Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis

Dipak Kotecha; Luis Manzano; Henry Krum; Giuseppe Rosano; Jane Holmes; Douglas G Altman; Peter D Collins; Milton Packer; John Wikstrand; Andrew J S Coats; John G F Cleland; Paulus Kirchhof; Thomas G von Lueder; Alan S Rigby; Bert Andersson; Gregory Yh Lip; Dirk J van Veldhuisen; Marcelo C Shibata; Hans Wedel; Michael Böhm; Marcus D Flather; Beta-Blockers in Heart Failure Collaborative Group

doi:10.1136/bmj.i1855

Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis

Dipak Kotecha
, Luis Manzano
, Henry Krum
, Giuseppe Rosano
, Jane Holmes
, Douglas G Altman
, Peter D Collins
, Milton Packer
, John Wikstrand
, Andrew J S Coats
, John G F Cleland
, Paulus Kirchhof
, Thomas G von Lueder
, Alan S Rigby
, Bert Andersson
, Gregory Yh Lip
, Dirk J van Veldhuisen
, Marcelo C Shibata
, Hans Wedel
, Michael Böhm

Marcus D Flather, Beta-Blockers in Heart Failure Collaborative Group

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

67 Citations (Scopus)

244 Downloads (Pure)

Abstract

OBJECTIVES: To determine the efficacy and tolerability of β blockers in a broad age range of women and men with heart failure with reduced ejection fraction (HFrEF) by pooling individual patient data from placebo controlled randomised trials.

DESIGN: Prospectively designed meta-analysis of individual patient data from patients aged 40-85 in sinus rhythm at baseline, with left ventricular ejection fraction <0.45.

PARTICIPANTS: 13 833 patients from 11 trials; median age 64; 24% women.

MAIN OUTCOME MEASURES: The primary outcome was all cause mortality; the major secondary outcome was admission to hospital for heart failure. Analysis was by intention to treat with an adjusted one stage Cox proportional hazards model.

RESULTS: Compared with placebo, β blockers were effective in reducing mortality across all ages: hazard ratios were 0.66 (95% confidence interval 0.53 to 0.83) for the first quarter of age distribution (median age 50); 0.71 (0.58 to 0.87) for the second quarter (median age 60); 0.65 (0.53 to 0.78) for the third quarter (median age 68); and 0.77 (0.64 to 0.92) for the fourth quarter (median age 75). There was no significant interaction when age was modelled continuously (P=0.1), and the absolute reduction in mortality was 4.3% over a median follow-up of 1.3 years (number needed to treat 23). Admission to hospital for heart failure was significantly reduced by β blockers, although this effect was attenuated at older ages (interaction P=0.05). There was no evidence of an interaction between treatment effect and sex in any age group. Drug discontinuation was similar regardless of treatment allocation, age, or sex (14.4% in those give β blockers, 15.6% in those receiving placebo).

CONCLUSION: Irrespective of age or sex, patients with HFrEF in sinus rhythm should receive β blockers to reduce the risk of death and admission to hospital.Registration PROSPERO CRD42014010012; Clinicaltrials.govNCT00832442.

Original language	English
Article number	i1855
Number of pages	10
Journal	BMJ
Volume	353
DOIs	https://doi.org/10.1136/bmj.i1855
Publication status	Published - 20 Apr 2016

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Kotecha, D., Manzano, L., Krum, H., Rosano, G., Holmes, J., Altman, D. G., Collins, P. D., Packer, M., Wikstrand, J., Coats, A. J. S., Cleland, J. G. F., Kirchhof, P., von Lueder, T. G., Rigby, A. S., Andersson, B., Lip, G. Y., van Veldhuisen, D. J., Shibata, M. C., Wedel, H., ... Beta-Blockers in Heart Failure Collaborative Group (2016). Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis. BMJ, 353, Article i1855. https://doi.org/10.1136/bmj.i1855

