Adherence-adjustment in placebo-controlled randomized trials: An application to the candesartan in heart failure randomized trial.

Journal Article (Journal Article)


The per-protocol effect provides important information in randomized trials with incomplete adherence. Yet, because valid estimation typically requires adjustment for prognostic factors that predict adherence, per-protocol effect estimates are often met with skepticism. In placebo-controlled trials, however, the validity of adjustment can be indirectly verified by demonstrating no association between adherence and the outcome among the placebo arm. Here, we describe a two-stage procedure in which we first adjust for time-varying adherence in the placebo arm and then use a similar procedure to estimate the per-protocol effect.


We use the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) randomized trial. First, we compare adherers versus non-adherers in the placebo arm, adjusting for pre- and post-randomization variables. Second, we use models validated in the placebo arm to estimate the per-protocol effect of adherence to candesartan versus placebo in the full trial.


We successfully estimated no association between adherence and mortality in the placebo arm; hazard ratio: 0.91 (95% CI: 0.51, 2.52). We then estimated the per-protocol effect under two sets of protocol-defined stopping criteria after adjustment for post-randomization confounders. The mortality hazard ratio estimates ranged from 0.91 to 0.93 for the per-protocol effect estimates, similar to the intention-to-treat effect estimates.


Adherence adjustment in the CHARM trial is feasible when appropriate assumptions about missing data and confounding are made. These assumptions cannot be verified but can be supported through the use of placebo-arm adherence assessment.

Full Text

Duke Authors

Cited Authors

  • Murray, EJ; Claggett, BL; Granger, B; Solomon, SD; Hernán, MA

Published Date

  • March 2020

Published In

Volume / Issue

  • 90 /

Start / End Page

  • 105937 -

PubMed ID

  • 31982649

Electronic International Standard Serial Number (EISSN)

  • 1559-2030

International Standard Serial Number (ISSN)

  • 1551-7144

Digital Object Identifier (DOI)

  • 10.1016/j.cct.2020.105937


  • eng