Li Shen1, Pardeep S Jhund1, Ulrik M Mogensen2, Lars Køber3, Brian Claggett4, Jennifer K Rogers5, John J V McMurray6. 1. BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. 2. BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom; Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark. 3. Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark. 4. Division of Cardiovascular Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts. 5. University of Oxford, Oxford, United Kingdom. 6. BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. Electronic address: john.mcmurray@glasgow.ac.uk.
Abstract
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).
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).
Authors: Javed Butler; Milton Packer; Stephen J Greene; Mona Fiuzat; Stefan D Anker; Kevin J Anstrom; Peter E Carson; Lauren B Cooper; Gregg C Fonarow; Adrian F Hernandez; James L Januzzi; Mariell Jessup; Rita R Kalyani; Sanjay Kaul; Mikhail Kosiborod; JoAnn Lindenfeld; Darren K McGuire; Marc S Sabatine; Scott D Solomon; John R Teerlink; Muthiah Vaduganathan; Clyde W Yancy; Norman Stockbridge; Christopher M O'Connor Journal: Circulation Date: 2019-12-16 Impact factor: 29.690
Authors: Stephen J Greene; Muthiah Vaduganathan; Muhammad Shahzeb Khan; George L Bakris; Matthew R Weir; Jonathan H Seltzer; Naveed Sattar; Darren K McGuire; James L Januzzi; Norman Stockbridge; Javed Butler Journal: J Am Coll Cardiol Date: 2018-03-10 Impact factor: 24.094
Authors: Pardeep S Jhund; Piotr Ponikowski; Kieran F Docherty; Samvel B Gasparyan; Michael Böhm; Chern-En Chiang; Akshay S Desai; Jonathon Howlett; Masafumi Kitakaze; Mark C Petrie; Subodh Verma; Olof Bengtsson; Anna-Maria Langkilde; Mikaela Sjöstrand; Silvio E Inzucchi; Lars Køber; Mikhail N Kosiborod; Felipe A Martinez; Marc S Sabatine; Scott D Solomon; John J V McMurray Journal: Circulation Date: 2021-04-09 Impact factor: 29.690
Authors: Meaghan Lunney; Marinella Ruospo; Patrizia Natale; Robert R Quinn; Paul E Ronksley; Ioannis Konstantinidis; Suetonia C Palmer; Marcello Tonelli; Giovanni Fm Strippoli; Pietro Ravani Journal: Cochrane Database Syst Rev Date: 2020-02-27
Authors: Ernest Spitzer; Rebecca T Hahn; Philippe Pibarot; Ton de Vries; Jeroen J Bax; Martin B Leon; Nicolas M Van Mieghem Journal: Card Fail Rev Date: 2019-05-24
Authors: Abhinav Sharma; Muthiah Vaduganathan; João Pedro Ferreira; Yuyin Liu; George L Bakris; Christopher P Cannon; William B White; Faiez Zannad Journal: J Am Heart Assoc Date: 2020-01-04 Impact factor: 5.501