What is the evidence for the use of Direct Oral Anticoagulants (DOACs) in patients with Peripheral Artery Disease (PAD)?

Evidence for DOACs in Peripheral Artery Disease (PAD)

The combination of low-dose rivaroxaban (2.5 mg twice daily) with aspirin (100 mg daily) should be considered for patients with PAD who have high ischemic risk and non-high bleeding risk, as this regimen reduces major adverse cardiovascular events (MACE) and major adverse limb events (MALE). 1

Current Antithrombotic Recommendations for PAD

First-line Therapy

• Single antiplatelet therapy (SAPT) with either aspirin (75-100 mg daily) or clopidogrel (75 mg daily) is recommended as first-line therapy for patients with symptomatic PAD 1, 2
• Clopidogrel may be preferred over aspirin based on some evidence suggesting marginally superior efficacy 3

Advanced Therapy Options

• For high-risk PAD patients (those with previous amputation, chronic limb-threatening ischemia, previous revascularization, or high-risk comorbidities such as heart failure, diabetes, multi-vascular disease, or moderate kidney dysfunction):
  • Low-dose rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) provides significant benefits 1, 4
  • This combination demonstrated reduction in:
    • Major adverse cardiovascular events (MACE)
    • Major adverse limb events (MALE)
    • Cardiovascular mortality 3

Evidence from COMPASS Trial

The COMPASS trial provides the strongest evidence for DOAC use in PAD:

• Rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily reduced:

  • Stroke, myocardial infarction, and cardiovascular death (HR 0.76,95% CI: 0.66-0.86) 4
  • Both MACE and MALE compared to aspirin alone 2
  • Total mortality and cardiovascular mortality (strongest evidence for secondary prevention) 5

• The benefit was observed early with a constant treatment effect over the entire treatment period 4

Important Considerations and Contraindications

When NOT to Use Full-Dose DOACs

• Standard doses of DOACs should NOT be used for PAD unless there is another indication such as atrial fibrillation or venous thromboembolism 2
• Full-intensity oral anticoagulation (with DOACs or warfarin) for PAD alone has consistently shown increased bleeding risk without improving cardiovascular outcomes 2
• Oral anticoagulant monotherapy for PAD (unless for another indication) is not recommended 1

Bleeding Risk Assessment

• The COMPASS trial showed that while the rivaroxaban-aspirin combination reduced MACE and MALE, it did increase bleeding risk 2, 3
• Benefit-risk analysis from COMPASS showed that for every 10,000 patient-years of treatment, rivaroxaban would prevent 70 CV events at the cost of 12 additional life-threatening bleeds 4

Special Scenarios

PAD with Atrial Fibrillation

• For patients with both PAD and atrial fibrillation:
  • DOACs are preferred over vitamin K antagonists 2
  • DOACs significantly reduced the risk of major adverse limb events (HR = 0.58,95% CI, 0.39-0.86) compared with warfarin 6
  • After endovascular intervention/stenting (within 1-3 months), consider single antiplatelet therapy plus DOAC 2

Post-Revascularization

• After infrainguinal stent implantation, at least four weeks of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is recommended 5
• For patients with PAD following lower-limb revascularization with non-high bleeding risk, combination of rivaroxaban (2.5 mg twice daily) and aspirin (100 mg daily) should be considered 1

Algorithm for Antithrombotic Selection in PAD

1. Asymptomatic PAD without other cardiovascular disease:

   • Antiplatelet therapy not routinely recommended 1

2. Symptomatic PAD with non-high risk features:

   • Single antiplatelet therapy (aspirin 75-100 mg daily or clopidogrel 75 mg daily) 1

3. Symptomatic PAD with high-risk features AND non-high bleeding risk:

   • Rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily 1, 2

4. PAD requiring long-term anticoagulation (e.g., atrial fibrillation):

   • Single oral anticoagulant monotherapy (preferably DOAC) 1, 2

The evidence strongly supports that for most patients with PAD, single antiplatelet therapy remains the foundation of treatment, but for those at high ischemic risk without high bleeding risk, the addition of low-dose rivaroxaban to aspirin provides significant benefits in reducing both cardiovascular and limb events.