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Source: CIBIS-II Investigators and Committees. Lancet 1999; 353:9-13.
Cibis-ii, the second cardiac insufficiency Bisoprolol Study, is the largest published trial supporting a robust benefit of beta blockers in patients with advanced heart failure. The study cohort consisted of 2647 patients from 18 countries in Western and Eastern Europe who had class III or IV heart failure and an ejection fraction of less than 35%, all on an ACE inhibitor and diuretic, who were randomized to bisoprolol or placebo. All patients were symptomatic from chronic heart failure. Active coronary artery disease or uncontrolled hypertension were among the exclusion criteria. There was no run-in period. All subjects were on a diuretic and an ACE inhibitor. Patients were started on bisoprolol 1.25 mg; the dose was increased incrementally to a target of 10 mg daily. The trial primary end point was all-cause mortality. Multiple secondary end points were assessed, including hospital admissions, cardiovascular mortality, and a combined end point of death and hospital admission. Sudden death was carefully defined.
The following results occurred. The study was stopped prematurely because of a significantly lower all-cause mortality in the bisoprolol cohort (P < 0.0001), 11.8% bisoprolol vs. 17.3% placebo (risk reduction, 34%). The mean follow-up was only 1.3 years. Bisoprolol patients also had significantly fewer hospitalizations and fewer cardiovascular deaths. Withdrawal from therapy was equal (15%) in beta blockers and placebo patients. No differences in outcome were noted between ischemic and cardiomyopathic heart failure. Sudden death was 42% less with bisoprolol (P = 0.001); admissions for ventricular arrythmias were less with bisoprolol.
The CIBIS investigators conclude that bisoprolol is effective in advanced heart failure, and they point out that the existing database supporting beta blocker therapy is quite robust. The carvedilol trials, MERIT-HF, and the CIBIS-II are convincing about the efficacy of these agents. An antiarrhythmic effect of bisoprolol was suggested by the large decrease in sudden death as well as lower rates of ventricular tachycardia or fibrillation. LV function was not measured at follow-up, but in the initial CIBIS study, a better prognosis was concordant with improved Left ventricular (LV) ejection fraction. Finally, the CIBIS investigators discuss the view of many experts that nonselective beta blockers may be better than beta-one selective agents, although the strongly positive results of this trial as well as the recent MERIT-HF study (metoprolol), clearly indicate that predominant beta-one selectivity also infers substantial treatment benefit in heart failure.
I agree with the CIBIS investigators that "the addition of a beta-blocker to standard therapy can be recommended in appropriate stable ambulatory patients who have heart failure caused by impaired LV systolic function." As of this writing, it is uncertain as to whether one agent is better than another; carvedilol is an alpha and beta nonselective drug with vasodilating and antioxidant properties; metoprolol is beta-one selective, as is bisoprolol. Ongoing comparative trials, such as COMET, may or may not show important differences among these agents. In my view, the beta blocker story parallels the early years of ACE inhibitors for heart failure, when "only specialists" used these agents. Widespread therapy for CHF with beta blockers is not yet a reality; this approach will involve a major change in current clinical practice. Americans tend to underuse beta blockers postmyocardial infarction, and their use in heart failure appears to be limited, although perhaps growing. This CIBIS II study provides considerable reassurance and "proof of principle" that beta adrenergic antagonism is beneficial in heart failure, improving both morbidity and mortality.
Dr. Abrams is a Professor of Medicine in the Division of Cardiology, University of New Mexico, Albuquerque.