Why are symptomatic patients with Peripheral Artery Disease (PAD) placed on Rivaroxaban (Xarelto) and Aspirin, but not asymptomatic patients?

Why Rivaroxaban Plus Aspirin Is Recommended for Symptomatic PAD But Not Asymptomatic PAD

The combination of rivaroxaban 2.5 mg twice daily and aspirin is specifically recommended for symptomatic PAD patients due to their significantly higher risk of major adverse cardiovascular and limb events compared to asymptomatic patients, with clinical evidence showing substantial risk reduction in this population but not in asymptomatic patients. 1

Risk Stratification in PAD

Symptomatic vs. Asymptomatic PAD

• Symptomatic PAD patients have demonstrated clinical manifestations (claudication, rest pain, tissue loss) indicating more advanced disease with higher risk of:

  • Major adverse cardiovascular events (MACE)
  • Major adverse limb events (MALE)
  • Acute limb ischemia
  • Major vascular amputation

• Asymptomatic PAD patients have:

  • Lower overall risk profile
  • No evidence of benefit from dual antithrombotic therapy
  • Potential for harm from bleeding that outweighs benefits

High-Risk Features in Symptomatic PAD

Patients with symptomatic PAD are considered at particularly high risk if they have:

1. High-risk limb presentations:

   • Prior amputation
   • Fontaine III or IV symptoms (rest pain, tissue loss)
   • Previous peripheral revascularization
   • Ischemic ulcers

2. High-risk comorbidities:

   • Kidney dysfunction
   • Heart failure
   • Diabetes mellitus
   • Polyvascular disease (PAD plus CAD or cerebrovascular disease) 2

Evidence Supporting Rivaroxaban in Symptomatic PAD

COMPASS Trial

• Demonstrated that rivaroxaban 2.5 mg twice daily plus aspirin reduced:
  • MACE by 28%
  • MALE by 46%
  • Major amputation by 70%
• In symptomatic PAD patients with high-risk features, the absolute risk reduction was 4.2% for MACE or MALE at 30 months 2

VOYAGER PAD Trial

• Showed rivaroxaban 2.5 mg twice daily plus aspirin reduced:
  • Primary composite endpoint (MACE + MALE) by 15%
  • Total vascular events by 14%
  • Estimated 12.5 vascular events per 100 participants avoided over 3 years 3
• Benefits were consistent across both endovascular and surgical revascularization 4

Antithrombotic Recommendations Based on PAD Status

For Symptomatic PAD:

1. First-line therapy: Rivaroxaban 2.5 mg twice daily plus aspirin (75-100 mg daily) for patients with:

   • High-risk limb presentations OR
   • High-risk comorbidities AND
   • Low bleeding risk 1, 5

2. Alternative: Single antiplatelet therapy (aspirin or clopidogrel) for patients with:

   • Higher bleeding risk
   • Lower ischemic risk
   • Concerns about medication burden 5

For Asymptomatic PAD:

1. Standard recommendation: Single antiplatelet therapy may be considered in asymptomatic PAD with diabetes mellitus 1
2. Not recommended: Combination therapy with rivaroxaban and aspirin is not indicated due to:
   • Lack of evidence for benefit
   • Potential for harm from bleeding complications
   • Unfavorable risk-benefit ratio 1

Bleeding Risk Considerations

• Rivaroxaban plus aspirin increases major bleeding risk (HR: 1.51) 6
• However, severe or fatal bleeding is not significantly increased (HR: 1.18) 6
• Patients should be assessed for bleeding risk factors:
  • Prior major bleeding
  • Severe renal impairment
  • Concomitant medications affecting hemostasis
  • Advanced age
  • Low body weight 7

Clinical Implications

The selective use of rivaroxaban plus aspirin in symptomatic PAD but not asymptomatic PAD represents a risk-stratified approach that:

1. Targets therapy to patients with the highest risk of adverse events
2. Provides substantial absolute risk reduction where it matters most
3. Avoids unnecessary bleeding risk in lower-risk patients
4. Optimizes the benefit-risk profile across the PAD spectrum

This approach is supported by both the American College of Cardiology/American Heart Association and European Society of Cardiology guidelines, which recommend combination therapy for symptomatic PAD patients but not for asymptomatic individuals 1, 5.