Abstract 041: Trends in Publication and Methodological Quality of Major Non-inferiority Cardiovascular Trials From 1990-2016: a Systematic Review

Abstract

Introduction: Randomized controlled trials (RCTs) designed to demonstrate non-inferiority of an intervention compared with control have become increasingly common in cardiovascular medicine. Such RCTs may be biased toward null findings through low enrollment, post-randomization exclusions, loss to follow-up, or wide inferiority margins. We characterized the features of non-inferiority cardiovascular RCTs published in high-impact journals that could lead to bias. Methods: We searched PubMed for non-inferiority cardiovascular RCTs published between January 1, 1990 and August 11, 2016 in The New England Journal of Medicine, Lancet , and JAMA . We reviewed methodological characteristics, including sample size, power estimates, selected non-inferiority margin, and success of studies in achieving non-inferiority. Results: Of 3,689 screened studies, we identified 104 non-inferiority RCTs. Publication increased over time (P<0.001), as more than 50% (n=53) were published since 2010. Of 101 trials with eligible data, 80 (77%) trials claimed non-inferiority (19 of which also demonstrated superiority), whereas 21 (20%) did not (including 7 which showed worse outcomes with the tested intervention, and 14 that had inconclusive results, Figure). Only 1 study had >10% of participants lost to follow-up. Of 75 studies with available data, 14 reported >10% post-randomization exclusions. Of 89 studies with available information, 10 analyzed a cohort >20% smaller than their calculated sample size. Only 55 studies (53%) reported all the randomized patients in the primary endpoint analyses. Only 52 trials (50%) reported analyses from both the intention-to-treat and per-protocol cohorts, of which 2 found a discrepancy in analyses. Treatment adherence was reported in 18 trials (34%). Pre-specified non-inferiority margins ranged widely, with absolute differences between 0.4-14%, hazard ratios between 1.05-2.85, odds ratios between 1.1-2.0, and relative risks between 1.1-2.0. Only 9 studies (8.7%) used a placebo or no-intervention arm. Conclusion: Non-inferiority designed RCTs in cardiovascular medicine are increasingly published in high-impact journals, commonly conclude non-inferiority of the new intervention, and frequently have design features that might bias the studies toward non-inferiority.