding patient preference for or against follow up in 55.4% (36 out of 65) of the patients. Notably, all 36 patients showed interest in receiving follow up; no patient indicated a preference for no follow up.

Furthermore, of the 65 patients that had follow up recommended, two patients were eventually diagnosed with lung cancer (one via lung biopsy, the other via positron emission tomography imaging); both patients did not receive timely follow-up imaging. While we did not include nodule size as an exclusion criterion, not one of the 65 patients included in the final cohort had nodules larger than 3 cm.

Physician Notification

In circumstances where we could not confirm that followed up had occurred, we notified the ordering physician by e-mail. Since 10 of the 35 patients who did not receive timely follow-up imaging went on to receive delayed repeat imaging, we notified 25 physicians. Of the 25 physicians that we e-mailed, 24 acknowledged receipt of the information. Of these 24 physicians, 14 reported conducting a detailed review of the chart, from which the following additional information was obtained: one patient expired, and five physicians notified the corresponding primary care physicians (two of whom were unaware of the nodule, and subsequently arranged further follow up with the patient).

Characteristics Associated with Timely Follow Up

Explicit mention that follow up was required in the discharge summary (P = .03), attending an outpatient follow-up visit (P < .001), and younger age (P = .03) were associated with receiving timely follow up; patient sex, smoking history, history of chronic obstructive pulmonary disease, lung nodule count, recommended follow-up time, and hospital department (defined as the discharging service) were not (Table).

In this multicenter cohort study, over 50% of patients with new high-risk pulmonary nodules detected incidentally on CTPA did not receive timely follow-up imaging. Including follow-up recommendations in the discharge summary, attending an outpatient follow-up visit, and younger age were associated with timely follow-up imaging.

Few studies have assessed the follow up of incidental nodules identified on CTPA. In a retrospective cohort study of ED patients in the United States, Blagev et al. found that only 29% received timely follow up.⁴ Our study contributes to the literature in several ways. First, our study included all hospitalized patients, not only those in the ED. Notably, most of our cohort were inpatients, a group of patients not previously described. Second, we examined factors associated with timely follow up, which may help to inform future quality improvement initiatives and interventions. Third, we included data from three different hospitals, which may improve generalization. Lastly, our study draws on contemporary Canadian data. Most of the studies investigating test result follow up have been conducted in the US^5,6 and Europe,⁷ with few empirical studies describing this phenomenon within the Canadian healthcare setting. We believe that our work contributes to the existing evidence that missed test results occur across diverse healthcare systems and have yet to be solved.^5-7

Our study had limitations. First, we defined follow up as repeat imaging and did not include office visits or biopsy in this definition. Second, we may have missed repeat imaging and outpatient follow-up visits that occurred outside the study hospitals. Although we were able to determine if repeat imaging and outpatient follow-up visits (eg, pulmonology or thoracic surgery clinics) had occurred within the study hospitals, we did not have access to follow-up encounters that occurred outside of the study hospitals (eg primary care clinics). We are unaware of any published regional data on the rate of outpatient follow up at the index facility following discharge. However, we know from provincial data of patients discharged from the ED with a new cardiac diagnosis that just under half are seen by a family physician, cardiologist, or internist within seven days, with just under 80% seen within 30 days.⁸ Third, although we attempted to capture patient preference for or against repeat imaging using chart review, the absence of documentation of patient preference did not confirm that a discussion regarding patient preferences had not occurred. Fourth, while we did exclude patients that had an active malignancy, we did not exclude patients who were younger than 35 years or were immunocompromised, which may have led to an overestimation of the percentage of patients who did not receive follow up.

Incidental findings detected on acute diagnostic tests requiring handoffs for chronic follow up are at risk of falling through the cracks. The inclusion of follow-up recommendations in discharge summaries has been shown to increase the likelihood of follow-up completion.⁹ Our study provides additional evidence of the urgent need for interventions aimed at closing the loop on test result follow up.^5,6

Disclosures

None of the authors have any conflicts of interest to disclose in reference to this study.

Funding

JLK is supported by the Mount Sinai Hospital Department of Medicine Research Fund. PC is supported by a K24 award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR062133).

Computed tomography pulmonary angiography (CTPA) is often used in the evaluation of suspected pulmonary embolism (PE). The detection of incidental findings that require follow-up is common; in just over 50% of cases, those incidental findings are pulmonary nodules.¹ Although the majority of these nodules are benign, Fleischner Society guidelines² recommend that patients with nodules at high risk for malignancy should undergo follow-up CT imaging within 3-12 months, with patients who smoke and have large nodules requiring closer follow up.

The failure to follow-up on abnormal test results is known to contribute to diagnostic error and can lead to patient harm.³ We sought to determine the proportion of high-risk pulmonary nodules on CTPA which did not undergo the recommended follow-up imaging.

Study Setting and Design

This retrospective cohort study included all patients who underwent CTPA in the emergency department (ED) and inpatient settings at three academic health centers (Mount Sinai Hospital, Toronto General Hospital, and Toronto Western Hospital) in Toronto, Canada between September 1, 2014, and August 31, 2015.

We examined the proportion of patients with pulmonary nodules requiring follow up who received repeat CT imaging within six weeks of the time frame recommended by the radiologist. Since we were interested in measuring the rate of an important test result that is missed (rather than accuracy of the test itself), we defined “requiring follow up” as the inclusion of explicit recommendations for follow up in the radiology report.

Montage (Philadelphia, Pennsylvania), a natural language processing software, was applied to a linked radiology information system (RIS) to identify all CTPAs that contained pulmonary nodules. We conducted manual chart review to confirm software accuracy. We initially searched the RIS for all CTPAs that were completed within the study period, resulting in the identification of 1932 imaging studies. Following a review of these 1,932 studies, we excluded 22 as they were not CTPAs. We then applied the search term, “nodule-” to 1,910 confirmed CTPAs, resulting in the identification of 836 imaging studies. Following a review of these 836 studies, we excluded 10 as they were duplicate studies. We also excluded 152 studies where the term “nodule-” did not identify a pulmonary nodule but instead referred to a radiologist reporting the absence of pulmonary nodules (eg “there were no pulmonary nodules found”) or the presence of non-lung nodules (eg thyroid nodules). This resulted in the identification of 674 CTPAs containing pulmonary nodules (Figure 1).

Thereafter, we generated a cohort with possible new lung malignancy eligible for follow-up imaging by reviewing available health records and applying the following prespecified exclusion criteria: (1) patients who died, (2) left against medical advice, (3) were critically ill during the follow-up period, (4) lived outside the hospital catchment area (Greater Toronto Area), (5) were seen in the outpatient setting, (6) identified as palliative, (7) had an active malignancy, (8) had nodules that were already being followed, or (9) had nodules with characteristics suggestive of alternate diagnoses to lung malignancy (such as infection or inflammation) with no follow up recommended as reported by the radiologist. For patients with multiple CTPAs, we included only the first study. For each eligible patient, we determined whether follow-up imaging was completed by manually reviewing the linked RIS. We reviewed available health records to determine whether the pulmonary nodule findings had been discussed with the patient and whether the patient had attended an outpatient follow-up visit. In patients for whom recommended follow-up imaging was not confirmed, we notified the ordering physician by e-mail.

Each radiology department followed the same protocol adherent to the 2005 Fleischner guidelines for identifying nodules requiring follow up.² Virtually all CTPAs at the three study institutions are read and reported within 72 hours. The ordering physician is sometimes called at the discretion of the reading radiologist when the findings are judged to be urgent and time-sensitive in nature. For example, the ordering physician may be contacted if a CTPA is positive for segmental PE but is not typically called for incidental pulmonary nodules. It is not common practice for ordering physicians to be notified of incidental findings above and beyond the radiology report. Primary care physicians are not typically copied on radiology reports and usually do not use the same electronic health record.

Statistical Analysis

We calculated simple descriptive statistics for all results. Mean values were compared using two-tailed t-tests, categorical groups using chi-square tests, and median values using Mann-Whitney U tests. We performed all analyses using Microsoft Excel version 16.14.1 (Redmond, Washington).

Ethics Approval

This study was approved by each institution’s research ethics board.

Follow Up of Incidental High-Risk Pulmonary Nodules

Of the 1910 CTPAs performed over the study period (Figure), 674 (35.3%) contained pulmonary nodules. Of the 259 patients with new pulmonary nodules eligible for follow-up imaging, 194 (74.9%) did not have an explicit suggestion for follow up by the radiologist. Ninety-five percent of radiologists (184 out of 194) provided an explanation for not recommending follow up in the radiology report; the two most common reasons were small nodule size (often described as “tiny”) and no interval change compared with the prior imaging study.² Of the 65 patients who did receive an explicit suggestion for follow up by radiology, 35 (53.8%) did not receive repeat imaging within the recommended time frame, allowing for a six-week grace period. Of these 35 patients, 10 eventually went on to receive delayed repeat imaging. The median follow-up time for the 30 patients who received timely repeat imaging was four months (IQR 2-6 months); in contrast, the median follow-up time for the 10 patients who received delayed repeat imaging was seven months (IQR 6-8 months), P = .01.

Of the 65 patients for whom follow up was recommended, the medical record showed evidence that there was a discussion between the medical team and the patient regarding patient preference for or against follow up in 55.4% (36 out of 65) of the patients. Notably, all 36 patients showed interest in receiving follow up; no patient indicated a preference for no follow up.

Furthermore, of the 65 patients that had follow up recommended, two patients were eventually diagnosed with lung cancer (one via lung biopsy, the other via positron emission tomography imaging); both patients did not receive timely follow-up imaging. While we did not include nodule size as an exclusion criterion, not one of the 65 patients included in the final cohort had nodules larger than 3 cm.

Physician Notification

In circumstances where we could not confirm that followed up had occurred, we notified the ordering physician by e-mail. Since 10 of the 35 patients who did not receive timely follow-up imaging went on to receive delayed repeat imaging, we notified 25 physicians. Of the 25 physicians that we e-mailed, 24 acknowledged receipt of the information. Of these 24 physicians, 14 reported conducting a detailed review of the chart, from which the following additional information was obtained: one patient expired, and five physicians notified the corresponding primary care physicians (two of whom were unaware of the nodule, and subsequently arranged further follow up with the patient).

Characteristics Associated with Timely Follow Up

Explicit mention that follow up was required in the discharge summary (P = .03), attending an outpatient follow-up visit (P < .001), and younger age (P = .03) were associated with receiving timely follow up; patient sex, smoking history, history of chronic obstructive pulmonary disease, lung nodule count, recommended follow-up time, and hospital department (defined as the discharging service) were not (Table).

In this multicenter cohort study, over 50% of patients with new high-risk pulmonary nodules detected incidentally on CTPA did not receive timely follow-up imaging. Including follow-up recommendations in the discharge summary, attending an outpatient follow-up visit, and younger age were associated with timely follow-up imaging.

Few studies have assessed the follow up of incidental nodules identified on CTPA. In a retrospective cohort study of ED patients in the United States, Blagev et al. found that only 29% received timely follow up.⁴ Our study contributes to the literature in several ways. First, our study included all hospitalized patients, not only those in the ED. Notably, most of our cohort were inpatients, a group of patients not previously described. Second, we examined factors associated with timely follow up, which may help to inform future quality improvement initiatives and interventions. Third, we included data from three different hospitals, which may improve generalization. Lastly, our study draws on contemporary Canadian data. Most of the studies investigating test result follow up have been conducted in the US^5,6 and Europe,⁷ with few empirical studies describing this phenomenon within the Canadian healthcare setting. We believe that our work contributes to the existing evidence that missed test results occur across diverse healthcare systems and have yet to be solved.^5-7

Our study had limitations. First, we defined follow up as repeat imaging and did not include office visits or biopsy in this definition. Second, we may have missed repeat imaging and outpatient follow-up visits that occurred outside the study hospitals. Although we were able to determine if repeat imaging and outpatient follow-up visits (eg, pulmonology or thoracic surgery clinics) had occurred within the study hospitals, we did not have access to follow-up encounters that occurred outside of the study hospitals (eg primary care clinics). We are unaware of any published regional data on the rate of outpatient follow up at the index facility following discharge. However, we know from provincial data of patients discharged from the ED with a new cardiac diagnosis that just under half are seen by a family physician, cardiologist, or internist within seven days, with just under 80% seen within 30 days.⁸ Third, although we attempted to capture patient preference for or against repeat imaging using chart review, the absence of documentation of patient preference did not confirm that a discussion regarding patient preferences had not occurred. Fourth, while we did exclude patients that had an active malignancy, we did not exclude patients who were younger than 35 years or were immunocompromised, which may have led to an overestimation of the percentage of patients who did not receive follow up.

Incidental findings detected on acute diagnostic tests requiring handoffs for chronic follow up are at risk of falling through the cracks. The inclusion of follow-up recommendations in discharge summaries has been shown to increase the likelihood of follow-up completion.⁹ Our study provides additional evidence of the urgent need for interventions aimed at closing the loop on test result follow up.^5,6

Disclosures

None of the authors have any conflicts of interest to disclose in reference to this study.

Funding

JLK is supported by the Mount Sinai Hospital Department of Medicine Research Fund. PC is supported by a K24 award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR062133).

Computed tomography pulmonary angiography (CTPA) is often used in the evaluation of suspected pulmonary embolism (PE). The detection of incidental findings that require follow-up is common; in just over 50% of cases, those incidental findings are pulmonary nodules.¹ Although the majority of these nodules are benign, Fleischner Society guidelines² recommend that patients with nodules at high risk for malignancy should undergo follow-up CT imaging within 3-12 months, with patients who smoke and have large nodules requiring closer follow up.

The failure to follow-up on abnormal test results is known to contribute to diagnostic error and can lead to patient harm.³ We sought to determine the proportion of high-risk pulmonary nodules on CTPA which did not undergo the recommended follow-up imaging.

Study Setting and Design

This retrospective cohort study included all patients who underwent CTPA in the emergency department (ED) and inpatient settings at three academic health centers (Mount Sinai Hospital, Toronto General Hospital, and Toronto Western Hospital) in Toronto, Canada between September 1, 2014, and August 31, 2015.

We examined the proportion of patients with pulmonary nodules requiring follow up who received repeat CT imaging within six weeks of the time frame recommended by the radiologist. Since we were interested in measuring the rate of an important test result that is missed (rather than accuracy of the test itself), we defined “requiring follow up” as the inclusion of explicit recommendations for follow up in the radiology report.

Montage (Philadelphia, Pennsylvania), a natural language processing software, was applied to a linked radiology information system (RIS) to identify all CTPAs that contained pulmonary nodules. We conducted manual chart review to confirm software accuracy. We initially searched the RIS for all CTPAs that were completed within the study period, resulting in the identification of 1932 imaging studies. Following a review of these 1,932 studies, we excluded 22 as they were not CTPAs. We then applied the search term, “nodule-” to 1,910 confirmed CTPAs, resulting in the identification of 836 imaging studies. Following a review of these 836 studies, we excluded 10 as they were duplicate studies. We also excluded 152 studies where the term “nodule-” did not identify a pulmonary nodule but instead referred to a radiologist reporting the absence of pulmonary nodules (eg “there were no pulmonary nodules found”) or the presence of non-lung nodules (eg thyroid nodules). This resulted in the identification of 674 CTPAs containing pulmonary nodules (Figure 1).

Thereafter, we generated a cohort with possible new lung malignancy eligible for follow-up imaging by reviewing available health records and applying the following prespecified exclusion criteria: (1) patients who died, (2) left against medical advice, (3) were critically ill during the follow-up period, (4) lived outside the hospital catchment area (Greater Toronto Area), (5) were seen in the outpatient setting, (6) identified as palliative, (7) had an active malignancy, (8) had nodules that were already being followed, or (9) had nodules with characteristics suggestive of alternate diagnoses to lung malignancy (such as infection or inflammation) with no follow up recommended as reported by the radiologist. For patients with multiple CTPAs, we included only the first study. For each eligible patient, we determined whether follow-up imaging was completed by manually reviewing the linked RIS. We reviewed available health records to determine whether the pulmonary nodule findings had been discussed with the patient and whether the patient had attended an outpatient follow-up visit. In patients for whom recommended follow-up imaging was not confirmed, we notified the ordering physician by e-mail.

Each radiology department followed the same protocol adherent to the 2005 Fleischner guidelines for identifying nodules requiring follow up.² Virtually all CTPAs at the three study institutions are read and reported within 72 hours. The ordering physician is sometimes called at the discretion of the reading radiologist when the findings are judged to be urgent and time-sensitive in nature. For example, the ordering physician may be contacted if a CTPA is positive for segmental PE but is not typically called for incidental pulmonary nodules. It is not common practice for ordering physicians to be notified of incidental findings above and beyond the radiology report. Primary care physicians are not typically copied on radiology reports and usually do not use the same electronic health record.

Statistical Analysis

We calculated simple descriptive statistics for all results. Mean values were compared using two-tailed t-tests, categorical groups using chi-square tests, and median values using Mann-Whitney U tests. We performed all analyses using Microsoft Excel version 16.14.1 (Redmond, Washington).

Ethics Approval

This study was approved by each institution’s research ethics board.

Follow Up of Incidental High-Risk Pulmonary Nodules

Of the 1910 CTPAs performed over the study period (Figure), 674 (35.3%) contained pulmonary nodules. Of the 259 patients with new pulmonary nodules eligible for follow-up imaging, 194 (74.9%) did not have an explicit suggestion for follow up by the radiologist. Ninety-five percent of radiologists (184 out of 194) provided an explanation for not recommending follow up in the radiology report; the two most common reasons were small nodule size (often described as “tiny”) and no interval change compared with the prior imaging study.² Of the 65 patients who did receive an explicit suggestion for follow up by radiology, 35 (53.8%) did not receive repeat imaging within the recommended time frame, allowing for a six-week grace period. Of these 35 patients, 10 eventually went on to receive delayed repeat imaging. The median follow-up time for the 30 patients who received timely repeat imaging was four months (IQR 2-6 months); in contrast, the median follow-up time for the 10 patients who received delayed repeat imaging was seven months (IQR 6-8 months), P = .01.

Of the 65 patients for whom follow up was recommended, the medical record showed evidence that there was a discussion between the medical team and the patient regarding patient preference for or against follow up in 55.4% (36 out of 65) of the patients. Notably, all 36 patients showed interest in receiving follow up; no patient indicated a preference for no follow up.

Furthermore, of the 65 patients that had follow up recommended, two patients were eventually diagnosed with lung cancer (one via lung biopsy, the other via positron emission tomography imaging); both patients did not receive timely follow-up imaging. While we did not include nodule size as an exclusion criterion, not one of the 65 patients included in the final cohort had nodules larger than 3 cm.

Physician Notification

In circumstances where we could not confirm that followed up had occurred, we notified the ordering physician by e-mail. Since 10 of the 35 patients who did not receive timely follow-up imaging went on to receive delayed repeat imaging, we notified 25 physicians. Of the 25 physicians that we e-mailed, 24 acknowledged receipt of the information. Of these 24 physicians, 14 reported conducting a detailed review of the chart, from which the following additional information was obtained: one patient expired, and five physicians notified the corresponding primary care physicians (two of whom were unaware of the nodule, and subsequently arranged further follow up with the patient).

Characteristics Associated with Timely Follow Up

Explicit mention that follow up was required in the discharge summary (P = .03), attending an outpatient follow-up visit (P < .001), and younger age (P = .03) were associated with receiving timely follow up; patient sex, smoking history, history of chronic obstructive pulmonary disease, lung nodule count, recommended follow-up time, and hospital department (defined as the discharging service) were not (Table).

In this multicenter cohort study, over 50% of patients with new high-risk pulmonary nodules detected incidentally on CTPA did not receive timely follow-up imaging. Including follow-up recommendations in the discharge summary, attending an outpatient follow-up visit, and younger age were associated with timely follow-up imaging.

Few studies have assessed the follow up of incidental nodules identified on CTPA. In a retrospective cohort study of ED patients in the United States, Blagev et al. found that only 29% received timely follow up.⁴ Our study contributes to the literature in several ways. First, our study included all hospitalized patients, not only those in the ED. Notably, most of our cohort were inpatients, a group of patients not previously described. Second, we examined factors associated with timely follow up, which may help to inform future quality improvement initiatives and interventions. Third, we included data from three different hospitals, which may improve generalization. Lastly, our study draws on contemporary Canadian data. Most of the studies investigating test result follow up have been conducted in the US^5,6 and Europe,⁷ with few empirical studies describing this phenomenon within the Canadian healthcare setting. We believe that our work contributes to the existing evidence that missed test results occur across diverse healthcare systems and have yet to be solved.^5-7

Our study had limitations. First, we defined follow up as repeat imaging and did not include office visits or biopsy in this definition. Second, we may have missed repeat imaging and outpatient follow-up visits that occurred outside the study hospitals. Although we were able to determine if repeat imaging and outpatient follow-up visits (eg, pulmonology or thoracic surgery clinics) had occurred within the study hospitals, we did not have access to follow-up encounters that occurred outside of the study hospitals (eg primary care clinics). We are unaware of any published regional data on the rate of outpatient follow up at the index facility following discharge. However, we know from provincial data of patients discharged from the ED with a new cardiac diagnosis that just under half are seen by a family physician, cardiologist, or internist within seven days, with just under 80% seen within 30 days.⁸ Third, although we attempted to capture patient preference for or against repeat imaging using chart review, the absence of documentation of patient preference did not confirm that a discussion regarding patient preferences had not occurred. Fourth, while we did exclude patients that had an active malignancy, we did not exclude patients who were younger than 35 years or were immunocompromised, which may have led to an overestimation of the percentage of patients who did not receive follow up.

Incidental findings detected on acute diagnostic tests requiring handoffs for chronic follow up are at risk of falling through the cracks. The inclusion of follow-up recommendations in discharge summaries has been shown to increase the likelihood of follow-up completion.⁹ Our study provides additional evidence of the urgent need for interventions aimed at closing the loop on test result follow up.^5,6

Disclosures

None of the authors have any conflicts of interest to disclose in reference to this study.

Funding

JLK is supported by the Mount Sinai Hospital Department of Medicine Research Fund. PC is supported by a K24 award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR062133).

As new standards for access dominated recent media coverage of veterans’ health care headlines, the launch of a historically unprecedented collaboration to prevent veterans’ suicide went completely unnoticed.

On January 31, the Department of Veterans Affairs (VA) announced a partnership with the National Shooting Sports Foundation (NSSF), a firearms industry association that works to promote, protect and preserve hunting and shooting sports, and the American Foundation for Suicide Prevention (AFSP), the nation’s largest suicide prevention organization. Together, they are developing a program that empowers communities to engage in safe firearm-storage practices. The program includes information on creating community coalitions that promote and sustain firearm safety, with an emphasis on reaching service members, veterans and their families.

This partnership represents the nation’s biggest advance in forging common ground on an issue where polarization has interfered with lifesaving initiatives. It’s a game changer.

In 2016, about 69% of veteran suicides in the US (71% among male and 41% among female veterans) resulted from a firearm injury. In comparison, the proportion of suicides resulting from a firearm injury among nonveteran adults was 48%.¹ The majority of veteran suicides occur with those who do not seek care within the VA healthcare system, which has led the VA to broaden its focus to reach all veterans.

Given the frequency of firearm use as a method of suicide, VA recognizes that suicide prevention efforts must address how veterans store their firearms. The decision to take an action to kill oneself is at times made impulsively—in just a matter of minutes. Securely storing firearms creates precious time and physical space between an individual’s period of risk and the means to act. Studies have demonstrated that delaying access to deadly means can save a life.

VA is striving to be a national leader in suicide prevention, and lethal means safety is an important component of the department’s approach. VA’s lethal means safety initiatives encourage veterans to voluntarily store their firearms safely. Key to this approach is to train mental health and peer providers in veteran-centric counseling methods while promoting resources, including a national consultation call line for both VA and community providers seeking guidance for treatment practices or engaging a veteran in care.  

Because many veterans believe that firearms must remain in their homes under all circumstances, in 2018 the VA held the first of its kind open-innovation challenge for safe firearm storage. This challenge led to the creation of numerous lifesaving product designs, which are now under development in the private sector.

The latest partnership further advances VA’s effort to ensure that lethal means safety counseling is culturally relevant, comes from a trusted source and contains no anti-firearm bias. VA respects the important role firearms play in many veterans’ lives and is committed to educating veterans and their families about safe storage of firearms in a way that is consistent with each veteran’s values and priorities.

Nothing will be more effective in diminishing suicide than correcting the false belief among many veterans that the VA wants to take away veterans’ guns. When that misperception is corrected, not only would more at-risk veterans seek out VA mental health care, but it also could become commonplace for veterans, families and friends to speak up because, “Buddies talk to buddies in crisis about safely storing guns.” This is especially important for veterans in rural areas, where the rates of firearm ownership and suicide are the highest. Joining forces with NSSF could spearhead such a shift.

The VA, NSSF and AFSP should be lauded for bridging the divide and driving this far-reaching breakthrough in firearm safety conversations and community alliances. The effort will not only save countless veterans’ lives, but also forge a path to mitigate our national tragedy of suicide.

As new standards for access dominated recent media coverage of veterans’ health care headlines, the launch of a historically unprecedented collaboration to prevent veterans’ suicide went completely unnoticed.

On January 31, the Department of Veterans Affairs (VA) announced a partnership with the National Shooting Sports Foundation (NSSF), a firearms industry association that works to promote, protect and preserve hunting and shooting sports, and the American Foundation for Suicide Prevention (AFSP), the nation’s largest suicide prevention organization. Together, they are developing a program that empowers communities to engage in safe firearm-storage practices. The program includes information on creating community coalitions that promote and sustain firearm safety, with an emphasis on reaching service members, veterans and their families.

This partnership represents the nation’s biggest advance in forging common ground on an issue where polarization has interfered with lifesaving initiatives. It’s a game changer.

In 2016, about 69% of veteran suicides in the US (71% among male and 41% among female veterans) resulted from a firearm injury. In comparison, the proportion of suicides resulting from a firearm injury among nonveteran adults was 48%.¹ The majority of veteran suicides occur with those who do not seek care within the VA healthcare system, which has led the VA to broaden its focus to reach all veterans.

Given the frequency of firearm use as a method of suicide, VA recognizes that suicide prevention efforts must address how veterans store their firearms. The decision to take an action to kill oneself is at times made impulsively—in just a matter of minutes. Securely storing firearms creates precious time and physical space between an individual’s period of risk and the means to act. Studies have demonstrated that delaying access to deadly means can save a life.

VA is striving to be a national leader in suicide prevention, and lethal means safety is an important component of the department’s approach. VA’s lethal means safety initiatives encourage veterans to voluntarily store their firearms safely. Key to this approach is to train mental health and peer providers in veteran-centric counseling methods while promoting resources, including a national consultation call line for both VA and community providers seeking guidance for treatment practices or engaging a veteran in care.  

Because many veterans believe that firearms must remain in their homes under all circumstances, in 2018 the VA held the first of its kind open-innovation challenge for safe firearm storage. This challenge led to the creation of numerous lifesaving product designs, which are now under development in the private sector.

The latest partnership further advances VA’s effort to ensure that lethal means safety counseling is culturally relevant, comes from a trusted source and contains no anti-firearm bias. VA respects the important role firearms play in many veterans’ lives and is committed to educating veterans and their families about safe storage of firearms in a way that is consistent with each veteran’s values and priorities.

Nothing will be more effective in diminishing suicide than correcting the false belief among many veterans that the VA wants to take away veterans’ guns. When that misperception is corrected, not only would more at-risk veterans seek out VA mental health care, but it also could become commonplace for veterans, families and friends to speak up because, “Buddies talk to buddies in crisis about safely storing guns.” This is especially important for veterans in rural areas, where the rates of firearm ownership and suicide are the highest. Joining forces with NSSF could spearhead such a shift.

The VA, NSSF and AFSP should be lauded for bridging the divide and driving this far-reaching breakthrough in firearm safety conversations and community alliances. The effort will not only save countless veterans’ lives, but also forge a path to mitigate our national tragedy of suicide.

As new standards for access dominated recent media coverage of veterans’ health care headlines, the launch of a historically unprecedented collaboration to prevent veterans’ suicide went completely unnoticed.

On January 31, the Department of Veterans Affairs (VA) announced a partnership with the National Shooting Sports Foundation (NSSF), a firearms industry association that works to promote, protect and preserve hunting and shooting sports, and the American Foundation for Suicide Prevention (AFSP), the nation’s largest suicide prevention organization. Together, they are developing a program that empowers communities to engage in safe firearm-storage practices. The program includes information on creating community coalitions that promote and sustain firearm safety, with an emphasis on reaching service members, veterans and their families.

This partnership represents the nation’s biggest advance in forging common ground on an issue where polarization has interfered with lifesaving initiatives. It’s a game changer.

In 2016, about 69% of veteran suicides in the US (71% among male and 41% among female veterans) resulted from a firearm injury. In comparison, the proportion of suicides resulting from a firearm injury among nonveteran adults was 48%.¹ The majority of veteran suicides occur with those who do not seek care within the VA healthcare system, which has led the VA to broaden its focus to reach all veterans.

Given the frequency of firearm use as a method of suicide, VA recognizes that suicide prevention efforts must address how veterans store their firearms. The decision to take an action to kill oneself is at times made impulsively—in just a matter of minutes. Securely storing firearms creates precious time and physical space between an individual’s period of risk and the means to act. Studies have demonstrated that delaying access to deadly means can save a life.

VA is striving to be a national leader in suicide prevention, and lethal means safety is an important component of the department’s approach. VA’s lethal means safety initiatives encourage veterans to voluntarily store their firearms safely. Key to this approach is to train mental health and peer providers in veteran-centric counseling methods while promoting resources, including a national consultation call line for both VA and community providers seeking guidance for treatment practices or engaging a veteran in care.  

Because many veterans believe that firearms must remain in their homes under all circumstances, in 2018 the VA held the first of its kind open-innovation challenge for safe firearm storage. This challenge led to the creation of numerous lifesaving product designs, which are now under development in the private sector.

The latest partnership further advances VA’s effort to ensure that lethal means safety counseling is culturally relevant, comes from a trusted source and contains no anti-firearm bias. VA respects the important role firearms play in many veterans’ lives and is committed to educating veterans and their families about safe storage of firearms in a way that is consistent with each veteran’s values and priorities.

Nothing will be more effective in diminishing suicide than correcting the false belief among many veterans that the VA wants to take away veterans’ guns. When that misperception is corrected, not only would more at-risk veterans seek out VA mental health care, but it also could become commonplace for veterans, families and friends to speak up because, “Buddies talk to buddies in crisis about safely storing guns.” This is especially important for veterans in rural areas, where the rates of firearm ownership and suicide are the highest. Joining forces with NSSF could spearhead such a shift.

The VA, NSSF and AFSP should be lauded for bridging the divide and driving this far-reaching breakthrough in firearm safety conversations and community alliances. The effort will not only save countless veterans’ lives, but also forge a path to mitigate our national tragedy of suicide.

Nonalcoholic fatty liver disease (NAFLD) is an umbrella term that covers a spectrum of phenotypes ranging from nonalcoholic fatty liver or simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) defined by histologic findings of steatosis, lobular inflammation, cytologic ballooning, and some degree of fibrosis.¹ While frequently observed in patients with at least 1 risk factor (eg, obesity, diabetes mellitus [DM], dyslipidemia, hypertension), NAFLD also is an independent risk factor for type 2 DM (T2DM), chronic kidney disease, and cardiovascular disease.² At early disease stages with absence of liver fibrosis, mortality is linked to cardiovascular and not liver disease. However, in the presence of NASH, fibrosis progression to liver cirrhosis, or hepatocellular carcinoma (HCC) represent the most important liver-related outcomes that determine morbidity and mortality.³ Mirroring the obesity and T2DM epidemics, the health care burden is projected to dramatically rise.

In the following article, we will discuss how the Veterans Health Administration (VHA) is well positioned to implement an organizational strategy of comprehensive care for veterans with NAFLD. This comprehensive care strategy should include the development of a NAFLD clinic offering care for comorbid conditions frequently present in these patients, point-of-care testing, access to clinical trials, and outcomes monitoring as a key performance target for providers and the respective facility.

NAFLD disease burden

To fully appreciate the burden of a chronic disease like NAFLD, it is important to assess its long- and short-term consequences in a comprehensive manner with regard to its clinical impact, impact on the patient, and economic impact (Figure 1).

