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 George Franklin Cleland, Paulus Kirchhof, Thomas G. Von Lueder, Alan S. Rigby, Bert Andersson, Gregory Y H Lip, Dirk Jan van Veldhuisen, Marcelo C. Shibata, Hans Wedel, Michael BöhmMarcus D. Flather

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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.gov NCT00832442.

Original languageEnglish
Article numberi1855
Pages (from-to)1-9
Number of pages10
JournalBMJ: British Medical Journal
Volume353
DOIs
Publication statusPublished - 20 Apr 2016

Cite this

Kotecha, Dipak ; Manzano, Luis ; Krum, Henry ; Rosano, Giuseppe ; Holmes, Jane ; Altman, Douglas G ; Collins, Peter D. ; Packer, Milton ; Wikstrand, John ; Coats, Andrew J.S. ; Cleland, John George Franklin ; Kirchhof, Paulus ; Von Lueder, Thomas G. ; Rigby, Alan S. ; Andersson, Bert ; Lip, Gregory Y H ; van Veldhuisen, Dirk Jan ; Shibata, Marcelo C. ; Wedel, Hans ; Böhm, Michael ; Flather, Marcus D. / 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. In: BMJ: British Medical Journal. 2016 ; Vol. 353. pp. 1-9.
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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.gov NCT00832442.",
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 George Franklin} and Paulus Kirchhof and {Von Lueder}, {Thomas G.} and Rigby, {Alan S.} and Bert Andersson and Lip, {Gregory Y H} and {van Veldhuisen}, {Dirk Jan} and Shibata, {Marcelo C.} and Hans Wedel and Michael B{\"o}hm and Flather, {Marcus D.}",
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doi = "10.1136/bmj.i1855",
language = "English",
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pages = "1--9",
journal = "BMJ: British Medical Journal",
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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, GYH, van Veldhuisen, DJ, Shibata, MC, Wedel, H, Böhm, M & Flather, MD 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: British Medical Journal, vol. 353, i1855, pp. 1-9. https://doi.org/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. / Kotecha, Dipak; Manzano, Luis; Krum, Henry; Rosano, Giuseppe; Holmes, Jane; Altman, Douglas G; Collins, Peter D.; Packer, Milton; Wikstrand, John; Coats, Andrew J.S.; Cleland, John George Franklin; Kirchhof, Paulus; Von Lueder, Thomas G.; Rigby, Alan S.; Andersson, Bert; Lip, Gregory Y H; van Veldhuisen, Dirk Jan; Shibata, Marcelo C.; Wedel, Hans; Böhm, Michael; Flather, Marcus D.

In: BMJ: British Medical Journal, Vol. 353, i1855, 20.04.2016, p. 1-9.

Research output: Contribution to journalArticleResearchpeer-review

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 George Franklin

AU - Kirchhof, Paulus

AU - Von Lueder, Thomas G.

AU - Rigby, Alan S.

AU - Andersson, Bert

AU - Lip, Gregory Y H

AU - van Veldhuisen, Dirk Jan

AU - Shibata, Marcelo C.

AU - Wedel, Hans

AU - Böhm, Michael

AU - Flather, Marcus D.

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.gov NCT00832442.

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.gov NCT00832442.

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