Efficacy of beta-blockers in heart failure Efficacy of beta-blockers - PowerPoint PPT Presentation

Efficacy of beta-blockers in heart failure Efficacy of beta-blockers in heart failure patients with atrial fibrillation: patients with atrial fibrillation: An individual patient patient data meta-analysis data meta-analysis An individual Dipak Kotecha, MD PhD on behalf of the Beta-blockers in Heart Failure Collaborative Group

Beta-blockers in Heart Failure Collaborative Group Coordinating Group Marcus Flather University of East Anglia, UK Jonny Lindqvist University of Gothenburg, Sweden Dipak Kotecha University of Birmingham, UK Thomas von Lueder Oslo University Hospital, Norway Henry Krum Monash University, Australia Alan Rigby Castle Hill Hospital, UK Luis Manzano Universidad de Alcala, Spain Investigators/Invited Experts Bert Andersson Sahlgrenska University Hospital, Sweden Statistical Team Douglas Altman University of Oxford, UK John Cleland University of Hull, UK Jane Holmes University of Oxford, UK Andrew Coats Monash University, Australia Nicola Williams University of Oxford, UK Michael Domanski Mount Sinai Hospital, USA Åke Hjalmarson Sahlgrenska University Hospital, Sweden Pharmaceutical Leads Paulus Kirchhof University of Birmingham, UK Philippe Lechat Agence Française de SSaPS, France Marilena Grana Menarini Farmaceutica, Italy Per Haglund AstraZeneca, Sweden Alain Leizorovicz Université de Lyon, France Mary Ann Lukas GlaxoSmithKline, USA Gregory Lip University of Birmingham, UK Wilfried Meyer Merck Serono, Germany Milton Packer UT Southwestern Medical Center, USA Rosemary Giuseppe Rosano IRCCS San Raffaele Pisana, Italy GlaxoSmithKline, USA Schroyer Marcelo Shibata University of Alberta, Canada Hans Wedel Nordic School of Public Health, Sweden Data Management John Wikstrand Wallenberg Laboratory, Sweden David Chen GlaxoSmithKline, USA and the late Philip Poole Wilson (Imperial College London, UK) Guliz Erdem Memorial Hospital Şişli, Turkey

Disclosures/Conflicts of interest Beta-blockers in Heart Failure Collaborative Group: The majority of the group have received speaker fees, honoraria or grant support from pharmaceutical companies involved in beta-blocker therapies. Personal: Honoraria/research grants; Menarini Farmaceutica. Steering committee lead for BB-meta-HF and the RATE-AF trial. Funding: Investigator-driven. Administrative financial support from Menarini Farmaceutica and data extraction support from GlaxoSmithKline. DK is funded by the National Institute for Health Research (NIHR); the opinions herein do not represent the views of the NIHR or the UK Department of Health.

Beta-blockers, heart failure and atrial fibrillation • Beta-blocker therapy has a class 1A recommendation for symptomatic heart failure due to reduced left-ventricular ejection fraction (LVEF). • There have been concerns over treatment efficacy in certain under- represented groups, notably women, the elderly and those with atrial fibrillation (AF). • Heart failure and AF are two emerging epidemics of the 21st century. • Beta-blocker therapy in AF is advocated in heart failure guidelines due to the benefit seen predominantly in patients with sinus rhythm.

Methods MDC CIBIS US-HF 1993 1994 1996 ▪ Randomised controlled trials ▪ Reporting mortality as a ANZ CIBIS-II MERIT-HF major trial endpoint 1997 1999 1999 ▪ Unconfounded head-to-head ▪ Planned >6m follow-up COPERNICUS CAPRICORN BEST ▪ >300 patients 2001 2001 2001 (accounts for >95% of eligible RCT participants) CHRISTMAS * SENIORS 2003 2005 Pooling of individual data from 18,254 heart failure patients randomised to beta-blockers or placebo, according to a published extraction and analysis plan. † * Excluded from sinus rhythm versus AF analysis due to study exclusion criteria † Kotecha et al. Syst Rev. 2013;2:7

Individual patient data meta-analysis • Considered the ‘gold-standard’ of meta-analysis* ü Appropriately combine original data, thereby improving data quality. ü Inclusion of outcomes not originally reported. ü Robust examination of sub-groups with enhanced sample size. ü Full time-to-event analyses and generation of hazard ratios adjusted for individual baseline covariates. • Stratified one-stage Cox proportional hazards model adjusted for age, gender, LVEF, heart rate and use of ACEi/ARB, presented as hazard ratios (HR) and 95% CI, censored at 40 months (3.3 years). • Intention-to-treat; range of sensitivity and exploratory analyses. * Stewart & Tierney. Eval Health Prof. 2002;25:76; Simmonds et al. Clin Trials. 2005;2:209

Pooled baseline characteristics 18,254 individual RCT participants from 10 trials Sinus rhythm Atrial fibrillation Other rhythms 13,946 (76% ) 3,066 (17%) 1,242 (7%) Heart Missing ECG block/Paced 118 (<1%) 1,124 (6%) • No differences in any group between those allocated to beta-blockers or placebo • Heart rhythm according to baseline ECG

