Ideal Aspirin Dose for Secondary Prevention in Patients With ASCVD

Quick Takes

  • Although the most recent European guidelines give a Class IA recommendation for daily low-dose aspirin for patients with chronic atherosclerotic cardiovascular disease (ASCVD), US guidelines have remained without a definitive stance on aspirin dosage in this patient population.
  • ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) was designed to address this aspirin-dose decision for patients and clinicians.
  • A lower-dose aspirin strategy is best for most patients with ASCVD given similar effectiveness, bleeding risk, and overall better adherence.


ASCVD is the leading cause of death in the United States, and over 800,000 Americans have a myocardial infarction annually.1 Prior randomized trials and clinical investigations have proven the efficacy of aspirin and made it a foundational recommendation in patients with established ASCVD to lower the risk of future events. However, the optimal dose of aspirin for long-term, secondary prevention has been unclear.2,3 The dosing strategy recommended by clinicians varies between 81 mg (low dose) and 325 mg (high dose) daily. In 2014, the National Cardiovascular Data Registry showed that more than 60% of patients discharged after surviving a myocardial infarction were treated with high-dose 325 mg aspirin4; and frequently patients were continued on this dose indefinitely.

Over the last several years, there has been a paradigm shift toward low-dose aspirin even without randomized clinical trial data to support these changes. The gastrointestinal side effects of aspirin are known to increase with higher doses, and observational evidence suggests low-dose daily aspirin is efficacious in secondary prevention.2,3,5 Although the most recent European guidelines give a Class IA recommendation for daily low-dose aspirin for patients with chronic ASCVD, the American College of Cardiology and American Heart Association guidelines have remained without a definitive stance on aspirin dosage in this patient population.6,7

ADAPTABLE Trial Design

ADAPTABLE was designed to address this everyday decision for patients and clinicians. ADAPTABLE was an open-label, pragmatic, randomized controlled trial that assigned patients to receive either 81 mg or 325 mg of aspirin daily for a median follow-up of 26 months. The trial was conducted across 40 US centers participating in PCORnet®, the National Patient-Centered Clinical Research Network, and enrolled 15,076 patients with established heart disease and at least one common risk enrichment factor. The study design had novel methods, such as direct-to-participant enrollment/recruitment, and used electronic health records and health insurance claims data for longitudinal outcomes. The pragmatic, low-contact design also allowed for follow-up measures such as adherence, recent hospitalization, and other patient-reported outcomes to be ascertained directly from patients via an internet portal or call center.8,9

Outcomes and Considerations

The primary prespecified composite outcome was the time to a first occurrence of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke. This outcome was similar between the low-dose and high-dose groups (7.28% vs. 7.51%; hazard ratio 1.02; 95% confidence interval, 0.91-1.14). A key secondary outcome of the study included coronary revascularization, whether surgical or percutaneous, and a primary safety outcome of hospitalization for major bleeding requiring blood transfusion. Notably, there were no significant differences in the occurrence of the primary safety endpoint, individual components of the primary effectiveness endpoint, or the key secondary endpoint. After randomization, 24% of patients switched doses, with 41% of patients in the high-dose 325 mg group switching to low-dose 81 mg. This likely impacted the main study results and has implications for patients and clinicians. Additional analyses are ongoing to determine reasons for switching and conduct an "on treatment" analysis, which may shed some light onto which dose is best for individual patients.

Practical Implications

ADAPTABLE was completed in a real-world environment and utilized multiple heterogenous datasets to show that treating patients with ASCVD with low-dose 81 mg aspirin is as effective as using the higher dose 325 mg for the prevention of major adverse cardiovascular events. Both are commonly recommended doses and available over the counter as an everyday option for patients with a low rate of bleeding. Although there was a high rate of dose switching in the 325 mg group, this may have been driven by 1) updates in European guidelines making a strong recommendation for low-dose aspirin or 2) decisions skewed by several recent studies suggesting aspirin was not beneficial in primary prevention of ASCVD. Almost 85% of patients were on low-dose aspirin prior to randomization, representing a change in practice patterns and patient preference from prior years. Importantly, ADAPTALBE was an open-label, pragmatic study, and the inability to blind study drug/dose likely influenced adherence and dose switching.

Despite the high rate of switching, there remained no conclusive evidence that higher dosing of aspirin was superior for secondary prevention. Post-randomization analysis of patients who did not switch doses suggested moderate benefit for high-dose aspirin; however, this post-randomization analysis comes with several caveats. For those patients currently tolerating 325 mg, it may be safe to continue this dose, and patients have been encouraged to speak with their clinicians about this. Ultimately, the ideal dose of aspirin for most patients with ASCVD is low-dose 81 mg daily. Particularly, if patients are on 81 mg or starting aspirin for secondary prevention of ASCVD, then a lower-dose aspirin strategy is best given similar effectiveness, bleeding risk, and overall better adherence. ADAPTABLE not only added real-world evidence to support aspirin-dosing strategies, but also provided a novel process to perform pragmatic clinical trials in the future.


  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. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
  3. Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, 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.
  4. Hall HM, de Lemos JA, Enriquez JR, et al. Contemporary patterns of discharge aspirin dosing after acute myocardial infarction in the United States: results from the National Cardiovascular Data Registry (NCDR). Circ Cardiovasc Qual Outcomes 2014;7:701-7.
  5. CURRENT-OASIS 7 Investigators, Mehta SR, Bassand JP, et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010;363:930-42.
  6. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407-77.
  7. Smith SC Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation 2011;124:2458-73.
  8. Marquis-Gravel G, Roe MT, Robertson HR, et al. Rationale and Design of the Aspirin Dosing-A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE) Trial. JAMA Cardiol 2020;5:598-607.
  9. Jones WS, Mulder H, Wruck LM, et al. Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease. N Engl J Med 2021;384:1981-90.

Clinical Topics: Cardiovascular Care Team, Prevention, Stable Ischemic Heart Disease

Keywords: Aspirin, Secondary Prevention, American Heart Association, Confidence Intervals, Patient Discharge, Electronic Health Records, Patient Preference, Cause of Death, Follow-Up Studies, Random Allocation, Primary Prevention, Stroke, Research Design, Myocardial Infarction, Heart Diseases, Registries, Blood Transfusion, Insurance, Health, Patient-Centered Care, Pharmaceutical Preparations

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