Total knee arthroplasty (TKA) is an efficacious procedure for end-stage knee arthritis. Although TKA is cost-effective and has a high rate of success,^1-6 TKAs fail and may require revision surgery. Failure mechanisms include periprosthetic fracture, aseptic loosening, wear, osteolysis, instability, and infection.^7-9 In these cases, revision arthroplasty may be needed in order to restore function.

There has been a steady increase in the number of primary and revision TKAs performed in the United States.^8,10,11 Revision rates are 4% at 5 years after index TKA and 8.9% at 9 years.¹² However, surgical techniques and improved implants have led to improved outcomes after primary TKA, as evidenced by the reduction in revisions performed for polyethylene wear and osteolysis.¹³ Given the continuing need for revision TKAs (despite technical improvements¹³), evidence-based standard protocols that improve outcomes after revision TKA are necessary.

The Total Joint Replacement Perioperative Surgical Home (TJR-PSH) implemented and used by surgeons and anesthesiologists at our institution has shown that an evidence-based perioperative protocol can provide consistent and improved outcomes in primary TKA.^14-16

Materials and Methods

In this study, which received Institutional Review Board approval, we performed a prospective cross-sectional analysis comparing the perioperative outcomes of patients who underwent primary TKA with those of patients who underwent revision TKA. Medical records and our institution’s data registry were queried for LOS, discharge disposition, readmission rates, and reoperation rates.

The study included all primary and revision TKAs performed at our institution since the inception of TJA-PSH. Unicompartmental knee arthroplasties and exchanges of a single component (patella, tibia, or femur) were excluded. We identified a total of 285 consecutive primary or revision TKAs, all performed by a single surgeon. Three cases lacked complete data and were excluded, leaving 282 cases: 235 primary and 50 revision TKAs (no simultaneous bilateral TKAs). The demographic data we collected included age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, calculated Charlson Comorbidity Index (CCI), LOS, and discharge disposition.

The same established perioperative surgical home clinical pathway was used to care for all patients, whether they underwent primary or revision TKA. The primary outcomes studied were LOS, discharge disposition (subacute nursing facility or home), 30-day orthopedic readmission, and return to operating room. All reoperations on the same knee were analyzed.

Statistical Analysis

Primary and revision TKAs were compared on LOS (with an independent-sample t test) and discharge disposition, 30-day readmissions, and reoperations (χ² Fisher exact test). Multivariate regression analysis was performed with each primary outcome, using age, sex, BMI, ASA score, and CCI as covariates. Statistical significance was set at P ≤ .05. All analyses were performed with SPSS Version 16.0 (SPSS Inc.) and Microsoft Excel 2011 (Microsoft).

Results

Mean (SD) age was 66 (13.2) years for primary TKA patients and 62 (12.8) years for revision TKA patients. The cohort had more women (62.5%) than men (37.5%). There was no statistical difference in patient demographics with respect to age (P = .169) or BMI (P = .701) between the 2 groups. There was an even age distribution within each group and between the groups (Table).

There was no statistically significant difference in LOS between the groups. Mean (SD) LOS was 2.55 (1.25) days for primary TKA and 2.92 (1.24) days for revision TKA (P = .061; 95% confidence interval [CI], 0.017-0.749). Regression analysis showed a correlation between ASA score and LOS for primary TKAs but not revision TKAs. For every unit increase in ASA score, there was a 0.39-day increase in LOS for primary TKA (P = .46; 95% CI, 0.006-0.781). There was no correlation between ASA score and LOS for revision TKA when controlling for covariates (P = .124). Eighty (34%) of the 235 primary TKA patients and 21 (41%) of the 50 revision TKA patients were discharged to a subacute nursing facility; the difference was not significant (P = .123). No patient was discharged to an acute inpatient rehabilitation unit. In addition, there was no significant difference in 30-day readmission rates between primary and revision TKA (P = .081). One primary TKA patient (0.4%) and 2 revision TKA patients (4%) were readmitted within 30 days after surgery (P = .081). The primary TKA readmission was for severe spasticity and a history of cerebral palsy leading to a quadriceps avulsion fracture from the superior pole of the patella. One revision TKA readmission was for acute periprosthetic joint infection, and the other for periprosthetic fracture around a press-fit distal femoral replacement stem. There was no significant difference in number of 30-day reoperations between the groups (P = .993). None of the primary TKAs and 2 (4%) of the revision TKAs underwent reoperation. Of the revision TKA patients who returned to the operating room within 30 days after surgery, one was treated for an acute periprosthetic joint infection, the other for a femoral periprosthetic fracture.

Discussion

Advances in multidisciplinary co-management of TKA patients and their clinical effects are highlighted in the TJR-PSH.¹⁴ TJR-PSH allows the health team and the patient to prepare for surgery with an understanding of probable outcomes and to optimize the patient’s medical and educational standing to better meet expectations and increase satisfaction.

Previous studies have focused on the etiologies of revision TKA^7,8 and on understanding the factors that may predict increased risk for a poor outcome after primary TKA and indicate a possible need for revision.^8,12 The present study focused on practical clinical processes that could potentially constitute a standardized perioperative protocol for revision TKA. An organized TJR-PSH may allow the health team to educate patients that LOS, rehabilitation and acute recovery, risk of acute (30-day) complications, and risk of readmission and return to the operating room within the first 30 days after surgery are similar for revision and primary TKAs, as long as proper preoperative optimization and education occur within the TJR-PSH.

Studies have found correlations between revision TKA and significantly increased LOS and postoperative complications.^20,21 In contrast, we found no significant difference in LOS between our primary and revision TKA groups. LOS was 2.6 days for primary TKA and 2.9 days for revision TKA—a significant improvement in care and cost for revision TKA patients. That the reduced mean LOS for revision TKA is similar to the mean LOS for primary TKA also implies a reduction in the higher cost of care in revision TKA.²⁰ In addition to obtaining similar LOS for primary and revision TKA, TJR-PSH achieved an overall reduction in LOS.^17,22Our results also showed no difference in discharge disposition between primary and revision TKA in our protocol. Discharge disposition also did not correlate with age, sex, BMI, ASA score, or CCI. In TJR-PSH, discharge planning starts before admission and is patient-oriented for optimal recovery. About 66% of primary TKA patients and 58% of revision TKA patients in our cohort were discharged home—implying we are able to send a majority of our postoperative patients home after a shorter hospital stay, while obtaining the same good outcomes. Discharging fewer revision TKA patients to extended-care facilities also indicates a possible reduction in the cost of postoperative care, bringing it in line with the cost in primary TKA. Early individualized discharge planning in TJA-PSH accounts for the similar outcomes in primary and revision TKAs.

There was no significant difference in 30-day readmission rates between our primary and revision TKA patients. An important component of the TJR-PSH pathway is the individualized postdischarge recovery plan, which helps with optimal recovery and reduces readmission rates. Our cohort’s 30-day readmission rate was 0.4% for primary TKA and 4% for revision TKA (P = .081). Thirty-day readmission is a good indicator of postoperative complications and recovery from surgery. We have previously reported on primary TKA outcomes.^{14,15,,18,22,23} In a study using an NSQIP (National Surgical Quality Improvement Program) database, 11,814 primary TKAs had a 30-day readmission rate of 4.2%.¹⁸ In an outcomes study of 17,994 patients who underwent primary TKA in a single fiscal year, the 30-day readmission rate was 5.9%.⁹ In addition, in a single-institution cohort study of 1032 primary TKA patients, Schairer and colleagues²³ found a 30-day unplanned readmission rate of 3.4%. Compared with primary TKA, revision TKA traditionally has had a higher postoperative complication rate.^20,21 There is also concern that shorter hospital stays may indicate that significant complications of revision TKAs are being missed. In this study, however, we established that the equal outcomes obtained in the perioperative period carry over to the 30-day postoperative period in our revision TKA group. Good postoperative follow-up and planning are important factors in readmission reduction. Readmissions also have significant overall cost implications.²⁴There was no statistical difference in 30-day reoperation rates between our primary and revision TKA patients. The primary TKA patients had no 30-day reoperations. Previous studies have found reoperation rates ranging from 1.8% to 4.7%.^25,26 Revision TKA patients are up to 6 times more likely than primary TKA patients to require reoperation.²⁰ Our study found no significant difference in outcomes between primary and revision TKAs.

Comparison of the outcomes of primary TKA and revision TKA in TJR-PSH showed no difference in acute recovery from surgery. LOS and discharge disposition, 30-day readmission rate, and 30-day return to the operating room were the same for primary and revision TKAs. The morbidity gap between primary and revision TKA patients has been closed in our research cohort. This outcome is important, as indications for primary TKA continue to expand and more primary TKAs are performed in younger patients.^18,23 The implication is that, in the future, more knees will need to be revised as patients outlive their prostheses.

Our study had some limitations. First, it involved a small sample of patients, operated on by a single surgeon in a well-organized TJR-PSH at a large academic center. This population might not represent the US patient population, but that should not have adversely affected data analysis, because patients were compared with a similar population. Second, the data might be incomplete because some patients with complications might have sought care at other medical facilities, and we might not have been aware of these cases. Third, we focused on objective clinical outcomes in order to measure the success of TKAs. We did not include any subjective, patient-reported data, such as rehabilitation advances and functioning levels. Fourth, multiple parameters can be used to address complication outcomes, but we used LOS, discharge disposition, 30-day readmission rate, and 30-day reoperation rate because current payers and institutions often consider these variables when assessing quality of care. These parameters can be influenced by factors such as inpatient physical therapy goals, facility discharge practices, individual social support structure, and hospital pay-for-performance model. The implication is that different facilities have different outcomes in terms of LOS, discharge disposition, readmissions, and reoperations. However, we expect proportionate similarities in these parameters as patient perioperative outcomes become more complicated. Nevertheless, a multicenter study would be able to answer questions raised by this limitation. Fifth, our statistical analysis might have been affected by decreased power of some of the outcome variables.

TJR-PSH has succeeded in closing the perioperative morbidity and outcomes gap between primary and revision TKAs. Outcome parameters used to measure the success of TJR-PSH are standard measures of the immediate postoperative recovery and short-term outcomes of TKA patients. These measures are linked to complication rates and overall outcomes in many TKA studies.^14,15,17,19 Also important is that hospital costs can be drastically cut by reducing LOS, readmissions, and reoperations. Presence of any complication of primary or revision TKA raises the cost up to 34%. This increase can go as high as 64% in the 90 days after surgery.²⁷

Conclusion

The major challenge of the changing medical landscape is to integrate quality care and a continually improving healthcare system with the goal of cost-effective delivery of healthcare. Surgical care costs can be significantly increased by evitable hospital stays, complications that lead to readmissions, and unplanned returns to the operating room after index surgery. The new perioperative surgical home created for TJA has helped drastically reduce LOS, discharge disposition, 30-day readmission rate, and 30-day reoperation rate in revision TKA. This study demonstrates similar outcomes in our revision TKA patients relative to their primary TKA counterparts.

Am J Orthop. 2016;45(7):E458-E464. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Total knee arthroplasty (TKA) is an efficacious procedure for end-stage knee arthritis. Although TKA is cost-effective and has a high rate of success,^1-6 TKAs fail and may require revision surgery. Failure mechanisms include periprosthetic fracture, aseptic loosening, wear, osteolysis, instability, and infection.^7-9 In these cases, revision arthroplasty may be needed in order to restore function.

There has been a steady increase in the number of primary and revision TKAs performed in the United States.^8,10,11 Revision rates are 4% at 5 years after index TKA and 8.9% at 9 years.¹² However, surgical techniques and improved implants have led to improved outcomes after primary TKA, as evidenced by the reduction in revisions performed for polyethylene wear and osteolysis.¹³ Given the continuing need for revision TKAs (despite technical improvements¹³), evidence-based standard protocols that improve outcomes after revision TKA are necessary.

The Total Joint Replacement Perioperative Surgical Home (TJR-PSH) implemented and used by surgeons and anesthesiologists at our institution has shown that an evidence-based perioperative protocol can provide consistent and improved outcomes in primary TKA.^14-16

Materials and Methods

In this study, which received Institutional Review Board approval, we performed a prospective cross-sectional analysis comparing the perioperative outcomes of patients who underwent primary TKA with those of patients who underwent revision TKA. Medical records and our institution’s data registry were queried for LOS, discharge disposition, readmission rates, and reoperation rates.

The study included all primary and revision TKAs performed at our institution since the inception of TJA-PSH. Unicompartmental knee arthroplasties and exchanges of a single component (patella, tibia, or femur) were excluded. We identified a total of 285 consecutive primary or revision TKAs, all performed by a single surgeon. Three cases lacked complete data and were excluded, leaving 282 cases: 235 primary and 50 revision TKAs (no simultaneous bilateral TKAs). The demographic data we collected included age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, calculated Charlson Comorbidity Index (CCI), LOS, and discharge disposition.

The same established perioperative surgical home clinical pathway was used to care for all patients, whether they underwent primary or revision TKA. The primary outcomes studied were LOS, discharge disposition (subacute nursing facility or home), 30-day orthopedic readmission, and return to operating room. All reoperations on the same knee were analyzed.

Statistical Analysis

Primary and revision TKAs were compared on LOS (with an independent-sample t test) and discharge disposition, 30-day readmissions, and reoperations (χ² Fisher exact test). Multivariate regression analysis was performed with each primary outcome, using age, sex, BMI, ASA score, and CCI as covariates. Statistical significance was set at P ≤ .05. All analyses were performed with SPSS Version 16.0 (SPSS Inc.) and Microsoft Excel 2011 (Microsoft).

Results

Mean (SD) age was 66 (13.2) years for primary TKA patients and 62 (12.8) years for revision TKA patients. The cohort had more women (62.5%) than men (37.5%). There was no statistical difference in patient demographics with respect to age (P = .169) or BMI (P = .701) between the 2 groups. There was an even age distribution within each group and between the groups (Table).

There was no statistically significant difference in LOS between the groups. Mean (SD) LOS was 2.55 (1.25) days for primary TKA and 2.92 (1.24) days for revision TKA (P = .061; 95% confidence interval [CI], 0.017-0.749). Regression analysis showed a correlation between ASA score and LOS for primary TKAs but not revision TKAs. For every unit increase in ASA score, there was a 0.39-day increase in LOS for primary TKA (P = .46; 95% CI, 0.006-0.781). There was no correlation between ASA score and LOS for revision TKA when controlling for covariates (P = .124). Eighty (34%) of the 235 primary TKA patients and 21 (41%) of the 50 revision TKA patients were discharged to a subacute nursing facility; the difference was not significant (P = .123). No patient was discharged to an acute inpatient rehabilitation unit. In addition, there was no significant difference in 30-day readmission rates between primary and revision TKA (P = .081). One primary TKA patient (0.4%) and 2 revision TKA patients (4%) were readmitted within 30 days after surgery (P = .081). The primary TKA readmission was for severe spasticity and a history of cerebral palsy leading to a quadriceps avulsion fracture from the superior pole of the patella. One revision TKA readmission was for acute periprosthetic joint infection, and the other for periprosthetic fracture around a press-fit distal femoral replacement stem. There was no significant difference in number of 30-day reoperations between the groups (P = .993). None of the primary TKAs and 2 (4%) of the revision TKAs underwent reoperation. Of the revision TKA patients who returned to the operating room within 30 days after surgery, one was treated for an acute periprosthetic joint infection, the other for a femoral periprosthetic fracture.

Discussion

Advances in multidisciplinary co-management of TKA patients and their clinical effects are highlighted in the TJR-PSH.¹⁴ TJR-PSH allows the health team and the patient to prepare for surgery with an understanding of probable outcomes and to optimize the patient’s medical and educational standing to better meet expectations and increase satisfaction.

Previous studies have focused on the etiologies of revision TKA^7,8 and on understanding the factors that may predict increased risk for a poor outcome after primary TKA and indicate a possible need for revision.^8,12 The present study focused on practical clinical processes that could potentially constitute a standardized perioperative protocol for revision TKA. An organized TJR-PSH may allow the health team to educate patients that LOS, rehabilitation and acute recovery, risk of acute (30-day) complications, and risk of readmission and return to the operating room within the first 30 days after surgery are similar for revision and primary TKAs, as long as proper preoperative optimization and education occur within the TJR-PSH.

Studies have found correlations between revision TKA and significantly increased LOS and postoperative complications.^20,21 In contrast, we found no significant difference in LOS between our primary and revision TKA groups. LOS was 2.6 days for primary TKA and 2.9 days for revision TKA—a significant improvement in care and cost for revision TKA patients. That the reduced mean LOS for revision TKA is similar to the mean LOS for primary TKA also implies a reduction in the higher cost of care in revision TKA.²⁰ In addition to obtaining similar LOS for primary and revision TKA, TJR-PSH achieved an overall reduction in LOS.^17,22Our results also showed no difference in discharge disposition between primary and revision TKA in our protocol. Discharge disposition also did not correlate with age, sex, BMI, ASA score, or CCI. In TJR-PSH, discharge planning starts before admission and is patient-oriented for optimal recovery. About 66% of primary TKA patients and 58% of revision TKA patients in our cohort were discharged home—implying we are able to send a majority of our postoperative patients home after a shorter hospital stay, while obtaining the same good outcomes. Discharging fewer revision TKA patients to extended-care facilities also indicates a possible reduction in the cost of postoperative care, bringing it in line with the cost in primary TKA. Early individualized discharge planning in TJA-PSH accounts for the similar outcomes in primary and revision TKAs.

There was no significant difference in 30-day readmission rates between our primary and revision TKA patients. An important component of the TJR-PSH pathway is the individualized postdischarge recovery plan, which helps with optimal recovery and reduces readmission rates. Our cohort’s 30-day readmission rate was 0.4% for primary TKA and 4% for revision TKA (P = .081). Thirty-day readmission is a good indicator of postoperative complications and recovery from surgery. We have previously reported on primary TKA outcomes.^{14,15,,18,22,23} In a study using an NSQIP (National Surgical Quality Improvement Program) database, 11,814 primary TKAs had a 30-day readmission rate of 4.2%.¹⁸ In an outcomes study of 17,994 patients who underwent primary TKA in a single fiscal year, the 30-day readmission rate was 5.9%.⁹ In addition, in a single-institution cohort study of 1032 primary TKA patients, Schairer and colleagues²³ found a 30-day unplanned readmission rate of 3.4%. Compared with primary TKA, revision TKA traditionally has had a higher postoperative complication rate.^20,21 There is also concern that shorter hospital stays may indicate that significant complications of revision TKAs are being missed. In this study, however, we established that the equal outcomes obtained in the perioperative period carry over to the 30-day postoperative period in our revision TKA group. Good postoperative follow-up and planning are important factors in readmission reduction. Readmissions also have significant overall cost implications.²⁴There was no statistical difference in 30-day reoperation rates between our primary and revision TKA patients. The primary TKA patients had no 30-day reoperations. Previous studies have found reoperation rates ranging from 1.8% to 4.7%.^25,26 Revision TKA patients are up to 6 times more likely than primary TKA patients to require reoperation.²⁰ Our study found no significant difference in outcomes between primary and revision TKAs.

Comparison of the outcomes of primary TKA and revision TKA in TJR-PSH showed no difference in acute recovery from surgery. LOS and discharge disposition, 30-day readmission rate, and 30-day return to the operating room were the same for primary and revision TKAs. The morbidity gap between primary and revision TKA patients has been closed in our research cohort. This outcome is important, as indications for primary TKA continue to expand and more primary TKAs are performed in younger patients.^18,23 The implication is that, in the future, more knees will need to be revised as patients outlive their prostheses.

Our study had some limitations. First, it involved a small sample of patients, operated on by a single surgeon in a well-organized TJR-PSH at a large academic center. This population might not represent the US patient population, but that should not have adversely affected data analysis, because patients were compared with a similar population. Second, the data might be incomplete because some patients with complications might have sought care at other medical facilities, and we might not have been aware of these cases. Third, we focused on objective clinical outcomes in order to measure the success of TKAs. We did not include any subjective, patient-reported data, such as rehabilitation advances and functioning levels. Fourth, multiple parameters can be used to address complication outcomes, but we used LOS, discharge disposition, 30-day readmission rate, and 30-day reoperation rate because current payers and institutions often consider these variables when assessing quality of care. These parameters can be influenced by factors such as inpatient physical therapy goals, facility discharge practices, individual social support structure, and hospital pay-for-performance model. The implication is that different facilities have different outcomes in terms of LOS, discharge disposition, readmissions, and reoperations. However, we expect proportionate similarities in these parameters as patient perioperative outcomes become more complicated. Nevertheless, a multicenter study would be able to answer questions raised by this limitation. Fifth, our statistical analysis might have been affected by decreased power of some of the outcome variables.

TJR-PSH has succeeded in closing the perioperative morbidity and outcomes gap between primary and revision TKAs. Outcome parameters used to measure the success of TJR-PSH are standard measures of the immediate postoperative recovery and short-term outcomes of TKA patients. These measures are linked to complication rates and overall outcomes in many TKA studies.^14,15,17,19 Also important is that hospital costs can be drastically cut by reducing LOS, readmissions, and reoperations. Presence of any complication of primary or revision TKA raises the cost up to 34%. This increase can go as high as 64% in the 90 days after surgery.²⁷

Conclusion

The major challenge of the changing medical landscape is to integrate quality care and a continually improving healthcare system with the goal of cost-effective delivery of healthcare. Surgical care costs can be significantly increased by evitable hospital stays, complications that lead to readmissions, and unplanned returns to the operating room after index surgery. The new perioperative surgical home created for TJA has helped drastically reduce LOS, discharge disposition, 30-day readmission rate, and 30-day reoperation rate in revision TKA. This study demonstrates similar outcomes in our revision TKA patients relative to their primary TKA counterparts.

Am J Orthop. 2016;45(7):E458-E464. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Total knee arthroplasty (TKA) is an efficacious procedure for end-stage knee arthritis. Although TKA is cost-effective and has a high rate of success,^1-6 TKAs fail and may require revision surgery. Failure mechanisms include periprosthetic fracture, aseptic loosening, wear, osteolysis, instability, and infection.^7-9 In these cases, revision arthroplasty may be needed in order to restore function.

There has been a steady increase in the number of primary and revision TKAs performed in the United States.^8,10,11 Revision rates are 4% at 5 years after index TKA and 8.9% at 9 years.¹² However, surgical techniques and improved implants have led to improved outcomes after primary TKA, as evidenced by the reduction in revisions performed for polyethylene wear and osteolysis.¹³ Given the continuing need for revision TKAs (despite technical improvements¹³), evidence-based standard protocols that improve outcomes after revision TKA are necessary.

The Total Joint Replacement Perioperative Surgical Home (TJR-PSH) implemented and used by surgeons and anesthesiologists at our institution has shown that an evidence-based perioperative protocol can provide consistent and improved outcomes in primary TKA.^14-16

Materials and Methods

In this study, which received Institutional Review Board approval, we performed a prospective cross-sectional analysis comparing the perioperative outcomes of patients who underwent primary TKA with those of patients who underwent revision TKA. Medical records and our institution’s data registry were queried for LOS, discharge disposition, readmission rates, and reoperation rates.

The study included all primary and revision TKAs performed at our institution since the inception of TJA-PSH. Unicompartmental knee arthroplasties and exchanges of a single component (patella, tibia, or femur) were excluded. We identified a total of 285 consecutive primary or revision TKAs, all performed by a single surgeon. Three cases lacked complete data and were excluded, leaving 282 cases: 235 primary and 50 revision TKAs (no simultaneous bilateral TKAs). The demographic data we collected included age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, calculated Charlson Comorbidity Index (CCI), LOS, and discharge disposition.

The same established perioperative surgical home clinical pathway was used to care for all patients, whether they underwent primary or revision TKA. The primary outcomes studied were LOS, discharge disposition (subacute nursing facility or home), 30-day orthopedic readmission, and return to operating room. All reoperations on the same knee were analyzed.

Statistical Analysis

Primary and revision TKAs were compared on LOS (with an independent-sample t test) and discharge disposition, 30-day readmissions, and reoperations (χ² Fisher exact test). Multivariate regression analysis was performed with each primary outcome, using age, sex, BMI, ASA score, and CCI as covariates. Statistical significance was set at P ≤ .05. All analyses were performed with SPSS Version 16.0 (SPSS Inc.) and Microsoft Excel 2011 (Microsoft).

Results

Mean (SD) age was 66 (13.2) years for primary TKA patients and 62 (12.8) years for revision TKA patients. The cohort had more women (62.5%) than men (37.5%). There was no statistical difference in patient demographics with respect to age (P = .169) or BMI (P = .701) between the 2 groups. There was an even age distribution within each group and between the groups (Table).

There was no statistically significant difference in LOS between the groups. Mean (SD) LOS was 2.55 (1.25) days for primary TKA and 2.92 (1.24) days for revision TKA (P = .061; 95% confidence interval [CI], 0.017-0.749). Regression analysis showed a correlation between ASA score and LOS for primary TKAs but not revision TKAs. For every unit increase in ASA score, there was a 0.39-day increase in LOS for primary TKA (P = .46; 95% CI, 0.006-0.781). There was no correlation between ASA score and LOS for revision TKA when controlling for covariates (P = .124). Eighty (34%) of the 235 primary TKA patients and 21 (41%) of the 50 revision TKA patients were discharged to a subacute nursing facility; the difference was not significant (P = .123). No patient was discharged to an acute inpatient rehabilitation unit. In addition, there was no significant difference in 30-day readmission rates between primary and revision TKA (P = .081). One primary TKA patient (0.4%) and 2 revision TKA patients (4%) were readmitted within 30 days after surgery (P = .081). The primary TKA readmission was for severe spasticity and a history of cerebral palsy leading to a quadriceps avulsion fracture from the superior pole of the patella. One revision TKA readmission was for acute periprosthetic joint infection, and the other for periprosthetic fracture around a press-fit distal femoral replacement stem. There was no significant difference in number of 30-day reoperations between the groups (P = .993). None of the primary TKAs and 2 (4%) of the revision TKAs underwent reoperation. Of the revision TKA patients who returned to the operating room within 30 days after surgery, one was treated for an acute periprosthetic joint infection, the other for a femoral periprosthetic fracture.

Discussion

Advances in multidisciplinary co-management of TKA patients and their clinical effects are highlighted in the TJR-PSH.¹⁴ TJR-PSH allows the health team and the patient to prepare for surgery with an understanding of probable outcomes and to optimize the patient’s medical and educational standing to better meet expectations and increase satisfaction.

Previous studies have focused on the etiologies of revision TKA^7,8 and on understanding the factors that may predict increased risk for a poor outcome after primary TKA and indicate a possible need for revision.^8,12 The present study focused on practical clinical processes that could potentially constitute a standardized perioperative protocol for revision TKA. An organized TJR-PSH may allow the health team to educate patients that LOS, rehabilitation and acute recovery, risk of acute (30-day) complications, and risk of readmission and return to the operating room within the first 30 days after surgery are similar for revision and primary TKAs, as long as proper preoperative optimization and education occur within the TJR-PSH.

Studies have found correlations between revision TKA and significantly increased LOS and postoperative complications.^20,21 In contrast, we found no significant difference in LOS between our primary and revision TKA groups. LOS was 2.6 days for primary TKA and 2.9 days for revision TKA—a significant improvement in care and cost for revision TKA patients. That the reduced mean LOS for revision TKA is similar to the mean LOS for primary TKA also implies a reduction in the higher cost of care in revision TKA.²⁰ In addition to obtaining similar LOS for primary and revision TKA, TJR-PSH achieved an overall reduction in LOS.^17,22Our results also showed no difference in discharge disposition between primary and revision TKA in our protocol. Discharge disposition also did not correlate with age, sex, BMI, ASA score, or CCI. In TJR-PSH, discharge planning starts before admission and is patient-oriented for optimal recovery. About 66% of primary TKA patients and 58% of revision TKA patients in our cohort were discharged home—implying we are able to send a majority of our postoperative patients home after a shorter hospital stay, while obtaining the same good outcomes. Discharging fewer revision TKA patients to extended-care facilities also indicates a possible reduction in the cost of postoperative care, bringing it in line with the cost in primary TKA. Early individualized discharge planning in TJA-PSH accounts for the similar outcomes in primary and revision TKAs.

There was no significant difference in 30-day readmission rates between our primary and revision TKA patients. An important component of the TJR-PSH pathway is the individualized postdischarge recovery plan, which helps with optimal recovery and reduces readmission rates. Our cohort’s 30-day readmission rate was 0.4% for primary TKA and 4% for revision TKA (P = .081). Thirty-day readmission is a good indicator of postoperative complications and recovery from surgery. We have previously reported on primary TKA outcomes.^{14,15,,18,22,23} In a study using an NSQIP (National Surgical Quality Improvement Program) database, 11,814 primary TKAs had a 30-day readmission rate of 4.2%.¹⁸ In an outcomes study of 17,994 patients who underwent primary TKA in a single fiscal year, the 30-day readmission rate was 5.9%.⁹ In addition, in a single-institution cohort study of 1032 primary TKA patients, Schairer and colleagues²³ found a 30-day unplanned readmission rate of 3.4%. Compared with primary TKA, revision TKA traditionally has had a higher postoperative complication rate.^20,21 There is also concern that shorter hospital stays may indicate that significant complications of revision TKAs are being missed. In this study, however, we established that the equal outcomes obtained in the perioperative period carry over to the 30-day postoperative period in our revision TKA group. Good postoperative follow-up and planning are important factors in readmission reduction. Readmissions also have significant overall cost implications.²⁴There was no statistical difference in 30-day reoperation rates between our primary and revision TKA patients. The primary TKA patients had no 30-day reoperations. Previous studies have found reoperation rates ranging from 1.8% to 4.7%.^25,26 Revision TKA patients are up to 6 times more likely than primary TKA patients to require reoperation.²⁰ Our study found no significant difference in outcomes between primary and revision TKAs.

Comparison of the outcomes of primary TKA and revision TKA in TJR-PSH showed no difference in acute recovery from surgery. LOS and discharge disposition, 30-day readmission rate, and 30-day return to the operating room were the same for primary and revision TKAs. The morbidity gap between primary and revision TKA patients has been closed in our research cohort. This outcome is important, as indications for primary TKA continue to expand and more primary TKAs are performed in younger patients.^18,23 The implication is that, in the future, more knees will need to be revised as patients outlive their prostheses.

Our study had some limitations. First, it involved a small sample of patients, operated on by a single surgeon in a well-organized TJR-PSH at a large academic center. This population might not represent the US patient population, but that should not have adversely affected data analysis, because patients were compared with a similar population. Second, the data might be incomplete because some patients with complications might have sought care at other medical facilities, and we might not have been aware of these cases. Third, we focused on objective clinical outcomes in order to measure the success of TKAs. We did not include any subjective, patient-reported data, such as rehabilitation advances and functioning levels. Fourth, multiple parameters can be used to address complication outcomes, but we used LOS, discharge disposition, 30-day readmission rate, and 30-day reoperation rate because current payers and institutions often consider these variables when assessing quality of care. These parameters can be influenced by factors such as inpatient physical therapy goals, facility discharge practices, individual social support structure, and hospital pay-for-performance model. The implication is that different facilities have different outcomes in terms of LOS, discharge disposition, readmissions, and reoperations. However, we expect proportionate similarities in these parameters as patient perioperative outcomes become more complicated. Nevertheless, a multicenter study would be able to answer questions raised by this limitation. Fifth, our statistical analysis might have been affected by decreased power of some of the outcome variables.

TJR-PSH has succeeded in closing the perioperative morbidity and outcomes gap between primary and revision TKAs. Outcome parameters used to measure the success of TJR-PSH are standard measures of the immediate postoperative recovery and short-term outcomes of TKA patients. These measures are linked to complication rates and overall outcomes in many TKA studies.^14,15,17,19 Also important is that hospital costs can be drastically cut by reducing LOS, readmissions, and reoperations. Presence of any complication of primary or revision TKA raises the cost up to 34%. This increase can go as high as 64% in the 90 days after surgery.²⁷

Conclusion

The major challenge of the changing medical landscape is to integrate quality care and a continually improving healthcare system with the goal of cost-effective delivery of healthcare. Surgical care costs can be significantly increased by evitable hospital stays, complications that lead to readmissions, and unplanned returns to the operating room after index surgery. The new perioperative surgical home created for TJA has helped drastically reduce LOS, discharge disposition, 30-day readmission rate, and 30-day reoperation rate in revision TKA. This study demonstrates similar outcomes in our revision TKA patients relative to their primary TKA counterparts.

Am J Orthop. 2016;45(7):E458-E464. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Internet-delivered cognitive-behavioral therapy is effective at overcoming chronic insomnia, a randomized controlled trial of 303 adults showed.

