title: Falling Cardiovascular Mortality in Heart Failure With Reduced Ejection Fraction and Implications for Clinical Trials.
abstract: OBJECTIVE
  This study examined the trends in the relative contributions of cardiovascular and noncardiovascular mortality to total mortality according to use of beta-blockers in clinical trials of patients with heart failure with reduced ejection fraction (HF-REF).
  
  
  BACKGROUND
  With the increasingly widespread use of disease-modifying therapies, particularly beta-blockers, in HF-REF, the proportion of patients dying from cardiovascular causes is likely to be decreasing.
  
  
  METHODS
  In a systematic review, 2 investigators independently searched online databases to identify clinical trials including >400 patients with chronic heart failure published between 1986 and 2014 and that adjudicated cause of death. Trials were divided into 3 groups on the basis of the proportion of patients treated with a beta-blocker (<33% [low], 33% to 66% [medium], and >66% [high]). Percentages of total deaths adjudicated as cardiovascular or noncardiovascular were calculated by weighted means and weighted standard deviations. Weighted Student t tests were used to compare results between groups.
  
  
  RESULTS
  Sixty-six trials met the inclusion criteria with a total of 136,182 patients and 32,140 deaths. There was a sequential increase in the percentage of noncardiovascular deaths with increasing beta-blocker use from 11.4% of all deaths in trials with low beta-blocker use to 19.1% in those with high beta-blocker use (p < 0.001).
  
  
  CONCLUSIONS
  In trials of patients with HF-REF, the proportion of deaths adjudicated as cardiovascular has decreased. Cardiovascular mortality, and not all-cause mortality, should be used as an endpoint for trials of new treatments for HF-REF.
authors.affiliation: Hairmyres Hospital, East Kilbride, Scotland, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rush
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Ross T
authors.initials: RT
authors.lastname: Campbell
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Pardeep S
authors.initials: PS
authors.lastname: Jhund
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Connolly
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Preiss
authors.affiliation: Golden Jubilee National Hospital, Glasgow, Scotland, United Kingdom.
authors.forename: Roy S
authors.initials: RS
authors.lastname: Gardner
authors.affiliation: Golden Jubilee National Hospital, Glasgow, Scotland, United Kingdom.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Petrie
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom. Electronic address: john.mcmurray@glasgow.ac.uk.
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000401:mortality*; D002423:Cause of Death / Q000639:trends*; D005544:Forecasting; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis
chemical_list: D000319:Adrenergic beta-Antagonists
keywords: beta-blocker; cause of death; heart failure; heart failure with reduced ejection fraction; mode of death