Author + information
- Received February 16, 2017
- Revision received April 13, 2017
- Accepted April 17, 2017
- Published online July 31, 2017.
- Li Shen, MBChBa,
- Pardeep S. Jhund, MBChB, PhDa,
- Ulrik M. Mogensen, MD, PhDa,b,
- Lars Køber, MD, DMScb,
- Brian Claggett, PhDc,
- Jennifer K. Rogers, PhDd and
- John J.V. McMurray, MDa,∗ ()
- aBHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
- bRigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
- cDivision of Cardiovascular Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- dUniversity of Oxford, Oxford, United Kingdom
- ↵∗Address for correspondence:
Prof. John J.V. McMurray, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom.
Objectives The influence of choice of endpoint on trial size, duration, and interpretation of results was examined in patients with heart failure who were enrolled in BEST (Beta-blocker Evaluation of Survival Trial).
Background The choice of endpoints in heart failure trials has evolved over the past 3 decades.
Methods In the BEST trial, we used Cox regression analysis to examine the effect of bucindolol on the current standard composite of cardiovascular death or heart failure hospitalization (CVD/HFH) compared with the original primary mortality endpoint and the expanded composite that included emergency department (ED) visits. We also undertook an analysis of recurrent events primarily using the Lin, Wei, Ying, and Yang model.
Results Overall, 448 (33%) patients on placebo and 411 (30%) patients on bucindolol died (hazard ratio [HR]: 0.90; 95% confidence interval [CI]: 0.78 to 1.02; p = 0.11). A total of 730 (54%) patients experienced CVD/HFH on placebo and 624 (46%) on bucindolol (HR: 0.80; 95% CI: 0.72 to 0.89; p < 0.001). Adding ED visits increased these numbers to 768 (57%) and 668 (49%), respectively (HR: 0.81; 95% CI: 0.73 to 0.90; p < 0.001). A total of 568 (42%) patients on placebo experienced HFH compared with 476 (35%) patients on bucindolol (HR: 0.78; 95% CI: 0.69 to 0.89; p < 0.001), with a total of 1,333 and 1,124 admissions, respectively. With the same statistical assumptions, using the composite endpoint instead of all-cause mortality would have reduced the trial size by 40% and follow-up duration by 69%. The rate ratio for recurrent events (CVD/HFH) was 0.83 (95% CI: 0.73 to 0.94; p = 0.003).
Conclusions Choice of endpoint has major implications for trial size and duration, as well as interpretation of results. The value of broader composite endpoints and inclusion of recurrent events needs further investigation. (Beta Blocker Evaluation in Survival Trial [BEST]; NCT00000560)
Dr. Shen is supported by a post doctoral research grant from the China Scholarship Council, China. Dr. Køber has received honoraria from Sanofi and Novartis for speaking. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received February 16, 2017.
- Revision received April 13, 2017.
- Accepted April 17, 2017.
- 2017 American College of Cardiology Foundation