Applying a hypothetical strategy to the intercurrent event of non-adherence with the parametric g-formula: a post hoc secondary analysis of the MET-PREVENT randomised controlled trial
Abstract
BACKGROUND: We conducted a post hoc secondary analysis of the MET-PREVENT randomised placebo-controlled trial to target an estimand that uses a hypothetical strategy on the intercurrent event of non-adherence.
METHODS: We viewed the targeting of this estimand that uses a hypothetical strategy to handle the intercurrent event of non-adherence as a type of causal mediation problem, where randomised treatment is a binary exposure, adherence is a binary mediator, there is an exposure-mediator interaction, and mediator-outcome confounders that are caused by the exposure (e.g. gastrointestinal symptoms) are present. We used the parametric g-formula to estimate the average controlled direct effect (CDE) of metformin (versus placebo) on 4-m walk speed, which is interpreted as the average treatment effect under the hypothetical scenario that all trial participants adhered to assigned treatment. Variables identified as confounders were informed by a literature review and discussions with an expert; assumptions about the causal structure were represented in a directed acyclic graph. We applied a probabilistic bias analysis (PBA) to understand the potential for bias assuming adherence had been misclassified; observed adherence based on returned tablet count may be an inaccurate version of "true adherence" based on actual consumption.
RESULTS: Our sample size was 70 trial participants (34 metformin, 36 placebo). Our estimate of the CDE was 0.072 m/s (percentile-based bootstrap 95% CI -…
How strong is the evidence?
Evidence Hub reads this as a secondary / pooled analysis, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 70 participants or records.
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