title: Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST).
abstract: BACKGROUND
  Randomized controlled trials have reported lower mortality among patients who adhere to placebo compared with those who do not. We explored this phenomenon by reanalyzing data from the placebo arm of the Beta Blocker Evaluation of Survival Trial (BEST), a randomized, double-blind, placebo-controlled trial of bucindolol and mortality.
  
  
  OBJECTIVE
  Our primary aim was to measure and explain the association between adherence to placebo and total mortality among the placebo-allocated participants in the BEST trial. Secondary aims included assessment of the association between placebo adherence and cause-specific mortality.
  
  
  METHODS
  Participants with "higher placebo adherence" were defined as having taken at least 75% of their placebo study medication over the entire course of each individual's participation in the study, while those with "lower placebo adherence" took <75%. Primary outcome was in-study all-cause mortality. To account for confounding, we adjusted for all available modifiable, non-modifiable and psychosocial variables.
  
  
  RESULTS
  Adherent participants had a significantly lower total mortality compared to less-adherent participants (HR=0.61, 95% Confidence Interval: 0.46-0.82). Adjusting for available confounders did not change the magnitude or significance of the estimates. When considering cause-specific mortality, CVD and pump failure showed similar associations.
  
  
  CONCLUSIONS
  Analyses of the BEST trial data support a strong association between adherence to placebo study medication and total mortality. While probably not due to publication bias or simple confounding by healthy lifestyle factors, the underlying explanation for the association remains a mystery. Prospective examination of this association is necessary to better understand the underlying mechanism of this observation.
authors.affiliation: Division of Research, Kaiser Permanente Northern California; Oakland, CA 94612, United States. alice.pressman@kp.org
authors.forename: Alice
authors.initials: A
authors.lastname: Pressman
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Avins
authors.forename: John
authors.initials: J
authors.lastname: Neuhaus
authors.forename: Lynn
authors.initials: L
authors.lastname: Ackerson
authors.forename: Peter
authors.initials: P
authors.lastname: Rudd
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D016001:Confidence Intervals; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000401:mortality*; D053208:Kaplan-Meier Estimate; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D015990:Placebo Effect; D010919:Placebos / Q000494:pharmacology; D011412:Propanolamines / Q000627:therapeutic use*; D016896:Treatment Outcome; D014481:United States
chemical_list: D000319:Adrenergic beta-Antagonists; D010919:Placebos; D011412:Propanolamines; C024307:bucindolol