Clinical Impact

Clinical impact is assessed based on the prevalence and natural history of NAFLD and the liver fibrosis stage and determines patient survival. Coinciding with the epidemic of obesity and T2DM, the prevalence of NAFLD in the general population in North America is 24% and even higher with older age and higher body mass index (BMI).^4,5 The prevalence for NAFLD is particularly high in patients with T2DM (47%). Of patients with T2DM and NAFLD, 65% have biopsy-proven NASH of which 15% have bridging fibrosis or liver cirrhosis.⁶

NAFLD is the fastest growing cause of cirrhosis in the US with a forecasted NAFLD population of 101 million by 2030.⁷ At the same time, the number of patients with NASH will rise to 27 million of which > 7 million will have bridging fibrosis or liver cirrhosis; hepatic decompensation events are estimated to occur in 105,430 patients with liver cirrhosis, posing a major public health threat related to organ availability for liver transplantation.⁸ Since 2013, NAFLD has been the second leading cause for liver transplantation and the top reason for transplantation in patients aged < 50 years.^9,10 As many patients with NAFLD are diagnosed with HCC at stages where liver transplantation is not an option, mortality from HCC in NAFLD patients is higher than with other etiologies as treatment options are restricted.^11,12

Compared with that of the general population, veterans seeking care are older and sicker with 43% of veterans taking > 5 prescribed medications.¹³ Of those receiving VHA care, 6.6 million veterans are either overweight or obese; 165,000 are morbidly obese with a BMI > 40.¹⁴ In addition, veterans are 2.5 times more likely to have T2DM compared with that of nonveterans. Because T2DM and obesity are the most common risk factors for NAFLD, it is not surprising that NAFLD prevalence among veterans rose 3-fold from 2003 to 2011.¹⁵ It is now estimated that 540,000 veterans will progress to NASH and 108,000 will develop bridging fibrosis or liver cirrhosis by 2030.⁸ Similar to that of the general population, liver cirrhosis is attributed to NAFLD in 15% of veterans.^15,16 NAFLD is the third most common cause of cirrhosis and HCC, occurring at an average age of 66 years and 70 years, respectively.^16,17 Shockingly, 20% of HCCs were not linked to liver cirrhosis and escaped recommended HCC screening for patients with cirrhosis.^18,19

Patient Impact

Assessment of disease burden should not be restricted to clinical outcomes as patients can experience a range of symptoms that may have significant impact on their health-related quality of life (QOL) and functional status.²⁰ Using general but not disease-specific instruments, NAFLD patients reported outcomes score low regarding fatigue, activity, and emotions.²¹ More disease-specific questionnaires may provide better and disease-specific insights as how NASH impacts patients’ QOL.^22-24

Economic Impact

There is mounting evidence that the clinical implications of NAFLD directly influence the economic burden of NAFLD.²⁵ The annual burden associated with all incident and prevalent NAFLD cases in the US has been estimated at $103 billion, and projections suggest that the expected 10-year burden of NAFLD may increase to $1.005 trillion.²⁶ It is anticipated that increased NAFLD costs will affect the VHA with billions of dollars in annual expenditures in addition to the $1.5 billion already spent annually for T2DM care (4% of the VA pharmacy budget is spent on T2DM treatment).^27-29

Current Patient Care

Obesity, DM, and dyslipidemia are common conditions managed by primary care providers (PCPs). Given the close association of these conditions with NAFLD, the PCP is often the first point of medical contact for patients with or at risk for NAFLD.³⁰ For that reason, PCP awareness of NAFLD is critical for effective management of these patients. PCPs should be actively involved in the management of patients with NAFLD with pathways in place for identifying patients at high risk of liver disease for timely referral to a specialist and adequate education on the follow-up and treatment of low-risk patients. Instead, diagnosis of NAFLD is primarily triggered by either abnormal aminotransferases or detection of steatosis on imaging performed for other indications.

Barriers to optimal management of NAFLD by PCPs have been identified and occur at different levels of patient care. In the absence of clinical practice guidelines by the American Association of Family Practice covering NAFLD and a substantial latency period without signs of symptoms, NAFLD may not be perceived as a potentially serious condition by PCPs and their patients; interestingly this holds true even for some medical specialties.^31-39 More than half of PCPs do not test their patients at highest risk for NAFLD (eg, patients with obesity or T2DM) and may be unaware of practice guidelines.^40-42

Guidelines from Europe and the US are not completely in accordance. The US guidelines are vague regarding screening and are supported by only 1 medical society, due to the lack of NASH-specific drug therapies. The European guidelines are built on the support of 3 different stakeholders covering liver diseases, obesity, and DM and the experience using noninvasive liver fibrosis assessments for patients with NAFLD. To overcome this apparent conflict, a more practical and risk-stratified approach is warranted.^41,42

Making the diagnosis can be challenging in cases with competing etiologies, such as T2DM and alcohol misuse. There also is an overreliance on aminotransferase levels to diagnose NAFLD. Significant liver disease can exist in the presence of normal aminotransferases, and this may be attributed to either spontaneous aminotransferase fluctuations or upper limits of normal that have been chosen too high.^43-47 Often additional workup by PCPs depends on the magnitude of aminotransferase abnormalities.

Even if NAFLD has been diagnosed by PCPs, identifying those with NASH is hindered by the absence of an accurate noninvasive diagnostic method and the need to perform a liver biopsy. Liver biopsy is often not considered or delayed to monitor patients with serial aminotransferases, regardless of the patient’s metabolic comorbidity profile or baseline aminotransferases.³² As a result, referral to a specialist often depends on the magnitude of the aminotransferase abnormality,^30,48 and often occurs when advanced liver disease is already present.⁴⁹ Finally, providers may not be aware of beneficial effects of lifestyle interventions and certain medications, including statins on NASH and liver fibrosis.^50-53 As NAFLD is associated with excess cardiovascular- and cancer-related morbidity and mortality, it is possible that regression of NAFLD may improve associated risk for these outcomes as well.

Framework for Comprehensive NAFLD Care

Chronic liver diseases and associated comorbidities have long been addressed by PCPs and specialty providers working in isolation and within the narrow focus of each discipline. Contrary to working in silos of the past, a coordinated management strategy with other disciplines that cover these comorbidities needs to be established, or alternatively the PCP must be aware of the management of comorbidities to execute them independently. Integration of hepatology-driven NAFLD care with other specialties involves communication, collaboration, and sharing of resources and expertise that will address patient care needs. Obviously, this cannot be undertaken in a single outpatient visit and requires vertical and longitudinal follow-up over time. One important aspect of comprehensive NAFLD care is the targeting of a particular patient population rather than being seen as a panacea for all; cost-utility analysis is hampered by uncertainties around accuracy of noninvasive biomarkers reflecting liver injury and a lack of effectiveness data for treatment. However, it seems reasonable to screen patients at high risk for NASH and adverse clinical outcomes. Such a risk stratification approach should be cost-effective.

A first key step by the PCP is to identify whether a patient is at risk, especially patients with NASH. The majority of patients at risk are already seen by PCPs. While there is no consensus on ideal screening for NAFLD by PCPs, the use of ultrasound in the at-risk population is recommended in Europe.⁴² Although NASH remains a histopathologic diagnosis, a reasonable approach is to define NASH based on clinical criteria as done similarly in a real-world observational NAFLD cohort study.⁵⁴ In the absence of chronic alcohol consumption and viral hepatitis and in a real-world scenario, NASH can be defined as steatosis shown on liver imaging or biopsy and alanine aminotransferase (ALT) levels of > 25 U/L. In addition, ≥ 1 of the following criteria must be met: BMI > 30, T2DM, dyslipidemia, or metabolic syndrome (Table 1). 

In the absence of easy-to-use validated tests, all patients with NAFLD need to be assessed with simple, noninvasive scores for the presence of clinically relevant liver fibrosis (F2-portal fibrosis with septa; F3-bridging fibrosis; F4-liver cirrhosis); those that meet the fibrosis criteria should receive further assessment usually only offered in a comprehensive NAFLD clinic.¹ PCPs should focus on addressing 2 aspects related to NAFLD: (1) Does my patient have NASH based on clinical criteria; and (2) Is my patient at risk for clinically relevant liver fibrosis? PCPs are integral in optimal management of comorbidities and metabolic syndrome abnormalities with lifestyle and exercise interventions.

The care needs of a typical patient with NAFLD can be classified into 3 categories: liver disease (NAFLD) management, addressing NAFLD associated comorbidities, and attending to the personal care needs of the patient. With considerable interactions between these categories, interventions done within the framework of 1 category can influence the needs pertaining to another, requiring closer monitoring of the patient and potentially modifying care. For example, initiating a low carbohydrate diet in a patient with DM and NAFLD who is on antidiabetic medication may require adjusting the medication; disease progression or failure to achieve treatment goals may affect the emotional state of the patient, which can affect adherence.

Referrals to a comprehensive NAFLD clinic need to be standardized. Clearly, the referral process depends in part on local resources, comprehensiveness of available services, and patient characteristics, among others. Most often, PCPs refer patients with suspected diagnosis of NAFLD, with or without abnormal aminotransferases, to a hepatologist to confirm the diagnosis and for disease staging and liver disease management. This may have the advantage of greatest extent of access and should limit the number of patients with advanced liver fibrosis who otherwise may have been missed. On the other hand, different thresholds of PCPs for referrals may delay the patient’s access to comprehensive NAFLD care. Of those referred by primary care, the hepatologist identifies patients with NAFLD who benefit most from a comprehensive care approach. This automated referral process without predefined criteria remains more a vision than reality as it would require an infrastructure and resources that no health care system can provide currently.

The alternative approach of automatic referral may use predefined criteria related to patients’ diagnoses and prognoses (Figure 2). 

Patient-Centered Care

At present the narrow focus of VHA specialty outpatient clinics associated with time constraints of providers and gaps in NAFLD awareness clearly does not address the complex metabolic needs of veterans with NAFLD. This is in striking contrast to the comprehensive care offered to patients with cancer. To overcome these limitations, new care delivery models need to be explored. At first it seems attractive to embed NAFLD patient care geographically into a hepatology clinic with the potential advantages of improving volume and timeliness of referral and reinforcing communication among specialty providers while maximizing convenience for patients. However, this is resource intensive not only concerning clinic space, but also in terms of staffing clinics with specialty providers.

Patient-centered care for veterans with NAFLD seems to be best organized around a comprehensive NAFLD clinic with access to specialized diagnostics and knowledge in day-to-day NAFLD management. This evolving care concept has been developed already for patients with liver cirrhosis and inflammatory bowel disease and considers NAFLD a chronic disease that cannot be addressed sufficiently by providing episodic care.^55,56 The development of comprehensive NAFLD care can build on the great success of the Hepatitis Innovation Team Collaborative that employed lean management strategies with local and regional teams to facilitate efforts to make chronic hepatitis C virus a rare disease in the VHA.⁵⁷

NAFLD Care Team

Given the central role of the liver and gastrointestinal tract in the field of nutrition, knowledge of the pathophysiology of the liver and digestive tract as well as emerging therapeutic options offered via metabolic endoscopy uniquely positions the hepatologist/gastroenterologist to take the lead in managing NAFLD. Treating NAFLD is best accomplished when the specialist partners with other health care providers who have expertise in the nutritional, behavioral, and physical activity aspects of treatment. The composition of the NAFLD care team and the roles that different providers fulfill can vary depending on the clinical setting; however, the hepatologist/gastroenterologist is best suited to lead the team, or alternatively, this role can be fulfilled by a provider with liver disease expertise.

Based on experiences from the United Kingdom, the minimum staffing of a NAFLD clinic should include a physician and nurse practitioner who has expertise in managing patients with chronic liver disease, a registered nurse, a dietitian, and a clinical pharmacy specialist (CPS).⁵⁸ With coexistent diseases common and many veterans who have > 5 prescribed medications, risk of polypharmacy and adverse drug reactions are a concern, particularly since adherence in patients with chronic diseases has been reported to be as low as 43%.^59-61 Risk of medication errors and serious adverse effects are magnified by difficulties with patient adherence, medication interactions, and potential need for frequent dose adjustments, particularly when on a weight-loss diet.

Without doubt, comprehensive medication management, offered by a highly trained CPS with independent prescriptive authority occurring while the veteran is in the NAFLD clinic, is highly desirable. Establishing a functional statement and care coordination agreement could describe the role of the CPS as a member of the NAFLD provider team. 

Patient Evaluation

After being referred to the NAFLD clinic, the veteran should have a thorough assessment, including medical, nutritional, physical activity, exercise, and psychosocial evaluations (Figure 4). 

The assessment also should include patient education to ensure that the patient has sufficient knowledge and skills to achieve the treatment goals. Educating on NAFLD is critical as most patients with NAFLD do not think of themselves as sick and have limited readiness for lifestyle changes.^63,64 A better understanding of NAFLD combined with a higher self-efficacy seems to be positively linked to better nutritional habits.⁶⁵

An online patient-reported outcomes measurement information system for a patient with NAFLD (eg, assessmentcenter.net) may be beneficial and can be applied within a routine NAFLD clinic visit because of its multidimensionality and compatibility with other chronic diseases.^66-68 Other tools to assess health-related QOL include questionnaires, such as the functional assessment of chronic illness therapy-fatigue, work productivity and activity impairment questionnaire: specific health problem, Short Form-36, and chronic liver disease questionnaire-NAFLD.^23,69

The medical evaluation includes assessment of secondary causes of NAFLD and identification of NAFLD-related comorbidities. Weight, height, blood pressure, waist circumference, and BMI should be recorded. The physical exam should focus on signs of chronic liver disease and include inspection for acanthosis nigricans, hirsutism, and large neck circumference, which are associated with insulin resistance, polycystic ovarian syndrome, and obstructive sleep apnea, respectively. NAFLD-associated comorbidities may contribute to frailty or physical limitations that affect treatment with diet and exercise and need to be assessed. A thorough medication reconciliation will reveal whether the patient is prescribed obesogenic medications and whether comorbidities (eg, DM and dyslipidemia) are being treated optimally and according to current society guidelines.

Making the diagnosis of NAFLD requires excluding other (concomitant) chronic liver diseases. While often this is done indirectly using order sets with a panoply of available serologic tests without accounting for risks for rare causes of liver injury, a more focused and cost-effective approach is warranted. As most patients will already have had imaging studies that show fatty liver, assessment of liver fibrosis is an important step for risk stratification. Noninvasive scores (eg, FIB-4) can be used by the PCP to identify high-risk patients requiring further workup and referral.^1,70 More sophisticated tools, including transient elastography and/or magnetic resonance elastography are applied for more sophisticated risk stratification and liver disease management (Table 2).⁷¹ 

A nutritional evaluation includes information about eating behavior and food choices, body composition analysis, and an assessment of short- and long-term alcohol consumption. Presence of bilateral muscle wasting, subcutaneous fat loss, and signs of micronutrient deficiencies also should be explored. The lifestyle evaluation should include the patient’s typical physical activity and exercise as well as limiting factors.

Finally, and equally important, the patient’s psychosocial situation should be assessed, as motivation and accountability are key to success and may require behavioral modification. Assessing readiness is done best with motivational interviewing, the 5As counseling framework (Ask, Advise, Assess, Assist, Arrange) or using open-ended questions, affirmation, reflections, and summaries.^72,73 Even if not personally delivering behavioral treatment, such an approach also can help move patients toward addressing important health-related behaviors.

Personalized Interventions

If available, patients should be offered participation in NAFLD clinical trials. A personalized treatment plan should be developed for each patient with input from all NAFLD care team members. The patient and providers should work together to make important decisions about the treatment plan and goals of care. Making the patient an active participant in their treatment rather than the passive recipient will lead to improvement in adherence and outcomes. Patients will engage when they are comfortable speaking with providers and are sufficiently educated about their disease.

Personalized interventions may be built by combining different strategies, such as lifestyle and dietary interventions, NASH-specific pharmacotherapy, comorbidity management, metabolic endoscopy, and bariatric surgery. Although NASH-specific medications are not currently available, approved medications, including pioglitazone or liraglutide, can be considered for therapy.^74,75 Ideally, the NAFLD team CPS would manage comorbidities, such as T2DM and dyslipidemia, but this also can be done by a hepatologist or other specialist. Metabolic endoscopy (eg, intragastric balloons) or bariatric surgery would be done by referral.

Resource-Limited Settings

Although the VHA offers care at > 150 medical centers and > 1,000 outpatient clinics, specialty care such as hepatology and sophisticated and novel testing modalities are not available at many facilities. In 2011 VHA launched the Specialty Care Access Network Extension for Community Healthcare Outcomes to bring hepatitis C therapy and liver transplantation evaluations to rural areas without specialists.^76-78 It is logical to explore how telehealth can be used for NAFLD care that requires complex management using new treatments and has a high societal impact, particularly when left untreated.

Telehealth must be easy to use and integrated into everyday routines to be useful for NAFLD management by addressing different aspects of promoting self-management, optimizing therapy, and care coordination. Participation in a structured face-to-face or group-based lifestyle program is often jeopardized by time and job constraints but can be successfully overcome using online approaches.⁷⁹ The Internet-based VA Video Connect videoconferencing, which incorporates cell phone, laptop, or tablet use could help expand lifestyle interventions to a much larger community of patients with NAFLD and overcome local resource constraints. Finally, e-consultation also can be used in circumstances where synchronous communication with specialists may not be necessary.

Patient Monitoring and Quality Metrics

Monitoring of the patient after initiation of an intervention is variable but occurs more frequently at the beginning. For high-intensity dietary interventions, weekly monitoring for the first several weeks can ensure ongoing motivation, and accountability may increase the patient’s confidence and provide encouragement for further weight loss. It also is an opportunity to reestablish goals with patients with declining motivation. Long-term monitoring of patients may occur in 6- to 12-month intervals to document patient-reported outcomes, liver-related mortality, cardiovascular events, malignancies, and disease progression or regression.

While quality indicators have been proposed for cirrhosis care, such indicators have yet to be defined for NALD care.⁸⁰ Such quality indicators assessed with validated questionnaires should include knowledge about NAFLD, satisfaction with care, perception of quality of care, and patient-reported outcomes. Other indicators may include use of therapies to treat dyslipidemia and T2DM. Last and likely the most important indicator of improved liver health in NAFLD will be either histologic improvement of NASH or improvement of the fibrosis risk category.

Outlook

With the enormous burden of NAFLD on the rise for many more years to come, quality care delivered to patients with NAFLD warrants resource-adaptive population health management strategies. With a limited number of providers specialized in liver disease, provider education assisted by clinical guidelines and decision support tools, development of referral and access to care mechanisms through integrated care, remote monitoring strategies as well as development of patient self-management and community resources will become more important. We have outlined essential components of an effective population health management strategy for NAFLD and actionable items for the VHA to consider when implementing these strategies. This is the time for the VHA to invest in efforts for NAFLD population care. Clearly, consideration must be given to local needs and resources and integration of technology platforms. Addressing NAFLD at a population level will provide yet another opportunity to demonstrate that VHA performs better on quality when compared with care systems in the private sector.⁸¹

Nonalcoholic fatty liver disease (NAFLD) is an umbrella term that covers a spectrum of phenotypes ranging from nonalcoholic fatty liver or simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) defined by histologic findings of steatosis, lobular inflammation, cytologic ballooning, and some degree of fibrosis.¹ While frequently observed in patients with at least 1 risk factor (eg, obesity, diabetes mellitus [DM], dyslipidemia, hypertension), NAFLD also is an independent risk factor for type 2 DM (T2DM), chronic kidney disease, and cardiovascular disease.² At early disease stages with absence of liver fibrosis, mortality is linked to cardiovascular and not liver disease. However, in the presence of NASH, fibrosis progression to liver cirrhosis, or hepatocellular carcinoma (HCC) represent the most important liver-related outcomes that determine morbidity and mortality.³ Mirroring the obesity and T2DM epidemics, the health care burden is projected to dramatically rise.

In the following article, we will discuss how the Veterans Health Administration (VHA) is well positioned to implement an organizational strategy of comprehensive care for veterans with NAFLD. This comprehensive care strategy should include the development of a NAFLD clinic offering care for comorbid conditions frequently present in these patients, point-of-care testing, access to clinical trials, and outcomes monitoring as a key performance target for providers and the respective facility.

NAFLD disease burden

To fully appreciate the burden of a chronic disease like NAFLD, it is important to assess its long- and short-term consequences in a comprehensive manner with regard to its clinical impact, impact on the patient, and economic impact (Figure 1).

Clinical Impact

Clinical impact is assessed based on the prevalence and natural history of NAFLD and the liver fibrosis stage and determines patient survival. Coinciding with the epidemic of obesity and T2DM, the prevalence of NAFLD in the general population in North America is 24% and even higher with older age and higher body mass index (BMI).^4,5 The prevalence for NAFLD is particularly high in patients with T2DM (47%). Of patients with T2DM and NAFLD, 65% have biopsy-proven NASH of which 15% have bridging fibrosis or liver cirrhosis.⁶

NAFLD is the fastest growing cause of cirrhosis in the US with a forecasted NAFLD population of 101 million by 2030.⁷ At the same time, the number of patients with NASH will rise to 27 million of which > 7 million will have bridging fibrosis or liver cirrhosis; hepatic decompensation events are estimated to occur in 105,430 patients with liver cirrhosis, posing a major public health threat related to organ availability for liver transplantation.⁸ Since 2013, NAFLD has been the second leading cause for liver transplantation and the top reason for transplantation in patients aged < 50 years.^9,10 As many patients with NAFLD are diagnosed with HCC at stages where liver transplantation is not an option, mortality from HCC in NAFLD patients is higher than with other etiologies as treatment options are restricted.^11,12

Compared with that of the general population, veterans seeking care are older and sicker with 43% of veterans taking > 5 prescribed medications.¹³ Of those receiving VHA care, 6.6 million veterans are either overweight or obese; 165,000 are morbidly obese with a BMI > 40.¹⁴ In addition, veterans are 2.5 times more likely to have T2DM compared with that of nonveterans. Because T2DM and obesity are the most common risk factors for NAFLD, it is not surprising that NAFLD prevalence among veterans rose 3-fold from 2003 to 2011.¹⁵ It is now estimated that 540,000 veterans will progress to NASH and 108,000 will develop bridging fibrosis or liver cirrhosis by 2030.⁸ Similar to that of the general population, liver cirrhosis is attributed to NAFLD in 15% of veterans.^15,16 NAFLD is the third most common cause of cirrhosis and HCC, occurring at an average age of 66 years and 70 years, respectively.^16,17 Shockingly, 20% of HCCs were not linked to liver cirrhosis and escaped recommended HCC screening for patients with cirrhosis.^18,19

Patient Impact

Assessment of disease burden should not be restricted to clinical outcomes as patients can experience a range of symptoms that may have significant impact on their health-related quality of life (QOL) and functional status.²⁰ Using general but not disease-specific instruments, NAFLD patients reported outcomes score low regarding fatigue, activity, and emotions.²¹ More disease-specific questionnaires may provide better and disease-specific insights as how NASH impacts patients’ QOL.^22-24

Economic Impact

There is mounting evidence that the clinical implications of NAFLD directly influence the economic burden of NAFLD.²⁵ The annual burden associated with all incident and prevalent NAFLD cases in the US has been estimated at $103 billion, and projections suggest that the expected 10-year burden of NAFLD may increase to $1.005 trillion.²⁶ It is anticipated that increased NAFLD costs will affect the VHA with billions of dollars in annual expenditures in addition to the $1.5 billion already spent annually for T2DM care (4% of the VA pharmacy budget is spent on T2DM treatment).^27-29

Current Patient Care

Obesity, DM, and dyslipidemia are common conditions managed by primary care providers (PCPs). Given the close association of these conditions with NAFLD, the PCP is often the first point of medical contact for patients with or at risk for NAFLD.³⁰ For that reason, PCP awareness of NAFLD is critical for effective management of these patients. PCPs should be actively involved in the management of patients with NAFLD with pathways in place for identifying patients at high risk of liver disease for timely referral to a specialist and adequate education on the follow-up and treatment of low-risk patients. Instead, diagnosis of NAFLD is primarily triggered by either abnormal aminotransferases or detection of steatosis on imaging performed for other indications.

Barriers to optimal management of NAFLD by PCPs have been identified and occur at different levels of patient care. In the absence of clinical practice guidelines by the American Association of Family Practice covering NAFLD and a substantial latency period without signs of symptoms, NAFLD may not be perceived as a potentially serious condition by PCPs and their patients; interestingly this holds true even for some medical specialties.^31-39 More than half of PCPs do not test their patients at highest risk for NAFLD (eg, patients with obesity or T2DM) and may be unaware of practice guidelines.^40-42

Guidelines from Europe and the US are not completely in accordance. The US guidelines are vague regarding screening and are supported by only 1 medical society, due to the lack of NASH-specific drug therapies. The European guidelines are built on the support of 3 different stakeholders covering liver diseases, obesity, and DM and the experience using noninvasive liver fibrosis assessments for patients with NAFLD. To overcome this apparent conflict, a more practical and risk-stratified approach is warranted.^41,42

Making the diagnosis can be challenging in cases with competing etiologies, such as T2DM and alcohol misuse. There also is an overreliance on aminotransferase levels to diagnose NAFLD. Significant liver disease can exist in the presence of normal aminotransferases, and this may be attributed to either spontaneous aminotransferase fluctuations or upper limits of normal that have been chosen too high.^43-47 Often additional workup by PCPs depends on the magnitude of aminotransferase abnormalities.

Even if NAFLD has been diagnosed by PCPs, identifying those with NASH is hindered by the absence of an accurate noninvasive diagnostic method and the need to perform a liver biopsy. Liver biopsy is often not considered or delayed to monitor patients with serial aminotransferases, regardless of the patient’s metabolic comorbidity profile or baseline aminotransferases.³² As a result, referral to a specialist often depends on the magnitude of the aminotransferase abnormality,^30,48 and often occurs when advanced liver disease is already present.⁴⁹ Finally, providers may not be aware of beneficial effects of lifestyle interventions and certain medications, including statins on NASH and liver fibrosis.^50-53 As NAFLD is associated with excess cardiovascular- and cancer-related morbidity and mortality, it is possible that regression of NAFLD may improve associated risk for these outcomes as well.

Framework for Comprehensive NAFLD Care

Chronic liver diseases and associated comorbidities have long been addressed by PCPs and specialty providers working in isolation and within the narrow focus of each discipline. Contrary to working in silos of the past, a coordinated management strategy with other disciplines that cover these comorbidities needs to be established, or alternatively the PCP must be aware of the management of comorbidities to execute them independently. Integration of hepatology-driven NAFLD care with other specialties involves communication, collaboration, and sharing of resources and expertise that will address patient care needs. Obviously, this cannot be undertaken in a single outpatient visit and requires vertical and longitudinal follow-up over time. One important aspect of comprehensive NAFLD care is the targeting of a particular patient population rather than being seen as a panacea for all; cost-utility analysis is hampered by uncertainties around accuracy of noninvasive biomarkers reflecting liver injury and a lack of effectiveness data for treatment. However, it seems reasonable to screen patients at high risk for NASH and adverse clinical outcomes. Such a risk stratification approach should be cost-effective.

A first key step by the PCP is to identify whether a patient is at risk, especially patients with NASH. The majority of patients at risk are already seen by PCPs. While there is no consensus on ideal screening for NAFLD by PCPs, the use of ultrasound in the at-risk population is recommended in Europe.⁴² Although NASH remains a histopathologic diagnosis, a reasonable approach is to define NASH based on clinical criteria as done similarly in a real-world observational NAFLD cohort study.⁵⁴ In the absence of chronic alcohol consumption and viral hepatitis and in a real-world scenario, NASH can be defined as steatosis shown on liver imaging or biopsy and alanine aminotransferase (ALT) levels of > 25 U/L. In addition, ≥ 1 of the following criteria must be met: BMI > 30, T2DM, dyslipidemia, or metabolic syndrome (Table 1). 

In the absence of easy-to-use validated tests, all patients with NAFLD need to be assessed with simple, noninvasive scores for the presence of clinically relevant liver fibrosis (F2-portal fibrosis with septa; F3-bridging fibrosis; F4-liver cirrhosis); those that meet the fibrosis criteria should receive further assessment usually only offered in a comprehensive NAFLD clinic.¹ PCPs should focus on addressing 2 aspects related to NAFLD: (1) Does my patient have NASH based on clinical criteria; and (2) Is my patient at risk for clinically relevant liver fibrosis? PCPs are integral in optimal management of comorbidities and metabolic syndrome abnormalities with lifestyle and exercise interventions.

The care needs of a typical patient with NAFLD can be classified into 3 categories: liver disease (NAFLD) management, addressing NAFLD associated comorbidities, and attending to the personal care needs of the patient. With considerable interactions between these categories, interventions done within the framework of 1 category can influence the needs pertaining to another, requiring closer monitoring of the patient and potentially modifying care. For example, initiating a low carbohydrate diet in a patient with DM and NAFLD who is on antidiabetic medication may require adjusting the medication; disease progression or failure to achieve treatment goals may affect the emotional state of the patient, which can affect adherence.

Referrals to a comprehensive NAFLD clinic need to be standardized. Clearly, the referral process depends in part on local resources, comprehensiveness of available services, and patient characteristics, among others. Most often, PCPs refer patients with suspected diagnosis of NAFLD, with or without abnormal aminotransferases, to a hepatologist to confirm the diagnosis and for disease staging and liver disease management. This may have the advantage of greatest extent of access and should limit the number of patients with advanced liver fibrosis who otherwise may have been missed. On the other hand, different thresholds of PCPs for referrals may delay the patient’s access to comprehensive NAFLD care. Of those referred by primary care, the hepatologist identifies patients with NAFLD who benefit most from a comprehensive care approach. This automated referral process without predefined criteria remains more a vision than reality as it would require an infrastructure and resources that no health care system can provide currently.

The alternative approach of automatic referral may use predefined criteria related to patients’ diagnoses and prognoses (Figure 2). 

Patient-Centered Care

At present the narrow focus of VHA specialty outpatient clinics associated with time constraints of providers and gaps in NAFLD awareness clearly does not address the complex metabolic needs of veterans with NAFLD. This is in striking contrast to the comprehensive care offered to patients with cancer. To overcome these limitations, new care delivery models need to be explored. At first it seems attractive to embed NAFLD patient care geographically into a hepatology clinic with the potential advantages of improving volume and timeliness of referral and reinforcing communication among specialty providers while maximizing convenience for patients. However, this is resource intensive not only concerning clinic space, but also in terms of staffing clinics with specialty providers.

Patient-centered care for veterans with NAFLD seems to be best organized around a comprehensive NAFLD clinic with access to specialized diagnostics and knowledge in day-to-day NAFLD management. This evolving care concept has been developed already for patients with liver cirrhosis and inflammatory bowel disease and considers NAFLD a chronic disease that cannot be addressed sufficiently by providing episodic care.^55,56 The development of comprehensive NAFLD care can build on the great success of the Hepatitis Innovation Team Collaborative that employed lean management strategies with local and regional teams to facilitate efforts to make chronic hepatitis C virus a rare disease in the VHA.⁵⁷

NAFLD Care Team

Given the central role of the liver and gastrointestinal tract in the field of nutrition, knowledge of the pathophysiology of the liver and digestive tract as well as emerging therapeutic options offered via metabolic endoscopy uniquely positions the hepatologist/gastroenterologist to take the lead in managing NAFLD. Treating NAFLD is best accomplished when the specialist partners with other health care providers who have expertise in the nutritional, behavioral, and physical activity aspects of treatment. The composition of the NAFLD care team and the roles that different providers fulfill can vary depending on the clinical setting; however, the hepatologist/gastroenterologist is best suited to lead the team, or alternatively, this role can be fulfilled by a provider with liver disease expertise.

Based on experiences from the United Kingdom, the minimum staffing of a NAFLD clinic should include a physician and nurse practitioner who has expertise in managing patients with chronic liver disease, a registered nurse, a dietitian, and a clinical pharmacy specialist (CPS).⁵⁸ With coexistent diseases common and many veterans who have > 5 prescribed medications, risk of polypharmacy and adverse drug reactions are a concern, particularly since adherence in patients with chronic diseases has been reported to be as low as 43%.^59-61 Risk of medication errors and serious adverse effects are magnified by difficulties with patient adherence, medication interactions, and potential need for frequent dose adjustments, particularly when on a weight-loss diet.

Without doubt, comprehensive medication management, offered by a highly trained CPS with independent prescriptive authority occurring while the veteran is in the NAFLD clinic, is highly desirable. Establishing a functional statement and care coordination agreement could describe the role of the CPS as a member of the NAFLD provider team. 

Patient Evaluation

After being referred to the NAFLD clinic, the veteran should have a thorough assessment, including medical, nutritional, physical activity, exercise, and psychosocial evaluations (Figure 4). 

The assessment also should include patient education to ensure that the patient has sufficient knowledge and skills to achieve the treatment goals. Educating on NAFLD is critical as most patients with NAFLD do not think of themselves as sick and have limited readiness for lifestyle changes.^63,64 A better understanding of NAFLD combined with a higher self-efficacy seems to be positively linked to better nutritional habits.⁶⁵

An online patient-reported outcomes measurement information system for a patient with NAFLD (eg, assessmentcenter.net) may be beneficial and can be applied within a routine NAFLD clinic visit because of its multidimensionality and compatibility with other chronic diseases.^66-68 Other tools to assess health-related QOL include questionnaires, such as the functional assessment of chronic illness therapy-fatigue, work productivity and activity impairment questionnaire: specific health problem, Short Form-36, and chronic liver disease questionnaire-NAFLD.^23,69

The medical evaluation includes assessment of secondary causes of NAFLD and identification of NAFLD-related comorbidities. Weight, height, blood pressure, waist circumference, and BMI should be recorded. The physical exam should focus on signs of chronic liver disease and include inspection for acanthosis nigricans, hirsutism, and large neck circumference, which are associated with insulin resistance, polycystic ovarian syndrome, and obstructive sleep apnea, respectively. NAFLD-associated comorbidities may contribute to frailty or physical limitations that affect treatment with diet and exercise and need to be assessed. A thorough medication reconciliation will reveal whether the patient is prescribed obesogenic medications and whether comorbidities (eg, DM and dyslipidemia) are being treated optimally and according to current society guidelines.

