New Heart Failure Clinical Trial
abstract & commentary
Synopsis: The results of CIBIS-II were reported at the Second Annual Scientific Meeting of the Heart Failure Society of America that should influence physician practice in the care of patients with left ventricular dysfunction and heart failure.
Source: The Second Annual Scientific Meeting of the Heart Failure Society of America, Boca Raton, FL. September 13-16, 1998.
This important trial evaluated the effects of bisoprolol, a selective beta 1 beta-blocker, in patients with heart failure. The trial was stopped prematurely at the second interim analysis because of positive results in the beta blocker arm. Approximately 2600 patients from throughout Europe with Class III or IV congestive heart failure were slowly up-titrated with bisoprolol or placebo over a period of several months. All were on an angiotensin converting enzyme (ACE) inhibitor and diuretics. Entry criteria included an ejection fraction (EF) of less than 35%; 16% of the patients were Class IV. Eighty percent were male, and more than 50% had coronary artery disease. The primary end point was all-cause mortality; a variety of traditional secondary end points were assessed. At the time the trial was stopped, all-cause mortality had decreased in the beta blocker group by 32% (P = 0.0005); death rates were 17.3% placebo vs. 11.8% bisoprolol, with a rate of 12% per year in the placebo arm and 8.2% in the beta blocker cohort. Average follow-up at trial cessation was 1.4 years. There was a 45% decrease in sudden death and a slight favorable trend in deaths from heart failure or unknown causes. There were no significant differences in outcome in subjects with an ischemic etiology (50% reduction in deaths) or different functional class. Total and heart failure hospitalizations were decreased in the beta blocker group. Virtually all secondary end points were positively affected, including in-hospital deaths. Withdrawal rates were 15% for both placebo and bisoprolol. In summary, CIBIS-2 resulted in a 32% reduction in all-cause mortality, 45% reduction in sudden death, 30% reduction in hospitalization for CHF, and 15% reduction in all-cause hospitalization. No significant adverse reactions occurred. The authors conclude that only 25 patients would need to be treated with bisoprolol to save one life.
COMMENT BY JONATHAN ABRAMS, MD
This important study confirms recent meta-analysis (Circulation, 1998;98:1184) demonstrating an advantage in death or heart failure hospitalization as well as EF in more than 3000 patients receiving a beta blocker who have congestive heart failure. While the mortality rates in CIBIS II suggest that these patients may have been less sick than traditional Class III-IV classification, the data are concordant with the recent carvedilol studies as well as outcomes in a number of small beta blocker trials. Thus, it would appear that all patients who have congestive heart failure with substantial depression of EF should be given a beta blocker unless there are contra-indications. Certainly, this is an attractive policy for stable Class II-III subjects. The question as to whether selective, non-selective, or vasodilator-beta blockers are superior is unresolved and awaits the results of ongoing trials (BEST, COMET, COPERNICUS). Recently, the MERIT-HT study was stopped because of a major benefit of long-acting metoprolol in 4000 cases of II-IV subjects with an EF less than 40%. The data are not available yet, but this study, along with CIBIS II and the carvedilol trials, underscores that beta blockers clearly increase survival in heart failure with impaired LV systolic function. (Dr. Abrams is Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque.)