title: Placebo adherence and mortality in the Heart and Estrogen/Progestin Replacement Study.
abstract: BACKGROUND
  Analyses from double-blind randomized trials have reported lower mortality among participants who were more adherent to placebo compared with those who were less adherent. We explored this phenomenon by analyzing data from the placebo arm of the Heart and Estrogen/Progestin Replacement Study (HERS), a randomized, double-blind, placebo-controlled trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Our primary aim was to measure and explain the association between adherence to placebo and total mortality among the placebo-allocated participants in the HERS. Secondary aims included assessment of the association between placebo adherence and cause-specific morbidity and mortality.
  
  
  METHODS
  Participants with "higher placebo adherence" were defined as having taken at least 75% of their placebo study medication during each individual's participation in the study, whereas those with "lower placebo adherence" took less than 75%. The primary outcome was in-study all-cause mortality.
  
  
  RESULTS
  More adherent participants had significantly lower total mortality compared with less adherent participants (hazard ratio, 0.52; 95% confidence interval, 0.29-0.93). Adjusting for available confounders did not change the magnitude or significance of the estimates. Analyses revealed that the association of higher adherence and mortality might be explained, in part, by time-dependent confounding.
  
  
  CONCLUSIONS
  Analyses of the HERS data support a strong association between adherence to placebo study medication and mortality. Although probably not due to simple confounding by healthy lifestyle factors, the underlying mechanism for the association remains unclear. Further analyses of this association are necessary to explain this observation.
authors: School of Public Health, University of California, Berkeley, CA, USA. ampadula@stanford.edu
authors: Amy M
authors: AM
authors: Padula
authors: Alice R
authors: AR
authors: Pressman
authors: Eric
authors: E
authors: Vittinghoff
authors: Deborah
authors: D
authors: Grady
authors: John
authors: J
authors: Neuhaus
authors: Lynn
authors: L
authors: Ackerson
authors: Peter
authors: P
authors: Rudd
authors: Andrew L
authors: AL
authors: Avins
mesh_terms: D000368:Aged; D002423:Cause of Death; D003327:Coronary Disease / Q000401:mortality* / Q000517:prevention & control*; D004311:Double-Blind Method; D015914:Estrogen Replacement Therapy / Q000401:mortality*; D005260:Female; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009369:Neoplasms / Q000401:mortality; D015990:Placebo Effect; D016016:Proportional Hazards Models; D012306:Risk; D014481:United States; D016903:Drug Monitoring