Janice Benson, MD

A 60-year-old man presents for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association class 3 heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and based on his self-administered 9-item Patient Health Questionnaire (PHQ-9) score of 17, you determine that he is having a concomitant major depressive episode. Should you start him on an SSRI?

Depression is widely recognized as an independent risk factor for cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying link between depression and CVD risk.^2,6 Conversely, a recent systematic review found that positive constructs, mediated primarily through lifestyle behaviors, may have a protective effect on outcomes.⁷

Recently, researchers have focused on treating depression to simultaneously improve CVD outcomes. While some studies have shown SSRIs to be a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD trial did suggest that SSRI treatment may improve mortality and morbidity post-MI.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with lower quality of life (QoL), poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure; it is an independent predictor of mortality in this patient population.¹ Until recently, only one RCT (the SADHART-CHF study) looked at SSRI treatment in patients with heart failure and depression.¹² In that 12-week trial, sertraline did not improve depression or CVD outcomes when compared with placebo—but the study period may have been too short to capture long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 mo).¹ Specifically, this RCT assessed whether treatment with escitalopram could reduce morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients with New York Heart Association class 2 to 4 heart failure and left ventricular ejection fractions < 45% were screened for depression using the PHQ-9. Patients with PHQ-9 scores ≥ 12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist, and those diagnosed with major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months, in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every six months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The study used a composite endpoint of all-cause death or hospitalization; the primary outcome was time to first event of this composite. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale, and health-related QoL as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 escitalopram, 187 placebo). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR], 0.99).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean MADRS score changed from 20.2 at baseline to 11.2 at 12 weeks with escitalopram, and from 21.4 to 12.5 in the placebo group (between-group difference, –0.9).¹⁰ Overall, the two treatment groups had comparable daily medication doses and mean treatment duration (18 mo), and both groups demonstrated partial remission of depression symptoms, improved health status, and improved QoL over the study period.

Interestingly, the placebo group experienced significantly improved QoL at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by conducting the study over a much longer duration (up to 24 mo vs 12 wk). Also, in contrast to SADHART-CHF, this trial studied escitalopram rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: SSRI treatment for patients with heart failure and depression did not reduce the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram versus placebo. Given that this high-quality trial replicated the findings of SADHART-CHF with a longer treatment period and a potentially more effective SSRI, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating severe depression has an impact on cardiovascular outcomes.

Lastly, and most importantly, this study only looked at initiating SSRIs for depression in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to mitigate the elevated risk for adverse clinical outcomes remains nuanced and elusive. The same can be said of non-CVD chronic conditions (eg, diabetes) based on recent systematic reviews.¹³ In sum, these studies suggest that a traditional screen-and-treat approach using SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

A recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought.¹⁴ Nevertheless, this area of research should continue to be explored, given the worsened chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change, we expect that it will be a challenge to convince providers to stop initiating SSRI treatment to affect cardiovascular outcomes in patients with depression and heart failure—especially given the body of evidence denoting depression as a risk factor for increased morbidity and mortality in this population.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquires Network and The Journal of Family Practice (2017;66[9]:564-567).

A 60-year-old man presents for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association class 3 heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and based on his self-administered 9-item Patient Health Questionnaire (PHQ-9) score of 17, you determine that he is having a concomitant major depressive episode. Should you start him on an SSRI?

Depression is widely recognized as an independent risk factor for cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying link between depression and CVD risk.^2,6 Conversely, a recent systematic review found that positive constructs, mediated primarily through lifestyle behaviors, may have a protective effect on outcomes.⁷

Recently, researchers have focused on treating depression to simultaneously improve CVD outcomes. While some studies have shown SSRIs to be a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD trial did suggest that SSRI treatment may improve mortality and morbidity post-MI.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with lower quality of life (QoL), poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure; it is an independent predictor of mortality in this patient population.¹ Until recently, only one RCT (the SADHART-CHF study) looked at SSRI treatment in patients with heart failure and depression.¹² In that 12-week trial, sertraline did not improve depression or CVD outcomes when compared with placebo—but the study period may have been too short to capture long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 mo).¹ Specifically, this RCT assessed whether treatment with escitalopram could reduce morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients with New York Heart Association class 2 to 4 heart failure and left ventricular ejection fractions < 45% were screened for depression using the PHQ-9. Patients with PHQ-9 scores ≥ 12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist, and those diagnosed with major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months, in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every six months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The study used a composite endpoint of all-cause death or hospitalization; the primary outcome was time to first event of this composite. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale, and health-related QoL as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 escitalopram, 187 placebo). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR], 0.99).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean MADRS score changed from 20.2 at baseline to 11.2 at 12 weeks with escitalopram, and from 21.4 to 12.5 in the placebo group (between-group difference, –0.9).¹⁰ Overall, the two treatment groups had comparable daily medication doses and mean treatment duration (18 mo), and both groups demonstrated partial remission of depression symptoms, improved health status, and improved QoL over the study period.

Interestingly, the placebo group experienced significantly improved QoL at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by conducting the study over a much longer duration (up to 24 mo vs 12 wk). Also, in contrast to SADHART-CHF, this trial studied escitalopram rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: SSRI treatment for patients with heart failure and depression did not reduce the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram versus placebo. Given that this high-quality trial replicated the findings of SADHART-CHF with a longer treatment period and a potentially more effective SSRI, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating severe depression has an impact on cardiovascular outcomes.

Lastly, and most importantly, this study only looked at initiating SSRIs for depression in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to mitigate the elevated risk for adverse clinical outcomes remains nuanced and elusive. The same can be said of non-CVD chronic conditions (eg, diabetes) based on recent systematic reviews.¹³ In sum, these studies suggest that a traditional screen-and-treat approach using SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

A recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought.¹⁴ Nevertheless, this area of research should continue to be explored, given the worsened chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change, we expect that it will be a challenge to convince providers to stop initiating SSRI treatment to affect cardiovascular outcomes in patients with depression and heart failure—especially given the body of evidence denoting depression as a risk factor for increased morbidity and mortality in this population.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquires Network and The Journal of Family Practice (2017;66[9]:564-567).

A 60-year-old man presents for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association class 3 heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and based on his self-administered 9-item Patient Health Questionnaire (PHQ-9) score of 17, you determine that he is having a concomitant major depressive episode. Should you start him on an SSRI?