In the trial, patients who were randomized to receive cognitive-behavioral therapy for insomnia (CBT-I) used a Web-based program called Sleep Healthy Using the Internet (SHUTi), which “incorporates the primary tenets of face-to-face CBT-I, including sleep restriction, stimulus control, cognitive restructuring, sleep hygiene, and relapse prevention,” wrote Lee M. Ritterband, PhD, and his associates. Meanwhile, patients in the control group received online, nonspecific patient education.

©Karen Winton/iStockphoto

[email protected]

Internet-delivered cognitive-behavioral therapy is effective at overcoming chronic insomnia, a randomized controlled trial of 303 adults showed.

In the trial, patients who were randomized to receive cognitive-behavioral therapy for insomnia (CBT-I) used a Web-based program called Sleep Healthy Using the Internet (SHUTi), which “incorporates the primary tenets of face-to-face CBT-I, including sleep restriction, stimulus control, cognitive restructuring, sleep hygiene, and relapse prevention,” wrote Lee M. Ritterband, PhD, and his associates. Meanwhile, patients in the control group received online, nonspecific patient education.

©Karen Winton/iStockphoto

[email protected]

Internet-delivered cognitive-behavioral therapy is effective at overcoming chronic insomnia, a randomized controlled trial of 303 adults showed.

In the trial, patients who were randomized to receive cognitive-behavioral therapy for insomnia (CBT-I) used a Web-based program called Sleep Healthy Using the Internet (SHUTi), which “incorporates the primary tenets of face-to-face CBT-I, including sleep restriction, stimulus control, cognitive restructuring, sleep hygiene, and relapse prevention,” wrote Lee M. Ritterband, PhD, and his associates. Meanwhile, patients in the control group received online, nonspecific patient education.

©Karen Winton/iStockphoto

[email protected]

For patients with submassive acute pulmonary embolism—the intermediate category between massive and low-risk—whether to give thrombolytic therapy is controversial. In general, patients with massive pulmonary embolism need this therapy, whereas those with low-risk pulmonary embolism do not—and neither do most of those with submassive embolism. But where should we draw the line?

See related editorial

More than 600,000 patients suffer pulmonary embolisms every year in the United States, and 50,000 to 200,000 people die of them.^1–3 In various studies,^4–6 within 1 year, 12.9% of patients had another pulmonary embolism, 7.3% developed chronic venous insufficiency, and 3.8% developed chronic thromboembolic pulmonary hypertension.

THREE CATEGORIES OF RISK

Episodes of acute pulmonary embolism are classified as low-risk (about 70% of cases), hemodynamically unstable or massive (5%), or submassive (25%).^7,8

Low-risk acute pulmonary embolism is defined by the absence of right ventricular dysfunction and the absence of myocardial necrosis. The death rate in such cases is less than 1%.⁹ Its pharmacologic management includes parenteral anticoagulation and early initiation of long-term anticoagulation therapy, which the American College of Chest Physicians (ACCP) gives a grade IB recommendation (strong, based on moderate-quality evidence).¹⁰

Massive or hemodynamically unstable pulmonary embolism is characterized by any of the following, in the absence of other causes⁸:

• Sustained hypotension (systolic blood pressure < 90 mm Hg for ≥ 15 minutes)
• An absolute decrease in systolic blood pressure of 40 mm Hg or more
• Need for inotropic support
• Cardiac arrest
• Bradycardia (heart rate < 40 beats per minute).

The death rate is more than 30% in patients presenting with shock and approaches 70% in those presenting with cardiac arrest.^11,12 Therefore, the consensus is that this category of pulmonary embolism merits aggressive treatment. Systemic thrombolytic therapy is recommended in those who are not at high risk of major bleeding, though the ACCP gives it only a grade 2C recommendation (weak, based on low-quality evidence).¹⁰

Submassive pulmonary embolism is defined by evidence of right ventricular dysfunction with normal blood pressure. According to the ACCP guidelines, thrombolytic therapy should be considered (grade 2C recommendation) for patients with acute pulmonary embolism without hypotension and with a low bleeding risk (with no renal failure and not on dual antiplatelet therapy), but at high risk of developing hypotension.¹⁰

DIAGNOSING SUBMASSIVE PULMONARY EMBOLISM, DELINEATING ITS SEVERITY

In managing acute pulmonary embolism, it is critical to recognize whether a patient is at high risk of clinical deterioration.

Blood pressure

The systolic blood pressure not only indicates whether the patient has hypotension (systolic blood pressure < 90 mm Hg) and therefore massive rather than submassive or low-risk pulmonary embolism; it is also important as a baseline value. A decrease in systolic blood pressure of 40 mm Hg or more is associated with worse outcomes.¹²

Right ventricular dysfunction

The physiologic response to occlusion of the pulmonary arteries can result in early myocardial injury and right ventricular dysfunction, which can be assessed by various methods (Table 1).

Electrocardiographic signs. Right heart strain may be recognized on electrocardiography as:

• Evidence of new complete or incomplete right bundle branch block
• T-wave inversion in the anterolateral leads V₁ to V₄
• S1Q3T3 (a large S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III, the classic pattern of acute cor pulmonale).¹³ 

These findings add incremental prognostic value to echocardiographic findings in patients with submassive pulmonary embolism.¹⁴

Cardiac biomarkers such as B-type natriuretic peptide (BNP), N-terminal-pro-BNP (NT-pro-BNP), cardiac troponins, and heart-type fatty acid-binding protein (H-FABP) are also markers of right-sided myocardial damage and strain and can be used to identify patients with submassive pulmonary embolism.¹⁵ Abnormal levels of these substances are as follows:

• Troponin T greater than 0.1 ng/mL
• Troponin I greater than 0.4 ng/mL
• BNP greater than 90 pg/mL
• NT-pro-BNP greater than 500 pg/mL
• H-FABP less than 6 ng/mL.

These levels have prognostic value, identifying patients with submassive pulmonary embolism at risk of deterioration or death,^14,16,17

Echocardiographic signs. Right ventricular dysfunction can be assessed quickly at the bedside with portable transthoracic echocardiography. A meta-analysis showed that close to 37% of hemodynamically stable patients with pulmonary embolism had echocardiographic evidence of right ventricular dysfunction on presentation and a higher short-term mortality rate.¹⁸ Evidence of right ventricular dysfunction includes the following:

• New-onset hypokinesis or akinesis
• Right ventricular dilation
• Right ventricular free-wall hypokinesis with apical sparing (the McConnell sign)
• Paradoxical movement of the interventricular septum
• Newly increased right ventricular systolic pressure
• Pulmonary hypertension, defined as tricuspid regurgitation jet velocity greater than 2.8 m/s.^15,19

Computed tomographic (CT) angiography is widely available. Findings that have prognostic value in determining those at higher risk of death include the following^20,21:

• A dilated right ventricle—ratio of right ventricle to left ventricle diameter (RV:LV ratio) greater than 0.9
• Interventricular septal bowing.

PESI and sPESI scores. The European Society of Cardiology 2014 guidelines stratify the risk in normotensive patients with pulmonary embolism according to their score on the Pulmonary Embolism Severity Index (PESI) or the simplified PESI (sPESI). There are five PESI classes. Those in PESI class III or IV or with an sPESI score of 1 or more (on a scale of 0 to 6) are considered at intermediate risk of clinical deterioration and are then further risk-stratified according to whether they have right ventricular dysfunction (based on echocardiography or computed tomography) and elevated cardiac biomarkers. These scoring systems are based on easily obtainable clinical information such as age, male sex, history of cancer, history of heart failure, history of chronic lung disease, heart rate, systolic blood pressure, respiratory rate, temperature, and altered mental status, and calculators are readily available.

Anticoagulation for all, plus thrombolysis for some

Patients with neither right ventricular dysfunction nor elevated cardiac biomarkers are at intermediate to low risk of clinical deterioration, and it is recommended that they be given anticoagulation therapy in an inpatient setting.

On the other hand, patients with both right ventricular dysfunction and elevated cardiac biomarkers are considered at intermediate to high risk of clinical deterioration; they should also be managed with anticoagulation and monitored closely for the need for rescue reperfusion therapy with thrombolytics.²²

THROMBOLYTIC AGENTS

Thrombolytic agents are the cornerstone of management for patients presenting with pulmonary embolism who are at high risk. As noted above, these agents are recommended in massive pulmonary embolism, but their role in submassive pulmonary embolism remains controversial.

Thrombolytics work by activating endogenous plasminogen. The resulting plasmin promotes clot lysis, reducing the size of the thrombus, decreasing pulmonary vasculature resistance, and improving right ventricular function.²³

To date, three thrombolytic agents have received US Food and Drug Administration approval for use in massive pulmonary embolism: alteplase, urokinase, and streptokinase. But only alteplase is still available in the United States. Alteplase is also the best tolerated, whereas streptokinase is highly antigenic and may cause further deterioration in an already unstable patient. Alteplase is also the most fibrin-specific and is considered the most potent of the three agents.²⁴

Additional thrombolytic agents under investigation for use in acute pulmonary embolism include reteplase, tenecteplase, and desmoteplase. These agents are more fibrin-specific than alteplase. Reteplase is a second-generation recombinant tissue-type plasminogen activator with a quicker onset of action and longer half-life than alteplase, allowing for bolus dosing. Tenecteplase, a variant of alteplase, is cleared more slowly and is 14 times more fibrin-specific than alteplase, also allowing for bolus dosing. Desmoteplase, a fibrin-specific agent currently in phase 2 trials, also has a longer half-life and appears to be more potent than alteplase. Table 2 lists the dosing and the degree of fibrin specificity of these agents.

Complications of thrombolytic therapy

Submassive pulmonary embolism has a low death rate, and the benefit of systemic thrombolytic therapy for this condition is controversial. Therefore, risk stratification is very important before pursuing this therapy.

A meta-analysis²⁵ of 16 randomized controlled trials included 2,125 patients with pulmonary embolism:

• 210 (9.88%) in the low-risk category
• 1,499 (70.54%) in the submassive category
• 31 (1.46%) in the massive category
• 385 (18.11%) whose disease severity could not be determined.

Major bleeding occurred in:

• 98 (9.24%) of 1,061 patients receiving anticoagulation plus thrombolytics
• 36 (3.42%) of 1,054 patients receiving anticoagulation without thrombolytics (odds ratio [OR] 2.73, 95% confidence interval [CI] 1.91–3.91; number needed to harm [NNH] 18, 95% CI 13–27).

Intracranial hemorrhage occurred in:

• 15 (1.46%) of 2,014 patients on thrombolytic therapy
• 2 (0.19%) of 1,019 patients not on thrombolytic therapy (OR 4.63, 95% CI 1.78–12.04; NNH 78, 95% CI 48–206).

Of note, the incidence of major bleeding was not significantly increased in those age 65 or younger receiving thrombolytics (OR 1.25, 95% CI 0.5–3.14).

Comments. Definitions of major bleeding varied in the individual trials. Additionally, intracranial hemorrhage was included as a major bleeding end point in any trial in which it was not prespecified.

These findings emphasize the importance of risk stratification before pursuing thrombolytic therapy in submassive pulmonary embolism.

Table 3 lists absolute and relative contraindications to thrombolytic therapy.

MAJOR STUDIES IN SUBMASSIVE PULMONARY EMBOLISM

The MAPPET-3 trial

The Management Strategies and Prognosis of Pulmonary Embolism-3 (MAPPET-3) trial,²⁶ in 2002, was the first major trial to study thrombolytic therapy in submassive pulmonary embolism.

In this prospective, randomized, double-blinded trial conducted in Germany, 118 patients received heparin with alteplase (100 mg over 2 hours) and 138 received heparin with placebo. The primary end point was in-hospital death or clinical deterioration requiring escalation of treatment. Secondary outcomes included recurrent pulmonary embolism, major bleeding, and stroke. Major bleeding was defined as fatal bleeding, hemorrhagic stroke, or drop in the hemoglobin concentration by more than 4 g/dL, with or without the need for red blood cell transfusion.

Right ventricular dysfunction was diagnosed by echocardiography in 30% of the participants, and the rest of the patients were classified as having submassive pulmonary embolism on the basis of electrocardiographic criteria alone. It is likely that the latter group had a less severe form of the disease and did not benefit from thrombolytic therapy as much as patients with echocardiographic findings of right ventricular dysfunction and elevated serum cardiac biomarkers.

Results. At 30 days, 11% of the alteplase-plus-heparin group had met the primary end point, compared with 24.6% of the placebo-plus-heparin group (P = .006). The difference was mostly driven by the need for secondary thrombolysis (7.6% vs 23.2%, P = .001), since 32 (23.2%) of the 138 patients in the control group required secondary thrombolysis, accounting for 94% of the 34 patients in this group who required escalation of treatment. Most cases of clinical deterioration in this group occurred within the first 5 days.

Mortality rates were 3.4% in the heparin-plus-alteplase group and 2.2% in the heparin-plus-placebo group, but the difference was not statistically significant (P = .71).

Major bleeding occurred in 1 patient in the heparin-plus-alteplase group and 5 patients in the heparin-plus-placebo group, but the trial’s definition of major bleeding may have resulted in underestimation of this event. The definition put forth by the International Society on Thrombosis and Haemostasis is less strict, defining bleeding in nonsurgical patients as major if it is fatal, symptomatic in a critical area or organ, or causing a fall in hemoglobin level of 2.0 g/dL or more, leading to transfusion of two or more units of whole blood or red cells.²⁷

MOPETT trial

The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial²⁸ was a single-center, randomized trial in 121 normotensive patients with “moderate” pulmonary embolism and right ventricular dysfunction. Moderate pulmonary embolism was defined as signs and symptoms of pulmonary embolism with evidence on computed tomographic angiography of greater than 70% involvement with thrombus in two or more lobes or left or right main pulmonary arteries, or by a high-probability ventilation-perfusion scan showing a mismatch in two or more lobes.

The authors defined right ventricular dysfunction by elevated cardiac markers or by findings on echocardiography. Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.

The primary outcome was the development of pulmonary hypertension, based on echocardiography.

Patients were randomized to either anticoagulation alone (unfractionated heparin or low-molecular-weight heparin) or anticoagulation plus half-dose alteplase (0.5 mg/kg, to a maximum of 50 mg). Echocardiography was performed within 2 hours of study entry, at 48 hours, and every 6 months thereafter. The mean duration of follow-up was 28 months.

Results. Pulmonary hypertension developed in 16% of the anticoagulation-plus-alteplase group vs 57% of the anticoagulation-only group (P < .001). However, the clinical relevance of elevated right-sided pressures observed by echocardiography in asymptomatic patients is uncertain. Alteplase had no impact on the rates of death or recurrent pulmonary embolism.

PEITHO trial

The 2014 Pulmonary Embolism Thrombolysis (PEITHO) trial²⁹ was a prospective, randomized, double-blinded, placebo-controlled trial conducted in 13 countries between 2007 and 2012. A total of 1,005 patients with submassive pulmonary embolism received unfractionated heparin and were randomized to also receive either tenecteplase or placebo.

The primary end point was death from any cause or hemodynamic compromise within 7 days of randomization. Secondary end points included death within 30 days, recurrence of pulmonary embolism, major bleeding, and stroke.

Echocardiography was strongly recommended for diagnosing right ventricular dysfunction in all patients. When this was unavailable, computed tomographic images were used to assess right ventricular dysfunction. Major bleeding was characterized as moderate or severe, and bleeding events were reported using the International Society on Thrombosis and Haemostasis criteria.

Results. The tenecteplase group had a lower rate of the primary end point at 7 days (2.6% vs 5.6%, P = .02), but no significant reduction in all-cause mortality at 30 days (2.4% vs 3.2%, P = .42). In addition, the tenecteplase group had higher rates of major extracranial bleeding (6.3% vs 1.2%, P < .001) and stroke (2.4% vs 0.2%, P = .004) at 7 days.

Although the PEITHO trial showed no reduction in mortality rates and showed a higher rate of major bleeding, this may have been related to using a higher dose of tenecteplase than needed in this population. Further studies should be conducted to confirm this theory.

TOPCOAT trial

The Tenecteplase or Placebo, Cardiopulmonary Outcomes at Three months (TOPCOAT) trial,³⁰ published in 2014, was a multicenter, double-blind, intention-to-treat, randomized trial carried out in eight centers in the United States. The authors evaluated a composite outcome (death, circulatory shock, intubation, major bleeding, recurrent pulmonary embolism, and functional capacity) with the use of tenecteplase in submassive pulmonary embolism.

A total of 83 patients received low-molecular-weight heparin and were randomized to also receive either tenecteplase or placebo. Submassive pulmonary embolism was defined as evidence of right ventricular strain based on echocardiographic findings and elevated cardiac markers (troponin, BNP, or NT-pro-BNP).

Results. Adverse outcomes occurred in 37% of the patients in the placebo group compared with 15% of those in the tenecteplase group (P = .017). The study was terminated early because the lead author relocated to another institution.

Wang et al

In a prospective, randomized, open-label, multicenter study³¹ conducted in China between 2002 and 2006, 118 patients received low-molecular-weight heparin plus alteplase in a dose of either 100 mg or 50 mg over 2 hours.

Results. There were significantly fewer bleeding episodes in patients receiving half-dose alteplase in the subgroups that weighed less than 65 kg (14.8% vs 41.2%, P = .049) or who had a body mass index less than 24 kg/m² (8.7% vs 42.9%, P = .014).

Meta-analysis

A subgroup analysis²⁵ of patients with submassive pulmonary embolism from a 2014 meta-analysis of randomized controlled trials of thrombolytic therapy in pulmonary embolism found that thrombolysis was associated with a lower mortality rate (OR 0.48; 95% CI 0.25–0.92) but a higher rate of major bleeding (OR 3.19, 95% CI 2.07–4.92).

Is there a role for low-dose thrombolytic therapy?

The MOPETT study, discussed above, evaluated the effect of thrombolysis in a low (“safe”) dose in reducing pulmonary artery pressure in moderate pulmonary embolism.²⁸ The primary end points were pulmonary hypertension and the composite end point of pulmonary hypertension and recurrent pulmonary embolism. In the thrombolysis group, the pulmonary arterial pressure fell immediately and was still lower at 28 months. As mentioned, although the incidence of pulmonary hypertension was lower with thrombolysis, no significant differences were noted in the rate of individual outcomes of death and recurrent pulmonary embolism when assessed independently. Furthermore, the definition of moderate pulmonary embolism used in this study is different from the submassive criteria.

Wang et al³¹ enrolled patients to receive low-molecular-weight heparin plus alteplase in a dose of either 50 or 100 mg. The rate of bleeding was lower with the 50-mg dose, but only in the subset of patients with lower weight and body mass index.

What is the role of catheter-guided therapy?

Catheter-directed therapy involves infusing thrombolytic agents directly into the pulmonary arteries where the clots are. The idea is to expose the patient to lower doses of systemic thrombolytics and thus decrease the risk of bleeding.

The ULTIMA study³² (Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism) evaluated whether this treatment would reverse right ventricular dilation in intermediate-risk patients, compared with anticoagulation. Intermediate-risk pulmonary embolism was defined as an embolus located in at least one main or proximal lower lobe pulmonary artery and an RV:LV ratio of at least 1.0 obtained from the echocardiographic apical four-chamber view.

The study showed hemodynamic improvement as evidenced by a lower RV:LV ratio. However, at 90 days the mortality rate was not significantly lower in the treatment group than in the control group. Of note, no major bleeding events were reported in the treatment group.

The SEATTLE II trial,³³ a nonrandomized study completed in April 2013, evaluated the efficacy and safety of ultrasonographically guided, catheter-based, low-dose fibrinolysis for patients with massive and submassive pulmonary embolism. Patients had CT evidence of proximal pulmonary embolism and a dilated right ventricle (RV:LV ratio ≥ 0.9). Patients received alteplase 24 mg, either as 1 mg/hour for 24 hours with a unilateral catheter or 1 mg/hour in each of two catheters for 12 hours.

At 48 hours after the procedure, the mean RV:LV ratio had decreased from 1.55 to 1.13, the mean pulmonary arterial systolic pressure had fallen, and the anatomical clot burden had decreased. A total of 15 patients (10%) experienced major bleeding but there were no reports of any fatal or intracranial bleeding. Patients with massive pulmonary embolism were more likely to experience major bleeding episodes than those with submassive pulmonary embolism (23% vs 7%, P = .02).

The weakness of this study is that it was a single-arm study and therefore limits comparisons with other therapies such as tissue plasminogen activator for massive pulmonary embolism or anticoagulation. Also, although there was an acute improvement in hemodynamics, it is unclear if that translates to improvement in mortality rate.

Based on the available literature,^29,31,33 patients presenting with submassive pulmonary embolism who are of low body weight (body mass index < 24 kg/m² or weight < 65 kg) or are over age 75 may benefit from low-dose catheter-guided thrombolysis therapy or low-dose systemic alteplase (50 mg). Further studies should be conducted comparing these two therapeutic strategies.

SURGICAL EMBOLECTOMY: STILL THE LAST RESORT

Surgery has been the last resort for patients with pulmonary embolism. Although recent reports show a decrease in mortality from advances in surgical embolectomy, the mortality rate is greater than 10%.³⁴

• Indications for surgical embolectomy are³⁵:
• Failure of or contraindications to thrombolytic therapy
• Continued hemodynamic instability despite maximal medical therapy
• Associated cardiac pathology such as patent foramen ovale, atrial septal defect, and free-floating right heart thrombi
• Inadequate time for systemic thrombolytics to take effect.

No large or randomized controlled trials of surgical embolectomy for submassive pulmonary embolism have been done. In one study, of 47 patients undergoing surgical embolectomy, 15 (32%) met the criteria for submassive pulmonary embolism based on right ventricular hemodynamic dysfunction. The report did not mention if biomarkers such as troponin and BNP were considered in the decision to operate.³⁶

At this time, surgical embolectomy remains a last resort for patients with acute massive pulmonary embolism who have contraindications to thrombolysis or for whom it has failed. Given the risk of death associated with surgical embolectomy, large randomized controlled trials need to be done to see if there is any benefit in the submassive pulmonary embolism population.

ONE TREATMENT DOES NOT FIT ALL

Given the evidence to date, we do not recommend thrombolytic therapy for all patients with submassive pulmonary embolism. The risk of complications (hemorrhage) is significant, and the benefit is unclear. A one-treatment-for-all approach cannot be applied in this situation.

Furthermore, each of the trials performed so far defined submassive pulmonary embolism slightly differently (Table 4), and many were underpowered to detect a difference in mortality rates between the treatment groups. Further studies are needed to determine the exact subset of patients with submassive pulmonary embolism that may truly benefit from thrombolytic therapy.

As such, patients with submassive pulmonary embolism should be managed by a multidisciplinary team to determine the need for thrombolytic therapy, especially in low doses, on a case-by-case basis according to the patient’s risk of further clinical deterioration.

For patients with submassive acute pulmonary embolism—the intermediate category between massive and low-risk—whether to give thrombolytic therapy is controversial. In general, patients with massive pulmonary embolism need this therapy, whereas those with low-risk pulmonary embolism do not—and neither do most of those with submassive embolism. But where should we draw the line?

See related editorial

More than 600,000 patients suffer pulmonary embolisms every year in the United States, and 50,000 to 200,000 people die of them.^1–3 In various studies,^4–6 within 1 year, 12.9% of patients had another pulmonary embolism, 7.3% developed chronic venous insufficiency, and 3.8% developed chronic thromboembolic pulmonary hypertension.

THREE CATEGORIES OF RISK

Episodes of acute pulmonary embolism are classified as low-risk (about 70% of cases), hemodynamically unstable or massive (5%), or submassive (25%).^7,8

Low-risk acute pulmonary embolism is defined by the absence of right ventricular dysfunction and the absence of myocardial necrosis. The death rate in such cases is less than 1%.⁹ Its pharmacologic management includes parenteral anticoagulation and early initiation of long-term anticoagulation therapy, which the American College of Chest Physicians (ACCP) gives a grade IB recommendation (strong, based on moderate-quality evidence).¹⁰

Massive or hemodynamically unstable pulmonary embolism is characterized by any of the following, in the absence of other causes⁸:

• Sustained hypotension (systolic blood pressure < 90 mm Hg for ≥ 15 minutes)
• An absolute decrease in systolic blood pressure of 40 mm Hg or more
• Need for inotropic support
• Cardiac arrest
• Bradycardia (heart rate < 40 beats per minute).

The death rate is more than 30% in patients presenting with shock and approaches 70% in those presenting with cardiac arrest.^11,12 Therefore, the consensus is that this category of pulmonary embolism merits aggressive treatment. Systemic thrombolytic therapy is recommended in those who are not at high risk of major bleeding, though the ACCP gives it only a grade 2C recommendation (weak, based on low-quality evidence).¹⁰

Submassive pulmonary embolism is defined by evidence of right ventricular dysfunction with normal blood pressure. According to the ACCP guidelines, thrombolytic therapy should be considered (grade 2C recommendation) for patients with acute pulmonary embolism without hypotension and with a low bleeding risk (with no renal failure and not on dual antiplatelet therapy), but at high risk of developing hypotension.¹⁰

DIAGNOSING SUBMASSIVE PULMONARY EMBOLISM, DELINEATING ITS SEVERITY

In managing acute pulmonary embolism, it is critical to recognize whether a patient is at high risk of clinical deterioration.

Blood pressure

The systolic blood pressure not only indicates whether the patient has hypotension (systolic blood pressure < 90 mm Hg) and therefore massive rather than submassive or low-risk pulmonary embolism; it is also important as a baseline value. A decrease in systolic blood pressure of 40 mm Hg or more is associated with worse outcomes.¹²

Right ventricular dysfunction

The physiologic response to occlusion of the pulmonary arteries can result in early myocardial injury and right ventricular dysfunction, which can be assessed by various methods (Table 1).

Electrocardiographic signs. Right heart strain may be recognized on electrocardiography as:

• Evidence of new complete or incomplete right bundle branch block
• T-wave inversion in the anterolateral leads V₁ to V₄
• S1Q3T3 (a large S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III, the classic pattern of acute cor pulmonale).¹³ 

These findings add incremental prognostic value to echocardiographic findings in patients with submassive pulmonary embolism.¹⁴

Cardiac biomarkers such as B-type natriuretic peptide (BNP), N-terminal-pro-BNP (NT-pro-BNP), cardiac troponins, and heart-type fatty acid-binding protein (H-FABP) are also markers of right-sided myocardial damage and strain and can be used to identify patients with submassive pulmonary embolism.¹⁵ Abnormal levels of these substances are as follows:

• Troponin T greater than 0.1 ng/mL
• Troponin I greater than 0.4 ng/mL
• BNP greater than 90 pg/mL
• NT-pro-BNP greater than 500 pg/mL
• H-FABP less than 6 ng/mL.

These levels have prognostic value, identifying patients with submassive pulmonary embolism at risk of deterioration or death,^14,16,17

Echocardiographic signs. Right ventricular dysfunction can be assessed quickly at the bedside with portable transthoracic echocardiography. A meta-analysis showed that close to 37% of hemodynamically stable patients with pulmonary embolism had echocardiographic evidence of right ventricular dysfunction on presentation and a higher short-term mortality rate.¹⁸ Evidence of right ventricular dysfunction includes the following:

• New-onset hypokinesis or akinesis
• Right ventricular dilation
• Right ventricular free-wall hypokinesis with apical sparing (the McConnell sign)
• Paradoxical movement of the interventricular septum
• Newly increased right ventricular systolic pressure
• Pulmonary hypertension, defined as tricuspid regurgitation jet velocity greater than 2.8 m/s.^15,19

Computed tomographic (CT) angiography is widely available. Findings that have prognostic value in determining those at higher risk of death include the following^20,21:

• A dilated right ventricle—ratio of right ventricle to left ventricle diameter (RV:LV ratio) greater than 0.9
• Interventricular septal bowing.

PESI and sPESI scores. The European Society of Cardiology 2014 guidelines stratify the risk in normotensive patients with pulmonary embolism according to their score on the Pulmonary Embolism Severity Index (PESI) or the simplified PESI (sPESI). There are five PESI classes. Those in PESI class III or IV or with an sPESI score of 1 or more (on a scale of 0 to 6) are considered at intermediate risk of clinical deterioration and are then further risk-stratified according to whether they have right ventricular dysfunction (based on echocardiography or computed tomography) and elevated cardiac biomarkers. These scoring systems are based on easily obtainable clinical information such as age, male sex, history of cancer, history of heart failure, history of chronic lung disease, heart rate, systolic blood pressure, respiratory rate, temperature, and altered mental status, and calculators are readily available.

Anticoagulation for all, plus thrombolysis for some

Patients with neither right ventricular dysfunction nor elevated cardiac biomarkers are at intermediate to low risk of clinical deterioration, and it is recommended that they be given anticoagulation therapy in an inpatient setting.

On the other hand, patients with both right ventricular dysfunction and elevated cardiac biomarkers are considered at intermediate to high risk of clinical deterioration; they should also be managed with anticoagulation and monitored closely for the need for rescue reperfusion therapy with thrombolytics.²²

THROMBOLYTIC AGENTS

Thrombolytic agents are the cornerstone of management for patients presenting with pulmonary embolism who are at high risk. As noted above, these agents are recommended in massive pulmonary embolism, but their role in submassive pulmonary embolism remains controversial.

Thrombolytics work by activating endogenous plasminogen. The resulting plasmin promotes clot lysis, reducing the size of the thrombus, decreasing pulmonary vasculature resistance, and improving right ventricular function.²³

To date, three thrombolytic agents have received US Food and Drug Administration approval for use in massive pulmonary embolism: alteplase, urokinase, and streptokinase. But only alteplase is still available in the United States. Alteplase is also the best tolerated, whereas streptokinase is highly antigenic and may cause further deterioration in an already unstable patient. Alteplase is also the most fibrin-specific and is considered the most potent of the three agents.²⁴

Additional thrombolytic agents under investigation for use in acute pulmonary embolism include reteplase, tenecteplase, and desmoteplase. These agents are more fibrin-specific than alteplase. Reteplase is a second-generation recombinant tissue-type plasminogen activator with a quicker onset of action and longer half-life than alteplase, allowing for bolus dosing. Tenecteplase, a variant of alteplase, is cleared more slowly and is 14 times more fibrin-specific than alteplase, also allowing for bolus dosing. Desmoteplase, a fibrin-specific agent currently in phase 2 trials, also has a longer half-life and appears to be more potent than alteplase. Table 2 lists the dosing and the degree of fibrin specificity of these agents.

Complications of thrombolytic therapy

Submassive pulmonary embolism has a low death rate, and the benefit of systemic thrombolytic therapy for this condition is controversial. Therefore, risk stratification is very important before pursuing this therapy.

A meta-analysis²⁵ of 16 randomized controlled trials included 2,125 patients with pulmonary embolism:

• 210 (9.88%) in the low-risk category
• 1,499 (70.54%) in the submassive category
• 31 (1.46%) in the massive category
• 385 (18.11%) whose disease severity could not be determined.

Major bleeding occurred in:

• 98 (9.24%) of 1,061 patients receiving anticoagulation plus thrombolytics
• 36 (3.42%) of 1,054 patients receiving anticoagulation without thrombolytics (odds ratio [OR] 2.73, 95% confidence interval [CI] 1.91–3.91; number needed to harm [NNH] 18, 95% CI 13–27).

Intracranial hemorrhage occurred in:

• 15 (1.46%) of 2,014 patients on thrombolytic therapy
• 2 (0.19%) of 1,019 patients not on thrombolytic therapy (OR 4.63, 95% CI 1.78–12.04; NNH 78, 95% CI 48–206).

Of note, the incidence of major bleeding was not significantly increased in those age 65 or younger receiving thrombolytics (OR 1.25, 95% CI 0.5–3.14).

Comments. Definitions of major bleeding varied in the individual trials. Additionally, intracranial hemorrhage was included as a major bleeding end point in any trial in which it was not prespecified.

These findings emphasize the importance of risk stratification before pursuing thrombolytic therapy in submassive pulmonary embolism.

Table 3 lists absolute and relative contraindications to thrombolytic therapy.

MAJOR STUDIES IN SUBMASSIVE PULMONARY EMBOLISM

The MAPPET-3 trial

The Management Strategies and Prognosis of Pulmonary Embolism-3 (MAPPET-3) trial,²⁶ in 2002, was the first major trial to study thrombolytic therapy in submassive pulmonary embolism.

In this prospective, randomized, double-blinded trial conducted in Germany, 118 patients received heparin with alteplase (100 mg over 2 hours) and 138 received heparin with placebo. The primary end point was in-hospital death or clinical deterioration requiring escalation of treatment. Secondary outcomes included recurrent pulmonary embolism, major bleeding, and stroke. Major bleeding was defined as fatal bleeding, hemorrhagic stroke, or drop in the hemoglobin concentration by more than 4 g/dL, with or without the need for red blood cell transfusion.