Making the diagnosis of NAFLD requires excluding other (concomitant) chronic liver diseases. While often this is done indirectly using order sets with a panoply of available serologic tests without accounting for risks for rare causes of liver injury, a more focused and cost-effective approach is warranted. As most patients will already have had imaging studies that show fatty liver, assessment of liver fibrosis is an important step for risk stratification. Noninvasive scores (eg, FIB-4) can be used by the PCP to identify high-risk patients requiring further workup and referral.^1,70 More sophisticated tools, including transient elastography and/or magnetic resonance elastography are applied for more sophisticated risk stratification and liver disease management (Table 2).⁷¹ 

A nutritional evaluation includes information about eating behavior and food choices, body composition analysis, and an assessment of short- and long-term alcohol consumption. Presence of bilateral muscle wasting, subcutaneous fat loss, and signs of micronutrient deficiencies also should be explored. The lifestyle evaluation should include the patient’s typical physical activity and exercise as well as limiting factors.

Finally, and equally important, the patient’s psychosocial situation should be assessed, as motivation and accountability are key to success and may require behavioral modification. Assessing readiness is done best with motivational interviewing, the 5As counseling framework (Ask, Advise, Assess, Assist, Arrange) or using open-ended questions, affirmation, reflections, and summaries.^72,73 Even if not personally delivering behavioral treatment, such an approach also can help move patients toward addressing important health-related behaviors.

Personalized Interventions

If available, patients should be offered participation in NAFLD clinical trials. A personalized treatment plan should be developed for each patient with input from all NAFLD care team members. The patient and providers should work together to make important decisions about the treatment plan and goals of care. Making the patient an active participant in their treatment rather than the passive recipient will lead to improvement in adherence and outcomes. Patients will engage when they are comfortable speaking with providers and are sufficiently educated about their disease.

Personalized interventions may be built by combining different strategies, such as lifestyle and dietary interventions, NASH-specific pharmacotherapy, comorbidity management, metabolic endoscopy, and bariatric surgery. Although NASH-specific medications are not currently available, approved medications, including pioglitazone or liraglutide, can be considered for therapy.^74,75 Ideally, the NAFLD team CPS would manage comorbidities, such as T2DM and dyslipidemia, but this also can be done by a hepatologist or other specialist. Metabolic endoscopy (eg, intragastric balloons) or bariatric surgery would be done by referral.

Resource-Limited Settings

Although the VHA offers care at > 150 medical centers and > 1,000 outpatient clinics, specialty care such as hepatology and sophisticated and novel testing modalities are not available at many facilities. In 2011 VHA launched the Specialty Care Access Network Extension for Community Healthcare Outcomes to bring hepatitis C therapy and liver transplantation evaluations to rural areas without specialists.^76-78 It is logical to explore how telehealth can be used for NAFLD care that requires complex management using new treatments and has a high societal impact, particularly when left untreated.

Telehealth must be easy to use and integrated into everyday routines to be useful for NAFLD management by addressing different aspects of promoting self-management, optimizing therapy, and care coordination. Participation in a structured face-to-face or group-based lifestyle program is often jeopardized by time and job constraints but can be successfully overcome using online approaches.⁷⁹ The Internet-based VA Video Connect videoconferencing, which incorporates cell phone, laptop, or tablet use could help expand lifestyle interventions to a much larger community of patients with NAFLD and overcome local resource constraints. Finally, e-consultation also can be used in circumstances where synchronous communication with specialists may not be necessary.

Patient Monitoring and Quality Metrics

Monitoring of the patient after initiation of an intervention is variable but occurs more frequently at the beginning. For high-intensity dietary interventions, weekly monitoring for the first several weeks can ensure ongoing motivation, and accountability may increase the patient’s confidence and provide encouragement for further weight loss. It also is an opportunity to reestablish goals with patients with declining motivation. Long-term monitoring of patients may occur in 6- to 12-month intervals to document patient-reported outcomes, liver-related mortality, cardiovascular events, malignancies, and disease progression or regression.

While quality indicators have been proposed for cirrhosis care, such indicators have yet to be defined for NALD care.⁸⁰ Such quality indicators assessed with validated questionnaires should include knowledge about NAFLD, satisfaction with care, perception of quality of care, and patient-reported outcomes. Other indicators may include use of therapies to treat dyslipidemia and T2DM. Last and likely the most important indicator of improved liver health in NAFLD will be either histologic improvement of NASH or improvement of the fibrosis risk category.

Outlook

With the enormous burden of NAFLD on the rise for many more years to come, quality care delivered to patients with NAFLD warrants resource-adaptive population health management strategies. With a limited number of providers specialized in liver disease, provider education assisted by clinical guidelines and decision support tools, development of referral and access to care mechanisms through integrated care, remote monitoring strategies as well as development of patient self-management and community resources will become more important. We have outlined essential components of an effective population health management strategy for NAFLD and actionable items for the VHA to consider when implementing these strategies. This is the time for the VHA to invest in efforts for NAFLD population care. Clearly, consideration must be given to local needs and resources and integration of technology platforms. Addressing NAFLD at a population level will provide yet another opportunity to demonstrate that VHA performs better on quality when compared with care systems in the private sector.⁸¹

Nonalcoholic fatty liver disease (NAFLD) is an umbrella term that covers a spectrum of phenotypes ranging from nonalcoholic fatty liver or simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) defined by histologic findings of steatosis, lobular inflammation, cytologic ballooning, and some degree of fibrosis.¹ While frequently observed in patients with at least 1 risk factor (eg, obesity, diabetes mellitus [DM], dyslipidemia, hypertension), NAFLD also is an independent risk factor for type 2 DM (T2DM), chronic kidney disease, and cardiovascular disease.² At early disease stages with absence of liver fibrosis, mortality is linked to cardiovascular and not liver disease. However, in the presence of NASH, fibrosis progression to liver cirrhosis, or hepatocellular carcinoma (HCC) represent the most important liver-related outcomes that determine morbidity and mortality.³ Mirroring the obesity and T2DM epidemics, the health care burden is projected to dramatically rise.

In the following article, we will discuss how the Veterans Health Administration (VHA) is well positioned to implement an organizational strategy of comprehensive care for veterans with NAFLD. This comprehensive care strategy should include the development of a NAFLD clinic offering care for comorbid conditions frequently present in these patients, point-of-care testing, access to clinical trials, and outcomes monitoring as a key performance target for providers and the respective facility.

NAFLD disease burden

To fully appreciate the burden of a chronic disease like NAFLD, it is important to assess its long- and short-term consequences in a comprehensive manner with regard to its clinical impact, impact on the patient, and economic impact (Figure 1).

Clinical Impact

Clinical impact is assessed based on the prevalence and natural history of NAFLD and the liver fibrosis stage and determines patient survival. Coinciding with the epidemic of obesity and T2DM, the prevalence of NAFLD in the general population in North America is 24% and even higher with older age and higher body mass index (BMI).^4,5 The prevalence for NAFLD is particularly high in patients with T2DM (47%). Of patients with T2DM and NAFLD, 65% have biopsy-proven NASH of which 15% have bridging fibrosis or liver cirrhosis.⁶

NAFLD is the fastest growing cause of cirrhosis in the US with a forecasted NAFLD population of 101 million by 2030.⁷ At the same time, the number of patients with NASH will rise to 27 million of which > 7 million will have bridging fibrosis or liver cirrhosis; hepatic decompensation events are estimated to occur in 105,430 patients with liver cirrhosis, posing a major public health threat related to organ availability for liver transplantation.⁸ Since 2013, NAFLD has been the second leading cause for liver transplantation and the top reason for transplantation in patients aged < 50 years.^9,10 As many patients with NAFLD are diagnosed with HCC at stages where liver transplantation is not an option, mortality from HCC in NAFLD patients is higher than with other etiologies as treatment options are restricted.^11,12

Compared with that of the general population, veterans seeking care are older and sicker with 43% of veterans taking > 5 prescribed medications.¹³ Of those receiving VHA care, 6.6 million veterans are either overweight or obese; 165,000 are morbidly obese with a BMI > 40.¹⁴ In addition, veterans are 2.5 times more likely to have T2DM compared with that of nonveterans. Because T2DM and obesity are the most common risk factors for NAFLD, it is not surprising that NAFLD prevalence among veterans rose 3-fold from 2003 to 2011.¹⁵ It is now estimated that 540,000 veterans will progress to NASH and 108,000 will develop bridging fibrosis or liver cirrhosis by 2030.⁸ Similar to that of the general population, liver cirrhosis is attributed to NAFLD in 15% of veterans.^15,16 NAFLD is the third most common cause of cirrhosis and HCC, occurring at an average age of 66 years and 70 years, respectively.^16,17 Shockingly, 20% of HCCs were not linked to liver cirrhosis and escaped recommended HCC screening for patients with cirrhosis.^18,19

Patient Impact

Assessment of disease burden should not be restricted to clinical outcomes as patients can experience a range of symptoms that may have significant impact on their health-related quality of life (QOL) and functional status.²⁰ Using general but not disease-specific instruments, NAFLD patients reported outcomes score low regarding fatigue, activity, and emotions.²¹ More disease-specific questionnaires may provide better and disease-specific insights as how NASH impacts patients’ QOL.^22-24

Economic Impact

There is mounting evidence that the clinical implications of NAFLD directly influence the economic burden of NAFLD.²⁵ The annual burden associated with all incident and prevalent NAFLD cases in the US has been estimated at $103 billion, and projections suggest that the expected 10-year burden of NAFLD may increase to $1.005 trillion.²⁶ It is anticipated that increased NAFLD costs will affect the VHA with billions of dollars in annual expenditures in addition to the $1.5 billion already spent annually for T2DM care (4% of the VA pharmacy budget is spent on T2DM treatment).^27-29

Current Patient Care

Obesity, DM, and dyslipidemia are common conditions managed by primary care providers (PCPs). Given the close association of these conditions with NAFLD, the PCP is often the first point of medical contact for patients with or at risk for NAFLD.³⁰ For that reason, PCP awareness of NAFLD is critical for effective management of these patients. PCPs should be actively involved in the management of patients with NAFLD with pathways in place for identifying patients at high risk of liver disease for timely referral to a specialist and adequate education on the follow-up and treatment of low-risk patients. Instead, diagnosis of NAFLD is primarily triggered by either abnormal aminotransferases or detection of steatosis on imaging performed for other indications.

Barriers to optimal management of NAFLD by PCPs have been identified and occur at different levels of patient care. In the absence of clinical practice guidelines by the American Association of Family Practice covering NAFLD and a substantial latency period without signs of symptoms, NAFLD may not be perceived as a potentially serious condition by PCPs and their patients; interestingly this holds true even for some medical specialties.^31-39 More than half of PCPs do not test their patients at highest risk for NAFLD (eg, patients with obesity or T2DM) and may be unaware of practice guidelines.^40-42

Guidelines from Europe and the US are not completely in accordance. The US guidelines are vague regarding screening and are supported by only 1 medical society, due to the lack of NASH-specific drug therapies. The European guidelines are built on the support of 3 different stakeholders covering liver diseases, obesity, and DM and the experience using noninvasive liver fibrosis assessments for patients with NAFLD. To overcome this apparent conflict, a more practical and risk-stratified approach is warranted.^41,42

Making the diagnosis can be challenging in cases with competing etiologies, such as T2DM and alcohol misuse. There also is an overreliance on aminotransferase levels to diagnose NAFLD. Significant liver disease can exist in the presence of normal aminotransferases, and this may be attributed to either spontaneous aminotransferase fluctuations or upper limits of normal that have been chosen too high.^43-47 Often additional workup by PCPs depends on the magnitude of aminotransferase abnormalities.

Even if NAFLD has been diagnosed by PCPs, identifying those with NASH is hindered by the absence of an accurate noninvasive diagnostic method and the need to perform a liver biopsy. Liver biopsy is often not considered or delayed to monitor patients with serial aminotransferases, regardless of the patient’s metabolic comorbidity profile or baseline aminotransferases.³² As a result, referral to a specialist often depends on the magnitude of the aminotransferase abnormality,^30,48 and often occurs when advanced liver disease is already present.⁴⁹ Finally, providers may not be aware of beneficial effects of lifestyle interventions and certain medications, including statins on NASH and liver fibrosis.^50-53 As NAFLD is associated with excess cardiovascular- and cancer-related morbidity and mortality, it is possible that regression of NAFLD may improve associated risk for these outcomes as well.

Framework for Comprehensive NAFLD Care

Chronic liver diseases and associated comorbidities have long been addressed by PCPs and specialty providers working in isolation and within the narrow focus of each discipline. Contrary to working in silos of the past, a coordinated management strategy with other disciplines that cover these comorbidities needs to be established, or alternatively the PCP must be aware of the management of comorbidities to execute them independently. Integration of hepatology-driven NAFLD care with other specialties involves communication, collaboration, and sharing of resources and expertise that will address patient care needs. Obviously, this cannot be undertaken in a single outpatient visit and requires vertical and longitudinal follow-up over time. One important aspect of comprehensive NAFLD care is the targeting of a particular patient population rather than being seen as a panacea for all; cost-utility analysis is hampered by uncertainties around accuracy of noninvasive biomarkers reflecting liver injury and a lack of effectiveness data for treatment. However, it seems reasonable to screen patients at high risk for NASH and adverse clinical outcomes. Such a risk stratification approach should be cost-effective.

A first key step by the PCP is to identify whether a patient is at risk, especially patients with NASH. The majority of patients at risk are already seen by PCPs. While there is no consensus on ideal screening for NAFLD by PCPs, the use of ultrasound in the at-risk population is recommended in Europe.⁴² Although NASH remains a histopathologic diagnosis, a reasonable approach is to define NASH based on clinical criteria as done similarly in a real-world observational NAFLD cohort study.⁵⁴ In the absence of chronic alcohol consumption and viral hepatitis and in a real-world scenario, NASH can be defined as steatosis shown on liver imaging or biopsy and alanine aminotransferase (ALT) levels of > 25 U/L. In addition, ≥ 1 of the following criteria must be met: BMI > 30, T2DM, dyslipidemia, or metabolic syndrome (Table 1). 

In the absence of easy-to-use validated tests, all patients with NAFLD need to be assessed with simple, noninvasive scores for the presence of clinically relevant liver fibrosis (F2-portal fibrosis with septa; F3-bridging fibrosis; F4-liver cirrhosis); those that meet the fibrosis criteria should receive further assessment usually only offered in a comprehensive NAFLD clinic.¹ PCPs should focus on addressing 2 aspects related to NAFLD: (1) Does my patient have NASH based on clinical criteria; and (2) Is my patient at risk for clinically relevant liver fibrosis? PCPs are integral in optimal management of comorbidities and metabolic syndrome abnormalities with lifestyle and exercise interventions.

The care needs of a typical patient with NAFLD can be classified into 3 categories: liver disease (NAFLD) management, addressing NAFLD associated comorbidities, and attending to the personal care needs of the patient. With considerable interactions between these categories, interventions done within the framework of 1 category can influence the needs pertaining to another, requiring closer monitoring of the patient and potentially modifying care. For example, initiating a low carbohydrate diet in a patient with DM and NAFLD who is on antidiabetic medication may require adjusting the medication; disease progression or failure to achieve treatment goals may affect the emotional state of the patient, which can affect adherence.

Referrals to a comprehensive NAFLD clinic need to be standardized. Clearly, the referral process depends in part on local resources, comprehensiveness of available services, and patient characteristics, among others. Most often, PCPs refer patients with suspected diagnosis of NAFLD, with or without abnormal aminotransferases, to a hepatologist to confirm the diagnosis and for disease staging and liver disease management. This may have the advantage of greatest extent of access and should limit the number of patients with advanced liver fibrosis who otherwise may have been missed. On the other hand, different thresholds of PCPs for referrals may delay the patient’s access to comprehensive NAFLD care. Of those referred by primary care, the hepatologist identifies patients with NAFLD who benefit most from a comprehensive care approach. This automated referral process without predefined criteria remains more a vision than reality as it would require an infrastructure and resources that no health care system can provide currently.

The alternative approach of automatic referral may use predefined criteria related to patients’ diagnoses and prognoses (Figure 2). 

Patient-Centered Care

At present the narrow focus of VHA specialty outpatient clinics associated with time constraints of providers and gaps in NAFLD awareness clearly does not address the complex metabolic needs of veterans with NAFLD. This is in striking contrast to the comprehensive care offered to patients with cancer. To overcome these limitations, new care delivery models need to be explored. At first it seems attractive to embed NAFLD patient care geographically into a hepatology clinic with the potential advantages of improving volume and timeliness of referral and reinforcing communication among specialty providers while maximizing convenience for patients. However, this is resource intensive not only concerning clinic space, but also in terms of staffing clinics with specialty providers.

Patient-centered care for veterans with NAFLD seems to be best organized around a comprehensive NAFLD clinic with access to specialized diagnostics and knowledge in day-to-day NAFLD management. This evolving care concept has been developed already for patients with liver cirrhosis and inflammatory bowel disease and considers NAFLD a chronic disease that cannot be addressed sufficiently by providing episodic care.^55,56 The development of comprehensive NAFLD care can build on the great success of the Hepatitis Innovation Team Collaborative that employed lean management strategies with local and regional teams to facilitate efforts to make chronic hepatitis C virus a rare disease in the VHA.⁵⁷

NAFLD Care Team

Given the central role of the liver and gastrointestinal tract in the field of nutrition, knowledge of the pathophysiology of the liver and digestive tract as well as emerging therapeutic options offered via metabolic endoscopy uniquely positions the hepatologist/gastroenterologist to take the lead in managing NAFLD. Treating NAFLD is best accomplished when the specialist partners with other health care providers who have expertise in the nutritional, behavioral, and physical activity aspects of treatment. The composition of the NAFLD care team and the roles that different providers fulfill can vary depending on the clinical setting; however, the hepatologist/gastroenterologist is best suited to lead the team, or alternatively, this role can be fulfilled by a provider with liver disease expertise.

Based on experiences from the United Kingdom, the minimum staffing of a NAFLD clinic should include a physician and nurse practitioner who has expertise in managing patients with chronic liver disease, a registered nurse, a dietitian, and a clinical pharmacy specialist (CPS).⁵⁸ With coexistent diseases common and many veterans who have > 5 prescribed medications, risk of polypharmacy and adverse drug reactions are a concern, particularly since adherence in patients with chronic diseases has been reported to be as low as 43%.^59-61 Risk of medication errors and serious adverse effects are magnified by difficulties with patient adherence, medication interactions, and potential need for frequent dose adjustments, particularly when on a weight-loss diet.

Without doubt, comprehensive medication management, offered by a highly trained CPS with independent prescriptive authority occurring while the veteran is in the NAFLD clinic, is highly desirable. Establishing a functional statement and care coordination agreement could describe the role of the CPS as a member of the NAFLD provider team. 

Patient Evaluation

After being referred to the NAFLD clinic, the veteran should have a thorough assessment, including medical, nutritional, physical activity, exercise, and psychosocial evaluations (Figure 4). 

The assessment also should include patient education to ensure that the patient has sufficient knowledge and skills to achieve the treatment goals. Educating on NAFLD is critical as most patients with NAFLD do not think of themselves as sick and have limited readiness for lifestyle changes.^63,64 A better understanding of NAFLD combined with a higher self-efficacy seems to be positively linked to better nutritional habits.⁶⁵

An online patient-reported outcomes measurement information system for a patient with NAFLD (eg, assessmentcenter.net) may be beneficial and can be applied within a routine NAFLD clinic visit because of its multidimensionality and compatibility with other chronic diseases.^66-68 Other tools to assess health-related QOL include questionnaires, such as the functional assessment of chronic illness therapy-fatigue, work productivity and activity impairment questionnaire: specific health problem, Short Form-36, and chronic liver disease questionnaire-NAFLD.^23,69

The medical evaluation includes assessment of secondary causes of NAFLD and identification of NAFLD-related comorbidities. Weight, height, blood pressure, waist circumference, and BMI should be recorded. The physical exam should focus on signs of chronic liver disease and include inspection for acanthosis nigricans, hirsutism, and large neck circumference, which are associated with insulin resistance, polycystic ovarian syndrome, and obstructive sleep apnea, respectively. NAFLD-associated comorbidities may contribute to frailty or physical limitations that affect treatment with diet and exercise and need to be assessed. A thorough medication reconciliation will reveal whether the patient is prescribed obesogenic medications and whether comorbidities (eg, DM and dyslipidemia) are being treated optimally and according to current society guidelines.

Making the diagnosis of NAFLD requires excluding other (concomitant) chronic liver diseases. While often this is done indirectly using order sets with a panoply of available serologic tests without accounting for risks for rare causes of liver injury, a more focused and cost-effective approach is warranted. As most patients will already have had imaging studies that show fatty liver, assessment of liver fibrosis is an important step for risk stratification. Noninvasive scores (eg, FIB-4) can be used by the PCP to identify high-risk patients requiring further workup and referral.^1,70 More sophisticated tools, including transient elastography and/or magnetic resonance elastography are applied for more sophisticated risk stratification and liver disease management (Table 2).⁷¹ 

A nutritional evaluation includes information about eating behavior and food choices, body composition analysis, and an assessment of short- and long-term alcohol consumption. Presence of bilateral muscle wasting, subcutaneous fat loss, and signs of micronutrient deficiencies also should be explored. The lifestyle evaluation should include the patient’s typical physical activity and exercise as well as limiting factors.

Finally, and equally important, the patient’s psychosocial situation should be assessed, as motivation and accountability are key to success and may require behavioral modification. Assessing readiness is done best with motivational interviewing, the 5As counseling framework (Ask, Advise, Assess, Assist, Arrange) or using open-ended questions, affirmation, reflections, and summaries.^72,73 Even if not personally delivering behavioral treatment, such an approach also can help move patients toward addressing important health-related behaviors.

Personalized Interventions

If available, patients should be offered participation in NAFLD clinical trials. A personalized treatment plan should be developed for each patient with input from all NAFLD care team members. The patient and providers should work together to make important decisions about the treatment plan and goals of care. Making the patient an active participant in their treatment rather than the passive recipient will lead to improvement in adherence and outcomes. Patients will engage when they are comfortable speaking with providers and are sufficiently educated about their disease.

Personalized interventions may be built by combining different strategies, such as lifestyle and dietary interventions, NASH-specific pharmacotherapy, comorbidity management, metabolic endoscopy, and bariatric surgery. Although NASH-specific medications are not currently available, approved medications, including pioglitazone or liraglutide, can be considered for therapy.^74,75 Ideally, the NAFLD team CPS would manage comorbidities, such as T2DM and dyslipidemia, but this also can be done by a hepatologist or other specialist. Metabolic endoscopy (eg, intragastric balloons) or bariatric surgery would be done by referral.

Resource-Limited Settings

Although the VHA offers care at > 150 medical centers and > 1,000 outpatient clinics, specialty care such as hepatology and sophisticated and novel testing modalities are not available at many facilities. In 2011 VHA launched the Specialty Care Access Network Extension for Community Healthcare Outcomes to bring hepatitis C therapy and liver transplantation evaluations to rural areas without specialists.^76-78 It is logical to explore how telehealth can be used for NAFLD care that requires complex management using new treatments and has a high societal impact, particularly when left untreated.

Telehealth must be easy to use and integrated into everyday routines to be useful for NAFLD management by addressing different aspects of promoting self-management, optimizing therapy, and care coordination. Participation in a structured face-to-face or group-based lifestyle program is often jeopardized by time and job constraints but can be successfully overcome using online approaches.⁷⁹ The Internet-based VA Video Connect videoconferencing, which incorporates cell phone, laptop, or tablet use could help expand lifestyle interventions to a much larger community of patients with NAFLD and overcome local resource constraints. Finally, e-consultation also can be used in circumstances where synchronous communication with specialists may not be necessary.

Patient Monitoring and Quality Metrics

Monitoring of the patient after initiation of an intervention is variable but occurs more frequently at the beginning. For high-intensity dietary interventions, weekly monitoring for the first several weeks can ensure ongoing motivation, and accountability may increase the patient’s confidence and provide encouragement for further weight loss. It also is an opportunity to reestablish goals with patients with declining motivation. Long-term monitoring of patients may occur in 6- to 12-month intervals to document patient-reported outcomes, liver-related mortality, cardiovascular events, malignancies, and disease progression or regression.

While quality indicators have been proposed for cirrhosis care, such indicators have yet to be defined for NALD care.⁸⁰ Such quality indicators assessed with validated questionnaires should include knowledge about NAFLD, satisfaction with care, perception of quality of care, and patient-reported outcomes. Other indicators may include use of therapies to treat dyslipidemia and T2DM. Last and likely the most important indicator of improved liver health in NAFLD will be either histologic improvement of NASH or improvement of the fibrosis risk category.

Outlook

With the enormous burden of NAFLD on the rise for many more years to come, quality care delivered to patients with NAFLD warrants resource-adaptive population health management strategies. With a limited number of providers specialized in liver disease, provider education assisted by clinical guidelines and decision support tools, development of referral and access to care mechanisms through integrated care, remote monitoring strategies as well as development of patient self-management and community resources will become more important. We have outlined essential components of an effective population health management strategy for NAFLD and actionable items for the VHA to consider when implementing these strategies. This is the time for the VHA to invest in efforts for NAFLD population care. Clearly, consideration must be given to local needs and resources and integration of technology platforms. Addressing NAFLD at a population level will provide yet another opportunity to demonstrate that VHA performs better on quality when compared with care systems in the private sector.⁸¹

Nonalcoholic fatty liver disease (NALFD) is now the most common chronic liver disease in the developed world and affects about 25% to 30% of adults in the US and 30% of veterans who receive care in the VHA system (Figure 1). 

Related: 

NAFLD is significantly associated with the presence of MetS, so much so that it has been considered the hepatic manifestation of MetS. NAFLD also is strongly associated with type 2 diabetes mellitus (T2DM), CVD, chronic kidney disease (CKD), and obstructive sleep apnea (OSA) (Figure 2). 

Obesity/Visceral Adiposity

Obesity (body mass index [BMI] > 30) prevalence in the US has almost doubled over the past 30 years and continues to climb.¹ Obesity affects 41% of veterans in the Veterans Health Administration and is the most common risk factor for NAFLD.² NAFLD is 4 times more prevalent in obese patients, thus, it is not surprising that 80% to 90% of patients evaluated in bariatric centers have NAFLD, reported in 2 large series.^3,4 Increased BMI and waist circumference predict the presence of NASH and advanced fibrosis.⁵

While obesity is a hallmark for NAFLD, particularly in the US, it is important to note that up to 20% of Americans with normal BMI have NAFLD, based on findings of steatosis on ultrasound.⁶ These patients with lean NAFLD are often underdiagnosed. In addition to the patient’s BMI, it is important to recognize that in NAFLD, the distribution and type of fat deposition is more important than just BMI. Visceral fat refers to fat accumulation within the abdominal cavity and is key to the pathogenesis of NAFLD. Visceral fat, compared with subcutaneous fat, is metabolically active and can deliver an overabundance of free fatty acids to the liver as well as secrete proinflammatory mediators in the setting of insulin resistance. Visceral fat stores can predict increased hepatic fat content, inflammation, and fibrosis.⁵ Thus, it is important to recognize that those patients with relatively more visceral fat are more prone to NAFLD. The best clinical indicator of visceral adiposity is abdominal obesity, indicated by waist circumference > 40 inches in men and > 35 inches in women.

Metabolic Syndrome

Hepatic fat deposition can be associated with or precede MetS. MetS is defined as having at least 3 of the following characteristics: abdominal obesity, elevated triglycerides (TGs) (≥ 150 mg/dL), reduced high-density lipoprotein cholesterol (< 40 mg/dL in men or < 50 mg/dL in women), elevated blood pressure (BP) (systolic BP ≥ 130 mm Hg or diastolic BP ≥ 85 mm Hg), or elevated fasting glucose (≥ 110 mg/dL). Population studies have found that 50% of patients with MetS have NAFLD, and liver fat content is strongly correlated with the number of MetS features present in an individual.^5,7 In addition to this association, NAFLD also promotes the development of MetS. Increased energy intake relative to energy expenditure will facilitate ectopic fat accumulation in the liver, which then increases hepatic gluconeogenesis and drives the pathogenesis of insulin resistance.⁸ Therefore, the presence of NAFLD is both a marker and a promotor of insulin resistance and its complications.

Related: 

Type 2 Diabetes Mellitus

At 70% to 75%, the prevalence of NAFLD in patients with T2DM is more than twice as high as that in the general US adult population. Conversely, about 23% of patients with NAFLD also have T2DM.⁹

Influence of NAFLD on T2DM

Patients with ultrasound-based evidence of NAFLD are 2 to 5 times more likely to develop T2DM after adjusting for lifestyle and metabolic risk factors in multiple epidemiologic studies.^10,11 The severity of hepaticfat content measured by ultrasound also is associated with an increasing risk of T2DM incidence over the next 5 years (normal,7%; mild, 9.8%; moderate-severe, 17.8%; P < .001).¹² In another study, 58% of patientswith biopsy-proven NAFLD developed T2DM after a mean follow-up of 13.7 years.¹³ Those who were found to have NASH had a 3-fold higher risk of developing T2DM than did those with simple steatosis. This finding was confirmed in another study where T2DM incidence was 2 times higher in patients predicted to have advanced fibrosis compared with those who did not.¹⁴

Because liver steatosis interferes with insulin-induced glycogen production and suppression of gluconeogenesis, hepatic fat content predicts the insulin dose required for adequate glucose control in patients with diabetes mellitus (DM) and NAFLD.¹⁵ Higher levels of insulin are required in patients with DM and NAFLD compared with those without NAFLD.⁵ 

Additionally, a 10-year cohort study found that resolution of ultrasound-based NAFLD in patients without baseline T2DM, was associated with a reduced T2DM incidence (multivariate odds ratio [OR] 0.27, 95% CI, 0.12-0.61) after controlling for factors such as age, BMI, and impaired fasting glucose.^11,17

Given this close relationship between T2DM and NAFLD, both the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver Diseases (EASL) guidelines recommend that patients found to have NAFLD should be screened for the presence of impaired fasting glucose/T2DM by testing hemoglobin A_1c or fasting glucose levels.^18,19 Recognizing the role that NAFLD can play in patients with DM also is important, as improving hepatic steatosis may also improve DM.

Influence of DM on NAFLD

Patients with T2DM and NAFLD are at increased risk of progressive liver disease and have increased rates of NASH, cirrhosis, and HCC. In a paired-biopsy study, the development of T2DM was the strongest predictor of progression of NASH and hepatic fibrosis.²⁰ This fibrosis progression can easily go undetected, as NASH can be present even with normal aminotransferases. This increased risk of fibrosis progression in the setting of comorbid T2DM is clinically important, as it is the severity of fibrosis that predicts all-cause and liver-related mortality in patients with NAFLD/NASH.^21,22 In fact, the prevalence of biopsy-proven NASH in overweight/obese patients with DM with normal liver aminotransferases (defined as aspartate aminotransferase and alanine aminotransferase < 40 U/L) was found to be 58%.²³ Because chronic liver disease, including NAFLD, is underrecognized in the “healthy population” used to establish normal aminotransferase levels, more recent AASLD and ACG guidelines now define normal aminotransferase levels as < 35 U/L for males and < 25 U/L for females.²⁴ These stricter cutoffs are based on populations with normal BMI and negative testing for chronic liver diseases.²⁴ The lower cutoffs may improve recognition of progressive liver disease in NAFLD and NASH patients.

Medications used in the treatment of T2DM, such as metformin, pioglitazone, and liraglutide, have been studied in patients with biopsy-proven NASH. The initial data showing histologic improvement in NAFLD patients taking metformin was more likely related to the associated weight loss in the treatment group. In a study by Loomba and colleagues the improvement in the NAFLD activity score was only seen in patients who lost ≥ 5% of their total body weight.²⁵ Pioglitazone is a PPAR-γ agonist that helps regulate glucose and lipid metabolism as well as inflammation. Pioglitazone helps adipose tissue, hepatocytes, and muscle cells restore insulin sensitivity. A recent trial in 100 patients with prediabetes or T2DM as well as NASH showed that 36 weeks of pioglitazone treatment was associated with significant improvements in steatosis, inflammation, and most important, in stage of fibrosis compared with that of placebo.²⁶

Related: 

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide, have effects on lipid and glucose metabolism as well. They can lower glucose levels by increasing insulin secretion, reducing glucagon concentration, suppressing appetite (resulting in weight loss), and increasing sensitivity to insulin in hepatocytes and adipocytes. Liraglutide has been studied in patients with NASH both with and without DM, and results of the largest study to date show that it is associated with significant improvement in hepatic inflammation compared with that of placebo.²⁷ Additional phase 3 clinical trials are currently underway.

