title: Influence of global region on outcomes in heart failure β-blocker trials.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine, Division of Cardiology, Division of Clinical Pharmacology, Duke University Medical Center, Durham, North Carolina, USA. oconn002@mc.duke.edu
authors.forename: Christopher M
authors.initials: CM
authors.lastname: O'Connor
authors.forename: Mona
authors.initials: M
authors.lastname: Fiuzat
authors.forename: Karl
authors.initials: K
authors.lastname: Swedberg
authors.forename: Michael
authors.initials: M
authors.lastname: Caron
authors.forename: Bruce
authors.initials: B
authors.lastname: Koch
authors.forename: Peter E
authors.initials: PE
authors.lastname: Carson
authors.forename: Wendy
authors.initials: W
authors.lastname: Gattis-Stough
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Davis
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000368:Aged; D005260:Female; D014943:Global Health; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic / Q000379:methods; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D015996:Survival Rate; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
chemical_list: D000319:Adrenergic beta-Antagonists