Early and Late Recurrent Cardiovascular Risk in Patients With Recent Acute Coronary Syndrome: Meta-Analysis and Implications in Trial Design†

Abstract

Lead Author's Financial Disclosures G.C. has receieved research grant support to the Beth Israel Deaconess Medical Center, Harvard Medical School from Portola Pharmaceuticals, Bayer, Janssen Scientific Affairs, and CSL Beh-ring. Study Funding CSL Behring. Background/Synopsis Despite optimal medical therapy, a substantial residual atherosclerotic risk exists among patients with an acute coronary syndrome (ACS). Objective/Purpose This study aimed to estimate the risk of early and late major adverse cardiovascular events (MACE) and address its implications in trial design. Methods A comprehensive search was performed to collect phase III interventional trials on high-risk ACS patients. Pooled event rates at 90 and 360 days were estimated with meta-analytic approaches by fitting a random-effects model using the DerSimonian-Laird method. Using the log-rank test (n=10,000; 1-sided α=0.025)), the relationship between power and relative risk reduction (RRR) or absolute risk reduction (ARR) was explored for early vs. late MACE endpoint. Results A total of 82,727 high-risk patients with recent ACS from 7 trials were analyzed. Pooled rates of recurrent MACE were 4.1% (95% CI: 3.0% to 5.7%) at 90 days and 8.3% (95% CI: 7.1% to 9.8%) at 360 days. Approximately 49% of events occurred within the first 90 days. To attain 90% statistical power, a lower RRR is required for late MACE (22% vs. 30%), whereas a lower ARR is required for early MACE (1.2% vs. 1.8%). Conclusions The initial 90-day window after an ACS event represents a vulnerable period for recurrent MACE. From a trial design perspective, determining a clinically important benefit by relative vs. absolute risk reduction may influence the choice between early vs. late MACE as the study endpoint. G.C. has receieved research grant support to the Beth Israel Deaconess Medical Center, Harvard Medical School from Portola Pharmaceuticals, Bayer, Janssen Scientific Affairs, and CSL Beh-ring.