Depression is widely recognized as an independent risk factor for cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying link between depression and CVD risk.^2,6 Conversely, a recent systematic review found that positive constructs, mediated primarily through lifestyle behaviors, may have a protective effect on outcomes.⁷

Recently, researchers have focused on treating depression to simultaneously improve CVD outcomes. While some studies have shown SSRIs to be a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD trial did suggest that SSRI treatment may improve mortality and morbidity post-MI.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with lower quality of life (QoL), poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure; it is an independent predictor of mortality in this patient population.¹ Until recently, only one RCT (the SADHART-CHF study) looked at SSRI treatment in patients with heart failure and depression.¹² In that 12-week trial, sertraline did not improve depression or CVD outcomes when compared with placebo—but the study period may have been too short to capture long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 mo).¹ Specifically, this RCT assessed whether treatment with escitalopram could reduce morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients with New York Heart Association class 2 to 4 heart failure and left ventricular ejection fractions < 45% were screened for depression using the PHQ-9. Patients with PHQ-9 scores ≥ 12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist, and those diagnosed with major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months, in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every six months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The study used a composite endpoint of all-cause death or hospitalization; the primary outcome was time to first event of this composite. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale, and health-related QoL as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 escitalopram, 187 placebo). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR], 0.99).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean MADRS score changed from 20.2 at baseline to 11.2 at 12 weeks with escitalopram, and from 21.4 to 12.5 in the placebo group (between-group difference, –0.9).¹⁰ Overall, the two treatment groups had comparable daily medication doses and mean treatment duration (18 mo), and both groups demonstrated partial remission of depression symptoms, improved health status, and improved QoL over the study period.

Interestingly, the placebo group experienced significantly improved QoL at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by conducting the study over a much longer duration (up to 24 mo vs 12 wk). Also, in contrast to SADHART-CHF, this trial studied escitalopram rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: SSRI treatment for patients with heart failure and depression did not reduce the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram versus placebo. Given that this high-quality trial replicated the findings of SADHART-CHF with a longer treatment period and a potentially more effective SSRI, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating severe depression has an impact on cardiovascular outcomes.

Lastly, and most importantly, this study only looked at initiating SSRIs for depression in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to mitigate the elevated risk for adverse clinical outcomes remains nuanced and elusive. The same can be said of non-CVD chronic conditions (eg, diabetes) based on recent systematic reviews.¹³ In sum, these studies suggest that a traditional screen-and-treat approach using SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

A recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought.¹⁴ Nevertheless, this area of research should continue to be explored, given the worsened chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change, we expect that it will be a challenge to convince providers to stop initiating SSRI treatment to affect cardiovascular outcomes in patients with depression and heart failure—especially given the body of evidence denoting depression as a risk factor for increased morbidity and mortality in this population.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquires Network and The Journal of Family Practice (2017;66[9]:564-567).

ILLUSTRATIVE CASE

A 60-year-old man comes to your office for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association Class III heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and after evaluation, including a score of 17 on a self-administered 9-item Patient Health Questionnaire (PHQ-9), you determine that he is having a concomitant major depressive episode. Should you start him on a selective serotonin reuptake inhibitor (SSRI)?

Depression is widely recognized as an independent risk factor for both the development of cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying mechanisms linking depression and the risk of CVD.^2,6 Conversely, a recent systematic review suggests that positive constructs—mediated primarily through lifestyle behaviors—may have a protective effect on CVD outcomes.⁷

As a result, researchers have focused on the treatment of depression to improve CVD outcomes in recent years, including in patients with heart failure. While some randomized studies have shown that SSRIs are a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD (Enhancing Recovery in Coronary Heart Disease) trial did suggest that SSRI treatment may improve mortality and morbidity post-myocardial infarction.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with worse quality of life, poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure, and is an independent predictor of mortality in this patient population.¹ Until recently, only one randomized controlled trial (RCT), the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) study, looked at treatment with SSRIs in patients with heart failure and depression.¹² In this trial, sertraline, when compared with placebo, did not improve depression or CVD outcomes over 12 weeks, but the study period may have been insufficiently long to capture the impact on long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF (The effects of selective serotonin re-uptake inhibition on morbidity, mortality, and mood in depressed heart failure patients) study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 months).¹ Specifically, this RCT assessed whether treatment with escitalopram vs placebo could reduce the increased morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

Using SSRIs for depression treatment to affect chronic disease outcomes that are likely lifestyle-related may not be cost-effective or patient-centered.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients established at heart failure clinics with New York Heart Association class II to IV heart failure and left ventricular ejection fractions <45% were screened for depression using the PHQ-9. Individuals with PHQ-9 scores ≥12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist. Those who received a diagnosis of major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded from participation.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every 6 months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The primary study outcome was time to a first event of the composite of all-cause death or hospitalization. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale (GAD-7), and health-related quality of life (QoL) as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 in the escitalopram group and 187 in the placebo group). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR]=0.99; 95% confidence interval [CI], 0.76 to 1.27]; P=.92).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean (SD) MADRS score changed from 20.2 (8.6) at baseline to 11.2 (8.1) at 12 weeks with escitalopram and from 21.4 (8.8) to 12.5 (7.6) in the placebo group (between-group difference = -0.9; 95% CI, -2.6 to 0.7; P =.26).¹⁰ Overall, participants in the 2 treatment groups had comparable daily doses of study medications, as well as mean treatment duration (18 months), and both groups demonstrated partial remission of depression symptoms over the study period, as well as improved health status and QoL as measured by KCCQ.

Interestingly, QoL as assessed by the KCCQ symptom score was significantly improved in the placebo group at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely on February 28, 2014, based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI doesn’t change earlier finding

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by looking at SSRI treatment of patients with heart failure and depression over a much longer study duration (up to 24 months vs 12 weeks). Also, in contrast to SADHART-CHF, this trial studied escitalopram, rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: treating patients with both heart failure and depression with an SSRI did not improve the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram vs placebo. Given that this high-quality trial, with a much longer treatment period and a possibly more effective SSRI, replicated the findings of SADHART-CHF, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating patients with severe depression has an impact on cardiovascular outcomes.

Although there are other SSRIs besides escitalopram and sertraline, it is likely that this is a class effect.

Lastly, and most importantly, this study only looked at screening patients for depression and initiating SSRIs in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to improve the elevated risk for adverse clinical outcomes remains nuanced and elusive. In fact, the same can be said of non-CVD chronic conditions—such as diabetes—based on recent systematic reviews.¹³ The summation of these studies suggests that a traditional screen-and-treat approach utilizing SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

The publication of a recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions¹⁴ reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought. Nevertheless, this is an area of research that should continue to be explored, given the obvious increased risk for poorer chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change among providers, we expect that it will be a challenge to convince providers to stop screening for depression and initiating treatment with an SSRI to affect CV outcomes in patients with heart failure. This is especially so given the body of evidence for depression as a risk factor for increased morbidity and mortality in this population.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 60-year-old man comes to your office for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association Class III heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and after evaluation, including a score of 17 on a self-administered 9-item Patient Health Questionnaire (PHQ-9), you determine that he is having a concomitant major depressive episode. Should you start him on a selective serotonin reuptake inhibitor (SSRI)?