Right ventricular dysfunction was diagnosed by echocardiography in 30% of the participants, and the rest of the patients were classified as having submassive pulmonary embolism on the basis of electrocardiographic criteria alone. It is likely that the latter group had a less severe form of the disease and did not benefit from thrombolytic therapy as much as patients with echocardiographic findings of right ventricular dysfunction and elevated serum cardiac biomarkers.

Results. At 30 days, 11% of the alteplase-plus-heparin group had met the primary end point, compared with 24.6% of the placebo-plus-heparin group (P = .006). The difference was mostly driven by the need for secondary thrombolysis (7.6% vs 23.2%, P = .001), since 32 (23.2%) of the 138 patients in the control group required secondary thrombolysis, accounting for 94% of the 34 patients in this group who required escalation of treatment. Most cases of clinical deterioration in this group occurred within the first 5 days.

Mortality rates were 3.4% in the heparin-plus-alteplase group and 2.2% in the heparin-plus-placebo group, but the difference was not statistically significant (P = .71).

Major bleeding occurred in 1 patient in the heparin-plus-alteplase group and 5 patients in the heparin-plus-placebo group, but the trial’s definition of major bleeding may have resulted in underestimation of this event. The definition put forth by the International Society on Thrombosis and Haemostasis is less strict, defining bleeding in nonsurgical patients as major if it is fatal, symptomatic in a critical area or organ, or causing a fall in hemoglobin level of 2.0 g/dL or more, leading to transfusion of two or more units of whole blood or red cells.²⁷

MOPETT trial

The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial²⁸ was a single-center, randomized trial in 121 normotensive patients with “moderate” pulmonary embolism and right ventricular dysfunction. Moderate pulmonary embolism was defined as signs and symptoms of pulmonary embolism with evidence on computed tomographic angiography of greater than 70% involvement with thrombus in two or more lobes or left or right main pulmonary arteries, or by a high-probability ventilation-perfusion scan showing a mismatch in two or more lobes.

The authors defined right ventricular dysfunction by elevated cardiac markers or by findings on echocardiography. Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.

The primary outcome was the development of pulmonary hypertension, based on echocardiography.

Patients were randomized to either anticoagulation alone (unfractionated heparin or low-molecular-weight heparin) or anticoagulation plus half-dose alteplase (0.5 mg/kg, to a maximum of 50 mg). Echocardiography was performed within 2 hours of study entry, at 48 hours, and every 6 months thereafter. The mean duration of follow-up was 28 months.

Results. Pulmonary hypertension developed in 16% of the anticoagulation-plus-alteplase group vs 57% of the anticoagulation-only group (P < .001). However, the clinical relevance of elevated right-sided pressures observed by echocardiography in asymptomatic patients is uncertain. Alteplase had no impact on the rates of death or recurrent pulmonary embolism.

PEITHO trial

The 2014 Pulmonary Embolism Thrombolysis (PEITHO) trial²⁹ was a prospective, randomized, double-blinded, placebo-controlled trial conducted in 13 countries between 2007 and 2012. A total of 1,005 patients with submassive pulmonary embolism received unfractionated heparin and were randomized to also receive either tenecteplase or placebo.

The primary end point was death from any cause or hemodynamic compromise within 7 days of randomization. Secondary end points included death within 30 days, recurrence of pulmonary embolism, major bleeding, and stroke.

Echocardiography was strongly recommended for diagnosing right ventricular dysfunction in all patients. When this was unavailable, computed tomographic images were used to assess right ventricular dysfunction. Major bleeding was characterized as moderate or severe, and bleeding events were reported using the International Society on Thrombosis and Haemostasis criteria.

Results. The tenecteplase group had a lower rate of the primary end point at 7 days (2.6% vs 5.6%, P = .02), but no significant reduction in all-cause mortality at 30 days (2.4% vs 3.2%, P = .42). In addition, the tenecteplase group had higher rates of major extracranial bleeding (6.3% vs 1.2%, P < .001) and stroke (2.4% vs 0.2%, P = .004) at 7 days.

Although the PEITHO trial showed no reduction in mortality rates and showed a higher rate of major bleeding, this may have been related to using a higher dose of tenecteplase than needed in this population. Further studies should be conducted to confirm this theory.

TOPCOAT trial

The Tenecteplase or Placebo, Cardiopulmonary Outcomes at Three months (TOPCOAT) trial,³⁰ published in 2014, was a multicenter, double-blind, intention-to-treat, randomized trial carried out in eight centers in the United States. The authors evaluated a composite outcome (death, circulatory shock, intubation, major bleeding, recurrent pulmonary embolism, and functional capacity) with the use of tenecteplase in submassive pulmonary embolism.

A total of 83 patients received low-molecular-weight heparin and were randomized to also receive either tenecteplase or placebo. Submassive pulmonary embolism was defined as evidence of right ventricular strain based on echocardiographic findings and elevated cardiac markers (troponin, BNP, or NT-pro-BNP).

Results. Adverse outcomes occurred in 37% of the patients in the placebo group compared with 15% of those in the tenecteplase group (P = .017). The study was terminated early because the lead author relocated to another institution.

Wang et al

In a prospective, randomized, open-label, multicenter study³¹ conducted in China between 2002 and 2006, 118 patients received low-molecular-weight heparin plus alteplase in a dose of either 100 mg or 50 mg over 2 hours.

Results. There were significantly fewer bleeding episodes in patients receiving half-dose alteplase in the subgroups that weighed less than 65 kg (14.8% vs 41.2%, P = .049) or who had a body mass index less than 24 kg/m² (8.7% vs 42.9%, P = .014).

Meta-analysis

A subgroup analysis²⁵ of patients with submassive pulmonary embolism from a 2014 meta-analysis of randomized controlled trials of thrombolytic therapy in pulmonary embolism found that thrombolysis was associated with a lower mortality rate (OR 0.48; 95% CI 0.25–0.92) but a higher rate of major bleeding (OR 3.19, 95% CI 2.07–4.92).

Is there a role for low-dose thrombolytic therapy?

The MOPETT study, discussed above, evaluated the effect of thrombolysis in a low (“safe”) dose in reducing pulmonary artery pressure in moderate pulmonary embolism.²⁸ The primary end points were pulmonary hypertension and the composite end point of pulmonary hypertension and recurrent pulmonary embolism. In the thrombolysis group, the pulmonary arterial pressure fell immediately and was still lower at 28 months. As mentioned, although the incidence of pulmonary hypertension was lower with thrombolysis, no significant differences were noted in the rate of individual outcomes of death and recurrent pulmonary embolism when assessed independently. Furthermore, the definition of moderate pulmonary embolism used in this study is different from the submassive criteria.

Wang et al³¹ enrolled patients to receive low-molecular-weight heparin plus alteplase in a dose of either 50 or 100 mg. The rate of bleeding was lower with the 50-mg dose, but only in the subset of patients with lower weight and body mass index.

What is the role of catheter-guided therapy?

Catheter-directed therapy involves infusing thrombolytic agents directly into the pulmonary arteries where the clots are. The idea is to expose the patient to lower doses of systemic thrombolytics and thus decrease the risk of bleeding.

The ULTIMA study³² (Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism) evaluated whether this treatment would reverse right ventricular dilation in intermediate-risk patients, compared with anticoagulation. Intermediate-risk pulmonary embolism was defined as an embolus located in at least one main or proximal lower lobe pulmonary artery and an RV:LV ratio of at least 1.0 obtained from the echocardiographic apical four-chamber view.

The study showed hemodynamic improvement as evidenced by a lower RV:LV ratio. However, at 90 days the mortality rate was not significantly lower in the treatment group than in the control group. Of note, no major bleeding events were reported in the treatment group.

The SEATTLE II trial,³³ a nonrandomized study completed in April 2013, evaluated the efficacy and safety of ultrasonographically guided, catheter-based, low-dose fibrinolysis for patients with massive and submassive pulmonary embolism. Patients had CT evidence of proximal pulmonary embolism and a dilated right ventricle (RV:LV ratio ≥ 0.9). Patients received alteplase 24 mg, either as 1 mg/hour for 24 hours with a unilateral catheter or 1 mg/hour in each of two catheters for 12 hours.

At 48 hours after the procedure, the mean RV:LV ratio had decreased from 1.55 to 1.13, the mean pulmonary arterial systolic pressure had fallen, and the anatomical clot burden had decreased. A total of 15 patients (10%) experienced major bleeding but there were no reports of any fatal or intracranial bleeding. Patients with massive pulmonary embolism were more likely to experience major bleeding episodes than those with submassive pulmonary embolism (23% vs 7%, P = .02).

The weakness of this study is that it was a single-arm study and therefore limits comparisons with other therapies such as tissue plasminogen activator for massive pulmonary embolism or anticoagulation. Also, although there was an acute improvement in hemodynamics, it is unclear if that translates to improvement in mortality rate.

Based on the available literature,^29,31,33 patients presenting with submassive pulmonary embolism who are of low body weight (body mass index < 24 kg/m² or weight < 65 kg) or are over age 75 may benefit from low-dose catheter-guided thrombolysis therapy or low-dose systemic alteplase (50 mg). Further studies should be conducted comparing these two therapeutic strategies.

SURGICAL EMBOLECTOMY: STILL THE LAST RESORT

Surgery has been the last resort for patients with pulmonary embolism. Although recent reports show a decrease in mortality from advances in surgical embolectomy, the mortality rate is greater than 10%.³⁴

• Indications for surgical embolectomy are³⁵:
• Failure of or contraindications to thrombolytic therapy
• Continued hemodynamic instability despite maximal medical therapy
• Associated cardiac pathology such as patent foramen ovale, atrial septal defect, and free-floating right heart thrombi
• Inadequate time for systemic thrombolytics to take effect.

No large or randomized controlled trials of surgical embolectomy for submassive pulmonary embolism have been done. In one study, of 47 patients undergoing surgical embolectomy, 15 (32%) met the criteria for submassive pulmonary embolism based on right ventricular hemodynamic dysfunction. The report did not mention if biomarkers such as troponin and BNP were considered in the decision to operate.³⁶

At this time, surgical embolectomy remains a last resort for patients with acute massive pulmonary embolism who have contraindications to thrombolysis or for whom it has failed. Given the risk of death associated with surgical embolectomy, large randomized controlled trials need to be done to see if there is any benefit in the submassive pulmonary embolism population.

ONE TREATMENT DOES NOT FIT ALL

Given the evidence to date, we do not recommend thrombolytic therapy for all patients with submassive pulmonary embolism. The risk of complications (hemorrhage) is significant, and the benefit is unclear. A one-treatment-for-all approach cannot be applied in this situation.

Furthermore, each of the trials performed so far defined submassive pulmonary embolism slightly differently (Table 4), and many were underpowered to detect a difference in mortality rates between the treatment groups. Further studies are needed to determine the exact subset of patients with submassive pulmonary embolism that may truly benefit from thrombolytic therapy.

As such, patients with submassive pulmonary embolism should be managed by a multidisciplinary team to determine the need for thrombolytic therapy, especially in low doses, on a case-by-case basis according to the patient’s risk of further clinical deterioration.

For patients with submassive acute pulmonary embolism—the intermediate category between massive and low-risk—whether to give thrombolytic therapy is controversial. In general, patients with massive pulmonary embolism need this therapy, whereas those with low-risk pulmonary embolism do not—and neither do most of those with submassive embolism. But where should we draw the line?

See related editorial

More than 600,000 patients suffer pulmonary embolisms every year in the United States, and 50,000 to 200,000 people die of them.^1–3 In various studies,^4–6 within 1 year, 12.9% of patients had another pulmonary embolism, 7.3% developed chronic venous insufficiency, and 3.8% developed chronic thromboembolic pulmonary hypertension.

THREE CATEGORIES OF RISK

Episodes of acute pulmonary embolism are classified as low-risk (about 70% of cases), hemodynamically unstable or massive (5%), or submassive (25%).^7,8

Low-risk acute pulmonary embolism is defined by the absence of right ventricular dysfunction and the absence of myocardial necrosis. The death rate in such cases is less than 1%.⁹ Its pharmacologic management includes parenteral anticoagulation and early initiation of long-term anticoagulation therapy, which the American College of Chest Physicians (ACCP) gives a grade IB recommendation (strong, based on moderate-quality evidence).¹⁰

Massive or hemodynamically unstable pulmonary embolism is characterized by any of the following, in the absence of other causes⁸:

• Sustained hypotension (systolic blood pressure < 90 mm Hg for ≥ 15 minutes)
• An absolute decrease in systolic blood pressure of 40 mm Hg or more
• Need for inotropic support
• Cardiac arrest
• Bradycardia (heart rate < 40 beats per minute).

The death rate is more than 30% in patients presenting with shock and approaches 70% in those presenting with cardiac arrest.^11,12 Therefore, the consensus is that this category of pulmonary embolism merits aggressive treatment. Systemic thrombolytic therapy is recommended in those who are not at high risk of major bleeding, though the ACCP gives it only a grade 2C recommendation (weak, based on low-quality evidence).¹⁰

Submassive pulmonary embolism is defined by evidence of right ventricular dysfunction with normal blood pressure. According to the ACCP guidelines, thrombolytic therapy should be considered (grade 2C recommendation) for patients with acute pulmonary embolism without hypotension and with a low bleeding risk (with no renal failure and not on dual antiplatelet therapy), but at high risk of developing hypotension.¹⁰

DIAGNOSING SUBMASSIVE PULMONARY EMBOLISM, DELINEATING ITS SEVERITY

In managing acute pulmonary embolism, it is critical to recognize whether a patient is at high risk of clinical deterioration.

Blood pressure

The systolic blood pressure not only indicates whether the patient has hypotension (systolic blood pressure < 90 mm Hg) and therefore massive rather than submassive or low-risk pulmonary embolism; it is also important as a baseline value. A decrease in systolic blood pressure of 40 mm Hg or more is associated with worse outcomes.¹²

Right ventricular dysfunction

The physiologic response to occlusion of the pulmonary arteries can result in early myocardial injury and right ventricular dysfunction, which can be assessed by various methods (Table 1).

Electrocardiographic signs. Right heart strain may be recognized on electrocardiography as:

• Evidence of new complete or incomplete right bundle branch block
• T-wave inversion in the anterolateral leads V₁ to V₄
• S1Q3T3 (a large S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III, the classic pattern of acute cor pulmonale).¹³ 

These findings add incremental prognostic value to echocardiographic findings in patients with submassive pulmonary embolism.¹⁴

Cardiac biomarkers such as B-type natriuretic peptide (BNP), N-terminal-pro-BNP (NT-pro-BNP), cardiac troponins, and heart-type fatty acid-binding protein (H-FABP) are also markers of right-sided myocardial damage and strain and can be used to identify patients with submassive pulmonary embolism.¹⁵ Abnormal levels of these substances are as follows:

• Troponin T greater than 0.1 ng/mL
• Troponin I greater than 0.4 ng/mL
• BNP greater than 90 pg/mL
• NT-pro-BNP greater than 500 pg/mL
• H-FABP less than 6 ng/mL.

These levels have prognostic value, identifying patients with submassive pulmonary embolism at risk of deterioration or death,^14,16,17

Echocardiographic signs. Right ventricular dysfunction can be assessed quickly at the bedside with portable transthoracic echocardiography. A meta-analysis showed that close to 37% of hemodynamically stable patients with pulmonary embolism had echocardiographic evidence of right ventricular dysfunction on presentation and a higher short-term mortality rate.¹⁸ Evidence of right ventricular dysfunction includes the following:

• New-onset hypokinesis or akinesis
• Right ventricular dilation
• Right ventricular free-wall hypokinesis with apical sparing (the McConnell sign)
• Paradoxical movement of the interventricular septum
• Newly increased right ventricular systolic pressure
• Pulmonary hypertension, defined as tricuspid regurgitation jet velocity greater than 2.8 m/s.^15,19

Computed tomographic (CT) angiography is widely available. Findings that have prognostic value in determining those at higher risk of death include the following^20,21:

• A dilated right ventricle—ratio of right ventricle to left ventricle diameter (RV:LV ratio) greater than 0.9
• Interventricular septal bowing.

PESI and sPESI scores. The European Society of Cardiology 2014 guidelines stratify the risk in normotensive patients with pulmonary embolism according to their score on the Pulmonary Embolism Severity Index (PESI) or the simplified PESI (sPESI). There are five PESI classes. Those in PESI class III or IV or with an sPESI score of 1 or more (on a scale of 0 to 6) are considered at intermediate risk of clinical deterioration and are then further risk-stratified according to whether they have right ventricular dysfunction (based on echocardiography or computed tomography) and elevated cardiac biomarkers. These scoring systems are based on easily obtainable clinical information such as age, male sex, history of cancer, history of heart failure, history of chronic lung disease, heart rate, systolic blood pressure, respiratory rate, temperature, and altered mental status, and calculators are readily available.

Anticoagulation for all, plus thrombolysis for some

Patients with neither right ventricular dysfunction nor elevated cardiac biomarkers are at intermediate to low risk of clinical deterioration, and it is recommended that they be given anticoagulation therapy in an inpatient setting.

On the other hand, patients with both right ventricular dysfunction and elevated cardiac biomarkers are considered at intermediate to high risk of clinical deterioration; they should also be managed with anticoagulation and monitored closely for the need for rescue reperfusion therapy with thrombolytics.²²

THROMBOLYTIC AGENTS

Thrombolytic agents are the cornerstone of management for patients presenting with pulmonary embolism who are at high risk. As noted above, these agents are recommended in massive pulmonary embolism, but their role in submassive pulmonary embolism remains controversial.

Thrombolytics work by activating endogenous plasminogen. The resulting plasmin promotes clot lysis, reducing the size of the thrombus, decreasing pulmonary vasculature resistance, and improving right ventricular function.²³

To date, three thrombolytic agents have received US Food and Drug Administration approval for use in massive pulmonary embolism: alteplase, urokinase, and streptokinase. But only alteplase is still available in the United States. Alteplase is also the best tolerated, whereas streptokinase is highly antigenic and may cause further deterioration in an already unstable patient. Alteplase is also the most fibrin-specific and is considered the most potent of the three agents.²⁴

Additional thrombolytic agents under investigation for use in acute pulmonary embolism include reteplase, tenecteplase, and desmoteplase. These agents are more fibrin-specific than alteplase. Reteplase is a second-generation recombinant tissue-type plasminogen activator with a quicker onset of action and longer half-life than alteplase, allowing for bolus dosing. Tenecteplase, a variant of alteplase, is cleared more slowly and is 14 times more fibrin-specific than alteplase, also allowing for bolus dosing. Desmoteplase, a fibrin-specific agent currently in phase 2 trials, also has a longer half-life and appears to be more potent than alteplase. Table 2 lists the dosing and the degree of fibrin specificity of these agents.

Complications of thrombolytic therapy

Submassive pulmonary embolism has a low death rate, and the benefit of systemic thrombolytic therapy for this condition is controversial. Therefore, risk stratification is very important before pursuing this therapy.

A meta-analysis²⁵ of 16 randomized controlled trials included 2,125 patients with pulmonary embolism:

• 210 (9.88%) in the low-risk category
• 1,499 (70.54%) in the submassive category
• 31 (1.46%) in the massive category
• 385 (18.11%) whose disease severity could not be determined.

Major bleeding occurred in:

• 98 (9.24%) of 1,061 patients receiving anticoagulation plus thrombolytics
• 36 (3.42%) of 1,054 patients receiving anticoagulation without thrombolytics (odds ratio [OR] 2.73, 95% confidence interval [CI] 1.91–3.91; number needed to harm [NNH] 18, 95% CI 13–27).

Intracranial hemorrhage occurred in:

• 15 (1.46%) of 2,014 patients on thrombolytic therapy
• 2 (0.19%) of 1,019 patients not on thrombolytic therapy (OR 4.63, 95% CI 1.78–12.04; NNH 78, 95% CI 48–206).

Of note, the incidence of major bleeding was not significantly increased in those age 65 or younger receiving thrombolytics (OR 1.25, 95% CI 0.5–3.14).

Comments. Definitions of major bleeding varied in the individual trials. Additionally, intracranial hemorrhage was included as a major bleeding end point in any trial in which it was not prespecified.

These findings emphasize the importance of risk stratification before pursuing thrombolytic therapy in submassive pulmonary embolism.

Table 3 lists absolute and relative contraindications to thrombolytic therapy.

MAJOR STUDIES IN SUBMASSIVE PULMONARY EMBOLISM

The MAPPET-3 trial

The Management Strategies and Prognosis of Pulmonary Embolism-3 (MAPPET-3) trial,²⁶ in 2002, was the first major trial to study thrombolytic therapy in submassive pulmonary embolism.

In this prospective, randomized, double-blinded trial conducted in Germany, 118 patients received heparin with alteplase (100 mg over 2 hours) and 138 received heparin with placebo. The primary end point was in-hospital death or clinical deterioration requiring escalation of treatment. Secondary outcomes included recurrent pulmonary embolism, major bleeding, and stroke. Major bleeding was defined as fatal bleeding, hemorrhagic stroke, or drop in the hemoglobin concentration by more than 4 g/dL, with or without the need for red blood cell transfusion.

Right ventricular dysfunction was diagnosed by echocardiography in 30% of the participants, and the rest of the patients were classified as having submassive pulmonary embolism on the basis of electrocardiographic criteria alone. It is likely that the latter group had a less severe form of the disease and did not benefit from thrombolytic therapy as much as patients with echocardiographic findings of right ventricular dysfunction and elevated serum cardiac biomarkers.

Results. At 30 days, 11% of the alteplase-plus-heparin group had met the primary end point, compared with 24.6% of the placebo-plus-heparin group (P = .006). The difference was mostly driven by the need for secondary thrombolysis (7.6% vs 23.2%, P = .001), since 32 (23.2%) of the 138 patients in the control group required secondary thrombolysis, accounting for 94% of the 34 patients in this group who required escalation of treatment. Most cases of clinical deterioration in this group occurred within the first 5 days.

Mortality rates were 3.4% in the heparin-plus-alteplase group and 2.2% in the heparin-plus-placebo group, but the difference was not statistically significant (P = .71).

Major bleeding occurred in 1 patient in the heparin-plus-alteplase group and 5 patients in the heparin-plus-placebo group, but the trial’s definition of major bleeding may have resulted in underestimation of this event. The definition put forth by the International Society on Thrombosis and Haemostasis is less strict, defining bleeding in nonsurgical patients as major if it is fatal, symptomatic in a critical area or organ, or causing a fall in hemoglobin level of 2.0 g/dL or more, leading to transfusion of two or more units of whole blood or red cells.²⁷

MOPETT trial

The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial²⁸ was a single-center, randomized trial in 121 normotensive patients with “moderate” pulmonary embolism and right ventricular dysfunction. Moderate pulmonary embolism was defined as signs and symptoms of pulmonary embolism with evidence on computed tomographic angiography of greater than 70% involvement with thrombus in two or more lobes or left or right main pulmonary arteries, or by a high-probability ventilation-perfusion scan showing a mismatch in two or more lobes.

The authors defined right ventricular dysfunction by elevated cardiac markers or by findings on echocardiography. Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.

The primary outcome was the development of pulmonary hypertension, based on echocardiography.

Patients were randomized to either anticoagulation alone (unfractionated heparin or low-molecular-weight heparin) or anticoagulation plus half-dose alteplase (0.5 mg/kg, to a maximum of 50 mg). Echocardiography was performed within 2 hours of study entry, at 48 hours, and every 6 months thereafter. The mean duration of follow-up was 28 months.

Results. Pulmonary hypertension developed in 16% of the anticoagulation-plus-alteplase group vs 57% of the anticoagulation-only group (P < .001). However, the clinical relevance of elevated right-sided pressures observed by echocardiography in asymptomatic patients is uncertain. Alteplase had no impact on the rates of death or recurrent pulmonary embolism.

PEITHO trial

The 2014 Pulmonary Embolism Thrombolysis (PEITHO) trial²⁹ was a prospective, randomized, double-blinded, placebo-controlled trial conducted in 13 countries between 2007 and 2012. A total of 1,005 patients with submassive pulmonary embolism received unfractionated heparin and were randomized to also receive either tenecteplase or placebo.

The primary end point was death from any cause or hemodynamic compromise within 7 days of randomization. Secondary end points included death within 30 days, recurrence of pulmonary embolism, major bleeding, and stroke.

Echocardiography was strongly recommended for diagnosing right ventricular dysfunction in all patients. When this was unavailable, computed tomographic images were used to assess right ventricular dysfunction. Major bleeding was characterized as moderate or severe, and bleeding events were reported using the International Society on Thrombosis and Haemostasis criteria.

Results. The tenecteplase group had a lower rate of the primary end point at 7 days (2.6% vs 5.6%, P = .02), but no significant reduction in all-cause mortality at 30 days (2.4% vs 3.2%, P = .42). In addition, the tenecteplase group had higher rates of major extracranial bleeding (6.3% vs 1.2%, P < .001) and stroke (2.4% vs 0.2%, P = .004) at 7 days.

Although the PEITHO trial showed no reduction in mortality rates and showed a higher rate of major bleeding, this may have been related to using a higher dose of tenecteplase than needed in this population. Further studies should be conducted to confirm this theory.

TOPCOAT trial

The Tenecteplase or Placebo, Cardiopulmonary Outcomes at Three months (TOPCOAT) trial,³⁰ published in 2014, was a multicenter, double-blind, intention-to-treat, randomized trial carried out in eight centers in the United States. The authors evaluated a composite outcome (death, circulatory shock, intubation, major bleeding, recurrent pulmonary embolism, and functional capacity) with the use of tenecteplase in submassive pulmonary embolism.

A total of 83 patients received low-molecular-weight heparin and were randomized to also receive either tenecteplase or placebo. Submassive pulmonary embolism was defined as evidence of right ventricular strain based on echocardiographic findings and elevated cardiac markers (troponin, BNP, or NT-pro-BNP).

Results. Adverse outcomes occurred in 37% of the patients in the placebo group compared with 15% of those in the tenecteplase group (P = .017). The study was terminated early because the lead author relocated to another institution.

Wang et al

In a prospective, randomized, open-label, multicenter study³¹ conducted in China between 2002 and 2006, 118 patients received low-molecular-weight heparin plus alteplase in a dose of either 100 mg or 50 mg over 2 hours.

Results. There were significantly fewer bleeding episodes in patients receiving half-dose alteplase in the subgroups that weighed less than 65 kg (14.8% vs 41.2%, P = .049) or who had a body mass index less than 24 kg/m² (8.7% vs 42.9%, P = .014).

Meta-analysis

A subgroup analysis²⁵ of patients with submassive pulmonary embolism from a 2014 meta-analysis of randomized controlled trials of thrombolytic therapy in pulmonary embolism found that thrombolysis was associated with a lower mortality rate (OR 0.48; 95% CI 0.25–0.92) but a higher rate of major bleeding (OR 3.19, 95% CI 2.07–4.92).

Is there a role for low-dose thrombolytic therapy?

The MOPETT study, discussed above, evaluated the effect of thrombolysis in a low (“safe”) dose in reducing pulmonary artery pressure in moderate pulmonary embolism.²⁸ The primary end points were pulmonary hypertension and the composite end point of pulmonary hypertension and recurrent pulmonary embolism. In the thrombolysis group, the pulmonary arterial pressure fell immediately and was still lower at 28 months. As mentioned, although the incidence of pulmonary hypertension was lower with thrombolysis, no significant differences were noted in the rate of individual outcomes of death and recurrent pulmonary embolism when assessed independently. Furthermore, the definition of moderate pulmonary embolism used in this study is different from the submassive criteria.

Wang et al³¹ enrolled patients to receive low-molecular-weight heparin plus alteplase in a dose of either 50 or 100 mg. The rate of bleeding was lower with the 50-mg dose, but only in the subset of patients with lower weight and body mass index.

What is the role of catheter-guided therapy?

Catheter-directed therapy involves infusing thrombolytic agents directly into the pulmonary arteries where the clots are. The idea is to expose the patient to lower doses of systemic thrombolytics and thus decrease the risk of bleeding.

The ULTIMA study³² (Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism) evaluated whether this treatment would reverse right ventricular dilation in intermediate-risk patients, compared with anticoagulation. Intermediate-risk pulmonary embolism was defined as an embolus located in at least one main or proximal lower lobe pulmonary artery and an RV:LV ratio of at least 1.0 obtained from the echocardiographic apical four-chamber view.

The study showed hemodynamic improvement as evidenced by a lower RV:LV ratio. However, at 90 days the mortality rate was not significantly lower in the treatment group than in the control group. Of note, no major bleeding events were reported in the treatment group.

The SEATTLE II trial,³³ a nonrandomized study completed in April 2013, evaluated the efficacy and safety of ultrasonographically guided, catheter-based, low-dose fibrinolysis for patients with massive and submassive pulmonary embolism. Patients had CT evidence of proximal pulmonary embolism and a dilated right ventricle (RV:LV ratio ≥ 0.9). Patients received alteplase 24 mg, either as 1 mg/hour for 24 hours with a unilateral catheter or 1 mg/hour in each of two catheters for 12 hours.

At 48 hours after the procedure, the mean RV:LV ratio had decreased from 1.55 to 1.13, the mean pulmonary arterial systolic pressure had fallen, and the anatomical clot burden had decreased. A total of 15 patients (10%) experienced major bleeding but there were no reports of any fatal or intracranial bleeding. Patients with massive pulmonary embolism were more likely to experience major bleeding episodes than those with submassive pulmonary embolism (23% vs 7%, P = .02).

The weakness of this study is that it was a single-arm study and therefore limits comparisons with other therapies such as tissue plasminogen activator for massive pulmonary embolism or anticoagulation. Also, although there was an acute improvement in hemodynamics, it is unclear if that translates to improvement in mortality rate.

Based on the available literature,^29,31,33 patients presenting with submassive pulmonary embolism who are of low body weight (body mass index < 24 kg/m² or weight < 65 kg) or are over age 75 may benefit from low-dose catheter-guided thrombolysis therapy or low-dose systemic alteplase (50 mg). Further studies should be conducted comparing these two therapeutic strategies.

SURGICAL EMBOLECTOMY: STILL THE LAST RESORT

Surgery has been the last resort for patients with pulmonary embolism. Although recent reports show a decrease in mortality from advances in surgical embolectomy, the mortality rate is greater than 10%.³⁴

• Indications for surgical embolectomy are³⁵:
• Failure of or contraindications to thrombolytic therapy
• Continued hemodynamic instability despite maximal medical therapy
• Associated cardiac pathology such as patent foramen ovale, atrial septal defect, and free-floating right heart thrombi
• Inadequate time for systemic thrombolytics to take effect.

No large or randomized controlled trials of surgical embolectomy for submassive pulmonary embolism have been done. In one study, of 47 patients undergoing surgical embolectomy, 15 (32%) met the criteria for submassive pulmonary embolism based on right ventricular hemodynamic dysfunction. The report did not mention if biomarkers such as troponin and BNP were considered in the decision to operate.³⁶

At this time, surgical embolectomy remains a last resort for patients with acute massive pulmonary embolism who have contraindications to thrombolysis or for whom it has failed. Given the risk of death associated with surgical embolectomy, large randomized controlled trials need to be done to see if there is any benefit in the submassive pulmonary embolism population.

ONE TREATMENT DOES NOT FIT ALL

Given the evidence to date, we do not recommend thrombolytic therapy for all patients with submassive pulmonary embolism. The risk of complications (hemorrhage) is significant, and the benefit is unclear. A one-treatment-for-all approach cannot be applied in this situation.

Furthermore, each of the trials performed so far defined submassive pulmonary embolism slightly differently (Table 4), and many were underpowered to detect a difference in mortality rates between the treatment groups. Further studies are needed to determine the exact subset of patients with submassive pulmonary embolism that may truly benefit from thrombolytic therapy.

As such, patients with submassive pulmonary embolism should be managed by a multidisciplinary team to determine the need for thrombolytic therapy, especially in low doses, on a case-by-case basis according to the patient’s risk of further clinical deterioration.

Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.¹

Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.

Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.²

This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.

MOST DAMAGE IS ENDOTHELIAL 

Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.³

Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.⁴ Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.⁵

RISK FACTORS

Risk factors for RIHD are summarized in Table 1.

The volume of heart irradiated is a major determinant of the development of RIHD.⁶ A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.⁷

Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.⁸

Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.⁹

In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation  (Table 1).¹⁰

CORONARY ARTERY DISEASE

Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.¹¹

A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.¹²

A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P <  .0001).¹³

A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.⁷

The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.¹⁴

The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.¹⁵ In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.¹⁶

The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.¹⁷

Management of radiation-associated coronary artery disease

Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.¹⁸ Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.

Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,¹⁹ and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.²⁰ Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.²¹

If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.²²

Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.²³ Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.

A large single-institution study by Wu et al²⁴ revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.

VALVULAR DISEASE

Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.²⁵

The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26

Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.²⁷ Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.

Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.²⁸

The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.²⁹

Management of radiation-induced valvular disease

Management of patients with valvular RIHD poses a major clinical conundrum because of  the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,²³ the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.²³

Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.³⁰

As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.

This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.³¹

PERICARDIAL DISEASE

Pericardial disease is a frequent manifestation of RIHD and covers a spectrum of manifestations from acute pericarditis, pericardial effusion, and tamponade to constrictive pericarditis. In a necropsy study, 70% of patients with RIHD were found to have pericardial involvement.³²

The mechanism is believed to be radiation-induced microvascular injury resulting in increased capillary permeability and the sometimes rapid development of a protein-rich exudate. Associated inflammation may cause acute pericarditis, which may eventually be complicated by chronic pericarditis. The parietal surface tends to be affected more severely than the epicardium.³³

Perhaps as a result of recent advances such as lower radiation doses, equal weighting of the anterior and posterior fields, and subcarinal blocking, incidence rates of pericarditis as low as 2.5% have been reported.³⁴

Pericardial RIHD may be divided into early acute pericarditis, delayed chronic pericardial effusion, and constrictive pericarditis.

Early acute pericarditis is rare and is thought to represent a reaction to tumor necrosis. It is defined as occurring during radiotherapy and occurs almost exclusively with high-dose radiotherapy for lymphoma. Due to the relatively benign course of acute pericarditis and fear of tumor recurrence, it is not an indication to withhold radiotherapy.³⁵

Delayed chronic pericardial effusion occurs months to years after radiotherapy, is typically asymptomatic, and presents as an enlarged cardiac silhouette on chest imaging.³⁵ Delayed pericardial effusion is followed with imaging. While in many cases it resolves within 2 years, it may also be long-standing. Pericardiocentesis or a pericardial window may be performed to treat symptomatic effusion or delayed effusion causing hemodynamic compromise.^35–37 Hypothyroidism should be ruled out, as it can complicate mantle irradiation and result in chronic pericardial effusion.³⁸

Constrictive pericarditis may occur as a late complication of radiotherapy and typically causes symptoms of congestive heart failure. Pericardial stripping in these patients is complicated by the possibility of coexisting RIHD of the valves, myocardium, or coronary arteries, as well as mediastinal fibrosis. A study of 163 patients who underwent pericardial stripping for chronic pericarditis found a 7-year overall survival rate of only 27%, far lower than the rate for those who had no history of radiation exposure.³⁹ Therefore, these patients are often treated for symptom control with diuretics and a low-salt diet rather than with surgery.

MYOCARDIAL DISEASE

Microvascular injury in the myocardium results in chronic ischemia, which may lead to myocardial fibrosis, typically manifesting as diastolic dysfunction. Chest radiotherapy may result in both systolic and diastolic dysfunction, and dilated and restrictive cardiomyopathy are well-recognized complications.⁴⁰

Historically, high radiation doses resulted in systolic dysfunction in more than half of patients who underwent thoracic radiotherapy.⁴¹ Now, however, fewer than 5% of patients develop reductions in left ventricular ejection fraction, and most cases of radiotherapy-induced cardiomyopathy have a restrictive pattern.⁴²

In a single-institution study, diastolic dysfunction was reported in as many as 14% of patients who underwent thoracic radiotherapy for Hodgkin lymphoma.⁴⁰ Systolic dysfunction is now seen almost exclusively in patients  treated concurrently with cardiotoxic chemotherapeutic agents such as anthracyclines in addition to radiotherapy.⁴³

In a childhood cancer survival series, the hazard ratio of congestive heart failure in patients who had undergone radiotherapy for Wilms tumor was 6.6—almost identical to the occurrence in sibling controls. By contrast, the hazard ratio increased to 18.3 in those who received doxorubicin in addition to radiotherapy.⁴⁴

Treatment of radiation-induced cardiomyopathy

Treatment of radiation-induced cardiomyopathy is similar to that for other forms of cardiomyopathy, with an emphasis on symptom management.

Heart transplant may be an option for highly selected patients with end-stage heart failure secondary to RIHD. In one report, a series of four RIHD patients received a heart transplant, and all four survived past 48 months.⁴⁵ However, data from the United Network of Organ Sharing revealed an increase in the all-cause mortality rate in patients undergoing heart transplant for RIHD compared with those undergoing transplant for cardiomyopathy due to other causes.⁴⁶ This trend may be confounded by a higher prevalence of prior cardiac surgery in the RIHD group—itself an established risk factor for poor posttransplant outcomes.

CONDUCTION SYSTEM DISEASE

Life-threatening arrhythmias have been reported that are distinct from the common, asymptomatic repolarization abnormalities that occur during radiotherapy. Atrioventricular nodal bradycardia, all degrees of heart block, and sick sinus syndrome have all been reported after chest radiotherapy. As conduction abnormalities do not typically manifest until years after radiotherapy, it is difficult to establish causation and, consequently, to define incidence.

Right bundle branch block is the most common conduction abnormality because of the proximity of the right bundle to the endocardium on the right side.⁴⁷

Chest radiotherapy is also associated with prolongation of the corrected QT interval (QTc). A study in patients with a history of thoracic radiotherapy found that the QTc characteristically increased with exercise, a poor prognostic indicator.⁴⁸ In a study of 134 survivors of childhood cancer, 12.5% of those who had undergone radiotherapy had a resting QTc of 0.44 msec or more.⁴⁹

Furthermore, a study of 69 breast cancer survivors found a higher incidence of conduction abnormalities at 6 months and 10 years after radiotherapy compared with baseline. The characteristic electrocardiographic changes at 6 months were T-wave changes. At 10 years, the T-wave abnormalities had resolved and were replaced by ST depression.⁵⁰

As mentioned above, establishing radiotherapy as a cause for these conduction abnormalities is challenging, given the lag between radiation therapy and electrocardiographic changes. The following criteria have been proposed for establishing a link between atrioventricular blockade and prior radiation⁵¹:

• Total radiation dose to the heart > 40 Gy
• Delay of 10 years or more since therapy
• Abnormal interval electrocardiographic changes such as bundle branch block
• Prior pericardial involvement
• Associated cardiac or mediastinal lesions.

SCREENING GUIDELINES

Consensus guidelines for identifying and monitoring RIHD have been published by the European Association of Cardiovascular Imaging and the American Society of Echocardiography (Table 2).¹⁰ The European Society of Medical Oncology has also issued guidelines for the prevention, diagnosis, and management of cardiovascular disease associated with cancer therapy.

Briefly, the guidelines call for aggressive cardiac risk-factor modification through weight loss, exercise, blood pressure control, and smoking cessation, in addition to early detection of RIHD. Cardiovascular screening for risk factors and a careful clinical examination should be performed in all patients. Baseline comprehensive transthoracic echocardiography is advocated in all patients before starting radiotherapy to detect cardiac anomalies. Beyond this, an annual history and physical examination, paying close attention to the signs and symptoms of cardiopulmonary disease, is essential. The development of new cardiopulmonary symptoms or a new physical finding such as a murmur should prompt evaluation with transthoracic echocardiography.

In patients without symptoms, screening transthoracic echocardiography at 10 years after the start of radiotherapy is recommended in light of the high probability of diagnosing cardiac disease at this juncture. In patients with no preexisting cardiac disease, surveillance transthoracic echocardiography should be at 5-year intervals thereafter.

In high-risk patients without symptoms (those who have undergone anterior or left-sided radiotherapy and have at least one risk factor for RIHD), initial screening transthoracic echocardiography is recommended 5 years after radiotherapy. These patients have a heightened risk of coronary events as described above and, consequently, are recommended to undergo noninvasive imaging 5 to 10 years after radiation exposure. If this initial examination is negative, stress testing should be repeated at 5-year intervals. Stress echocardiography and stress cardiac magnetic resonance imaging have higher specificity than stress electrocardiography and therefore are generally preferred. Stress scintigraphy should be used with caution, as it adds to the cumulative radiation exposure.

The role of magnetic resonance imaging and computed tomography depends on the results of initial transthoracic echocardiography and the clinical indication, in addition to the center’s expertise and facilities. However, there are currently no data advocating their use as screening tools, except for early detection of porcelain aorta in high-risk patients.¹⁰

MODERN RADIOTHERAPY TECHNIQUES

In recent years, there has been emphasis on exposing the patient to as little radiation as possible without compromising cure.⁵² The three major strategies employed to decrease cardiac exposure include reducing the radiation dose, reducing the radiation field and volume, and using newer planning and delivery techniques.

Reducing the radiation dose. It is well recognized that the mean dose of radiation to the heart is a significant predictor of cardiovascular disease, with one study demonstrating a linear increase in the risk of coronary artery disease with increasing mean heart radiation dose (excess relative risk per Gy 7.4%, 95% confidence interval 3.3%–14.8%).⁵³

Reducing the radiation field and volume. Modern strategies and computed tomography-based radiotherapy planning have enabled a transition from older techniques such as extended-field radiation therapy, mantle-field radiation therapy, and involved-field radiation therapy to new techniques such as involved-node and involved-site radiation therapy.⁵⁴ These have shown promise. For instance, a study in patients with early Hodgkin lymphoma found a mean heart dose of 27.5 Gy with mantle-field therapy compared with 7.7 Gy with involved-node therapy. This decrease in mean heart dose was associated with a reduction in the 25-year absolute excess cardiac risk from 9.1% to 1.4% and a reduction in cardiac mortality from 2.1% to 1%.⁵⁵

Employing newer planning and delivery systems has also demonstrated some promise in reducing rates of cardiac morbidity and mortality. Extended-field radiation therapy, mantle-field radiotherapy, and involved-field radiation therapy were traditionally based on two-dimensional planning and often resulted in large volumes of myocardium being unnecessarily exposed to large doses of radiation because of the uncertainty in targeting. Involved-site and involved-node radiotherapy are based on computed tomography, resulting in more accurate targeting and sparing of normal tissue.

In addition, newer techniques such as intensity-modulated radiotherapy and proton beam therapy have resulted in further improvements in conformality compared with three-dimensional conformal radiotherapy.^56,57 Respiratory motion management, including deep inspiration breath-holding and end-inspiration breath-holding, have decreased the radiation dose to the heart in patients undergoing mediastinal radiotherapy.^58,59

TOWARD THE GOALS OF PREVENTION AND EARLIER DETECTION

As survival from breast cancer and lymphoma has increased, we continue to see legacy or latent effects of therapy, such as RIHD. Radiation therapy can affect any cardiac structure and is a major cause of morbidity and death in cancer survivors.

Modern radiation techniques use a variety of mechanisms to decrease the radiation dose to the heart. A large body of evidence emanating from an era of higher radiation doses and a lack of knowledge of the cardiac effects of radiation highlight the perilous cardiac consequences of chest radiation. With advances in radiotherapy and the development and widespread implementation of consensus guidelines, we envision earlier detection and less frequent occurrence of RIHD, although the latter trend could be blunted by increased cardiovascular risk factors within the population. Given the lag between irradiation and the cardiac consequences, it may be a number of years before any comparisons can be drawn.

Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.¹

Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.

Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.²

This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.

MOST DAMAGE IS ENDOTHELIAL 

Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.³

Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.⁴ Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.⁵

RISK FACTORS

Risk factors for RIHD are summarized in Table 1.

The volume of heart irradiated is a major determinant of the development of RIHD.⁶ A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.⁷

Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.⁸

Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.⁹

In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation  (Table 1).¹⁰

CORONARY ARTERY DISEASE

Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.¹¹

A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.¹²

A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P <  .0001).¹³

A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.⁷

The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.¹⁴

The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.¹⁵ In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.¹⁶

The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.¹⁷

Management of radiation-associated coronary artery disease

Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.¹⁸ Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.

Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,¹⁹ and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.²⁰ Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.²¹

If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.²²

Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.²³ Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.

A large single-institution study by Wu et al²⁴ revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.

VALVULAR DISEASE

Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.²⁵

The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26

Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.²⁷ Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.

Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.²⁸

The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.²⁹

Management of radiation-induced valvular disease

Management of patients with valvular RIHD poses a major clinical conundrum because of  the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,²³ the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.²³

Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.³⁰

As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.

This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.³¹

PERICARDIAL DISEASE

Pericardial disease is a frequent manifestation of RIHD and covers a spectrum of manifestations from acute pericarditis, pericardial effusion, and tamponade to constrictive pericarditis. In a necropsy study, 70% of patients with RIHD were found to have pericardial involvement.³²

The mechanism is believed to be radiation-induced microvascular injury resulting in increased capillary permeability and the sometimes rapid development of a protein-rich exudate. Associated inflammation may cause acute pericarditis, which may eventually be complicated by chronic pericarditis. The parietal surface tends to be affected more severely than the epicardium.³³

Perhaps as a result of recent advances such as lower radiation doses, equal weighting of the anterior and posterior fields, and subcarinal blocking, incidence rates of pericarditis as low as 2.5% have been reported.³⁴

Pericardial RIHD may be divided into early acute pericarditis, delayed chronic pericardial effusion, and constrictive pericarditis.

Early acute pericarditis is rare and is thought to represent a reaction to tumor necrosis. It is defined as occurring during radiotherapy and occurs almost exclusively with high-dose radiotherapy for lymphoma. Due to the relatively benign course of acute pericarditis and fear of tumor recurrence, it is not an indication to withhold radiotherapy.³⁵

Delayed chronic pericardial effusion occurs months to years after radiotherapy, is typically asymptomatic, and presents as an enlarged cardiac silhouette on chest imaging.³⁵ Delayed pericardial effusion is followed with imaging. While in many cases it resolves within 2 years, it may also be long-standing. Pericardiocentesis or a pericardial window may be performed to treat symptomatic effusion or delayed effusion causing hemodynamic compromise.^35–37 Hypothyroidism should be ruled out, as it can complicate mantle irradiation and result in chronic pericardial effusion.³⁸

Constrictive pericarditis may occur as a late complication of radiotherapy and typically causes symptoms of congestive heart failure. Pericardial stripping in these patients is complicated by the possibility of coexisting RIHD of the valves, myocardium, or coronary arteries, as well as mediastinal fibrosis. A study of 163 patients who underwent pericardial stripping for chronic pericarditis found a 7-year overall survival rate of only 27%, far lower than the rate for those who had no history of radiation exposure.³⁹ Therefore, these patients are often treated for symptom control with diuretics and a low-salt diet rather than with surgery.

MYOCARDIAL DISEASE

Microvascular injury in the myocardium results in chronic ischemia, which may lead to myocardial fibrosis, typically manifesting as diastolic dysfunction. Chest radiotherapy may result in both systolic and diastolic dysfunction, and dilated and restrictive cardiomyopathy are well-recognized complications.⁴⁰

Historically, high radiation doses resulted in systolic dysfunction in more than half of patients who underwent thoracic radiotherapy.⁴¹ Now, however, fewer than 5% of patients develop reductions in left ventricular ejection fraction, and most cases of radiotherapy-induced cardiomyopathy have a restrictive pattern.⁴²

In a single-institution study, diastolic dysfunction was reported in as many as 14% of patients who underwent thoracic radiotherapy for Hodgkin lymphoma.⁴⁰ Systolic dysfunction is now seen almost exclusively in patients  treated concurrently with cardiotoxic chemotherapeutic agents such as anthracyclines in addition to radiotherapy.⁴³

In a childhood cancer survival series, the hazard ratio of congestive heart failure in patients who had undergone radiotherapy for Wilms tumor was 6.6—almost identical to the occurrence in sibling controls. By contrast, the hazard ratio increased to 18.3 in those who received doxorubicin in addition to radiotherapy.⁴⁴

Treatment of radiation-induced cardiomyopathy

Treatment of radiation-induced cardiomyopathy is similar to that for other forms of cardiomyopathy, with an emphasis on symptom management.

Heart transplant may be an option for highly selected patients with end-stage heart failure secondary to RIHD. In one report, a series of four RIHD patients received a heart transplant, and all four survived past 48 months.⁴⁵ However, data from the United Network of Organ Sharing revealed an increase in the all-cause mortality rate in patients undergoing heart transplant for RIHD compared with those undergoing transplant for cardiomyopathy due to other causes.⁴⁶ This trend may be confounded by a higher prevalence of prior cardiac surgery in the RIHD group—itself an established risk factor for poor posttransplant outcomes.

CONDUCTION SYSTEM DISEASE

Life-threatening arrhythmias have been reported that are distinct from the common, asymptomatic repolarization abnormalities that occur during radiotherapy. Atrioventricular nodal bradycardia, all degrees of heart block, and sick sinus syndrome have all been reported after chest radiotherapy. As conduction abnormalities do not typically manifest until years after radiotherapy, it is difficult to establish causation and, consequently, to define incidence.

Right bundle branch block is the most common conduction abnormality because of the proximity of the right bundle to the endocardium on the right side.⁴⁷

Chest radiotherapy is also associated with prolongation of the corrected QT interval (QTc). A study in patients with a history of thoracic radiotherapy found that the QTc characteristically increased with exercise, a poor prognostic indicator.⁴⁸ In a study of 134 survivors of childhood cancer, 12.5% of those who had undergone radiotherapy had a resting QTc of 0.44 msec or more.⁴⁹

Furthermore, a study of 69 breast cancer survivors found a higher incidence of conduction abnormalities at 6 months and 10 years after radiotherapy compared with baseline. The characteristic electrocardiographic changes at 6 months were T-wave changes. At 10 years, the T-wave abnormalities had resolved and were replaced by ST depression.⁵⁰

As mentioned above, establishing radiotherapy as a cause for these conduction abnormalities is challenging, given the lag between radiation therapy and electrocardiographic changes. The following criteria have been proposed for establishing a link between atrioventricular blockade and prior radiation⁵¹:

• Total radiation dose to the heart > 40 Gy
• Delay of 10 years or more since therapy
• Abnormal interval electrocardiographic changes such as bundle branch block
• Prior pericardial involvement
• Associated cardiac or mediastinal lesions.

SCREENING GUIDELINES

Consensus guidelines for identifying and monitoring RIHD have been published by the European Association of Cardiovascular Imaging and the American Society of Echocardiography (Table 2).¹⁰ The European Society of Medical Oncology has also issued guidelines for the prevention, diagnosis, and management of cardiovascular disease associated with cancer therapy.

Briefly, the guidelines call for aggressive cardiac risk-factor modification through weight loss, exercise, blood pressure control, and smoking cessation, in addition to early detection of RIHD. Cardiovascular screening for risk factors and a careful clinical examination should be performed in all patients. Baseline comprehensive transthoracic echocardiography is advocated in all patients before starting radiotherapy to detect cardiac anomalies. Beyond this, an annual history and physical examination, paying close attention to the signs and symptoms of cardiopulmonary disease, is essential. The development of new cardiopulmonary symptoms or a new physical finding such as a murmur should prompt evaluation with transthoracic echocardiography.

In patients without symptoms, screening transthoracic echocardiography at 10 years after the start of radiotherapy is recommended in light of the high probability of diagnosing cardiac disease at this juncture. In patients with no preexisting cardiac disease, surveillance transthoracic echocardiography should be at 5-year intervals thereafter.

In high-risk patients without symptoms (those who have undergone anterior or left-sided radiotherapy and have at least one risk factor for RIHD), initial screening transthoracic echocardiography is recommended 5 years after radiotherapy. These patients have a heightened risk of coronary events as described above and, consequently, are recommended to undergo noninvasive imaging 5 to 10 years after radiation exposure. If this initial examination is negative, stress testing should be repeated at 5-year intervals. Stress echocardiography and stress cardiac magnetic resonance imaging have higher specificity than stress electrocardiography and therefore are generally preferred. Stress scintigraphy should be used with caution, as it adds to the cumulative radiation exposure.

The role of magnetic resonance imaging and computed tomography depends on the results of initial transthoracic echocardiography and the clinical indication, in addition to the center’s expertise and facilities. However, there are currently no data advocating their use as screening tools, except for early detection of porcelain aorta in high-risk patients.¹⁰

MODERN RADIOTHERAPY TECHNIQUES

In recent years, there has been emphasis on exposing the patient to as little radiation as possible without compromising cure.⁵² The three major strategies employed to decrease cardiac exposure include reducing the radiation dose, reducing the radiation field and volume, and using newer planning and delivery techniques.

Reducing the radiation dose. It is well recognized that the mean dose of radiation to the heart is a significant predictor of cardiovascular disease, with one study demonstrating a linear increase in the risk of coronary artery disease with increasing mean heart radiation dose (excess relative risk per Gy 7.4%, 95% confidence interval 3.3%–14.8%).⁵³

Reducing the radiation field and volume. Modern strategies and computed tomography-based radiotherapy planning have enabled a transition from older techniques such as extended-field radiation therapy, mantle-field radiation therapy, and involved-field radiation therapy to new techniques such as involved-node and involved-site radiation therapy.⁵⁴ These have shown promise. For instance, a study in patients with early Hodgkin lymphoma found a mean heart dose of 27.5 Gy with mantle-field therapy compared with 7.7 Gy with involved-node therapy. This decrease in mean heart dose was associated with a reduction in the 25-year absolute excess cardiac risk from 9.1% to 1.4% and a reduction in cardiac mortality from 2.1% to 1%.⁵⁵

Employing newer planning and delivery systems has also demonstrated some promise in reducing rates of cardiac morbidity and mortality. Extended-field radiation therapy, mantle-field radiotherapy, and involved-field radiation therapy were traditionally based on two-dimensional planning and often resulted in large volumes of myocardium being unnecessarily exposed to large doses of radiation because of the uncertainty in targeting. Involved-site and involved-node radiotherapy are based on computed tomography, resulting in more accurate targeting and sparing of normal tissue.

In addition, newer techniques such as intensity-modulated radiotherapy and proton beam therapy have resulted in further improvements in conformality compared with three-dimensional conformal radiotherapy.^56,57 Respiratory motion management, including deep inspiration breath-holding and end-inspiration breath-holding, have decreased the radiation dose to the heart in patients undergoing mediastinal radiotherapy.^58,59

TOWARD THE GOALS OF PREVENTION AND EARLIER DETECTION

As survival from breast cancer and lymphoma has increased, we continue to see legacy or latent effects of therapy, such as RIHD. Radiation therapy can affect any cardiac structure and is a major cause of morbidity and death in cancer survivors.

Modern radiation techniques use a variety of mechanisms to decrease the radiation dose to the heart. A large body of evidence emanating from an era of higher radiation doses and a lack of knowledge of the cardiac effects of radiation highlight the perilous cardiac consequences of chest radiation. With advances in radiotherapy and the development and widespread implementation of consensus guidelines, we envision earlier detection and less frequent occurrence of RIHD, although the latter trend could be blunted by increased cardiovascular risk factors within the population. Given the lag between irradiation and the cardiac consequences, it may be a number of years before any comparisons can be drawn.

Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.¹

Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.

Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.²

This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.

MOST DAMAGE IS ENDOTHELIAL 

Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.³

Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.⁴ Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.⁵

RISK FACTORS

Risk factors for RIHD are summarized in Table 1.

The volume of heart irradiated is a major determinant of the development of RIHD.⁶ A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.⁷

Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.⁸

Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.⁹

In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation  (Table 1).¹⁰

CORONARY ARTERY DISEASE

Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.¹¹

A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.¹²

A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P <  .0001).¹³

A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.⁷

The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.¹⁴

The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.¹⁵ In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.¹⁶

The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.¹⁷

Management of radiation-associated coronary artery disease

Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.¹⁸ Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.

Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,¹⁹ and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.²⁰ Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.²¹

If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.²²

Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.²³ Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.

A large single-institution study by Wu et al²⁴ revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.

VALVULAR DISEASE

Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.²⁵

The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26

Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.²⁷ Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.

Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.²⁸

The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.²⁹

Management of radiation-induced valvular disease

Management of patients with valvular RIHD poses a major clinical conundrum because of  the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,²³ the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.²³

Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.³⁰

As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.

This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.³¹

PERICARDIAL DISEASE

Pericardial disease is a frequent manifestation of RIHD and covers a spectrum of manifestations from acute pericarditis, pericardial effusion, and tamponade to constrictive pericarditis. In a necropsy study, 70% of patients with RIHD were found to have pericardial involvement.³²

The mechanism is believed to be radiation-induced microvascular injury resulting in increased capillary permeability and the sometimes rapid development of a protein-rich exudate. Associated inflammation may cause acute pericarditis, which may eventually be complicated by chronic pericarditis. The parietal surface tends to be affected more severely than the epicardium.³³

Perhaps as a result of recent advances such as lower radiation doses, equal weighting of the anterior and posterior fields, and subcarinal blocking, incidence rates of pericarditis as low as 2.5% have been reported.³⁴

Pericardial RIHD may be divided into early acute pericarditis, delayed chronic pericardial effusion, and constrictive pericarditis.

Early acute pericarditis is rare and is thought to represent a reaction to tumor necrosis. It is defined as occurring during radiotherapy and occurs almost exclusively with high-dose radiotherapy for lymphoma. Due to the relatively benign course of acute pericarditis and fear of tumor recurrence, it is not an indication to withhold radiotherapy.³⁵

Delayed chronic pericardial effusion occurs months to years after radiotherapy, is typically asymptomatic, and presents as an enlarged cardiac silhouette on chest imaging.³⁵ Delayed pericardial effusion is followed with imaging. While in many cases it resolves within 2 years, it may also be long-standing. Pericardiocentesis or a pericardial window may be performed to treat symptomatic effusion or delayed effusion causing hemodynamic compromise.^35–37 Hypothyroidism should be ruled out, as it can complicate mantle irradiation and result in chronic pericardial effusion.³⁸

Constrictive pericarditis may occur as a late complication of radiotherapy and typically causes symptoms of congestive heart failure. Pericardial stripping in these patients is complicated by the possibility of coexisting RIHD of the valves, myocardium, or coronary arteries, as well as mediastinal fibrosis. A study of 163 patients who underwent pericardial stripping for chronic pericarditis found a 7-year overall survival rate of only 27%, far lower than the rate for those who had no history of radiation exposure.³⁹ Therefore, these patients are often treated for symptom control with diuretics and a low-salt diet rather than with surgery.

MYOCARDIAL DISEASE

Microvascular injury in the myocardium results in chronic ischemia, which may lead to myocardial fibrosis, typically manifesting as diastolic dysfunction. Chest radiotherapy may result in both systolic and diastolic dysfunction, and dilated and restrictive cardiomyopathy are well-recognized complications.⁴⁰

Historically, high radiation doses resulted in systolic dysfunction in more than half of patients who underwent thoracic radiotherapy.⁴¹ Now, however, fewer than 5% of patients develop reductions in left ventricular ejection fraction, and most cases of radiotherapy-induced cardiomyopathy have a restrictive pattern.⁴²

In a single-institution study, diastolic dysfunction was reported in as many as 14% of patients who underwent thoracic radiotherapy for Hodgkin lymphoma.⁴⁰ Systolic dysfunction is now seen almost exclusively in patients  treated concurrently with cardiotoxic chemotherapeutic agents such as anthracyclines in addition to radiotherapy.⁴³

In a childhood cancer survival series, the hazard ratio of congestive heart failure in patients who had undergone radiotherapy for Wilms tumor was 6.6—almost identical to the occurrence in sibling controls. By contrast, the hazard ratio increased to 18.3 in those who received doxorubicin in addition to radiotherapy.⁴⁴

Treatment of radiation-induced cardiomyopathy

Treatment of radiation-induced cardiomyopathy is similar to that for other forms of cardiomyopathy, with an emphasis on symptom management.

Heart transplant may be an option for highly selected patients with end-stage heart failure secondary to RIHD. In one report, a series of four RIHD patients received a heart transplant, and all four survived past 48 months.⁴⁵ However, data from the United Network of Organ Sharing revealed an increase in the all-cause mortality rate in patients undergoing heart transplant for RIHD compared with those undergoing transplant for cardiomyopathy due to other causes.⁴⁶ This trend may be confounded by a higher prevalence of prior cardiac surgery in the RIHD group—itself an established risk factor for poor posttransplant outcomes.

CONDUCTION SYSTEM DISEASE

Life-threatening arrhythmias have been reported that are distinct from the common, asymptomatic repolarization abnormalities that occur during radiotherapy. Atrioventricular nodal bradycardia, all degrees of heart block, and sick sinus syndrome have all been reported after chest radiotherapy. As conduction abnormalities do not typically manifest until years after radiotherapy, it is difficult to establish causation and, consequently, to define incidence.

Right bundle branch block is the most common conduction abnormality because of the proximity of the right bundle to the endocardium on the right side.⁴⁷

Chest radiotherapy is also associated with prolongation of the corrected QT interval (QTc). A study in patients with a history of thoracic radiotherapy found that the QTc characteristically increased with exercise, a poor prognostic indicator.⁴⁸ In a study of 134 survivors of childhood cancer, 12.5% of those who had undergone radiotherapy had a resting QTc of 0.44 msec or more.⁴⁹

Furthermore, a study of 69 breast cancer survivors found a higher incidence of conduction abnormalities at 6 months and 10 years after radiotherapy compared with baseline. The characteristic electrocardiographic changes at 6 months were T-wave changes. At 10 years, the T-wave abnormalities had resolved and were replaced by ST depression.⁵⁰

As mentioned above, establishing radiotherapy as a cause for these conduction abnormalities is challenging, given the lag between radiation therapy and electrocardiographic changes. The following criteria have been proposed for establishing a link between atrioventricular blockade and prior radiation⁵¹:

• Total radiation dose to the heart > 40 Gy
• Delay of 10 years or more since therapy
• Abnormal interval electrocardiographic changes such as bundle branch block
• Prior pericardial involvement
• Associated cardiac or mediastinal lesions.

SCREENING GUIDELINES

Consensus guidelines for identifying and monitoring RIHD have been published by the European Association of Cardiovascular Imaging and the American Society of Echocardiography (Table 2).¹⁰ The European Society of Medical Oncology has also issued guidelines for the prevention, diagnosis, and management of cardiovascular disease associated with cancer therapy.

Briefly, the guidelines call for aggressive cardiac risk-factor modification through weight loss, exercise, blood pressure control, and smoking cessation, in addition to early detection of RIHD. Cardiovascular screening for risk factors and a careful clinical examination should be performed in all patients. Baseline comprehensive transthoracic echocardiography is advocated in all patients before starting radiotherapy to detect cardiac anomalies. Beyond this, an annual history and physical examination, paying close attention to the signs and symptoms of cardiopulmonary disease, is essential. The development of new cardiopulmonary symptoms or a new physical finding such as a murmur should prompt evaluation with transthoracic echocardiography.

In patients without symptoms, screening transthoracic echocardiography at 10 years after the start of radiotherapy is recommended in light of the high probability of diagnosing cardiac disease at this juncture. In patients with no preexisting cardiac disease, surveillance transthoracic echocardiography should be at 5-year intervals thereafter.

In high-risk patients without symptoms (those who have undergone anterior or left-sided radiotherapy and have at least one risk factor for RIHD), initial screening transthoracic echocardiography is recommended 5 years after radiotherapy. These patients have a heightened risk of coronary events as described above and, consequently, are recommended to undergo noninvasive imaging 5 to 10 years after radiation exposure. If this initial examination is negative, stress testing should be repeated at 5-year intervals. Stress echocardiography and stress cardiac magnetic resonance imaging have higher specificity than stress electrocardiography and therefore are generally preferred. Stress scintigraphy should be used with caution, as it adds to the cumulative radiation exposure.

The role of magnetic resonance imaging and computed tomography depends on the results of initial transthoracic echocardiography and the clinical indication, in addition to the center’s expertise and facilities. However, there are currently no data advocating their use as screening tools, except for early detection of porcelain aorta in high-risk patients.¹⁰

MODERN RADIOTHERAPY TECHNIQUES

In recent years, there has been emphasis on exposing the patient to as little radiation as possible without compromising cure.⁵² The three major strategies employed to decrease cardiac exposure include reducing the radiation dose, reducing the radiation field and volume, and using newer planning and delivery techniques.

