Consequences of Inaccurate Assumptions in Coronary Stent Noninferiority Trials: A Systematic Review and Meta-analysis

IMPORTANCE: The outcome and interpretation of noninferiority trials depend on the magnitude of the noninferiority margin and whether a relative or absolute noninferiority margin is used and may be affected by imprecision in event rate estimation. OBJECTIVE: To assess the consequence of imprecise event rate estimations on interpretation of peer-reviewed randomized clinical trials. DATA SOURCES: PubMed/MEDLINE was searched for articles published between January 1, 2015, and April 30, 2021. STUDY SELECTION: Noninferiority randomized clinical trials of coronary stents published in selected journals with clinical events as the primary end point. DATA EXTRACTION AND SYNTHESIS: Two reviewers (M.S. and F.V.) independently extracted data on trial characteristics, noninferiority assumptions, primary end point clinical outcomes, and study conclusions. Overestimation or underestimation of the control event rate was evaluated by dividing the assumed control event rate by the observed control event rate. For noninferiority end points with absolute margins, the assumed corresponding relative margin was defined as the ratio of the absolute margin and the assumed event rate, and the observed corresponding relative margin as the ratio between the absolute margin and the observed event rate in the control arm. Noninferiority comparisons with absolute margins were reanalyzed using the assumed corresponding relative margin and the Farrington-Manning score test for relative risk. MAIN OUTCOMES AND MEASURES: Overestimation or underestimation, assumed and observed corresponding relative margins, and relative reanalysis of the primary end points of trials with absolute margins. RESULTS: A total of 106 989 patients from 58 trials were included. The event rate in the control arms was overestimated by a median (IQR) of 28% (2%-74%). Most noninferiority trials used absolute rather than relative margins (55 of 58 trials [94.8%]). Owing to overestimation, absolute noninferiority margins became more permissive than originally assumed (median [IQR] of observed relative noninferiority margin, 1.62 [1.50-1.80] vs assumed relative noninferiority margin, 1.47 [1.39-1.55]; P < .001). Among trial comparisons that met noninferiority with an absolute noninferiority margin, 17 of 50 trials (34.0%) would not have met noninferiority with a corresponding assumed relative noninferiority margin. CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, assumed event rates were often overestimated in noninferiority coronary stent trials. Because most of these trials use absolute margins to define noninferiority, such overestimation results in excessively permissive relative noninferiority margins.