Depression is widely recognized as an independent risk factor for both the development of cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying mechanisms linking depression and the risk of CVD.^2,6 Conversely, a recent systematic review suggests that positive constructs—mediated primarily through lifestyle behaviors—may have a protective effect on CVD outcomes.⁷

As a result, researchers have focused on the treatment of depression to improve CVD outcomes in recent years, including in patients with heart failure. While some randomized studies have shown that SSRIs are a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD (Enhancing Recovery in Coronary Heart Disease) trial did suggest that SSRI treatment may improve mortality and morbidity post-myocardial infarction.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with worse quality of life, poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure, and is an independent predictor of mortality in this patient population.¹ Until recently, only one randomized controlled trial (RCT), the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) study, looked at treatment with SSRIs in patients with heart failure and depression.¹² In this trial, sertraline, when compared with placebo, did not improve depression or CVD outcomes over 12 weeks, but the study period may have been insufficiently long to capture the impact on long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF (The effects of selective serotonin re-uptake inhibition on morbidity, mortality, and mood in depressed heart failure patients) study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 months).¹ Specifically, this RCT assessed whether treatment with escitalopram vs placebo could reduce the increased morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

Using SSRIs for depression treatment to affect chronic disease outcomes that are likely lifestyle-related may not be cost-effective or patient-centered.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients established at heart failure clinics with New York Heart Association class II to IV heart failure and left ventricular ejection fractions <45% were screened for depression using the PHQ-9. Individuals with PHQ-9 scores ≥12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist. Those who received a diagnosis of major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded from participation.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every 6 months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The primary study outcome was time to a first event of the composite of all-cause death or hospitalization. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale (GAD-7), and health-related quality of life (QoL) as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 in the escitalopram group and 187 in the placebo group). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR]=0.99; 95% confidence interval [CI], 0.76 to 1.27]; P=.92).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean (SD) MADRS score changed from 20.2 (8.6) at baseline to 11.2 (8.1) at 12 weeks with escitalopram and from 21.4 (8.8) to 12.5 (7.6) in the placebo group (between-group difference = -0.9; 95% CI, -2.6 to 0.7; P =.26).¹⁰ Overall, participants in the 2 treatment groups had comparable daily doses of study medications, as well as mean treatment duration (18 months), and both groups demonstrated partial remission of depression symptoms over the study period, as well as improved health status and QoL as measured by KCCQ.

Interestingly, QoL as assessed by the KCCQ symptom score was significantly improved in the placebo group at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely on February 28, 2014, based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI doesn’t change earlier finding

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by looking at SSRI treatment of patients with heart failure and depression over a much longer study duration (up to 24 months vs 12 weeks). Also, in contrast to SADHART-CHF, this trial studied escitalopram, rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: treating patients with both heart failure and depression with an SSRI did not improve the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram vs placebo. Given that this high-quality trial, with a much longer treatment period and a possibly more effective SSRI, replicated the findings of SADHART-CHF, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating patients with severe depression has an impact on cardiovascular outcomes.

Although there are other SSRIs besides escitalopram and sertraline, it is likely that this is a class effect.

Lastly, and most importantly, this study only looked at screening patients for depression and initiating SSRIs in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to improve the elevated risk for adverse clinical outcomes remains nuanced and elusive. In fact, the same can be said of non-CVD chronic conditions—such as diabetes—based on recent systematic reviews.¹³ The summation of these studies suggests that a traditional screen-and-treat approach utilizing SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

The publication of a recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions¹⁴ reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought. Nevertheless, this is an area of research that should continue to be explored, given the obvious increased risk for poorer chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change among providers, we expect that it will be a challenge to convince providers to stop screening for depression and initiating treatment with an SSRI to affect CV outcomes in patients with heart failure. This is especially so given the body of evidence for depression as a risk factor for increased morbidity and mortality in this population.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 60-year-old man comes to your office for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association Class III heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and after evaluation, including a score of 17 on a self-administered 9-item Patient Health Questionnaire (PHQ-9), you determine that he is having a concomitant major depressive episode. Should you start him on a selective serotonin reuptake inhibitor (SSRI)?

Depression is widely recognized as an independent risk factor for both the development of cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying mechanisms linking depression and the risk of CVD.^2,6 Conversely, a recent systematic review suggests that positive constructs—mediated primarily through lifestyle behaviors—may have a protective effect on CVD outcomes.⁷

As a result, researchers have focused on the treatment of depression to improve CVD outcomes in recent years, including in patients with heart failure. While some randomized studies have shown that SSRIs are a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD (Enhancing Recovery in Coronary Heart Disease) trial did suggest that SSRI treatment may improve mortality and morbidity post-myocardial infarction.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with worse quality of life, poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure, and is an independent predictor of mortality in this patient population.¹ Until recently, only one randomized controlled trial (RCT), the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) study, looked at treatment with SSRIs in patients with heart failure and depression.¹² In this trial, sertraline, when compared with placebo, did not improve depression or CVD outcomes over 12 weeks, but the study period may have been insufficiently long to capture the impact on long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF (The effects of selective serotonin re-uptake inhibition on morbidity, mortality, and mood in depressed heart failure patients) study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 months).¹ Specifically, this RCT assessed whether treatment with escitalopram vs placebo could reduce the increased morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

Using SSRIs for depression treatment to affect chronic disease outcomes that are likely lifestyle-related may not be cost-effective or patient-centered.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients established at heart failure clinics with New York Heart Association class II to IV heart failure and left ventricular ejection fractions <45% were screened for depression using the PHQ-9. Individuals with PHQ-9 scores ≥12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist. Those who received a diagnosis of major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded from participation.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every 6 months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The primary study outcome was time to a first event of the composite of all-cause death or hospitalization. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale (GAD-7), and health-related quality of life (QoL) as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 in the escitalopram group and 187 in the placebo group). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR]=0.99; 95% confidence interval [CI], 0.76 to 1.27]; P=.92).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean (SD) MADRS score changed from 20.2 (8.6) at baseline to 11.2 (8.1) at 12 weeks with escitalopram and from 21.4 (8.8) to 12.5 (7.6) in the placebo group (between-group difference = -0.9; 95% CI, -2.6 to 0.7; P =.26).¹⁰ Overall, participants in the 2 treatment groups had comparable daily doses of study medications, as well as mean treatment duration (18 months), and both groups demonstrated partial remission of depression symptoms over the study period, as well as improved health status and QoL as measured by KCCQ.

Interestingly, QoL as assessed by the KCCQ symptom score was significantly improved in the placebo group at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely on February 28, 2014, based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI doesn’t change earlier finding

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by looking at SSRI treatment of patients with heart failure and depression over a much longer study duration (up to 24 months vs 12 weeks). Also, in contrast to SADHART-CHF, this trial studied escitalopram, rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: treating patients with both heart failure and depression with an SSRI did not improve the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram vs placebo. Given that this high-quality trial, with a much longer treatment period and a possibly more effective SSRI, replicated the findings of SADHART-CHF, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating patients with severe depression has an impact on cardiovascular outcomes.

Although there are other SSRIs besides escitalopram and sertraline, it is likely that this is a class effect.

