Early and late recurrent cardiovascular events among high-risk patients with an acute coronary syndrome: Meta-analysis of phase III studies and implications on trial design

Background: Despite low-density lipoprotein cholesterol-lowering therapies and other standard-of-care therapy, there remains a substantial residual atherosclerotic risk among patients with an acute coronary syndrome (ACS). This study aims to estimate the risk of early and late recurrent major adverse cardiovascular events (MACE) and address its implications on trial design. Methods: A literature search was performed to collect phase III interventional trials on high-risk ACS patients. Pooled event rates at 90 and 360 days were estimated by fitting random-effects models using the DerSimonian–Laird method. Under the assumption of a total sample size of 10,000 and 1:1 allocation at a one-sided alpha of 0.025 using the log-rank test, the relationship between power and relative risk reduction (RRR) or absolute risk reduction (ARR) was explored for early versus late MACE endpoint. Results: Seven trials representing 82,727 recent ACS patients were analyzed. The pooled rates of recurrent MACE were 4.1% and 8.3% at 90 and 360 days. Approximately 49% of events occurred within the first 90 days. Based on the estimated risks at 90 and 360 days, to attain 90% statistical power, a lower magnitude of RRR is required for late MACE than early MACE (22% vs. 30%), whereas a lower magnitude of ARR is required for early MACE than late MACE (1.2% vs. 1.8%). Conclusion: The initial 90-day window after ACS represents a vulnerable period for recurrent events. From a trial design perspective, determining a clinically important benefit by RRR versus ARR may influence the decision between early and late MACE as the study endpoint.