Beta-blockers for heart failure with reduced, mid-range and preserved ejection fraction: an individual patient-level analysis of double-blind randomised trials

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, randomised, placebo-controlled trials.
Methods and Results: Individual patient data meta-analysis of eleven trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: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%] randomised to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 (95% 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 randomisation, LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50% (n=4,601). For patients in atrial fibrillation at baseline (n=3,050), 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%.