Lastly, and most importantly, this study only looked at screening patients for depression and initiating SSRIs in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to improve the elevated risk for adverse clinical outcomes remains nuanced and elusive. In fact, the same can be said of non-CVD chronic conditions—such as diabetes—based on recent systematic reviews.¹³ The summation of these studies suggests that a traditional screen-and-treat approach utilizing SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

The publication of a recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions¹⁴ reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought. Nevertheless, this is an area of research that should continue to be explored, given the obvious increased risk for poorer chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change among providers, we expect that it will be a challenge to convince providers to stop screening for depression and initiating treatment with an SSRI to affect CV outcomes in patients with heart failure. This is especially so given the body of evidence for depression as a risk factor for increased morbidity and mortality in this population.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

PRACTICE CHANGER
Do not recommend elastic compression stockings to decrease the incidence of postthrombotic syndrome after deep vein thrombosis.¹

STRENGTH OF RECOMMENDATION
B: Based on a large randomized controlled trial¹

ILLUSTRATIVE CASE
A 56-year-old man presents to your clinic three days after receiving a diagnosis of lower extremity deep vein thrombosis (DVT). He was prescribed warfarin (5 mg/d) with enoxaparin bridging (120 mg/d). He has read about postthrombotic syndrome (PTS) online and is very concerned about this possible adverse effect. He asks about using elastic compression stockings (ECS). What should you tell him?

PTS can be a frustrating, debilitating condition. Its clinical features range from minor limb swelling to severe edema and pain, irreversible skin changes, and leg ulcerations.² It occurs in 25% to 50% of patients after DVT.³ Because current PTS treatments are not very effective, prevention is essential.^4,5

Patients are frequently encouraged to wear ECS after DVT to reduce the incidence of PTS by decreasing venous hypertension and reflux. These stockings are expensive and uncomfortable. Prior research suggested that use of ECS can reduce PTS incidence by half, but the studies were small, single-center, and not placebo-controlled.^6,7

On the next page: Study summary >> 

STUDY SUMMARY
RCT sets aside a common practice
Kahn et al¹ conducted a randomized, placebo-controlled trial of active versus placebo ECS in patients from 24 centers in the United States and Canada who’d had an ultrasound-confirmed proximal DVT (in the popliteal or more proximal deep leg vein) within the previous 14 days. Most patients received standard anticoagulation therapy to treat their DVT (five to 10 days of heparin and three to six months of warfarin). Patients were excluded if they had received thrombolytics, had arterial claudication, had a life expectancy of less than six months, were unable to put on ECS due to physical disabilities or allergy, or were unable to participate in follow-up visits.

Patients were randomly assigned to wear active (30 to 40 mm Hg graduated) ECS or identical-looking placebo ECS (< 5 mm Hg compression at the ankle) for two years. Providers, study personnel and statisticians, and patients were all blinded to treatment allocation. Patients were asked to wear the stocking on the affected leg each day from waking until bedtime.

Follow-up occurred at one, six, 12, 18, and 24 months. The primary outcome was cumulative incidence of PTS diagnosed at six months or later using the Ginsberg criteria of ipsilateral pain and swelling of at least one month’s duration.⁸ Secondary outcomes included severity of PTS, leg ulcers, recurrence of ­venous thromboembolism (VTE), death, adverse events, venous valvular reflux, and quality of life (QOL). Outcomes were measured objectively through use of a validated scale (the Villalta scale) for PTS severity and two questionnaires to assess QOL.^9-11

There were 409 patients in the ECS group and 394 in the placebo group. Baseline characteristics, including BMI, VTE risk factors, and anticoagulation treatment regimens, were similar between groups. The average age of participants in the study group was 55.4 years and in the placebo group, 54.8 years. Men comprised 62.4% of the active group and 57.9% of the placebo group. Approximately 90% of the participants in both groups were white.

At one month, approximately 95% of participants in both groups used the stockings; at 24 months, that was reduced to a little less than 70%. The percentage of people who used the stockings for at least three days per week was similar in both groups.

The cumulative incidence of PTS during follow-up was 14.2% in the active group and 12.7% in the placebo group (hazard ratio, 1.13). There were no differences in any of the secondary outcomes. Prespecified subgroup analyses found that age, BMI, and severity of DVT had no effect on outcomes. There was a marginal benefit for ECS for women versus men, but this does not likely reflect a true difference because the confidence intervals surrounding the hazard ratios for men and women overlapped and crossed the null value.

On the next page: What's new & challenges to implementation >>

WHAT’S NEW
New evidence contradicts ­previous studies
Two prior studies showed that using 30 to 40 mm Hg ECS decreased the incidence of PTS after proximal DVT.^6,7 However, these were smaller, open-label, single-center studies. This study by Kahn et al¹ was the first placebo-controlled, randomized, multicenter study that used validated instruments to measure PTS and QOL. It found no benefit in using ECS, thus contradicting the results of the prior studies.

There are currently no guidelines or consensus statements that recommend for or against the use of ECS after DVT.

CAVEATS
High nonadherence rates might have affected results
In both groups, adherence to the assigned intervention diminished throughout the study (from 95% at one month to slightly less than 70% at two years). Theoretically, this could have affected efficacy outcomes. However, the decrease was similar in both groups and represents what is observed in clinical practice. A prespecified per protocol analysis of patients who wore their ECS more regularly found no benefit.

It is possible that a “placebo effect” could explain the lack of difference between groups. However, the placebo stockings provided virtually no compression, and the two-year cumulative incidence of PTS in both the treatment and placebo groups was similar to that seen in control groups in prior studies.^6,7

Finally, the incidence of PTS in this study was much lower than the 25% to 50% incidence reported previously. Kahn et al¹ suggested that this was because they used more stringent and standardized criteria for PTS than was used in previous research.

CHALLENGES TO IMPLEMENTATION
There are no barriers to ending this practice
We can identify no challenges to implementation of this recommendation.

On the next page: References >>

REFERENCES
1. Kahn SR, Shapiro S, Wells PS, et al; SOX trial investigators. Compression stockings to ­prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383:880-888.

2. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149:698-707.

3. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996; 125:1-7.

4. Cohen JM, Akl EA, Kahn SR. Pharmacologic and compression therapies for postthrombotic syndrome: a systematic review of randomized controlled trials. Chest. 2012;141: 308-320.

5. Henke PK, Comerota AJ. An update on etiology, prevention, and therapy of postthrombotic syndrome. J Vasc Surg. 2011;53:
500-509.

6. Brandjes DP, Büller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997;349:
759-762.

7. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med. 2004;141:249-256.

8. Ginsberg JS, Hirsh J, Julian J, et al. Prevention and treatment of postphlebitic syndrome: results of a 3-part study. Arch Intern Med. 2001;161:2105-2109.

9. Villalta S, Bagatella P, Piccioli A, et al. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome. Haemostasis. 1994;24:158a.

10. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care. 1993;31:247-263.

11. Kahn SR, Lamping DL, Ducruet T, et al; VETO Study Investigators. VEINES-QOL/Sym questionnaire was a reliable and valid disease-specific quality of life measure for deep venous thrombosis. J Clin Epidemiol. 2006; 59:1049-1056.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(7):388-390.

PRACTICE CHANGER
Do not recommend elastic compression stockings to decrease the incidence of postthrombotic syndrome after deep vein thrombosis.¹

STRENGTH OF RECOMMENDATION
B: Based on a large randomized controlled trial¹

ILLUSTRATIVE CASE
A 56-year-old man presents to your clinic three days after receiving a diagnosis of lower extremity deep vein thrombosis (DVT). He was prescribed warfarin (5 mg/d) with enoxaparin bridging (120 mg/d). He has read about postthrombotic syndrome (PTS) online and is very concerned about this possible adverse effect. He asks about using elastic compression stockings (ECS). What should you tell him?