@article{0170dde31411431c95cce1010fc652e4,

title = "Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis",

abstract = "OBJECTIVES: To determine the efficacy and tolerability of β blockers in a broad age range of women and men with heart failure with reduced ejection fraction (HFrEF) by pooling individual patient data from placebo controlled randomised trials.DESIGN: Prospectively designed meta-analysis of individual patient data from patients aged 40-85 in sinus rhythm at baseline, with left ventricular ejection fraction <0.45.PARTICIPANTS: 13 833 patients from 11 trials; median age 64; 24\% women.MAIN OUTCOME MEASURES: The primary outcome was all cause mortality; the major secondary outcome was admission to hospital for heart failure. Analysis was by intention to treat with an adjusted one stage Cox proportional hazards model.RESULTS: Compared with placebo, β blockers were effective in reducing mortality across all ages: hazard ratios were 0.66 (95\% confidence interval 0.53 to 0.83) for the first quarter of age distribution (median age 50); 0.71 (0.58 to 0.87) for the second quarter (median age 60); 0.65 (0.53 to 0.78) for the third quarter (median age 68); and 0.77 (0.64 to 0.92) for the fourth quarter (median age 75). There was no significant interaction when age was modelled continuously (P=0.1), and the absolute reduction in mortality was 4.3\% over a median follow-up of 1.3 years (number needed to treat 23). Admission to hospital for heart failure was significantly reduced by β blockers, although this effect was attenuated at older ages (interaction P=0.05). There was no evidence of an interaction between treatment effect and sex in any age group. Drug discontinuation was similar regardless of treatment allocation, age, or sex (14.4\% in those give β blockers, 15.6\% in those receiving placebo).CONCLUSION: Irrespective of age or sex, patients with HFrEF in sinus rhythm should receive β blockers to reduce the risk of death and admission to hospital.Registration PROSPERO CRD42014010012; Clinicaltrials.govNCT00832442.",

author = "Dipak Kotecha and Luis Manzano and Henry Krum and Giuseppe Rosano and Jane Holmes and Altman, \{Douglas G\} and Collins, \{Peter D\} and Milton Packer and John Wikstrand and Coats, \{Andrew J S\} and Cleland, \{John G F\} and Paulus Kirchhof and \{von Lueder\}, \{Thomas G\} and Rigby, \{Alan S\} and Bert Andersson and Lip, \{Gregory Yh\} and \{van Veldhuisen\}, \{Dirk J\} and Shibata, \{Marcelo C\} and Hans Wedel and Michael B{\"o}hm and Flather, \{Marcus D\} and \{Beta-Blockers in Heart Failure Collaborative Group\}",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",

year = "2016",

month = apr,

day = "20",

doi = "10.1136/bmj.i1855",

language = "English",

volume = "353",

journal = "BMJ",

issn = "0959-535X",

publisher = "BMJ Publishing Group",

}

Kotecha, D, Manzano, L, Krum, H, Rosano, G, Holmes, J, Altman, DG, Collins, PD, Packer, M, Wikstrand, J, Coats, AJS, Cleland, JGF, Kirchhof, P, von Lueder, TG, Rigby, AS, Andersson, B, Lip, GY, van Veldhuisen, DJ, Shibata, MC, Wedel, H, Böhm, M, Flather, MD & Beta-Blockers in Heart Failure Collaborative Group 2016, 'Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis', BMJ, vol. 353, i1855. https://doi.org/10.1136/bmj.i1855

