Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the ENABLE Trials

Milton Packer, John J.V. McMurray, Henry Krum, Wolfgang Kiowski, Barry M. Massie, Avi Caspi, Craig M. Pratt, Mark C. Petrie, David DeMets, Isaac Kobrin, Sebastien Roux, Karl Swedberg, Milton Packer, Avi Caspi, Wolfgang Kiowski, Henry Krum, Craig Pratt, Karl Swedberg, Barry Massie, John McMurrayJohn McMurray, Eugene Connally, Mark Petrie, David DeMets, Susan Anderson, Jody Barnet, Robert Cody, Henry Dargie, Gary Francis, Barry Greenberg, Juerg Reichen, J. Karrasch, H. Krum, J. Horowitz, J. Amerena, A. Sindone, P. MacDonald, I. Jeffrey, I. Button, E. DeAngelis, R. Pacher, R. Davies, F. McAlister, P. Tanser, B. Sussex, G. Baumann, E. Fleck, H. G. Olbrich, K. Werdan, H. Klein, on behalf of the, ENABLE Investigators and Committees, ENABLE Investigators and Committees

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Objectives The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure. Background Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking. Methods In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction <35% to receive placebo or bosentan (target dose 125 mg twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or hospitalization for heart failure. Results Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure. Conclusions Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.

Original languageEnglish (US)
Pages (from-to)317-326
Number of pages10
JournalJACC: Heart Failure
Volume5
Issue number5
DOIs
StatePublished - May 1 2017

Fingerprint

Endothelin Receptors
Heart Failure
Morbidity
Mortality
Placebos
Clinical Trials
Confidence Intervals
End Stage Liver Disease
bosentan
Endothelins
Transaminases
Natural History
Diuretics
Weight Gain
Cause of Death
Edema
Hemoglobins
Hospitalization
Liver

Keywords

  • bosentan
  • clinical trial
  • endothelin
  • heart failure
  • placebo

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure : Primary Results of the ENABLE Trials. / Packer, Milton; McMurray, John J.V.; Krum, Henry; Kiowski, Wolfgang; Massie, Barry M.; Caspi, Avi; Pratt, Craig M.; Petrie, Mark C.; DeMets, David; Kobrin, Isaac; Roux, Sebastien; Swedberg, Karl; Packer, Milton; Caspi, Avi; Kiowski, Wolfgang; Krum, Henry; Pratt, Craig; Swedberg, Karl; Massie, Barry; McMurray, John; McMurray, John; Connally, Eugene; Petrie, Mark; DeMets, David; Anderson, Susan; Barnet, Jody; Cody, Robert; Dargie, Henry; Francis, Gary; Greenberg, Barry; Reichen, Juerg; Karrasch, J.; Krum, H.; Horowitz, J.; Amerena, J.; Sindone, A.; MacDonald, P.; Jeffrey, I.; Button, I.; DeAngelis, E.; Pacher, R.; Davies, R.; McAlister, F.; Tanser, P.; Sussex, B.; Baumann, G.; Fleck, E.; Olbrich, H. G.; Werdan, K.; Klein, H.; on behalf of the; ENABLE Investigators and Committees; ENABLE Investigators and Committees.

In: JACC: Heart Failure, Vol. 5, No. 5, 01.05.2017, p. 317-326.

