In a trial designed to try to answer the longstanding question of the optimal dose of aspirin for secondary prevention in patients with established atherosclerotic cardiovascular disease, no significant difference was found in cardiovascular events or major bleeding between the 81 mg and 325 mg daily doses, according to results of the ADAPTABLE study presented May 15 during ACC.21 and simultaneously published in the New England Journal of Medicine.

The open-label pragmatic trial is the first to use the National Patient-Centered Clinical Research Network (PCORnet) – an integrated partnership of clinical research networks funded by the Patient-Centered Outcomes Research Institute (PCORI) – which also funded the study.

William Schuyler Jones, MD, FACC, et al., looked at 15,076 patients from 40 centers across the U.S. who were self-enrolled and self-randomized between April 2016 through June 2019. The two groups were well balanced at baseline. Participants were a median age of 67 years and the majority were White, with 9%, 3% and 1% self-reporting as Black, Hispanic and Asian, respectively. About 30% were women. At enrollment, 35.3% had a history of myocardial infarction (MI) and 53% had a coronary revascularization within the previous five years.

Results showed over the median 26.2 months of follow-up, 590 patients in the 81 mg group and 569 patients in the 325 mg group experienced a primary effectiveness outcome, defined as a composite of all-cause death or a hospitalization for an MI or stroke (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.91-1.14).

The primary safety outcome of hospitalization for major bleeding occurred in 53 and 44 patients, respectively, in the 81 mg and 325 mg groups (HR, 1.18; 95% CI, 0.79-1.77). Both outcomes were time-to-event analyses. The researchers noted that results were consistent across subgroups of patients, including age, race/ethnicity, gender, prior use of dual antiplatelet therapy, or coexisting diabetes or chronic kidney disease.

Before the study, most patients (96%) were taking aspirin, and of these, most (85%) were taking low-dose aspirin (81 mg). Of note, there was a significantly higher rate of dose switching in the high-dose (325 mg) group, with 41.6% switching the dose at least once, compared with only 7.1% of the low-dose group. This translated to fewer median days of exposure to the assigned dose (434 days vs. 650 days). Discontinuation of aspirin was 7% and 11% in the low- and high-dose groups.

According to Jones, patients were encouraged to stay on their assigned dose through direct-to-participant emails and mailers. He adds that many patients in both groups remained on the assigned dose for more than a year, and additional analyses will explore the timing, clinical predictors and reasons for dose switching during the study.

"It's imperative that we counsel our patients that aspirin is still recommended for people with established heart disease," said Jones.

"Based on our presentation of a generally neutral trial result, we recommend that most patients not change their aspirin dose. If restarting aspirin, choose low-dose aspirin given no clear evidence that 325 mg is better. Patients who are clearly tolerating 325 mg over time should speak to their clinician about staying on that dose."

Jones, et al., further explain, "As interest grows for real-world evidence, the trial provides a demonstration that randomized clinical trials can leverage electronic health record data, direct-to-patient methods, and patient-reported outcomes to address important patient-centered questions."

In a related editorial comment, Colin Baigent, FMedSci, writes, "The ADAPTABLE experience is a reminder of the importance of certain fundamentals when designing and conducting randomized trials: comparability between treatment groups, good adherence to assigned treatment, complete ascertainment of outcomes, and unbiased statistical analysis are all essential." While noting the benefit of a pilot study as part of the overall study planning and adjusting design, he wrote the study is a major achievement, "because it has shown a method of conducting trials efficiently and at low cost in the United States."

Read more about the study design, including the role of patient partners who helped guide the study, in a Cardiology Magazine article.

Clinical Topics: Acute Coronary Syndromes, Heart Failure and Cardiomyopathies, Prevention, Stable Ischemic Heart Disease, Acute Heart Failure, Chronic Angina

Keywords: ACC Annual Scientific Session, ACC21, Aspirin, Heart Failure, Primary Prevention, Angina, Stable, Acute Coronary Syndrome

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