Improved adherence adjustment in the Coronary Drug Project

Abstract

Abstract Background The survival difference between adherers and non-adherers to placebo in the Coronary Drug Project has been used to support the thesis that adherence adjustment in randomized trials is not generally possible and, therefore, that only intention-to-treat analyses should be trusted. We previously demonstrated that adherence adjustment can be validly conducted in the Coronary Drug Project using a simplistic approach. Here, we re-analyze the data using an approach that takes full advantage of recent methodological developments. Methods We used inverse-probability weighted hazards models to estimate the 5-year survival and mortality risk when individuals in the placebo arm of the Coronary Drug Project adhere to at least 80% of the drug continuously or never during the 5-year follow-up period. Results Adjustment for post-randomization covariates resulted in 5-year mortality risk difference estimates ranging from − 0.7 (95% confidence intervals (CI), − 12.2, 10.7) to 4.5 (95% CI, − 6.3, 15.3) percentage points. Conclusions Our analysis confirms that appropriate adjustment for post-randomization predictors of adherence largely removes the association between adherence to placebo and mortality originally described in this trial. Trial registration ClinicalTrials.gov, Identifier: NCT00000482. Registered retrospectively on 27 October 1999.

Keywords

• Per-protocol effect
• Intention-to-treat effect
• Inverse-probability weighting
• Coronary Drug Project
• Adherence