Reference: N Engl J Med. 2021 May 27;384(21):1981-1990
For patients with established cardiovascular disease, it’s clear that aspirin reduces the risk of subsequent events and improves overall survival. However, the evidence and guidelines are fuzzy on the optimal dose of aspirin therapy for secondary prevention. Investigators set out to answer this question in a pragmatic trial design comparing the efficacy of 81 mg vs. 325 mg aspirin therapy in routine clinical practice.
In this open-label trial, patients with known atherosclerotic cardiovascular disease were recruited at 40 centers throughout the US. Investigators sent invitations to nearly five million eligible patients through electronic patient portals but at 1 year were unable to meet the prespecified sample size of 20,000 patients. After adjusting the power analysis, 15,000 patients were randomized to 81 mg or 325 mg of aspirin. Patients were instructed to purchase the medication over the counter. Baseline data were collected via patient report, mostly through the online patient portal and electronic health records. More than half of patients had prior coronary revascularization (53.6% with 81 mg vs. 52.4% with 325 mg); 20% of patients in both groups reported taking a P2Y12 inhibitor and nearly all were taking aspirin at the start of the trial. During a median follow-up of 26.2 months, patients were contacted via telephone and email every 3-6 months to ask about adherence, current medications, and patient-reported outcomes. Outcomes were also ascertained through private health plans, Medicare and Medicaid claims, and electronic health records.
The primary outcome, a composite of death from any cause, hospitalization due to myocardial infarction, or hospitalization due to stroke, occurred in 7.3% of the 81 mg group and 7.5% of the 325 mg group (not significant). Rates of the individual components of the composite were also similar in the two groups. Major bleeding requiring hospitalization for transfusion occurred in 0.63% of the 81 mg group and 0.6% of the 325 mg group (not significant). Patients randomized to 325 mg had higher rates of discontinuation (11.1% vs. 7% in the 81 mg group). They also had much higher rates of dose switching; 41.6% of patients randomized to 325 mg switched to 81 mg, while 7.1% of those randomized to 81 mg switched to 325 mg. In a modified per-protocol analysis using reported aspirin dose over time, the rate of the primary outcome was higher in the 81 mg group than in the 325 mg group (HR 1.25, 95% CI 1.1-1.43).
Recruiting and ascertaining outcomes using a large administrative database makes such a large trial practical but leaves it susceptible to multiple forms of bias. The investigators adjusted the power analysis at 1 year and extended the study by 6 months despite having a higher than expected event rate. The sub-target enrollment and high crossover rate to the 81 mg group both favor a null outcome and limit the ability to detect harm from the higher dose of aspirin. This trial demonstrates that patients seem to prefer 81 mg of aspirin to a higher dose. At the same time, the trial failed to clearly demonstrate that using a higher dose has superior clinical effectiveness for secondary prevention of cardiovascular events.
For more information, see the topic Antiplatelet and Anticoagulant Drugs for Coronary Artery Disease Aspirin Efficacy in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Carina Brown, MD, Assistant Professor at Cone Health Family Medicine Residency. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School, Dan Randall, MD, Deputy Editor for Internal Medicine at DynaMed, and Katharine DeGeorge, MD, MS, Associate Professor of Family Medicine at the University of Virginia and Clinical Editor at DynaMed.