Abstract 345: Non-inferiority Trials With a Primary Surrogate Endpoint: An Increasing Phenotype in Cardiovascular Trials

Abstract

Background: Non-inferiority trials are increasing in cardiovascular medicine, with approval of many drugs and devices on the basis of such studies. Surrogate endpoints have been also increasingly used for efficient assessment of cardiovascular interventions, but there is uncertainty about their concordance with clinical outcomes. Non-inferiority designs using a primary surrogate endpoint in cardiovascular trials may pose particular challenges in clinical interpretation. Methods: We searched six high-impact journals (NEJM, JAMA, Lancet, JACC, Circulation, and EHJ) from 01/01/1990-12/31/2018 and identified non-inferiority cardiovascular trials that used a primary surrogate endpoint. We assessed the non-inferiority margin reported in the manuscript and other publicly available platforms (e.g. protocol, clinicaltrials.gov). We determined whether surrogate outcome non-inferiority trials were followed by clinical outcome trials. Results: We screened 15,553 publications and identified 247 cardiovascular trials that used a non-inferiority design. Of these, 37 had a primary surrogate endpoint (18 drug trials, 13 device trials, 6 others). All of these non-inferiority trials with surrogate outcomes were published after 2000, mostly in cardiology journals (13 in JACC, 9 in European Heart Journal, 8 in Circulation, 6 in Lancet, 1 in NEJM), and their publication rate increased over time (P<0.001 for linear trend). The median number of patients in the primary analysis was 263 (IQR: 191 - 460). The study protocol or a methods paper was publicly available for only 12 (32.4%) trials, of which the non-inferiority margin was not reported in 4. In 16 (43.2%) studies the manuscript did not acknowledge the limitations of using a surrogate endpoint, or the need for a definitive clinical outcome trial. Thirty-four trials (91.9%) concluded that the tested intervention met non-inferiority ocriteria. However, only 3 (9.1%) were followed by clinical outcomes trials the results of which did not always confirm non-inferiority (Figure). Conclusion: Non-inferiority trials with a primary surrogate endpoint are being increasingly performed. However, these trials pose particular challenges with design, reporting and interpretation, which are not systematically and consistently addressed or reported.