Endpoint selection for noninferiority percutaneous coronary intervention trials: a methodological description

Abstract

Background: The objective of this review is to provide a practical update on endpoint selection for noninferiority (NI) studies in percutaneous coronary intervention studies. Methods: A PubMed search was conducted for predefined terms to explore the use of NI designs and intrapatient comparisons to determine their current importance. Sample size calculations for the most frequently used endpoints with NI hypotheses were done to increase statistical awareness. Results: Reported NI trials, with the most frequently chosen clinical endpoint of major adverse cardiac events (MACE), had NI margins ranging from 1.66% to 5.00%, resulting in patient populations of 400–1500 per treatment group. Clinical study endpoints comprising of MACE complemented with rates of bleeding complications and stent thrombosis (ST) are suggested to conduct a statistically and clinically meaningful NI trial. Study designs with surrogate endpoints amenable to intrapatient randomizations, are a very attractive option to reduce the number of necessary patients by about half. Comparative clinical endpoint studies with MACE and ST/bleeding rates to study a shortened dual antiplatelet therapy (DAPT) in coronary stent trials are feasible, whereas ST as the sole primary endpoint is not useful. Conclusions: Expanded composite clinical endpoints (MACE complemented by ST and bleeding rates and intrapatient randomization for selected surrogate endpoints) may be suitable tools to meet future needs in device approval, recertification and reimbursement.

Decrementally cost-effective health technologies in non-inferiority studies: A systematic review

“…The comparability of study results was limited by the heterogeneity of endpoints in studies that did not use QALYs, and by the lack of standardization in the selection of non-inferiority margins for clinical trials ( Waliszewski et al, 2020 ). We did not address the ethical process of ensuring that disinvestment decisions are acceptable by the population at large ( Pace et al, 2020 ).…”

Noninferiority Margins in Clinical Trials—A Moving Target?

“…Most of the trials investigated by Simonato et al assumed control event rates of approximately 10%, which were overestimations vs the rates observed in the trials. As a result, the prespecified NIMs were relatively more permissive than anticipated during the study design …”