Re-Examination of the BEST Trial Using Composite Outcomes, Including Emergency Department Visits

Li Shen; Pardeep S. Jhund; Ulrik M. Mogensen; Lars Køber; Brian Claggett; Jennifer K. Rogers; John J.V. McMurray

doi:10.1016/j.jchf.2017.04.005

Re-Examination of the BEST Trial Using Composite Outcomes, Including Emergency Department Visits

Li Shen, Pardeep S. Jhund, Ulrik M. Mogensen, Lars Køber, Brian Claggett, Jennifer K. Rogers, John J.V. McMurray^*

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

10 Citationer (Scopus)

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)

Originalsprog	Engelsk
Tidsskrift	JACC: Heart Failure
Vol/bind	5
Udgave nummer	8
Sider (fra-til)	591-599
Antal sider	9
ISSN	2213-1779
DOI	https://doi.org/10.1016/j.jchf.2017.04.005
Status	Udgivet - aug. 2017

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10.1016/j.jchf.2017.04.005

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@article{acd24e1e745446f79b8fae826a0e1717,

title = "Re-Examination of the BEST Trial Using Composite Outcomes, Including Emergency Department Visits",

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)",

keywords = "BEST, endpoint, heart failure, recurrent events",

author = "Li Shen and Jhund, {Pardeep S.} and Mogensen, {Ulrik M.} and Lars K{\o}ber and Brian Claggett and Rogers, {Jennifer K.} and McMurray, {John J.V.}",

year = "2017",

month = aug,

doi = "10.1016/j.jchf.2017.04.005",

language = "English",

volume = "5",

pages = "591--599",

journal = "J A C C: Heart Failure",

issn = "2213-1779",

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number = "8",

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TY - JOUR

T1 - Re-Examination of the BEST Trial Using Composite Outcomes, Including Emergency Department Visits

AU - Shen, Li

AU - Jhund, Pardeep S.

AU - Mogensen, Ulrik M.

AU - Køber, Lars

AU - Claggett, Brian

AU - Rogers, Jennifer K.

AU - McMurray, John J.V.

PY - 2017/8

Y1 - 2017/8

N2 - 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)

AB - 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)

KW - BEST

KW - endpoint

KW - heart failure

KW - recurrent events

U2 - 10.1016/j.jchf.2017.04.005

DO - 10.1016/j.jchf.2017.04.005

M3 - Journal article

C2 - 28774394

AN - SCOPUS:85026544019

SN - 2213-1779

VL - 5

SP - 591

EP - 599

JO - J A C C: Heart Failure

JF - J A C C: Heart Failure

IS - 8

ER -

Re-Examination of the BEST Trial Using Composite Outcomes, Including Emergency Department Visits

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