Reducing the radiation dose. It is well recognized that the mean dose of radiation to the heart is a significant predictor of cardiovascular disease, with one study demonstrating a linear increase in the risk of coronary artery disease with increasing mean heart radiation dose (excess relative risk per Gy 7.4%, 95% confidence interval 3.3%–14.8%).⁵³

Reducing the radiation field and volume. Modern strategies and computed tomography-based radiotherapy planning have enabled a transition from older techniques such as extended-field radiation therapy, mantle-field radiation therapy, and involved-field radiation therapy to new techniques such as involved-node and involved-site radiation therapy.⁵⁴ These have shown promise. For instance, a study in patients with early Hodgkin lymphoma found a mean heart dose of 27.5 Gy with mantle-field therapy compared with 7.7 Gy with involved-node therapy. This decrease in mean heart dose was associated with a reduction in the 25-year absolute excess cardiac risk from 9.1% to 1.4% and a reduction in cardiac mortality from 2.1% to 1%.⁵⁵

Employing newer planning and delivery systems has also demonstrated some promise in reducing rates of cardiac morbidity and mortality. Extended-field radiation therapy, mantle-field radiotherapy, and involved-field radiation therapy were traditionally based on two-dimensional planning and often resulted in large volumes of myocardium being unnecessarily exposed to large doses of radiation because of the uncertainty in targeting. Involved-site and involved-node radiotherapy are based on computed tomography, resulting in more accurate targeting and sparing of normal tissue.

In addition, newer techniques such as intensity-modulated radiotherapy and proton beam therapy have resulted in further improvements in conformality compared with three-dimensional conformal radiotherapy.^56,57 Respiratory motion management, including deep inspiration breath-holding and end-inspiration breath-holding, have decreased the radiation dose to the heart in patients undergoing mediastinal radiotherapy.^58,59

TOWARD THE GOALS OF PREVENTION AND EARLIER DETECTION

As survival from breast cancer and lymphoma has increased, we continue to see legacy or latent effects of therapy, such as RIHD. Radiation therapy can affect any cardiac structure and is a major cause of morbidity and death in cancer survivors.

Modern radiation techniques use a variety of mechanisms to decrease the radiation dose to the heart. A large body of evidence emanating from an era of higher radiation doses and a lack of knowledge of the cardiac effects of radiation highlight the perilous cardiac consequences of chest radiation. With advances in radiotherapy and the development and widespread implementation of consensus guidelines, we envision earlier detection and less frequent occurrence of RIHD, although the latter trend could be blunted by increased cardiovascular risk factors within the population. Given the lag between irradiation and the cardiac consequences, it may be a number of years before any comparisons can be drawn.

A 64-year-old woman had a remote history of generalized fatigue, tightness of the hands, tingling and numbness of the face, joint stiffness, and bluish discoloration of the fingers that worsened with cold weather. Laboratory testing at that time had revealed an antinuclear antibody titer over 1:320 (reference range < 1:10), anti-Scl-70 antibody 100 U/mL (< 32 U/mL), and thyroid-stimulating hormone 10.78 mIU/L (0.4–5.5). Pulmonary function testing showed a pattern of restrictive lung disease. She was diagnosed with hypothyroidism, Raynaud phenomenon, and scleroderma. She was referred to a rheumatologist, who prescribed levothyroxine and penicillamine.

Despite treatment, she continued to feel fatigued, and she requested the addition of minocycline to the scleroderma treatment after seeing a report on television. Minocycline 100 mg twice daily was prescribed. She reported improvement of her symptoms for the next 2 years but was then lost to follow-up with the rheumatologist. She continued to take penicillamine and minocycline as prescribed by her primary care physician.

She presented to our clinic with bluish discoloration (Figure 1) that had started 1 year before as a small area but had spread to involve the entire face, fingers, gums, teeth, and sclera, and included a dark discoloration of the neck and upper chest. She had been taking minocycline for nearly 9 years. We referred her to a dermatologist, who diagnosed minocycline-induced hyperpigmentation. Her minocycline was stopped. Skin biopsy was not done, as the dermatologist was confident making the diagnosis without biopsy. At 1 year later, she continued to have the widespread skin pigmentation with no improvement at all.

DIFFERENTIAL DIAGNOSIS

Hyperpigmentation is the darkening in the natural color of the skin, usually from increased deposition of melanin in the epidermis or dermis, or both. It can occur in different degrees of blue, brown, and black (from lightest to darkest). Less frequently, it may be caused by the deposition in the dermis of an endogenous or exogenous pigment, such as hemosiderin, iron, or heavy metal.¹ The hyperpigmentation can be circumscribed or more diffuse.

The differential diagnosis of diffuse skin pigmentation includes Addison disease, hyperthyroidism, hemochromatosis, erythema dyschromicum perstans, cutaneous malignancies, sunburn, and drug-induced hyperpigmentation.^1,2 Medications commonly cited as causing hyperpigmentation include minocycline, amiodarone, bleomycin, prostaglandins, oral contraceptives, phenothiazine, and antimalarial drugs.^1,3 In Addison disease, the pigmentation is typically diffuse, with accentuation in sun-exposed areas, flexures, palmar and plantar creases, and areas of pressure or friction.² The bronze discoloration of hemochromatosis is from a combination of hemosiderin deposition and increased melanin production.¹ Erythema dyschromicum perstans presents with brownish oval-shaped macules and patches. Early lesions may have thin, raised, erythematous borders that typically involve the trunk, but they may spread to the neck, upper extremities, and face.⁴

The role of minocycline in the treatment of scleroderma is controversial. Early reports involving a small number of patients showed a benefit of minocycline in decreasing symptoms,^5,6 but these findings were not achieved in a larger multicenter trial.⁷

Types of minocycline-induced hyperpigmentation

Three types of minocycline-induced hyperpigmentation occur^3,8:

• Type 1—blue-grey coloration on the face in areas of inflammation
• Type 2—blue-grey coloration on normal skin on the skin of the shins and forearms
• Type 3—the least common, characterized by diffuse muddy brown or blue-grey discoloration in sun-exposed areas, as in our patient.

The prevalence of minocycline-induced hyperpigmentation varies between 2.4% and 41% and is highest in patients with rheumatoid arthritis.^3,9 Type 1 pigmentation is not correlated with treatment duration or cumulative dose, while type 2 and 3 are associated with long-term therapy.⁸ In type 3, changes are nonspecific, consisting of increased melanin in basal keratinocytes and melanin-only staining dermal melanophages. Types 1 and 2 may resolve slowly, whereas type 3 can persist indefinitely.^3,8,10

TREATMENT

Treatment involves early recognition, discontinuation of the drug, and avoidance of sun exposure. Treatment with pigment-specific lasers has shown promise.^8,10

A 64-year-old woman had a remote history of generalized fatigue, tightness of the hands, tingling and numbness of the face, joint stiffness, and bluish discoloration of the fingers that worsened with cold weather. Laboratory testing at that time had revealed an antinuclear antibody titer over 1:320 (reference range < 1:10), anti-Scl-70 antibody 100 U/mL (< 32 U/mL), and thyroid-stimulating hormone 10.78 mIU/L (0.4–5.5). Pulmonary function testing showed a pattern of restrictive lung disease. She was diagnosed with hypothyroidism, Raynaud phenomenon, and scleroderma. She was referred to a rheumatologist, who prescribed levothyroxine and penicillamine.

Despite treatment, she continued to feel fatigued, and she requested the addition of minocycline to the scleroderma treatment after seeing a report on television. Minocycline 100 mg twice daily was prescribed. She reported improvement of her symptoms for the next 2 years but was then lost to follow-up with the rheumatologist. She continued to take penicillamine and minocycline as prescribed by her primary care physician.

She presented to our clinic with bluish discoloration (Figure 1) that had started 1 year before as a small area but had spread to involve the entire face, fingers, gums, teeth, and sclera, and included a dark discoloration of the neck and upper chest. She had been taking minocycline for nearly 9 years. We referred her to a dermatologist, who diagnosed minocycline-induced hyperpigmentation. Her minocycline was stopped. Skin biopsy was not done, as the dermatologist was confident making the diagnosis without biopsy. At 1 year later, she continued to have the widespread skin pigmentation with no improvement at all.

DIFFERENTIAL DIAGNOSIS

Hyperpigmentation is the darkening in the natural color of the skin, usually from increased deposition of melanin in the epidermis or dermis, or both. It can occur in different degrees of blue, brown, and black (from lightest to darkest). Less frequently, it may be caused by the deposition in the dermis of an endogenous or exogenous pigment, such as hemosiderin, iron, or heavy metal.¹ The hyperpigmentation can be circumscribed or more diffuse.

The differential diagnosis of diffuse skin pigmentation includes Addison disease, hyperthyroidism, hemochromatosis, erythema dyschromicum perstans, cutaneous malignancies, sunburn, and drug-induced hyperpigmentation.^1,2 Medications commonly cited as causing hyperpigmentation include minocycline, amiodarone, bleomycin, prostaglandins, oral contraceptives, phenothiazine, and antimalarial drugs.^1,3 In Addison disease, the pigmentation is typically diffuse, with accentuation in sun-exposed areas, flexures, palmar and plantar creases, and areas of pressure or friction.² The bronze discoloration of hemochromatosis is from a combination of hemosiderin deposition and increased melanin production.¹ Erythema dyschromicum perstans presents with brownish oval-shaped macules and patches. Early lesions may have thin, raised, erythematous borders that typically involve the trunk, but they may spread to the neck, upper extremities, and face.⁴

The role of minocycline in the treatment of scleroderma is controversial. Early reports involving a small number of patients showed a benefit of minocycline in decreasing symptoms,^5,6 but these findings were not achieved in a larger multicenter trial.⁷

Types of minocycline-induced hyperpigmentation

Three types of minocycline-induced hyperpigmentation occur^3,8:

• Type 1—blue-grey coloration on the face in areas of inflammation
• Type 2—blue-grey coloration on normal skin on the skin of the shins and forearms
• Type 3—the least common, characterized by diffuse muddy brown or blue-grey discoloration in sun-exposed areas, as in our patient.

The prevalence of minocycline-induced hyperpigmentation varies between 2.4% and 41% and is highest in patients with rheumatoid arthritis.^3,9 Type 1 pigmentation is not correlated with treatment duration or cumulative dose, while type 2 and 3 are associated with long-term therapy.⁸ In type 3, changes are nonspecific, consisting of increased melanin in basal keratinocytes and melanin-only staining dermal melanophages. Types 1 and 2 may resolve slowly, whereas type 3 can persist indefinitely.^3,8,10

TREATMENT

Treatment involves early recognition, discontinuation of the drug, and avoidance of sun exposure. Treatment with pigment-specific lasers has shown promise.^8,10

A 64-year-old woman had a remote history of generalized fatigue, tightness of the hands, tingling and numbness of the face, joint stiffness, and bluish discoloration of the fingers that worsened with cold weather. Laboratory testing at that time had revealed an antinuclear antibody titer over 1:320 (reference range < 1:10), anti-Scl-70 antibody 100 U/mL (< 32 U/mL), and thyroid-stimulating hormone 10.78 mIU/L (0.4–5.5). Pulmonary function testing showed a pattern of restrictive lung disease. She was diagnosed with hypothyroidism, Raynaud phenomenon, and scleroderma. She was referred to a rheumatologist, who prescribed levothyroxine and penicillamine.

Despite treatment, she continued to feel fatigued, and she requested the addition of minocycline to the scleroderma treatment after seeing a report on television. Minocycline 100 mg twice daily was prescribed. She reported improvement of her symptoms for the next 2 years but was then lost to follow-up with the rheumatologist. She continued to take penicillamine and minocycline as prescribed by her primary care physician.

She presented to our clinic with bluish discoloration (Figure 1) that had started 1 year before as a small area but had spread to involve the entire face, fingers, gums, teeth, and sclera, and included a dark discoloration of the neck and upper chest. She had been taking minocycline for nearly 9 years. We referred her to a dermatologist, who diagnosed minocycline-induced hyperpigmentation. Her minocycline was stopped. Skin biopsy was not done, as the dermatologist was confident making the diagnosis without biopsy. At 1 year later, she continued to have the widespread skin pigmentation with no improvement at all.

DIFFERENTIAL DIAGNOSIS

Hyperpigmentation is the darkening in the natural color of the skin, usually from increased deposition of melanin in the epidermis or dermis, or both. It can occur in different degrees of blue, brown, and black (from lightest to darkest). Less frequently, it may be caused by the deposition in the dermis of an endogenous or exogenous pigment, such as hemosiderin, iron, or heavy metal.¹ The hyperpigmentation can be circumscribed or more diffuse.

The differential diagnosis of diffuse skin pigmentation includes Addison disease, hyperthyroidism, hemochromatosis, erythema dyschromicum perstans, cutaneous malignancies, sunburn, and drug-induced hyperpigmentation.^1,2 Medications commonly cited as causing hyperpigmentation include minocycline, amiodarone, bleomycin, prostaglandins, oral contraceptives, phenothiazine, and antimalarial drugs.^1,3 In Addison disease, the pigmentation is typically diffuse, with accentuation in sun-exposed areas, flexures, palmar and plantar creases, and areas of pressure or friction.² The bronze discoloration of hemochromatosis is from a combination of hemosiderin deposition and increased melanin production.¹ Erythema dyschromicum perstans presents with brownish oval-shaped macules and patches. Early lesions may have thin, raised, erythematous borders that typically involve the trunk, but they may spread to the neck, upper extremities, and face.⁴

The role of minocycline in the treatment of scleroderma is controversial. Early reports involving a small number of patients showed a benefit of minocycline in decreasing symptoms,^5,6 but these findings were not achieved in a larger multicenter trial.⁷

Types of minocycline-induced hyperpigmentation

Three types of minocycline-induced hyperpigmentation occur^3,8:

• Type 1—blue-grey coloration on the face in areas of inflammation
• Type 2—blue-grey coloration on normal skin on the skin of the shins and forearms
• Type 3—the least common, characterized by diffuse muddy brown or blue-grey discoloration in sun-exposed areas, as in our patient.

The prevalence of minocycline-induced hyperpigmentation varies between 2.4% and 41% and is highest in patients with rheumatoid arthritis.^3,9 Type 1 pigmentation is not correlated with treatment duration or cumulative dose, while type 2 and 3 are associated with long-term therapy.⁸ In type 3, changes are nonspecific, consisting of increased melanin in basal keratinocytes and melanin-only staining dermal melanophages. Types 1 and 2 may resolve slowly, whereas type 3 can persist indefinitely.^3,8,10

TREATMENT

Treatment involves early recognition, discontinuation of the drug, and avoidance of sun exposure. Treatment with pigment-specific lasers has shown promise.^8,10

An indwelling pleural catheter should be considered when a malignant pleural effusion causes symptoms and recurs after thoracentesis, especially in patients with short to intermediate life expectancy or trapped lung, or who underwent unsuccessful pleurodesis.¹

MALIGNANT PLEURAL EFFUSION

Malignant pleural effusion affects about 150,000 people in the United States each year. It occurs in 15% of patients with advanced malignancies, most often lung cancer, breast cancer, lymphoma, and ovarian cancer, which account for more than 50% of cases.²

In most patients with malignant pleural effusion, disabling dyspnea causes poor quality of life. The prognosis is unfavorable, with life expectancy of 3 to 12 months. Patients with poor performance status and lower glucose concentrations in the pleural fluid face a worse prognosis and a shorter life expectancy.²

In general, management focuses on relieving symptoms rather than on cure. Symptoms can be controlled by thoracentesis, but if the effusion recurs, the patient needs repeated visits to the emergency room or clinic or a hospital admission to drain the fluid. Frequent hospital visits can be grueling for a patient with a poor functional status, and so can the adverse effects of repeated thoracentesis. For that reason, an early palliative approach to malignant pleural effusion in patients with cancer and a poor prognosis leads to better symptom control and a better quality of life.³ Multiple treatments can be offered to control the symptoms in patients with recurrent malignant pleural effusion (Table 1).

PLEURODESIS HAS BEEN THE TREATMENT OF CHOICE

Pleurodesis has been the treatment of choice for malignant pleural effusion for decades. In this procedure, adhesion of the visceral and parietal pleura is achxieved by inducing inflammation either mechanically or chemically between the pleural surfaces. Injection of a sclerosant into the pleural space generates the inflammation. The sclerosant can be introduced through a chest tube or thoracoscope such as in video-assisted thoracic surgery or medical pleuroscopy. The use of talc is associated with a higher success rate than other sclerosing agents such as bleomycin and doxycycline.⁴

The downside of this procedure is that pleural effusion recurs in 10% to 40% of cases, and patients require 2 to 4 days in the hospital. Also, the use of talc can lead to acute lung injury–acute respiratory distress syndrome, a rare but potentially life-threatening complication. The incidence of this complication may be related to particle size, with small particles posing a higher risk than large ones.^5,6

PLACEMENT OF AN INDWELLING PLEURAL CATHETER

Indwelling pleural catheters are currently used as palliative therapy for patients with recurrent malignant pleural effusion who suffer from respiratory distress due to rapid reaccumulation of pleural fluids that require multiple thoracentesis procedures.

An indwelling pleural catheter is contraindicated in patients with uncontrolled coagulopathy, multiloculated pleural effusions, or extensive malignancy in the skin.³ Other factors that need to be considered are the patient’s social circumstances: ie, the patient must be in a clean and safe environment and must have insurance coverage for the supplies.

Catheters are 66 cm long and 15.5F and are made of silicone rubber with fenestrations along the distal 24 cm. They have a one-way valve at the proximal end that allows fluids and air to go out but not in (Figure 1).¹ Several systems are commercially available in the United States.

The catheter is inserted and tunneled percutaneously with the patient under local anesthesia and conscious sedation (Figure 2). Insertion is a same-day outpatient procedure, and intermittent pleural fluid drainage can be done at home by a home heathcare provider or a trained family member.⁷

In a meta-analysis, insertion difficulties were reported in only 4% of cases, particularly in patients who underwent prior pleural interventions. Spontaneous pleurodesis occurred in 45% of patients at a mean of 52 days after insertion.⁸

After catheter insertion, the pleural space should be drained three times a week. No more than 1,000 mL of fluid should be removed at a time—or less if drainage causes chest pain or cough secondary to trapped lung (see below). When the drainage declines to 150 mL per session, the sessions can be reduced to twice a week. If the volume drops to less than 50 mL per session, imaging (computed tomography or bedside thoracic ultrasonography) is recommended to ensure the achievement of pleurodesis and to rule out catheter blockage.

A large multicenter randomized controlled trial⁹ compared indwelling pleural catheter therapy and chest tube insertion with talc pleurodesis. Both procedures relieved symptoms for the first 42 days, and there was no significant difference in quality of life. However, the median length of hospital stay was 4 days for the talc pleurodesis group compared with 0 days for the indwelling pleural catheter group. Twenty-two percent of the talc group required a further pleural procedure such as a video-assisted thoracic surgery or thoracoscopy, compared with 6% of the indwelling catheter group. On the other hand, 36% of those in the indwelling catheter group experienced nonserious adverse events such as pleural infections that mandated outpatient oral antibiotic therapy, cellulitis, and catheter blockage, compared with 7% of the talc group.⁹

Symptomatic, inoperable trapped lung is another condition for which an indwelling pleural catheter is a reasonable strategy compared with pleurodesis. Trapped lung is a condition in which the lung fails to fully expand despite proper pleural fluid removal, creating a vacuum space between the parietal and visceral pleura (Figure 3).

Patients with trapped lung complain of severe dull or sharp pain during drainage of pleural fluids due to stretching of the visceral pleura against the intrathoracic vacuum space. Trapped lung can be detected objectively by using intrathoracic manometry while draining fluids, looking for more than a 20-cm H₂O drop in the intrathoracic pressure. Radiographically, this may be identified as a pneumothorax ex vacuo¹⁰ (ie, caused by inability of the lung to expand to fill the thoracic cavity after pleural fluid has been drained) and is not a procedure complication.

Placement of an indwelling pleural catheter is the treatment of choice for trapped lung, since chemical pleurodesis is not feasible without the potential of parietal and visceral pleural apposition. In a retrospective study of indwelling catheter placement for palliative symptom control, a catheter relieved symptoms, improved quality of life, and afforded a substantial increase in mobility.^1,11

In another multicenter pilot study,¹² rapid pleurodesis was achieved in 30 patients with recurrent malignant pleural effusion by combining chemical pleurodesis and indwelling catheter placement. Both were done under direct vision with medical thoracoscopy. Pleurodesis succeeded in 92% of patients by day 8 after the procedure. The hospital stay was reduced to a mean of 2 days after the procedure. In the catheter group, fluids were drained three times in the first day after the procedure and twice a day on the second and third days. Of the 30 patients in this study, 2 had fever, 1 needed to have the catheter replaced, and 1 contracted empyema.

AN EFFECTIVE INITIAL TREATMENT

Placement of an indwelling pleural catheter is an effective initial treatment for recurrent malignant pleural effusion. Compared with chemical pleurodesis, it has a comparable success rate and complication rate. It offers the advantages of being a same-day surgical procedure entailing a shorter hospital stay and less need for further pleural intervention. This treatment should be considered for patients with symptomatic malignant pleural effusion, especially those in whom symptomatic malignant pleural effusion recurred after thoracentesis.⁸

An indwelling pleural catheter should be considered when a malignant pleural effusion causes symptoms and recurs after thoracentesis, especially in patients with short to intermediate life expectancy or trapped lung, or who underwent unsuccessful pleurodesis.¹

MALIGNANT PLEURAL EFFUSION

Malignant pleural effusion affects about 150,000 people in the United States each year. It occurs in 15% of patients with advanced malignancies, most often lung cancer, breast cancer, lymphoma, and ovarian cancer, which account for more than 50% of cases.²

In most patients with malignant pleural effusion, disabling dyspnea causes poor quality of life. The prognosis is unfavorable, with life expectancy of 3 to 12 months. Patients with poor performance status and lower glucose concentrations in the pleural fluid face a worse prognosis and a shorter life expectancy.²

In general, management focuses on relieving symptoms rather than on cure. Symptoms can be controlled by thoracentesis, but if the effusion recurs, the patient needs repeated visits to the emergency room or clinic or a hospital admission to drain the fluid. Frequent hospital visits can be grueling for a patient with a poor functional status, and so can the adverse effects of repeated thoracentesis. For that reason, an early palliative approach to malignant pleural effusion in patients with cancer and a poor prognosis leads to better symptom control and a better quality of life.³ Multiple treatments can be offered to control the symptoms in patients with recurrent malignant pleural effusion (Table 1).

PLEURODESIS HAS BEEN THE TREATMENT OF CHOICE

Pleurodesis has been the treatment of choice for malignant pleural effusion for decades. In this procedure, adhesion of the visceral and parietal pleura is achxieved by inducing inflammation either mechanically or chemically between the pleural surfaces. Injection of a sclerosant into the pleural space generates the inflammation. The sclerosant can be introduced through a chest tube or thoracoscope such as in video-assisted thoracic surgery or medical pleuroscopy. The use of talc is associated with a higher success rate than other sclerosing agents such as bleomycin and doxycycline.⁴

The downside of this procedure is that pleural effusion recurs in 10% to 40% of cases, and patients require 2 to 4 days in the hospital. Also, the use of talc can lead to acute lung injury–acute respiratory distress syndrome, a rare but potentially life-threatening complication. The incidence of this complication may be related to particle size, with small particles posing a higher risk than large ones.^5,6

PLACEMENT OF AN INDWELLING PLEURAL CATHETER

Indwelling pleural catheters are currently used as palliative therapy for patients with recurrent malignant pleural effusion who suffer from respiratory distress due to rapid reaccumulation of pleural fluids that require multiple thoracentesis procedures.

An indwelling pleural catheter is contraindicated in patients with uncontrolled coagulopathy, multiloculated pleural effusions, or extensive malignancy in the skin.³ Other factors that need to be considered are the patient’s social circumstances: ie, the patient must be in a clean and safe environment and must have insurance coverage for the supplies.

Catheters are 66 cm long and 15.5F and are made of silicone rubber with fenestrations along the distal 24 cm. They have a one-way valve at the proximal end that allows fluids and air to go out but not in (Figure 1).¹ Several systems are commercially available in the United States.

The catheter is inserted and tunneled percutaneously with the patient under local anesthesia and conscious sedation (Figure 2). Insertion is a same-day outpatient procedure, and intermittent pleural fluid drainage can be done at home by a home heathcare provider or a trained family member.⁷

In a meta-analysis, insertion difficulties were reported in only 4% of cases, particularly in patients who underwent prior pleural interventions. Spontaneous pleurodesis occurred in 45% of patients at a mean of 52 days after insertion.⁸

After catheter insertion, the pleural space should be drained three times a week. No more than 1,000 mL of fluid should be removed at a time—or less if drainage causes chest pain or cough secondary to trapped lung (see below). When the drainage declines to 150 mL per session, the sessions can be reduced to twice a week. If the volume drops to less than 50 mL per session, imaging (computed tomography or bedside thoracic ultrasonography) is recommended to ensure the achievement of pleurodesis and to rule out catheter blockage.

A large multicenter randomized controlled trial⁹ compared indwelling pleural catheter therapy and chest tube insertion with talc pleurodesis. Both procedures relieved symptoms for the first 42 days, and there was no significant difference in quality of life. However, the median length of hospital stay was 4 days for the talc pleurodesis group compared with 0 days for the indwelling pleural catheter group. Twenty-two percent of the talc group required a further pleural procedure such as a video-assisted thoracic surgery or thoracoscopy, compared with 6% of the indwelling catheter group. On the other hand, 36% of those in the indwelling catheter group experienced nonserious adverse events such as pleural infections that mandated outpatient oral antibiotic therapy, cellulitis, and catheter blockage, compared with 7% of the talc group.⁹

Symptomatic, inoperable trapped lung is another condition for which an indwelling pleural catheter is a reasonable strategy compared with pleurodesis. Trapped lung is a condition in which the lung fails to fully expand despite proper pleural fluid removal, creating a vacuum space between the parietal and visceral pleura (Figure 3).

Patients with trapped lung complain of severe dull or sharp pain during drainage of pleural fluids due to stretching of the visceral pleura against the intrathoracic vacuum space. Trapped lung can be detected objectively by using intrathoracic manometry while draining fluids, looking for more than a 20-cm H₂O drop in the intrathoracic pressure. Radiographically, this may be identified as a pneumothorax ex vacuo¹⁰ (ie, caused by inability of the lung to expand to fill the thoracic cavity after pleural fluid has been drained) and is not a procedure complication.

Placement of an indwelling pleural catheter is the treatment of choice for trapped lung, since chemical pleurodesis is not feasible without the potential of parietal and visceral pleural apposition. In a retrospective study of indwelling catheter placement for palliative symptom control, a catheter relieved symptoms, improved quality of life, and afforded a substantial increase in mobility.^1,11

In another multicenter pilot study,¹² rapid pleurodesis was achieved in 30 patients with recurrent malignant pleural effusion by combining chemical pleurodesis and indwelling catheter placement. Both were done under direct vision with medical thoracoscopy. Pleurodesis succeeded in 92% of patients by day 8 after the procedure. The hospital stay was reduced to a mean of 2 days after the procedure. In the catheter group, fluids were drained three times in the first day after the procedure and twice a day on the second and third days. Of the 30 patients in this study, 2 had fever, 1 needed to have the catheter replaced, and 1 contracted empyema.

AN EFFECTIVE INITIAL TREATMENT

Placement of an indwelling pleural catheter is an effective initial treatment for recurrent malignant pleural effusion. Compared with chemical pleurodesis, it has a comparable success rate and complication rate. It offers the advantages of being a same-day surgical procedure entailing a shorter hospital stay and less need for further pleural intervention. This treatment should be considered for patients with symptomatic malignant pleural effusion, especially those in whom symptomatic malignant pleural effusion recurred after thoracentesis.⁸

An indwelling pleural catheter should be considered when a malignant pleural effusion causes symptoms and recurs after thoracentesis, especially in patients with short to intermediate life expectancy or trapped lung, or who underwent unsuccessful pleurodesis.¹

MALIGNANT PLEURAL EFFUSION

Malignant pleural effusion affects about 150,000 people in the United States each year. It occurs in 15% of patients with advanced malignancies, most often lung cancer, breast cancer, lymphoma, and ovarian cancer, which account for more than 50% of cases.²

In most patients with malignant pleural effusion, disabling dyspnea causes poor quality of life. The prognosis is unfavorable, with life expectancy of 3 to 12 months. Patients with poor performance status and lower glucose concentrations in the pleural fluid face a worse prognosis and a shorter life expectancy.²

In general, management focuses on relieving symptoms rather than on cure. Symptoms can be controlled by thoracentesis, but if the effusion recurs, the patient needs repeated visits to the emergency room or clinic or a hospital admission to drain the fluid. Frequent hospital visits can be grueling for a patient with a poor functional status, and so can the adverse effects of repeated thoracentesis. For that reason, an early palliative approach to malignant pleural effusion in patients with cancer and a poor prognosis leads to better symptom control and a better quality of life.³ Multiple treatments can be offered to control the symptoms in patients with recurrent malignant pleural effusion (Table 1).

PLEURODESIS HAS BEEN THE TREATMENT OF CHOICE

Pleurodesis has been the treatment of choice for malignant pleural effusion for decades. In this procedure, adhesion of the visceral and parietal pleura is achxieved by inducing inflammation either mechanically or chemically between the pleural surfaces. Injection of a sclerosant into the pleural space generates the inflammation. The sclerosant can be introduced through a chest tube or thoracoscope such as in video-assisted thoracic surgery or medical pleuroscopy. The use of talc is associated with a higher success rate than other sclerosing agents such as bleomycin and doxycycline.⁴

The downside of this procedure is that pleural effusion recurs in 10% to 40% of cases, and patients require 2 to 4 days in the hospital. Also, the use of talc can lead to acute lung injury–acute respiratory distress syndrome, a rare but potentially life-threatening complication. The incidence of this complication may be related to particle size, with small particles posing a higher risk than large ones.^5,6

PLACEMENT OF AN INDWELLING PLEURAL CATHETER

Indwelling pleural catheters are currently used as palliative therapy for patients with recurrent malignant pleural effusion who suffer from respiratory distress due to rapid reaccumulation of pleural fluids that require multiple thoracentesis procedures.

An indwelling pleural catheter is contraindicated in patients with uncontrolled coagulopathy, multiloculated pleural effusions, or extensive malignancy in the skin.³ Other factors that need to be considered are the patient’s social circumstances: ie, the patient must be in a clean and safe environment and must have insurance coverage for the supplies.

Catheters are 66 cm long and 15.5F and are made of silicone rubber with fenestrations along the distal 24 cm. They have a one-way valve at the proximal end that allows fluids and air to go out but not in (Figure 1).¹ Several systems are commercially available in the United States.

The catheter is inserted and tunneled percutaneously with the patient under local anesthesia and conscious sedation (Figure 2). Insertion is a same-day outpatient procedure, and intermittent pleural fluid drainage can be done at home by a home heathcare provider or a trained family member.⁷

In a meta-analysis, insertion difficulties were reported in only 4% of cases, particularly in patients who underwent prior pleural interventions. Spontaneous pleurodesis occurred in 45% of patients at a mean of 52 days after insertion.⁸

After catheter insertion, the pleural space should be drained three times a week. No more than 1,000 mL of fluid should be removed at a time—or less if drainage causes chest pain or cough secondary to trapped lung (see below). When the drainage declines to 150 mL per session, the sessions can be reduced to twice a week. If the volume drops to less than 50 mL per session, imaging (computed tomography or bedside thoracic ultrasonography) is recommended to ensure the achievement of pleurodesis and to rule out catheter blockage.

A large multicenter randomized controlled trial⁹ compared indwelling pleural catheter therapy and chest tube insertion with talc pleurodesis. Both procedures relieved symptoms for the first 42 days, and there was no significant difference in quality of life. However, the median length of hospital stay was 4 days for the talc pleurodesis group compared with 0 days for the indwelling pleural catheter group. Twenty-two percent of the talc group required a further pleural procedure such as a video-assisted thoracic surgery or thoracoscopy, compared with 6% of the indwelling catheter group. On the other hand, 36% of those in the indwelling catheter group experienced nonserious adverse events such as pleural infections that mandated outpatient oral antibiotic therapy, cellulitis, and catheter blockage, compared with 7% of the talc group.⁹

Symptomatic, inoperable trapped lung is another condition for which an indwelling pleural catheter is a reasonable strategy compared with pleurodesis. Trapped lung is a condition in which the lung fails to fully expand despite proper pleural fluid removal, creating a vacuum space between the parietal and visceral pleura (Figure 3).

Patients with trapped lung complain of severe dull or sharp pain during drainage of pleural fluids due to stretching of the visceral pleura against the intrathoracic vacuum space. Trapped lung can be detected objectively by using intrathoracic manometry while draining fluids, looking for more than a 20-cm H₂O drop in the intrathoracic pressure. Radiographically, this may be identified as a pneumothorax ex vacuo¹⁰ (ie, caused by inability of the lung to expand to fill the thoracic cavity after pleural fluid has been drained) and is not a procedure complication.

