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, M. et al. (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, 5(5), pp. 317-326. (doi: 10.1016/j.jchf.2017.02.021) (PMID:28449795)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Petrie, Professor Mark and McMurray, Professor John
Authors: Packer, M., McMurray, J. J.V., Krum, H., Kiowski, W., Massie, B. M., Caspi, A., Pratt, C. M., Petrie, M. C., 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, H.-G., Werdan, K., Klein, H., Staffeld, F., Zeiher, A.M., Roediger, C., Caspi, A., Marmor, A., Reisin, L., Vered, Z., Klainman, E., Roguin, N., Tzivoni, D., David, D., Lewis, B., Abinader, E., Omary, M., Rosenman, Y., Kaluski, E., Breedveld, R.W., van der Burgh, P.H., Dunselman, P.H.J.M., Schaafsma, H.J., Hertzberger, D.P., Holwerda, N.J., Kragten, J.A., van Wijngaarden, J., Posma, J.L., Said, S.A.M., Slegers, L.C., Tjon Joe Gin, R.M., Wempe, F.N., Wesdorp, J.C.L., Willems, A.R., Withagen, A.J.A.M., Cornel, J.M., van Kempen, L.H.J., Kiowski, W., Bertel, O., Moccetti, T., McMurray, J.J.V., Greenbaum, R.A., Bennett, P., Swan, J., Davies, G., Findlay, I., Gould, B., Ball, S., Hubner, P., Lahiri, A., McLay, J., Northcote, R., Saltissi, S., Squire, I., Stephens, J., Stewart, M., Bridgen, G., Walsh, J., Webb, D.J., Ansari, Z., Baron, S., Bellinger, R., Bennet, W., Benvenuti, D., Dawley, D., Egbujiobi, L.C., Eisenstein, I., Little, T., Hertsberg, A., Greenspan, M., Grossman, R.J., Hanley, P., Jesrani, M., Kashou, H., Levites, R., Malik, R., Marmorstein, B., Schwartz, M., Nisar, A., Perelman, R., Schwarz, M.L., Sedlis, S., Srebro, J., Taveras, M., Weiss, R., Weitzman, P., Wetherley, G.K., El Shahawy, M., Kereiakes, D., Campos, L., Peterson, G., Small, R.S., Davis, W.R., Olivari, M.-T., Meengs, W., Koren, M., Slagona, P., Jennison, S., Hershberger, R., Browne, K.F., Farnham, D.J., Zelenkofske, S., Lawless, C., Nathan, M., Meyer, T., Kukin, M., Parekh, H., Berkowitz, R., Boehmer, J., Brozena, S., Dandona, P., Dec, G.W., DeQuattro, V., Fenster, P., Fowler, M., Ellaham, S., Geller, M., Gheorgiade, M., Ghali, J., Murali, S., Katz, S., Bott-Silverman, C., Singh, B., Thadani, U., Torre, G., Teerlink, J., Chandraratna, T., Kesselbrenner, M., Mukherjee, A., Che-Pin Tsai, C., Abbo, K., Goldberg, M., Smith, T., and Martin, R.T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:JACC: Heart Failure
Publisher:Elsevier
ISSN:2213-1779
ISSN (Online):2213-1787
Published Online:24 April 2017

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