Data show ‘vulnerable window’ for recurrent ACS
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The initial 90‐day window after ACS represents a vulnerable period for recurrent events, possibly attributable to atherothrombosis mechanisms not currently addressed with optimal therapy, researchers reported.
Data from a meta-analysis of seven large phase 3 trials suggest that, from a trial design perspective, determining a clinically important benefit by relative risk reduction (RRR) compared with absolute risk reduction (ARR) may influence the decision between early and late major adverse CV events as the study endpoint.
“This report indicates that most recurrent ACS events occur early and that the statistical power to ascertain a treatment effect might be highest during the first 90 days after an ACS event,” C. Michael Gibson, MD, MS, consultant at Boston Clinical Research Institute, told Healio.
Despite LDL-lowering therapies and other standard of care therapy, there remains a substantial residual atherosclerotic risk among patients with ACS, Gibson and colleagues wrote in Clinical Cardiology.
“The primary aim of the study was to estimate the early (at 90 days) vs. late (at 360 days) risk of major adverse cardiovascular events (MACE) from recent landmark CV trials to better characterize the time course of the residual risk among patients who receive standard of care therapies following ACS,” the researchers wrote. “Furthermore, the incidence of early or late recurrent MACE and its potential implications with respect to statistical power has never been quantitatively assessed.”
Events across trials
Gibson and colleagues analyzed data from seven phase 3 interventional trials with 82,727 high‐risk patients with ACS, conducted through June 2019. Patients were followed for at least 12 months and the primary efficacy endpoint was MACE, defined as a composite of MI, stroke or CV death. Researchers estimated pooled event rates at 90 days and 360 days using meta-analytic approaches and explored the relationship between power and RRR or ARR for early vs. late MACE endpoints.
The pooled rates of recurrent MACE were 4.1% at 90 days and 8.3% at 360 days, with a high degree of heterogeneity across studies (P < .01). Approximately 49% of events occurred within the first 90 days.
“Therefore, the time course of residual atherosclerotic risk likely follows a nonlinear trajectory, with a steeper slope in the first 90 days, as opposed to the period after 90 days,” the researchers wrote. “Despite standard of care medications, the initial 90 days following an ACS episode should be considered as a vulnerable window for recurrent events.”
Statistical power of early vs. late events
The researchers applied two separate approaches to compute the statistical power for early vs. late MACE as the primary endpoint when prospectively designing an interventional trial. Based on the estimated risks at 90 days 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 events than late events (1.2% vs. 1.8%), Gibson and colleagues wrote.
The researchers noted exact patient‐level event rates at 90 days and at 360 days were not available; the results “only serve the purposes of hypothesis‐generating and benchmarking for trial design.” The timing of the index ACS event and treatment initiation also varied across the studies.
“When designing an interventional trial, a clinically important reduction in absolute risk vs. relative risk should be predetermined, as the decision affects the selection between early MACE vs. late MACE as the primary endpoint,” the researchers wrote.
For more information:
C. Michael Gibson, MD, MS, can be reached at charlesmichaelgibson@gmail.com.
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