'Next-Gen' ADAPTABLE Study Says Low-Dose Aspirin Equal to High-Dose for ASCVD Patients
High-tech, low-cost study reflects real-world data and finds 81mg aspirin superior, although critics say high switching rate impacts reliability of findings
Recent ADAPTABLE findings showed daily low-dose (81 mg) aspirin is better than a 325 mg dose for preventing secondary coronary events in atherosclerotic cardiovascular disease (ASCVD) patients.
Although aspirin has been established as an effective therapy for secondary prevention in ASCVD, the appropriate dose for lowering the risk of death, myocardial infarction, stroke, and bleeding risk has been a subject of a long-standing controversy.
Schuyler Jones, MD (Duke University School of Medicine, North Carolina, USA) presented the findings at the annual American College of Cardiology¡¯s Scientific Session (ACC 2021) last month as the lead author with the results published in the New England Journal of Medicine on May 271.
¡°There hasn¡¯t been a clear answer about the most effective and safe dose of aspirin for these patients. Instead, there have been conflicting findings with some research suggesting 81 mg may reduce the risk of bleeding, but the higher dose may provide more effective prevention of heart attacks and stroke,¡± Jones said2. ¡°But these earlier studies have primarily investigated aspirin (either 81 or 325 mg daily dose) compared to placebo whereas ADAPTABLE was a direct comparison of the two doses.¡±
Jones noted that ADAPTABLE - funded by the Patient-Centered Outcomes Research Institute (PCORI) - was the most extensive study set to find the optimal daily aspirin dose and examine patient outcomes regarding effectiveness and safety.
The open-label, parallel, randomized trial heralded as a ¡°next-generation¡± clinical trial is also the first to be conducted within the National Patient-Centered Clinical Research Network (PCORnet) electronic data infrastructure and the first large-scale electronic health record (EHR)-enabled trial conducted in the U.S.
According to the trial design, eligible patients received invitations to participate in the study via mail, email, or phone. Patients further enrolled and randomized themselves into the study through the trial website and completed follow-up every 3 or 6 months. Investigators collected patients¡¯ medical history and clinical events through EHR and insurance documentation.
The trial included 15,076 patients with established ASCVD across 40 centers in the U.S. who were randomized to either a daily 81 mg aspirin group (n=7,540) or a daily 325 mg aspirin group (n=7,536). The mean patient age was 68 years, 31% were female, and 38% had diabetes.
Analysis of patient characteristics also showed that 96% (13,537) of patients had been taking aspirin before randomization, and among them, 85.3% had been taking a daily 81 mg dose.
The primary effectiveness endpoint was defined as a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis.
The primary safety outcome was hospitalization for major bleeding that was also assessed in a time-to-event analysis.
After a median follow-up of 26.2 months, the primary endpoint occurred in 590 patients (7.28%) of the low-dose group and 569 patients (7.51%) of the high-dose group, indicating no statistically significant difference between the two arms (HR 1.02, 95% CI, 0.91-1.14).
The same went for the primary safety endpoint, with hospitalization for major bleeding occurring in 53 patients (0.63%) in the low-dose group and 44 patients (0.6%) in the high-dose group, indicating no significant difference (HR 1.18, 95% CI, 0.79-1.77).
However, investigators noted a high incidence of dose-switching from the 325 mg to the 81 mg arm, with 41.6% crossing over to the low-dose group, whereas only 7.1% crossed over from a low-dose to a high-dose arm.
Patients on the high dose also adhered to the prescription for a shorter period than those on the low dose, results showed (high-dose: 434 days vs. low-dose: 650 days).
Some patients also discontinued aspirin, with 11% in the 325 mg arm stopping treatment and 7% in the 81 mg arm doing the same.
¡°In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose-switching to 81 mg daily with no significant differences in cardiovascular events or major bleeding between patients assigned to either 81 or 325 mg daily,¡± study authors wrote.
While presenting trial findings, Jones recommended the 81 mg over the high dose as the ¡°best choice for patients,¡± citing improvements in long-term adherence.
Despite the positive findings, an accompanying editorial (aptly titled the ¡°need for ADAPTABLE design¡±)3 identified weaknesses regarding trial design that could have impacted the results.
Colin Baigent, MD (University of Oxford, England, UK) wrote that while the ¡°innovative and low-cost methods¡± to simplify trial execution were noteworthy, the trial fell short in setting up fair comparisons between treatment groups and protecting against biased statistical analyses.
These problems, Baigent argued, could have and should have been tested for and weeded out with a pilot study wherein investigators could have reviewed and used unblinded data to tweak the trial design before the main study began.
¡°In the case of ADAPTABLE, one could speculate that a pilot study might have identified the observed preference for the 81 mg dose of daily aspirin,¡± Baigent wrote. ¡°This may, in turn, have yielded methods to ensure equipoise between aspirin dose preferences, which could have included a run-in period in which patients were sequentially exposed to both aspirin doses, with only those adhering to both regimens being considered for randomization.¡±
Jones, also acknowledging the high cross-over rate, added that he and his colleagues would run additional exploratory analyses to determine the timing, clinical predictors, and reasons for dose switching in the study.
¡°We made every effort to encourage [patients] to stay on their study dose, but people felt very strongly about it,¡± he said. ¡°In turn, the differential effects of the two doses are less clear since dose switching occurred very frequently, especially in the 325 mg group.¡±
Despite limitations, investigators noted that many patients stayed on the assigned dose for over a year, and the findings are highly generalizable due to the study¡¯s pragmatic set-up: ¡°Patients and clinicians should use the information from the study to talk about the dose of aspirin [patients] prefer.¡±