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.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form (www.icmje.org/coi_disclosure.pdf) and declare: DK received grants from Menarini during the conduct of the study, and non-financial support from Daiitchi Sankyo, outside the submitted work. PDC has received lecture fees from Menarini, outside the submitted work. MP has received personal fees from AstraZeneca, Amgen, BioControl, Boston Scientific, Cardiokinetix, Cardiorentis, Cardio3, Novartis, Pfizer, and Takeda, all outside the submitted work. JW has received grants and personal fees from AstraZeneca during the conduct of the MERIT-HF study. AJSC reports personal fees from Menarini during the conduct of the study but outside the submitted work. JGFC has received grants and personal fees from GlaxoSmithkline and personal fees from AstraZeneca, outside the submitted work. PK has received grants from British Heart Foundation, German Ministry of Education and Research, DZHK, Leducq Foundation, several industry partners and personal fees from several industry companies, outside the submitted work. TGvL has received personal fees from Novartis and Vifor, outside the submitted work. BA has received grants and personal fees from AstraZeneca, during the conduct of the study; grants and personal fees from Servier, outside the submitted work. GYHL has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi, BMS/Pfizer, Biotronik, Portola, and Boehringer Ingelheim and has been on the speakers’ bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, and Sanofi-Aventis, all outside the submitted work. HW has received personal fees from Astra-Zeneca, during the conduct of the study. MB has received personal fees from Servier, Boehringer Ingelheim, Medtronic, Bayer, during the conduct of the study but outside the submitted work.

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Figures

Fig 1 Flowchart for included and excluded participants in analysis of effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction. LVEF= left ventricular ejection fraction. *MDC trial contributes only to mortality outcomes

Fig 2 β blockers versus placebo hazard model for all cause mortality and age. Hazard ratio for β blockers compared with placebo in HFrEF patients with sinus rhythm. Age modelled as continuous variable, with results for each quarter superimposed

Fig 3 Kaplan-Meier event curves according to quarter of age distribution for primary outcome (all cause mortality) and major secondary outcome (admission for heart failure) for β blockers v placebo by age. ARR=absolute risk reduction; NNT=number needed to treat

Fig 4 Kaplan-Meier event curves according to sex for primary outcome (all cause mortality) and major secondary outcome (admission for heart failure) for β blockers v placebo by sex. ARR=absolute risk reduction; NNT=number needed to treat