PTS can be a frustrating, debilitating condition. Its clinical features range from minor limb swelling to severe edema and pain, irreversible skin changes, and leg ulcerations.² It occurs in 25% to 50% of patients after DVT.³ Because current PTS treatments are not very effective, prevention is essential.^4,5

Patients are frequently encouraged to wear ECS after DVT to reduce the incidence of PTS by decreasing venous hypertension and reflux. These stockings are expensive and uncomfortable. Prior research suggested that use of ECS can reduce PTS incidence by half, but the studies were small, single-center, and not placebo-controlled.^6,7

On the next page: Study summary >> 

STUDY SUMMARY
RCT sets aside a common practice
Kahn et al¹ conducted a randomized, placebo-controlled trial of active versus placebo ECS in patients from 24 centers in the United States and Canada who’d had an ultrasound-confirmed proximal DVT (in the popliteal or more proximal deep leg vein) within the previous 14 days. Most patients received standard anticoagulation therapy to treat their DVT (five to 10 days of heparin and three to six months of warfarin). Patients were excluded if they had received thrombolytics, had arterial claudication, had a life expectancy of less than six months, were unable to put on ECS due to physical disabilities or allergy, or were unable to participate in follow-up visits.

Patients were randomly assigned to wear active (30 to 40 mm Hg graduated) ECS or identical-looking placebo ECS (< 5 mm Hg compression at the ankle) for two years. Providers, study personnel and statisticians, and patients were all blinded to treatment allocation. Patients were asked to wear the stocking on the affected leg each day from waking until bedtime.

Follow-up occurred at one, six, 12, 18, and 24 months. The primary outcome was cumulative incidence of PTS diagnosed at six months or later using the Ginsberg criteria of ipsilateral pain and swelling of at least one month’s duration.⁸ Secondary outcomes included severity of PTS, leg ulcers, recurrence of ­venous thromboembolism (VTE), death, adverse events, venous valvular reflux, and quality of life (QOL). Outcomes were measured objectively through use of a validated scale (the Villalta scale) for PTS severity and two questionnaires to assess QOL.^9-11

There were 409 patients in the ECS group and 394 in the placebo group. Baseline characteristics, including BMI, VTE risk factors, and anticoagulation treatment regimens, were similar between groups. The average age of participants in the study group was 55.4 years and in the placebo group, 54.8 years. Men comprised 62.4% of the active group and 57.9% of the placebo group. Approximately 90% of the participants in both groups were white.

At one month, approximately 95% of participants in both groups used the stockings; at 24 months, that was reduced to a little less than 70%. The percentage of people who used the stockings for at least three days per week was similar in both groups.

The cumulative incidence of PTS during follow-up was 14.2% in the active group and 12.7% in the placebo group (hazard ratio, 1.13). There were no differences in any of the secondary outcomes. Prespecified subgroup analyses found that age, BMI, and severity of DVT had no effect on outcomes. There was a marginal benefit for ECS for women versus men, but this does not likely reflect a true difference because the confidence intervals surrounding the hazard ratios for men and women overlapped and crossed the null value.

On the next page: What's new & challenges to implementation >>

WHAT’S NEW
New evidence contradicts ­previous studies
Two prior studies showed that using 30 to 40 mm Hg ECS decreased the incidence of PTS after proximal DVT.^6,7 However, these were smaller, open-label, single-center studies. This study by Kahn et al¹ was the first placebo-controlled, randomized, multicenter study that used validated instruments to measure PTS and QOL. It found no benefit in using ECS, thus contradicting the results of the prior studies.

There are currently no guidelines or consensus statements that recommend for or against the use of ECS after DVT.

CAVEATS
High nonadherence rates might have affected results
In both groups, adherence to the assigned intervention diminished throughout the study (from 95% at one month to slightly less than 70% at two years). Theoretically, this could have affected efficacy outcomes. However, the decrease was similar in both groups and represents what is observed in clinical practice. A prespecified per protocol analysis of patients who wore their ECS more regularly found no benefit.

It is possible that a “placebo effect” could explain the lack of difference between groups. However, the placebo stockings provided virtually no compression, and the two-year cumulative incidence of PTS in both the treatment and placebo groups was similar to that seen in control groups in prior studies.^6,7

Finally, the incidence of PTS in this study was much lower than the 25% to 50% incidence reported previously. Kahn et al¹ suggested that this was because they used more stringent and standardized criteria for PTS than was used in previous research.

CHALLENGES TO IMPLEMENTATION
There are no barriers to ending this practice
We can identify no challenges to implementation of this recommendation.

On the next page: References >>

REFERENCES
1. Kahn SR, Shapiro S, Wells PS, et al; SOX trial investigators. Compression stockings to ­prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383:880-888.

2. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149:698-707.

3. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996; 125:1-7.

4. Cohen JM, Akl EA, Kahn SR. Pharmacologic and compression therapies for postthrombotic syndrome: a systematic review of randomized controlled trials. Chest. 2012;141: 308-320.

5. Henke PK, Comerota AJ. An update on etiology, prevention, and therapy of postthrombotic syndrome. J Vasc Surg. 2011;53:
500-509.

6. Brandjes DP, Büller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997;349:
759-762.

7. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med. 2004;141:249-256.

8. Ginsberg JS, Hirsh J, Julian J, et al. Prevention and treatment of postphlebitic syndrome: results of a 3-part study. Arch Intern Med. 2001;161:2105-2109.

9. Villalta S, Bagatella P, Piccioli A, et al. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome. Haemostasis. 1994;24:158a.

10. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care. 1993;31:247-263.

11. Kahn SR, Lamping DL, Ducruet T, et al; VETO Study Investigators. VEINES-QOL/Sym questionnaire was a reliable and valid disease-specific quality of life measure for deep venous thrombosis. J Clin Epidemiol. 2006; 59:1049-1056.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(7):388-390.

PRACTICE CHANGER
Do not recommend elastic compression stockings to decrease the incidence of postthrombotic syndrome after deep vein thrombosis.¹

STRENGTH OF RECOMMENDATION
B: Based on a large randomized controlled trial¹

ILLUSTRATIVE CASE
A 56-year-old man presents to your clinic three days after receiving a diagnosis of lower extremity deep vein thrombosis (DVT). He was prescribed warfarin (5 mg/d) with enoxaparin bridging (120 mg/d). He has read about postthrombotic syndrome (PTS) online and is very concerned about this possible adverse effect. He asks about using elastic compression stockings (ECS). What should you tell him?

