Understanding the Merits and Drawbacks of Noninferiority Trials in Cardiovascular Medicine

Abstract

A noninferiority trial is designed to show that the new treatment is not unacceptably worse than the standard treatment by more than a predefined noninferiority margin. These trials are typically performed when standard placebo-controlled trials are considered to be unethical or impractical and the new treatment offers advantages over the existing standard treatment in terms of safety, convenience, or cost. Given that noninferiority trials are being performed with increasing frequency in cardiovascular applications, it is important to understand their complex trial design and analysis. This narrative review aims to provide readers with a detailed perspective on the goals, characteristics, design, and analysis of noninferiority trials. Trials designed to show noninferiority require an appropriate reference population, a proven standard treatment and dose, an appropriate margin of noninferiority that is statistically justifiable (based on historical placebo-controlled trials evaluating standard treatment effect) and clinically reasonable (choosing the fraction of the effect of the standard drug that should be "preserved" by the new drug), a high level of adherence to treatment, and adequate statistical power to reliably conclude that a treatment is truly noninferior and therefore effective. The merits and pitfalls of noninferiority trials, with representative contemporary cardiovascular clinical trials in interventional cardiology, cardiac surgery, and atrial fibrillation management as exemplars, are described. The key issues that challenge the design, conduct, analysis, interpretation, and implementation of these trials are discussed, and a variety of ways to identify and mitigate key errors are recommended to allow for optimal evaluation of noninferiority trials conducted in cardiovascular medicine.