ADAPTABLE: A Pragmatic Clinical Trial on Aspirin Dosing in Cardiovascular Disease

Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness (ADAPTABLE) aimed to answer an important question: What dose of aspirin should be used for secondary prevention of cardiovascular events? The large, open-label, pragmatic, multicenter trial showed no difference between 81 mg and 325 mg in effectiveness or safety at 26 months, although the results were limited by the large proportion of patients who switched from the 325 mg to 81 mg.

Most notable, however, was the design of the trial. ADAPTABLE was a patient-centred trial that maximized the pace of enrolment of a large number of participants through PCORnet, the National Patient-Centered Clinical Research Network, representing more than 30 U.S. healthcare systems, one health plan research network, and one patient-powered research network. The trial was collaborative, performed remotely, integrated into the routine care of patients, and involved researchers, patients, and healthcare professionals.

More than 15,000 eligible patients with histories of atherosclerotic cardiovascular disease were identified from electronic health records and randomized to receive 81 mg or 325 mg of aspirin. Eligible patients performed confirmatory screening, electronic consent, self-randomization, entered data, and reported outcomes through an online portal. Other trial data were collected by querying the PCORnet Common Data Model to extract standardized data from electronic health records with links to health plan data.

ADAPTABLE is the first pragmatic clinical trial conducted with PCORnet. It demonstrates the feasibility and benefits of conducting trials using simple pragmatic methods.

The following NEJM Journal Watch summary provides more details of the study.

Allan S. Brett, MD, reviewing Jones WS et al. N Engl J Med 2021 May 15

For secondary prevention of cardiovascular (CV) events with aspirin, how do 81-mg and 325-mg doses compare? In this study, 15,000 U.S. patients with histories of atherosclerotic CV disease were randomized to receive one of these two doses daily. The trial was conducted through a national clinical research network in which recruitment, data collection, and follow-up were all conducted “virtually” (online or by phone). Patients were instructed to purchase their assigned aspirin themselves.

During median follow-up of 26 months, intent-to-treat analysis revealed no differences between groups in the incidence of the primary effectiveness outcome (i.e., myocardial infarction, stroke, or all-cause death) or the incidence of hospitalization for major bleeding. During the study, 41% of patients assigned to the 325-mg dose switched to 81 mg, and 7% of those assigned to 81 mg switched to 325 mg.

Comment: This study demonstrated no difference between 81 mg and 325 mg of aspirin for major effectiveness and safety outcomes. Although the researchers deserve credit for performing a relatively inexpensive pragmatic trial using the methodology noted above, the results are not decisive, given how many patients crossed over from 325 to 81 mg (for unclear reasons). Additionally, nonlethal side effects of aspirin that might be important to patients (e.g., easy bruising, dyspepsia) were not reported. For now, the dose favored by most U.S. authorities — 81 mg — still stands.

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James is a 2020-2021 NEJM Editorial Fellow and a graduate of the National University of Ireland, Galway. He has a Masters of Science in Evidence-Based Healthcare from University College London and completed Basic Specialist Training in general internal medicine with the Royal College of Physicians in Ireland.