1. Efficacy of beta-blockers in heart failure according to left ventricular ejection fraction
An individual patient level analysis of double-blind randomised trials
Dipak Kotecha, MBChB PhD MRCP FESC FHEA
on behalf of the
Beta-blockers in Heart Failure Collaborative Group

2. Disclosures 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 & Atricure. Professional development support: Daiichi-Sankyo.
Steering committee lead for BB-meta-HF and Chief Investigator for RATE-AF trial.
Funding:
Investigator-driven; supported by the Royal Brompton Hospital, London ( ) and the University of Birmingham (2013-). Administrative financial support from Menarini Farmaceutica & IRCCS San Raffaele, and data extraction support from GlaxoSmithKline.

3. Question
What is the effect of beta-blockers in heart failure patients across the spectrum of left ventricular ejection fraction (LVEF) ?
Heart failure with reduced LVEF
(HFrEF)
LVEF <40%
Heart failure with mid-range LVEF
(HFmrEF)
LVEF 40-49%
Heart failure with preserved LVEF
(HFpEF)
LVEF ≥50%
No double-blind RCTs specifically in these populations
ESC guidelines suggest managing LVEF 40-49% similar to ≥50%
2016 ESC HF Guidelines. Eur Heart J 2016;37:2129

4. Question
What is the effect of beta-blockers in heart failure patients across the spectrum of left ventricular ejection fraction (LVEF) ?
Heart failure with reduced LVEF
(HFrEF)
LVEF <40%
Heart failure with mid-range LVEF
(HFmrEF)
LVEF 40-49%
Heart failure with preserved LVEF
(HFpEF)
LVEF ≥50%
No double-blind RCTs specifically in these populations
ESC guidelines suggest managing LVEF 40-49% similar to ≥50%
2016 ESC HF Guidelines. Eur Heart J 2016;37:2129

5. IndMivDidCual paCtIiBeInSt dataUmS-HetFa-analysis
Randomised controlled trials
Reporting mortality as a major trial endpoint
Unconfounded head-to-head
Planned >6m follow-up
ANZ
1997
CIBIS-II
1999
MERIT-HF
1999
COPERNICUS
2001
CAPRICORN
2001
BEST
2001
>300 patients (accounts for >95% of
eligible RCT participants)
CHRISTMAS
2003
SENIORS
2005
Pooling of individual patient data from 18,637 heart failure patients in double-blind RCTs according to a published extraction and analysis plan.

6. Individual patient data meta-analysis
Est. 2008
Considered the ‘gold-standard’ approach *
Systematic (not just datasets that happen to be available).
Can appropriately combine original data, thereby improving data quality.
Inclusion of outcomes not originally reported.
Robust examination of sub-groups with enhanced sample size.
Full time-to-event analyses and generation of hazard ratios adjusted for individual baseline covariates.
* Stewart. Eval Health Prof 2002;25:76 Simmonds. Clin Trials 2005;2:209

7. Beta-blockers in Heart Failure Collaborative Group
Thomas von Lueder John Kjekshus
AstraZeneca Bert Andersson Åke Hjalmarson Jonny Lindqvist Hans Wedel John Wikstrand
Michael Böhm Merck
Douglas Altman Peter Collins John Cleland Marcus Flather Jane Holmes
Paulus Kirchhof Dipak Kotecha Gregory Lip John McMurray
Alan Rigby
Dirk van Veldhuisen Frank Ruschitzka
Beta-blockers in Heart Failure Collaborative Group
Marcelo Shibata
GlaxoSmithKline
Michael Domanski
Menarini Giuseppe Rosano
Luis Manzano
Milton Packer
Group members
Andrew Coats
In memory of the late Philip Poole Wilson (Imperial College London, UK) and Henry Krum (Monash University, Melbourne)
Syst Rev 2013;2:7 Lancet 2014;384:2235
Invited experts Pharma collaborators
BMJ 2016;353:i1855 JACC 2017;69:2885

8. Trial data Primary outcomes: All-cause mortality Cardiovascular
Patients with stable heart failure and ischemic wall motion abnormalities.
Either LVEF ≤35%, or a hospital admission for heart failure within 12 months regardless of LVEF.
Primary outcomes:
All-cause mortality Cardiovascular
mortality
(mean 1.5, median 1.3 *
years follow-up)
* Kotecha et al. Lancet 2014;384:223
n=16274
n=721
n=317

9. LVEF and mortality Baseline rhythm
Adjusted all-cause mortality per 5% lower LVEF
Events / patients
HR, 95% CI; p-value
Sinus rhythm
2,160 / 14,261
1.24, ; p<0.0001
Atrial fibrillation
609 / 3,034
1.09, ; p=0.002

10. Effect of beta-blockers in sinus rhythm

11. Effect of beta-blockers in sinus
rhythm

12. Effect of beta-blockers in sinus rhythm
NNT=21
* Post-hoc excluding LVEF=40%: Log-rank p=0.039

13. Effect of beta-blockers in AF

14. Change in LVEF Survivors with a second measurement of LVEF:
n=4,601 in sinus
n=996 in AF
Median 1.0 years after baseline

15. Change in LVEF Survivors with a second measurement of LVEF:
n=4,601 in sinus
n=996 in AF
Median 1.0 years after baseline

16. Change in LVEF Survivors with a second measurement of LVEF:
n=4,601 in sinus
n=996 in AF
Median 1.0 years after baseline
LVEF +2%
Mortality -5%
LVEF +5%
Mortality +3%

17. Limitations Strengths * Solomon. Eur Heart Jp2r0o16g;3r7a:4m55 †
Sparse data for LVEF >40%
Double-blind RCT data
Insufficient data in the LVEF
≥50% group
Individual patient data, hence most trials contribute to LVEF 40
-49%
LVEF is continuous but distribution here was not normal
Categorisation is helpful for clinical management of heart failure
Data on BNP, diastolic function and atrial function
Consistent with emerging data from TOPCAT * and CHARM
not available
* Solomon. Eur Heart Jp2r0o16g;3r7a:4m55 †
† HFA 2017 Paris Late-breaking

18. Summary
1. Beta-blockers improve LVEF and reduce cardiovascular mortality in patients with heart failure in sinus rhythm and LVEF <40% or 40-49%.
Too few patients in double-blind RCTs to comment on heart failure with LVEF ≥50%.
Disconnect in AF patients warrants further investigation * – no consistent evidence of prognostic benefit with beta- blockers.
* Kotecha et al. Europace 2017 Kotecha et al. BMJ Open 2017;7:e015099