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.