Placement of an indwelling pleural catheter is the treatment of choice for trapped lung, since chemical pleurodesis is not feasible without the potential of parietal and visceral pleural apposition. In a retrospective study of indwelling catheter placement for palliative symptom control, a catheter relieved symptoms, improved quality of life, and afforded a substantial increase in mobility.^1,11

In another multicenter pilot study,¹² rapid pleurodesis was achieved in 30 patients with recurrent malignant pleural effusion by combining chemical pleurodesis and indwelling catheter placement. Both were done under direct vision with medical thoracoscopy. Pleurodesis succeeded in 92% of patients by day 8 after the procedure. The hospital stay was reduced to a mean of 2 days after the procedure. In the catheter group, fluids were drained three times in the first day after the procedure and twice a day on the second and third days. Of the 30 patients in this study, 2 had fever, 1 needed to have the catheter replaced, and 1 contracted empyema.

AN EFFECTIVE INITIAL TREATMENT

Placement of an indwelling pleural catheter is an effective initial treatment for recurrent malignant pleural effusion. Compared with chemical pleurodesis, it has a comparable success rate and complication rate. It offers the advantages of being a same-day surgical procedure entailing a shorter hospital stay and less need for further pleural intervention. This treatment should be considered for patients with symptomatic malignant pleural effusion, especially those in whom symptomatic malignant pleural effusion recurred after thoracentesis.⁸

Women's health encompasses a variety of topics relevant to the daily practice of internists. Staying up to date with the evidence in this wide field is a challenge.

This article reviews important studies published in 2015 and early 2016 on treatment of urinary tract infections, the optimal duration of bisphosphonate use, ovarian cancer screening, the impact of oral contraceptives and lactation on mortality rates, and the risks and benefits of intrauterine contraception. We critically appraised the studies and judged that their methodology was strong and appropriate for inclusion in this review.

IBUPROFEN FOR URINARY TRACT INFECTIONS

A 36-year-old woman reports 4 days of mild to moderate dysuria, frequency, and urgency. She denies fever, nausea, or back pain. Her last urinary tract infection was 2 years ago. Office urinalysis reveals leukocyte esterase and nitrites. She has read an article about antibiotic resistance and Clostridium difficile infection and asks you if antibiotics are truly necessary. What do you recommend?

Urinary tract infections are often self-limited

Uncomplicated urinary tract infections account for 25% of antibiotic prescriptions in primary care.¹

Several small studies have suggested that many of these infections are self-limited, resolving within 3 to 14 days without antibiotics (Table 1).^2–6 A potential disadvantage of withholding treatment is slower bacterial clearance and resolution of symptoms, but reducing the number of antibiotic prescriptions may help slow antibiotic resistance.^7,8 Surveys and qualitative studies have suggested that women are concerned about the harms of antibiotic treatment and so may be willing to avoid or postpone antibiotic use.^9–11

Ibuprofen vs fosfomycin

Gágyor et al⁶ conducted a double-blind, randomized multicenter trial in 42 general practices in Germany to assess whether treating the symptoms of uncomplicated urinary tract infection with ibuprofen would reduce antibiotic use without worsening outcomes.

Of the 779 eligible women with suspected urinary tract infection, 281 declined to participate in the study, 4 did not participate for reasons not specified, 246 received a single dose of fosfomycin 3 g, and 248 were treated with ibuprofen 400 mg three times a day for 3 days. Participants scored their daily symptoms and activity impairment, and safety data were collected for adverse events and relapses up to day 28 and within 6 and 12 months. In both groups, if symptoms worsened or persisted, antibiotic therapy was initiated at the discretion of the treating physician.

Exclusion criteria included fever, “loin” (back) tenderness, pregnancy, renal disease, a previous urinary tract infection within 2 weeks, urinary catheterization, and a contraindication to nonsteroidal anti-inflammatory medications.

Results. Within 28 days of symptom onset, women in the ibuprofen group had received 81 courses of antibiotics for symptoms of urinary tract infection (plus another 13 courses for other reasons), compared with 277 courses for urinary tract infection in the fosfomycin group (plus 6 courses for other reasons), for a relative rate reduction in antibiotic use of 66.5% (95% confidence interval [CI] 58.8%–74.4%, P < .001). The women who received ibuprofen were more likely to need antibiotics after initial treatment because of refractory symptoms but were still less likely to receive antibiotics overall (Table 1).

The mean duration of symptoms was slightly shorter in the fosfomycin group (4.6 vs 5.6 days, P < .001). However, the percentage of patients who had a recurrent urinary tract infection within 2 to 4 weeks was higher in the fosfomycin-treated patients (11% vs 6% P = .049).

Although the study was not powered to show significant differences in pyelonephritis, five patients in the ibuprofen group developed pyelonephritis compared with one in the antibiotic-treated group (P = .12).

An important limitation of the study was that nonparticipants had higher symptom scores, which may mean that the results are not generalizable to women who have recurrent urinary tract infections, longer duration of symptoms, or symptoms that are more severe. The strengths of the study were that more than half of all potentially eligible women were enrolled, and baseline data were collected from nonparticipants.

Can our patient avoid antibiotics?

Given the mild nature of her symptoms, the clinician should discuss with her the risks vs benefits of delaying antibiotics, once it has been determined that she has no risk factors for severe urinary tract infection. Her symptoms are likely to resolve within 1 week even if she declines antibiotic treatment, though they may last a day longer with ibuprofen alone than if she had received antibiotics. She should watch for symptoms of pyelonephritis (eg, flank pain, fever, chills, vomiting) and should seek prompt medical care if such symptoms occur.

DISCONTINUING BISPHOSPHONATES

A 64-year-old woman has taken alendronate for her osteoporosis for 5 years. She has no history of fractures. Her original bone density scans showed a T-score of –2.6 at the spine and –1.5 at the hip. Since she started to take alendronate, there has been no further loss in bone mineral density. She is tolerating the drug well and does not take any other medications. Should she continue the bisphosphonate?

Optimal duration of therapy unknown

The risks and benefits of long-term bisphosphonate use are debated.

In the Fracture Intervention Trial (FIT),¹² women with low bone mineral density of the femoral neck were randomized to receive alendronate or placebo and were followed for 36 months. The alendronate group had significantly fewer vertebral fractures and clinical fractures overall. Then, in the FIT Long-term Extension (FLEX) study,¹³ 1,009 alendronate-treated women in the FIT study were rerandomized to receive 5 years of additional treatment or to stop treatment. Bone density in the untreated women decreased, although not to the level it was before treatment. At the end of the study, there was no difference in hip fracture rate between the two groups (3% of each group had had a hip fracture), although women in the treated group had a lower rate of clinical vertebral fracture (2% vs 5%, relative risk 0.5, 95% CI 0.2–0.8).

In addition, rare but serious risks have been associated with bisphosphonate use, specifically atypical femoral fracture and osteonecrosis of the jaw. A US Food and Drug Administration (FDA) evaluation of long-term bisphosphonate use concluded that there was evidence of an increased risk of osteonecrosis of the jaw with longer duration of use, but causality was not established. The evaluation also noted conflicting results about the association with atypical femoral fracture.¹⁴

Based on this report and focusing on the absence of nonspine benefit after 5 years, the FDA suggested that bisphosphonates may be safely discontinued in some patients without compromising therapeutic gains, but no adequate clinical trial has yet delineated how long the benefits of treatment are maintained after cessation. A periodic reevaluation of continued need was recommended.¹⁴

New recommendations from the American Society for Bone and Mineral Research

Age is the greatest risk factor for fracture.¹⁵ Therefore, deciding whether to discontinue a bisphosphonate when a woman is older, and hence at higher risk, is a challenge.

A task force of the American Society for Bone and Mineral Research (ASBMR) has developed an evidence-based guideline on managing osteoporosis in patients on long-term bisphosphonate treatment.¹⁶ The goal was to provide guidance on the duration of bisphosphonate therapy from the perspective of risk vs benefit. The authors conducted a systematic review focusing on two randomized controlled trials (FLEX¹³ and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture Trial¹⁷) that provided data on long-term bisphosphonate use.

The task force recommended¹⁶ that after 5 years of oral bisphosphonates or 3 years of intravenous bisphosphonates, risk should be reassessed. In women at high fracture risk, they recommended continuing the oral bisphosphonate for 10 years or the intravenous bisphosphonate for 6 years. Factors that favored continuation of bisphosphonate therapy were as follows:

• An osteoporotic fracture before or during therapy
• A hip bone mineral density T-score ≤ –2.5
• High risk of fracture, defined as age older than 70 or 75, other strong risk factors for fracture, or a FRAX fracture risk score¹⁸ above a country-specific threshold.

(The FRAX score is based on age, sex, weight, height, previous fracture, hip fracture in a parent, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol use, and bone mineral density in the femoral neck. It gives an estimate of the 10-year risk of major osteoporotic fracture and hip fracture. High risk would be a 10-year risk of major osteoporotic fracture greater than 20% or a 10-year risk of hip fracture greater than 3%.)

For women at high risk, the risks of atypical femoral fracture and osteonecrosis of the jaw are outweighed by the benefit of a reduction in vertebral fracture risk. For women not at high risk of fracture, a drug holiday of 2 to 3 years can be considered after 3 to 5 years of treatment.

Although the task force recommended reassessment after 2 to 3 years of drug holiday, how best to do this is not clear. The task force did not recommend a specific approach to reassessment, so decisions about when to restart therapy after a drug holiday could potentially be informed by subsequent bone mineral density testing if it were to show persistent bone loss. Another option could be to restart bisphosphonates after a defined amount of time (eg, 3–5 years) for women who have previously experienced benefit.

The task force recommendations are in line with those of other societies, the FDA, and expert opinion.^19–23

The American Association of Clinical Endocrinologists recommends considering a drug holiday in low-risk patients after 4 to 5 years of treatment. For high-risk patients, they recommend 1 to 2 years of drug holiday after 10 years of treatment. They encourage restarting treatment if bone mineral density decreases, bone turnover markers rise, or fracture occurs.¹⁹ This is a grade C recommendation, meaning the advice is based on descriptive studies and expert opinion.

Although some clinicians restart bisphosphonates when markers of bone turnover such as NTX (N-telopeptide of type 1 collagen) rise to premenopausal levels, there is no evidence to support this strategy.²⁴

The task force recommendations are based on limited evidence that primarily comes from white postmenopausal women. Another important limitation is that the outcomes are primarily vertebral fractures. However, until additional evidence is available, these guidelines can be useful in guiding decision-making.

Should our patient continue therapy?

Our patient is relatively young and does not have any of the high-risk features noted within the task force recommendations. She has responded well to bisphosphonate treatment and so can consider a drug holiday at this time.

OVARIAN CANCER SCREENING

A 50-year-old woman requests screening for ovarian cancer. She is postmenopausal and has no personal or family history of cancer. She is concerned because a friend forwarded an e-mail stating, “Please tell all your female friends and relatives to insist on a cancer antigen (CA) 125 blood test every year as part of their annual exam. This is an inexpensive and simple blood test. Don’t take no for an answer. If I had known then what I know now, we would have caught my cancer much earlier, before it was stage III!” What should you tell the patient?

Ovarian cancer is the most deadly of female reproductive cancers, largely because in most patients the cancer has already spread beyond the ovary by the time of clinical detection. Death rates from ovarian cancer have decreased only slightly in the past 30 years.

Little benefit and considerable harm of screening

In 2011, the Prostate Lung Colorectal Ovarian (PLCO) Cancer Screening trial²⁵ randomized more than 68,000 women ages 55 to 74 from the general US population to annual screening with CA 125 testing and transvaginal ultrasonography compared with usual care. They were followed for a median of 12.4 years.

Screening did not affect stage at diagnosis (77%–78% were in stage III or IV in both the screening and usual care groups), nor did it reduce the rate of death from ovarian cancer. In addition, false-positive findings led to some harm: nearly one in three women who had a positive screening test underwent surgery. Of 3,285 women with false-positive results, 1,080 underwent surgery, and 15% of these had at least one serious complication. The trial was stopped early due to evidence of futility.

A new UK study also found no benefit from screening

In the PLCO study, a CA 125 result of 35 U/mL or greater was classified as abnormal. However, researchers in the United Kingdom postulated that instead of using a single cutoff for a normal or abnormal CA 125 level, it would be better to interpret the CA 125 result according to a somewhat complicated (and proprietary) algorithm called the Risk of Ovarian Cancer Algorithm (ROCA).^26,27 The ROCA takes into account a woman’s age, menopausal status, known genetic mutations (BRCA 1 or 2 or Lynch syndrome), Ashkenazi Jewish descent, and family history of ovarian or breast cancer, as well as any change in CA 125 level over time.

In a 2016 UK study,²⁶ 202,638 postmenopausal women ages 50 to 74 were randomized to no screening, annual screening with transvaginal ultrasonography, or multimodal screening with an annual CA 125 blood test interpreted with the ROCA algorithm, adding transvaginal ultrasonography as a second-line test when needed if the CA 125 level was abnormal based on the ROCA. Women with abnormal findings on multimodal screening or ultrasonography had repeat tests, and women with persistent abnormalities underwent clinical evaluation and, when appropriate, surgery.

Participants were at average risk of ovarian cancer; those with suspected familial ovarian cancer syndrome were excluded, as were those with a personal history of ovarian cancer or other active cancer.

Results. At a median follow-up of 11.1 years, the percentage of women who were diagnosed with ovarian cancer was 0.7% in the multimodal screening group, 0.6% in the screening ultrasonography group, and 0.6% in the no-screening group. Comparing either multimodal or screening ultrasonography with no screening, there was no statistically significant reduction in mortality rate over 14 years of follow-up.

Screening had significant costs and potential harms. For every ovarian or peritoneal cancer detected by screening, an additional 2 women in the multimodal screening group and 10 women in the ultrasonography group underwent needless surgery.

Strengths of this trial included its large size, allowing adequate power to detect differences in outcomes, its multicenter setting, its high compliance rate, and the low crossover rate in the no-screening group. However, the design of the study makes it difficult to anticipate the late effects of screening. Also, the patient must purchase ROCA testing online and must also pay a consultation fee. Insurance providers do not cover this test.

Should our patient proceed with ovarian cancer screening?

No. Current evidence shows no clear benefit to ovarian cancer screening for average-risk women, and we should not recommend yearly ultrasonography and CA 125 level testing, as they are likely to cause harm without providing benefit. The US Preventive Services Task Force recommends against screening for ovarian cancer.²⁸ For premenopausal women, pregnancy, hormonal contraception, and breastfeeding all significantly decrease ovarian cancer risk by suppressing ovulation.^29–31

REPRODUCTIVE FACTORS AND THE RISK OF DEATH

A 26-year-old woman comes in to discuss her contraceptive options. She has been breastfeeding since the birth of her first baby 6 months ago, and wonders how lactation and contraception may affect her long-term health.

Questions about the safety of contraceptive options are common, especially in breastfeeding mothers.

In 2010, the long-term Royal College of General Practitioners’ Oral Contraceptive Study reported that the all-cause mortality rate was actually lower in women who used oral contraceptives.³² Similarly, in 2013, an Oxford study that followed 17,032 women for over 30 years reported no association between oral contraceptives and breast cancer.³³

However, in 2014, results from the Nurses’ Health Study indicated that breast cancer rates were higher in oral contraceptive users, although reassuringly, the study found no difference in all-cause mortality rates in women who had used oral contraception.³⁴

The European Prospective Investigation Into Cancer and Nutrition

To further characterize relationships between reproductive characteristics and mortality rates, investigators analyzed data from the European Prospective Investigation Into Cancer and Nutrition,³⁵ which recruited 322,972 women from 10 countries between 1992 and 2000. Analyses were stratified by study center and participant age and were adjusted for body mass index, physical activity, education level, smoking, and menopausal status; alcohol intake was examined as a potential confounder but was excluded from final models.

Findings. Over an average 13 years of follow-up, the rate of all-cause mortality was 20% lower in parous than in nulliparous women. In parous women, the all-cause mortality rate was additionally 18% lower in those who had breastfed vs those who had never breastfed, although breastfeeding duration was not associated with mortality. Use of oral contraceptives lowered all-cause mortality by 10% among nonsmokers; in smokers, no association with all-cause mortality was seen for oral contraceptive use, as smoking is such a powerful risk factor for mortality. The primary contributor to all-cause mortality appeared to be ischemic heart disease, the incidence of which was significantly lower in parous women (by 14%) and those who breastfed (by 20%) and was not related to oral contraceptive use.³⁵

Strengths of this study included the large sample size recruited from countries across Europe, with varying rates of breastfeeding and contraceptive use. However, as with all observational studies, it remains subject to the possibility of residual confounding.

What should we tell this patient?

After congratulating her for breastfeeding, we can reassure her about the safety of all available contraceptives. According to the US Centers for Disease Control and Prevention (CDC),³⁶ after 42 days postpartum most women can use combined hormonal contraception. All other methods can be used immediately postpartum, including progestin-only pills.

As lactational amenorrhea is only effective while mothers are exclusively breastfeeding, and short interpregnancy intervals have been associated with higher rates of adverse pregnancy outcomes,³⁷ this patient will likely benefit from promptly starting a prescription contraceptive.

HIGHLY EFFECTIVE REVERSIBLE CONTRACEPTION

This same 26-year-old patient is concerned that she will not remember to take an oral contraceptive every day, and expresses interest in a more convenient method of contraception. However, she is concerned about the potential risks.

Although intrauterine contraceptives (IUCs) are typically 20 times more effective than oral contraceptives³⁸ and have been used by millions of women worldwide, rates of use in the United States have been lower than in many other countries.³⁹

A study of intrauterine contraception

To clarify the safety of IUCs, researchers followed 61,448 women who underwent IUC placement in six European countries between 2006 and 2013.⁴⁰ Most participants received an IUC containing levonorgestrel, while 30% received a copper IUC.

Findings. Overall, rates of uterine perforation were low (approximately 1 per 1,000 insertions). The most significant risk factors for perforation were breastfeeding at the time of insertion and insertion less than 36 weeks after the last delivery. None of the perforations in the study led to serious illness or injury of intra-abdominal or pelvic structures. Interestingly, women using a levonorgestrel IUC were considerably less likely to experience a contraceptive failure than those using a copper IUC.⁴¹

Strengths of this study included the prospective data collection and power to examine rare clinical outcomes. However, it was industry-funded.

The risk of pelvic infection with an IUC is so low that the CDC does not recommend prophylactic antibiotics with the insertion procedure. If women have other indications for testing for sexually transmitted disease, an IUC can be placed the same day as testing, and before results are available.⁴² If a woman is found to have a sexually transmitted disease while she has an IUC in place, she should be treated with antibiotics, and there is no need to remove the IUC.⁴³

Subdermal implants

Another highly effective contraceptive option for this patient is the progestin-only subdermal contraceptive implant (marketed in the United States as Nexplanon). Implants have been well-studied and found to have no adverse effect on lactation.⁴⁴

Learning to place a subdermal contraceptive is far easier than learning to place an IUC, but it requires a few hours of FDA-mandated in-person training. Unfortunately, relatively few clinicians have obtained this training.⁴⁵ As placing a subdermal contraceptive is like placing an intravenous line without needing to hit the vein, this procedure can easily be incorporated into a primary care practice. Training from the manufacturer is available to providers who request it.

What should we tell this patient?

An IUC is a great option for many women. When pregnancy is desired, the device is easily removed. Of the three IUCs now available in the United States, those containing 52 mg of levonorgestrel (marketed in the United States as Mirena and Liletta) are the most effective.

The only option more effective than these IUCs is subdermal contraception.⁴⁶ These reversible contraceptives are typically more effective than permanent contraceptives (ie, tubal ligation)⁴⁷ and can be removed at any time if a patient wishes to switch to another method or to become pregnant.

Pregnancy rates following attempts at “sterilization” are higher than many realize. There are a variety of approaches to “tying tubes,” some of which may not result in complete tubal occlusion. The failure rate of the laparoscopic approach, according to the US Collaborative Review of Sterilization, ranges from 7.5 per 1,000 procedures for unipolar coagulation to a high of 36.5 per 1,000 for the spring clip.⁴⁸ The relatively commonly used Filshie clip was not included in this study, but its failure rate is reported to be between 1% and 2%.

Women's health encompasses a variety of topics relevant to the daily practice of internists. Staying up to date with the evidence in this wide field is a challenge.

This article reviews important studies published in 2015 and early 2016 on treatment of urinary tract infections, the optimal duration of bisphosphonate use, ovarian cancer screening, the impact of oral contraceptives and lactation on mortality rates, and the risks and benefits of intrauterine contraception. We critically appraised the studies and judged that their methodology was strong and appropriate for inclusion in this review.

IBUPROFEN FOR URINARY TRACT INFECTIONS

A 36-year-old woman reports 4 days of mild to moderate dysuria, frequency, and urgency. She denies fever, nausea, or back pain. Her last urinary tract infection was 2 years ago. Office urinalysis reveals leukocyte esterase and nitrites. She has read an article about antibiotic resistance and Clostridium difficile infection and asks you if antibiotics are truly necessary. What do you recommend?

Urinary tract infections are often self-limited

Uncomplicated urinary tract infections account for 25% of antibiotic prescriptions in primary care.¹

Several small studies have suggested that many of these infections are self-limited, resolving within 3 to 14 days without antibiotics (Table 1).^2–6 A potential disadvantage of withholding treatment is slower bacterial clearance and resolution of symptoms, but reducing the number of antibiotic prescriptions may help slow antibiotic resistance.^7,8 Surveys and qualitative studies have suggested that women are concerned about the harms of antibiotic treatment and so may be willing to avoid or postpone antibiotic use.^9–11

Ibuprofen vs fosfomycin

Gágyor et al⁶ conducted a double-blind, randomized multicenter trial in 42 general practices in Germany to assess whether treating the symptoms of uncomplicated urinary tract infection with ibuprofen would reduce antibiotic use without worsening outcomes.

Of the 779 eligible women with suspected urinary tract infection, 281 declined to participate in the study, 4 did not participate for reasons not specified, 246 received a single dose of fosfomycin 3 g, and 248 were treated with ibuprofen 400 mg three times a day for 3 days. Participants scored their daily symptoms and activity impairment, and safety data were collected for adverse events and relapses up to day 28 and within 6 and 12 months. In both groups, if symptoms worsened or persisted, antibiotic therapy was initiated at the discretion of the treating physician.

Exclusion criteria included fever, “loin” (back) tenderness, pregnancy, renal disease, a previous urinary tract infection within 2 weeks, urinary catheterization, and a contraindication to nonsteroidal anti-inflammatory medications.

Results. Within 28 days of symptom onset, women in the ibuprofen group had received 81 courses of antibiotics for symptoms of urinary tract infection (plus another 13 courses for other reasons), compared with 277 courses for urinary tract infection in the fosfomycin group (plus 6 courses for other reasons), for a relative rate reduction in antibiotic use of 66.5% (95% confidence interval [CI] 58.8%–74.4%, P < .001). The women who received ibuprofen were more likely to need antibiotics after initial treatment because of refractory symptoms but were still less likely to receive antibiotics overall (Table 1).

The mean duration of symptoms was slightly shorter in the fosfomycin group (4.6 vs 5.6 days, P < .001). However, the percentage of patients who had a recurrent urinary tract infection within 2 to 4 weeks was higher in the fosfomycin-treated patients (11% vs 6% P = .049).

Although the study was not powered to show significant differences in pyelonephritis, five patients in the ibuprofen group developed pyelonephritis compared with one in the antibiotic-treated group (P = .12).

An important limitation of the study was that nonparticipants had higher symptom scores, which may mean that the results are not generalizable to women who have recurrent urinary tract infections, longer duration of symptoms, or symptoms that are more severe. The strengths of the study were that more than half of all potentially eligible women were enrolled, and baseline data were collected from nonparticipants.

Can our patient avoid antibiotics?

Given the mild nature of her symptoms, the clinician should discuss with her the risks vs benefits of delaying antibiotics, once it has been determined that she has no risk factors for severe urinary tract infection. Her symptoms are likely to resolve within 1 week even if she declines antibiotic treatment, though they may last a day longer with ibuprofen alone than if she had received antibiotics. She should watch for symptoms of pyelonephritis (eg, flank pain, fever, chills, vomiting) and should seek prompt medical care if such symptoms occur.

DISCONTINUING BISPHOSPHONATES

A 64-year-old woman has taken alendronate for her osteoporosis for 5 years. She has no history of fractures. Her original bone density scans showed a T-score of –2.6 at the spine and –1.5 at the hip. Since she started to take alendronate, there has been no further loss in bone mineral density. She is tolerating the drug well and does not take any other medications. Should she continue the bisphosphonate?

Optimal duration of therapy unknown

The risks and benefits of long-term bisphosphonate use are debated.

In the Fracture Intervention Trial (FIT),¹² women with low bone mineral density of the femoral neck were randomized to receive alendronate or placebo and were followed for 36 months. The alendronate group had significantly fewer vertebral fractures and clinical fractures overall. Then, in the FIT Long-term Extension (FLEX) study,¹³ 1,009 alendronate-treated women in the FIT study were rerandomized to receive 5 years of additional treatment or to stop treatment. Bone density in the untreated women decreased, although not to the level it was before treatment. At the end of the study, there was no difference in hip fracture rate between the two groups (3% of each group had had a hip fracture), although women in the treated group had a lower rate of clinical vertebral fracture (2% vs 5%, relative risk 0.5, 95% CI 0.2–0.8).

In addition, rare but serious risks have been associated with bisphosphonate use, specifically atypical femoral fracture and osteonecrosis of the jaw. A US Food and Drug Administration (FDA) evaluation of long-term bisphosphonate use concluded that there was evidence of an increased risk of osteonecrosis of the jaw with longer duration of use, but causality was not established. The evaluation also noted conflicting results about the association with atypical femoral fracture.¹⁴

Based on this report and focusing on the absence of nonspine benefit after 5 years, the FDA suggested that bisphosphonates may be safely discontinued in some patients without compromising therapeutic gains, but no adequate clinical trial has yet delineated how long the benefits of treatment are maintained after cessation. A periodic reevaluation of continued need was recommended.¹⁴

New recommendations from the American Society for Bone and Mineral Research

Age is the greatest risk factor for fracture.¹⁵ Therefore, deciding whether to discontinue a bisphosphonate when a woman is older, and hence at higher risk, is a challenge.

A task force of the American Society for Bone and Mineral Research (ASBMR) has developed an evidence-based guideline on managing osteoporosis in patients on long-term bisphosphonate treatment.¹⁶ The goal was to provide guidance on the duration of bisphosphonate therapy from the perspective of risk vs benefit. The authors conducted a systematic review focusing on two randomized controlled trials (FLEX¹³ and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture Trial¹⁷) that provided data on long-term bisphosphonate use.

The task force recommended¹⁶ that after 5 years of oral bisphosphonates or 3 years of intravenous bisphosphonates, risk should be reassessed. In women at high fracture risk, they recommended continuing the oral bisphosphonate for 10 years or the intravenous bisphosphonate for 6 years. Factors that favored continuation of bisphosphonate therapy were as follows:

• An osteoporotic fracture before or during therapy
• A hip bone mineral density T-score ≤ –2.5
• High risk of fracture, defined as age older than 70 or 75, other strong risk factors for fracture, or a FRAX fracture risk score¹⁸ above a country-specific threshold.

(The FRAX score is based on age, sex, weight, height, previous fracture, hip fracture in a parent, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol use, and bone mineral density in the femoral neck. It gives an estimate of the 10-year risk of major osteoporotic fracture and hip fracture. High risk would be a 10-year risk of major osteoporotic fracture greater than 20% or a 10-year risk of hip fracture greater than 3%.)

For women at high risk, the risks of atypical femoral fracture and osteonecrosis of the jaw are outweighed by the benefit of a reduction in vertebral fracture risk. For women not at high risk of fracture, a drug holiday of 2 to 3 years can be considered after 3 to 5 years of treatment.

Although the task force recommended reassessment after 2 to 3 years of drug holiday, how best to do this is not clear. The task force did not recommend a specific approach to reassessment, so decisions about when to restart therapy after a drug holiday could potentially be informed by subsequent bone mineral density testing if it were to show persistent bone loss. Another option could be to restart bisphosphonates after a defined amount of time (eg, 3–5 years) for women who have previously experienced benefit.

The task force recommendations are in line with those of other societies, the FDA, and expert opinion.^19–23

The American Association of Clinical Endocrinologists recommends considering a drug holiday in low-risk patients after 4 to 5 years of treatment. For high-risk patients, they recommend 1 to 2 years of drug holiday after 10 years of treatment. They encourage restarting treatment if bone mineral density decreases, bone turnover markers rise, or fracture occurs.¹⁹ This is a grade C recommendation, meaning the advice is based on descriptive studies and expert opinion.

Although some clinicians restart bisphosphonates when markers of bone turnover such as NTX (N-telopeptide of type 1 collagen) rise to premenopausal levels, there is no evidence to support this strategy.²⁴

The task force recommendations are based on limited evidence that primarily comes from white postmenopausal women. Another important limitation is that the outcomes are primarily vertebral fractures. However, until additional evidence is available, these guidelines can be useful in guiding decision-making.

Should our patient continue therapy?

Our patient is relatively young and does not have any of the high-risk features noted within the task force recommendations. She has responded well to bisphosphonate treatment and so can consider a drug holiday at this time.

OVARIAN CANCER SCREENING

A 50-year-old woman requests screening for ovarian cancer. She is postmenopausal and has no personal or family history of cancer. She is concerned because a friend forwarded an e-mail stating, “Please tell all your female friends and relatives to insist on a cancer antigen (CA) 125 blood test every year as part of their annual exam. This is an inexpensive and simple blood test. Don’t take no for an answer. If I had known then what I know now, we would have caught my cancer much earlier, before it was stage III!” What should you tell the patient?

Ovarian cancer is the most deadly of female reproductive cancers, largely because in most patients the cancer has already spread beyond the ovary by the time of clinical detection. Death rates from ovarian cancer have decreased only slightly in the past 30 years.

Little benefit and considerable harm of screening

In 2011, the Prostate Lung Colorectal Ovarian (PLCO) Cancer Screening trial²⁵ randomized more than 68,000 women ages 55 to 74 from the general US population to annual screening with CA 125 testing and transvaginal ultrasonography compared with usual care. They were followed for a median of 12.4 years.

Screening did not affect stage at diagnosis (77%–78% were in stage III or IV in both the screening and usual care groups), nor did it reduce the rate of death from ovarian cancer. In addition, false-positive findings led to some harm: nearly one in three women who had a positive screening test underwent surgery. Of 3,285 women with false-positive results, 1,080 underwent surgery, and 15% of these had at least one serious complication. The trial was stopped early due to evidence of futility.

A new UK study also found no benefit from screening

In the PLCO study, a CA 125 result of 35 U/mL or greater was classified as abnormal. However, researchers in the United Kingdom postulated that instead of using a single cutoff for a normal or abnormal CA 125 level, it would be better to interpret the CA 125 result according to a somewhat complicated (and proprietary) algorithm called the Risk of Ovarian Cancer Algorithm (ROCA).^26,27 The ROCA takes into account a woman’s age, menopausal status, known genetic mutations (BRCA 1 or 2 or Lynch syndrome), Ashkenazi Jewish descent, and family history of ovarian or breast cancer, as well as any change in CA 125 level over time.

In a 2016 UK study,²⁶ 202,638 postmenopausal women ages 50 to 74 were randomized to no screening, annual screening with transvaginal ultrasonography, or multimodal screening with an annual CA 125 blood test interpreted with the ROCA algorithm, adding transvaginal ultrasonography as a second-line test when needed if the CA 125 level was abnormal based on the ROCA. Women with abnormal findings on multimodal screening or ultrasonography had repeat tests, and women with persistent abnormalities underwent clinical evaluation and, when appropriate, surgery.

Participants were at average risk of ovarian cancer; those with suspected familial ovarian cancer syndrome were excluded, as were those with a personal history of ovarian cancer or other active cancer.

Results. At a median follow-up of 11.1 years, the percentage of women who were diagnosed with ovarian cancer was 0.7% in the multimodal screening group, 0.6% in the screening ultrasonography group, and 0.6% in the no-screening group. Comparing either multimodal or screening ultrasonography with no screening, there was no statistically significant reduction in mortality rate over 14 years of follow-up.

Screening had significant costs and potential harms. For every ovarian or peritoneal cancer detected by screening, an additional 2 women in the multimodal screening group and 10 women in the ultrasonography group underwent needless surgery.

