What are the recommendations for using aspirin (acetylsalicylic acid) together with rivaroxaban (Xarelto) in therapy?

Aspirin and Rivaroxaban Combination Therapy: Evidence-Based Recommendations

In patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD) at high ischemic risk without high bleeding risk, the combination of aspirin 75-100 mg once daily plus rivaroxaban 2.5 mg twice daily should be considered to reduce major cardiovascular events, though this increases major bleeding risk. 1

Clinical Context and Indications

The dual pathway concept combining aspirin (antiplatelet) with very low-dose rivaroxaban (anticoagulant) targets both platelet activation and coagulation cascade mechanisms. 1

Approved Indications for Combination Therapy

For Chronic Coronary Syndromes:

• Aspirin 75-100 mg once daily PLUS rivaroxaban 2.5 mg twice daily is recommended in high ischemic risk patients without high bleeding risk (HBR). 1
• The COMPASS trial demonstrated this combination reduced ischemic events (cardiovascular death, MI, stroke) with a number needed to treat (NNT) of 77, versus number needed to harm (NNH) for bleeding of 84. 1
• Mortality was reduced by 23% compared to aspirin alone (HR 0.77,95% CI 0.65-0.90). 1, 2

For Peripheral Artery Disease:

• The same regimen (aspirin 75-100 mg daily + rivaroxaban 2.5 mg twice daily) reduces major thrombotic vascular events including acute limb ischemia and major amputation. 1, 3
• After lower extremity revascularization, initiate once hemostasis is established. 3

High-Risk Populations Who Benefit Most

Subgroup analyses show greater benefit in patients with: 1

• Diabetes mellitus
• Multivessel coronary artery disease
• Peripheral artery disease
• Mild chronic kidney disease (CrCl 30-60 mL/min)
• Active smoking
• Age >65 years

Critical Dosing Specifications

Standard Dosing

• Rivaroxaban: 2.5 mg twice daily (approximately 12 hours apart) 1, 3
• Aspirin: 75-100 mg once daily 1, 3
• Take with or without food 3

Important Dosing Caveats

The 2.5 mg twice daily dose is the ONLY approved dose for combination with aspirin in stable atherosclerotic disease. 1, 3 The rivaroxaban 5 mg twice daily monotherapy arm in COMPASS did NOT show significant benefit and should not be used. 1, 2

Bleeding Risk Assessment and Contraindications

Absolute Contraindications

• Active pathological bleeding 3
• Severe hepatic impairment (Child-Pugh B or C with coagulopathy) 3
• CrCl <15 mL/min 3

High Bleeding Risk (HBR) Criteria - Avoid Combination

Do NOT use this combination in patients meeting HBR criteria, which include: 1

• Prior intracranial hemorrhage
• Active gastrointestinal bleeding or peptic ulcer disease within 6 months
• Hemoglobin <10 g/dL
• Platelet count <100,000/μL
• Chronic bleeding diathesis
• Liver cirrhosis with portal hypertension
• Active malignancy at high bleeding risk
• Recent major surgery or trauma

Expected Bleeding Rates

• Major bleeding increases from 1.9% per year with aspirin alone to 3.1% per year with combination therapy (HR 1.66). 1, 2
• Most common site: gastrointestinal bleeding (approximately 2% per year). 2
• No significant increase in intracranial or fatal bleeding. 1, 2

Special Clinical Scenarios

Patients with Atrial Fibrillation Requiring Anticoagulation

This is a completely different scenario requiring different dosing. 1, 4

After PCI in AF patients:

• Use rivaroxaban 15 mg once daily (or 10 mg if CrCl 30-49 mL/min) PLUS clopidogrel 75 mg daily, WITHOUT aspirin (dual antithrombotic therapy). 1, 4
• Triple therapy (rivaroxaban + aspirin + clopidogrel) should be limited to ≤1 week post-PCI in standard risk, up to 1 month in high ischemic risk. 1, 4
• After 12 months post-PCI, discontinue clopidogrel and continue rivaroxaban 20 mg once daily (or 15 mg if CrCl 30-49 mL/min) as monotherapy for stroke prevention. 1, 4

The 2.5 mg twice daily dose used with aspirin in stable CAD is NOT approved for stroke prevention in atrial fibrillation. 1, 4

Patients with Moderate Renal Impairment (CrCl 30-60 mL/min)

• No dose adjustment needed for the 2.5 mg twice daily + aspirin regimen in stable CAD/PAD. 1, 3
• Benefits are preserved with similar relative risk reduction. 5
• Absolute event rates (both ischemic and bleeding) are higher, but the benefit-risk ratio remains favorable. 5

Post-PCI Patients Without Atrial Fibrillation

Do NOT start the combination immediately after PCI. 1

Standard approach:

• First 6-12 months: Dual antiplatelet therapy (aspirin + clopidogrel) as per standard PCI guidelines. 1
• After completing DAPT duration: Consider transitioning to aspirin + rivaroxaban 2.5 mg twice daily if high ischemic risk without HBR. 1

Monitoring Requirements

Before Initiating Therapy

• Calculate creatinine clearance (CrCl) using actual body weight 3
• Assess liver function 3
• Complete blood count (hemoglobin, platelets) 1
• Screen for active bleeding sources 3
• Review all concomitant medications for drug interactions 3

During Therapy

• Renal function: At least annually, more frequently if CrCl <60 mL/min 1
• Regular reassessment of bleeding and ischemic risk is essential - no specific interval defined but clinical judgment at each visit. 1
• Monitor for signs of bleeding: unusual bruising, blood in stool/urine, severe headache. 3

Drug Interactions and Concomitant Medications

Avoid Concomitant Use With:

• NSAIDs (ibuprofen, naproxen, diclofenac) - markedly increase bleeding risk 3
• Strong dual CYP3A4 and P-glycoprotein inhibitors (ketoconazole, itraconazole, ritonavir) - contraindicated 3
• Strong CYP3A4 inducers (rifampin, phenytoin, carbamazepine) - reduce rivaroxaban efficacy 3
• Additional antiplatelet agents (clopidogrel, prasugrel, ticagrelor) unless specific indication like recent ACS/PCI 1

Safer Alternatives

• Acetaminophen (up to 3-4 g/day) for analgesia 3
• Proton pump inhibitors for gastroprotection in high GI bleeding risk 1

Duration of Therapy

• No defined endpoint - continue as long as the patient remains at high ischemic risk without developing HBR or contraindications. 1
• Randomized evidence beyond 3 years of follow-up is unavailable. 1
• Requires ongoing reassessment of benefit-risk balance. 1

When NOT to Use This Combination

Do not use aspirin + rivaroxaban 2.5 mg twice daily in: 1, 3

• Patients meeting high bleeding risk criteria
• Patients with atrial fibrillation requiring anticoagulation for stroke prevention (use therapeutic-dose rivaroxaban instead)
• Patients within 12 months of PCI (use standard DAPT)
• Patients with CrCl <15 mL/min
• Patients with active malignancy at high bleeding risk
• Patients requiring concomitant therapeutic anticoagulation for other indications

Comparison with Alternative Strategies

Aspirin + ticagrelor 60 mg twice daily is an alternative extended antithrombotic strategy with similar efficacy profile but different bleeding pattern. 1 Choice between these options depends on:

• Patient comorbidities (renal function, diabetes, PAD presence)
• Prior bleeding history
• Concomitant medication burden
• Patient preference and tolerability

Both strategies are superior to aspirin monotherapy in high-risk patients, and the choice should be based on individual patient characteristics rather than one being universally preferred. 1