Effect of a Run‐In Period on Estimated Treatment Effects in Cardiovascular Randomized Clinical Trials: A Meta‐Analytic Review

Abstract

Background A run‐in period may increase adherence to intervention and reduce loss to follow‐up. Whether use of a run‐in period affects the magnitude of treatment effects is unknown. Methods and Results We conducted a meta‐analysis comparing treatment effects from 11 systematic reviews of cardiovascular prevention trials using a run‐in period with matched trials not using a run‐in period. We matched run‐in with non–run‐in trials by population, intervention, control, and outcome. We calculated a ratio of relative risks (RRRs) using a random‐effects meta‐analysis. Our primary outcome was a composite of cardiovascular events, and the primary analysis was a matched comparison of clinical trials using a run‐in period versus without a run‐in period. We identified 66 run‐in trials and 111 non–run‐in trials (n=668 901). On meta‐analysis there was no statistically significant difference in the magnitude of treatment effect between run‐in trials (relative risk [RR], 0.83 [95% CI, 0.80–0.87]) compared with non–run‐in trials (RR, 0.88 [95% CI, 0.84–0.91]; RRR, 0.95 [95% CI, 0.90–1.01]). There was no significant difference in the RRR for secondary outcomes of all‐cause mortality (RRR, 0.97 [95% CI, 0.91–1.03]) or medication discontinuation because of adverse events (RRR, 1.05 [95% CI, 0.85–1.21]). Post hoc exploratory univariate meta‐regression showed that on average a run‐in period is associated with a statistically significant difference in treatment effect (RRR, 0.94 [95% CI, 0.90–0.99]) for cardiovascular composite outcome, but this was not statistically significant on multivariable meta‐regression analysis (RRR, 0.95 [95% CI, 0.90–1.0]). Conclusions The use of a run‐in period was not associated with a difference in the magnitude of treatment effect among cardiovascular prevention trials.

Keywords

• cardiovascular prevention
• meta‐analysis
• run‐in
• trial methodology