Strengths of this trial included its large size, allowing adequate power to detect differences in outcomes, its multicenter setting, its high compliance rate, and the low crossover rate in the no-screening group. However, the design of the study makes it difficult to anticipate the late effects of screening. Also, the patient must purchase ROCA testing online and must also pay a consultation fee. Insurance providers do not cover this test.

Should our patient proceed with ovarian cancer screening?

No. Current evidence shows no clear benefit to ovarian cancer screening for average-risk women, and we should not recommend yearly ultrasonography and CA 125 level testing, as they are likely to cause harm without providing benefit. The US Preventive Services Task Force recommends against screening for ovarian cancer.²⁸ For premenopausal women, pregnancy, hormonal contraception, and breastfeeding all significantly decrease ovarian cancer risk by suppressing ovulation.^29–31

REPRODUCTIVE FACTORS AND THE RISK OF DEATH

A 26-year-old woman comes in to discuss her contraceptive options. She has been breastfeeding since the birth of her first baby 6 months ago, and wonders how lactation and contraception may affect her long-term health.

Questions about the safety of contraceptive options are common, especially in breastfeeding mothers.

In 2010, the long-term Royal College of General Practitioners’ Oral Contraceptive Study reported that the all-cause mortality rate was actually lower in women who used oral contraceptives.³² Similarly, in 2013, an Oxford study that followed 17,032 women for over 30 years reported no association between oral contraceptives and breast cancer.³³

However, in 2014, results from the Nurses’ Health Study indicated that breast cancer rates were higher in oral contraceptive users, although reassuringly, the study found no difference in all-cause mortality rates in women who had used oral contraception.³⁴

The European Prospective Investigation Into Cancer and Nutrition

To further characterize relationships between reproductive characteristics and mortality rates, investigators analyzed data from the European Prospective Investigation Into Cancer and Nutrition,³⁵ which recruited 322,972 women from 10 countries between 1992 and 2000. Analyses were stratified by study center and participant age and were adjusted for body mass index, physical activity, education level, smoking, and menopausal status; alcohol intake was examined as a potential confounder but was excluded from final models.

Findings. Over an average 13 years of follow-up, the rate of all-cause mortality was 20% lower in parous than in nulliparous women. In parous women, the all-cause mortality rate was additionally 18% lower in those who had breastfed vs those who had never breastfed, although breastfeeding duration was not associated with mortality. Use of oral contraceptives lowered all-cause mortality by 10% among nonsmokers; in smokers, no association with all-cause mortality was seen for oral contraceptive use, as smoking is such a powerful risk factor for mortality. The primary contributor to all-cause mortality appeared to be ischemic heart disease, the incidence of which was significantly lower in parous women (by 14%) and those who breastfed (by 20%) and was not related to oral contraceptive use.³⁵

Strengths of this study included the large sample size recruited from countries across Europe, with varying rates of breastfeeding and contraceptive use. However, as with all observational studies, it remains subject to the possibility of residual confounding.

What should we tell this patient?

After congratulating her for breastfeeding, we can reassure her about the safety of all available contraceptives. According to the US Centers for Disease Control and Prevention (CDC),³⁶ after 42 days postpartum most women can use combined hormonal contraception. All other methods can be used immediately postpartum, including progestin-only pills.

As lactational amenorrhea is only effective while mothers are exclusively breastfeeding, and short interpregnancy intervals have been associated with higher rates of adverse pregnancy outcomes,³⁷ this patient will likely benefit from promptly starting a prescription contraceptive.

HIGHLY EFFECTIVE REVERSIBLE CONTRACEPTION

This same 26-year-old patient is concerned that she will not remember to take an oral contraceptive every day, and expresses interest in a more convenient method of contraception. However, she is concerned about the potential risks.

Although intrauterine contraceptives (IUCs) are typically 20 times more effective than oral contraceptives³⁸ and have been used by millions of women worldwide, rates of use in the United States have been lower than in many other countries.³⁹

A study of intrauterine contraception

To clarify the safety of IUCs, researchers followed 61,448 women who underwent IUC placement in six European countries between 2006 and 2013.⁴⁰ Most participants received an IUC containing levonorgestrel, while 30% received a copper IUC.

Findings. Overall, rates of uterine perforation were low (approximately 1 per 1,000 insertions). The most significant risk factors for perforation were breastfeeding at the time of insertion and insertion less than 36 weeks after the last delivery. None of the perforations in the study led to serious illness or injury of intra-abdominal or pelvic structures. Interestingly, women using a levonorgestrel IUC were considerably less likely to experience a contraceptive failure than those using a copper IUC.⁴¹

Strengths of this study included the prospective data collection and power to examine rare clinical outcomes. However, it was industry-funded.

The risk of pelvic infection with an IUC is so low that the CDC does not recommend prophylactic antibiotics with the insertion procedure. If women have other indications for testing for sexually transmitted disease, an IUC can be placed the same day as testing, and before results are available.⁴² If a woman is found to have a sexually transmitted disease while she has an IUC in place, she should be treated with antibiotics, and there is no need to remove the IUC.⁴³

Subdermal implants

Another highly effective contraceptive option for this patient is the progestin-only subdermal contraceptive implant (marketed in the United States as Nexplanon). Implants have been well-studied and found to have no adverse effect on lactation.⁴⁴

Learning to place a subdermal contraceptive is far easier than learning to place an IUC, but it requires a few hours of FDA-mandated in-person training. Unfortunately, relatively few clinicians have obtained this training.⁴⁵ As placing a subdermal contraceptive is like placing an intravenous line without needing to hit the vein, this procedure can easily be incorporated into a primary care practice. Training from the manufacturer is available to providers who request it.

What should we tell this patient?

An IUC is a great option for many women. When pregnancy is desired, the device is easily removed. Of the three IUCs now available in the United States, those containing 52 mg of levonorgestrel (marketed in the United States as Mirena and Liletta) are the most effective.

The only option more effective than these IUCs is subdermal contraception.⁴⁶ These reversible contraceptives are typically more effective than permanent contraceptives (ie, tubal ligation)⁴⁷ and can be removed at any time if a patient wishes to switch to another method or to become pregnant.

Pregnancy rates following attempts at “sterilization” are higher than many realize. There are a variety of approaches to “tying tubes,” some of which may not result in complete tubal occlusion. The failure rate of the laparoscopic approach, according to the US Collaborative Review of Sterilization, ranges from 7.5 per 1,000 procedures for unipolar coagulation to a high of 36.5 per 1,000 for the spring clip.⁴⁸ The relatively commonly used Filshie clip was not included in this study, but its failure rate is reported to be between 1% and 2%.

Women's health encompasses a variety of topics relevant to the daily practice of internists. Staying up to date with the evidence in this wide field is a challenge.

This article reviews important studies published in 2015 and early 2016 on treatment of urinary tract infections, the optimal duration of bisphosphonate use, ovarian cancer screening, the impact of oral contraceptives and lactation on mortality rates, and the risks and benefits of intrauterine contraception. We critically appraised the studies and judged that their methodology was strong and appropriate for inclusion in this review.

IBUPROFEN FOR URINARY TRACT INFECTIONS

A 36-year-old woman reports 4 days of mild to moderate dysuria, frequency, and urgency. She denies fever, nausea, or back pain. Her last urinary tract infection was 2 years ago. Office urinalysis reveals leukocyte esterase and nitrites. She has read an article about antibiotic resistance and Clostridium difficile infection and asks you if antibiotics are truly necessary. What do you recommend?

Urinary tract infections are often self-limited

Uncomplicated urinary tract infections account for 25% of antibiotic prescriptions in primary care.¹

Several small studies have suggested that many of these infections are self-limited, resolving within 3 to 14 days without antibiotics (Table 1).^2–6 A potential disadvantage of withholding treatment is slower bacterial clearance and resolution of symptoms, but reducing the number of antibiotic prescriptions may help slow antibiotic resistance.^7,8 Surveys and qualitative studies have suggested that women are concerned about the harms of antibiotic treatment and so may be willing to avoid or postpone antibiotic use.^9–11

Ibuprofen vs fosfomycin

Gágyor et al⁶ conducted a double-blind, randomized multicenter trial in 42 general practices in Germany to assess whether treating the symptoms of uncomplicated urinary tract infection with ibuprofen would reduce antibiotic use without worsening outcomes.

Of the 779 eligible women with suspected urinary tract infection, 281 declined to participate in the study, 4 did not participate for reasons not specified, 246 received a single dose of fosfomycin 3 g, and 248 were treated with ibuprofen 400 mg three times a day for 3 days. Participants scored their daily symptoms and activity impairment, and safety data were collected for adverse events and relapses up to day 28 and within 6 and 12 months. In both groups, if symptoms worsened or persisted, antibiotic therapy was initiated at the discretion of the treating physician.

Exclusion criteria included fever, “loin” (back) tenderness, pregnancy, renal disease, a previous urinary tract infection within 2 weeks, urinary catheterization, and a contraindication to nonsteroidal anti-inflammatory medications.

Results. Within 28 days of symptom onset, women in the ibuprofen group had received 81 courses of antibiotics for symptoms of urinary tract infection (plus another 13 courses for other reasons), compared with 277 courses for urinary tract infection in the fosfomycin group (plus 6 courses for other reasons), for a relative rate reduction in antibiotic use of 66.5% (95% confidence interval [CI] 58.8%–74.4%, P < .001). The women who received ibuprofen were more likely to need antibiotics after initial treatment because of refractory symptoms but were still less likely to receive antibiotics overall (Table 1).

The mean duration of symptoms was slightly shorter in the fosfomycin group (4.6 vs 5.6 days, P < .001). However, the percentage of patients who had a recurrent urinary tract infection within 2 to 4 weeks was higher in the fosfomycin-treated patients (11% vs 6% P = .049).

Although the study was not powered to show significant differences in pyelonephritis, five patients in the ibuprofen group developed pyelonephritis compared with one in the antibiotic-treated group (P = .12).

An important limitation of the study was that nonparticipants had higher symptom scores, which may mean that the results are not generalizable to women who have recurrent urinary tract infections, longer duration of symptoms, or symptoms that are more severe. The strengths of the study were that more than half of all potentially eligible women were enrolled, and baseline data were collected from nonparticipants.

Can our patient avoid antibiotics?

Given the mild nature of her symptoms, the clinician should discuss with her the risks vs benefits of delaying antibiotics, once it has been determined that she has no risk factors for severe urinary tract infection. Her symptoms are likely to resolve within 1 week even if she declines antibiotic treatment, though they may last a day longer with ibuprofen alone than if she had received antibiotics. She should watch for symptoms of pyelonephritis (eg, flank pain, fever, chills, vomiting) and should seek prompt medical care if such symptoms occur.

DISCONTINUING BISPHOSPHONATES

A 64-year-old woman has taken alendronate for her osteoporosis for 5 years. She has no history of fractures. Her original bone density scans showed a T-score of –2.6 at the spine and –1.5 at the hip. Since she started to take alendronate, there has been no further loss in bone mineral density. She is tolerating the drug well and does not take any other medications. Should she continue the bisphosphonate?

Optimal duration of therapy unknown

The risks and benefits of long-term bisphosphonate use are debated.

In the Fracture Intervention Trial (FIT),¹² women with low bone mineral density of the femoral neck were randomized to receive alendronate or placebo and were followed for 36 months. The alendronate group had significantly fewer vertebral fractures and clinical fractures overall. Then, in the FIT Long-term Extension (FLEX) study,¹³ 1,009 alendronate-treated women in the FIT study were rerandomized to receive 5 years of additional treatment or to stop treatment. Bone density in the untreated women decreased, although not to the level it was before treatment. At the end of the study, there was no difference in hip fracture rate between the two groups (3% of each group had had a hip fracture), although women in the treated group had a lower rate of clinical vertebral fracture (2% vs 5%, relative risk 0.5, 95% CI 0.2–0.8).

In addition, rare but serious risks have been associated with bisphosphonate use, specifically atypical femoral fracture and osteonecrosis of the jaw. A US Food and Drug Administration (FDA) evaluation of long-term bisphosphonate use concluded that there was evidence of an increased risk of osteonecrosis of the jaw with longer duration of use, but causality was not established. The evaluation also noted conflicting results about the association with atypical femoral fracture.¹⁴

Based on this report and focusing on the absence of nonspine benefit after 5 years, the FDA suggested that bisphosphonates may be safely discontinued in some patients without compromising therapeutic gains, but no adequate clinical trial has yet delineated how long the benefits of treatment are maintained after cessation. A periodic reevaluation of continued need was recommended.¹⁴

New recommendations from the American Society for Bone and Mineral Research

Age is the greatest risk factor for fracture.¹⁵ Therefore, deciding whether to discontinue a bisphosphonate when a woman is older, and hence at higher risk, is a challenge.

A task force of the American Society for Bone and Mineral Research (ASBMR) has developed an evidence-based guideline on managing osteoporosis in patients on long-term bisphosphonate treatment.¹⁶ The goal was to provide guidance on the duration of bisphosphonate therapy from the perspective of risk vs benefit. The authors conducted a systematic review focusing on two randomized controlled trials (FLEX¹³ and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture Trial¹⁷) that provided data on long-term bisphosphonate use.

The task force recommended¹⁶ that after 5 years of oral bisphosphonates or 3 years of intravenous bisphosphonates, risk should be reassessed. In women at high fracture risk, they recommended continuing the oral bisphosphonate for 10 years or the intravenous bisphosphonate for 6 years. Factors that favored continuation of bisphosphonate therapy were as follows:

• An osteoporotic fracture before or during therapy
• A hip bone mineral density T-score ≤ –2.5
• High risk of fracture, defined as age older than 70 or 75, other strong risk factors for fracture, or a FRAX fracture risk score¹⁸ above a country-specific threshold.

(The FRAX score is based on age, sex, weight, height, previous fracture, hip fracture in a parent, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol use, and bone mineral density in the femoral neck. It gives an estimate of the 10-year risk of major osteoporotic fracture and hip fracture. High risk would be a 10-year risk of major osteoporotic fracture greater than 20% or a 10-year risk of hip fracture greater than 3%.)

For women at high risk, the risks of atypical femoral fracture and osteonecrosis of the jaw are outweighed by the benefit of a reduction in vertebral fracture risk. For women not at high risk of fracture, a drug holiday of 2 to 3 years can be considered after 3 to 5 years of treatment.

Although the task force recommended reassessment after 2 to 3 years of drug holiday, how best to do this is not clear. The task force did not recommend a specific approach to reassessment, so decisions about when to restart therapy after a drug holiday could potentially be informed by subsequent bone mineral density testing if it were to show persistent bone loss. Another option could be to restart bisphosphonates after a defined amount of time (eg, 3–5 years) for women who have previously experienced benefit.

The task force recommendations are in line with those of other societies, the FDA, and expert opinion.^19–23

The American Association of Clinical Endocrinologists recommends considering a drug holiday in low-risk patients after 4 to 5 years of treatment. For high-risk patients, they recommend 1 to 2 years of drug holiday after 10 years of treatment. They encourage restarting treatment if bone mineral density decreases, bone turnover markers rise, or fracture occurs.¹⁹ This is a grade C recommendation, meaning the advice is based on descriptive studies and expert opinion.

Although some clinicians restart bisphosphonates when markers of bone turnover such as NTX (N-telopeptide of type 1 collagen) rise to premenopausal levels, there is no evidence to support this strategy.²⁴

The task force recommendations are based on limited evidence that primarily comes from white postmenopausal women. Another important limitation is that the outcomes are primarily vertebral fractures. However, until additional evidence is available, these guidelines can be useful in guiding decision-making.

Should our patient continue therapy?

Our patient is relatively young and does not have any of the high-risk features noted within the task force recommendations. She has responded well to bisphosphonate treatment and so can consider a drug holiday at this time.

OVARIAN CANCER SCREENING

A 50-year-old woman requests screening for ovarian cancer. She is postmenopausal and has no personal or family history of cancer. She is concerned because a friend forwarded an e-mail stating, “Please tell all your female friends and relatives to insist on a cancer antigen (CA) 125 blood test every year as part of their annual exam. This is an inexpensive and simple blood test. Don’t take no for an answer. If I had known then what I know now, we would have caught my cancer much earlier, before it was stage III!” What should you tell the patient?

Ovarian cancer is the most deadly of female reproductive cancers, largely because in most patients the cancer has already spread beyond the ovary by the time of clinical detection. Death rates from ovarian cancer have decreased only slightly in the past 30 years.

Little benefit and considerable harm of screening

In 2011, the Prostate Lung Colorectal Ovarian (PLCO) Cancer Screening trial²⁵ randomized more than 68,000 women ages 55 to 74 from the general US population to annual screening with CA 125 testing and transvaginal ultrasonography compared with usual care. They were followed for a median of 12.4 years.

Screening did not affect stage at diagnosis (77%–78% were in stage III or IV in both the screening and usual care groups), nor did it reduce the rate of death from ovarian cancer. In addition, false-positive findings led to some harm: nearly one in three women who had a positive screening test underwent surgery. Of 3,285 women with false-positive results, 1,080 underwent surgery, and 15% of these had at least one serious complication. The trial was stopped early due to evidence of futility.

A new UK study also found no benefit from screening

In the PLCO study, a CA 125 result of 35 U/mL or greater was classified as abnormal. However, researchers in the United Kingdom postulated that instead of using a single cutoff for a normal or abnormal CA 125 level, it would be better to interpret the CA 125 result according to a somewhat complicated (and proprietary) algorithm called the Risk of Ovarian Cancer Algorithm (ROCA).^26,27 The ROCA takes into account a woman’s age, menopausal status, known genetic mutations (BRCA 1 or 2 or Lynch syndrome), Ashkenazi Jewish descent, and family history of ovarian or breast cancer, as well as any change in CA 125 level over time.

In a 2016 UK study,²⁶ 202,638 postmenopausal women ages 50 to 74 were randomized to no screening, annual screening with transvaginal ultrasonography, or multimodal screening with an annual CA 125 blood test interpreted with the ROCA algorithm, adding transvaginal ultrasonography as a second-line test when needed if the CA 125 level was abnormal based on the ROCA. Women with abnormal findings on multimodal screening or ultrasonography had repeat tests, and women with persistent abnormalities underwent clinical evaluation and, when appropriate, surgery.

Participants were at average risk of ovarian cancer; those with suspected familial ovarian cancer syndrome were excluded, as were those with a personal history of ovarian cancer or other active cancer.

Results. At a median follow-up of 11.1 years, the percentage of women who were diagnosed with ovarian cancer was 0.7% in the multimodal screening group, 0.6% in the screening ultrasonography group, and 0.6% in the no-screening group. Comparing either multimodal or screening ultrasonography with no screening, there was no statistically significant reduction in mortality rate over 14 years of follow-up.

Screening had significant costs and potential harms. For every ovarian or peritoneal cancer detected by screening, an additional 2 women in the multimodal screening group and 10 women in the ultrasonography group underwent needless surgery.

Strengths of this trial included its large size, allowing adequate power to detect differences in outcomes, its multicenter setting, its high compliance rate, and the low crossover rate in the no-screening group. However, the design of the study makes it difficult to anticipate the late effects of screening. Also, the patient must purchase ROCA testing online and must also pay a consultation fee. Insurance providers do not cover this test.

Should our patient proceed with ovarian cancer screening?

No. Current evidence shows no clear benefit to ovarian cancer screening for average-risk women, and we should not recommend yearly ultrasonography and CA 125 level testing, as they are likely to cause harm without providing benefit. The US Preventive Services Task Force recommends against screening for ovarian cancer.²⁸ For premenopausal women, pregnancy, hormonal contraception, and breastfeeding all significantly decrease ovarian cancer risk by suppressing ovulation.^29–31

REPRODUCTIVE FACTORS AND THE RISK OF DEATH

A 26-year-old woman comes in to discuss her contraceptive options. She has been breastfeeding since the birth of her first baby 6 months ago, and wonders how lactation and contraception may affect her long-term health.

Questions about the safety of contraceptive options are common, especially in breastfeeding mothers.

In 2010, the long-term Royal College of General Practitioners’ Oral Contraceptive Study reported that the all-cause mortality rate was actually lower in women who used oral contraceptives.³² Similarly, in 2013, an Oxford study that followed 17,032 women for over 30 years reported no association between oral contraceptives and breast cancer.³³

However, in 2014, results from the Nurses’ Health Study indicated that breast cancer rates were higher in oral contraceptive users, although reassuringly, the study found no difference in all-cause mortality rates in women who had used oral contraception.³⁴

The European Prospective Investigation Into Cancer and Nutrition

To further characterize relationships between reproductive characteristics and mortality rates, investigators analyzed data from the European Prospective Investigation Into Cancer and Nutrition,³⁵ which recruited 322,972 women from 10 countries between 1992 and 2000. Analyses were stratified by study center and participant age and were adjusted for body mass index, physical activity, education level, smoking, and menopausal status; alcohol intake was examined as a potential confounder but was excluded from final models.

Findings. Over an average 13 years of follow-up, the rate of all-cause mortality was 20% lower in parous than in nulliparous women. In parous women, the all-cause mortality rate was additionally 18% lower in those who had breastfed vs those who had never breastfed, although breastfeeding duration was not associated with mortality. Use of oral contraceptives lowered all-cause mortality by 10% among nonsmokers; in smokers, no association with all-cause mortality was seen for oral contraceptive use, as smoking is such a powerful risk factor for mortality. The primary contributor to all-cause mortality appeared to be ischemic heart disease, the incidence of which was significantly lower in parous women (by 14%) and those who breastfed (by 20%) and was not related to oral contraceptive use.³⁵

Strengths of this study included the large sample size recruited from countries across Europe, with varying rates of breastfeeding and contraceptive use. However, as with all observational studies, it remains subject to the possibility of residual confounding.

What should we tell this patient?

After congratulating her for breastfeeding, we can reassure her about the safety of all available contraceptives. According to the US Centers for Disease Control and Prevention (CDC),³⁶ after 42 days postpartum most women can use combined hormonal contraception. All other methods can be used immediately postpartum, including progestin-only pills.

As lactational amenorrhea is only effective while mothers are exclusively breastfeeding, and short interpregnancy intervals have been associated with higher rates of adverse pregnancy outcomes,³⁷ this patient will likely benefit from promptly starting a prescription contraceptive.

HIGHLY EFFECTIVE REVERSIBLE CONTRACEPTION

This same 26-year-old patient is concerned that she will not remember to take an oral contraceptive every day, and expresses interest in a more convenient method of contraception. However, she is concerned about the potential risks.

Although intrauterine contraceptives (IUCs) are typically 20 times more effective than oral contraceptives³⁸ and have been used by millions of women worldwide, rates of use in the United States have been lower than in many other countries.³⁹

A study of intrauterine contraception

To clarify the safety of IUCs, researchers followed 61,448 women who underwent IUC placement in six European countries between 2006 and 2013.⁴⁰ Most participants received an IUC containing levonorgestrel, while 30% received a copper IUC.

Findings. Overall, rates of uterine perforation were low (approximately 1 per 1,000 insertions). The most significant risk factors for perforation were breastfeeding at the time of insertion and insertion less than 36 weeks after the last delivery. None of the perforations in the study led to serious illness or injury of intra-abdominal or pelvic structures. Interestingly, women using a levonorgestrel IUC were considerably less likely to experience a contraceptive failure than those using a copper IUC.⁴¹

Strengths of this study included the prospective data collection and power to examine rare clinical outcomes. However, it was industry-funded.

The risk of pelvic infection with an IUC is so low that the CDC does not recommend prophylactic antibiotics with the insertion procedure. If women have other indications for testing for sexually transmitted disease, an IUC can be placed the same day as testing, and before results are available.⁴² If a woman is found to have a sexually transmitted disease while she has an IUC in place, she should be treated with antibiotics, and there is no need to remove the IUC.⁴³

Subdermal implants

Another highly effective contraceptive option for this patient is the progestin-only subdermal contraceptive implant (marketed in the United States as Nexplanon). Implants have been well-studied and found to have no adverse effect on lactation.⁴⁴

Learning to place a subdermal contraceptive is far easier than learning to place an IUC, but it requires a few hours of FDA-mandated in-person training. Unfortunately, relatively few clinicians have obtained this training.⁴⁵ As placing a subdermal contraceptive is like placing an intravenous line without needing to hit the vein, this procedure can easily be incorporated into a primary care practice. Training from the manufacturer is available to providers who request it.

What should we tell this patient?

An IUC is a great option for many women. When pregnancy is desired, the device is easily removed. Of the three IUCs now available in the United States, those containing 52 mg of levonorgestrel (marketed in the United States as Mirena and Liletta) are the most effective.

The only option more effective than these IUCs is subdermal contraception.⁴⁶ These reversible contraceptives are typically more effective than permanent contraceptives (ie, tubal ligation)⁴⁷ and can be removed at any time if a patient wishes to switch to another method or to become pregnant.

Pregnancy rates following attempts at “sterilization” are higher than many realize. There are a variety of approaches to “tying tubes,” some of which may not result in complete tubal occlusion. The failure rate of the laparoscopic approach, according to the US Collaborative Review of Sterilization, ranges from 7.5 per 1,000 procedures for unipolar coagulation to a high of 36.5 per 1,000 for the spring clip.⁴⁸ The relatively commonly used Filshie clip was not included in this study, but its failure rate is reported to be between 1% and 2%.

A 72-year-old woman is admitted with fever and shortness of breath. Chest radiography demonstrates a consolidation in the right lower lobe, and ceftriaxone and azithromycin are given to treat community-acquired pneumonia. After initial improvement she develops abdominal discomfort and profuse diarrhea on day 5 of hospitalization. What stool testing should be ordered?

Most cases of diarrhea in hospitalized patients are not due to infection, but the most common infectious cause is Clostridium difficile. In the absence of unusual circumstances such as a norovirus outbreak or diarrhea in an immunocompromised patient, testing for C difficile is the only recommended assay. A multistep algorithm with a combination of antigen detection and nucleic acid amplification techniques provides the best sensitivity and specificity. Repeated testing after an initially negative test and performing a test of cure are of limited utility and incur added costs, and thus are not recommended.

CAUSES OF DIARRHEA IN THE HOSPITAL

Diarrhea is defined as at least 1 day with three or more unformed stools or a significant increase in stool frequency above baseline.

Nosocomial diarrhea is an acute episode of diarrhea in a hospitalized patient that was not present on admission and that arises after 3 days of hospitalization. It is fairly common, developing in 12% to 32% of patients at some point during their hospitalization.¹

Most cases of nosocomial diarrhea are not due to infection, but rather secondary to enteral feeding, medications, and underlying illness. C difficile is the most common infectious cause and accounts for 10% to 20% of all cases of nosocomial diarrhea.² Other pathogens associated with nosocomial diarrhea are unusual, although outbreaks of norovirus in healthcare facilities have occurred,³ and isolated cases of Klebsiella oxytoca causing acute abdominal pain, bloody diarrhea, and leukocytosis after exposure to antibiotics have been reported.¹

RECOMMENDED TESTING

The evaluation of a hospitalized patient in whom diarrhea develops should initially focus on the clinical presentation, with attention to signs of sepsis. Stable patients with mild symptoms may respond to withdrawal of the offending agent (if any), while patients with moderate or severe symptoms (including those with fever, hypotension, leukocytosis, acute kidney injury, or a decreased serum bicarbonate level) should be tested for C difficile infection (Figure 1).

In general, stool testing should adhere to the “3-day rule”—ie, fecal specimens from patients with diarrhea that develops after 3 days of hospitalization have a very low yield when cultured for standard bacteria or examined for ova and parasites. Thus, only testing for C difficile infection should be ordered.⁴

In an outbreak of norovirus, especially if vomiting is present, norovirus testing by reverse transcriptase polymerase chain reaction (PCR) could be considered.

Fecal white blood cell testing should not be ordered, as it neither sensitive nor specific.⁵

Immunocompromised patients (such as those with organ transplants or late-stage human immunodeficiency virus infection) occasionally contract diarrhea due to causes other than C difficile, and consultation with a gastroenterologist or an infectious diseases physician could be considered if diarrhea persists and no cause is apparent.

In the rare situation when a patient is hospitalized after very recent overseas travel and then contracts diarrhea, causes of traveler’s diarrhea should be considered.

TESTING FOR C DIFFICILE INFECTION

A number of diagnostic tests for C difficile infection are available.

Toxigenic culture (culture followed by detection of a toxigenic isolate) and C difficile cytotoxin neutralization assay are considered the reference standards, having high sensitivity and specificity. However, both are time- and labor-intensive, with turnaround times of at least 2 to 3 days and up to 9 days, limiting their clinical utility and resulting in delay in both diagnosis and implementation of infection control measures.^2,6

Enzyme immunoassays (EIAs) are faster. EIAs are available to detect glutamate dehydrogenase (GDH) and toxins A and B, all produced by C difficile. The GDH EIA is 92% sensitive and 93% specific but should not be used alone as it does not distinguish between toxigenic and nontoxigenic strains of C difficile.^2,6 The toxin A/B EIA is 97% specific, but since its sensitivity may be as low as 73%, it too should not be used alone.⁶

Nucleic acid amplification tests such as PCR and loop-mediated isothermal amplification (LAMP) identify toxigenic C difficile by detecting tcdA, tcdB, or tcdC genes, which regulate toxin production. These tests have sensitivities and specificities well over 90%.⁶

Since molecular tests (ie, nucleic acid amplification tests) for C difficile infection became available in 2009, they have been widely adopted and are commercially available.⁷ Facilities that use them have reported a 50% to 100% increase in C difficile infection rates,⁷ but the increase may not be real. Rather, it may reflect increased detection of colonization by the more-sensitive tests.

In a prospective, observational, cohort study,⁷ 1,416 hospitalized patients with diarrhea that developed 72 hours after hospitalization were tested for C difficile infection by both toxin EIA and PCR. Those with positive results on both tests had a longer duration of diarrhea, more C difficile infection-related complications, more C difficile infection-related deaths, and greater risk of diarrhea during follow-up. For those who had negative results on toxin EIA testing, the results of PCR testing made no difference, and neither did treatment for C difficile infection, suggesting that most patients with negative toxin test results do not need treatment for C difficile even if PCR testing is positive.

In light of the limited sensitivity of some toxin EIAs and the increased identification of asymptomatic colonization with nucleic acid amplification testing, the optimal approach may be to combine rapid testing methods. Algorithms that include nucleic acid amplification testing have the best sensitivity (68% to 100%) and specificity (92% to 100%).⁷ Clinical guidelines suggest using a GDH EIA as the initial step, and then confirming positive results with either nucleic acid amplification testing alone or toxin EIA followed by nucleic acid amplification testing if the toxin EIA is negative.⁸ However, the best diagnostic approach remains controversial, and multistep algorithms may be impractical in some laboratories.

Knowledge of the laboratory test used can help clinicians appreciate the limitations of specimen testing. Table 1 outlines some of the performance characteristics of the available assays.^9–11

The preferred approach at our institution is a multistep algorithm using both the GDH and toxin EIAs in the initial step, followed by a LAMP assay for the C difficile toxin genes in cases of discordant EIA results.

Repeat testing after an initial negative test may be positive in fewer than 5% of cases, can increase the chance of false-positive results, does not improve sensitivity and negative predictive values, and is therefore not recommended.^2,8 Similarly, a test of cure after symptoms resolve is not recommended, as the toxin EIA can be positive for up to 30 days after resolution of symptoms, and a positive nucleic acid amplification test may only reflect colonization.^2,8

RETURNING TO OUR PATIENT

Returning to the patient hospitalized with community-acquired pneumonia, C difficile infection is the most likely cause of her diarrhea. If her respiratory symptoms have improved, then cessation of ceftriaxone and azithromycin should be considered because she has completed 5 days of therapy. In addition, given her profuse diarrhea, testing for C difficile is recommended with a multistep approach.

A 72-year-old woman is admitted with fever and shortness of breath. Chest radiography demonstrates a consolidation in the right lower lobe, and ceftriaxone and azithromycin are given to treat community-acquired pneumonia. After initial improvement she develops abdominal discomfort and profuse diarrhea on day 5 of hospitalization. What stool testing should be ordered?

Most cases of diarrhea in hospitalized patients are not due to infection, but the most common infectious cause is Clostridium difficile. In the absence of unusual circumstances such as a norovirus outbreak or diarrhea in an immunocompromised patient, testing for C difficile is the only recommended assay. A multistep algorithm with a combination of antigen detection and nucleic acid amplification techniques provides the best sensitivity and specificity. Repeated testing after an initially negative test and performing a test of cure are of limited utility and incur added costs, and thus are not recommended.

CAUSES OF DIARRHEA IN THE HOSPITAL

Diarrhea is defined as at least 1 day with three or more unformed stools or a significant increase in stool frequency above baseline.