PTS can be a frustrating, debilitating condition. Its clinical features range from minor limb swelling to severe edema and pain, irreversible skin changes, and leg ulcerations.² It occurs in 25% to 50% of patients after DVT.³ Because current PTS treatments are not very effective, prevention is essential.^4,5

Patients are frequently encouraged to wear ECS after DVT to reduce the incidence of PTS by decreasing venous hypertension and reflux. These stockings are expensive and uncomfortable. Prior research suggested that use of ECS can reduce PTS incidence by half, but the studies were small, single-center, and not placebo-controlled.^6,7

On the next page: Study summary >> 

STUDY SUMMARY
RCT sets aside a common practice
Kahn et al¹ conducted a randomized, placebo-controlled trial of active versus placebo ECS in patients from 24 centers in the United States and Canada who’d had an ultrasound-confirmed proximal DVT (in the popliteal or more proximal deep leg vein) within the previous 14 days. Most patients received standard anticoagulation therapy to treat their DVT (five to 10 days of heparin and three to six months of warfarin). Patients were excluded if they had received thrombolytics, had arterial claudication, had a life expectancy of less than six months, were unable to put on ECS due to physical disabilities or allergy, or were unable to participate in follow-up visits.

Patients were randomly assigned to wear active (30 to 40 mm Hg graduated) ECS or identical-looking placebo ECS (< 5 mm Hg compression at the ankle) for two years. Providers, study personnel and statisticians, and patients were all blinded to treatment allocation. Patients were asked to wear the stocking on the affected leg each day from waking until bedtime.

Follow-up occurred at one, six, 12, 18, and 24 months. The primary outcome was cumulative incidence of PTS diagnosed at six months or later using the Ginsberg criteria of ipsilateral pain and swelling of at least one month’s duration.⁸ Secondary outcomes included severity of PTS, leg ulcers, recurrence of ­venous thromboembolism (VTE), death, adverse events, venous valvular reflux, and quality of life (QOL). Outcomes were measured objectively through use of a validated scale (the Villalta scale) for PTS severity and two questionnaires to assess QOL.^9-11

There were 409 patients in the ECS group and 394 in the placebo group. Baseline characteristics, including BMI, VTE risk factors, and anticoagulation treatment regimens, were similar between groups. The average age of participants in the study group was 55.4 years and in the placebo group, 54.8 years. Men comprised 62.4% of the active group and 57.9% of the placebo group. Approximately 90% of the participants in both groups were white.

At one month, approximately 95% of participants in both groups used the stockings; at 24 months, that was reduced to a little less than 70%. The percentage of people who used the stockings for at least three days per week was similar in both groups.

The cumulative incidence of PTS during follow-up was 14.2% in the active group and 12.7% in the placebo group (hazard ratio, 1.13). There were no differences in any of the secondary outcomes. Prespecified subgroup analyses found that age, BMI, and severity of DVT had no effect on outcomes. There was a marginal benefit for ECS for women versus men, but this does not likely reflect a true difference because the confidence intervals surrounding the hazard ratios for men and women overlapped and crossed the null value.

On the next page: What's new & challenges to implementation >>

WHAT’S NEW
New evidence contradicts ­previous studies
Two prior studies showed that using 30 to 40 mm Hg ECS decreased the incidence of PTS after proximal DVT.^6,7 However, these were smaller, open-label, single-center studies. This study by Kahn et al¹ was the first placebo-controlled, randomized, multicenter study that used validated instruments to measure PTS and QOL. It found no benefit in using ECS, thus contradicting the results of the prior studies.

There are currently no guidelines or consensus statements that recommend for or against the use of ECS after DVT.

CAVEATS
High nonadherence rates might have affected results
In both groups, adherence to the assigned intervention diminished throughout the study (from 95% at one month to slightly less than 70% at two years). Theoretically, this could have affected efficacy outcomes. However, the decrease was similar in both groups and represents what is observed in clinical practice. A prespecified per protocol analysis of patients who wore their ECS more regularly found no benefit.

It is possible that a “placebo effect” could explain the lack of difference between groups. However, the placebo stockings provided virtually no compression, and the two-year cumulative incidence of PTS in both the treatment and placebo groups was similar to that seen in control groups in prior studies.^6,7

Finally, the incidence of PTS in this study was much lower than the 25% to 50% incidence reported previously. Kahn et al¹ suggested that this was because they used more stringent and standardized criteria for PTS than was used in previous research.

CHALLENGES TO IMPLEMENTATION
There are no barriers to ending this practice
We can identify no challenges to implementation of this recommendation.

On the next page: References >>

REFERENCES
1. Kahn SR, Shapiro S, Wells PS, et al; SOX trial investigators. Compression stockings to ­prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383:880-888.

2. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149:698-707.

3. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996; 125:1-7.

4. Cohen JM, Akl EA, Kahn SR. Pharmacologic and compression therapies for postthrombotic syndrome: a systematic review of randomized controlled trials. Chest. 2012;141: 308-320.

5. Henke PK, Comerota AJ. An update on etiology, prevention, and therapy of postthrombotic syndrome. J Vasc Surg. 2011;53:
500-509.

6. Brandjes DP, Büller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997;349:
759-762.

7. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med. 2004;141:249-256.

8. Ginsberg JS, Hirsh J, Julian J, et al. Prevention and treatment of postphlebitic syndrome: results of a 3-part study. Arch Intern Med. 2001;161:2105-2109.

9. Villalta S, Bagatella P, Piccioli A, et al. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome. Haemostasis. 1994;24:158a.

10. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care. 1993;31:247-263.

11. Kahn SR, Lamping DL, Ducruet T, et al; VETO Study Investigators. VEINES-QOL/Sym questionnaire was a reliable and valid disease-specific quality of life measure for deep venous thrombosis. J Clin Epidemiol. 2006; 59:1049-1056.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(7):388-390.

Illustrative case

A 56-year-old man comes to your clinic 3 days after receiving a diagnosis of lower extremity deep vein thrombosis (DVT). He was prescribed warfarin, 5 mg/d, with enoxaparin bridging, 120 mg/d. He has read about post-thrombotic syndrome (PTS) online and is very concerned about this possible side effect. He is asking about using elastic compression stockings (ECS). What should you tell him?

PTS can be a frustrating, debilitating condition. Its clinical features range from minor limb swelling to severe edema and pain, irreversible skin changes, and leg ulcerations.² It occurs in 25% to 50% of patients after DVT.³ Because current PTS treatments are not very effective, prevention is essential.^4,5

Patients are frequently encouraged to wear ECS after DVT to reduce the incidence of PTS by reducing venous hypertension and reflux. These stockings are expensive and uncomfortable. Prior studies suggested that using ECS can cut the incidence of PTS in half.^6,7 However, these were small, single-center studies, and they were not placebo-controlled.^6,7

STUDY SUMMARY: RCT sets aside a common practice

Kahn et al¹ conducted a randomized, placebo-controlled trial of active vs placebo ECS in patients from 24 centers in the United States and Canada who’d had an ultrasound-confirmed proximal DVT (in the popliteal or more proximal deep leg vein) within the previous 14 days. Most patients received standard anticoagulation therapy to treat their DVT (5-10 days of heparin and 3-6 months of warfarin). Patients were excluded if they had received thrombolytics, had arterial claudication, had a life expectancy of <6 months, were unable to put on ECS due to physical disabilities or allergy, or were unable to participate in follow-up visits.

Patients were randomly assigned to wear active (30-40 mm Hg graduated) ECS or identical-looking placebo ECS with <5 mm Hg compression at the ankle for 2 years. Providers, study personnel and statisticians, and patients were all blinded to treatment allocation. Patients were asked to wear the stocking on the affected leg each day from when they woke until they went to bed.

