Elsevier

The Lancet

Volume 353, Issue 9146, 2 January 1999, Pages 9-13
The Lancet

Articles
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial*

https://doi.org/10.1016/S0140-6736(98)11181-9Get rights and content

Summary

Background

In patients with heart failure, β-blockade has improved morbidity and left-ventricular function, but the impact on survival is uncertain. We investigated the efficacy of bisoprolol, a β, selective adrenoceptor blocker in decreasing all-cause mortality in chronic heart failure.

Methods

In a multicentre double-blind randomised placebo-controlled trial in Europe, we enrolled 2647 symptomatic patients in New York Heart Association class III or IV, with left-ventricular ejection fraction of 35% or less receiving standard therapy with diuretics and inhibitors of angiotensin-converting enzyme. We randomly assigned patients bisoprolol 1·25 mg (n=1327) or placebo (n=1320) daily, the drug being progressively increased to a maximum of 10 mg per day. Patients were followed up for a mean of 1·3 years. Analysis was by intention to treat.

Findings

CIBIS-II was stopped early, after the second interim analysis, because bisoprolol showed a significant mortality benefit. All-cause mortality was significantly lower with bisoprolol than on placebo (156 [11·8%] vs 228 [17·3%] deaths with a hazard ratio of 0·66 (95% CI 0·54–0·81, p<0·0001). There were significantly fewer sudden deaths among patients on bisoprolol than in those on placebo (48 [3·6%] vs 83 [6·3%] deaths), with a hazard ratio of 0·56 (0·39–0·80, p=0·0011). Treatment effects were independent of the severity or cause of heart failure.

Interpretation

β-blocker therapy had benefits for survival in stable heart-failure patients. Results should not, however, be extrapolated to patients with severe class IV symptoms and recent instability because safety and efficacy has not been established in these patients.

Introduction

Experimental and clinical trials have shown beneficial effects with β-blockade in heart failure.1, 2, 3 There is reluctance to use β-blockade therapy, however, and unequivocal evidence of benefit from randomised placebo controlled trials is needed to convince the medical community of its safety and efficacy.

Clinical trials in heart failure have tested compounds with different pharmacological profiles.2, 3 Meta-analyses of placebo-controlled trials of β-blockers have suggested an overall effect on mortality of 32%.4, 5, 6 The Cardiac Insufficiency Bisoprolol Study (CIBIS) studied bisoprolol, a highly selective antagonist of β1, adrenoceptors, which are found mainly in the heart and especially in ventricular tissue.7 That trial showed a non-significant trend towards 20% lower mortality in the bisoprolol group and 30% fewer admissions to hospital for worsening heart failure.8 We designed the CIBIS-II trial to test this evidence further, based on the CIBIS trial results.

Section snippets

Methods

The study design and protocol of CIBIS has been published.9 We did a double-blind placebo-controlled randomised trial, analysed by intention to treat.

Results

2647 patients were enrolled into the study and followed up for a mean of 1·3 years. Baseline characteristics were similar in the two groups (table 1).

The trial was stopped early because all-cause mortality was significantly less in the bisoprolol group than in the placebo group (figure 1). In the bisoprolol group, 156 (11·8%) patients died, compared with 228 (17·3%) in the placebo group (p<0·0001). The estimated annual mortality rate was 8·8% in the bisoprolol group and 13·2% in the placebo

Discussion

β-blockade had benefits for all-cause mortality in patients with chronic heart failure. Benefits were also seen for morbidity, assessed by admissions to hospital for all causes, especially for worsening heart failure.

The magnitude of the treatment effect (a 32% lower risk of mortality and admission to hospital for heart failure) is in accordance with findings from meta-analyses of previous randomised placebo-controlled trials.4 Our results were obtained in patients already taking diuretics and

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