Current AASLD guidelines do not recommend routine screening for NAFLD, even among high-risk patients, such as patients with DM.¹⁸ This is due to the widespread prevalence of NAFLD, the unclear utility of diagnostic tests, and limited efficacy of available treatment. Lifestyle modification to achieve weight loss remains the backbone of management, and rates of successful adherence are low.²⁸ Contrary to this, EASL guidelines state that NAFLD screening with ultrasound even in patients with normal liver enzymes should be performed in high-risk patients with T2DM.¹⁹

Once detected, T2DM should be diligently treated in patients with NAFLD, and pioglitazone may be considered in patients with biopsy-proven NASH per AASLD guidelines.¹⁸ Pioglitazone has been studied in patients with biopsy-proven NASH both with and without DM and has been associated with significant resolution of NASH, as well as improvement in histologic changes of NASH and improvement in fibrosis.^29,30 Because of potential medication AEs, including a mean weight gain of 2.5 kg to 4.7 kg in trials of 12- to 36-months’ duration, as well as potential bone loss in women, discussions about the risks and benefits of treatment should occur prior to treatment initiation.¹⁸ Additionally, pioglitazone is not safe in the setting of left ventricular heart failure. Future studies may point to the utility of other DM medications, such as GLP-receptor agonists.

Cardiovascular Disease

Given the association between features of MetS and NAFLD, it is not surprising that the primary cause of death in patients with NAFLD is related to CVD.^21,22,31 However, it is increasingly recognized that NAFLD predicts CVD independently of the traditional risk factors associated with MetS. The increase in cardiovascular risk in the setting of NAFLD can be partly explained by the increased hepatic de novo lipogenesis that is associated with increased production of highly atherogenic small dense low-density lipoproteins (sd-LDL) independent of BMI and presence of insulin resistance.³² Additionally, increased intracellular free fatty acids can activate proinflammatory cytokine production by hepatocytes in addition to the increase in systemic inflammatory mediators and oxidative stress associated with NASH.

A recent meta-analysis of 27 studies confirmed the association between NAFLD and many subclinical features of CVD, including increases in coronary-artery calcium score, carotid artery intimal media thickness, and arterial wall stiffness, as well as impaired flow-mediated vasodilation after controlling for classic CVD risk factors.³³ The risk of subclinical carotid and coronary atherosclerosis progression was higher in NAFLD patients with evidence of advanced fibrosis using noninvasive measures. Additionally, NAFLD was associated with increased severity of coronary artery disease in > 600 patients undergoing cardiac angiograms.³⁴ Conversely, the regression of NAFLD on ultrasound was associated with a decreased risk of carotid atherosclerosis progression.³⁵

Multiple epidemiologic studies have found an increased incidence of clinically overt CVD in patients with NAFLD after controlling for confounders. The largest updated meta-analysis, which included more than 34,000 patients with 2,600 CVD outcomes over a median of 6.9 years found that the presence of NAFLD (based on imaging or biopsy) was associated with an odds ratio (OR) of 1.64 (95% CI, 1.26-2.13) for fatal and nonfatal incident CVD.³⁶ In the same meta-analysis, patients with NASH, with or without fibrosis, were at an even higher risk, with an OR of 2.58 (95% CI, 1.78-3.75).

Initial studies of statin medications for the treatment of NASH using surrogate endpoints like improvement in aminotransferases or imaging, suggested a potential liver-related benefit. However, there was no histologic improvement in the single study comparing 12 months of simvastatin therapy with placebo in patients with NASH.³⁷ Although it is unclear whether statin use will directly improve NAFLD, there is no evidence to suggest that statin use should be avoided in patients with elevated CVD risk.³⁸ Treatment with atorvastatin has been shown to be associated with a greater reduction in cardiovascular events in patients with NAFLD compared with that of patients without NAFLD.³⁹

The strong association between CVD and NAFLD has important clinical implications that may influence the decision to initiate treatment for primary prevention, including lipid-lowering, antihypertensive, or antiplatelet therapies. The clinical algorithms currently used to help risk stratify patients and determine appropriate preventative strategies, the Framingham risk equation or the systemic coronary risk evaluation, do not incorporate NAFLD as a potential risk factor for CVD. Additional studies are needed to determine whether adding NAFLD to the assessment will improve the predictive accuracy of future CVD events. Nevertheless, European clinical guidelines recommend performing a CVD risk assessment for patients with NAFLD.¹⁹

Chronic Kidney Disease

The prevalence of CKD, defined as estimated glomerular filtration rate (GFR) < 60 mL/min/1.72 m², abnormal albuminuria, or proteinuria, is significantly increased in patients with NAFLD. Several epidemiologic studies have shown the prevalence of CKD in NAFLD patients ranges from 20% to 55% compared with 5% to 30% among patients without NAFLD.⁴⁰ Overall, patients with NAFLD have a 2-fold increased risk of prevalent (OR 2.12; 95% CI, 1.69-2.66) or incident (hazard ratio 1.79; 95% CI, 1.65-1.95) CKD, even after adjusting for T2DM, visceral fat, and insulin resistance.⁴⁰ There is an additional 2-fold increase in CKD risk in patients with NASH and advanced fibrosis compared with those with NASH and mild/no fibrosis. Additionally, advancing NASH fibrosis stage is independently associated with worsening stage of CKD.⁴¹

Data regarding the exact mechanism of kidney pathology in the setting of NAFLD is lacking. The accelerated atherogenesis in NAFLD likely contributes to renal damage. Another potential mechanism to explain the association between NASH and CKD involves the increased activation of the angiotensin-aldosterone system (RAAS) seen in NASH, which leads to increased hepatic fibrogenesis as well as kidney damage.⁴²

Similar to the previously listed comorbidities, there is evidence that improvement in NAFLD can lead to improvements in renal disease. A prospective study of NASH patients undergoing 52 weeks of lifestyle modification found that the patients who had improvements in histologic NASH endpoints also had improvement in renal function.⁴³

There are currently no specific recommendations on screening for CKD in professionalguidelines, but many experts propose monitoring for CKD yearly with serum creatinine and urinalysis and referring to nephrology if needed. Given the association between NASH and activation of the RAAS pathway that is associated with worsening hepatic fibrosis, RAAS-inhibitors should be a first-line agent in the treatment of hypertension in patients with NAFLD.

Obstructive Sleep Apnea

OSA is characterized by repeated pharyngeal collapse during sleep, which leads to chronic intermittent hypoxia and is associated with increased metabolic and cardiovascular morbidity and mortality. The cycle of intermittent hypoxia and reoxygenation in OSA results in inflammation and oxidative stress. Multiple studies have supported a link between NAFLD and OSA.

Hepatic fat content on ultrasound was increased in patients with OSA independent of BMI. There also has been evidence of a positive association between the severity of chronic intermittent hypoxia and increased hepatic fibrosis based on liver elastography.⁴⁴ A meta-analysis using histologic NAFLD diagnosis showed that the presence of OSA was associated with a higher risk of fibrosis compared with that of patients with NAFLD without OSA (OR 2.6; 95% CI, 1.3-5.2).⁴⁵

Based on animal models, hypoxia can drive fat accumulation and inflammation in the liver via multiple different pathways. Hypoxia can increase fasting glucose and systemic TG levels and induce hepatic lipogenesis by altering gene expression.⁴⁵ Hypoxia also can increase oxidative stress and reduce β-oxidation, which leads to the production of lipotoxic lipids. These hypoxia-induced changes are typically more pronounced in subjects with obesity compared with that in subjects without obesity. Despite multiple adverse metabolic effects of OSA-induced hypoxia in the setting of NAFLD, preliminary, short-term studies have failed to find an association with OSA treatment with continuous positive airway pressure and improvement in NAFLD.⁴⁵ Perhaps larger, long-term prospective trials will clarify this question.

Malignancy

Extrahepatic malignancy (colon, esophagus, stomach, pancreas, kidney, and breast) is the second most common cause of death in patients with NAFLD.^21,22 The primary association between NAFLD and malignancy is found in the colon. Most large population-based studies have been performed in East Asia and have found that NAFLD is associated with a 1.5 to 1.7-fold increased risk for colonic adenomas and a 1.9 to 3.1-fold increased risk of colorectal cancer.^46-49 Using magnetic resonance spectroscopy and liver biopsy to diagnose NAFLD and NASH, respectively, Wong and colleagues found that NASH, but not simple steatosis, is associated with a higher risk of advanced colorectalneoplasia (OR 5.34; 95% CI, 1.9-14.8), after adjusting for age, gender, BMI, family history, smoking, and T2DM.⁵⁰

Data showing a definitive causative role of NAFLD in the development of colorectal cancer are lacking, but the presence of increased insulin levels has many potential effects on carcinogenesis in general, including stimulation of cell proliferation and apoptosis. Currently, there are no recommended changes to the standard colorectal cancer screening recommendations specifically for patients with NAFLD.

Conclusion

NAFLD is a multisystem disease that is associated with increased liver-related and all-cause mortality. Data on the close association between NAFLD and several extrahepatic complications, including MetS, T2DM, CVD, CKD, and malignancy are well established. There also is growing evidence of a bidirectional relationship between some of these diagnoses, whereas NAFLD is not only a consequence, but also a cause of MetS, T2DM, and CKD independent of other typical risk factors.

Given the multiple comorbidities associated with NAFLD and its potential to influence the severity of these diagnoses, management of these complex patients requires diligence and a multidisciplinary approach. In order to engage in early recognition and intervention to prevent potential morbidity and mortality, regular screening and surveillance for the development of NAFLD in patients with metabolic risk factors can be considered, and careful screening for metabolic complications in patients with established NAFLD is important.

Nonalcoholic fatty liver disease (NALFD) is now the most common chronic liver disease in the developed world and affects about 25% to 30% of adults in the US and 30% of veterans who receive care in the VHA system (Figure 1). 

Related: 

NAFLD is significantly associated with the presence of MetS, so much so that it has been considered the hepatic manifestation of MetS. NAFLD also is strongly associated with type 2 diabetes mellitus (T2DM), CVD, chronic kidney disease (CKD), and obstructive sleep apnea (OSA) (Figure 2). 

Obesity/Visceral Adiposity

Obesity (body mass index [BMI] > 30) prevalence in the US has almost doubled over the past 30 years and continues to climb.¹ Obesity affects 41% of veterans in the Veterans Health Administration and is the most common risk factor for NAFLD.² NAFLD is 4 times more prevalent in obese patients, thus, it is not surprising that 80% to 90% of patients evaluated in bariatric centers have NAFLD, reported in 2 large series.^3,4 Increased BMI and waist circumference predict the presence of NASH and advanced fibrosis.⁵

While obesity is a hallmark for NAFLD, particularly in the US, it is important to note that up to 20% of Americans with normal BMI have NAFLD, based on findings of steatosis on ultrasound.⁶ These patients with lean NAFLD are often underdiagnosed. In addition to the patient’s BMI, it is important to recognize that in NAFLD, the distribution and type of fat deposition is more important than just BMI. Visceral fat refers to fat accumulation within the abdominal cavity and is key to the pathogenesis of NAFLD. Visceral fat, compared with subcutaneous fat, is metabolically active and can deliver an overabundance of free fatty acids to the liver as well as secrete proinflammatory mediators in the setting of insulin resistance. Visceral fat stores can predict increased hepatic fat content, inflammation, and fibrosis.⁵ Thus, it is important to recognize that those patients with relatively more visceral fat are more prone to NAFLD. The best clinical indicator of visceral adiposity is abdominal obesity, indicated by waist circumference > 40 inches in men and > 35 inches in women.

Metabolic Syndrome

Hepatic fat deposition can be associated with or precede MetS. MetS is defined as having at least 3 of the following characteristics: abdominal obesity, elevated triglycerides (TGs) (≥ 150 mg/dL), reduced high-density lipoprotein cholesterol (< 40 mg/dL in men or < 50 mg/dL in women), elevated blood pressure (BP) (systolic BP ≥ 130 mm Hg or diastolic BP ≥ 85 mm Hg), or elevated fasting glucose (≥ 110 mg/dL). Population studies have found that 50% of patients with MetS have NAFLD, and liver fat content is strongly correlated with the number of MetS features present in an individual.^5,7 In addition to this association, NAFLD also promotes the development of MetS. Increased energy intake relative to energy expenditure will facilitate ectopic fat accumulation in the liver, which then increases hepatic gluconeogenesis and drives the pathogenesis of insulin resistance.⁸ Therefore, the presence of NAFLD is both a marker and a promotor of insulin resistance and its complications.

Related: 

Type 2 Diabetes Mellitus

At 70% to 75%, the prevalence of NAFLD in patients with T2DM is more than twice as high as that in the general US adult population. Conversely, about 23% of patients with NAFLD also have T2DM.⁹

Influence of NAFLD on T2DM

Patients with ultrasound-based evidence of NAFLD are 2 to 5 times more likely to develop T2DM after adjusting for lifestyle and metabolic risk factors in multiple epidemiologic studies.^10,11 The severity of hepaticfat content measured by ultrasound also is associated with an increasing risk of T2DM incidence over the next 5 years (normal,7%; mild, 9.8%; moderate-severe, 17.8%; P < .001).¹² In another study, 58% of patientswith biopsy-proven NAFLD developed T2DM after a mean follow-up of 13.7 years.¹³ Those who were found to have NASH had a 3-fold higher risk of developing T2DM than did those with simple steatosis. This finding was confirmed in another study where T2DM incidence was 2 times higher in patients predicted to have advanced fibrosis compared with those who did not.¹⁴

Because liver steatosis interferes with insulin-induced glycogen production and suppression of gluconeogenesis, hepatic fat content predicts the insulin dose required for adequate glucose control in patients with diabetes mellitus (DM) and NAFLD.¹⁵ Higher levels of insulin are required in patients with DM and NAFLD compared with those without NAFLD.⁵ 

Additionally, a 10-year cohort study found that resolution of ultrasound-based NAFLD in patients without baseline T2DM, was associated with a reduced T2DM incidence (multivariate odds ratio [OR] 0.27, 95% CI, 0.12-0.61) after controlling for factors such as age, BMI, and impaired fasting glucose.^11,17

Given this close relationship between T2DM and NAFLD, both the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver Diseases (EASL) guidelines recommend that patients found to have NAFLD should be screened for the presence of impaired fasting glucose/T2DM by testing hemoglobin A_1c or fasting glucose levels.^18,19 Recognizing the role that NAFLD can play in patients with DM also is important, as improving hepatic steatosis may also improve DM.

Influence of DM on NAFLD

Patients with T2DM and NAFLD are at increased risk of progressive liver disease and have increased rates of NASH, cirrhosis, and HCC. In a paired-biopsy study, the development of T2DM was the strongest predictor of progression of NASH and hepatic fibrosis.²⁰ This fibrosis progression can easily go undetected, as NASH can be present even with normal aminotransferases. This increased risk of fibrosis progression in the setting of comorbid T2DM is clinically important, as it is the severity of fibrosis that predicts all-cause and liver-related mortality in patients with NAFLD/NASH.^21,22 In fact, the prevalence of biopsy-proven NASH in overweight/obese patients with DM with normal liver aminotransferases (defined as aspartate aminotransferase and alanine aminotransferase < 40 U/L) was found to be 58%.²³ Because chronic liver disease, including NAFLD, is underrecognized in the “healthy population” used to establish normal aminotransferase levels, more recent AASLD and ACG guidelines now define normal aminotransferase levels as < 35 U/L for males and < 25 U/L for females.²⁴ These stricter cutoffs are based on populations with normal BMI and negative testing for chronic liver diseases.²⁴ The lower cutoffs may improve recognition of progressive liver disease in NAFLD and NASH patients.

Medications used in the treatment of T2DM, such as metformin, pioglitazone, and liraglutide, have been studied in patients with biopsy-proven NASH. The initial data showing histologic improvement in NAFLD patients taking metformin was more likely related to the associated weight loss in the treatment group. In a study by Loomba and colleagues the improvement in the NAFLD activity score was only seen in patients who lost ≥ 5% of their total body weight.²⁵ Pioglitazone is a PPAR-γ agonist that helps regulate glucose and lipid metabolism as well as inflammation. Pioglitazone helps adipose tissue, hepatocytes, and muscle cells restore insulin sensitivity. A recent trial in 100 patients with prediabetes or T2DM as well as NASH showed that 36 weeks of pioglitazone treatment was associated with significant improvements in steatosis, inflammation, and most important, in stage of fibrosis compared with that of placebo.²⁶

Related: 

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide, have effects on lipid and glucose metabolism as well. They can lower glucose levels by increasing insulin secretion, reducing glucagon concentration, suppressing appetite (resulting in weight loss), and increasing sensitivity to insulin in hepatocytes and adipocytes. Liraglutide has been studied in patients with NASH both with and without DM, and results of the largest study to date show that it is associated with significant improvement in hepatic inflammation compared with that of placebo.²⁷ Additional phase 3 clinical trials are currently underway.

Current AASLD guidelines do not recommend routine screening for NAFLD, even among high-risk patients, such as patients with DM.¹⁸ This is due to the widespread prevalence of NAFLD, the unclear utility of diagnostic tests, and limited efficacy of available treatment. Lifestyle modification to achieve weight loss remains the backbone of management, and rates of successful adherence are low.²⁸ Contrary to this, EASL guidelines state that NAFLD screening with ultrasound even in patients with normal liver enzymes should be performed in high-risk patients with T2DM.¹⁹

Once detected, T2DM should be diligently treated in patients with NAFLD, and pioglitazone may be considered in patients with biopsy-proven NASH per AASLD guidelines.¹⁸ Pioglitazone has been studied in patients with biopsy-proven NASH both with and without DM and has been associated with significant resolution of NASH, as well as improvement in histologic changes of NASH and improvement in fibrosis.^29,30 Because of potential medication AEs, including a mean weight gain of 2.5 kg to 4.7 kg in trials of 12- to 36-months’ duration, as well as potential bone loss in women, discussions about the risks and benefits of treatment should occur prior to treatment initiation.¹⁸ Additionally, pioglitazone is not safe in the setting of left ventricular heart failure. Future studies may point to the utility of other DM medications, such as GLP-receptor agonists.

Cardiovascular Disease

Given the association between features of MetS and NAFLD, it is not surprising that the primary cause of death in patients with NAFLD is related to CVD.^21,22,31 However, it is increasingly recognized that NAFLD predicts CVD independently of the traditional risk factors associated with MetS. The increase in cardiovascular risk in the setting of NAFLD can be partly explained by the increased hepatic de novo lipogenesis that is associated with increased production of highly atherogenic small dense low-density lipoproteins (sd-LDL) independent of BMI and presence of insulin resistance.³² Additionally, increased intracellular free fatty acids can activate proinflammatory cytokine production by hepatocytes in addition to the increase in systemic inflammatory mediators and oxidative stress associated with NASH.

A recent meta-analysis of 27 studies confirmed the association between NAFLD and many subclinical features of CVD, including increases in coronary-artery calcium score, carotid artery intimal media thickness, and arterial wall stiffness, as well as impaired flow-mediated vasodilation after controlling for classic CVD risk factors.³³ The risk of subclinical carotid and coronary atherosclerosis progression was higher in NAFLD patients with evidence of advanced fibrosis using noninvasive measures. Additionally, NAFLD was associated with increased severity of coronary artery disease in > 600 patients undergoing cardiac angiograms.³⁴ Conversely, the regression of NAFLD on ultrasound was associated with a decreased risk of carotid atherosclerosis progression.³⁵

Multiple epidemiologic studies have found an increased incidence of clinically overt CVD in patients with NAFLD after controlling for confounders. The largest updated meta-analysis, which included more than 34,000 patients with 2,600 CVD outcomes over a median of 6.9 years found that the presence of NAFLD (based on imaging or biopsy) was associated with an odds ratio (OR) of 1.64 (95% CI, 1.26-2.13) for fatal and nonfatal incident CVD.³⁶ In the same meta-analysis, patients with NASH, with or without fibrosis, were at an even higher risk, with an OR of 2.58 (95% CI, 1.78-3.75).

Initial studies of statin medications for the treatment of NASH using surrogate endpoints like improvement in aminotransferases or imaging, suggested a potential liver-related benefit. However, there was no histologic improvement in the single study comparing 12 months of simvastatin therapy with placebo in patients with NASH.³⁷ Although it is unclear whether statin use will directly improve NAFLD, there is no evidence to suggest that statin use should be avoided in patients with elevated CVD risk.³⁸ Treatment with atorvastatin has been shown to be associated with a greater reduction in cardiovascular events in patients with NAFLD compared with that of patients without NAFLD.³⁹

The strong association between CVD and NAFLD has important clinical implications that may influence the decision to initiate treatment for primary prevention, including lipid-lowering, antihypertensive, or antiplatelet therapies. The clinical algorithms currently used to help risk stratify patients and determine appropriate preventative strategies, the Framingham risk equation or the systemic coronary risk evaluation, do not incorporate NAFLD as a potential risk factor for CVD. Additional studies are needed to determine whether adding NAFLD to the assessment will improve the predictive accuracy of future CVD events. Nevertheless, European clinical guidelines recommend performing a CVD risk assessment for patients with NAFLD.¹⁹

Chronic Kidney Disease

The prevalence of CKD, defined as estimated glomerular filtration rate (GFR) < 60 mL/min/1.72 m², abnormal albuminuria, or proteinuria, is significantly increased in patients with NAFLD. Several epidemiologic studies have shown the prevalence of CKD in NAFLD patients ranges from 20% to 55% compared with 5% to 30% among patients without NAFLD.⁴⁰ Overall, patients with NAFLD have a 2-fold increased risk of prevalent (OR 2.12; 95% CI, 1.69-2.66) or incident (hazard ratio 1.79; 95% CI, 1.65-1.95) CKD, even after adjusting for T2DM, visceral fat, and insulin resistance.⁴⁰ There is an additional 2-fold increase in CKD risk in patients with NASH and advanced fibrosis compared with those with NASH and mild/no fibrosis. Additionally, advancing NASH fibrosis stage is independently associated with worsening stage of CKD.⁴¹

Data regarding the exact mechanism of kidney pathology in the setting of NAFLD is lacking. The accelerated atherogenesis in NAFLD likely contributes to renal damage. Another potential mechanism to explain the association between NASH and CKD involves the increased activation of the angiotensin-aldosterone system (RAAS) seen in NASH, which leads to increased hepatic fibrogenesis as well as kidney damage.⁴²

Similar to the previously listed comorbidities, there is evidence that improvement in NAFLD can lead to improvements in renal disease. A prospective study of NASH patients undergoing 52 weeks of lifestyle modification found that the patients who had improvements in histologic NASH endpoints also had improvement in renal function.⁴³

There are currently no specific recommendations on screening for CKD in professionalguidelines, but many experts propose monitoring for CKD yearly with serum creatinine and urinalysis and referring to nephrology if needed. Given the association between NASH and activation of the RAAS pathway that is associated with worsening hepatic fibrosis, RAAS-inhibitors should be a first-line agent in the treatment of hypertension in patients with NAFLD.

Obstructive Sleep Apnea

OSA is characterized by repeated pharyngeal collapse during sleep, which leads to chronic intermittent hypoxia and is associated with increased metabolic and cardiovascular morbidity and mortality. The cycle of intermittent hypoxia and reoxygenation in OSA results in inflammation and oxidative stress. Multiple studies have supported a link between NAFLD and OSA.

Hepatic fat content on ultrasound was increased in patients with OSA independent of BMI. There also has been evidence of a positive association between the severity of chronic intermittent hypoxia and increased hepatic fibrosis based on liver elastography.⁴⁴ A meta-analysis using histologic NAFLD diagnosis showed that the presence of OSA was associated with a higher risk of fibrosis compared with that of patients with NAFLD without OSA (OR 2.6; 95% CI, 1.3-5.2).⁴⁵

Based on animal models, hypoxia can drive fat accumulation and inflammation in the liver via multiple different pathways. Hypoxia can increase fasting glucose and systemic TG levels and induce hepatic lipogenesis by altering gene expression.⁴⁵ Hypoxia also can increase oxidative stress and reduce β-oxidation, which leads to the production of lipotoxic lipids. These hypoxia-induced changes are typically more pronounced in subjects with obesity compared with that in subjects without obesity. Despite multiple adverse metabolic effects of OSA-induced hypoxia in the setting of NAFLD, preliminary, short-term studies have failed to find an association with OSA treatment with continuous positive airway pressure and improvement in NAFLD.⁴⁵ Perhaps larger, long-term prospective trials will clarify this question.

Malignancy

Extrahepatic malignancy (colon, esophagus, stomach, pancreas, kidney, and breast) is the second most common cause of death in patients with NAFLD.^21,22 The primary association between NAFLD and malignancy is found in the colon. Most large population-based studies have been performed in East Asia and have found that NAFLD is associated with a 1.5 to 1.7-fold increased risk for colonic adenomas and a 1.9 to 3.1-fold increased risk of colorectal cancer.^46-49 Using magnetic resonance spectroscopy and liver biopsy to diagnose NAFLD and NASH, respectively, Wong and colleagues found that NASH, but not simple steatosis, is associated with a higher risk of advanced colorectalneoplasia (OR 5.34; 95% CI, 1.9-14.8), after adjusting for age, gender, BMI, family history, smoking, and T2DM.⁵⁰

Data showing a definitive causative role of NAFLD in the development of colorectal cancer are lacking, but the presence of increased insulin levels has many potential effects on carcinogenesis in general, including stimulation of cell proliferation and apoptosis. Currently, there are no recommended changes to the standard colorectal cancer screening recommendations specifically for patients with NAFLD.

Conclusion

NAFLD is a multisystem disease that is associated with increased liver-related and all-cause mortality. Data on the close association between NAFLD and several extrahepatic complications, including MetS, T2DM, CVD, CKD, and malignancy are well established. There also is growing evidence of a bidirectional relationship between some of these diagnoses, whereas NAFLD is not only a consequence, but also a cause of MetS, T2DM, and CKD independent of other typical risk factors.

Given the multiple comorbidities associated with NAFLD and its potential to influence the severity of these diagnoses, management of these complex patients requires diligence and a multidisciplinary approach. In order to engage in early recognition and intervention to prevent potential morbidity and mortality, regular screening and surveillance for the development of NAFLD in patients with metabolic risk factors can be considered, and careful screening for metabolic complications in patients with established NAFLD is important.

Nonalcoholic fatty liver disease (NALFD) is now the most common chronic liver disease in the developed world and affects about 25% to 30% of adults in the US and 30% of veterans who receive care in the VHA system (Figure 1). 

Related: 

NAFLD is significantly associated with the presence of MetS, so much so that it has been considered the hepatic manifestation of MetS. NAFLD also is strongly associated with type 2 diabetes mellitus (T2DM), CVD, chronic kidney disease (CKD), and obstructive sleep apnea (OSA) (Figure 2). 

Obesity/Visceral Adiposity

Obesity (body mass index [BMI] > 30) prevalence in the US has almost doubled over the past 30 years and continues to climb.¹ Obesity affects 41% of veterans in the Veterans Health Administration and is the most common risk factor for NAFLD.² NAFLD is 4 times more prevalent in obese patients, thus, it is not surprising that 80% to 90% of patients evaluated in bariatric centers have NAFLD, reported in 2 large series.^3,4 Increased BMI and waist circumference predict the presence of NASH and advanced fibrosis.⁵

While obesity is a hallmark for NAFLD, particularly in the US, it is important to note that up to 20% of Americans with normal BMI have NAFLD, based on findings of steatosis on ultrasound.⁶ These patients with lean NAFLD are often underdiagnosed. In addition to the patient’s BMI, it is important to recognize that in NAFLD, the distribution and type of fat deposition is more important than just BMI. Visceral fat refers to fat accumulation within the abdominal cavity and is key to the pathogenesis of NAFLD. Visceral fat, compared with subcutaneous fat, is metabolically active and can deliver an overabundance of free fatty acids to the liver as well as secrete proinflammatory mediators in the setting of insulin resistance. Visceral fat stores can predict increased hepatic fat content, inflammation, and fibrosis.⁵ Thus, it is important to recognize that those patients with relatively more visceral fat are more prone to NAFLD. The best clinical indicator of visceral adiposity is abdominal obesity, indicated by waist circumference > 40 inches in men and > 35 inches in women.

Metabolic Syndrome

Hepatic fat deposition can be associated with or precede MetS. MetS is defined as having at least 3 of the following characteristics: abdominal obesity, elevated triglycerides (TGs) (≥ 150 mg/dL), reduced high-density lipoprotein cholesterol (< 40 mg/dL in men or < 50 mg/dL in women), elevated blood pressure (BP) (systolic BP ≥ 130 mm Hg or diastolic BP ≥ 85 mm Hg), or elevated fasting glucose (≥ 110 mg/dL). Population studies have found that 50% of patients with MetS have NAFLD, and liver fat content is strongly correlated with the number of MetS features present in an individual.^5,7 In addition to this association, NAFLD also promotes the development of MetS. Increased energy intake relative to energy expenditure will facilitate ectopic fat accumulation in the liver, which then increases hepatic gluconeogenesis and drives the pathogenesis of insulin resistance.⁸ Therefore, the presence of NAFLD is both a marker and a promotor of insulin resistance and its complications.

Related: 

Type 2 Diabetes Mellitus

At 70% to 75%, the prevalence of NAFLD in patients with T2DM is more than twice as high as that in the general US adult population. Conversely, about 23% of patients with NAFLD also have T2DM.⁹

Influence of NAFLD on T2DM

Patients with ultrasound-based evidence of NAFLD are 2 to 5 times more likely to develop T2DM after adjusting for lifestyle and metabolic risk factors in multiple epidemiologic studies.^10,11 The severity of hepaticfat content measured by ultrasound also is associated with an increasing risk of T2DM incidence over the next 5 years (normal,7%; mild, 9.8%; moderate-severe, 17.8%; P < .001).¹² In another study, 58% of patientswith biopsy-proven NAFLD developed T2DM after a mean follow-up of 13.7 years.¹³ Those who were found to have NASH had a 3-fold higher risk of developing T2DM than did those with simple steatosis. This finding was confirmed in another study where T2DM incidence was 2 times higher in patients predicted to have advanced fibrosis compared with those who did not.¹⁴

Because liver steatosis interferes with insulin-induced glycogen production and suppression of gluconeogenesis, hepatic fat content predicts the insulin dose required for adequate glucose control in patients with diabetes mellitus (DM) and NAFLD.¹⁵ Higher levels of insulin are required in patients with DM and NAFLD compared with those without NAFLD.⁵ 

Additionally, a 10-year cohort study found that resolution of ultrasound-based NAFLD in patients without baseline T2DM, was associated with a reduced T2DM incidence (multivariate odds ratio [OR] 0.27, 95% CI, 0.12-0.61) after controlling for factors such as age, BMI, and impaired fasting glucose.^11,17

Given this close relationship between T2DM and NAFLD, both the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver Diseases (EASL) guidelines recommend that patients found to have NAFLD should be screened for the presence of impaired fasting glucose/T2DM by testing hemoglobin A_1c or fasting glucose levels.^18,19 Recognizing the role that NAFLD can play in patients with DM also is important, as improving hepatic steatosis may also improve DM.

Influence of DM on NAFLD

Patients with T2DM and NAFLD are at increased risk of progressive liver disease and have increased rates of NASH, cirrhosis, and HCC. In a paired-biopsy study, the development of T2DM was the strongest predictor of progression of NASH and hepatic fibrosis.²⁰ This fibrosis progression can easily go undetected, as NASH can be present even with normal aminotransferases. This increased risk of fibrosis progression in the setting of comorbid T2DM is clinically important, as it is the severity of fibrosis that predicts all-cause and liver-related mortality in patients with NAFLD/NASH.^21,22 In fact, the prevalence of biopsy-proven NASH in overweight/obese patients with DM with normal liver aminotransferases (defined as aspartate aminotransferase and alanine aminotransferase < 40 U/L) was found to be 58%.²³ Because chronic liver disease, including NAFLD, is underrecognized in the “healthy population” used to establish normal aminotransferase levels, more recent AASLD and ACG guidelines now define normal aminotransferase levels as < 35 U/L for males and < 25 U/L for females.²⁴ These stricter cutoffs are based on populations with normal BMI and negative testing for chronic liver diseases.²⁴ The lower cutoffs may improve recognition of progressive liver disease in NAFLD and NASH patients.

Medications used in the treatment of T2DM, such as metformin, pioglitazone, and liraglutide, have been studied in patients with biopsy-proven NASH. The initial data showing histologic improvement in NAFLD patients taking metformin was more likely related to the associated weight loss in the treatment group. In a study by Loomba and colleagues the improvement in the NAFLD activity score was only seen in patients who lost ≥ 5% of their total body weight.²⁵ Pioglitazone is a PPAR-γ agonist that helps regulate glucose and lipid metabolism as well as inflammation. Pioglitazone helps adipose tissue, hepatocytes, and muscle cells restore insulin sensitivity. A recent trial in 100 patients with prediabetes or T2DM as well as NASH showed that 36 weeks of pioglitazone treatment was associated with significant improvements in steatosis, inflammation, and most important, in stage of fibrosis compared with that of placebo.²⁶

Related: 

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide, have effects on lipid and glucose metabolism as well. They can lower glucose levels by increasing insulin secretion, reducing glucagon concentration, suppressing appetite (resulting in weight loss), and increasing sensitivity to insulin in hepatocytes and adipocytes. Liraglutide has been studied in patients with NASH both with and without DM, and results of the largest study to date show that it is associated with significant improvement in hepatic inflammation compared with that of placebo.²⁷ Additional phase 3 clinical trials are currently underway.

