Beta-blockers for Heart Failure With Reduced, Mid-range, and Preserved Ejection Fraction

An Individual Patient-level Analysis of Double-blind Randomized Trials

John G.F. Cleland; Karina V. Bunting; Marcus D. Flather; Douglas G. Altman; Jane Holmes; Andrew J.S. Coats; Luis Manzano; John J.V. McMurray; Frank Ruschitzka; Dirk J. van Veldhuisen; Thomas G. von Lueder; Michael Böhm; Bert Andersson; John Kjekshus; Milton Packer; Alan S. Rigby; Giuseppe Rosano; HansWedel; A° ke Hjalmarson; John Wikstrand; Dipak Kotecha


Eur Heart J. 2018;39(1):26-35. 

In This Article

Abstract and Introduction


Aims Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40–49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials.

Methods and results Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm ( NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21–33%), including 575 patients with LVEF 40–49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40–49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34–1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24–0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when < 50% at baseline, but did not improve prognosis.

Conclusion Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF < 40%, but similar benefit was observed in the subgroup of patients with LVEF 40–49%.


Double-blind, randomized, placebo-controlled trials (RCTs) show that beta-blockers increase left ventricular ejection fraction (LVEF) and reduce morbidity and mortality for a broad range of patients with a reduced LVEF in sinus rhythm.[1,2] Until recently, international guidelines on heart failure have recognized two left ventricular phenotypes; heart failure with reduced LVEF (HFrEF) or preserved LVEF (HFpEF).[3,4] Values for LVEF are continuously distributed but measurement precision is imperfect; differences of up to 10% for an individual patient may be attributed to measurement error[5] and therefore precise cut-points of LVEF cannot reliably differentiate between phenotypes. Recently, the European Society of Cardiology (ESC) suggested there should be a third intermediate phenotype, called mid-range ejection fraction (HFmrEF; 40–49%), thereby creating a clear separation between HFrEF (<40%) and HFpEF (≥50%).[4] These guidelines suggest that until more information becomes available, patients with HFmrEF should be managed similarly to those with HFpEF, for which no therapy has been shown to improve mortality.[4]

The Beta-blockers in Heart Failure Collaborative Group (BB-meta-HF) was created to pool individual patient data (IPD) from the major heart failure RCTs comparing beta-blockers and placebo to address key issues in relevant patient subgroups.[6] Most, but not all of these trials recruited patients with an LVEF ≤35% predominantly in sinus rhythm; IPD provides an opportunity to collate high-quality data from double-blind trials on the smaller number of patients with higher LVEF where the efficacy of beta-blockers is uncertain. Why beta-blockers appear ineffective in patients with heart failure and concomitant atrial fibrillation (AF),[2,7,8] and whether this holds true regardless of LVEF is also unclear. In this paper, we investigate the effect of beta-blockers on LVEF and prognosis, stratified according to the baseline LVEF and heart rhythm.