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, Hans Wedel, Åke Hjalmarson, John WikstrandDipak Kotecha

Research output: Contribution to journalArticle

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%.

Original languageEnglish
JournalEuropean Heart Journal
DOIs
Publication statusAccepted/In press - 2017

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Stroke Volume
Heart Failure
Placebos
Confidence Intervals
Intention to Treat Analysis
Mortality
Random Allocation
Atrial Fibrillation
Meta-Analysis
Randomized Controlled Trials

Keywords

  • Atrial fibrillation
  • Beta-blockers
  • Ejection fraction
  • Heart failure
  • Mortality
  • Sinus rhythm

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction : An individual patient-level analysis of double-blind randomized trials. / Cleland, John G.F.; Bunting, Karina V.; Flather, Marcus D.; Altman, Douglas G.; Holmes, Jane; Coats, Andrew J.S.; Manzano, Luis; McMurray, John J.V.; Ruschitzka, Frank; Van Veldhuisen, Dirk J.; Von Lueder, Thomas G.; Böhm, Michael; Andersson, Bert; Kjekshus, John; Packer, Milton; Rigby, Alan S.; Rosano, Giuseppe; Wedel, Hans; Hjalmarson, Åke; Wikstrand, John; Kotecha, Dipak.

In: European Heart Journal, 2017.

Research output: Contribution to journalArticle

Cleland, JGF, Bunting, KV, Flather, MD, Altman, DG, Holmes, J, Coats, AJS, Manzano, L, McMurray, JJV, Ruschitzka, F, Van Veldhuisen, DJ, Von Lueder, TG, Böhm, M, Andersson, B, Kjekshus, J, Packer, M, Rigby, AS, Rosano, G, Wedel, H, Hjalmarson, Å, Wikstrand, J & Kotecha, D 2017, 'Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: An individual patient-level analysis of double-blind randomized trials', European Heart Journal. https://doi.org/10.1093/eurheartj/ehx564
Cleland, John G.F. ; Bunting, Karina V. ; Flather, Marcus D. ; Altman, Douglas G. ; Holmes, Jane ; Coats, Andrew J.S. ; Manzano, Luis ; McMurray, John J.V. ; Ruschitzka, Frank ; Van Veldhuisen, Dirk J. ; Von Lueder, Thomas G. ; Böhm, Michael ; Andersson, Bert ; Kjekshus, John ; Packer, Milton ; Rigby, Alan S. ; Rosano, Giuseppe ; Wedel, Hans ; Hjalmarson, Åke ; Wikstrand, John ; Kotecha, Dipak. / Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction : An individual patient-level analysis of double-blind randomized trials. In: European Heart Journal. 2017.
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title = "Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: An individual patient-level analysis of double-blind randomized trials",
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",
author = "Cleland, {John G.F.} and Bunting, {Karina V.} and Flather, {Marcus D.} and Altman, {Douglas G.} and Jane Holmes and Coats, {Andrew J.S.} and Luis Manzano and McMurray, {John J.V.} and Frank Ruschitzka and {Van Veldhuisen}, {Dirk J.} and {Von Lueder}, {Thomas G.} and Michael B{\"o}hm and Bert Andersson and John Kjekshus and Milton Packer and Rigby, {Alan S.} and Giuseppe Rosano and Hans Wedel and {\AA}ke Hjalmarson and John Wikstrand and Dipak Kotecha",
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TY - JOUR

T1 - Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction

T2 - An individual patient-level analysis of double-blind randomized trials

AU - Cleland, John G.F.

AU - Bunting, Karina V.

AU - Flather, Marcus D.

AU - Altman, Douglas G.

AU - Holmes, Jane

AU - Coats, Andrew J.S.

AU - Manzano, Luis

AU - McMurray, John J.V.

AU - Ruschitzka, Frank

AU - Van Veldhuisen, Dirk J.

AU - Von Lueder, Thomas G.

AU - Böhm, Michael

AU - Andersson, Bert

AU - Kjekshus, John

AU - Packer, Milton

AU - Rigby, Alan S.

AU - Rosano, Giuseppe

AU - Wedel, Hans

AU - Hjalmarson, Åke

AU - Wikstrand, John

AU - Kotecha, Dipak

PY - 2017

Y1 - 2017

N2 - 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%.

AB - 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%.

KW - Atrial fibrillation

KW - Beta-blockers

KW - Ejection fraction

KW - Heart failure

KW - Mortality

KW - Sinus rhythm

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DO - 10.1093/eurheartj/ehx564

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