Nosocomial diarrhea is an acute episode of diarrhea in a hospitalized patient that was not present on admission and that arises after 3 days of hospitalization. It is fairly common, developing in 12% to 32% of patients at some point during their hospitalization.¹

Most cases of nosocomial diarrhea are not due to infection, but rather secondary to enteral feeding, medications, and underlying illness. C difficile is the most common infectious cause and accounts for 10% to 20% of all cases of nosocomial diarrhea.² Other pathogens associated with nosocomial diarrhea are unusual, although outbreaks of norovirus in healthcare facilities have occurred,³ and isolated cases of Klebsiella oxytoca causing acute abdominal pain, bloody diarrhea, and leukocytosis after exposure to antibiotics have been reported.¹

RECOMMENDED TESTING

The evaluation of a hospitalized patient in whom diarrhea develops should initially focus on the clinical presentation, with attention to signs of sepsis. Stable patients with mild symptoms may respond to withdrawal of the offending agent (if any), while patients with moderate or severe symptoms (including those with fever, hypotension, leukocytosis, acute kidney injury, or a decreased serum bicarbonate level) should be tested for C difficile infection (Figure 1).

In general, stool testing should adhere to the “3-day rule”—ie, fecal specimens from patients with diarrhea that develops after 3 days of hospitalization have a very low yield when cultured for standard bacteria or examined for ova and parasites. Thus, only testing for C difficile infection should be ordered.⁴

In an outbreak of norovirus, especially if vomiting is present, norovirus testing by reverse transcriptase polymerase chain reaction (PCR) could be considered.

Fecal white blood cell testing should not be ordered, as it neither sensitive nor specific.⁵

Immunocompromised patients (such as those with organ transplants or late-stage human immunodeficiency virus infection) occasionally contract diarrhea due to causes other than C difficile, and consultation with a gastroenterologist or an infectious diseases physician could be considered if diarrhea persists and no cause is apparent.

In the rare situation when a patient is hospitalized after very recent overseas travel and then contracts diarrhea, causes of traveler’s diarrhea should be considered.

TESTING FOR C DIFFICILE INFECTION

A number of diagnostic tests for C difficile infection are available.

Toxigenic culture (culture followed by detection of a toxigenic isolate) and C difficile cytotoxin neutralization assay are considered the reference standards, having high sensitivity and specificity. However, both are time- and labor-intensive, with turnaround times of at least 2 to 3 days and up to 9 days, limiting their clinical utility and resulting in delay in both diagnosis and implementation of infection control measures.^2,6

Enzyme immunoassays (EIAs) are faster. EIAs are available to detect glutamate dehydrogenase (GDH) and toxins A and B, all produced by C difficile. The GDH EIA is 92% sensitive and 93% specific but should not be used alone as it does not distinguish between toxigenic and nontoxigenic strains of C difficile.^2,6 The toxin A/B EIA is 97% specific, but since its sensitivity may be as low as 73%, it too should not be used alone.⁶

Nucleic acid amplification tests such as PCR and loop-mediated isothermal amplification (LAMP) identify toxigenic C difficile by detecting tcdA, tcdB, or tcdC genes, which regulate toxin production. These tests have sensitivities and specificities well over 90%.⁶

Since molecular tests (ie, nucleic acid amplification tests) for C difficile infection became available in 2009, they have been widely adopted and are commercially available.⁷ Facilities that use them have reported a 50% to 100% increase in C difficile infection rates,⁷ but the increase may not be real. Rather, it may reflect increased detection of colonization by the more-sensitive tests.

In a prospective, observational, cohort study,⁷ 1,416 hospitalized patients with diarrhea that developed 72 hours after hospitalization were tested for C difficile infection by both toxin EIA and PCR. Those with positive results on both tests had a longer duration of diarrhea, more C difficile infection-related complications, more C difficile infection-related deaths, and greater risk of diarrhea during follow-up. For those who had negative results on toxin EIA testing, the results of PCR testing made no difference, and neither did treatment for C difficile infection, suggesting that most patients with negative toxin test results do not need treatment for C difficile even if PCR testing is positive.

In light of the limited sensitivity of some toxin EIAs and the increased identification of asymptomatic colonization with nucleic acid amplification testing, the optimal approach may be to combine rapid testing methods. Algorithms that include nucleic acid amplification testing have the best sensitivity (68% to 100%) and specificity (92% to 100%).⁷ Clinical guidelines suggest using a GDH EIA as the initial step, and then confirming positive results with either nucleic acid amplification testing alone or toxin EIA followed by nucleic acid amplification testing if the toxin EIA is negative.⁸ However, the best diagnostic approach remains controversial, and multistep algorithms may be impractical in some laboratories.

Knowledge of the laboratory test used can help clinicians appreciate the limitations of specimen testing. Table 1 outlines some of the performance characteristics of the available assays.^9–11

The preferred approach at our institution is a multistep algorithm using both the GDH and toxin EIAs in the initial step, followed by a LAMP assay for the C difficile toxin genes in cases of discordant EIA results.

Repeat testing after an initial negative test may be positive in fewer than 5% of cases, can increase the chance of false-positive results, does not improve sensitivity and negative predictive values, and is therefore not recommended.^2,8 Similarly, a test of cure after symptoms resolve is not recommended, as the toxin EIA can be positive for up to 30 days after resolution of symptoms, and a positive nucleic acid amplification test may only reflect colonization.^2,8

RETURNING TO OUR PATIENT

Returning to the patient hospitalized with community-acquired pneumonia, C difficile infection is the most likely cause of her diarrhea. If her respiratory symptoms have improved, then cessation of ceftriaxone and azithromycin should be considered because she has completed 5 days of therapy. In addition, given her profuse diarrhea, testing for C difficile is recommended with a multistep approach.

A 72-year-old woman is admitted with fever and shortness of breath. Chest radiography demonstrates a consolidation in the right lower lobe, and ceftriaxone and azithromycin are given to treat community-acquired pneumonia. After initial improvement she develops abdominal discomfort and profuse diarrhea on day 5 of hospitalization. What stool testing should be ordered?

Most cases of diarrhea in hospitalized patients are not due to infection, but the most common infectious cause is Clostridium difficile. In the absence of unusual circumstances such as a norovirus outbreak or diarrhea in an immunocompromised patient, testing for C difficile is the only recommended assay. A multistep algorithm with a combination of antigen detection and nucleic acid amplification techniques provides the best sensitivity and specificity. Repeated testing after an initially negative test and performing a test of cure are of limited utility and incur added costs, and thus are not recommended.

CAUSES OF DIARRHEA IN THE HOSPITAL

Diarrhea is defined as at least 1 day with three or more unformed stools or a significant increase in stool frequency above baseline.

Nosocomial diarrhea is an acute episode of diarrhea in a hospitalized patient that was not present on admission and that arises after 3 days of hospitalization. It is fairly common, developing in 12% to 32% of patients at some point during their hospitalization.¹

Most cases of nosocomial diarrhea are not due to infection, but rather secondary to enteral feeding, medications, and underlying illness. C difficile is the most common infectious cause and accounts for 10% to 20% of all cases of nosocomial diarrhea.² Other pathogens associated with nosocomial diarrhea are unusual, although outbreaks of norovirus in healthcare facilities have occurred,³ and isolated cases of Klebsiella oxytoca causing acute abdominal pain, bloody diarrhea, and leukocytosis after exposure to antibiotics have been reported.¹

RECOMMENDED TESTING

The evaluation of a hospitalized patient in whom diarrhea develops should initially focus on the clinical presentation, with attention to signs of sepsis. Stable patients with mild symptoms may respond to withdrawal of the offending agent (if any), while patients with moderate or severe symptoms (including those with fever, hypotension, leukocytosis, acute kidney injury, or a decreased serum bicarbonate level) should be tested for C difficile infection (Figure 1).

In general, stool testing should adhere to the “3-day rule”—ie, fecal specimens from patients with diarrhea that develops after 3 days of hospitalization have a very low yield when cultured for standard bacteria or examined for ova and parasites. Thus, only testing for C difficile infection should be ordered.⁴

In an outbreak of norovirus, especially if vomiting is present, norovirus testing by reverse transcriptase polymerase chain reaction (PCR) could be considered.

Fecal white blood cell testing should not be ordered, as it neither sensitive nor specific.⁵

Immunocompromised patients (such as those with organ transplants or late-stage human immunodeficiency virus infection) occasionally contract diarrhea due to causes other than C difficile, and consultation with a gastroenterologist or an infectious diseases physician could be considered if diarrhea persists and no cause is apparent.

In the rare situation when a patient is hospitalized after very recent overseas travel and then contracts diarrhea, causes of traveler’s diarrhea should be considered.

TESTING FOR C DIFFICILE INFECTION

A number of diagnostic tests for C difficile infection are available.

Toxigenic culture (culture followed by detection of a toxigenic isolate) and C difficile cytotoxin neutralization assay are considered the reference standards, having high sensitivity and specificity. However, both are time- and labor-intensive, with turnaround times of at least 2 to 3 days and up to 9 days, limiting their clinical utility and resulting in delay in both diagnosis and implementation of infection control measures.^2,6

Enzyme immunoassays (EIAs) are faster. EIAs are available to detect glutamate dehydrogenase (GDH) and toxins A and B, all produced by C difficile. The GDH EIA is 92% sensitive and 93% specific but should not be used alone as it does not distinguish between toxigenic and nontoxigenic strains of C difficile.^2,6 The toxin A/B EIA is 97% specific, but since its sensitivity may be as low as 73%, it too should not be used alone.⁶

Nucleic acid amplification tests such as PCR and loop-mediated isothermal amplification (LAMP) identify toxigenic C difficile by detecting tcdA, tcdB, or tcdC genes, which regulate toxin production. These tests have sensitivities and specificities well over 90%.⁶

Since molecular tests (ie, nucleic acid amplification tests) for C difficile infection became available in 2009, they have been widely adopted and are commercially available.⁷ Facilities that use them have reported a 50% to 100% increase in C difficile infection rates,⁷ but the increase may not be real. Rather, it may reflect increased detection of colonization by the more-sensitive tests.

In a prospective, observational, cohort study,⁷ 1,416 hospitalized patients with diarrhea that developed 72 hours after hospitalization were tested for C difficile infection by both toxin EIA and PCR. Those with positive results on both tests had a longer duration of diarrhea, more C difficile infection-related complications, more C difficile infection-related deaths, and greater risk of diarrhea during follow-up. For those who had negative results on toxin EIA testing, the results of PCR testing made no difference, and neither did treatment for C difficile infection, suggesting that most patients with negative toxin test results do not need treatment for C difficile even if PCR testing is positive.

In light of the limited sensitivity of some toxin EIAs and the increased identification of asymptomatic colonization with nucleic acid amplification testing, the optimal approach may be to combine rapid testing methods. Algorithms that include nucleic acid amplification testing have the best sensitivity (68% to 100%) and specificity (92% to 100%).⁷ Clinical guidelines suggest using a GDH EIA as the initial step, and then confirming positive results with either nucleic acid amplification testing alone or toxin EIA followed by nucleic acid amplification testing if the toxin EIA is negative.⁸ However, the best diagnostic approach remains controversial, and multistep algorithms may be impractical in some laboratories.

Knowledge of the laboratory test used can help clinicians appreciate the limitations of specimen testing. Table 1 outlines some of the performance characteristics of the available assays.^9–11

The preferred approach at our institution is a multistep algorithm using both the GDH and toxin EIAs in the initial step, followed by a LAMP assay for the C difficile toxin genes in cases of discordant EIA results.

Repeat testing after an initial negative test may be positive in fewer than 5% of cases, can increase the chance of false-positive results, does not improve sensitivity and negative predictive values, and is therefore not recommended.^2,8 Similarly, a test of cure after symptoms resolve is not recommended, as the toxin EIA can be positive for up to 30 days after resolution of symptoms, and a positive nucleic acid amplification test may only reflect colonization.^2,8

RETURNING TO OUR PATIENT

Returning to the patient hospitalized with community-acquired pneumonia, C difficile infection is the most likely cause of her diarrhea. If her respiratory symptoms have improved, then cessation of ceftriaxone and azithromycin should be considered because she has completed 5 days of therapy. In addition, given her profuse diarrhea, testing for C difficile is recommended with a multistep approach.

In this issue of the Journal, Ota et al provide a clinical image and vignette of a woman with emphysematous cystitis and a psoas abscess. Genitourinary infections with Escherichia coli are well known to occasionally produce gas—especially, it seems, in people with diabetes. But I thought it valuable to publish these images to provide a reminder of this infectious complication, as well as to highlight the cloaking effect of pharmacologic immunosuppression.

The patient they describe was receiving corticosteroids for brain metastases and was thus likely receiving a high dose. She had experienced abdominal pain for 3 days before seeking medical attention, but the infectious process undoubtedly predated that. Despite receiving appropriate antibiotics for more than 3 weeks, she harbored an expanding psoas abscess that was heralded by fever after the antibiotics were discontinued. This scenario is of little surprise in an ill 69-year-old diabetic woman with metastatic cancer who was receiving high-dose corticosteroids. We have all been taught about and likely have witnessed the devastating effect of delayed diagnosis of abdominal infections in patients on high-dose steroids.

With the current explosion of new targeted therapies for systemic and organ-specific inflammatory diseases, it is hard to keep up with their names, not to mention their mechanisms of action and potential complications. Much attention has been given, highlighted by the requisite warnings in direct-to-consumer advertising, to the reactivation of tuberculosis, the occurrence of fungal infections, and the risk of malignancy in patients taking many of these drugs. The risk of cancer seems to have been overstated, at least for the anti-tumor necrosis factor (anti-TNF) agents, but there is no question that some new biologics carry a real risk of reactivating latent tuberculosis and even some viral infections. But I have seen a more common problem, one that is inadequately emphasized: the delayed diagnosis of deep-tissue infection due to a blunting of the signs of inflammation that would normally accompany the infection.

Anti-TNF therapies (eg, infliximab, etanercept, adalimumab) are being increasingly prescribed for the gamut of systemic and organ-specific inflammatory diseases, from sarcoidosis and rheumatoid arthritis to uveitis. I have no doubt that these agents suppress the inflammatory response in ways that can delay diagnosis. I have seen it happen in patients with diverticular abscess, bacterial pneumonia, epidural abscess, and bacterial septic arthritis, and I believe it is a more concerning clinical issue than any actual increase in the number of opportunistic infections.

The anti-interleukin 6 biologic agent tocilizumab, like the anti-TNF agents, not only blunts the inflammatory response and masks infection, but also seems to contribute to an increased occurrence of lower intestinal perforation.¹ This is potentially important, as it seems likely that indications for this agent will be expanded to diseases other than rheumatoid arthritis.

Equal concern is likely warranted at the present time in patients receiving newer drugs such as Janus kinase (JAK) inhibitors and blockers of the interleukin 17 and 23 pathways, at least until more “real-life” patient experience is accumulated. Not all anti-inflammatory and immunosuppressive drugs have this dramatic blunting effect on findings of infection-associated inflammation (methotrexate seems not to), but we need to be wary and should perform extra-fastidious physical examinations followed by imaging studies when our patients complain of any localizing symptoms that are not readily and completely explained.

At the end of a tumultuous and divisive year, we at the Journal send to you, our readers, our heartfelt wishes for personal tranquility and for a universally peaceful and harmonious 2017.

In this issue of the Journal, Ota et al provide a clinical image and vignette of a woman with emphysematous cystitis and a psoas abscess. Genitourinary infections with Escherichia coli are well known to occasionally produce gas—especially, it seems, in people with diabetes. But I thought it valuable to publish these images to provide a reminder of this infectious complication, as well as to highlight the cloaking effect of pharmacologic immunosuppression.

The patient they describe was receiving corticosteroids for brain metastases and was thus likely receiving a high dose. She had experienced abdominal pain for 3 days before seeking medical attention, but the infectious process undoubtedly predated that. Despite receiving appropriate antibiotics for more than 3 weeks, she harbored an expanding psoas abscess that was heralded by fever after the antibiotics were discontinued. This scenario is of little surprise in an ill 69-year-old diabetic woman with metastatic cancer who was receiving high-dose corticosteroids. We have all been taught about and likely have witnessed the devastating effect of delayed diagnosis of abdominal infections in patients on high-dose steroids.

With the current explosion of new targeted therapies for systemic and organ-specific inflammatory diseases, it is hard to keep up with their names, not to mention their mechanisms of action and potential complications. Much attention has been given, highlighted by the requisite warnings in direct-to-consumer advertising, to the reactivation of tuberculosis, the occurrence of fungal infections, and the risk of malignancy in patients taking many of these drugs. The risk of cancer seems to have been overstated, at least for the anti-tumor necrosis factor (anti-TNF) agents, but there is no question that some new biologics carry a real risk of reactivating latent tuberculosis and even some viral infections. But I have seen a more common problem, one that is inadequately emphasized: the delayed diagnosis of deep-tissue infection due to a blunting of the signs of inflammation that would normally accompany the infection.

Anti-TNF therapies (eg, infliximab, etanercept, adalimumab) are being increasingly prescribed for the gamut of systemic and organ-specific inflammatory diseases, from sarcoidosis and rheumatoid arthritis to uveitis. I have no doubt that these agents suppress the inflammatory response in ways that can delay diagnosis. I have seen it happen in patients with diverticular abscess, bacterial pneumonia, epidural abscess, and bacterial septic arthritis, and I believe it is a more concerning clinical issue than any actual increase in the number of opportunistic infections.

The anti-interleukin 6 biologic agent tocilizumab, like the anti-TNF agents, not only blunts the inflammatory response and masks infection, but also seems to contribute to an increased occurrence of lower intestinal perforation.¹ This is potentially important, as it seems likely that indications for this agent will be expanded to diseases other than rheumatoid arthritis.

Equal concern is likely warranted at the present time in patients receiving newer drugs such as Janus kinase (JAK) inhibitors and blockers of the interleukin 17 and 23 pathways, at least until more “real-life” patient experience is accumulated. Not all anti-inflammatory and immunosuppressive drugs have this dramatic blunting effect on findings of infection-associated inflammation (methotrexate seems not to), but we need to be wary and should perform extra-fastidious physical examinations followed by imaging studies when our patients complain of any localizing symptoms that are not readily and completely explained.

At the end of a tumultuous and divisive year, we at the Journal send to you, our readers, our heartfelt wishes for personal tranquility and for a universally peaceful and harmonious 2017.

In this issue of the Journal, Ota et al provide a clinical image and vignette of a woman with emphysematous cystitis and a psoas abscess. Genitourinary infections with Escherichia coli are well known to occasionally produce gas—especially, it seems, in people with diabetes. But I thought it valuable to publish these images to provide a reminder of this infectious complication, as well as to highlight the cloaking effect of pharmacologic immunosuppression.

The patient they describe was receiving corticosteroids for brain metastases and was thus likely receiving a high dose. She had experienced abdominal pain for 3 days before seeking medical attention, but the infectious process undoubtedly predated that. Despite receiving appropriate antibiotics for more than 3 weeks, she harbored an expanding psoas abscess that was heralded by fever after the antibiotics were discontinued. This scenario is of little surprise in an ill 69-year-old diabetic woman with metastatic cancer who was receiving high-dose corticosteroids. We have all been taught about and likely have witnessed the devastating effect of delayed diagnosis of abdominal infections in patients on high-dose steroids.

With the current explosion of new targeted therapies for systemic and organ-specific inflammatory diseases, it is hard to keep up with their names, not to mention their mechanisms of action and potential complications. Much attention has been given, highlighted by the requisite warnings in direct-to-consumer advertising, to the reactivation of tuberculosis, the occurrence of fungal infections, and the risk of malignancy in patients taking many of these drugs. The risk of cancer seems to have been overstated, at least for the anti-tumor necrosis factor (anti-TNF) agents, but there is no question that some new biologics carry a real risk of reactivating latent tuberculosis and even some viral infections. But I have seen a more common problem, one that is inadequately emphasized: the delayed diagnosis of deep-tissue infection due to a blunting of the signs of inflammation that would normally accompany the infection.

Anti-TNF therapies (eg, infliximab, etanercept, adalimumab) are being increasingly prescribed for the gamut of systemic and organ-specific inflammatory diseases, from sarcoidosis and rheumatoid arthritis to uveitis. I have no doubt that these agents suppress the inflammatory response in ways that can delay diagnosis. I have seen it happen in patients with diverticular abscess, bacterial pneumonia, epidural abscess, and bacterial septic arthritis, and I believe it is a more concerning clinical issue than any actual increase in the number of opportunistic infections.

The anti-interleukin 6 biologic agent tocilizumab, like the anti-TNF agents, not only blunts the inflammatory response and masks infection, but also seems to contribute to an increased occurrence of lower intestinal perforation.¹ This is potentially important, as it seems likely that indications for this agent will be expanded to diseases other than rheumatoid arthritis.

Equal concern is likely warranted at the present time in patients receiving newer drugs such as Janus kinase (JAK) inhibitors and blockers of the interleukin 17 and 23 pathways, at least until more “real-life” patient experience is accumulated. Not all anti-inflammatory and immunosuppressive drugs have this dramatic blunting effect on findings of infection-associated inflammation (methotrexate seems not to), but we need to be wary and should perform extra-fastidious physical examinations followed by imaging studies when our patients complain of any localizing symptoms that are not readily and completely explained.

At the end of a tumultuous and divisive year, we at the Journal send to you, our readers, our heartfelt wishes for personal tranquility and for a universally peaceful and harmonious 2017.

A 77-year-old man presented with a 5-day history of painful swelling of his right leg. He reported no trauma, no recent surgery, no history of thrombophilic disorder, and no prolonged immobilization. However, he had a history of prostate cancer, treated 10 years earlier with pelvic radiation.

Examination revealed massive right leg swelling extending from the thigh to the ankle, along with bluish-red skin discoloration (Figure 1). Doppler ultrasonography demonstrated acute thrombosis involving the right iliofemoral veins. These findings were consistent with phlegmasia cerulea dolens.

Urgent percutaneous catheter-directed thrombolysis was performed. Venography revealed extensive thrombosis of the femoral vein (Figure 2A) extending into the right external iliac vein. This was treated with catheter-directed pharmacomechanical thrombectomy.

Venography after this procedure showed significant improvement in venous blood flow (Figure 2B). However, stenosis of the right external iliac vein was also noted (Figure 2C) and was treated with balloon angioplasty (Figure 2D) followed by placement of a stent (14 × 40 mm).

In the immediate postprocedural period, there was marked reduction in swelling and normalization of skin color (Figure 3). The patient did not experience significant bleeding during or after the procedure. Treatment with intravenous unfractionated heparin was continued during the hospital stay, and he was discharged on warfarin with a therapeutic international normalized ratio. At a follow-up visit 3 months later, he was asymptomatic.

A RARE BUT SEVERE TYPE OF ACUTE DEEP VEIN THROMBOSIS

Phlegmasia cerulea dolens (painful cyanotic swollen leg) is a rare and severe form of acute deep vein thrombosis (DVT) characterized by marked limb pain, swelling, and blue discoloration.¹ DVT is the most common cause of acute-onset unilateral leg pain, swelling, and skin discoloration.²

The differential diagnosis

The differential diagnosis includes infection (cellulitis, necrotizing fasciitis), compartment syndrome from limb injury, musculoskeletal conditions such as ruptured Baker cyst, venous stasis due to external compression (May-Thurner syndrome, iliac vein compression syndrome, pelvic tumor), acute limb ischemia from arterial obstruction, and complex regional pain syndrome (reflex sympathetic dystrophy).

Management recommendations

As in most cases of DVT, initial treatment of phlegmasia cerulea dolens involves systemic anticoagulation with heparin, elevation of the affected extremity, and fluid resuscitation if the patient is hypotensive. However, phlegmasia cerulea dolens is a major indication for catheter-directed thrombolysis,^3,4 so an urgent vascular surgery or interventional cardiology consultation is also required. The American College of Chest Physicians recommends catheter-directed thrombolysis for acute DVT of the iliofemoral veins in patients with symptoms for less than 14 days, good functional capacity, and a life expectancy beyond 1 year.⁵ This intervention results in reduced incidence of postthrombotic syndrome and improved quality of life^5,6 compared with anticoagulation therapy alone.

Who is at risk?

Risk factors for phlegmasia cerulea dolens include a history of malignancy, inherited or acquired thrombophilia, surgery, radiation therapy, trauma, placement of an inferior vena cava filter, and pregnancy. In our patient, the iliac vein stenosis most likely was the result of the radiation therapy he had undergone for prostate cancer.

Arterial stenosis is a well-known complication of radiation therapy and is associated with an increased risk of cardiovascular events.^7,8 Radiation induces endothelial damage followed by proliferation of smooth muscle cells, resulting in luminal stenosis and thrombosis. At the cellular level, radiation leads to an acute increase in pro-inflammatory cytokines and endothelial adhesion molecules, causing the recruitment of inflammatory cells to radiation-exposed vessels and chronic activation of transcription factor NF-kappa B, leading to long-term inflammation and angiogenesis.⁹

Carotid, coronary, and iliac artery stenosis are known to occur around 10 years after radiation therapy to the head, neck, breast, and pelvis. Radiation-induced iliac vein stenosis is rare and can manifest as acute proximal DVT.

A 77-year-old man presented with a 5-day history of painful swelling of his right leg. He reported no trauma, no recent surgery, no history of thrombophilic disorder, and no prolonged immobilization. However, he had a history of prostate cancer, treated 10 years earlier with pelvic radiation.

Examination revealed massive right leg swelling extending from the thigh to the ankle, along with bluish-red skin discoloration (Figure 1). Doppler ultrasonography demonstrated acute thrombosis involving the right iliofemoral veins. These findings were consistent with phlegmasia cerulea dolens.

Urgent percutaneous catheter-directed thrombolysis was performed. Venography revealed extensive thrombosis of the femoral vein (Figure 2A) extending into the right external iliac vein. This was treated with catheter-directed pharmacomechanical thrombectomy.

Venography after this procedure showed significant improvement in venous blood flow (Figure 2B). However, stenosis of the right external iliac vein was also noted (Figure 2C) and was treated with balloon angioplasty (Figure 2D) followed by placement of a stent (14 × 40 mm).

In the immediate postprocedural period, there was marked reduction in swelling and normalization of skin color (Figure 3). The patient did not experience significant bleeding during or after the procedure. Treatment with intravenous unfractionated heparin was continued during the hospital stay, and he was discharged on warfarin with a therapeutic international normalized ratio. At a follow-up visit 3 months later, he was asymptomatic.

A RARE BUT SEVERE TYPE OF ACUTE DEEP VEIN THROMBOSIS

Phlegmasia cerulea dolens (painful cyanotic swollen leg) is a rare and severe form of acute deep vein thrombosis (DVT) characterized by marked limb pain, swelling, and blue discoloration.¹ DVT is the most common cause of acute-onset unilateral leg pain, swelling, and skin discoloration.²

The differential diagnosis

The differential diagnosis includes infection (cellulitis, necrotizing fasciitis), compartment syndrome from limb injury, musculoskeletal conditions such as ruptured Baker cyst, venous stasis due to external compression (May-Thurner syndrome, iliac vein compression syndrome, pelvic tumor), acute limb ischemia from arterial obstruction, and complex regional pain syndrome (reflex sympathetic dystrophy).

Management recommendations

As in most cases of DVT, initial treatment of phlegmasia cerulea dolens involves systemic anticoagulation with heparin, elevation of the affected extremity, and fluid resuscitation if the patient is hypotensive. However, phlegmasia cerulea dolens is a major indication for catheter-directed thrombolysis,^3,4 so an urgent vascular surgery or interventional cardiology consultation is also required. The American College of Chest Physicians recommends catheter-directed thrombolysis for acute DVT of the iliofemoral veins in patients with symptoms for less than 14 days, good functional capacity, and a life expectancy beyond 1 year.⁵ This intervention results in reduced incidence of postthrombotic syndrome and improved quality of life^5,6 compared with anticoagulation therapy alone.

Who is at risk?

Risk factors for phlegmasia cerulea dolens include a history of malignancy, inherited or acquired thrombophilia, surgery, radiation therapy, trauma, placement of an inferior vena cava filter, and pregnancy. In our patient, the iliac vein stenosis most likely was the result of the radiation therapy he had undergone for prostate cancer.

Arterial stenosis is a well-known complication of radiation therapy and is associated with an increased risk of cardiovascular events.^7,8 Radiation induces endothelial damage followed by proliferation of smooth muscle cells, resulting in luminal stenosis and thrombosis. At the cellular level, radiation leads to an acute increase in pro-inflammatory cytokines and endothelial adhesion molecules, causing the recruitment of inflammatory cells to radiation-exposed vessels and chronic activation of transcription factor NF-kappa B, leading to long-term inflammation and angiogenesis.⁹

Carotid, coronary, and iliac artery stenosis are known to occur around 10 years after radiation therapy to the head, neck, breast, and pelvis. Radiation-induced iliac vein stenosis is rare and can manifest as acute proximal DVT.

A 77-year-old man presented with a 5-day history of painful swelling of his right leg. He reported no trauma, no recent surgery, no history of thrombophilic disorder, and no prolonged immobilization. However, he had a history of prostate cancer, treated 10 years earlier with pelvic radiation.

Examination revealed massive right leg swelling extending from the thigh to the ankle, along with bluish-red skin discoloration (Figure 1). Doppler ultrasonography demonstrated acute thrombosis involving the right iliofemoral veins. These findings were consistent with phlegmasia cerulea dolens.

Urgent percutaneous catheter-directed thrombolysis was performed. Venography revealed extensive thrombosis of the femoral vein (Figure 2A) extending into the right external iliac vein. This was treated with catheter-directed pharmacomechanical thrombectomy.

Venography after this procedure showed significant improvement in venous blood flow (Figure 2B). However, stenosis of the right external iliac vein was also noted (Figure 2C) and was treated with balloon angioplasty (Figure 2D) followed by placement of a stent (14 × 40 mm).

In the immediate postprocedural period, there was marked reduction in swelling and normalization of skin color (Figure 3). The patient did not experience significant bleeding during or after the procedure. Treatment with intravenous unfractionated heparin was continued during the hospital stay, and he was discharged on warfarin with a therapeutic international normalized ratio. At a follow-up visit 3 months later, he was asymptomatic.

A RARE BUT SEVERE TYPE OF ACUTE DEEP VEIN THROMBOSIS

Phlegmasia cerulea dolens (painful cyanotic swollen leg) is a rare and severe form of acute deep vein thrombosis (DVT) characterized by marked limb pain, swelling, and blue discoloration.¹ DVT is the most common cause of acute-onset unilateral leg pain, swelling, and skin discoloration.²

The differential diagnosis

The differential diagnosis includes infection (cellulitis, necrotizing fasciitis), compartment syndrome from limb injury, musculoskeletal conditions such as ruptured Baker cyst, venous stasis due to external compression (May-Thurner syndrome, iliac vein compression syndrome, pelvic tumor), acute limb ischemia from arterial obstruction, and complex regional pain syndrome (reflex sympathetic dystrophy).

Management recommendations

As in most cases of DVT, initial treatment of phlegmasia cerulea dolens involves systemic anticoagulation with heparin, elevation of the affected extremity, and fluid resuscitation if the patient is hypotensive. However, phlegmasia cerulea dolens is a major indication for catheter-directed thrombolysis,^3,4 so an urgent vascular surgery or interventional cardiology consultation is also required. The American College of Chest Physicians recommends catheter-directed thrombolysis for acute DVT of the iliofemoral veins in patients with symptoms for less than 14 days, good functional capacity, and a life expectancy beyond 1 year.⁵ This intervention results in reduced incidence of postthrombotic syndrome and improved quality of life^5,6 compared with anticoagulation therapy alone.

Who is at risk?

Risk factors for phlegmasia cerulea dolens include a history of malignancy, inherited or acquired thrombophilia, surgery, radiation therapy, trauma, placement of an inferior vena cava filter, and pregnancy. In our patient, the iliac vein stenosis most likely was the result of the radiation therapy he had undergone for prostate cancer.

Arterial stenosis is a well-known complication of radiation therapy and is associated with an increased risk of cardiovascular events.^7,8 Radiation induces endothelial damage followed by proliferation of smooth muscle cells, resulting in luminal stenosis and thrombosis. At the cellular level, radiation leads to an acute increase in pro-inflammatory cytokines and endothelial adhesion molecules, causing the recruitment of inflammatory cells to radiation-exposed vessels and chronic activation of transcription factor NF-kappa B, leading to long-term inflammation and angiogenesis.⁹

Carotid, coronary, and iliac artery stenosis are known to occur around 10 years after radiation therapy to the head, neck, breast, and pelvis. Radiation-induced iliac vein stenosis is rare and can manifest as acute proximal DVT.