Improved adherence adjustment in the Coronary Drug Project

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: Adherence; Coronary Drug Project; Intention-to-treat effect; Inverse-probability weighting; Per-protocol effect.

Conflict of interest statement

Ethics approval

This project was reviewed and exempted by the Harvard T.H. Chan School of Public Health IRB office. No consent was needed from study participants.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

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