ADAPTABLE is a pragmatic clinical trial in which 15,000 patients who are at high risk for ischemic events will be randomly assigned in a 1:1 ratio to receive an aspirin dose of 81 mg/day vs. 325 mg/day. Study participants will be enrolled over 38 months. Maximum follow-up will be 50 months. The purpose of the study is to identify the optimal dose of aspirin for secondary prevention in patients with Atherosclerotic cardiovascular disease (ASCVD). The primary endpoint is a composite of all-cause death, hospitalization for MI, or hospitalization for stroke. The primary safety endpoint is hospitalization for major bleeding with an associated blood product transfusion.

In this pragmatic, patient-centered clinical trial, the investigators will compare the effectiveness of two doses of aspirin (81 mg and 325 mg) currently in widespread use in the United States in the secondary-prevention population of patients with established ASCVD. The trial will use a novel format that uses existing electronic health records (EHRs), as well as a web-based patient portal to collect patient-reported outcomes (PROs), and available patient encounter data to supplement/support the EHR. Patients who are identified as candidates for the trial will be directed to the electronic patient portal for the eConsent as well as an abbreviated eligibility confirmation and randomization. One of the important aims of ADAPTABLE is to engage patients, their healthcare providers, and trial investigators in using the infrastructure PCORnet has developed and continues to refine. A total of 15,000 high-risk patients with ASCVD will be randomly assigned (in an open-label fashion) in a 1:1 ratio to instructions to use a daily aspirin dose of either 81 mg or 325 mg daily. The investigators expect the entire sample of patients will be enrolled over 38 months, with a maximum follow-up of 50 months.

Inclusion Criteria:

• Known atherosclerotic cardiovascular disease (ASCVD), defined by a history of prior myocardial infarction, prior coronary angiography showing ≥75% stenosis of at least one epicardial coronary vessel, or prior coronary revascularization procedures (either PCI or CABG), or history of chronic heart disease, CAD, ASCVD
• Age ≥ 18 years
• No known safety concerns or side effects considered to be related to aspirin, including
• No history of significant allergy to aspirin such as anaphylaxis, urticaria, or significant gastrointestinal intolerances
• No history of significant GI bleed within the past 12 months
• Significant bleeding disorders that preclude the use of aspirin
• Access to the Internet. In the event that the CDRNs are notified that a cohort of patients without internet access can be included, then patient agreement will be obtained during the consent process to provide follow-up information by telephone contact with the DCRI Call Center.
• Not currently treated with an oral anticoagulant - either warfarin or a novel anticoagulant (dabigatran, rivaroxaban, apixaban, edoxaban) - and not planned to be treated in the future with an oral anticoagulant for existing indications such as atrial fibrillation, deep venous thrombosis, or pulmonary embolism.
• Not currently treated with ticagrelor and not planned to be treated in the future with ticagrelor.
• Female patients who are not pregnant or nursing an infant
• Estimated risk of a major cardiovascular event (MACE) > 8% over next 3 years as defined by the presence of at least one or more of the following enrichment factors:
• Age > 65 years
• Serum creatinine > 1.5 mg/dL
• Diabetes mellitus (Type 1 or Type 2)
• 3-vessel coronary artery disease
• Cerebrovascular disease and/or peripheral arterial disease
• Left ventricular ejection fraction (LVEF) < 50%
• Current cigarette smoker
• Chronic systolic or diastolic heart failure
• SBP > 140 (within past 12 mos)
• LDL > 130 (within past 12 mos)

Exclusion Criteria:

• There will be no exclusions for any upper age limit, comorbid conditions, or concomitant medications other than oral anticoagulants and ticagrelor that are used at the time of randomization, or are planned to be used during the study follow-up.
• Patients and sites interested in participating must be part of the listed health systems collaborators.