Current AASLD guidelines do not recommend routine screening for NAFLD, even among high-risk patients, such as patients with DM.¹⁸ This is due to the widespread prevalence of NAFLD, the unclear utility of diagnostic tests, and limited efficacy of available treatment. Lifestyle modification to achieve weight loss remains the backbone of management, and rates of successful adherence are low.²⁸ Contrary to this, EASL guidelines state that NAFLD screening with ultrasound even in patients with normal liver enzymes should be performed in high-risk patients with T2DM.¹⁹

Once detected, T2DM should be diligently treated in patients with NAFLD, and pioglitazone may be considered in patients with biopsy-proven NASH per AASLD guidelines.¹⁸ Pioglitazone has been studied in patients with biopsy-proven NASH both with and without DM and has been associated with significant resolution of NASH, as well as improvement in histologic changes of NASH and improvement in fibrosis.^29,30 Because of potential medication AEs, including a mean weight gain of 2.5 kg to 4.7 kg in trials of 12- to 36-months’ duration, as well as potential bone loss in women, discussions about the risks and benefits of treatment should occur prior to treatment initiation.¹⁸ Additionally, pioglitazone is not safe in the setting of left ventricular heart failure. Future studies may point to the utility of other DM medications, such as GLP-receptor agonists.

Cardiovascular Disease

Given the association between features of MetS and NAFLD, it is not surprising that the primary cause of death in patients with NAFLD is related to CVD.^21,22,31 However, it is increasingly recognized that NAFLD predicts CVD independently of the traditional risk factors associated with MetS. The increase in cardiovascular risk in the setting of NAFLD can be partly explained by the increased hepatic de novo lipogenesis that is associated with increased production of highly atherogenic small dense low-density lipoproteins (sd-LDL) independent of BMI and presence of insulin resistance.³² Additionally, increased intracellular free fatty acids can activate proinflammatory cytokine production by hepatocytes in addition to the increase in systemic inflammatory mediators and oxidative stress associated with NASH.

A recent meta-analysis of 27 studies confirmed the association between NAFLD and many subclinical features of CVD, including increases in coronary-artery calcium score, carotid artery intimal media thickness, and arterial wall stiffness, as well as impaired flow-mediated vasodilation after controlling for classic CVD risk factors.³³ The risk of subclinical carotid and coronary atherosclerosis progression was higher in NAFLD patients with evidence of advanced fibrosis using noninvasive measures. Additionally, NAFLD was associated with increased severity of coronary artery disease in > 600 patients undergoing cardiac angiograms.³⁴ Conversely, the regression of NAFLD on ultrasound was associated with a decreased risk of carotid atherosclerosis progression.³⁵

Multiple epidemiologic studies have found an increased incidence of clinically overt CVD in patients with NAFLD after controlling for confounders. The largest updated meta-analysis, which included more than 34,000 patients with 2,600 CVD outcomes over a median of 6.9 years found that the presence of NAFLD (based on imaging or biopsy) was associated with an odds ratio (OR) of 1.64 (95% CI, 1.26-2.13) for fatal and nonfatal incident CVD.³⁶ In the same meta-analysis, patients with NASH, with or without fibrosis, were at an even higher risk, with an OR of 2.58 (95% CI, 1.78-3.75).

Initial studies of statin medications for the treatment of NASH using surrogate endpoints like improvement in aminotransferases or imaging, suggested a potential liver-related benefit. However, there was no histologic improvement in the single study comparing 12 months of simvastatin therapy with placebo in patients with NASH.³⁷ Although it is unclear whether statin use will directly improve NAFLD, there is no evidence to suggest that statin use should be avoided in patients with elevated CVD risk.³⁸ Treatment with atorvastatin has been shown to be associated with a greater reduction in cardiovascular events in patients with NAFLD compared with that of patients without NAFLD.³⁹

The strong association between CVD and NAFLD has important clinical implications that may influence the decision to initiate treatment for primary prevention, including lipid-lowering, antihypertensive, or antiplatelet therapies. The clinical algorithms currently used to help risk stratify patients and determine appropriate preventative strategies, the Framingham risk equation or the systemic coronary risk evaluation, do not incorporate NAFLD as a potential risk factor for CVD. Additional studies are needed to determine whether adding NAFLD to the assessment will improve the predictive accuracy of future CVD events. Nevertheless, European clinical guidelines recommend performing a CVD risk assessment for patients with NAFLD.¹⁹

Chronic Kidney Disease

The prevalence of CKD, defined as estimated glomerular filtration rate (GFR) < 60 mL/min/1.72 m², abnormal albuminuria, or proteinuria, is significantly increased in patients with NAFLD. Several epidemiologic studies have shown the prevalence of CKD in NAFLD patients ranges from 20% to 55% compared with 5% to 30% among patients without NAFLD.⁴⁰ Overall, patients with NAFLD have a 2-fold increased risk of prevalent (OR 2.12; 95% CI, 1.69-2.66) or incident (hazard ratio 1.79; 95% CI, 1.65-1.95) CKD, even after adjusting for T2DM, visceral fat, and insulin resistance.⁴⁰ There is an additional 2-fold increase in CKD risk in patients with NASH and advanced fibrosis compared with those with NASH and mild/no fibrosis. Additionally, advancing NASH fibrosis stage is independently associated with worsening stage of CKD.⁴¹

Data regarding the exact mechanism of kidney pathology in the setting of NAFLD is lacking. The accelerated atherogenesis in NAFLD likely contributes to renal damage. Another potential mechanism to explain the association between NASH and CKD involves the increased activation of the angiotensin-aldosterone system (RAAS) seen in NASH, which leads to increased hepatic fibrogenesis as well as kidney damage.⁴²

Similar to the previously listed comorbidities, there is evidence that improvement in NAFLD can lead to improvements in renal disease. A prospective study of NASH patients undergoing 52 weeks of lifestyle modification found that the patients who had improvements in histologic NASH endpoints also had improvement in renal function.⁴³

There are currently no specific recommendations on screening for CKD in professionalguidelines, but many experts propose monitoring for CKD yearly with serum creatinine and urinalysis and referring to nephrology if needed. Given the association between NASH and activation of the RAAS pathway that is associated with worsening hepatic fibrosis, RAAS-inhibitors should be a first-line agent in the treatment of hypertension in patients with NAFLD.

Obstructive Sleep Apnea

OSA is characterized by repeated pharyngeal collapse during sleep, which leads to chronic intermittent hypoxia and is associated with increased metabolic and cardiovascular morbidity and mortality. The cycle of intermittent hypoxia and reoxygenation in OSA results in inflammation and oxidative stress. Multiple studies have supported a link between NAFLD and OSA.

Hepatic fat content on ultrasound was increased in patients with OSA independent of BMI. There also has been evidence of a positive association between the severity of chronic intermittent hypoxia and increased hepatic fibrosis based on liver elastography.⁴⁴ A meta-analysis using histologic NAFLD diagnosis showed that the presence of OSA was associated with a higher risk of fibrosis compared with that of patients with NAFLD without OSA (OR 2.6; 95% CI, 1.3-5.2).⁴⁵

Based on animal models, hypoxia can drive fat accumulation and inflammation in the liver via multiple different pathways. Hypoxia can increase fasting glucose and systemic TG levels and induce hepatic lipogenesis by altering gene expression.⁴⁵ Hypoxia also can increase oxidative stress and reduce β-oxidation, which leads to the production of lipotoxic lipids. These hypoxia-induced changes are typically more pronounced in subjects with obesity compared with that in subjects without obesity. Despite multiple adverse metabolic effects of OSA-induced hypoxia in the setting of NAFLD, preliminary, short-term studies have failed to find an association with OSA treatment with continuous positive airway pressure and improvement in NAFLD.⁴⁵ Perhaps larger, long-term prospective trials will clarify this question.

Malignancy

Extrahepatic malignancy (colon, esophagus, stomach, pancreas, kidney, and breast) is the second most common cause of death in patients with NAFLD.^21,22 The primary association between NAFLD and malignancy is found in the colon. Most large population-based studies have been performed in East Asia and have found that NAFLD is associated with a 1.5 to 1.7-fold increased risk for colonic adenomas and a 1.9 to 3.1-fold increased risk of colorectal cancer.^46-49 Using magnetic resonance spectroscopy and liver biopsy to diagnose NAFLD and NASH, respectively, Wong and colleagues found that NASH, but not simple steatosis, is associated with a higher risk of advanced colorectalneoplasia (OR 5.34; 95% CI, 1.9-14.8), after adjusting for age, gender, BMI, family history, smoking, and T2DM.⁵⁰

Data showing a definitive causative role of NAFLD in the development of colorectal cancer are lacking, but the presence of increased insulin levels has many potential effects on carcinogenesis in general, including stimulation of cell proliferation and apoptosis. Currently, there are no recommended changes to the standard colorectal cancer screening recommendations specifically for patients with NAFLD.

Conclusion

NAFLD is a multisystem disease that is associated with increased liver-related and all-cause mortality. Data on the close association between NAFLD and several extrahepatic complications, including MetS, T2DM, CVD, CKD, and malignancy are well established. There also is growing evidence of a bidirectional relationship between some of these diagnoses, whereas NAFLD is not only a consequence, but also a cause of MetS, T2DM, and CKD independent of other typical risk factors.

Given the multiple comorbidities associated with NAFLD and its potential to influence the severity of these diagnoses, management of these complex patients requires diligence and a multidisciplinary approach. In order to engage in early recognition and intervention to prevent potential morbidity and mortality, regular screening and surveillance for the development of NAFLD in patients with metabolic risk factors can be considered, and careful screening for metabolic complications in patients with established NAFLD is important.

Diabetes mellitus (DM) was the third most common medical diagnosis in 2016.¹ Uncontrolled DM can lead to cardiovascular disease, nephropathy, neuropathy, and retinopathy. It is estimated that only 52.5% of patients with DM have achieved their goal hemoglobin A_1c (HbA_1c) level. The 2018 American Diabetes Association (ADA) clinical guidelines lack strong recommendations on sequential therapy for patients who have received a diagnosis of type 2 diabetes mellitus (T2DM) and have been unable to achieve their goal HbA_1c level with lifestyle changes and maximum-dose metformin.² Although those guidelines support treatment intensification with a glucagon-like peptide 1 receptor agonist (GLP-1 RA), prescribing patterns for T2DM most commonly include adding insulin to try to control blood glucose and reduce long-term comorbidities.^2,3

Related: 

Insulin therapy is known for its ability to effectively lower blood glucose and HbA_1c levels but comes with many limitations. Mealtime insulin has the highest risk of hypoglycemia, causes significant weight gain, requires several additional injections per day, and additional monitoring of blood glucose.^4,5 The 2018 ADA guidelines state that hypoglycemia is the major limiting factor in the management of insulin-treated T2DM.²

Compared with mealtime insulin, GLP-1 RAs have the benefit of reducing the risk of hypoglycemia, weight gain, and number of daily injections.⁵ In addition, compared with insulin alone, GLP-1 RAs have the advantage of reducing glycemic variability.⁶ These advantages are especially attractive in the treatment of geriatric patients. Given its mechanism of action, liraglutide is expected to have an effect on both fasting and postprandial blood glucose. There are no recommendations on how to empirically reduce the dose of insulin when starting liraglutide.⁷

Background

GLP-1 is an incretin hormone that is secreted in response to meal ingestion. GLP-1 stimulates insulin release, suppresses elevated glucagon levels, and delays gastric emptying. Patients with a DM diagnosis have impaired secretion of GLP-1.⁸

The GLP-1 RA liraglutide was approved by the FDA in January 2010 as a once-daily injection for patients with uncontrolled T2DM despite lifestyle changes and metformin monotherapy. Because of its intermediate half-life, liraglutide has an effect on both fasting and postprandial blood glucose.⁷ GLP-1 RAs are associated with reduced hypoglycemic episodes—an association attributable to the mechanism of action and potentially to improved pancreatic α-cell function.^3,4 In July 2016, results of the LEADER trial showed that liraglutide therapy had a cardiovascular benefit in high-risk patients.⁸ In October 2017, liraglutide was FDAapproved for reducing 3-point major adverse cardiac events.⁷

Xultophy (Novo Nordisk, Plainsboro, NJ) is a fixed-dose medication combining degludec, a long-acting basal insulin analog, with liraglutide. As seen in the DUAL trials, Xultophy was more beneficial in reducing HbA_1c levels than each component alone, and minimized hypoglycemic events, weight gain, and complexity of insulin treatment intensification.^9-11 Therapy that combines basal insulin and a GLP-1 RA may be more effective than either agent as monotherapy and may have a significant impact on cardiovascular risk because of the synergistic vasodilatory, anti-inflammatory, and antioxidant properties of insulin and GLP-1 RA.⁶ In addition, combination therapy offers many benefits over traditional basal and bolus insulin regimens. These benefits include fewer daily injections, additional weight reduction resulting from the reduced insulin requirement, and fewer episodes of hypoglycemia. Reported gastrointestinal adverse effects have been transient and were not augmented when a GLP-1 RA was used in combination with basal insulin.¹¹

Methods

We performed a retrospective chart analysis to quantify the benefit of using liraglutide as an add-on therapy to basal and bolus insulin regimens in veterans treated at VA Boston Healthcare System (VABHS). The analysis evaluated changes in insulin doses and HbA_1c levels when liraglutide was added to these regimens. Patients identified for the study had electronic medication orders for concurrent therapy with liraglutide, insulin glargine, and insulin aspart filled through outpatient VABHS campus pharmacies for at least 3 months between January 2010 and December 2016. Sixty-nine patients who were on basal-bolus insulin for T2DM and who were prescribed liraglutide for treatment intensification were screened for inclusion and exclusion criteria. Data were analyzed at baseline and 3 months after liraglutide treatment.

Study Protocol

The inclusion criteria were patients aged ≥ 18 years, T2DM diagnosis, and therapy with insulin glargine and insulin aspart for at least 3 months before treatment intensi fication with liraglutide. Exclusion criteria were diagnosis of type 1 DM. To accurately quantify mean change in number of insulin units used, the study included patients only if they had been prescribed insulin glargine and insulin aspart before starting liraglutide. All other insulin regimens were excluded. To detect the true change that occurs when liraglutide is added to basal-bolus insulin, the study also excluded patients if they had been previously prescribed another GLP-1 RA. Patients with contraindications to liraglutide, insulin aspart, or insulin glargine were excluded as well. In addition, patients were excluded from the exposed arm if they were injecting < 1.2 mg of liraglutide once daily or if they had been on liraglutide for < 3 months.

Study Outcomes

All 35 patients who met the inclusion and exclusion criteria were included in this retrospective chart review. The primary outcome was determined by changes in HbA_1c level and number of insulin doses 3 months after treatment with liraglutide. For each patient, a chart review was performed to determine the amount of insulin added or reduced during the study period. Data were collected at baseline and 3 months after initiation of liraglutide.

Statistical Analysis

Statistical analyses were performed with SPSS Version 20.0 (IBM, Armonk, NY). Population characteristics and study outcomes with normal distribution were compared using a paired t test and are reported as means with standard deviations. Nonnormally distributed variables (bolus insulin, HbA_1c level) were compared using the nonparametric Wilcoxon rank sum test and are reported as median values with interquartile ranges. Normality was tested with the Shapiro-Wilk test. The primary outcome evaluated was change in number of insulin units used. Secondary outcomes included change in HbA_1c level and change in body weight. A Bonferroni correction for multiple comparisons was used to prevent type I error. Significance at the Bonferroni-corrected level of .01 (.05/5 = .01) is indicated.

Results

Patients were included if they were previously on insulin glargine and insulin aspart before starting liraglutide for treatment intensification. 

As Table 1 indicates, 100% of patients were male, and mean (SD) age was 65.5 (9.3) years. 

Discussion

After 3 months of treatment with liraglutide, patients experienced a significant decrease in HbA_1c levels. Insulin doses also decreased, but this finding was not statistically significant after correcting for multiple testing. These results are similar with those in larger studies of the effectiveness of liraglutide and the addition of liraglutide to insulin therapy. ^6,8,12,13 Liraglutide has been shown to decrease HbA_1c levels, lower rates of progression of kidney failure, decrease weight, and provide cardiovascular benefit.

In a prospective, randomized controlled trial evaluating the effect of adding liraglutide to insulin therapy, 21 of the 37 patients who had T2DM and required more than 100 total units of basal-bolus insulin daily were initiated on liraglutide, and changes in HbA_1c level, body weight, and glycemic variability were compared. Results showed statistically significant improvement in all 3 outcomes in the group treated with liraglutide.⁶ Our findings, in conjunction with those of the larger studies, suggest that many of these results are generalizable to our local veteran population. Importantly, liraglutide was successfully started in pharmacy clinics—an indication that this treatment need not be initiated by an endocrine specialist.

Limitations

Given the lack of gender and racial diversity in this study population, our findings have limited generalizability to other populations. It is possible that, with a larger sample size, these results regarding reduced basal insulin doses would be significant. It has been hypothesized that patients experience fewer episodes of hypoglycemia when insulin doses are reduced, but we were unable to measure the frequency of these episodes. Other study limitations include inability to assess adherence and inability to account for concurrent regimens and/or for lifestyle changes that may have been made during the study period. Further, the study did not collect data on changes made to current DM medication regimens during the study period, and these changes may have influenced outcomes.

Conclusion

Patients who require treatment intensification for insulin-dependent T2DM may benefit from having liraglutide added to their basal-bolus insulin regimen. Liraglutide may prove to be more favorable than bolus insulin when choosing add-on therapy to basal insulin. Benefits include reductions in insulin doses, HbA_1c levels, number of daily injections, and body weight. Therefore, we suggest that empirically reducing basal insulin by 10% to 25% and bolus insulin by 25% to 50% will avoid relative hypoglycemia. Prescribers must keep in mind patient-specific factors when adjusting insulin doses, if these doses are adjusted at all. Follow-up of 2 to 4 weeks is recommended for review of home monitoring of glucose for further insulin adjustments.

This study has important clinical implications. First, the finding of a reduction in HbA_1c levels supports use of liraglutide therapy for HbA_1c reduction in veterans. Second, the number of veterans who were successfully initiated on liraglutide therapy by nonphysician providers indicates that liraglutide can be effectively and safely started in primary care pharmacy clinics, increasing access to the medication.

Diabetes mellitus (DM) was the third most common medical diagnosis in 2016.¹ Uncontrolled DM can lead to cardiovascular disease, nephropathy, neuropathy, and retinopathy. It is estimated that only 52.5% of patients with DM have achieved their goal hemoglobin A_1c (HbA_1c) level. The 2018 American Diabetes Association (ADA) clinical guidelines lack strong recommendations on sequential therapy for patients who have received a diagnosis of type 2 diabetes mellitus (T2DM) and have been unable to achieve their goal HbA_1c level with lifestyle changes and maximum-dose metformin.² Although those guidelines support treatment intensification with a glucagon-like peptide 1 receptor agonist (GLP-1 RA), prescribing patterns for T2DM most commonly include adding insulin to try to control blood glucose and reduce long-term comorbidities.^2,3

Related: 

Insulin therapy is known for its ability to effectively lower blood glucose and HbA_1c levels but comes with many limitations. Mealtime insulin has the highest risk of hypoglycemia, causes significant weight gain, requires several additional injections per day, and additional monitoring of blood glucose.^4,5 The 2018 ADA guidelines state that hypoglycemia is the major limiting factor in the management of insulin-treated T2DM.²

Compared with mealtime insulin, GLP-1 RAs have the benefit of reducing the risk of hypoglycemia, weight gain, and number of daily injections.⁵ In addition, compared with insulin alone, GLP-1 RAs have the advantage of reducing glycemic variability.⁶ These advantages are especially attractive in the treatment of geriatric patients. Given its mechanism of action, liraglutide is expected to have an effect on both fasting and postprandial blood glucose. There are no recommendations on how to empirically reduce the dose of insulin when starting liraglutide.⁷

Background

GLP-1 is an incretin hormone that is secreted in response to meal ingestion. GLP-1 stimulates insulin release, suppresses elevated glucagon levels, and delays gastric emptying. Patients with a DM diagnosis have impaired secretion of GLP-1.⁸

The GLP-1 RA liraglutide was approved by the FDA in January 2010 as a once-daily injection for patients with uncontrolled T2DM despite lifestyle changes and metformin monotherapy. Because of its intermediate half-life, liraglutide has an effect on both fasting and postprandial blood glucose.⁷ GLP-1 RAs are associated with reduced hypoglycemic episodes—an association attributable to the mechanism of action and potentially to improved pancreatic α-cell function.^3,4 In July 2016, results of the LEADER trial showed that liraglutide therapy had a cardiovascular benefit in high-risk patients.⁸ In October 2017, liraglutide was FDAapproved for reducing 3-point major adverse cardiac events.⁷

Xultophy (Novo Nordisk, Plainsboro, NJ) is a fixed-dose medication combining degludec, a long-acting basal insulin analog, with liraglutide. As seen in the DUAL trials, Xultophy was more beneficial in reducing HbA_1c levels than each component alone, and minimized hypoglycemic events, weight gain, and complexity of insulin treatment intensification.^9-11 Therapy that combines basal insulin and a GLP-1 RA may be more effective than either agent as monotherapy and may have a significant impact on cardiovascular risk because of the synergistic vasodilatory, anti-inflammatory, and antioxidant properties of insulin and GLP-1 RA.⁶ In addition, combination therapy offers many benefits over traditional basal and bolus insulin regimens. These benefits include fewer daily injections, additional weight reduction resulting from the reduced insulin requirement, and fewer episodes of hypoglycemia. Reported gastrointestinal adverse effects have been transient and were not augmented when a GLP-1 RA was used in combination with basal insulin.¹¹

Methods

We performed a retrospective chart analysis to quantify the benefit of using liraglutide as an add-on therapy to basal and bolus insulin regimens in veterans treated at VA Boston Healthcare System (VABHS). The analysis evaluated changes in insulin doses and HbA_1c levels when liraglutide was added to these regimens. Patients identified for the study had electronic medication orders for concurrent therapy with liraglutide, insulin glargine, and insulin aspart filled through outpatient VABHS campus pharmacies for at least 3 months between January 2010 and December 2016. Sixty-nine patients who were on basal-bolus insulin for T2DM and who were prescribed liraglutide for treatment intensification were screened for inclusion and exclusion criteria. Data were analyzed at baseline and 3 months after liraglutide treatment.

Study Protocol

The inclusion criteria were patients aged ≥ 18 years, T2DM diagnosis, and therapy with insulin glargine and insulin aspart for at least 3 months before treatment intensi fication with liraglutide. Exclusion criteria were diagnosis of type 1 DM. To accurately quantify mean change in number of insulin units used, the study included patients only if they had been prescribed insulin glargine and insulin aspart before starting liraglutide. All other insulin regimens were excluded. To detect the true change that occurs when liraglutide is added to basal-bolus insulin, the study also excluded patients if they had been previously prescribed another GLP-1 RA. Patients with contraindications to liraglutide, insulin aspart, or insulin glargine were excluded as well. In addition, patients were excluded from the exposed arm if they were injecting < 1.2 mg of liraglutide once daily or if they had been on liraglutide for < 3 months.

Study Outcomes

All 35 patients who met the inclusion and exclusion criteria were included in this retrospective chart review. The primary outcome was determined by changes in HbA_1c level and number of insulin doses 3 months after treatment with liraglutide. For each patient, a chart review was performed to determine the amount of insulin added or reduced during the study period. Data were collected at baseline and 3 months after initiation of liraglutide.

Statistical Analysis

Statistical analyses were performed with SPSS Version 20.0 (IBM, Armonk, NY). Population characteristics and study outcomes with normal distribution were compared using a paired t test and are reported as means with standard deviations. Nonnormally distributed variables (bolus insulin, HbA_1c level) were compared using the nonparametric Wilcoxon rank sum test and are reported as median values with interquartile ranges. Normality was tested with the Shapiro-Wilk test. The primary outcome evaluated was change in number of insulin units used. Secondary outcomes included change in HbA_1c level and change in body weight. A Bonferroni correction for multiple comparisons was used to prevent type I error. Significance at the Bonferroni-corrected level of .01 (.05/5 = .01) is indicated.

Results

Patients were included if they were previously on insulin glargine and insulin aspart before starting liraglutide for treatment intensification. 

As Table 1 indicates, 100% of patients were male, and mean (SD) age was 65.5 (9.3) years. 

Discussion

After 3 months of treatment with liraglutide, patients experienced a significant decrease in HbA_1c levels. Insulin doses also decreased, but this finding was not statistically significant after correcting for multiple testing. These results are similar with those in larger studies of the effectiveness of liraglutide and the addition of liraglutide to insulin therapy. ^6,8,12,13 Liraglutide has been shown to decrease HbA_1c levels, lower rates of progression of kidney failure, decrease weight, and provide cardiovascular benefit.

In a prospective, randomized controlled trial evaluating the effect of adding liraglutide to insulin therapy, 21 of the 37 patients who had T2DM and required more than 100 total units of basal-bolus insulin daily were initiated on liraglutide, and changes in HbA_1c level, body weight, and glycemic variability were compared. Results showed statistically significant improvement in all 3 outcomes in the group treated with liraglutide.⁶ Our findings, in conjunction with those of the larger studies, suggest that many of these results are generalizable to our local veteran population. Importantly, liraglutide was successfully started in pharmacy clinics—an indication that this treatment need not be initiated by an endocrine specialist.

Limitations

Given the lack of gender and racial diversity in this study population, our findings have limited generalizability to other populations. It is possible that, with a larger sample size, these results regarding reduced basal insulin doses would be significant. It has been hypothesized that patients experience fewer episodes of hypoglycemia when insulin doses are reduced, but we were unable to measure the frequency of these episodes. Other study limitations include inability to assess adherence and inability to account for concurrent regimens and/or for lifestyle changes that may have been made during the study period. Further, the study did not collect data on changes made to current DM medication regimens during the study period, and these changes may have influenced outcomes.

Conclusion

Patients who require treatment intensification for insulin-dependent T2DM may benefit from having liraglutide added to their basal-bolus insulin regimen. Liraglutide may prove to be more favorable than bolus insulin when choosing add-on therapy to basal insulin. Benefits include reductions in insulin doses, HbA_1c levels, number of daily injections, and body weight. Therefore, we suggest that empirically reducing basal insulin by 10% to 25% and bolus insulin by 25% to 50% will avoid relative hypoglycemia. Prescribers must keep in mind patient-specific factors when adjusting insulin doses, if these doses are adjusted at all. Follow-up of 2 to 4 weeks is recommended for review of home monitoring of glucose for further insulin adjustments.

This study has important clinical implications. First, the finding of a reduction in HbA_1c levels supports use of liraglutide therapy for HbA_1c reduction in veterans. Second, the number of veterans who were successfully initiated on liraglutide therapy by nonphysician providers indicates that liraglutide can be effectively and safely started in primary care pharmacy clinics, increasing access to the medication.

Diabetes mellitus (DM) was the third most common medical diagnosis in 2016.¹ Uncontrolled DM can lead to cardiovascular disease, nephropathy, neuropathy, and retinopathy. It is estimated that only 52.5% of patients with DM have achieved their goal hemoglobin A_1c (HbA_1c) level. The 2018 American Diabetes Association (ADA) clinical guidelines lack strong recommendations on sequential therapy for patients who have received a diagnosis of type 2 diabetes mellitus (T2DM) and have been unable to achieve their goal HbA_1c level with lifestyle changes and maximum-dose metformin.² Although those guidelines support treatment intensification with a glucagon-like peptide 1 receptor agonist (GLP-1 RA), prescribing patterns for T2DM most commonly include adding insulin to try to control blood glucose and reduce long-term comorbidities.^2,3

Related: 

Insulin therapy is known for its ability to effectively lower blood glucose and HbA_1c levels but comes with many limitations. Mealtime insulin has the highest risk of hypoglycemia, causes significant weight gain, requires several additional injections per day, and additional monitoring of blood glucose.^4,5 The 2018 ADA guidelines state that hypoglycemia is the major limiting factor in the management of insulin-treated T2DM.²

Compared with mealtime insulin, GLP-1 RAs have the benefit of reducing the risk of hypoglycemia, weight gain, and number of daily injections.⁵ In addition, compared with insulin alone, GLP-1 RAs have the advantage of reducing glycemic variability.⁶ These advantages are especially attractive in the treatment of geriatric patients. Given its mechanism of action, liraglutide is expected to have an effect on both fasting and postprandial blood glucose. There are no recommendations on how to empirically reduce the dose of insulin when starting liraglutide.⁷

Background

GLP-1 is an incretin hormone that is secreted in response to meal ingestion. GLP-1 stimulates insulin release, suppresses elevated glucagon levels, and delays gastric emptying. Patients with a DM diagnosis have impaired secretion of GLP-1.⁸

The GLP-1 RA liraglutide was approved by the FDA in January 2010 as a once-daily injection for patients with uncontrolled T2DM despite lifestyle changes and metformin monotherapy. Because of its intermediate half-life, liraglutide has an effect on both fasting and postprandial blood glucose.⁷ GLP-1 RAs are associated with reduced hypoglycemic episodes—an association attributable to the mechanism of action and potentially to improved pancreatic α-cell function.^3,4 In July 2016, results of the LEADER trial showed that liraglutide therapy had a cardiovascular benefit in high-risk patients.⁸ In October 2017, liraglutide was FDAapproved for reducing 3-point major adverse cardiac events.⁷

Xultophy (Novo Nordisk, Plainsboro, NJ) is a fixed-dose medication combining degludec, a long-acting basal insulin analog, with liraglutide. As seen in the DUAL trials, Xultophy was more beneficial in reducing HbA_1c levels than each component alone, and minimized hypoglycemic events, weight gain, and complexity of insulin treatment intensification.^9-11 Therapy that combines basal insulin and a GLP-1 RA may be more effective than either agent as monotherapy and may have a significant impact on cardiovascular risk because of the synergistic vasodilatory, anti-inflammatory, and antioxidant properties of insulin and GLP-1 RA.⁶ In addition, combination therapy offers many benefits over traditional basal and bolus insulin regimens. These benefits include fewer daily injections, additional weight reduction resulting from the reduced insulin requirement, and fewer episodes of hypoglycemia. Reported gastrointestinal adverse effects have been transient and were not augmented when a GLP-1 RA was used in combination with basal insulin.¹¹

Methods

We performed a retrospective chart analysis to quantify the benefit of using liraglutide as an add-on therapy to basal and bolus insulin regimens in veterans treated at VA Boston Healthcare System (VABHS). The analysis evaluated changes in insulin doses and HbA_1c levels when liraglutide was added to these regimens. Patients identified for the study had electronic medication orders for concurrent therapy with liraglutide, insulin glargine, and insulin aspart filled through outpatient VABHS campus pharmacies for at least 3 months between January 2010 and December 2016. Sixty-nine patients who were on basal-bolus insulin for T2DM and who were prescribed liraglutide for treatment intensification were screened for inclusion and exclusion criteria. Data were analyzed at baseline and 3 months after liraglutide treatment.

Study Protocol

The inclusion criteria were patients aged ≥ 18 years, T2DM diagnosis, and therapy with insulin glargine and insulin aspart for at least 3 months before treatment intensi fication with liraglutide. Exclusion criteria were diagnosis of type 1 DM. To accurately quantify mean change in number of insulin units used, the study included patients only if they had been prescribed insulin glargine and insulin aspart before starting liraglutide. All other insulin regimens were excluded. To detect the true change that occurs when liraglutide is added to basal-bolus insulin, the study also excluded patients if they had been previously prescribed another GLP-1 RA. Patients with contraindications to liraglutide, insulin aspart, or insulin glargine were excluded as well. In addition, patients were excluded from the exposed arm if they were injecting < 1.2 mg of liraglutide once daily or if they had been on liraglutide for < 3 months.

Study Outcomes

All 35 patients who met the inclusion and exclusion criteria were included in this retrospective chart review. The primary outcome was determined by changes in HbA_1c level and number of insulin doses 3 months after treatment with liraglutide. For each patient, a chart review was performed to determine the amount of insulin added or reduced during the study period. Data were collected at baseline and 3 months after initiation of liraglutide.

Statistical Analysis

Statistical analyses were performed with SPSS Version 20.0 (IBM, Armonk, NY). Population characteristics and study outcomes with normal distribution were compared using a paired t test and are reported as means with standard deviations. Nonnormally distributed variables (bolus insulin, HbA_1c level) were compared using the nonparametric Wilcoxon rank sum test and are reported as median values with interquartile ranges. Normality was tested with the Shapiro-Wilk test. The primary outcome evaluated was change in number of insulin units used. Secondary outcomes included change in HbA_1c level and change in body weight. A Bonferroni correction for multiple comparisons was used to prevent type I error. Significance at the Bonferroni-corrected level of .01 (.05/5 = .01) is indicated.

Results

Patients were included if they were previously on insulin glargine and insulin aspart before starting liraglutide for treatment intensification. 

