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Meta-Analysis
. 2018 Jan 1;39(1):26-35.
doi: 10.1093/eurheartj/ehx564.

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  1 , Karina V Bunting  2 , Marcus D Flather  3 , Douglas G Altman  4 , Jane Holmes  4 , Andrew J S Coats  5 , Luis Manzano  6 , John J V McMurray  7 , Frank Ruschitzka  8 , Dirk J van Veldhuisen  9 , Thomas G von Lueder  10   11 , Michael Böhm  12 , Bert Andersson  13 , John Kjekshus  14 , Milton Packer  15 , Alan S Rigby  16 , Giuseppe Rosano  17   18 , Hans Wedel  19 , Åke Hjalmarson  13 , John Wikstrand  20 , Dipak Kotecha  21   11 ; Beta-blockers in Heart Failure Collaborative Group
Affiliations
Meta-Analysis

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 et al. Eur Heart J. .

Abstract

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 (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%] 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%.

Keywords: Atrial fibrillation; Beta-blockers; Ejection fraction; Heart failure; Mortality; Sinus rhythm.

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Figures

Figure 1
Figure 1
Hazard of all-cause mortality across the spectrum of LVEF. Hazard ratio and 95% confidence intervals for all-cause mortality according to baseline left ventricular ejection fraction (LVEF), relative to a patient with an LVEF of 35%. Hazard ratios are fitted using a Cox proportional hazards regression model, adjusted for treatment, age, gender, previous myocardial infarction, systolic blood pressure, heart rate, use of angiotensin inhibitors/receptor blockers and diuretics, and stratified by study.
Figure 2
Figure 2
Beta-blockers vs. placebo according to baseline LVEF in sinus rhythm. Intention to treat, one-stage Cox proportional hazards model in categories of left ventricular ejection fraction (LVEF) at baseline, adjusted for age, gender, previous myocardial infarction, systolic blood pressure, heart rate, and use of angiotensin inhibitors/receptor blockers, and diuretics. ‘n’ is the number of individual patients analysed from double-blind, randomized controlled trials for the primary outcomes with complete case data.
Figure 3
Figure 3
Beta-blockers vs. placebo in sinus rhythm according to heart failure phenotype. Kaplan Meier plots for unadjusted (A) all-cause mortality and (B) cardiovascular mortality according to baseline left ventricular ejection fraction (LVEF). * Similar results in post hoc analysis when excluding patients with an LVEF reported as exactly 40% from the 40–49% group: (A) log-rank P = 0.030 and (B) log-rank P = 0.039; n = 147 placebo, and n = 143 beta-blockers.
Figure 4
Figure 4
Beta-blockers vs. placebo according to baseline LVEF in atrial fibrillation. Intention to treat, one-stage Cox proportional hazards model in categories of left ventricular ejection fraction (LVEF) at baseline, adjusted for age, gender, previous myocardial infarction, systolic blood pressure, heart rate, and use of angiotensin inhibitors/receptor blockers, and diuretics. ‘n’ is the number of individual patients analysed from double-blind, randomized controlled trials for the primary outcomes with complete case data.
Figure 5
Figure 5
Observed change in LVEF in survivors. Change in left ventricular ejection fraction (LVEF) from baseline in patients who survived to follow-up, with median time between measurements of 1.0 years (interquartile range 0.3–2.0 years). Those with follow-up LVEF were older in age compared to those without follow-up LVEF [67 (IQR 56–74) vs. 64 (55–71) years, respectively], but with similar baseline LVEF [27% (20–33) vs. 27% (21–33)] and frequency of ischaemic cardiomyopathy (65% vs. 67%). The variance for each category of change in LVEF (beta-blockers vs. placebo) is presented in Table 3. (A) Sinus rhythm; n = 4, 601 patients. (B) Atrial fibrillation; n = 996.
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