Participants were followed at one, 6, 12, 18, and 24 months. The primary outcome was the cumulative incidence of PTS diagnosed at 6 months or later using Ginsberg’s criteria of ipsilateral pain and swelling of at least 1 month’s duration.⁸ Secondary outcomes included severity of PTS, presence of leg ulcers, recurrence of venous thromboembolism (VTE), death, adverse events, venous valvular reflux, and quality of life (QOL). Outcomes were measured objectively using a validated scale (the Villalta scale) for PTS severity and the 36-item Short Form Health Survey (SF-36) and the Venous Insufficiency Epidemiological and Economic Study Quality of Life (VEINES-QOL) questionnaire to measure QOL.^9-11

There were 409 patients in the ECS group and 394 in the placebo group. Baseline characteristics, including body mass index (BMI), VTE risk factors, and anticoagulation treatment regimens, were similar between groups. The average age was 55.4 years in the study group (standard deviation [SD] ± 15.3 years) and 54.8 years (SD ± 15.8 years) in the place- bo group. Men comprised 62.4% of the active group and 57.9% of the placebo group. Approximately 90% of the participants in both groups were white.

At one month, approximately 95% of participants in both the active and placebo groups used the stockings; at 24 months, a little less than 70% of the participants in both groups continued to use the stockings. The percentage of people who used the stockings for at least 3 days a week was similar across both groups.

The cumulative incidence of PTS during follow-up was 14.2% in the active group vs 12.7% in the placebo group, with a hazard ratio of 1.13 (95% confidence interval [CI], .73-1.76; P=.58). There were no differences in any of the secondary outcomes. Prespecified subgroup analyses found that age, BMI, and severity of DVT had no effect on the outcomes. There was a marginal benefit for ECS for women (P=.047) over men, but this does not likely reflect a true difference because the CIs surrounding the hazard ratios for men and women overlapped and crossed the null value.

WHAT'S NEW: New evidence contradicts previous studies

This placebo-controlled randomized trial found no benefit in using compression stockings to prevent post-thrombotic syndrome.

Two prior studies showed that using 30 to 40 mm Hg ECS decreased the incidence of PTS after proximal DVT.^6,7 However, these were smaller, open-label, single-center studies. This study by Kahn et al¹ was the first placebo-controlled, randomized, multicenter study that used validated instruments to measure PTS and QOL. It found no benefit in using ECS, thus contradicting the results of the prior studies.

There are currently no guidelines or consensus statements for or against the use of ECS after DVT.

CAVEATS: High nonadherence rates might have affected the results

In both groups, adherence to the assigned intervention diminished throughout the study. Overall, approximately 95% of patients reported wearing their stockings at one month; this dropped to just under 70% by 2 years. Theoretically, this could have affected efficacy outcomes. However, the decrease was similar in both groups and represents what is observed in clinical practice. A prespecified per protocol analysis of patients who wore their ECS more regularly found no benefit.

It is possible that a “placebo effect” could explain the lack of difference between groups. However, the placebo stockings provided virtually no compression, and the 2-year cumulative incidence of PTS in both the treatment and placebo groups was similar to that seen in control groups in prior studies.^6,7

Finally, the incidence of PTS in this study was much lower than the 25% to 50% incidence reported in previous studies. Kahn et al¹ suggested that this was because they used more stringent and standardized criteria for PTS than was used in previous research.

CHALLENGES TO IMPLEMENTATION: There are no barriers to ending this practice

We see no challenges to implementation of this recommendation.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 56-year-old man comes to your clinic 3 days after receiving a diagnosis of lower extremity deep vein thrombosis (DVT). He was prescribed warfarin, 5 mg/d, with enoxaparin bridging, 120 mg/d. He has read about post-thrombotic syndrome (PTS) online and is very concerned about this possible side effect. He is asking about using elastic compression stockings (ECS). What should you tell him?

PTS can be a frustrating, debilitating condition. Its clinical features range from minor limb swelling to severe edema and pain, irreversible skin changes, and leg ulcerations.² It occurs in 25% to 50% of patients after DVT.³ Because current PTS treatments are not very effective, prevention is essential.^4,5

Patients are frequently encouraged to wear ECS after DVT to reduce the incidence of PTS by reducing venous hypertension and reflux. These stockings are expensive and uncomfortable. Prior studies suggested that using ECS can cut the incidence of PTS in half.^6,7 However, these were small, single-center studies, and they were not placebo-controlled.^6,7

STUDY SUMMARY: RCT sets aside a common practice

Kahn et al¹ conducted a randomized, placebo-controlled trial of active vs placebo ECS in patients from 24 centers in the United States and Canada who’d had an ultrasound-confirmed proximal DVT (in the popliteal or more proximal deep leg vein) within the previous 14 days. Most patients received standard anticoagulation therapy to treat their DVT (5-10 days of heparin and 3-6 months of warfarin). Patients were excluded if they had received thrombolytics, had arterial claudication, had a life expectancy of <6 months, were unable to put on ECS due to physical disabilities or allergy, or were unable to participate in follow-up visits.

Patients were randomly assigned to wear active (30-40 mm Hg graduated) ECS or identical-looking placebo ECS with <5 mm Hg compression at the ankle for 2 years. Providers, study personnel and statisticians, and patients were all blinded to treatment allocation. Patients were asked to wear the stocking on the affected leg each day from when they woke until they went to bed.

Participants were followed at one, 6, 12, 18, and 24 months. The primary outcome was the cumulative incidence of PTS diagnosed at 6 months or later using Ginsberg’s criteria of ipsilateral pain and swelling of at least 1 month’s duration.⁸ Secondary outcomes included severity of PTS, presence of leg ulcers, recurrence of venous thromboembolism (VTE), death, adverse events, venous valvular reflux, and quality of life (QOL). Outcomes were measured objectively using a validated scale (the Villalta scale) for PTS severity and the 36-item Short Form Health Survey (SF-36) and the Venous Insufficiency Epidemiological and Economic Study Quality of Life (VEINES-QOL) questionnaire to measure QOL.^9-11

There were 409 patients in the ECS group and 394 in the placebo group. Baseline characteristics, including body mass index (BMI), VTE risk factors, and anticoagulation treatment regimens, were similar between groups. The average age was 55.4 years in the study group (standard deviation [SD] ± 15.3 years) and 54.8 years (SD ± 15.8 years) in the place- bo group. Men comprised 62.4% of the active group and 57.9% of the placebo group. Approximately 90% of the participants in both groups were white.

At one month, approximately 95% of participants in both the active and placebo groups used the stockings; at 24 months, a little less than 70% of the participants in both groups continued to use the stockings. The percentage of people who used the stockings for at least 3 days a week was similar across both groups.

The cumulative incidence of PTS during follow-up was 14.2% in the active group vs 12.7% in the placebo group, with a hazard ratio of 1.13 (95% confidence interval [CI], .73-1.76; P=.58). There were no differences in any of the secondary outcomes. Prespecified subgroup analyses found that age, BMI, and severity of DVT had no effect on the outcomes. There was a marginal benefit for ECS for women (P=.047) over men, but this does not likely reflect a true difference because the CIs surrounding the hazard ratios for men and women overlapped and crossed the null value.

