Cardiovascular disease, including coronary heart disease, heart failure, stroke, and hypertension, is widespread, affecting nearly half of adults in the United States (US).¹ While the utility of aspirin in primary prevention remains controversial, data in high risk patients with established atherosclerotic cardiovascular disease (ASCVD) supports the use of antiplatelet therapy to prevent major cardiovascular events.² However, the optimal dose of aspirin for secondary prevention is unclear with some studies showing no difference in safety or efficacy while other studies have suggested a potential higher efficacy but also higher bleeding risk with higher doses of aspirin.² The European Society of Cardiology (ESC) guidelines recommend low-dose aspirin (81-100 mg/day), and the American Diabetes Association (ADA) recommends aspiring 75–162 mg/day as a secondary prevention strategy in those with diabetes and ASCVD. However, the American College of Cardiology/American Heart Association (ACC/AHA) guidelines have not made a definitive recommendation regarding ideal dosage given the conflicting evidence.

The ADAPTABLE trial is a randomized, parallel, open label trial involving 40 centers participating in PCORnet® (National Patient-Centered Clinical Research Network) aimed at differentiating cardiovascular events and major bleeding episodes between secondary prevention patients assigned to two different commonly prescribed doses of aspirin.^3,4 The trialists set out with the hypothesis that 325 mg of daily aspirin would result in a 15% lower risk of the composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke compared to an 81 mg daily dose. After 26.2 months of follow-up in 15,076 patients, no significant differences in the primary composite outcome were seen between the two aspirin doses with an estimated percentage event rate of 7.28% in the 81 mg aspirin group versus 7.51% in the 325 mg group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.91 to 1.14). Likewise, no significant difference was detected in rates of hospitalization for major bleeding between the groups (0.63% for 81 mg aspirin vs. 0.60% for 325 mg, HR, 1.18; 95% CI, 0.79 to 1.77).

A major limitation of the trial was a rate of 41.6% patient crossover from the aspirin 325 mg group to the aspirin 81 mg group compared with a crossover rate of 7.1% in those randomized to the 81 mg arm. As such, random misclassification may have significantly biased the results of this analysis towards the null. The design was also open-label and approximately 10% of study participants discontinued aspirin during the study and the follow-up period of just over 2 years is relatively brief given the primary outcome. The higher adherence rate observed in the low dose aspirin group may be related to patient familiarity with that dose as the majority (85.3%) of patients already taking low dose aspirin prior to trial participation. Moreover, side effects of bruising and bleeding may have contributed to crossover from high to low dose aspirin. It is possible that competing guidelines influenced clinicians to reduce the aspirin dose as well. This includes the ESC and ADA guidelines as noted above which prefer low dose aspirin. Comorbid conditions increasing bleeding risk such as liver disease may have influenced aspirin dose reduction, and other conditions involving concomitant use of blood thinners (in patients with cancer or atrial fibrillation) would have been more appropriate for low dose aspirin. Other clinical scenarios where low dose aspirin would have been more appropriate include situations of "triple therapy" in which patients with atrial fibrillation undergo percutaneous coronary intervention (PCI) and are treated with dual antiplatelet therapy in addition to a blood thinner, especially in conjunction with ticagrelor, to minimize bleeding risk.

A modified per-protocol analysis was performed and demonstrated slightly higher cardiovascular event rates with the 81 mg dose, suggesting a potential small cardiovascular benefit with the 325 mg dose of aspirin. The unfortunate limitations of this trial do significantly reduce the clinical utility of ADAPTABLE and clinicians should be cautious in making recommendations for treatment changes based on the trial results.

However, despite the limitations of the study, ADAPTABLE does represent significant progress in cardiovascular research in the US due to its novel methodology. Leveraging a pragmatic trial design, the study authors took advantage of the PCORnet® for participant identification, recruitment, and follow-up. Consent was done electronically. All trial visits were done virtually or by telephone, with outcomes ascertained remotely. These novel methods allowed for a trial with a reduced research burden on both patients and research sites as well as substantially reduced costs. Still, this trial design is limited in its open label methodology and the outcome determination without adjudication. Surprisingly, as noted in the article, the enrollment of women and traditionally underrepresented groups was not improved by the pragmatic trial design, mirroring the enrollment challenges seen in traditional cardiovascular studies. However, the trial did focus on older adults (inclusion criteria was age ≥65 years) which is typically a population that is underrepresented in prior research.

The ADAPTABLE trial did not detect a difference in cardiovascular outcomes or major bleeding episodes when comparing aspirin 325 mg to aspirin 81 mg daily dosing when utilized for secondary prevention of ASCVD. However, the results may be biased by significant crossover between arms. Given the lack of increased efficacy with high dose aspirin in ADAPTABLE, the higher cross-over and discontinuation rate, as well as the minimal cardiovascular benefit and elevated bleeding risk seen in the recent trials with longer follow-up studying aspirin for primary prevention, low dose aspirin likely remains the preferred option for most patients with established cardiovascular disease. An additional, important legacy of ADAPTABLE will likely be that it demonstrated the ability to identify and execute novel, efficient and economic methods of trial design, further enabling researchers to continue to advance the science of cardiovascular disease prevention and treatment.

References

1. Virani SS, Alonso A, Aparicio HJ, et al. Heart Disease and Stroke Statistics—2021 Update: a report from the American Heart Association. Circulation 2021;143:e254-e743.
2. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849-60.
3. Jones WS, Mulder H, Wruck LM, et al. Comparative effectiveness of aspirin dosing in cardiovascular disease. N Engl J Med 2021;384:1981-90.
4. Baigent C. Pragmatic trials — need for ADAPTABLE design. N Engl J Med 2021;384:2065-66.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Hypertension

Keywords: Primary Prevention, Secondary Prevention, Platelet Aggregation Inhibitors, Purinergic P2Y Receptor Antagonists, Aspirin, Cardiovascular Diseases, Atrial Fibrillation, American Heart Association, Percutaneous Coronary Intervention, Follow-Up Studies, Confidence Intervals, Myocardial Infarction, Hemorrhage, Diabetes Mellitus, Stroke, Neoplasms, Hypertension, Coronary Disease, Liver Diseases, Hospitalization, Patient-Centered Care, Heart Failure, Informed Consent, ACC Annual Scientific Session, ACC21

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