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 An individual patient patient data meta-analysis data meta-analysis

Dipak Kotecha, MD PhD

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

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

Pooling of individual data from 18,254 heart failure patients randomised to beta-blockers or placebo, according to a published extraction and analysis plan.†

† Kotecha et al. Syst Rev. 2013;2:7

* Excluded from sinus rhythm versus AF analysis due to study exclusion criteria

MDC 1993 CIBIS 1994 US-HF 1996 ANZ 1997 CIBIS-II 1999 MERIT-HF 1999 COPERNICUS 2001 CAPRICORN 2001 BEST 2001 CHRISTMAS * 2003 SENIORS 2005

▪ Randomised controlled trials ▪ Reporting mortality as a major trial endpoint ▪ Unconfounded head-to-head ▪ Planned >6m follow-up ▪ >300 patients (accounts for >95% of eligible RCT participants)

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 13,946 (76%) Atrial fibrillation 3,066 (17%) Other rhythms 1,242 (7%) Heart block/Paced 1,124 (6%) Missing ECG 118 (<1%)

• 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

Hazard ratios derived from the one-stage Cox regression model, adjusted for age, gender, baseline LVEF, heart rate and use of ACEi/ARB.

Outcome Events/ sample size Sinus rhythm Beta-blockers versus placebo Atrial fibrillation Beta-blockers versus placebo Interaction AF versus sinus rhythm 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

Sensitivity/exploratory analyses

Outcome Sinus rhythm Beta-blockers versus placebo Atrial fibrillation Beta-blockers versus placebo Interaction AF versus sinus rhythm 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

Two stage Cox regression model, adjusted for age, gender, baseline LVEF, heart rate and use of ACEi/ARB. Includes all reported deaths.

Heterogeneity: I2=56%, p=0.016 Heterogeneity: I2=0%, p=0.65

All-cause mortality: Sinus rhythm All-cause mortality: Atrial fibrillation

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

MDC does not contribute to hospitalisation outcomes.

Outcome Events/ sample size Sinus rhythm Beta-blockers versus placebo Atrial fibrillation Beta-blockers versus placebo Interaction AF versus sinus rhythm 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

Study drug dosage & effect on heart rate

• 1. Achieved at interim time point for each study. Data not available for BEST, with an additional n=5,413 missing data (total n=11,599).

Beta-blocker arm Sinus rhythm Atrial fibrillation Pooled average dose as a percentage of maximum 1 74% 72% Change from baseline heart rate (bpm) 2

• 12 (-20, -4)
• 12 (-22, -1)
• 2. Median heart rate change (IQR) from baseline to interim study time-point (median 0.5 years, IQR 0.3-0.6 with n=118 missing data).

Adverse effects and discontinuation

* Data available for all trials (total n=8,813 allocated to beta-blockers). † Data not available for MERIT-HF, CIBIS-I and MDC (total n=6,445).

• No significant difference in primary outcome analysis comparing ITT to

per-protocol assessment for AF patients

• P-value for interaction of study drug discontinuation = 0.09

Reason Discontinuation of beta-blockers Sinus rhythm Atrial fibrillation

• any adverse event*

1051 (14%) 231 (15%)

• hypotension†

65 (1%) 14 (1%)

• bradycardia†

68 (1%) 18 (2%)

• HF exacerbation*

262 (4%) 71 (5%)

• respiratory dysfunction†

43 (<1%) 4 (<1%)

Strengths & limitations

• Individual patient data from

large, high-quality RCTs

• Near totality of randomised

data (>95% eligible)

• Improved data quality,

harmonised across trials

• Largest adjusted time-to-event

analysis of treatment efficacy in patients with heart failure with AF

• Limited to data collected in the

individual trials; retrospective

• Grouped according to baseline

ECG; no data for AF type

• AF group included atrial flutter

(approximately 4%)

• Insufficient patients with

preserved LVEF for separate analysis of treatment efficacy (<2% with LVEF≥0.50)

Summary

• HF patients with AF have more hospital admissions, longer length of

stay and higher death rates compared to sinus rhythm.

• For HF patients with reduced LVEF in sinus rhythm, there were clear

benefits associated with beta-blocker therapy (27% reduction for incidence of death over 3.3 years).

• Beta-blockers in patients with concomitant AF had no significant impact
• n all-cause mortality, CV mortality, CV hospitalisation or HF-related

hospitalisation.

• Our results dispute the preferential use of beta-blockers compared to
• ther rate-control medications and suggest that current guideline

recommendations should be revised.

Thank you for your attention The full article is now available in the Lancet Dipak Kotecha

d.kotecha@bham.ac.uk

• n behalf of the

Beta-blockers in Heart Failure Collaborative Group

http://www.thelancet.com/ journals/lancet/onlinefirst