As Table 1 indicates, 100% of patients were male, and mean (SD) age was 65.5 (9.3) years. 

Discussion

After 3 months of treatment with liraglutide, patients experienced a significant decrease in HbA_1c levels. Insulin doses also decreased, but this finding was not statistically significant after correcting for multiple testing. These results are similar with those in larger studies of the effectiveness of liraglutide and the addition of liraglutide to insulin therapy. ^6,8,12,13 Liraglutide has been shown to decrease HbA_1c levels, lower rates of progression of kidney failure, decrease weight, and provide cardiovascular benefit.

In a prospective, randomized controlled trial evaluating the effect of adding liraglutide to insulin therapy, 21 of the 37 patients who had T2DM and required more than 100 total units of basal-bolus insulin daily were initiated on liraglutide, and changes in HbA_1c level, body weight, and glycemic variability were compared. Results showed statistically significant improvement in all 3 outcomes in the group treated with liraglutide.⁶ Our findings, in conjunction with those of the larger studies, suggest that many of these results are generalizable to our local veteran population. Importantly, liraglutide was successfully started in pharmacy clinics—an indication that this treatment need not be initiated by an endocrine specialist.

Limitations

Given the lack of gender and racial diversity in this study population, our findings have limited generalizability to other populations. It is possible that, with a larger sample size, these results regarding reduced basal insulin doses would be significant. It has been hypothesized that patients experience fewer episodes of hypoglycemia when insulin doses are reduced, but we were unable to measure the frequency of these episodes. Other study limitations include inability to assess adherence and inability to account for concurrent regimens and/or for lifestyle changes that may have been made during the study period. Further, the study did not collect data on changes made to current DM medication regimens during the study period, and these changes may have influenced outcomes.

Conclusion

Patients who require treatment intensification for insulin-dependent T2DM may benefit from having liraglutide added to their basal-bolus insulin regimen. Liraglutide may prove to be more favorable than bolus insulin when choosing add-on therapy to basal insulin. Benefits include reductions in insulin doses, HbA_1c levels, number of daily injections, and body weight. Therefore, we suggest that empirically reducing basal insulin by 10% to 25% and bolus insulin by 25% to 50% will avoid relative hypoglycemia. Prescribers must keep in mind patient-specific factors when adjusting insulin doses, if these doses are adjusted at all. Follow-up of 2 to 4 weeks is recommended for review of home monitoring of glucose for further insulin adjustments.

This study has important clinical implications. First, the finding of a reduction in HbA_1c levels supports use of liraglutide therapy for HbA_1c reduction in veterans. Second, the number of veterans who were successfully initiated on liraglutide therapy by nonphysician providers indicates that liraglutide can be effectively and safely started in primary care pharmacy clinics, increasing access to the medication.

Health care providers face many challenges in utilizing cardiovascular therapies, such as anticipated shortages in physicians, patients with more complicated conditions, shifting medication regimens, management needs, and increased accountability for quality and performance measures.¹ To meet the potential increase in service demand, cardiology practices are embracing cardiovascular team-based care.¹ Advanced practice providers, such as advanced practice registered nurses (APRNs), physician assistants (PAs), and clinical pharmacy specialists (CPSs), have education, training, and experience to extend the team’s capability to meet these complex management needs.¹

The role of CPSs within a cardiovascular care team includes providing a variety of patient-specific services, such as collaborating with other cardiology providers, to optimize evidence-based pharmacotherapy, preventing medication-related adverse events/errors, improving patient understanding of their medication regimen, and ultimately, improving patient outcomes.² Health care systems, such as Kaiser Permanente of Colorado, have demonstrated improved clinical outcomes for patients with coronary artery disease (CAD) by implementing a multidisciplinary collaborative cardiac care service, including a clinical pharmacy cardiac risk service, in which CPSs assisted with management of cholesterol-lowering, hypertension, diabetes mellitus (DM), and smoking-cessation therapies, which resulted in a 76% to 89% reduction in all-cause mortality associated with CAD in multiple evaluations.^3,4

Pharmacists providing medication therapy management (MTM) services in Minnesota had higher goal attainment for patients with hypertension and hyperlipidemia than did pharmacists who did not provide MTM services.⁵ MTM services provided by pharmacists led to an improvement in clinical outcomes for patients as well as a reduction in overall health care expenditures compared with that of a control group of patients who did not receive MTM services.⁵ Furthermore, CPS integration in the heart failure (HF) setting has led to improvements in utilization and optimization of guideline-directed medical therapies, an area in which recent data have suggested deficiencies exist.^6-8 A full review of the outcomes associated with CPS involvement in cardiovascular care is beyond the scope of this article; but the recent review by Dunn and colleagues provides more detail.²

With the increasing number of patients with cardiovascular disease,expanding integration of CPSs in the cardiovascular team providing MTM services may reduce the burden of other providers (MD, PA, APRN, etc), thereby increasing access for not only new patients, but also diagnostic and interventional work, while potentially improving clinical and economic outcomes.² The value of integrating CPSs as members of the cardiovascular care team is recognized in a variety of inpatient and ambulatory practice settings.^2-6 However, data are limited on the number and types of interventions made per encounter as direct patient care providers. Expanded granularity regarding the effect of CPSs as active members of the cardiovascular team is an essential component to evaluate the potential benefit of CPS integration into direct patient care.

Methods

The West Palm Beach (WPB) Veteran Affairs Medical Center (VAMC) outpatient cardiology clinic consists of 6 full-time employee (FTE) cardiologists, 4 PAs or APRNs, 10 other cardiology health care staff members (registered/license practical nurses and technicians), and 2 cardiology CPSs providing direct patient care and, cumulatively, 1 clinic-assigned clinical pharmacy FTE. The cardiology CPSs provide comprehensive MTM based on patient-specific needs in an ambulatory cardiology pharmacotherapy clinic.

The cardiology pharmacotherapy clinic is open 20.5 hours per week with 41 appointment slots (30 minutes each), of which 7 appointments are delivered via clinic video telehealth and 34 appointments are traditional face-to-face visits.⁹ The remaining CPS time is assigned to other clinical care and administrative areas to fit facility need, including oversight of the CPS-run 24-hour ambulatory blood pressure clinic, postgraduate year 2 cardiology pharmacy practice residency program directorship, and other administrative activities for the facility.¹⁰

The cardiology CPSs practice under an advanced scope of practice in which they independently manage medications (initiate, modify, discontinue), order diagnostic testing (laboratory, monitoring, imaging, etc) needed for medication management, and create monitoring and treatment plans for patients referred to the cardiology pharmacotherapy clinic by other cardiology providers. The diseases managed within the clinic vary based on patient-specific needs, but may include HF, dyslipidemia, hypertension, anticoagulation, CAD, arrhythmias, cardiovascular risk factor assessment and reduction, and medication reconciliation and teaching. Patients are referred for CPS management directly from facility cardiologist and cardiology clinic PAs and APRNs. Workload and interventions carried out are captured in the Pharmacists Achieve Results with Medications Demonstration (PhARMD) tool and patient care encounter tracking.⁹

Data Collection

Using local data from workload tracking, the number of CPS encounters was determined from July 6, 2015, to October 1, 2015. Data were collected on the types and volume of interventions made by CPSs in the cardiology pharmacotherapy clinic using the PhARMD tool (Figure). 

The PhARMD tool was initially developed and implemented for CPSs in primary care pharmacotherapy clinics and was used to evaluate the types and volume of CPS interventions made in this setting.¹¹ Since this initial evaluation, the tool has been updated, standardized nationally by the Department of Veterans Affairs (VA) Pharmacy Benefits Management Clinical Pharmacy Practice Office, and integrated across numerous VAMCs and associated outpatient clinics. The tool remains embedded within the VA electronic health record (EHR) and allows the capture of specific CPS interventions of several types (ie, both pharmacologic and nonpharmacologic interventions, including adjust dose or frequency; change or discontinue medication; initiate medication; monitor medication; counsel on adherence, contraindications, drug interactions, and drugs not indicated; reconcile medication; and prevent or manage adverse drug events [ADEs]) specific to certain diseases, such as anemia, anticoagulation, HF, type 2 DM (T2DM), hypertension, dyslipidemia, and tobacco cessation.

Given that the interventions captured by the PhARMD tool are based on self-report of the CPS performing the intervention, a quality assurance (QA) measure was taken to audit a random sample of interventions to validate the accuracy of reported data. A Pharmacy Benefits Management PhARMD Project QA report provided the 20% random sample of encounters for each cardiology CPS to be reviewed. This percentage was determined by VAMC Clinical Pharmacy Program Office (CPPO) directives on implementation of the PhARMD tool. During the QA period, the provided sample was reviewed to determine whether the intervention(s) recorded with the PhARMD tool matched the actions documented in the EHR. The QA review was done through a manual chart review by an author not involved in recording the original interventions. Both WPB VAMC cardiology CPSs passed the QA review (> 80% concurrence with tool logged and chart documented interventions as required by VA CPPO directive), with a 90.9% concurrence between the EHR and PhARMD tool documentation.

Statistical Analyses

Data on intervention type and encounter number were evaluated with descriptive statistics. The information was characterized and diagrammed with Excel (Microsoft, Redmond, WA) charts and graphs.

Cost-avoidance calculations were done using previously described methods and are included for exploratory analysis.^11,12 Briefly, published estimates of cost avoidance associated with various interventions from the outpatient setting within a VAMC setting were applied as appropriate to the various interventions captured with the PhARMD tool.^11,12 These estimates from Lee and colleagues were derived from detailed chart review of interventions made and the potential harm prevented.¹² Costs or cost avoidances associated with interventions were calculated from pooled examination of 600 interventions in a VAMC with drug costs before and after the intervention, costs associated with harms prevented by the intervention, as well as the VAMC hourly pharmacist wages associated with making an intervention and processing and filling original vs recommended therapies.

The costs presented represent a “best-case” scenario in which all interventions made are expected to prevent patient harms. The costs related to avoided outcomes, facility overhead, and auxiliary staff cannot be included but highlight the many considerations that must be considered when examining potential cost-avoidance calculations. The estimates and methods at hand were chosen because, to our knowledge, no other consensus model exists that would be more appropriate for use in the situation and health care system at hand. Cost-avoidance estimates were calculated by extrapolating the 88-day study period values to a yearly estimate. All cost estimates were adjusted for inflation using the consumer price index calculator as per convention in previous analyses using the cost-avoidance estimates at hand.^11-13

Results

From July 6, 2015, through October 1, 2015, 301 patient encounters occurred, and 529 interventions were documented with the PhARMD tool. The mean number of interventions per encounter was 1.8. Interventions were 65.2% pharmacologic and 34.8% nonpharmacologic. Of pharmacologic interventions, 27.1% were for HF, 12.7% for hypertension, 8.8% for dyslipidemia, 2.8% for anticoagulation, 1.4% for tobacco cessation, 1.1% for T2DM, 0.3% for anemia, and 45.8% for other conditions (Table 1). 

The main types of pharmacologic interventions across all diseases were related to adjustments in medication dose or frequency (42.3%) and change or discontinuation of medications (20.0%). 

Discussion

Evaluation of the interventions and encounters at the WPB VAMC ambulatory cardiology pharmacotherapy clinic suggests that CPSs are able to contribute to direct patient care independently of interventions performed by other cardiology providers. Specifically, 1.8 interventions per encounter were made by CPSs in this study. In a prior evaluation of CPS interventions recorded with the PhARMD tool in a VAMC primary care setting, 2.3 interventions per encounter were recorded.¹¹ In comparing the present volume of interventions with the volume recorded in the study by Hough and colleagues, the difference in practice setting may account for differences seen.¹¹

The primary care medication management setting would capture a broader array of clinical interventions than would the ambulatory cardiology clinic of the present study, so it is reasonable that more interventions would be captured per encounter in the primary care clinic. The difference in practice settings affecting the character of collected interventions can be seen because most interventions in this study at an ambulatory cardiology clinic were related to HF, whereas in Hough and colleagues 39.2% of the disease-specific interventions were related to DM, and only 2.9% were related to HF.¹¹ The differences inherent in the intervention populations can also be seen by comparing the percentage of interventions related to hypertension and dyslipidemia: 30% and 28% in the study by Hough and colleagues compared with 13% and 9%, respectively, in the present study.¹¹

Comparison of the present evaluation and Hough and colleagues is also hindered by the PhARMD tool used. The PhARMD tool used in the initial evaluation has been modified on a national level to improve the granularity of intervention data collected. This modification limits functional comparisons between the evaluations at hand, although the current form of the PhARMD tool allows for better understanding of the interventions made by CPSs going forward and within different practice settings. The PhARMD tool is periodically updated nationally based on clinical practice changes or updates and clinical/administrative need of the tool.

Our cost-avoidance estimate of $433,324.06 per year seems lower than that estimated in the previous evaluation when all applicable interventions were included.¹¹ However, this study had several differences compared with those of previous VAMC studies looking at clinical interventions performed by CPSs. The main differences are the volume and setting in which interventions were being made. For example, in comparison with Hough and colleagues, the studies include different practice settings (primary care vs cardiology specialty clinic) and number of FTEs involved in the study (4.65 vs 1). If the cost avoidance is distributed evenly per FTE in the previous study, the following calculation is observed: $649,551.99 per FTE, which is closer to this study’s estimation. Given that primary care is a broader setting than is ambulatory cardiology, it is not surprising that more types of interventions and the overall volume/absolute number of interventions would be higher. Thus, the lower estimated cost avoidance in our study may be attributed to the lower volume of intervention opportunities availed to the cardiology CPS. Another difference is that detailed types of interventions related to hypertension, DM, dyslipidemia, and HF were not included in Hough and colleagues, whereas our study included all applicable interventions regardless of relation to diseases, which may account for a degree of the variation in intervention breakdown between the 2 studies.¹¹ However, as noted previously, some interventions for these particular diseases may not fully capture the rationale for pharmacotherapy interventions, such as drug dose changes or discontinuations, which may misrepresent the potential cost avoidance associated with them in reality.

Limitations

Of general importance, the PhARMD tool may underestimate the number of interventions made such that multiple interventions for a medical condition may have been completed but only captured as 1 intervention, which may represent a limitation of the tool when multiple interventions are made for the same disease (eg, titration of both β-blocker and angiotensin-converting enzyme inhibitor doses at a single appointment in a patient with HF with reduced left ventricular ejection fraction). Improved clarity about interventions made would require laborious chart review, which was not feasible. The evaluation at hand included a preliminary QA review, adding confidence that overdocumentation was not being done and the values represented at worst an underestimation of actual CPS intervention impact. Because this study was an initial evaluation of interventions made by CPSs in an ambulatory cardiology pharmacotherapy setting, whether these same outcomes would exist in other patient cohorts is unclear. However, these data do provide a foundational understanding of what may be expected from CPS integration into a cardiovascular care team.

These findings may be limited in generalizability to other health care systems and situations in which CPSs are afforded the regulatory opportunity to practice independently within an established scope of practice or collaborative practice agreements. The Veterans Health Administration system has been a leader in integrating CPSs into direct patient care roles and serves as a potential model for application by other groups. This evaluation’s data support continued efforts to create such independent practice environments as they allow for qualified CPSs to practice to their full clinical potential and have the fullest possible effect on cardiovascular outcomes.

Previous studies looking at cost savings in MTM programs have established a substantial return in economic investment with patients being managed by pharmacists.^5,14 Given that the interventions made in this study were not tied to attainment of clinical outcomes, a limitation to our study, the cost-avoidance estimates should be interpreted cautiously. However, we know of no such tool that is available to allow accurate capture of clinical event reduction in a single center with consistent CPS involvement in care. A clear opportunity exists regarding design of a model that measures clinical, economic, and humanistic outcomes related to the interventions performed by cardiology CPSs, but developing and deploying such a model may be challenging because guideline-directed medical therapies vary significantly based on many patient-specific issues, and identifying optimal or truly optimized medical therapy is at times a subjective task, especially in a single center. Using the types and volumes of interventions made by CPSs as a surrogate for these higher-level outcomes is still of value in order to understand the effect and role of CPSs in cardiovascular care. At present, the cost-avoidance estimates presented in this evaluation are based on the most appropriate system-specific data at hand, with the realization that actual cost avoidance in practice may vary widely and should be the topic of future research.

Conclusion

As cardiovascular team-based care continues to expand with the support of large organizations, such as the American College of Cardiology Foundation, Heart Failure Society of America, and American College of Clinical Pharmacy Cardiology Practice and Research Network, the need for understanding the effect of CPSs on patient care measures and health care costs becomes more pronounced.^2,15 The results of this study demonstrate how integration of CPSs in an ambulatory cardiology clinic may translate to cost avoidance and a reduction in workload burden for cardiology physicians and providers, allowing more availability for diagnostic testing and care.

Interventions made by CPSs functioning as independent providers delivering comprehensive MTM services within an interdisciplinary ambulatory cardiology clinic have a potential positive effect on patient care and cost avoidance.

Health care providers face many challenges in utilizing cardiovascular therapies, such as anticipated shortages in physicians, patients with more complicated conditions, shifting medication regimens, management needs, and increased accountability for quality and performance measures.¹ To meet the potential increase in service demand, cardiology practices are embracing cardiovascular team-based care.¹ Advanced practice providers, such as advanced practice registered nurses (APRNs), physician assistants (PAs), and clinical pharmacy specialists (CPSs), have education, training, and experience to extend the team’s capability to meet these complex management needs.¹

The role of CPSs within a cardiovascular care team includes providing a variety of patient-specific services, such as collaborating with other cardiology providers, to optimize evidence-based pharmacotherapy, preventing medication-related adverse events/errors, improving patient understanding of their medication regimen, and ultimately, improving patient outcomes.² Health care systems, such as Kaiser Permanente of Colorado, have demonstrated improved clinical outcomes for patients with coronary artery disease (CAD) by implementing a multidisciplinary collaborative cardiac care service, including a clinical pharmacy cardiac risk service, in which CPSs assisted with management of cholesterol-lowering, hypertension, diabetes mellitus (DM), and smoking-cessation therapies, which resulted in a 76% to 89% reduction in all-cause mortality associated with CAD in multiple evaluations.^3,4

Pharmacists providing medication therapy management (MTM) services in Minnesota had higher goal attainment for patients with hypertension and hyperlipidemia than did pharmacists who did not provide MTM services.⁵ MTM services provided by pharmacists led to an improvement in clinical outcomes for patients as well as a reduction in overall health care expenditures compared with that of a control group of patients who did not receive MTM services.⁵ Furthermore, CPS integration in the heart failure (HF) setting has led to improvements in utilization and optimization of guideline-directed medical therapies, an area in which recent data have suggested deficiencies exist.^6-8 A full review of the outcomes associated with CPS involvement in cardiovascular care is beyond the scope of this article; but the recent review by Dunn and colleagues provides more detail.²

With the increasing number of patients with cardiovascular disease,expanding integration of CPSs in the cardiovascular team providing MTM services may reduce the burden of other providers (MD, PA, APRN, etc), thereby increasing access for not only new patients, but also diagnostic and interventional work, while potentially improving clinical and economic outcomes.² The value of integrating CPSs as members of the cardiovascular care team is recognized in a variety of inpatient and ambulatory practice settings.^2-6 However, data are limited on the number and types of interventions made per encounter as direct patient care providers. Expanded granularity regarding the effect of CPSs as active members of the cardiovascular team is an essential component to evaluate the potential benefit of CPS integration into direct patient care.

Methods

The West Palm Beach (WPB) Veteran Affairs Medical Center (VAMC) outpatient cardiology clinic consists of 6 full-time employee (FTE) cardiologists, 4 PAs or APRNs, 10 other cardiology health care staff members (registered/license practical nurses and technicians), and 2 cardiology CPSs providing direct patient care and, cumulatively, 1 clinic-assigned clinical pharmacy FTE. The cardiology CPSs provide comprehensive MTM based on patient-specific needs in an ambulatory cardiology pharmacotherapy clinic.

The cardiology pharmacotherapy clinic is open 20.5 hours per week with 41 appointment slots (30 minutes each), of which 7 appointments are delivered via clinic video telehealth and 34 appointments are traditional face-to-face visits.⁹ The remaining CPS time is assigned to other clinical care and administrative areas to fit facility need, including oversight of the CPS-run 24-hour ambulatory blood pressure clinic, postgraduate year 2 cardiology pharmacy practice residency program directorship, and other administrative activities for the facility.¹⁰

The cardiology CPSs practice under an advanced scope of practice in which they independently manage medications (initiate, modify, discontinue), order diagnostic testing (laboratory, monitoring, imaging, etc) needed for medication management, and create monitoring and treatment plans for patients referred to the cardiology pharmacotherapy clinic by other cardiology providers. The diseases managed within the clinic vary based on patient-specific needs, but may include HF, dyslipidemia, hypertension, anticoagulation, CAD, arrhythmias, cardiovascular risk factor assessment and reduction, and medication reconciliation and teaching. Patients are referred for CPS management directly from facility cardiologist and cardiology clinic PAs and APRNs. Workload and interventions carried out are captured in the Pharmacists Achieve Results with Medications Demonstration (PhARMD) tool and patient care encounter tracking.⁹

Data Collection

Using local data from workload tracking, the number of CPS encounters was determined from July 6, 2015, to October 1, 2015. Data were collected on the types and volume of interventions made by CPSs in the cardiology pharmacotherapy clinic using the PhARMD tool (Figure). 

The PhARMD tool was initially developed and implemented for CPSs in primary care pharmacotherapy clinics and was used to evaluate the types and volume of CPS interventions made in this setting.¹¹ Since this initial evaluation, the tool has been updated, standardized nationally by the Department of Veterans Affairs (VA) Pharmacy Benefits Management Clinical Pharmacy Practice Office, and integrated across numerous VAMCs and associated outpatient clinics. The tool remains embedded within the VA electronic health record (EHR) and allows the capture of specific CPS interventions of several types (ie, both pharmacologic and nonpharmacologic interventions, including adjust dose or frequency; change or discontinue medication; initiate medication; monitor medication; counsel on adherence, contraindications, drug interactions, and drugs not indicated; reconcile medication; and prevent or manage adverse drug events [ADEs]) specific to certain diseases, such as anemia, anticoagulation, HF, type 2 DM (T2DM), hypertension, dyslipidemia, and tobacco cessation.

Given that the interventions captured by the PhARMD tool are based on self-report of the CPS performing the intervention, a quality assurance (QA) measure was taken to audit a random sample of interventions to validate the accuracy of reported data. A Pharmacy Benefits Management PhARMD Project QA report provided the 20% random sample of encounters for each cardiology CPS to be reviewed. This percentage was determined by VAMC Clinical Pharmacy Program Office (CPPO) directives on implementation of the PhARMD tool. During the QA period, the provided sample was reviewed to determine whether the intervention(s) recorded with the PhARMD tool matched the actions documented in the EHR. The QA review was done through a manual chart review by an author not involved in recording the original interventions. Both WPB VAMC cardiology CPSs passed the QA review (> 80% concurrence with tool logged and chart documented interventions as required by VA CPPO directive), with a 90.9% concurrence between the EHR and PhARMD tool documentation.

Statistical Analyses

Data on intervention type and encounter number were evaluated with descriptive statistics. The information was characterized and diagrammed with Excel (Microsoft, Redmond, WA) charts and graphs.

Cost-avoidance calculations were done using previously described methods and are included for exploratory analysis.^11,12 Briefly, published estimates of cost avoidance associated with various interventions from the outpatient setting within a VAMC setting were applied as appropriate to the various interventions captured with the PhARMD tool.^11,12 These estimates from Lee and colleagues were derived from detailed chart review of interventions made and the potential harm prevented.¹² Costs or cost avoidances associated with interventions were calculated from pooled examination of 600 interventions in a VAMC with drug costs before and after the intervention, costs associated with harms prevented by the intervention, as well as the VAMC hourly pharmacist wages associated with making an intervention and processing and filling original vs recommended therapies.

The costs presented represent a “best-case” scenario in which all interventions made are expected to prevent patient harms. The costs related to avoided outcomes, facility overhead, and auxiliary staff cannot be included but highlight the many considerations that must be considered when examining potential cost-avoidance calculations. The estimates and methods at hand were chosen because, to our knowledge, no other consensus model exists that would be more appropriate for use in the situation and health care system at hand. Cost-avoidance estimates were calculated by extrapolating the 88-day study period values to a yearly estimate. All cost estimates were adjusted for inflation using the consumer price index calculator as per convention in previous analyses using the cost-avoidance estimates at hand.^11-13

Results

From July 6, 2015, through October 1, 2015, 301 patient encounters occurred, and 529 interventions were documented with the PhARMD tool. The mean number of interventions per encounter was 1.8. Interventions were 65.2% pharmacologic and 34.8% nonpharmacologic. Of pharmacologic interventions, 27.1% were for HF, 12.7% for hypertension, 8.8% for dyslipidemia, 2.8% for anticoagulation, 1.4% for tobacco cessation, 1.1% for T2DM, 0.3% for anemia, and 45.8% for other conditions (Table 1). 

The main types of pharmacologic interventions across all diseases were related to adjustments in medication dose or frequency (42.3%) and change or discontinuation of medications (20.0%). 

Discussion

Evaluation of the interventions and encounters at the WPB VAMC ambulatory cardiology pharmacotherapy clinic suggests that CPSs are able to contribute to direct patient care independently of interventions performed by other cardiology providers. Specifically, 1.8 interventions per encounter were made by CPSs in this study. In a prior evaluation of CPS interventions recorded with the PhARMD tool in a VAMC primary care setting, 2.3 interventions per encounter were recorded.¹¹ In comparing the present volume of interventions with the volume recorded in the study by Hough and colleagues, the difference in practice setting may account for differences seen.¹¹

The primary care medication management setting would capture a broader array of clinical interventions than would the ambulatory cardiology clinic of the present study, so it is reasonable that more interventions would be captured per encounter in the primary care clinic. The difference in practice settings affecting the character of collected interventions can be seen because most interventions in this study at an ambulatory cardiology clinic were related to HF, whereas in Hough and colleagues 39.2% of the disease-specific interventions were related to DM, and only 2.9% were related to HF.¹¹ The differences inherent in the intervention populations can also be seen by comparing the percentage of interventions related to hypertension and dyslipidemia: 30% and 28% in the study by Hough and colleagues compared with 13% and 9%, respectively, in the present study.¹¹

Comparison of the present evaluation and Hough and colleagues is also hindered by the PhARMD tool used. The PhARMD tool used in the initial evaluation has been modified on a national level to improve the granularity of intervention data collected. This modification limits functional comparisons between the evaluations at hand, although the current form of the PhARMD tool allows for better understanding of the interventions made by CPSs going forward and within different practice settings. The PhARMD tool is periodically updated nationally based on clinical practice changes or updates and clinical/administrative need of the tool.

Our cost-avoidance estimate of $433,324.06 per year seems lower than that estimated in the previous evaluation when all applicable interventions were included.¹¹ However, this study had several differences compared with those of previous VAMC studies looking at clinical interventions performed by CPSs. The main differences are the volume and setting in which interventions were being made. For example, in comparison with Hough and colleagues, the studies include different practice settings (primary care vs cardiology specialty clinic) and number of FTEs involved in the study (4.65 vs 1). If the cost avoidance is distributed evenly per FTE in the previous study, the following calculation is observed: $649,551.99 per FTE, which is closer to this study’s estimation. Given that primary care is a broader setting than is ambulatory cardiology, it is not surprising that more types of interventions and the overall volume/absolute number of interventions would be higher. Thus, the lower estimated cost avoidance in our study may be attributed to the lower volume of intervention opportunities availed to the cardiology CPS. Another difference is that detailed types of interventions related to hypertension, DM, dyslipidemia, and HF were not included in Hough and colleagues, whereas our study included all applicable interventions regardless of relation to diseases, which may account for a degree of the variation in intervention breakdown between the 2 studies.¹¹ However, as noted previously, some interventions for these particular diseases may not fully capture the rationale for pharmacotherapy interventions, such as drug dose changes or discontinuations, which may misrepresent the potential cost avoidance associated with them in reality.

Limitations

Of general importance, the PhARMD tool may underestimate the number of interventions made such that multiple interventions for a medical condition may have been completed but only captured as 1 intervention, which may represent a limitation of the tool when multiple interventions are made for the same disease (eg, titration of both β-blocker and angiotensin-converting enzyme inhibitor doses at a single appointment in a patient with HF with reduced left ventricular ejection fraction). Improved clarity about interventions made would require laborious chart review, which was not feasible. The evaluation at hand included a preliminary QA review, adding confidence that overdocumentation was not being done and the values represented at worst an underestimation of actual CPS intervention impact. Because this study was an initial evaluation of interventions made by CPSs in an ambulatory cardiology pharmacotherapy setting, whether these same outcomes would exist in other patient cohorts is unclear. However, these data do provide a foundational understanding of what may be expected from CPS integration into a cardiovascular care team.

These findings may be limited in generalizability to other health care systems and situations in which CPSs are afforded the regulatory opportunity to practice independently within an established scope of practice or collaborative practice agreements. The Veterans Health Administration system has been a leader in integrating CPSs into direct patient care roles and serves as a potential model for application by other groups. This evaluation’s data support continued efforts to create such independent practice environments as they allow for qualified CPSs to practice to their full clinical potential and have the fullest possible effect on cardiovascular outcomes.

Previous studies looking at cost savings in MTM programs have established a substantial return in economic investment with patients being managed by pharmacists.^5,14 Given that the interventions made in this study were not tied to attainment of clinical outcomes, a limitation to our study, the cost-avoidance estimates should be interpreted cautiously. However, we know of no such tool that is available to allow accurate capture of clinical event reduction in a single center with consistent CPS involvement in care. A clear opportunity exists regarding design of a model that measures clinical, economic, and humanistic outcomes related to the interventions performed by cardiology CPSs, but developing and deploying such a model may be challenging because guideline-directed medical therapies vary significantly based on many patient-specific issues, and identifying optimal or truly optimized medical therapy is at times a subjective task, especially in a single center. Using the types and volumes of interventions made by CPSs as a surrogate for these higher-level outcomes is still of value in order to understand the effect and role of CPSs in cardiovascular care. At present, the cost-avoidance estimates presented in this evaluation are based on the most appropriate system-specific data at hand, with the realization that actual cost avoidance in practice may vary widely and should be the topic of future research.

Conclusion

As cardiovascular team-based care continues to expand with the support of large organizations, such as the American College of Cardiology Foundation, Heart Failure Society of America, and American College of Clinical Pharmacy Cardiology Practice and Research Network, the need for understanding the effect of CPSs on patient care measures and health care costs becomes more pronounced.^2,15 The results of this study demonstrate how integration of CPSs in an ambulatory cardiology clinic may translate to cost avoidance and a reduction in workload burden for cardiology physicians and providers, allowing more availability for diagnostic testing and care.

Interventions made by CPSs functioning as independent providers delivering comprehensive MTM services within an interdisciplinary ambulatory cardiology clinic have a potential positive effect on patient care and cost avoidance.

Health care providers face many challenges in utilizing cardiovascular therapies, such as anticipated shortages in physicians, patients with more complicated conditions, shifting medication regimens, management needs, and increased accountability for quality and performance measures.¹ To meet the potential increase in service demand, cardiology practices are embracing cardiovascular team-based care.¹ Advanced practice providers, such as advanced practice registered nurses (APRNs), physician assistants (PAs), and clinical pharmacy specialists (CPSs), have education, training, and experience to extend the team’s capability to meet these complex management needs.¹

The role of CPSs within a cardiovascular care team includes providing a variety of patient-specific services, such as collaborating with other cardiology providers, to optimize evidence-based pharmacotherapy, preventing medication-related adverse events/errors, improving patient understanding of their medication regimen, and ultimately, improving patient outcomes.² Health care systems, such as Kaiser Permanente of Colorado, have demonstrated improved clinical outcomes for patients with coronary artery disease (CAD) by implementing a multidisciplinary collaborative cardiac care service, including a clinical pharmacy cardiac risk service, in which CPSs assisted with management of cholesterol-lowering, hypertension, diabetes mellitus (DM), and smoking-cessation therapies, which resulted in a 76% to 89% reduction in all-cause mortality associated with CAD in multiple evaluations.^3,4

Pharmacists providing medication therapy management (MTM) services in Minnesota had higher goal attainment for patients with hypertension and hyperlipidemia than did pharmacists who did not provide MTM services.⁵ MTM services provided by pharmacists led to an improvement in clinical outcomes for patients as well as a reduction in overall health care expenditures compared with that of a control group of patients who did not receive MTM services.⁵ Furthermore, CPS integration in the heart failure (HF) setting has led to improvements in utilization and optimization of guideline-directed medical therapies, an area in which recent data have suggested deficiencies exist.^6-8 A full review of the outcomes associated with CPS involvement in cardiovascular care is beyond the scope of this article; but the recent review by Dunn and colleagues provides more detail.²

With the increasing number of patients with cardiovascular disease,expanding integration of CPSs in the cardiovascular team providing MTM services may reduce the burden of other providers (MD, PA, APRN, etc), thereby increasing access for not only new patients, but also diagnostic and interventional work, while potentially improving clinical and economic outcomes.² The value of integrating CPSs as members of the cardiovascular care team is recognized in a variety of inpatient and ambulatory practice settings.^2-6 However, data are limited on the number and types of interventions made per encounter as direct patient care providers. Expanded granularity regarding the effect of CPSs as active members of the cardiovascular team is an essential component to evaluate the potential benefit of CPS integration into direct patient care.

