Investigating causal mechanisms in randomised controlled trials

INTRODUCTION: In some randomised trials, the primary interest is in the mechanisms by which an intervention exerts its effects on health outcomes. That is, clinicians and policy-makers may be interested in how the intervention works (or why it does not work) through hypothesised causal mechanisms. In this article, we highlight the value of understanding causal mechanisms in randomised trials by applying causal mediation analysis to two randomised trials of complex interventions. MAIN BODY: In the first example, we examine a potential mechanism by which an exercise programme for rheumatoid arthritis of the hand could improve hand function. In the second example, we explore why a rehabilitation programme for ankle fractures failed to improve lower-limb function through hypothesised mechanisms. We outline critical assumptions that are required for making valid causal inferences from these analyses, and provide results of sensitivity analyses that are used to assess the degree to which the estimated causal mediation effects could have been biased by residual confounding. CONCLUSION: This paper demonstrates how the application of causal mediation analyses to randomised trials can identify the mechanisms by which complex interventions exert their effects. We discuss methodological issues and assumptions that should be considered when mediation analyses of randomised trials are used to inform clinical practice and policy decisions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13063-019-3593-z) contains supplementary material, which is available to authorized users.