Indications for Rivaroxaban and Aspirin
Rivaroxaban 2.5 mg twice daily combined with aspirin 75-100 mg once daily is indicated for patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD) who are at high ischemic risk and low bleeding risk to reduce major cardiovascular events and major adverse limb events. 1
FDA-Approved Indications for Rivaroxaban
Monotherapy Indications
- Nonvalvular atrial fibrillation: Reduce risk of stroke and systemic embolism 2
- Deep vein thrombosis (DVT) treatment 2
- Pulmonary embolism (PE) treatment 2
- Reduction of recurrent DVT/PE after completing at least 6 months of initial treatment 2
- VTE prophylaxis following hip or knee replacement surgery (10 mg once daily for 35 days post-hip replacement, 12 days post-knee replacement) 2
- VTE prophylaxis in acutely ill medical patients at risk for thromboembolic complications not at high bleeding risk (10 mg once daily for 31-39 days) 2
- Pediatric VTE treatment (birth to <18 years) after at least 5 days of parenteral anticoagulation 2
- Thromboprophylaxis in pediatric patients ≥2 years with congenital heart disease after Fontan procedure 2
Combination Therapy with Aspirin
- Reduction of major cardiovascular events in CAD: Rivaroxaban 2.5 mg twice daily plus aspirin 75-100 mg once daily to reduce cardiovascular death, myocardial infarction, and stroke 2
- Reduction of major thrombotic vascular events in PAD: Rivaroxaban 2.5 mg twice daily plus aspirin 75-100 mg once daily to reduce myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of vascular etiology, including patients after lower extremity revascularization 2
FDA-Approved Indications for Aspirin
Primary Prevention
- Aspirin 75-162 mg daily may be considered for primary prevention in patients with diabetes at increased cardiovascular risk (≥50 years with ≥1 additional major risk factor) after comprehensive discussion of bleeding risk 1
- Generally not recommended in adults >70 years for primary prevention due to bleeding risk exceeding benefit 1
Secondary Prevention
- Aspirin 75-162 mg daily is indicated for secondary prevention in patients with diabetes and history of atherosclerotic cardiovascular disease (ASCVD) 1
- Aspirin is strongly recommended for secondary prevention in patients with prior myocardial infarction or stroke 1
- Clopidogrel 75 mg daily should be used in patients with documented aspirin allergy 1
Specific Clinical Scenarios for Rivaroxaban Plus Aspirin
Stable Coronary Artery Disease
Rivaroxaban 2.5 mg twice daily plus aspirin should be considered in patients with stable CAD who have high ischemic risk and low bleeding risk 1. The COMPASS trial demonstrated a 24% reduction in the composite outcome of cardiovascular death, myocardial infarction, or stroke compared to aspirin alone 3, 4. This combination also reduced all-cause mortality by 23% 3.
Peripheral Artery Disease
Rivaroxaban 2.5 mg twice daily plus aspirin is recommended for patients with symptomatic PAD to prevent major adverse limb events (acute limb ischemia, major amputation) and major cardiovascular events 1. In patients undergoing lower extremity revascularization, initiate therapy once hemostasis is established 2.
Patients with Diabetes and Stable CAD or PAD
The combination of rivaroxaban 2.5 mg twice daily plus aspirin is recommended for patients with type 2 diabetes and established CAD or PAD to reduce cardiovascular death, myocardial infarction, stroke, and PAD events 1. The ischemic benefits were consistent in the diabetes subgroup of COMPASS 1.
Patients with Heart Failure and Chronic CAD/PAD
Rivaroxaban plus aspirin produces larger absolute risk reduction in patients with mild to moderate heart failure (NYHA class I-II, ejection fraction ≥30%) and chronic CAD or PAD compared to those without heart failure (absolute risk reduction 2.4% vs 1.0%, number needed to treat 42 vs 103) 5.
Acute Coronary Syndrome Setting
Rivaroxaban 2.5 mg twice daily may be considered in patients with acute coronary syndrome (ACS) who are receiving aspirin and clopidogrel (not ticagrelor or prasugrel), with no prior stroke/TIA, high ischemic risk, and low bleeding risk, for approximately 1 year after discontinuation of parenteral anticoagulation 1, 6. This indication carries a Class IIb recommendation due to increased bleeding risk 1.
Important Contraindications and Cautions
Bleeding Risk Considerations
- Major bleeding risk increases with rivaroxaban plus aspirin (HR 1.66) compared to aspirin alone, primarily gastrointestinal bleeding 3
- No significant increase in intracranial or fatal bleeding was observed 3, 4
- Avoid rivaroxaban in patients with creatinine clearance <15 mL/min 2
- Dose adjustment to 15 mg once daily for atrial fibrillation indication when creatinine clearance 30-49 mL/min 7
Post-TAVR Patients
Do not use rivaroxaban plus aspirin in patients after transcatheter aortic valve replacement (TAVR), as a trial was terminated early due to higher rates of death/thromboembolic events and bleeding compared to aspirin alone 1.
Drug Interactions
Avoid concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) or additional antiplatelet drugs unless specifically indicated 7, 2. Consider proton pump inhibitor prophylaxis in all patients receiving simultaneous antiplatelet and anticoagulant therapy 8.
Patient Selection Algorithm for Rivaroxaban Plus Aspirin
Step 1: Confirm diagnosis of stable CAD or symptomatic PAD 1
Step 2: Assess ischemic risk - High risk features include:
- Prior myocardial infarction 1
- Polyvascular disease (CAD plus PAD) 1
- Diabetes mellitus 1
- History of percutaneous coronary intervention 1
- Younger age, tobacco use 1
Step 3: Assess bleeding risk - Exclude if:
- Creatinine clearance <15 mL/min 2
- History of intracranial hemorrhage 2
- Active pathological bleeding 2
- High bleeding risk (e.g., elderly >75 years requires caution) 7
Step 4: If high ischemic risk and acceptable bleeding risk, initiate rivaroxaban 2.5 mg twice daily plus aspirin 75-100 mg once daily 1, 2