Research output: Contribution to journalArticle

Packer, M, McMurray, JJV, Krum, H, Kiowski, W, Massie, BM, Caspi, A, Pratt, CM, Petrie, MC, DeMets, D, Kobrin, I, Roux, S, Swedberg, K, Packer, M, Caspi, A, Kiowski, W, Krum, H, Pratt, C, Swedberg, K, Massie, B, McMurray, J, McMurray, J, Connally, E, Petrie, M, DeMets, D, Anderson, S, Barnet, J, Cody, R, Dargie, H, Francis, G, Greenberg, B, Reichen, J, Karrasch, J, Krum, H, Horowitz, J, Amerena, J, Sindone, A, MacDonald, P, Jeffrey, I, Button, I, DeAngelis, E, Pacher, R, Davies, R, McAlister, F, Tanser, P, Sussex, B, Baumann, G, Fleck, E, Olbrich, HG, Werdan, K, Klein, H, on behalf of the, ENABLE Investigators and Committees & ENABLE Investigators and Committees 2017, 'Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the ENABLE Trials', JACC: Heart Failure, vol. 5, no. 5, pp. 317-326. https://doi.org/10.1016/j.jchf.2017.02.021
Packer, Milton ; McMurray, John J.V. ; Krum, Henry ; Kiowski, Wolfgang ; Massie, Barry M. ; Caspi, Avi ; Pratt, Craig M. ; Petrie, Mark C. ; DeMets, David ; Kobrin, Isaac ; Roux, Sebastien ; Swedberg, Karl ; Packer, Milton ; Caspi, Avi ; Kiowski, Wolfgang ; Krum, Henry ; Pratt, Craig ; Swedberg, Karl ; Massie, Barry ; McMurray, John ; McMurray, John ; Connally, Eugene ; Petrie, Mark ; DeMets, David ; Anderson, Susan ; Barnet, Jody ; Cody, Robert ; Dargie, Henry ; Francis, Gary ; Greenberg, Barry ; Reichen, Juerg ; Karrasch, J. ; Krum, H. ; Horowitz, J. ; Amerena, J. ; Sindone, A. ; MacDonald, P. ; Jeffrey, I. ; Button, I. ; DeAngelis, E. ; Pacher, R. ; Davies, R. ; McAlister, F. ; Tanser, P. ; Sussex, B. ; Baumann, G. ; Fleck, E. ; Olbrich, H. G. ; Werdan, K. ; Klein, H. ; on behalf of the ; ENABLE Investigators and Committees ; ENABLE Investigators and Committees. / Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure : Primary Results of the ENABLE Trials. In: JACC: Heart Failure. 2017 ; Vol. 5, No. 5. pp. 317-326.
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abstract = "Objectives The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure. Background Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking. Methods In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction <35{\%} to receive placebo or bosentan (target dose 125 mg twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or hospitalization for heart failure. Results Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95{\%} confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95{\%} CI: 0.75 to 1.16). About 10{\%} of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure. Conclusions Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.",
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author = "Milton Packer and McMurray, {John J.V.} and Henry Krum and Wolfgang Kiowski and Massie, {Barry M.} and Avi Caspi and Pratt, {Craig M.} and Petrie, {Mark C.} and David DeMets and Isaac Kobrin and Sebastien Roux and Karl Swedberg and Milton Packer and Avi Caspi and Wolfgang Kiowski and Henry Krum and Craig Pratt and Karl Swedberg and Barry Massie and John McMurray and John McMurray and Eugene Connally and Mark Petrie and David DeMets and Susan Anderson and Jody Barnet and Robert Cody and Henry Dargie and Gary Francis and Barry Greenberg and Juerg Reichen and J. Karrasch and H. Krum and J. Horowitz and J. Amerena and A. Sindone and P. MacDonald and I. Jeffrey and I. Button and E. DeAngelis and R. Pacher and R. Davies and F. McAlister and P. Tanser and B. Sussex and G. Baumann and E. Fleck and Olbrich, {H. G.} and K. Werdan and H. Klein and {on behalf of the} and {ENABLE Investigators and Committees} and {ENABLE Investigators and Committees}",
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TY - JOUR

T1 - Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure

T2 - Primary Results of the ENABLE Trials

AU - Packer, Milton

AU - McMurray, John J.V.

AU - Krum, Henry

AU - Kiowski, Wolfgang

AU - Massie, Barry M.

AU - Caspi, Avi

AU - Pratt, Craig M.

AU - Petrie, Mark C.

AU - DeMets, David

AU - Kobrin, Isaac

AU - Roux, Sebastien

AU - Swedberg, Karl

AU - Packer, Milton

AU - Caspi, Avi

AU - Kiowski, Wolfgang

AU - Krum, Henry

AU - Pratt, Craig

AU - Swedberg, Karl

AU - Massie, Barry

AU - McMurray, John

AU - McMurray, John

AU - Connally, Eugene

AU - Petrie, Mark

AU - DeMets, David

AU - Anderson, Susan

AU - Barnet, Jody

AU - Cody, Robert

AU - Dargie, Henry

AU - Francis, Gary

AU - Greenberg, Barry

AU - Reichen, Juerg

AU - Karrasch, J.

AU - Krum, H.

AU - Horowitz, J.

AU - Amerena, J.

AU - Sindone, A.

AU - MacDonald, P.

AU - Jeffrey, I.

AU - Button, I.

AU - DeAngelis, E.

AU - Pacher, R.

AU - Davies, R.

AU - McAlister, F.

AU - Tanser, P.

AU - Sussex, B.

AU - Baumann, G.

AU - Fleck, E.

AU - Olbrich, H. G.

AU - Werdan, K.

AU - Klein, H.

AU - on behalf of the

AU - ENABLE Investigators and Committees

AU - ENABLE Investigators and Committees

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Objectives The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure. Background Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking. Methods In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction <35% to receive placebo or bosentan (target dose 125 mg twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or hospitalization for heart failure. Results Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure. Conclusions Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.

AB - Objectives The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure. Background Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking. Methods In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction <35% to receive placebo or bosentan (target dose 125 mg twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or hospitalization for heart failure. Results Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure. Conclusions Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.

KW - bosentan

KW - clinical trial

KW - endothelin

KW - heart failure

KW - placebo

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