Adherence adjustment in the Coronary Drug Project: A call for better per-protocol effect estimates in randomized trials

Abstract

Background: In many randomized controlled trials, patients and doctors are more interested in the per-protocol effect than in the intention-to-treat effect. However, valid estimation of the per-protocol effect generally requires adjustment for prognostic factors associated with adherence. These adherence adjustments have been strongly questioned in the clinical trials community, especially after 1980 when the Coronary Drug Project team found that adherers to placebo had lower 5-year mortality than non-adherers to placebo.

Methods: We replicated the original Coronary Drug Project findings from 1980 and re-analyzed the Coronary Drug Project data using technical and conceptual developments that have become established since 1980. Specifically, we used logistic models for binary outcomes, decoupled the definition of adherence from loss to follow-up, and adjusted for pre-randomization covariates via standardization and for post-randomization covariates via inverse probability weighting.

Results: The original Coronary Drug Project analysis reported a difference in 5-year mortality between adherers and non-adherers in the placebo arm of 9.4 percentage points. Using modern approaches, we found that this difference was reduced to 2.5 (95% confidence interval: -2.1 to 7.0).

Conclusion: Valid estimation of per-protocol effects may be possible in randomized clinical trials when analysts use appropriate methods to adjust for post-randomization variables.

Keywords: Coronary Drug Project; Per-protocol effect; adherence; intention-to-treat effect; inverse probability weighting.

Conflict of interest statement

Conflict of interest statement: The Authors declare that there is no conflict of interest.

© The Author(s) 2016.

Figures

Figure A1

Censoring scheme for re-analyses of the Coronary Drug Project. Lt is the vector of covariates measured at visit t and At is an indicator for adherence level for the period from t to just before t+1. When an individual misses a study visit, the most recent covariate and adherence values are carried over from the previous inter-visit period. An individual is censored at the date of their third consecutive missed study visit. Covariates are therefore carried forward up to two consecutive missed visits, and adherence is carried forward up to three intervals between missed visits.

Figure 1

Study timeline, Coronary Drug Project. Timing of study visits and variable measurement. Lt is the vector of post-randomization covariates measured at visit t and At is an indicator for adherence level for the period from t to just before t+1 measured at visit t+1. A0 is measured at follow-up visit 1 (FV1) or, for individuals who died or dropped out before FV1, at IV4 and IV5.