Re-Examination of the BEST Trial Using Composite Outcomes, Including Emergency Department Visits.
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).
['Shen|Li|L|', 'Jhund|Pardeep S|PS|', 'Mogensen|Ulrik M|UM|', 'Køber|Lars|L|', 'Claggett|Brian|B|', 'Rogers|Jennifer K|JK|', 'McMurray|John J V|JJV|']
D000319:Adrenergic beta-Antagonists D004311:Double-Blind Method D004636:Emergency Service, Hospital D023381:Endpoint Determination D005260:Female D006333:Heart Failure D006760:Hospitalization D006801:Humans D053208:Kaplan-Meier Estimate D008297:Male D008875:Middle Aged D011412:Propanolamines D012008:Recurrence D018401:Sample Size D016896:Treatment Outcome
BEST endpoint heart failure recurrent events