WHAT'S NEW: New evidence contradicts previous studies

This placebo-controlled randomized trial found no benefit in using compression stockings to prevent post-thrombotic syndrome.

Two prior studies showed that using 30 to 40 mm Hg ECS decreased the incidence of PTS after proximal DVT.^6,7 However, these were smaller, open-label, single-center studies. This study by Kahn et al¹ was the first placebo-controlled, randomized, multicenter study that used validated instruments to measure PTS and QOL. It found no benefit in using ECS, thus contradicting the results of the prior studies.

There are currently no guidelines or consensus statements for or against the use of ECS after DVT.

CAVEATS: High nonadherence rates might have affected the results

In both groups, adherence to the assigned intervention diminished throughout the study. Overall, approximately 95% of patients reported wearing their stockings at one month; this dropped to just under 70% by 2 years. Theoretically, this could have affected efficacy outcomes. However, the decrease was similar in both groups and represents what is observed in clinical practice. A prespecified per protocol analysis of patients who wore their ECS more regularly found no benefit.

It is possible that a “placebo effect” could explain the lack of difference between groups. However, the placebo stockings provided virtually no compression, and the 2-year cumulative incidence of PTS in both the treatment and placebo groups was similar to that seen in control groups in prior studies.^6,7

Finally, the incidence of PTS in this study was much lower than the 25% to 50% incidence reported in previous studies. Kahn et al¹ suggested that this was because they used more stringent and standardized criteria for PTS than was used in previous research.

CHALLENGES TO IMPLEMENTATION: There are no barriers to ending this practice

We see no challenges to implementation of this recommendation.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 56-year-old man comes to your clinic 3 days after receiving a diagnosis of lower extremity deep vein thrombosis (DVT). He was prescribed warfarin, 5 mg/d, with enoxaparin bridging, 120 mg/d. He has read about post-thrombotic syndrome (PTS) online and is very concerned about this possible side effect. He is asking about using elastic compression stockings (ECS). What should you tell him?

PTS can be a frustrating, debilitating condition. Its clinical features range from minor limb swelling to severe edema and pain, irreversible skin changes, and leg ulcerations.² It occurs in 25% to 50% of patients after DVT.³ Because current PTS treatments are not very effective, prevention is essential.^4,5

Patients are frequently encouraged to wear ECS after DVT to reduce the incidence of PTS by reducing venous hypertension and reflux. These stockings are expensive and uncomfortable. Prior studies suggested that using ECS can cut the incidence of PTS in half.^6,7 However, these were small, single-center studies, and they were not placebo-controlled.^6,7

STUDY SUMMARY: RCT sets aside a common practice

Kahn et al¹ conducted a randomized, placebo-controlled trial of active vs placebo ECS in patients from 24 centers in the United States and Canada who’d had an ultrasound-confirmed proximal DVT (in the popliteal or more proximal deep leg vein) within the previous 14 days. Most patients received standard anticoagulation therapy to treat their DVT (5-10 days of heparin and 3-6 months of warfarin). Patients were excluded if they had received thrombolytics, had arterial claudication, had a life expectancy of <6 months, were unable to put on ECS due to physical disabilities or allergy, or were unable to participate in follow-up visits.

Patients were randomly assigned to wear active (30-40 mm Hg graduated) ECS or identical-looking placebo ECS with <5 mm Hg compression at the ankle for 2 years. Providers, study personnel and statisticians, and patients were all blinded to treatment allocation. Patients were asked to wear the stocking on the affected leg each day from when they woke until they went to bed.

Participants were followed at one, 6, 12, 18, and 24 months. The primary outcome was the cumulative incidence of PTS diagnosed at 6 months or later using Ginsberg’s criteria of ipsilateral pain and swelling of at least 1 month’s duration.⁸ Secondary outcomes included severity of PTS, presence of leg ulcers, recurrence of venous thromboembolism (VTE), death, adverse events, venous valvular reflux, and quality of life (QOL). Outcomes were measured objectively using a validated scale (the Villalta scale) for PTS severity and the 36-item Short Form Health Survey (SF-36) and the Venous Insufficiency Epidemiological and Economic Study Quality of Life (VEINES-QOL) questionnaire to measure QOL.^9-11

There were 409 patients in the ECS group and 394 in the placebo group. Baseline characteristics, including body mass index (BMI), VTE risk factors, and anticoagulation treatment regimens, were similar between groups. The average age was 55.4 years in the study group (standard deviation [SD] ± 15.3 years) and 54.8 years (SD ± 15.8 years) in the place- bo group. Men comprised 62.4% of the active group and 57.9% of the placebo group. Approximately 90% of the participants in both groups were white.

At one month, approximately 95% of participants in both the active and placebo groups used the stockings; at 24 months, a little less than 70% of the participants in both groups continued to use the stockings. The percentage of people who used the stockings for at least 3 days a week was similar across both groups.

The cumulative incidence of PTS during follow-up was 14.2% in the active group vs 12.7% in the placebo group, with a hazard ratio of 1.13 (95% confidence interval [CI], .73-1.76; P=.58). There were no differences in any of the secondary outcomes. Prespecified subgroup analyses found that age, BMI, and severity of DVT had no effect on the outcomes. There was a marginal benefit for ECS for women (P=.047) over men, but this does not likely reflect a true difference because the CIs surrounding the hazard ratios for men and women overlapped and crossed the null value.

WHAT'S NEW: New evidence contradicts previous studies

This placebo-controlled randomized trial found no benefit in using compression stockings to prevent post-thrombotic syndrome.

Two prior studies showed that using 30 to 40 mm Hg ECS decreased the incidence of PTS after proximal DVT.^6,7 However, these were smaller, open-label, single-center studies. This study by Kahn et al¹ was the first placebo-controlled, randomized, multicenter study that used validated instruments to measure PTS and QOL. It found no benefit in using ECS, thus contradicting the results of the prior studies.

There are currently no guidelines or consensus statements for or against the use of ECS after DVT.

CAVEATS: High nonadherence rates might have affected the results

In both groups, adherence to the assigned intervention diminished throughout the study. Overall, approximately 95% of patients reported wearing their stockings at one month; this dropped to just under 70% by 2 years. Theoretically, this could have affected efficacy outcomes. However, the decrease was similar in both groups and represents what is observed in clinical practice. A prespecified per protocol analysis of patients who wore their ECS more regularly found no benefit.

It is possible that a “placebo effect” could explain the lack of difference between groups. However, the placebo stockings provided virtually no compression, and the 2-year cumulative incidence of PTS in both the treatment and placebo groups was similar to that seen in control groups in prior studies.^6,7

Finally, the incidence of PTS in this study was much lower than the 25% to 50% incidence reported in previous studies. Kahn et al¹ suggested that this was because they used more stringent and standardized criteria for PTS than was used in previous research.

CHALLENGES TO IMPLEMENTATION: There are no barriers to ending this practice

We see no challenges to implementation of this recommendation.

Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.