Improving rheumatoid arthritis comparative effectiveness research through causal inference principles: systematic review using a target trial emulation framework.

Target trial emulation is an intuitive design framework that encourages investigators to formulate their comparative effectiveness research (CER) question as a hypothetical randomised controlled trial (RCT). Our aim was to systematically review CER studies in rheumatoid arthritis (RA) to provide examples of design limitations that could be avoided using target trial emulation, and how these limitations might introduce bias.We searched for head-to-head CER studies of biologic disease modifying anti-rheumatic drugs (DMARDs) in RA. Study designs were reviewed for seven components of the target trial emulation framework: eligibility criteria, treatment strategies, assignment procedures, follow-up period, outcome, causal contrasts of interest (ie, intention-to-treat (ITT) or per-protocol effect) and analysis plan. Hypothetical trials corresponding to the reported methods were assessed to identify design limitations that would have been avoided with an explicit target trial protocol. Analysis of the primary effectiveness outcome was chosen where multiple analyses were performed.We found 31 CER studies, of which 29 (94%) had at least one design limitation belonging to seven components. The most common limitations related to: (1) eligibility criteria: 19/31 (61%) studies used post-baseline information to define baseline eligibility; (2) causal contrasts: 25 (81%) did not define whether ITT or per-protocol effects were estimated and (3) assignment procedures: 13 (42%) studies did not account for confounding by indication or relied solely on statistical confounder selection.Design limitations were found in 94% of observational CER studies in RA. Target trial emulation is a structured approach for designing observational CER studies that helps to avoid potential sources of bias.

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