Clinical Research
Heart Failure
Influence of Global Region on Outcomes in Heart Failure Beta-Blocker Trials

https://doi.org/10.1016/j.jacc.2011.03.057Get rights and content
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Objectives

We sought to describe the United States and the rest of the world (ROW) outcomes from the major β-blocker heart failure (HF) trials.

Background

HF trials have demonstrated differences in outcomes by geographic region.

Methods

Randomized, double-blind, placebo-controlled studies that evaluated β-blockers in HF patients, had a primary endpoint of mortality, and enrolled U.S. patients were included. Relative risk (RR) was calculated for patients enrolled in the United States and ROW. Meta-analysis of the combined mortality rates was performed using the Cochran-Mantel-Haenszel statistic, stratified by study.

Results

A total of 8,988 patients were enrolled in the MERIT-HF (Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure), COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival trial), and BEST (β-Blocker Evaluation of Survival Trial) combined; 4,198 (46.7%) were from the United States. In the U.S. cohort, the RR reduction for each β-blocker was of smaller magnitude than in the overall cohort and no longer significant, whereas in the ROW subgroup, the mortality benefit for β-blockade persisted. In the pooled analysis (n = 11,635), the RR of death was reduced by 23% (p < 0.001) with β-blockade compared with placebo. In contrast, the mortality reduction associated with β-blockade in the U.S. cohort was small and not statistically significant (RR: 0.92, 95% confidence interval [CI]: 0.82 to 1.02, p = 0.11). The survival benefit persisted in the ROW cohort (RR: 0.64, 95% CI: 0.56 to 0.72, p < 0.001).

Conclusions

Among patients enrolled in the United States, β-blockade was associated with a lower magnitude of survival benefit, whereas the ROW response was similar to the total study population. This geographic difference in treatment response may be a reflection of population differences, genetics, cultural or social differences in disease management, or low power and statistical chance.

Key Words

adrenergic beta-antagonists
geography
heart failure
mortality

Abbreviations and Acronyms

CI
confidence interval
HF
heart failure
ICD
implantable cardioverter-defibrillator
ROW
rest of the world
RR
relative risk

Cited by (0)

Statistical support was provided by ARCA biopharma, Inc. Dr. O'Connor is a consultant for Merck & Co., Inc., Trevena, Novella, Forest, Pfizer Inc., GE Healthcare, Roche, Medtronic, Amgen, MedPace, Martek, Actelion, and JNJ. Dr. Fiuzat is a consultant for Roche Diagnostics, Forest, and ARCA biopharma, Inc., and is a shareholder of ARCA biopharma, Inc. Dr. Caron is an employee of Gilead Sciences and a shareholder of ARCA biopharma, Inc. Dr. Koch is a shareholder of ARCA biopharma, Inc. Mr. Davis is an employee of ARCA biopharma, Inc. Dr. Bristow is the founder and CEO of ARCA biopharma, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. O'Connor and Fiuzat contributed equally to this work.