Targeting a hypothetical estimand based on adherence with the parametric g-formula: A post hoc secondary analysis of the MET-PREVENT randomised controlled trial

Background We conducted a post hoc secondary analysis of the MET-PREVENT randomised placebo-controlled trial to target a hypothetical estimand - the mean difference in physical performance, as measured by the 4-metre walk speed at four months after randomisation, between treatment arms - under the hypothetical scenario that all participants adhered to assigned treatment. Methods We viewed the targeting of this hypothetical estimand as a type of causal mediation problem, where randomisation 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-metre 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 [percentile-based bootstrap 95% CI -0.292, 0.445]. Results from PBA indicated that the greater the extent of misclassification, the more the CDE may be estimated with bias and with over-optimistic precision. Conclusions Our study provided supporting information on metformin's potential role as a repurposed medication to improve physical performance in nondiabetic older adult patients with physical prefrailty/frailty and probable sarcopenia. Unlike the main trial results, our results do not rule out the possibility of a meaningful benefit of metformin, provided that full adherence can be assured. We highlighted the parametric g-formula as a useful method in trials to target hypothetical estimands that are concerned with treatment adherence.