Methods

The West Palm Beach (WPB) Veteran Affairs Medical Center (VAMC) outpatient cardiology clinic consists of 6 full-time employee (FTE) cardiologists, 4 PAs or APRNs, 10 other cardiology health care staff members (registered/license practical nurses and technicians), and 2 cardiology CPSs providing direct patient care and, cumulatively, 1 clinic-assigned clinical pharmacy FTE. The cardiology CPSs provide comprehensive MTM based on patient-specific needs in an ambulatory cardiology pharmacotherapy clinic.

The cardiology pharmacotherapy clinic is open 20.5 hours per week with 41 appointment slots (30 minutes each), of which 7 appointments are delivered via clinic video telehealth and 34 appointments are traditional face-to-face visits.⁹ The remaining CPS time is assigned to other clinical care and administrative areas to fit facility need, including oversight of the CPS-run 24-hour ambulatory blood pressure clinic, postgraduate year 2 cardiology pharmacy practice residency program directorship, and other administrative activities for the facility.¹⁰

The cardiology CPSs practice under an advanced scope of practice in which they independently manage medications (initiate, modify, discontinue), order diagnostic testing (laboratory, monitoring, imaging, etc) needed for medication management, and create monitoring and treatment plans for patients referred to the cardiology pharmacotherapy clinic by other cardiology providers. The diseases managed within the clinic vary based on patient-specific needs, but may include HF, dyslipidemia, hypertension, anticoagulation, CAD, arrhythmias, cardiovascular risk factor assessment and reduction, and medication reconciliation and teaching. Patients are referred for CPS management directly from facility cardiologist and cardiology clinic PAs and APRNs. Workload and interventions carried out are captured in the Pharmacists Achieve Results with Medications Demonstration (PhARMD) tool and patient care encounter tracking.⁹

Data Collection

Using local data from workload tracking, the number of CPS encounters was determined from July 6, 2015, to October 1, 2015. Data were collected on the types and volume of interventions made by CPSs in the cardiology pharmacotherapy clinic using the PhARMD tool (Figure). 

The PhARMD tool was initially developed and implemented for CPSs in primary care pharmacotherapy clinics and was used to evaluate the types and volume of CPS interventions made in this setting.¹¹ Since this initial evaluation, the tool has been updated, standardized nationally by the Department of Veterans Affairs (VA) Pharmacy Benefits Management Clinical Pharmacy Practice Office, and integrated across numerous VAMCs and associated outpatient clinics. The tool remains embedded within the VA electronic health record (EHR) and allows the capture of specific CPS interventions of several types (ie, both pharmacologic and nonpharmacologic interventions, including adjust dose or frequency; change or discontinue medication; initiate medication; monitor medication; counsel on adherence, contraindications, drug interactions, and drugs not indicated; reconcile medication; and prevent or manage adverse drug events [ADEs]) specific to certain diseases, such as anemia, anticoagulation, HF, type 2 DM (T2DM), hypertension, dyslipidemia, and tobacco cessation.

Given that the interventions captured by the PhARMD tool are based on self-report of the CPS performing the intervention, a quality assurance (QA) measure was taken to audit a random sample of interventions to validate the accuracy of reported data. A Pharmacy Benefits Management PhARMD Project QA report provided the 20% random sample of encounters for each cardiology CPS to be reviewed. This percentage was determined by VAMC Clinical Pharmacy Program Office (CPPO) directives on implementation of the PhARMD tool. During the QA period, the provided sample was reviewed to determine whether the intervention(s) recorded with the PhARMD tool matched the actions documented in the EHR. The QA review was done through a manual chart review by an author not involved in recording the original interventions. Both WPB VAMC cardiology CPSs passed the QA review (> 80% concurrence with tool logged and chart documented interventions as required by VA CPPO directive), with a 90.9% concurrence between the EHR and PhARMD tool documentation.

Statistical Analyses

Data on intervention type and encounter number were evaluated with descriptive statistics. The information was characterized and diagrammed with Excel (Microsoft, Redmond, WA) charts and graphs.

Cost-avoidance calculations were done using previously described methods and are included for exploratory analysis.^11,12 Briefly, published estimates of cost avoidance associated with various interventions from the outpatient setting within a VAMC setting were applied as appropriate to the various interventions captured with the PhARMD tool.^11,12 These estimates from Lee and colleagues were derived from detailed chart review of interventions made and the potential harm prevented.¹² Costs or cost avoidances associated with interventions were calculated from pooled examination of 600 interventions in a VAMC with drug costs before and after the intervention, costs associated with harms prevented by the intervention, as well as the VAMC hourly pharmacist wages associated with making an intervention and processing and filling original vs recommended therapies.

The costs presented represent a “best-case” scenario in which all interventions made are expected to prevent patient harms. The costs related to avoided outcomes, facility overhead, and auxiliary staff cannot be included but highlight the many considerations that must be considered when examining potential cost-avoidance calculations. The estimates and methods at hand were chosen because, to our knowledge, no other consensus model exists that would be more appropriate for use in the situation and health care system at hand. Cost-avoidance estimates were calculated by extrapolating the 88-day study period values to a yearly estimate. All cost estimates were adjusted for inflation using the consumer price index calculator as per convention in previous analyses using the cost-avoidance estimates at hand.^11-13

Results

From July 6, 2015, through October 1, 2015, 301 patient encounters occurred, and 529 interventions were documented with the PhARMD tool. The mean number of interventions per encounter was 1.8. Interventions were 65.2% pharmacologic and 34.8% nonpharmacologic. Of pharmacologic interventions, 27.1% were for HF, 12.7% for hypertension, 8.8% for dyslipidemia, 2.8% for anticoagulation, 1.4% for tobacco cessation, 1.1% for T2DM, 0.3% for anemia, and 45.8% for other conditions (Table 1). 

The main types of pharmacologic interventions across all diseases were related to adjustments in medication dose or frequency (42.3%) and change or discontinuation of medications (20.0%). 

Discussion

Evaluation of the interventions and encounters at the WPB VAMC ambulatory cardiology pharmacotherapy clinic suggests that CPSs are able to contribute to direct patient care independently of interventions performed by other cardiology providers. Specifically, 1.8 interventions per encounter were made by CPSs in this study. In a prior evaluation of CPS interventions recorded with the PhARMD tool in a VAMC primary care setting, 2.3 interventions per encounter were recorded.¹¹ In comparing the present volume of interventions with the volume recorded in the study by Hough and colleagues, the difference in practice setting may account for differences seen.¹¹

The primary care medication management setting would capture a broader array of clinical interventions than would the ambulatory cardiology clinic of the present study, so it is reasonable that more interventions would be captured per encounter in the primary care clinic. The difference in practice settings affecting the character of collected interventions can be seen because most interventions in this study at an ambulatory cardiology clinic were related to HF, whereas in Hough and colleagues 39.2% of the disease-specific interventions were related to DM, and only 2.9% were related to HF.¹¹ The differences inherent in the intervention populations can also be seen by comparing the percentage of interventions related to hypertension and dyslipidemia: 30% and 28% in the study by Hough and colleagues compared with 13% and 9%, respectively, in the present study.¹¹

Comparison of the present evaluation and Hough and colleagues is also hindered by the PhARMD tool used. The PhARMD tool used in the initial evaluation has been modified on a national level to improve the granularity of intervention data collected. This modification limits functional comparisons between the evaluations at hand, although the current form of the PhARMD tool allows for better understanding of the interventions made by CPSs going forward and within different practice settings. The PhARMD tool is periodically updated nationally based on clinical practice changes or updates and clinical/administrative need of the tool.

Our cost-avoidance estimate of $433,324.06 per year seems lower than that estimated in the previous evaluation when all applicable interventions were included.¹¹ However, this study had several differences compared with those of previous VAMC studies looking at clinical interventions performed by CPSs. The main differences are the volume and setting in which interventions were being made. For example, in comparison with Hough and colleagues, the studies include different practice settings (primary care vs cardiology specialty clinic) and number of FTEs involved in the study (4.65 vs 1). If the cost avoidance is distributed evenly per FTE in the previous study, the following calculation is observed: $649,551.99 per FTE, which is closer to this study’s estimation. Given that primary care is a broader setting than is ambulatory cardiology, it is not surprising that more types of interventions and the overall volume/absolute number of interventions would be higher. Thus, the lower estimated cost avoidance in our study may be attributed to the lower volume of intervention opportunities availed to the cardiology CPS. Another difference is that detailed types of interventions related to hypertension, DM, dyslipidemia, and HF were not included in Hough and colleagues, whereas our study included all applicable interventions regardless of relation to diseases, which may account for a degree of the variation in intervention breakdown between the 2 studies.¹¹ However, as noted previously, some interventions for these particular diseases may not fully capture the rationale for pharmacotherapy interventions, such as drug dose changes or discontinuations, which may misrepresent the potential cost avoidance associated with them in reality.

Limitations

Of general importance, the PhARMD tool may underestimate the number of interventions made such that multiple interventions for a medical condition may have been completed but only captured as 1 intervention, which may represent a limitation of the tool when multiple interventions are made for the same disease (eg, titration of both β-blocker and angiotensin-converting enzyme inhibitor doses at a single appointment in a patient with HF with reduced left ventricular ejection fraction). Improved clarity about interventions made would require laborious chart review, which was not feasible. The evaluation at hand included a preliminary QA review, adding confidence that overdocumentation was not being done and the values represented at worst an underestimation of actual CPS intervention impact. Because this study was an initial evaluation of interventions made by CPSs in an ambulatory cardiology pharmacotherapy setting, whether these same outcomes would exist in other patient cohorts is unclear. However, these data do provide a foundational understanding of what may be expected from CPS integration into a cardiovascular care team.

These findings may be limited in generalizability to other health care systems and situations in which CPSs are afforded the regulatory opportunity to practice independently within an established scope of practice or collaborative practice agreements. The Veterans Health Administration system has been a leader in integrating CPSs into direct patient care roles and serves as a potential model for application by other groups. This evaluation’s data support continued efforts to create such independent practice environments as they allow for qualified CPSs to practice to their full clinical potential and have the fullest possible effect on cardiovascular outcomes.

Previous studies looking at cost savings in MTM programs have established a substantial return in economic investment with patients being managed by pharmacists.^5,14 Given that the interventions made in this study were not tied to attainment of clinical outcomes, a limitation to our study, the cost-avoidance estimates should be interpreted cautiously. However, we know of no such tool that is available to allow accurate capture of clinical event reduction in a single center with consistent CPS involvement in care. A clear opportunity exists regarding design of a model that measures clinical, economic, and humanistic outcomes related to the interventions performed by cardiology CPSs, but developing and deploying such a model may be challenging because guideline-directed medical therapies vary significantly based on many patient-specific issues, and identifying optimal or truly optimized medical therapy is at times a subjective task, especially in a single center. Using the types and volumes of interventions made by CPSs as a surrogate for these higher-level outcomes is still of value in order to understand the effect and role of CPSs in cardiovascular care. At present, the cost-avoidance estimates presented in this evaluation are based on the most appropriate system-specific data at hand, with the realization that actual cost avoidance in practice may vary widely and should be the topic of future research.

Conclusion

As cardiovascular team-based care continues to expand with the support of large organizations, such as the American College of Cardiology Foundation, Heart Failure Society of America, and American College of Clinical Pharmacy Cardiology Practice and Research Network, the need for understanding the effect of CPSs on patient care measures and health care costs becomes more pronounced.^2,15 The results of this study demonstrate how integration of CPSs in an ambulatory cardiology clinic may translate to cost avoidance and a reduction in workload burden for cardiology physicians and providers, allowing more availability for diagnostic testing and care.

Interventions made by CPSs functioning as independent providers delivering comprehensive MTM services within an interdisciplinary ambulatory cardiology clinic have a potential positive effect on patient care and cost avoidance.

Granuloma annulare (GA) is a granulomatous skin disorder of uncertain etiology. A number of clinical variants exist, most commonly localized annular plaques on the hands or feet, generalized lesions, or subcutaneous nodules in children. Histologically, GA exhibits granulomatous inflammation with either interstitial or palisading lymphocytes and histiocytes with mucin deposition.

Few data exist regarding the epidemiology of GA. Although the pathogenesis of GA is unknown, associations between GA and underlying systemic processes, such as diabetes mellitus, hyperlipidemia, thyroid disease, and human immunodeficiency virus (HIV), have been suggested.

The purpose of this retrospective study was to determine the number of cases of GA seen annually at the Department of Dermatology at the University of Pennsylvania (Philadelphia, Pennsylvania) from 2008 to 2014. Additionally, we reviewed all cases of biopsy-proven GA from 2010 to 2014 and reported the demographics, underlying medical comorbidities, medications, treatments, and outcomes seen in this patient population.

Methods

We identified the number of outpatients presenting with GA annually using PennSeek, a tool developed by the Penn Medicine Data Analytics Center to search electronic medical records (EMRs). We queried the EMR database to determine the number of discrete patients seen at the Department of Dermatology at the University of Pennsylvania annually from 2008 (the year the EMR was established) to 2014. We then used PennSeek to determine the number of patients given a diagnosis of GA annually from 2008 to 2014 based on the International Classification of Diseases, Ninth Revision (ICD-9).

After using PennSeek to identify all patients given the ICD-9 diagnosis of GA from 2008 to 2014, we reviewed the EMRs of these patients to identify cases that were biopsy proven. For the biopsy-proven cases of GA seen at the University of Pennsylvania from 2010 to 2014, we reviewed the EMRs of these patients for clinical characteristics and treatment outcomes. For each case, we recorded the patient’s age, sex, medical comorbidities, GA subtype, and medications.

This study was approved by the University of Pennsylvania’s institutional review board.

Results

On average, the percentage of patients given a diagnosis of GA annually was 0.22% (95% CI, 0.19%-0.24%). A Pearson χ² test was used to determine if any single annual percentage was significantly different from the others. We found a P value of .321, which suggests that the percentage of patients with GA seen annually has been stable from 2008 to 2014 (Figure).

There were 133 cases of biopsy-proven GA that were reviewed for clinical characteristics; of them, 86.5% were female. Thyroid disease was noted in 30.1% of patients, hyperlipidemia in 30.1%, and hematologic malignancies in 3.8%. Type 1 diabetes mellitus was noted in 1.5% of patients. None of the patients were HIV-positive, 1.5% were hepatitis B–positive, and 2.3% were hepatitis C–positive. Of the 133 cases, 64.7% had localized GA and 30.8% had generalized GA. Photosensitive and papular GA were rarer (1.5% and 2.3% of cases, respectively). Use of a selective serotonin reuptake inhibitor (SSRI) was noted in 18.1% of patients; use of a calcium channel blocker was noted in 9.0% (Table 1).

Comment

We attempted to determine the period of prevalence of GA in a tertiary care, university-based referral practice and evaluate disease associations, treatments, and outcomes of patients with biopsy-proven GA. Our calculated period prevalence of GA of 0.22% to 0.27% is consistent with another review, which reported that 0.1% to 0.4% of new patients presenting to a dermatology practice were given a diagnosis of GA.¹ More than 85% of the cases we reviewed were seen in females, a finding that is more heavily skewed compared to prior reports that have suggested a female to male ratio of approximately 1:1 to 2:1.^1-7 Our findings suggest that GA is a female-predominant condition, or women may be more likely to seek evaluation for the condition.

More than 95% of the cases we reviewed were localized (64.7%) or generalized (30.8%) GA, making these variants the most common forms of GA, which is consistent with prior reports.^1-3,8,9 Other varieties of GA—drug induced, patch, perforating, photosensitive, palmar, and papular—appear rare. Because this study was conducted at an adult hospital, subcutaneous GA, which often is seen in children, may be underrepresented. As a retrospective chart review, it is possible that documentation is insufficient to capture each rare variant.

At 1.5%, the prevalence of type 1 diabetes mellitus in our patients is slightly higher than the national average of 0.3%.²⁵ However, based on a Fisher exact test of analysis of proportions, this difference is not statistically significant (P=.106).

At 1.5% and 2.3%, the prevalence of hepatitis B and hepatitis C, respectively, in our patients is slightly higher than the national average of 0.5% and 1%, respectively.²⁶ However, based on a Fisher exact test of analysis of proportions, these differences are not statistically significant (P=.142 and P=.146, respectively).

Given the high prevalence of hyperlipidemia in the United States (31.7%), this disease is not overrepresented in our sample (30.1%), though others have suggested there may be a connection.^27,28 Based on a Fisher exact test, this difference of proportions is not statistically significant (P=.780).

Selective serotonin reuptake inhibitor use is common in the United States; approximately 11% of Americans older than 12 years use an SSRI.²⁹ At 18.1%, the use of SSRIs in our patient group was statistically significantly higher than the national average (Fisher exact test, P=.017), suggesting a possible association between SSRI use and development of GA, warranting further investigation.

The use of calcium channel blockers, interferon, and tumor necrosis factor inhibitors was not significantly associated with GA in our series.

GA Therapy
The most commonly used treatments for GA in our study were topical steroids and intralesional triamcinolone, followed by hydroxychloroquine; all treatments employed exhibited a widely variable response. Assessing treatment response via retrospective chart review is challenging and response rates may not be accurately captured.

Study Limitations
Our study had several limitations. In calculating the period prevalence of GA, our query was limited by the number of years that the EMR has been in place. The number of cases we reviewed for clinical characteristics was limited to 133, as many cases with the ICD-9 diagnosis of GA were not biopsy proven and therefore were not included in our review. Many of the cases we reviewed were lost to follow-up, which prevented us from determining treatment outcomes.

Another weakness of our study was that our query did not provide an estimate of incidence or prevalence of GA overall, as this analysis was not a population-based study. The power of our study was limited by the number of cases of GA seen annually and the number of patients lost to follow-up. Additionally, our study population may only be generalizable to other large academic centers.

Conclusion

This study further solidifies our understanding of the epidemiology of GA and diseases that can be associated with GA. We identified a higher female to male ratio than previous reports, and consistent with prior reports, we noted potential associations with conditions such as thyroid disease and hyperlipidemia. Our population demonstrated higher rates of SSRI use than expected, warranting further investigation. Dermatologists should be aware of potential disease associations with GA, but as a whole we need better data and larger studies to determine the appropriate evaluation and treatment for patients with GA.

Granuloma annulare (GA) is a granulomatous skin disorder of uncertain etiology. A number of clinical variants exist, most commonly localized annular plaques on the hands or feet, generalized lesions, or subcutaneous nodules in children. Histologically, GA exhibits granulomatous inflammation with either interstitial or palisading lymphocytes and histiocytes with mucin deposition.

Few data exist regarding the epidemiology of GA. Although the pathogenesis of GA is unknown, associations between GA and underlying systemic processes, such as diabetes mellitus, hyperlipidemia, thyroid disease, and human immunodeficiency virus (HIV), have been suggested.

The purpose of this retrospective study was to determine the number of cases of GA seen annually at the Department of Dermatology at the University of Pennsylvania (Philadelphia, Pennsylvania) from 2008 to 2014. Additionally, we reviewed all cases of biopsy-proven GA from 2010 to 2014 and reported the demographics, underlying medical comorbidities, medications, treatments, and outcomes seen in this patient population.

Methods

We identified the number of outpatients presenting with GA annually using PennSeek, a tool developed by the Penn Medicine Data Analytics Center to search electronic medical records (EMRs). We queried the EMR database to determine the number of discrete patients seen at the Department of Dermatology at the University of Pennsylvania annually from 2008 (the year the EMR was established) to 2014. We then used PennSeek to determine the number of patients given a diagnosis of GA annually from 2008 to 2014 based on the International Classification of Diseases, Ninth Revision (ICD-9).

After using PennSeek to identify all patients given the ICD-9 diagnosis of GA from 2008 to 2014, we reviewed the EMRs of these patients to identify cases that were biopsy proven. For the biopsy-proven cases of GA seen at the University of Pennsylvania from 2010 to 2014, we reviewed the EMRs of these patients for clinical characteristics and treatment outcomes. For each case, we recorded the patient’s age, sex, medical comorbidities, GA subtype, and medications.

This study was approved by the University of Pennsylvania’s institutional review board.

Results

On average, the percentage of patients given a diagnosis of GA annually was 0.22% (95% CI, 0.19%-0.24%). A Pearson χ² test was used to determine if any single annual percentage was significantly different from the others. We found a P value of .321, which suggests that the percentage of patients with GA seen annually has been stable from 2008 to 2014 (Figure).

There were 133 cases of biopsy-proven GA that were reviewed for clinical characteristics; of them, 86.5% were female. Thyroid disease was noted in 30.1% of patients, hyperlipidemia in 30.1%, and hematologic malignancies in 3.8%. Type 1 diabetes mellitus was noted in 1.5% of patients. None of the patients were HIV-positive, 1.5% were hepatitis B–positive, and 2.3% were hepatitis C–positive. Of the 133 cases, 64.7% had localized GA and 30.8% had generalized GA. Photosensitive and papular GA were rarer (1.5% and 2.3% of cases, respectively). Use of a selective serotonin reuptake inhibitor (SSRI) was noted in 18.1% of patients; use of a calcium channel blocker was noted in 9.0% (Table 1).

Comment

We attempted to determine the period of prevalence of GA in a tertiary care, university-based referral practice and evaluate disease associations, treatments, and outcomes of patients with biopsy-proven GA. Our calculated period prevalence of GA of 0.22% to 0.27% is consistent with another review, which reported that 0.1% to 0.4% of new patients presenting to a dermatology practice were given a diagnosis of GA.¹ More than 85% of the cases we reviewed were seen in females, a finding that is more heavily skewed compared to prior reports that have suggested a female to male ratio of approximately 1:1 to 2:1.^1-7 Our findings suggest that GA is a female-predominant condition, or women may be more likely to seek evaluation for the condition.

More than 95% of the cases we reviewed were localized (64.7%) or generalized (30.8%) GA, making these variants the most common forms of GA, which is consistent with prior reports.^1-3,8,9 Other varieties of GA—drug induced, patch, perforating, photosensitive, palmar, and papular—appear rare. Because this study was conducted at an adult hospital, subcutaneous GA, which often is seen in children, may be underrepresented. As a retrospective chart review, it is possible that documentation is insufficient to capture each rare variant.

At 1.5%, the prevalence of type 1 diabetes mellitus in our patients is slightly higher than the national average of 0.3%.²⁵ However, based on a Fisher exact test of analysis of proportions, this difference is not statistically significant (P=.106).

At 1.5% and 2.3%, the prevalence of hepatitis B and hepatitis C, respectively, in our patients is slightly higher than the national average of 0.5% and 1%, respectively.²⁶ However, based on a Fisher exact test of analysis of proportions, these differences are not statistically significant (P=.142 and P=.146, respectively).

Given the high prevalence of hyperlipidemia in the United States (31.7%), this disease is not overrepresented in our sample (30.1%), though others have suggested there may be a connection.^27,28 Based on a Fisher exact test, this difference of proportions is not statistically significant (P=.780).

Selective serotonin reuptake inhibitor use is common in the United States; approximately 11% of Americans older than 12 years use an SSRI.²⁹ At 18.1%, the use of SSRIs in our patient group was statistically significantly higher than the national average (Fisher exact test, P=.017), suggesting a possible association between SSRI use and development of GA, warranting further investigation.

The use of calcium channel blockers, interferon, and tumor necrosis factor inhibitors was not significantly associated with GA in our series.

GA Therapy
The most commonly used treatments for GA in our study were topical steroids and intralesional triamcinolone, followed by hydroxychloroquine; all treatments employed exhibited a widely variable response. Assessing treatment response via retrospective chart review is challenging and response rates may not be accurately captured.

Study Limitations
Our study had several limitations. In calculating the period prevalence of GA, our query was limited by the number of years that the EMR has been in place. The number of cases we reviewed for clinical characteristics was limited to 133, as many cases with the ICD-9 diagnosis of GA were not biopsy proven and therefore were not included in our review. Many of the cases we reviewed were lost to follow-up, which prevented us from determining treatment outcomes.

Another weakness of our study was that our query did not provide an estimate of incidence or prevalence of GA overall, as this analysis was not a population-based study. The power of our study was limited by the number of cases of GA seen annually and the number of patients lost to follow-up. Additionally, our study population may only be generalizable to other large academic centers.

Conclusion

This study further solidifies our understanding of the epidemiology of GA and diseases that can be associated with GA. We identified a higher female to male ratio than previous reports, and consistent with prior reports, we noted potential associations with conditions such as thyroid disease and hyperlipidemia. Our population demonstrated higher rates of SSRI use than expected, warranting further investigation. Dermatologists should be aware of potential disease associations with GA, but as a whole we need better data and larger studies to determine the appropriate evaluation and treatment for patients with GA.

Granuloma annulare (GA) is a granulomatous skin disorder of uncertain etiology. A number of clinical variants exist, most commonly localized annular plaques on the hands or feet, generalized lesions, or subcutaneous nodules in children. Histologically, GA exhibits granulomatous inflammation with either interstitial or palisading lymphocytes and histiocytes with mucin deposition.

Few data exist regarding the epidemiology of GA. Although the pathogenesis of GA is unknown, associations between GA and underlying systemic processes, such as diabetes mellitus, hyperlipidemia, thyroid disease, and human immunodeficiency virus (HIV), have been suggested.

The purpose of this retrospective study was to determine the number of cases of GA seen annually at the Department of Dermatology at the University of Pennsylvania (Philadelphia, Pennsylvania) from 2008 to 2014. Additionally, we reviewed all cases of biopsy-proven GA from 2010 to 2014 and reported the demographics, underlying medical comorbidities, medications, treatments, and outcomes seen in this patient population.

Methods

We identified the number of outpatients presenting with GA annually using PennSeek, a tool developed by the Penn Medicine Data Analytics Center to search electronic medical records (EMRs). We queried the EMR database to determine the number of discrete patients seen at the Department of Dermatology at the University of Pennsylvania annually from 2008 (the year the EMR was established) to 2014. We then used PennSeek to determine the number of patients given a diagnosis of GA annually from 2008 to 2014 based on the International Classification of Diseases, Ninth Revision (ICD-9).

After using PennSeek to identify all patients given the ICD-9 diagnosis of GA from 2008 to 2014, we reviewed the EMRs of these patients to identify cases that were biopsy proven. For the biopsy-proven cases of GA seen at the University of Pennsylvania from 2010 to 2014, we reviewed the EMRs of these patients for clinical characteristics and treatment outcomes. For each case, we recorded the patient’s age, sex, medical comorbidities, GA subtype, and medications.

This study was approved by the University of Pennsylvania’s institutional review board.

Results

On average, the percentage of patients given a diagnosis of GA annually was 0.22% (95% CI, 0.19%-0.24%). A Pearson χ² test was used to determine if any single annual percentage was significantly different from the others. We found a P value of .321, which suggests that the percentage of patients with GA seen annually has been stable from 2008 to 2014 (Figure).

There were 133 cases of biopsy-proven GA that were reviewed for clinical characteristics; of them, 86.5% were female. Thyroid disease was noted in 30.1% of patients, hyperlipidemia in 30.1%, and hematologic malignancies in 3.8%. Type 1 diabetes mellitus was noted in 1.5% of patients. None of the patients were HIV-positive, 1.5% were hepatitis B–positive, and 2.3% were hepatitis C–positive. Of the 133 cases, 64.7% had localized GA and 30.8% had generalized GA. Photosensitive and papular GA were rarer (1.5% and 2.3% of cases, respectively). Use of a selective serotonin reuptake inhibitor (SSRI) was noted in 18.1% of patients; use of a calcium channel blocker was noted in 9.0% (Table 1).

Comment

We attempted to determine the period of prevalence of GA in a tertiary care, university-based referral practice and evaluate disease associations, treatments, and outcomes of patients with biopsy-proven GA. Our calculated period prevalence of GA of 0.22% to 0.27% is consistent with another review, which reported that 0.1% to 0.4% of new patients presenting to a dermatology practice were given a diagnosis of GA.¹ More than 85% of the cases we reviewed were seen in females, a finding that is more heavily skewed compared to prior reports that have suggested a female to male ratio of approximately 1:1 to 2:1.^1-7 Our findings suggest that GA is a female-predominant condition, or women may be more likely to seek evaluation for the condition.

More than 95% of the cases we reviewed were localized (64.7%) or generalized (30.8%) GA, making these variants the most common forms of GA, which is consistent with prior reports.^1-3,8,9 Other varieties of GA—drug induced, patch, perforating, photosensitive, palmar, and papular—appear rare. Because this study was conducted at an adult hospital, subcutaneous GA, which often is seen in children, may be underrepresented. As a retrospective chart review, it is possible that documentation is insufficient to capture each rare variant.

At 1.5%, the prevalence of type 1 diabetes mellitus in our patients is slightly higher than the national average of 0.3%.²⁵ However, based on a Fisher exact test of analysis of proportions, this difference is not statistically significant (P=.106).

At 1.5% and 2.3%, the prevalence of hepatitis B and hepatitis C, respectively, in our patients is slightly higher than the national average of 0.5% and 1%, respectively.²⁶ However, based on a Fisher exact test of analysis of proportions, these differences are not statistically significant (P=.142 and P=.146, respectively).

Given the high prevalence of hyperlipidemia in the United States (31.7%), this disease is not overrepresented in our sample (30.1%), though others have suggested there may be a connection.^27,28 Based on a Fisher exact test, this difference of proportions is not statistically significant (P=.780).

Selective serotonin reuptake inhibitor use is common in the United States; approximately 11% of Americans older than 12 years use an SSRI.²⁹ At 18.1%, the use of SSRIs in our patient group was statistically significantly higher than the national average (Fisher exact test, P=.017), suggesting a possible association between SSRI use and development of GA, warranting further investigation.

The use of calcium channel blockers, interferon, and tumor necrosis factor inhibitors was not significantly associated with GA in our series.

GA Therapy
The most commonly used treatments for GA in our study were topical steroids and intralesional triamcinolone, followed by hydroxychloroquine; all treatments employed exhibited a widely variable response. Assessing treatment response via retrospective chart review is challenging and response rates may not be accurately captured.

Study Limitations
Our study had several limitations. In calculating the period prevalence of GA, our query was limited by the number of years that the EMR has been in place. The number of cases we reviewed for clinical characteristics was limited to 133, as many cases with the ICD-9 diagnosis of GA were not biopsy proven and therefore were not included in our review. Many of the cases we reviewed were lost to follow-up, which prevented us from determining treatment outcomes.

Another weakness of our study was that our query did not provide an estimate of incidence or prevalence of GA overall, as this analysis was not a population-based study. The power of our study was limited by the number of cases of GA seen annually and the number of patients lost to follow-up. Additionally, our study population may only be generalizable to other large academic centers.

Conclusion

This study further solidifies our understanding of the epidemiology of GA and diseases that can be associated with GA. We identified a higher female to male ratio than previous reports, and consistent with prior reports, we noted potential associations with conditions such as thyroid disease and hyperlipidemia. Our population demonstrated higher rates of SSRI use than expected, warranting further investigation. Dermatologists should be aware of potential disease associations with GA, but as a whole we need better data and larger studies to determine the appropriate evaluation and treatment for patients with GA.

Psoriasis is a chronic, immune-mediated, inflammatory disease affecting almost 2% of the population.^1-3 It is characterized by patches of raised reddish skin covered by silvery-white scales. Most patients have limited disease (<5% body surface area [BSA] involvement) that can be managed with topical agents.⁴ Topical corticosteroids (TCSs) are considered first-line therapy for mild to moderate disease because of the inflammatory nature of the condition and often are used in conjunction with systemic agents in more severe psoriasis.⁴

As many as 20% to 30% of patients with moderate to severe plaque psoriasis have inadequate disease control.⁵ Several factors may affect patient outcomes; however, drug selection and patient adherence are important given the chronic nature of the disease. A survey of 1200 patients with psoriasis reported nonadherence rates of 73% with topical therapy.⁶ In addition, patients tend to apply less than the recommended dose or abandon treatment altogether if rapid improvement does not occur^7,8; it is not uncommon for patients with psoriasis to mistakenly believe treatment will improve their condition within 1 to 2 weeks.⁹ Patient satisfaction with topical treatments is low, partly because of these false expectations and formulation issues. Treatments can be greasy and sticky, with unpleasant odors and the potential to stain clothes and linens.^7,10 Safety concerns with TCSs also limit their consecutive use beyond 2 to 4 weeks, which is not ideal for a disease that requires a long-term management strategy.

A potent/superpotent TCS that is administered once daily and has a safety profile that affords longer-term, once-daily treatment in an aesthetically pleasing formulation would seem ideal. Herein, we investigate the safety and tolerability of a novel low-concentration (0.01%) lotion formulation of halobetasol propionate (HP), reporting on the pooled data from 2 phase 3 clinical studies in participants with moderate to severe psoriasis.