TY - JOUR

T1 - Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction

T2 - individual patient data meta-analysis

AU - Kotecha, Dipak

AU - Manzano, Luis

AU - Krum, Henry

AU - Rosano, Giuseppe

AU - Holmes, Jane

AU - Altman, Douglas G

AU - Collins, Peter D

AU - Packer, Milton

AU - Wikstrand, John

AU - Coats, Andrew J S

AU - Cleland, John G F

AU - Kirchhof, Paulus

AU - von Lueder, Thomas G

AU - Rigby, Alan S

AU - Andersson, Bert

AU - Lip, Gregory Yh

AU - van Veldhuisen, Dirk J

AU - Shibata, Marcelo C

AU - Wedel, Hans

AU - Böhm, Michael

AU - Flather, Marcus D

AU - Beta-Blockers in Heart Failure Collaborative Group

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2016/4/20

Y1 - 2016/4/20

N2 - OBJECTIVES: To determine the efficacy and tolerability of β blockers in a broad age range of women and men with heart failure with reduced ejection fraction (HFrEF) by pooling individual patient data from placebo controlled randomised trials.DESIGN: Prospectively designed meta-analysis of individual patient data from patients aged 40-85 in sinus rhythm at baseline, with left ventricular ejection fraction <0.45.PARTICIPANTS: 13 833 patients from 11 trials; median age 64; 24% women.MAIN OUTCOME MEASURES: The primary outcome was all cause mortality; the major secondary outcome was admission to hospital for heart failure. Analysis was by intention to treat with an adjusted one stage Cox proportional hazards model.RESULTS: Compared with placebo, β blockers were effective in reducing mortality across all ages: hazard ratios were 0.66 (95% confidence interval 0.53 to 0.83) for the first quarter of age distribution (median age 50); 0.71 (0.58 to 0.87) for the second quarter (median age 60); 0.65 (0.53 to 0.78) for the third quarter (median age 68); and 0.77 (0.64 to 0.92) for the fourth quarter (median age 75). There was no significant interaction when age was modelled continuously (P=0.1), and the absolute reduction in mortality was 4.3% over a median follow-up of 1.3 years (number needed to treat 23). Admission to hospital for heart failure was significantly reduced by β blockers, although this effect was attenuated at older ages (interaction P=0.05). There was no evidence of an interaction between treatment effect and sex in any age group. Drug discontinuation was similar regardless of treatment allocation, age, or sex (14.4% in those give β blockers, 15.6% in those receiving placebo).CONCLUSION: Irrespective of age or sex, patients with HFrEF in sinus rhythm should receive β blockers to reduce the risk of death and admission to hospital.Registration PROSPERO CRD42014010012; Clinicaltrials.govNCT00832442.

AB - OBJECTIVES: To determine the efficacy and tolerability of β blockers in a broad age range of women and men with heart failure with reduced ejection fraction (HFrEF) by pooling individual patient data from placebo controlled randomised trials.DESIGN: Prospectively designed meta-analysis of individual patient data from patients aged 40-85 in sinus rhythm at baseline, with left ventricular ejection fraction <0.45.PARTICIPANTS: 13 833 patients from 11 trials; median age 64; 24% women.MAIN OUTCOME MEASURES: The primary outcome was all cause mortality; the major secondary outcome was admission to hospital for heart failure. Analysis was by intention to treat with an adjusted one stage Cox proportional hazards model.RESULTS: Compared with placebo, β blockers were effective in reducing mortality across all ages: hazard ratios were 0.66 (95% confidence interval 0.53 to 0.83) for the first quarter of age distribution (median age 50); 0.71 (0.58 to 0.87) for the second quarter (median age 60); 0.65 (0.53 to 0.78) for the third quarter (median age 68); and 0.77 (0.64 to 0.92) for the fourth quarter (median age 75). There was no significant interaction when age was modelled continuously (P=0.1), and the absolute reduction in mortality was 4.3% over a median follow-up of 1.3 years (number needed to treat 23). Admission to hospital for heart failure was significantly reduced by β blockers, although this effect was attenuated at older ages (interaction P=0.05). There was no evidence of an interaction between treatment effect and sex in any age group. Drug discontinuation was similar regardless of treatment allocation, age, or sex (14.4% in those give β blockers, 15.6% in those receiving placebo).CONCLUSION: Irrespective of age or sex, patients with HFrEF in sinus rhythm should receive β blockers to reduce the risk of death and admission to hospital.Registration PROSPERO CRD42014010012; Clinicaltrials.govNCT00832442.

U2 - 10.1136/bmj.i1855

DO - 10.1136/bmj.i1855

M3 - Article

C2 - 27098105

SN - 0959-535X

VL - 353

JO - BMJ

JF - BMJ

M1 - i1855

ER -

Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis

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