Pooled baseline characteristics Characteristic Sinus rhythm (n=13,946) Atrial fibrillation (n=3,066) Age, median years (IQR) 64 (54-71) 69 (60-74) Women 25% 19% Diabetes mellitus 25% 23% Years with HF diagnosis, median (IQR) 3.0 (1.0-6.0) 3.0 (1.0-7.0) LVEF, median (IQR) 0.27 (0.21-0.33) 0.27 (0.22-0.33) NYHA class III/IV 63% 72% Systolic BP, median mmHg (IQR) 123 (110-140) 127 (113-140) Heart rate, median bpm (IQR) 80 (72-88) 81 (72-92) ACEi or ARB 95% 95% Any diuretic therapy 85% 94% Digoxin 53% 84% Oral anticoagulation 26% 58%

Mortality according to baseline rhythm Number of deaths (%) Sinus rhythm Atrial fibrillation All reported deaths* 2,237 / 13,946 (16%) 633 / 3,066 (21%) Cause of death (% of group): Sudden death 927 (41%) 231 (37%) Heart failure 539 (24%) 184 (29%) Acute myocardial infarction 126 (6%) 13 (2%) Stroke 43 (2%) 27 (4%) Other cardiac/vascular 158 (7%) 49 (8%) Non-cardiovascular/unknown 444 (20%) 129 (20%) * Mean 1.5 years until death or censoring (SD 1.1).

Efficacy of beta-blockers for preventing death Unadjusted Kaplan-Meier survival (includes all reported deaths). Hazard ratios (HR) derived from the adjusted one-stage Cox model.

Efficacy of beta-blockers for preventing death Unadjusted Kaplan-Meier survival (includes all reported deaths). Hazard ratios (HR) derived from the adjusted one-stage Cox model.

Mortality outcomes Sinus rhythm Atrial fibrillation Interaction Beta-blockers Beta-blockers AF versus versus placebo versus placebo sinus rhythm Events/ Outcome sample size HR (95% CI) p-value HR (95% CI) p-value p-value All-cause mortality (all reported deaths) 2870/17009 0.73 (0.67, 0.80) <0.001 0.97 (0.83, 1.14) 0.73 0.002 All-cause mortality (study period only) 2577/17009 0.73 (0.67, 0.80) <0.001 0.93 (0.79, 1.10) 0.43 0.01 Cardiovascular death (all reported deaths) 2297/17009 0.72 (0.65, 0.79) <0.001 0.92 (0.77, 1.10) 0.35 0.02 Hazard ratios derived from the one-stage Cox regression model, adjusted for age, gender, baseline LVEF, heart rate and use of ACEi/ARB.

Sensitivity/exploratory analyses Sinus rhythm Atrial fibrillation Interaction Beta-blockers Beta-blockers AF versus versus placebo versus placebo sinus rhythm Outcome HR (95% CI) p-value HR (95% CI) p-value p-value Additional adjustment* 0.73 (0.67, 0.80) <0.001 0.95 (0.81, 1.12) 0.53 0.002 Exclusion of BEST 0.66 (0.60, 0.74) <0.001 1.03 (0.86, 1.24) 0.74 <0.001 Censor at 365 days 0.69 (0.61, 0.77) <0.001 0.97 (0.79, 1.19) 0.75 0.005 * Hazard ratio here presented for additional adjustment for baseline digoxin, oral anticoagulation, amiodarone and other anti-arrhythmic drugs.

Sensitivity/exploratory analyses All-cause mortality: Sinus rhythm All-cause mortality: Atrial fibrillation Heterogeneity: I 2 =56%, p=0.016 Heterogeneity: I 2 =0%, p=0.65 Two stage Cox regression model, adjusted for age, gender, baseline LVEF, heart rate and use of ACEi/ARB. Includes all reported deaths.

Sensitivity/exploratory analyses Sub-group analysis of all reported deaths for patients in AF at baseline:

Sensitivity/exploratory analyses Sub-group analysis of all reported deaths for patients in AF at baseline:

Hospitalisation according to baseline rhythm Hospitalisation type Sinus rhythm Atrial fibrillation CV-hospitalisation: Percentage with 1 or more admission 26% 29% Annualised hospitalisation rate per patient 0.52/year 0.60/year Average length of first five admissions Mean 10, median 6 days Mean 12, median 8 days HF-related hospitalisation: Percentage with 1 or more admission 16% 21% Annualised hospitalisation rate per patient 0.36/year 0.41/year Average length of first five admissions Mean 10, median 6 days Mean 12, median 8 days

Hospitalisation and composite outcomes Sinus rhythm Atrial fibrillation Interaction Beta-blockers Beta-blockers AF versus versus placebo versus placebo sinus rhythm Events/ Outcome sample size HR (95% CI) p-value HR (95% CI) p-value p-value First CV hospitalisation 4374/16644 0.78 (0.73, 0.83) <0.001 0.91 (0.79, 1.04) 0.15 0.05 First HF-related hospitalisation 2872/16644 0.71 (0.65, 0.77) <0.001 0.91 (0.78, 1.07) 0.26 0.005 MDC does not contribute to hospitalisation outcomes.