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.
OBJECTIVE
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.


METHODS
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.


METHODS
13,833 patients from 11 trials; median age 64; 24% women.


METHODS
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).


CONCLUSIONS
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.
University of Birmingham Institute of Cardiovascular Sciences, Birmingham, UK Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Australia d.kotecha@bham.ac.uk.
Dipak
D
Kotecha
Internal Medicine Department, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, Spain.
Luis
L
Manzano
Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Australia.
Henry
H
Krum
Department of Medical Sciences, IRCCS San Raffaele Pisana, Roma, Italy Cardiovascular and Cell Science Institute, St George's University of London, London, UK.
Giuseppe
G
Rosano
Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Jane
J
Holmes
Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Douglas G
DG
Altman
National Heart and Lung Institute, Imperial College, London, UK.
Peter D
PD
Collins
Baylor University Medical Center, Dallas, USA.
Milton
M
Packer
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
John
J
Wikstrand
Monash Warwick Alliance, Monash University, Melbourne, Australia Monash Warwick Alliance, University of Warwick, Warwick, UK.
Andrew J S
AJ
Coats
National Heart and Lung Institute, Imperial College, London, UK.
John G F
JG
Cleland
University of Birmingham Institute of Cardiovascular Sciences, Birmingham, UK.
Paulus
P
Kirchhof
Department of Cardiology, Oslo University Hospital, Oslo, Norway.
Thomas G
TG
von Lueder
Academic Cardiology, Castle Hill Hospital, Kingston upon Hull, UK.
Alan S
AS
Rigby
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
Bert
B
Andersson
University of Birmingham Institute of Cardiovascular Sciences, Birmingham, UK.
Gregory Y H
GY
Lip
Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands.
Dirk J
DJ
van Veldhuisen
Division of Cardiology, University of Alberta, Edmonton, Canada.
Marcelo C
MC
Shibata
Nordic School of Public Health, Gothenburg, Sweden.
Hans
H
Wedel
Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
Michael
M
Böhm
Norwich Medical School, University of East Anglia, Norwich, UK.
Marcus D
MD
Flather
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D012737:Sex Factors; D013318:Stroke Volume / Q000502:physiology; D016896:Treatment Outcome
D000319:Adrenergic beta-Antagonists