What are the indications for Xarelto (rivaroxaban) 2.5mg twice daily and aspirin in patients with coronary artery disease (CAD) or peripheral artery disease (PAD)?

Indications for Xarelto 2.5 mg BID Plus Aspirin in CAD and PAD

Rivaroxaban 2.5 mg twice daily combined with low-dose aspirin (75-100 mg daily) is FDA-approved and strongly recommended for patients with coronary artery disease (CAD) or peripheral artery disease (PAD) to reduce major adverse cardiovascular events (MACE) and major adverse limb events (MALE), particularly in those at high ischemic risk without high bleeding risk. 1, 2

FDA-Approved Indications

Coronary Artery Disease:

• Rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily is FDA-approved to reduce the risk of stroke, myocardial infarction, and cardiovascular death in patients with established CAD 1
• The COMPASS trial demonstrated a 24% relative risk reduction in MACE (HR 0.76,95% CI: 0.66-0.86, p<0.0001) compared to aspirin alone 1, 3
• This combination also reduced cardiovascular mortality by 22% (HR 0.78) and all-cause mortality by 18% (HR 0.82) 1, 4

Peripheral Artery Disease:

• FDA-approved for patients with symptomatic PAD to reduce risk of MACE and MALE 1
• After lower extremity revascularization (endovascular or surgical), rivaroxaban 2.5 mg BID plus aspirin receives a Class I (strongest) recommendation from ACC/AHA guidelines 2, 5
• In PAD patients, the combination reduced MALE and MACE but with increased major bleeding risk 2

Patient Selection Criteria

High Ischemic Risk Features (Favor Combination Therapy):

• Previous amputation for vascular disease 5
• Chronic limb-threatening ischemia (CLTI) 5
• Previous lower extremity revascularization 2, 5
• Heart failure 5
• Diabetes mellitus 5, 3
• Vascular disease in two or more vascular beds 5
• Moderate kidney dysfunction (eGFR 15-60 mL/min/1.73 m²) 5
• Active smoking 3

Exclusion Criteria (High Bleeding Risk):

• History of hemorrhagic or lacunar stroke at any time 2, 1
• Severe kidney disease (eGFR <15 mL/min) 2, 1
• Need for dual antiplatelet therapy or full-dose anticoagulation for another indication 2, 1
• Active gastroduodenal ulcer or bleeding in previous 3 months 1
• Bronchiectasis or pulmonary cavitation 1
• Active cancer 1

Treatment Algorithm by Clinical Scenario

Symptomatic PAD WITHOUT Recent Revascularization:

• First-line option: Rivaroxaban 2.5 mg BID plus aspirin 75-100 mg daily (Class IIa recommendation) 2
• Alternative: Single antiplatelet therapy with clopidogrel 75 mg daily or aspirin 75-325 mg daily (Class I recommendation) 2
• Dual antiplatelet therapy (aspirin plus clopidogrel) is NOT recommended due to increased bleeding without proven benefit 2, 5

After Lower Extremity Revascularization (Endovascular or Surgical):

• Preferred regimen: Rivaroxaban 2.5 mg BID plus aspirin 75-100 mg daily immediately post-procedure (Class I recommendation) 2, 5
• Alternative if rivaroxaban contraindicated: Dual antiplatelet therapy (clopidogrel 75 mg plus aspirin 81-100 mg) for 1-6 months after endovascular procedures 2, 5
• After surgical revascularization with prosthetic graft, DAPT may be reasonable for at least 1 month (Class IIb) 2

Asymptomatic PAD:

• Single antiplatelet therapy is reasonable (Class IIa) 2
• Rivaroxaban plus aspirin combination is NOT routinely recommended for asymptomatic PAD 2

CAD Patients (with or without PAD):

• Rivaroxaban 2.5 mg BID plus aspirin 100 mg daily for stable CAD, especially if age ≥65 years OR younger with atherosclerosis in ≥2 vascular beds OR ≥2 additional CV risk factors 1
• Greatest absolute benefit observed in patients with highest CHADS2 scores (3-6), preventing 25 events per 1000 patients treated for 30 months 6

Critical Bleeding Considerations

Expected Bleeding Rates:

• Major bleeding increases with combination therapy: HR 1.70 (95% CI: 1.40-2.05) compared to aspirin alone 3
• Most common bleeding site is gastrointestinal 1
• Fatal bleeding remains low (<0.1% per year) and similar between groups 1
• Intracranial hemorrhage risk: 0.3% per year with combination vs 0.3% with aspirin alone (not significantly different) 1

Benefit-Risk Balance:

• Per 10,000 patient-years of treatment, rivaroxaban plus aspirin prevents 70 CV events while causing 12 additional life-threatening bleeds, demonstrating favorable net clinical benefit 1
• In PAD patients specifically, the combination reduces composite CV death/MI/stroke/acute limb ischemia/major amputation by 21% (HR 0.79,95% CI: 0.65-0.95) 7

What NOT to Do: Critical Pitfalls

Avoid full-intensity anticoagulation (warfarin or therapeutic-dose DOACs) for PAD or CAD alone without another indication such as atrial fibrillation—this is harmful (Class III: Harm recommendation) 2, 5

Do NOT use long-term dual antiplatelet therapy (aspirin plus clopidogrel) beyond 6 months post-revascularization in chronic PAD—increases bleeding without additional benefit 2, 5

Do NOT combine rivaroxaban with dual antiplatelet therapy—this triples bleeding risk without evidence of benefit 2, 1

Do NOT use vorapaxar added to existing antiplatelet therapy in PAD—benefit is uncertain with increased bleeding (Class IIb) 2

Special Populations

Patients Requiring Full-Dose Anticoagulation for Another Indication (e.g., Atrial Fibrillation):

• If already on full-intensity anticoagulation, adding single antiplatelet therapy is reasonable if bleeding risk is not high (Class IIa) 2, 5
• Do NOT add rivaroxaban 2.5 mg BID to full-dose anticoagulation 2

Post-Revascularization with Atrial Fibrillation:

• Use full-intensity anticoagulation plus single antiplatelet therapy rather than the vascular-dose rivaroxaban combination 2

Duration of Therapy

• The combination therapy showed sustained benefit during extended treatment for median 1 year and maximum 3 years without new safety signals 4
• Bleeding rates during extended treatment were similar to or lower than during initial randomized phase 4
• Continue indefinitely unless bleeding complications occur or contraindications develop 2, 1