Per-Protocol analyses produced larger treatment effect sizes than intention to treat: a meta-epidemiological study

Objective To undertake meta-analysis and compare treatment effects estimated by the intention-to-treat (ITT) method per-protocol (PP) in randomized controlled trials (RCTs). PP excludes trial participants who are non-adherent to protocol terms of eligibility, interventions, or outcome assessment. Study design setting Five high impact journals were searched for all RCTs published between July 2017 June 2019. Primary was a pooled estimate that quantified difference two methods. Results presented as ratio odds ratios (ROR). Meta-regression used explore association level non-adherence effect. Sensitivity analyses compared results with varying within-study correlations across various study characteristics. Random-effects (N = 156) showed estimates on average 2% greater ITT (ROR: 1.02, 95% CI: 1.00–1.04, P 0.03). The divergence further increased higher degree non-adherence. reassured consistent Conclusion There evidence larger effect analysis. analysis should not be assess RCTs. Instead, addition ITT, investigators consider randomization based casual such Complier Average Causal Effect (CACE).