• The trial will compare two anticoagulants ("blood thinners") that are currently used in the VA and are considered standard care to prevent strokes in patients with atrial fibrillation. The two most commonly-used anticoagulants will be compared: apixaban (Eliquis) and rivaroxaban (Xarelto). They are considered by many doctors to have similar benefits and risks, but no one knows for sure.
• The trial only enrolls patients with a diagnosis of atrial fibrillation ("A Fib") or atrial flutter. Most participants will be age 65 or older, and should already be taking apixaban or rivaroxaban.
• The investigators will measure, in about 10,000 VA patients nationally, whether the rates of stroke, major bleeding, or death differ between these two drugs.
• The trial will last about 7 years, but after the first prescription, all information will be collected from electronic medical records.

Study hypothesis and design:

The study hypothesizes that apixaban will be superior to rivaroxaban for safety (using the International Society on Thrombosis and Haemostasis [ISTH] definition of major bleeding) and at least non inferior for efficacy among patients with atrial fibrillation (AF) or atrial flutter (AFL), henceforth collectively "AF." This is a phase 4, pragmatic, point of care, parallel group, unblinded randomized trial embedded in VA clinical care.

Enrollment and allocation:

Approximately 10,000 Veterans ages 65 years or older with AF and CHA2DS2-Vasc of 3 or more will be randomized 1:1 to apixaban or rivaroxaban; Veterans aged 22-64 may also enroll and will be included in exploratory analyses. Randomization uses site specific permuted blocks with random block sizes via a centralized Interactive Web Response System (IWRS).

Co Primary Objectives

1. Determine whether apixaban is superior to rivaroxaban for ISTH major bleeding (safety).
2. Determine whether apixaban is non inferior to rivaroxaban for the composite efficacy outcome (ischemic stroke, systemic embolism, or all cause death).

Secondary Objectives

1. Test superiority of apixaban vs rivaroxaban for the composite efficacy outcome.
2. Assess impact on hospitalization for heart failure, myocardial infarction, or acute coronary syndrome/unstable angina.
3. Examine each component of the composite efficacy endpoint individually (ischemic stroke, systemic embolism, all cause mortality).

Co Primary Endpoints

1. Time to first ISTH defined major bleeding (Superiority Hypothesis).
2. Time to first ischemic stroke, systemic embolism, or all cause mortality (Non Inferiority Hypothesis).

Secondary Endpoints (hierarchically ranked)

1. Time to first ischemic stroke, systemic embolism, or all cause mortality (Superiority Hypothesis).
2. Time to first ischemic stroke.
3. Time to first hospitalization for heart failure, myocardial infarction, or acute coronary syndrome.
4. Time to first systemic embolism.
5. Time to all cause death.

Sites and representation:

About 100 VA Medical Centers across the United States will enroll participants, representing both tertiary urban centers and rural CBOCs, with a goal of broad representation across VISNs. Efforts will promote enrollment of women and racial/ethnic minority Veterans. Site selection will give strong consideration to prior experience with ambulatory cardiac monitors, particularly the 14 day Zio patch. The study will not include sites outside the U.S.

Population and eligibility:

The primary analysis comprises Veterans ages 65 years or older with AF/AFL and CHA2DS2-Vasc of 3 or more. Inclusion requires a diagnosis of AF/AFL and current use of either apixaban or rivaroxaban. Antiplatelet therapy is permitted. Key exclusions include inability to switch anticoagulants if needed, other indications for anticoagulation, contraindication to OAC, bleeding diathesis, pregnancy/lactation, allergy/intolerance to study drugs, eGFR <30 mL/min/1.73 m², mechanical valve, moderate-severe mitral stenosis, prior left atrial occlusion/excision/ligation, certain interacting medications (e.g., systemic ritonavir, itraconazole, ketoconazole; topical ketoconazole allowed), recent cardiac/thoracic surgery, cognitive impairment precluding consent, or concurrent interventional trial participation without waiver.

Interventions and dosing:

• Apixaban: 5 mg BID; 2.5 mg BID if 2 or more of: age 80 years, body weight 60 kg, serum creatinine 1.5 mg/dL.
• Rivaroxaban: 20 mg QD if creatinine clearance is 50 mL/min or more; 15 mg QD if creatinine clearance 15-50 mL/min. (Note: eGFR <30 is an exclusion.) Medications are dispensed via VA pharmacy/CMOP per usual practice, with routine co pay policies; switching instructions are provided to avoid double dosing.

Operations, follow up, and data capture:

Enrollment and initiation typically occur within <1 month, and can extend to up to 90 days for participants randomized to switch who recently received a 90 day supply. After randomization, all clinical management is per participants' usual VA providers. Outcomes (bleeding, stroke, systemic embolism, hospitalizations, death) are ascertained remotely from the VA EHR/CDW and, for participants ages 65 or older, from Medicare data; no protocol mandated study visits are required. Adherence is assessed via VA pharmacy refill data.

Timeline:

Planned 3 years of enrollment plus 3 or more years of follow up after the last participant (total ~6 years of data collection), with ~1 year for completion of analyses (~7 years total, 84 months).

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Male or female Veteran, aged 22 years or older
2. Diagnosis of atrial fibrillation (AF) or atrial flutter (AFL) and currently taking either apixaban or rivaroxaban.
3. CHA2DS2-Vasc of 3 or more
4. Ability to take oral medication and self-reported willingness to adhere to the prespecified apixaban or rivaroxaban regimen

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study; notably use of antiplatelet agents or prior OAC use will not be an exclusion criterion:

1. Current use of oral or injectable anticoagulation, without ability to switch to the assigned study medication
2. Another indication for anticoagulation, such as pulmonary embolism
3. Contraindication to oral anticoagulation
4. Known bleeding diathesis
5. Documented current pregnancy or lactation in the EHR or self-reported current pregnancy or lactation
6. Known allergic reactions or intolerance to apixaban or rivaroxaban
7. Most recent estimated glomerular filtration rate (eGFR) is < 30 mL/minute/1.73m2. An eGFR result must have been obtained within 18 months before randomization.
8. Known mechanical heart valve
9. Known moderate-severe mitral stenosis
10. Known history of left atrial occlusion, excision, or ligation
11. Current or planned use of systemic ritonavir, itraconazole, or ketoconazole (topical use of ketoconazole only is allowed)
12. Cardiac or thoracic surgery in the past 3 months

Drug assignment will be unblinded and distributed through VA's usual mechanism for filling medications (i.e., local pharmacy or Consolidated Mail Outpatient Pharmacy [CMOP]).

Randomization: Allocation occurs via a centralized online tool (IWRS). Each site uses permuted-block randomization with random block sizes, pre-programmed before study start; no stratification is applied at randomization.