METHODS
Study Design

We conducted 2 multicenter, double-blind, randomized, parallel-group phase 3 studies to assess the safety, tolerability, and efficacy of HP lotion 0.01% in participants with a clinical diagnosis of moderate to severe psoriasis with an investigator global assessment (IGA) score of 3 or 4 and an affected BSA of 3% to 12%. Participants were randomized (2:1) to receive HP lotion or vehicle applied topically to the affected area once daily for 8 weeks.

Inclusion and Exclusion Criteria
The studies included individuals of either sex aged 18 years or older. A target lesion was defined primarily to assess signs of psoriasis, measuring 16 to 100 cm², with a score of 3 (moderate) or higher for 2 of 3 different psoriasis signs—erythema, plaque elevation, and scaling—and summed score of 8 or higher, with no sign scoring less than 2. Participants who had pustular psoriasis or used phototherapy, photochemotherapy, or systemic psoriasis therapy within the prior 4 weeks or biologics within the prior 3 months, or those who were diagnosed with skin conditions that would interfere with the interpretation of results were excluded from the studies.

Study Oversight
Participants provided written informed consent before study-related procedures were performed, and the protocol and consent were approved by institutional review boards or ethics committees at all investigational sites. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.

Efficacy Assessment

A 5-point scale ranging from 0 (clear) to 4 (severe) was used by the investigator at each study visit to assess the overall psoriasis severity of the treatable areas. Treatment success (the percentage of participants with at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]) was evaluated at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Signs of psoriasis at the target lesion were assessed at each visit using individual 5-point scales ranging from 0 (clear) to 4 (severe). Treatment success was defined as at least a 2-grade improvement from baseline score for each of the key signs—erythema, plaque elevation, and scaling—and reported at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Affected BSA also was evaluated at each visit. In addition, an IGA×BSA composite score was calculated by multiplying the IGA by the BSA (range, 9–48 [eg, maximum IGA=4 and maximum BSA=12]) at each time point. The mean percentage change in IGA×BSA from baseline was calculated for each study visit. Additional end points included the achievement of a 50%, 75%, and 90% or greater reduction from baseline IGA×BSA score—IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90—at week 8.

Safety Assessment

Safety evaluations including adverse events (AEs), local skin reactions (LSRs), vital signs, laboratory evaluations, and physical examinations were performed. Information on reported and observed AEs was obtained at each visit. Routine safety laboratory tests were performed at screening, week 4, and week 8. An abbreviated physical examination was performed at baseline, week 8 (end of treatment), and week 12 (end of study). Treatment areas also were examined by the investigator at baseline and each subsequent visit for the presence or absence of marked known drug-related AEs including skin atrophy, striae, telangiectasia, and folliculitis.

LSR Assessment
Local skin reactions such as itching, dryness, and burning/stinging were evaluated at each study visit using 4-point scales ranging from 0 (clear) to 3 (severe). Given the nature of the disease, the presence of LSRs and symptoms at baseline is commonplace, and as such, these evaluations identified both improvement and any emergent issues.

Statistical Analysis

The primary study goal was to assess differences in treatment efficacy between HP lotion and vehicle with respect to IGA. All statistical processing was performed using SAS unless otherwise stated; statistical tests were 2-sided and performed at the 0.05 level of significance. Markov Chain Monte Carlo multiple imputation was the primary method used to handle missing efficacy data. No imputations were made for missing safety data. All participants were randomized, and the dispensed study drug was included in the intention-to-treat analysis set. This analysis was considered primary for the evaluation of efficacy. Data were analyzed using Cochran-Mantel-Haenszel tests, stratified by analysis center.

Body surface area data were analyzed in a post hoc analysis of covariance with factors of treatment and analysis center and baseline BSA as a covariate. P values for comparisons of percentage change in IGA×BSA were derived from a Wilcoxon rank sum test. For IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90, P values were derived from a Cochran-Mantel-Haenszel test. Last observation carried forward was used to impute data for IGA and BSA through week 8 prior to analysis.

The primary safety analysis was conducted at week 8 using the safety analysis set, which included all participants who were randomized, received at least 1 confirmed dose of the study drug, and had at least 1 postbaseline safety assessment. Adverse events were recorded and classified using the Medical Dictionary for Regulatory Activities (MedDRA, Version 18.0). A post hoc Wilcoxon rank sum test was conducted to compare itching, dryness, and burning/stinging scores at week 8 for HP lotion versus vehicle.

RESULTS
Participant Disposition

Overall, 430 participants were randomized (2:1) to HP lotion (n=285) or vehicle (n=145)(eFigure 1) and included in the intention-to-treat population. Across the 2 studies, 93.3% (n=266) of participants treated with HP lotion and 89.7% (n=130) of participants treated with vehicle completed treatment. The main reasons for study discontinuation with HP lotion were lost to follow-up (3.2%; n=9), participant request (1.8%; n=5), and AEs (1.4%; n=4). Participant request (4.8%; n=7), lost to follow-up (4.1%; n=6), and AEs (1.4%; n=2) also were the main reasons for treatment discontinuation in the vehicle arm.

A total of 426 participants were included in the safety population, with no postbaseline safety evaluation in 4 participants.

Baseline Participant Demographics
Demographic data were comparable across the 2 studies. The mean age (SD) was 52.6 (14.13) years. Overall, the majority of participants were male (58.8%; n=253) and white (86.5%; n=372)(eTable 1).

Efficacy Evaluation

IGA of Disease Severity
Halobetasol propionate lotion was consistently more effective than its vehicle in achieving treatment success (at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]). Halobetasol propionate lotion demonstrated statistically significant superiority over vehicle as early as week 2 (P=.003). By week 8, 37.43% of participants in the HP lotion group achieved treatment success compared with 10.03% in the vehicle group (P<.001)(Figure 1).

Overall, 39% of participants who had moderate disease (IGA score, 3) at baseline were treatment successes with HP lotion at week 8 compared with 11.53% of participants treated with vehicle; 27.97% of participants with severe disease (IGA score, 4) were treatment successes, with at least a 3-grade improvement in IGA. No participants with severe psoriasis who were treated with vehicle achieved treatment success at week 8. Efficacy was similar in female and male participants, allowing for vehicle effects.

Severity of Signs of Psoriasis (Erythema, Plaque Elevation, and Scaling) at Target Lesion Site
Halobetasol propionate lotion was statistically superior to vehicle in reducing the psoriasis signs of erythema, plaque elevation, and scaling at the target lesion from week 2. At week 8, treatment success (at least a 2-grade improvement from baseline) was achieved by 51.48% (erythema), 57.64% (plaque elevation), and 58.98% (scaling) of participants compared with 17.85%, 23.61%, and 22.82%, respectively, with vehicle (all P<.001)(Figure 2).

Safety Evaluation

Adverse event reports were low and similar between the active and vehicle groups. Overall, 61 participants (21.5%) treated with HP lotion reported AEs compared with 34 participants (23.9%) treated with vehicle (Table). The majority of participants treated with HP lotion (90.2%) had AEs that were mild or moderate. There was 1 AE of telangiectasia, not considered treatment related. There were 5 treatment-related AEs for HP lotion, all at the application site: dermatitis (0.7%; n=2), infection (0.4%; n=1), pruritus (0.4%; n=1), and discoloration (0.4%; n=1). There were no AE reports of skin atrophy or folliculitis.

Local Skin Reactions
Most LSRs at baseline were mild to moderate in severity. Itching was the most common, present in 76.8% of participants. Participant-reported burning/stinging was less common, reported by 40.6% of participants. Investigator-reported dryness was noted in 65.7% of participants. There was a rapid improvement in participant-reported itching as early as week 2 that was sustained to the end of the studies, with more gradual improvements in skin dryness and burning/stinging.

COMMENT

Plaque psoriasis is a chronic condition. The rationale behind the development of HP lotion 0.01% was to provide optimal topical treatment of moderate to severe psoriasis, allowing for the potential of prolonged use beyond the 2-week consecutive use normally applied to HP cream 0.05% in a light, once-daily, aesthetically pleasing lotion formulation that patients would prefer.

Treatment success was rapid and achieved in more than 37% of participants by week 8, with significant improvements in psoriasis signs and symptoms (erythema, plaque elevation, and scaling) compared with vehicle. However, IGA does not consider BSA involvement, a key aspect of disease severity,^11,12 and improvements in psoriasis signs of erythema, plaque elevation, and scaling were only assessed at the target lesion. Recently, the product of the IGA and BSA involvement (IGA×BSA) has been proposed as a simple alternative for assessing response to therapy that has been consistently shown to be highly correlated with the psoriasis area and severity index.^13-19 Halobetasol propionate lotion 0.01% achieved a 50% reduction in IGA×BSA score by week 8. This efficacy compares well with results reported with apremilast in patients with moderate plaque psoriasis.²⁰

Achieving clinically meaningful outcomes is an important aspect of disease management, especially in psoriasis with its disease burden and detriment to quality of life. It has been suggested that achieving a 75% or greater reduction from baseline IGA×BSA score (IGA×BSA-75) is an appropriate clinical goal.²⁰ In our investigation, IGA×BSA-75 was achieved by 39% of participants treated with HP lotion by week 8, which again compares favorably with 35% of participants in the apremilast study who achieved IGA×BSA-75 at week 16.²⁰

Physicians continue to have long-term safety concerns with TCSs,^4,11,12 participants remain concerned about the risk for skin thinning,¹³ and product labelling restricts HP cream 0.05% consecutive use to 2 weeks. In clinical experience, HP cream 0.05% is well tolerated, with potential local AEs similar to those experienced with other superpotent TCSs. In short-term clinical trials, local AEs at the site of application were reported in up to 13% of patients^21-26; itching, burning, or stinging were the most common local AEs (reported in 4.4% of patients).²⁷

There were minimal safety concerns in our 2 studies using an 8-week, once-daily treatment regimen with HP lotion 0.01%. Local AEs at the application site were reported in less than 1% of participants. Baseline itching, dryness, and burning/stinging all improved with treatment.

CONCLUSION

Halobetasol propionate lotion 0.01% provides rapid improvement in disease severity. Halobetasol propionate lotion was consistently more effective than vehicle in achieving treatment success; reducing the BSA affected by the disease; reducing erythema, plaque elevation, and scaling at the target lesion; and improving IGA×BSA score over 8 weeks, which is a realistic time frame to see improvement in psoriasis with a topical steroid. There were minimal safety concerns with prolonged use. Halobetasol propionate lotion may provide an effective and reasonable treatment option in patients with moderate to severe plaque psoriasis.

Acknowledgment
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of this article. Ortho Dermatologics funded Mr. Bulley’s activities pertaining to this article.

Psoriasis is a chronic, immune-mediated, inflammatory disease affecting almost 2% of the population.^1-3 It is characterized by patches of raised reddish skin covered by silvery-white scales. Most patients have limited disease (<5% body surface area [BSA] involvement) that can be managed with topical agents.⁴ Topical corticosteroids (TCSs) are considered first-line therapy for mild to moderate disease because of the inflammatory nature of the condition and often are used in conjunction with systemic agents in more severe psoriasis.⁴

As many as 20% to 30% of patients with moderate to severe plaque psoriasis have inadequate disease control.⁵ Several factors may affect patient outcomes; however, drug selection and patient adherence are important given the chronic nature of the disease. A survey of 1200 patients with psoriasis reported nonadherence rates of 73% with topical therapy.⁶ In addition, patients tend to apply less than the recommended dose or abandon treatment altogether if rapid improvement does not occur^7,8; it is not uncommon for patients with psoriasis to mistakenly believe treatment will improve their condition within 1 to 2 weeks.⁹ Patient satisfaction with topical treatments is low, partly because of these false expectations and formulation issues. Treatments can be greasy and sticky, with unpleasant odors and the potential to stain clothes and linens.^7,10 Safety concerns with TCSs also limit their consecutive use beyond 2 to 4 weeks, which is not ideal for a disease that requires a long-term management strategy.

A potent/superpotent TCS that is administered once daily and has a safety profile that affords longer-term, once-daily treatment in an aesthetically pleasing formulation would seem ideal. Herein, we investigate the safety and tolerability of a novel low-concentration (0.01%) lotion formulation of halobetasol propionate (HP), reporting on the pooled data from 2 phase 3 clinical studies in participants with moderate to severe psoriasis.

METHODS
Study Design

We conducted 2 multicenter, double-blind, randomized, parallel-group phase 3 studies to assess the safety, tolerability, and efficacy of HP lotion 0.01% in participants with a clinical diagnosis of moderate to severe psoriasis with an investigator global assessment (IGA) score of 3 or 4 and an affected BSA of 3% to 12%. Participants were randomized (2:1) to receive HP lotion or vehicle applied topically to the affected area once daily for 8 weeks.

Inclusion and Exclusion Criteria
The studies included individuals of either sex aged 18 years or older. A target lesion was defined primarily to assess signs of psoriasis, measuring 16 to 100 cm², with a score of 3 (moderate) or higher for 2 of 3 different psoriasis signs—erythema, plaque elevation, and scaling—and summed score of 8 or higher, with no sign scoring less than 2. Participants who had pustular psoriasis or used phototherapy, photochemotherapy, or systemic psoriasis therapy within the prior 4 weeks or biologics within the prior 3 months, or those who were diagnosed with skin conditions that would interfere with the interpretation of results were excluded from the studies.

Study Oversight
Participants provided written informed consent before study-related procedures were performed, and the protocol and consent were approved by institutional review boards or ethics committees at all investigational sites. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.

Efficacy Assessment

A 5-point scale ranging from 0 (clear) to 4 (severe) was used by the investigator at each study visit to assess the overall psoriasis severity of the treatable areas. Treatment success (the percentage of participants with at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]) was evaluated at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Signs of psoriasis at the target lesion were assessed at each visit using individual 5-point scales ranging from 0 (clear) to 4 (severe). Treatment success was defined as at least a 2-grade improvement from baseline score for each of the key signs—erythema, plaque elevation, and scaling—and reported at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Affected BSA also was evaluated at each visit. In addition, an IGA×BSA composite score was calculated by multiplying the IGA by the BSA (range, 9–48 [eg, maximum IGA=4 and maximum BSA=12]) at each time point. The mean percentage change in IGA×BSA from baseline was calculated for each study visit. Additional end points included the achievement of a 50%, 75%, and 90% or greater reduction from baseline IGA×BSA score—IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90—at week 8.

Safety Assessment

Safety evaluations including adverse events (AEs), local skin reactions (LSRs), vital signs, laboratory evaluations, and physical examinations were performed. Information on reported and observed AEs was obtained at each visit. Routine safety laboratory tests were performed at screening, week 4, and week 8. An abbreviated physical examination was performed at baseline, week 8 (end of treatment), and week 12 (end of study). Treatment areas also were examined by the investigator at baseline and each subsequent visit for the presence or absence of marked known drug-related AEs including skin atrophy, striae, telangiectasia, and folliculitis.

LSR Assessment
Local skin reactions such as itching, dryness, and burning/stinging were evaluated at each study visit using 4-point scales ranging from 0 (clear) to 3 (severe). Given the nature of the disease, the presence of LSRs and symptoms at baseline is commonplace, and as such, these evaluations identified both improvement and any emergent issues.

Statistical Analysis

The primary study goal was to assess differences in treatment efficacy between HP lotion and vehicle with respect to IGA. All statistical processing was performed using SAS unless otherwise stated; statistical tests were 2-sided and performed at the 0.05 level of significance. Markov Chain Monte Carlo multiple imputation was the primary method used to handle missing efficacy data. No imputations were made for missing safety data. All participants were randomized, and the dispensed study drug was included in the intention-to-treat analysis set. This analysis was considered primary for the evaluation of efficacy. Data were analyzed using Cochran-Mantel-Haenszel tests, stratified by analysis center.

Body surface area data were analyzed in a post hoc analysis of covariance with factors of treatment and analysis center and baseline BSA as a covariate. P values for comparisons of percentage change in IGA×BSA were derived from a Wilcoxon rank sum test. For IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90, P values were derived from a Cochran-Mantel-Haenszel test. Last observation carried forward was used to impute data for IGA and BSA through week 8 prior to analysis.

The primary safety analysis was conducted at week 8 using the safety analysis set, which included all participants who were randomized, received at least 1 confirmed dose of the study drug, and had at least 1 postbaseline safety assessment. Adverse events were recorded and classified using the Medical Dictionary for Regulatory Activities (MedDRA, Version 18.0). A post hoc Wilcoxon rank sum test was conducted to compare itching, dryness, and burning/stinging scores at week 8 for HP lotion versus vehicle.

RESULTS
Participant Disposition

Overall, 430 participants were randomized (2:1) to HP lotion (n=285) or vehicle (n=145)(eFigure 1) and included in the intention-to-treat population. Across the 2 studies, 93.3% (n=266) of participants treated with HP lotion and 89.7% (n=130) of participants treated with vehicle completed treatment. The main reasons for study discontinuation with HP lotion were lost to follow-up (3.2%; n=9), participant request (1.8%; n=5), and AEs (1.4%; n=4). Participant request (4.8%; n=7), lost to follow-up (4.1%; n=6), and AEs (1.4%; n=2) also were the main reasons for treatment discontinuation in the vehicle arm.

A total of 426 participants were included in the safety population, with no postbaseline safety evaluation in 4 participants.

Baseline Participant Demographics
Demographic data were comparable across the 2 studies. The mean age (SD) was 52.6 (14.13) years. Overall, the majority of participants were male (58.8%; n=253) and white (86.5%; n=372)(eTable 1).

Efficacy Evaluation

IGA of Disease Severity
Halobetasol propionate lotion was consistently more effective than its vehicle in achieving treatment success (at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]). Halobetasol propionate lotion demonstrated statistically significant superiority over vehicle as early as week 2 (P=.003). By week 8, 37.43% of participants in the HP lotion group achieved treatment success compared with 10.03% in the vehicle group (P<.001)(Figure 1).

Overall, 39% of participants who had moderate disease (IGA score, 3) at baseline were treatment successes with HP lotion at week 8 compared with 11.53% of participants treated with vehicle; 27.97% of participants with severe disease (IGA score, 4) were treatment successes, with at least a 3-grade improvement in IGA. No participants with severe psoriasis who were treated with vehicle achieved treatment success at week 8. Efficacy was similar in female and male participants, allowing for vehicle effects.

Severity of Signs of Psoriasis (Erythema, Plaque Elevation, and Scaling) at Target Lesion Site
Halobetasol propionate lotion was statistically superior to vehicle in reducing the psoriasis signs of erythema, plaque elevation, and scaling at the target lesion from week 2. At week 8, treatment success (at least a 2-grade improvement from baseline) was achieved by 51.48% (erythema), 57.64% (plaque elevation), and 58.98% (scaling) of participants compared with 17.85%, 23.61%, and 22.82%, respectively, with vehicle (all P<.001)(Figure 2).

Safety Evaluation

Adverse event reports were low and similar between the active and vehicle groups. Overall, 61 participants (21.5%) treated with HP lotion reported AEs compared with 34 participants (23.9%) treated with vehicle (Table). The majority of participants treated with HP lotion (90.2%) had AEs that were mild or moderate. There was 1 AE of telangiectasia, not considered treatment related. There were 5 treatment-related AEs for HP lotion, all at the application site: dermatitis (0.7%; n=2), infection (0.4%; n=1), pruritus (0.4%; n=1), and discoloration (0.4%; n=1). There were no AE reports of skin atrophy or folliculitis.

Local Skin Reactions
Most LSRs at baseline were mild to moderate in severity. Itching was the most common, present in 76.8% of participants. Participant-reported burning/stinging was less common, reported by 40.6% of participants. Investigator-reported dryness was noted in 65.7% of participants. There was a rapid improvement in participant-reported itching as early as week 2 that was sustained to the end of the studies, with more gradual improvements in skin dryness and burning/stinging.

COMMENT

Plaque psoriasis is a chronic condition. The rationale behind the development of HP lotion 0.01% was to provide optimal topical treatment of moderate to severe psoriasis, allowing for the potential of prolonged use beyond the 2-week consecutive use normally applied to HP cream 0.05% in a light, once-daily, aesthetically pleasing lotion formulation that patients would prefer.

Treatment success was rapid and achieved in more than 37% of participants by week 8, with significant improvements in psoriasis signs and symptoms (erythema, plaque elevation, and scaling) compared with vehicle. However, IGA does not consider BSA involvement, a key aspect of disease severity,^11,12 and improvements in psoriasis signs of erythema, plaque elevation, and scaling were only assessed at the target lesion. Recently, the product of the IGA and BSA involvement (IGA×BSA) has been proposed as a simple alternative for assessing response to therapy that has been consistently shown to be highly correlated with the psoriasis area and severity index.^13-19 Halobetasol propionate lotion 0.01% achieved a 50% reduction in IGA×BSA score by week 8. This efficacy compares well with results reported with apremilast in patients with moderate plaque psoriasis.²⁰

Achieving clinically meaningful outcomes is an important aspect of disease management, especially in psoriasis with its disease burden and detriment to quality of life. It has been suggested that achieving a 75% or greater reduction from baseline IGA×BSA score (IGA×BSA-75) is an appropriate clinical goal.²⁰ In our investigation, IGA×BSA-75 was achieved by 39% of participants treated with HP lotion by week 8, which again compares favorably with 35% of participants in the apremilast study who achieved IGA×BSA-75 at week 16.²⁰

Physicians continue to have long-term safety concerns with TCSs,^4,11,12 participants remain concerned about the risk for skin thinning,¹³ and product labelling restricts HP cream 0.05% consecutive use to 2 weeks. In clinical experience, HP cream 0.05% is well tolerated, with potential local AEs similar to those experienced with other superpotent TCSs. In short-term clinical trials, local AEs at the site of application were reported in up to 13% of patients^21-26; itching, burning, or stinging were the most common local AEs (reported in 4.4% of patients).²⁷

There were minimal safety concerns in our 2 studies using an 8-week, once-daily treatment regimen with HP lotion 0.01%. Local AEs at the application site were reported in less than 1% of participants. Baseline itching, dryness, and burning/stinging all improved with treatment.

CONCLUSION

Halobetasol propionate lotion 0.01% provides rapid improvement in disease severity. Halobetasol propionate lotion was consistently more effective than vehicle in achieving treatment success; reducing the BSA affected by the disease; reducing erythema, plaque elevation, and scaling at the target lesion; and improving IGA×BSA score over 8 weeks, which is a realistic time frame to see improvement in psoriasis with a topical steroid. There were minimal safety concerns with prolonged use. Halobetasol propionate lotion may provide an effective and reasonable treatment option in patients with moderate to severe plaque psoriasis.

Acknowledgment
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of this article. Ortho Dermatologics funded Mr. Bulley’s activities pertaining to this article.

Psoriasis is a chronic, immune-mediated, inflammatory disease affecting almost 2% of the population.^1-3 It is characterized by patches of raised reddish skin covered by silvery-white scales. Most patients have limited disease (<5% body surface area [BSA] involvement) that can be managed with topical agents.⁴ Topical corticosteroids (TCSs) are considered first-line therapy for mild to moderate disease because of the inflammatory nature of the condition and often are used in conjunction with systemic agents in more severe psoriasis.⁴

As many as 20% to 30% of patients with moderate to severe plaque psoriasis have inadequate disease control.⁵ Several factors may affect patient outcomes; however, drug selection and patient adherence are important given the chronic nature of the disease. A survey of 1200 patients with psoriasis reported nonadherence rates of 73% with topical therapy.⁶ In addition, patients tend to apply less than the recommended dose or abandon treatment altogether if rapid improvement does not occur^7,8; it is not uncommon for patients with psoriasis to mistakenly believe treatment will improve their condition within 1 to 2 weeks.⁹ Patient satisfaction with topical treatments is low, partly because of these false expectations and formulation issues. Treatments can be greasy and sticky, with unpleasant odors and the potential to stain clothes and linens.^7,10 Safety concerns with TCSs also limit their consecutive use beyond 2 to 4 weeks, which is not ideal for a disease that requires a long-term management strategy.

A potent/superpotent TCS that is administered once daily and has a safety profile that affords longer-term, once-daily treatment in an aesthetically pleasing formulation would seem ideal. Herein, we investigate the safety and tolerability of a novel low-concentration (0.01%) lotion formulation of halobetasol propionate (HP), reporting on the pooled data from 2 phase 3 clinical studies in participants with moderate to severe psoriasis.

METHODS
Study Design

We conducted 2 multicenter, double-blind, randomized, parallel-group phase 3 studies to assess the safety, tolerability, and efficacy of HP lotion 0.01% in participants with a clinical diagnosis of moderate to severe psoriasis with an investigator global assessment (IGA) score of 3 or 4 and an affected BSA of 3% to 12%. Participants were randomized (2:1) to receive HP lotion or vehicle applied topically to the affected area once daily for 8 weeks.

Inclusion and Exclusion Criteria
The studies included individuals of either sex aged 18 years or older. A target lesion was defined primarily to assess signs of psoriasis, measuring 16 to 100 cm², with a score of 3 (moderate) or higher for 2 of 3 different psoriasis signs—erythema, plaque elevation, and scaling—and summed score of 8 or higher, with no sign scoring less than 2. Participants who had pustular psoriasis or used phototherapy, photochemotherapy, or systemic psoriasis therapy within the prior 4 weeks or biologics within the prior 3 months, or those who were diagnosed with skin conditions that would interfere with the interpretation of results were excluded from the studies.

Study Oversight
Participants provided written informed consent before study-related procedures were performed, and the protocol and consent were approved by institutional review boards or ethics committees at all investigational sites. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.

Efficacy Assessment

A 5-point scale ranging from 0 (clear) to 4 (severe) was used by the investigator at each study visit to assess the overall psoriasis severity of the treatable areas. Treatment success (the percentage of participants with at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]) was evaluated at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Signs of psoriasis at the target lesion were assessed at each visit using individual 5-point scales ranging from 0 (clear) to 4 (severe). Treatment success was defined as at least a 2-grade improvement from baseline score for each of the key signs—erythema, plaque elevation, and scaling—and reported at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Affected BSA also was evaluated at each visit. In addition, an IGA×BSA composite score was calculated by multiplying the IGA by the BSA (range, 9–48 [eg, maximum IGA=4 and maximum BSA=12]) at each time point. The mean percentage change in IGA×BSA from baseline was calculated for each study visit. Additional end points included the achievement of a 50%, 75%, and 90% or greater reduction from baseline IGA×BSA score—IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90—at week 8.

Safety Assessment

Safety evaluations including adverse events (AEs), local skin reactions (LSRs), vital signs, laboratory evaluations, and physical examinations were performed. Information on reported and observed AEs was obtained at each visit. Routine safety laboratory tests were performed at screening, week 4, and week 8. An abbreviated physical examination was performed at baseline, week 8 (end of treatment), and week 12 (end of study). Treatment areas also were examined by the investigator at baseline and each subsequent visit for the presence or absence of marked known drug-related AEs including skin atrophy, striae, telangiectasia, and folliculitis.

LSR Assessment
Local skin reactions such as itching, dryness, and burning/stinging were evaluated at each study visit using 4-point scales ranging from 0 (clear) to 3 (severe). Given the nature of the disease, the presence of LSRs and symptoms at baseline is commonplace, and as such, these evaluations identified both improvement and any emergent issues.

Statistical Analysis

The primary study goal was to assess differences in treatment efficacy between HP lotion and vehicle with respect to IGA. All statistical processing was performed using SAS unless otherwise stated; statistical tests were 2-sided and performed at the 0.05 level of significance. Markov Chain Monte Carlo multiple imputation was the primary method used to handle missing efficacy data. No imputations were made for missing safety data. All participants were randomized, and the dispensed study drug was included in the intention-to-treat analysis set. This analysis was considered primary for the evaluation of efficacy. Data were analyzed using Cochran-Mantel-Haenszel tests, stratified by analysis center.

Body surface area data were analyzed in a post hoc analysis of covariance with factors of treatment and analysis center and baseline BSA as a covariate. P values for comparisons of percentage change in IGA×BSA were derived from a Wilcoxon rank sum test. For IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90, P values were derived from a Cochran-Mantel-Haenszel test. Last observation carried forward was used to impute data for IGA and BSA through week 8 prior to analysis.

The primary safety analysis was conducted at week 8 using the safety analysis set, which included all participants who were randomized, received at least 1 confirmed dose of the study drug, and had at least 1 postbaseline safety assessment. Adverse events were recorded and classified using the Medical Dictionary for Regulatory Activities (MedDRA, Version 18.0). A post hoc Wilcoxon rank sum test was conducted to compare itching, dryness, and burning/stinging scores at week 8 for HP lotion versus vehicle.

RESULTS
Participant Disposition

Overall, 430 participants were randomized (2:1) to HP lotion (n=285) or vehicle (n=145)(eFigure 1) and included in the intention-to-treat population. Across the 2 studies, 93.3% (n=266) of participants treated with HP lotion and 89.7% (n=130) of participants treated with vehicle completed treatment. The main reasons for study discontinuation with HP lotion were lost to follow-up (3.2%; n=9), participant request (1.8%; n=5), and AEs (1.4%; n=4). Participant request (4.8%; n=7), lost to follow-up (4.1%; n=6), and AEs (1.4%; n=2) also were the main reasons for treatment discontinuation in the vehicle arm.

A total of 426 participants were included in the safety population, with no postbaseline safety evaluation in 4 participants.

Baseline Participant Demographics
Demographic data were comparable across the 2 studies. The mean age (SD) was 52.6 (14.13) years. Overall, the majority of participants were male (58.8%; n=253) and white (86.5%; n=372)(eTable 1).

Efficacy Evaluation

IGA of Disease Severity
Halobetasol propionate lotion was consistently more effective than its vehicle in achieving treatment success (at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]). Halobetasol propionate lotion demonstrated statistically significant superiority over vehicle as early as week 2 (P=.003). By week 8, 37.43% of participants in the HP lotion group achieved treatment success compared with 10.03% in the vehicle group (P<.001)(Figure 1).

Overall, 39% of participants who had moderate disease (IGA score, 3) at baseline were treatment successes with HP lotion at week 8 compared with 11.53% of participants treated with vehicle; 27.97% of participants with severe disease (IGA score, 4) were treatment successes, with at least a 3-grade improvement in IGA. No participants with severe psoriasis who were treated with vehicle achieved treatment success at week 8. Efficacy was similar in female and male participants, allowing for vehicle effects.

Severity of Signs of Psoriasis (Erythema, Plaque Elevation, and Scaling) at Target Lesion Site
Halobetasol propionate lotion was statistically superior to vehicle in reducing the psoriasis signs of erythema, plaque elevation, and scaling at the target lesion from week 2. At week 8, treatment success (at least a 2-grade improvement from baseline) was achieved by 51.48% (erythema), 57.64% (plaque elevation), and 58.98% (scaling) of participants compared with 17.85%, 23.61%, and 22.82%, respectively, with vehicle (all P<.001)(Figure 2).

Safety Evaluation

Adverse event reports were low and similar between the active and vehicle groups. Overall, 61 participants (21.5%) treated with HP lotion reported AEs compared with 34 participants (23.9%) treated with vehicle (Table). The majority of participants treated with HP lotion (90.2%) had AEs that were mild or moderate. There was 1 AE of telangiectasia, not considered treatment related. There were 5 treatment-related AEs for HP lotion, all at the application site: dermatitis (0.7%; n=2), infection (0.4%; n=1), pruritus (0.4%; n=1), and discoloration (0.4%; n=1). There were no AE reports of skin atrophy or folliculitis.

Local Skin Reactions
Most LSRs at baseline were mild to moderate in severity. Itching was the most common, present in 76.8% of participants. Participant-reported burning/stinging was less common, reported by 40.6% of participants. Investigator-reported dryness was noted in 65.7% of participants. There was a rapid improvement in participant-reported itching as early as week 2 that was sustained to the end of the studies, with more gradual improvements in skin dryness and burning/stinging.

COMMENT

Plaque psoriasis is a chronic condition. The rationale behind the development of HP lotion 0.01% was to provide optimal topical treatment of moderate to severe psoriasis, allowing for the potential of prolonged use beyond the 2-week consecutive use normally applied to HP cream 0.05% in a light, once-daily, aesthetically pleasing lotion formulation that patients would prefer.

Treatment success was rapid and achieved in more than 37% of participants by week 8, with significant improvements in psoriasis signs and symptoms (erythema, plaque elevation, and scaling) compared with vehicle. However, IGA does not consider BSA involvement, a key aspect of disease severity,^11,12 and improvements in psoriasis signs of erythema, plaque elevation, and scaling were only assessed at the target lesion. Recently, the product of the IGA and BSA involvement (IGA×BSA) has been proposed as a simple alternative for assessing response to therapy that has been consistently shown to be highly correlated with the psoriasis area and severity index.^13-19 Halobetasol propionate lotion 0.01% achieved a 50% reduction in IGA×BSA score by week 8. This efficacy compares well with results reported with apremilast in patients with moderate plaque psoriasis.²⁰

Achieving clinically meaningful outcomes is an important aspect of disease management, especially in psoriasis with its disease burden and detriment to quality of life. It has been suggested that achieving a 75% or greater reduction from baseline IGA×BSA score (IGA×BSA-75) is an appropriate clinical goal.²⁰ In our investigation, IGA×BSA-75 was achieved by 39% of participants treated with HP lotion by week 8, which again compares favorably with 35% of participants in the apremilast study who achieved IGA×BSA-75 at week 16.²⁰