What is the role of oral anticoagulants, such as rivaroxaban (Xarelto) or apixaban (Eliquis), in the management of peripheral arterial disease (PAD)?

Oral Anticoagulant in Peripheral Arterial Disease

Primary Recommendation

For patients with symptomatic PAD at high ischemic risk and without high bleeding risk, combination therapy with low-dose rivaroxaban 2.5 mg twice daily plus aspirin 75-100 mg daily should be considered over aspirin monotherapy to reduce major adverse cardiovascular events (MACE) and major adverse limb events (MALE). 1

Evidence-Based Treatment Algorithm

For Symptomatic PAD Without Recent Revascularization

High Ischemic Risk + Non-High Bleeding Risk:

• Rivaroxaban 2.5 mg twice daily + aspirin 100 mg daily is the preferred regimen 1
• This combination reduces MACE and MALE compared to aspirin alone, with an absolute reduction of approximately 70 fewer cardiovascular events per 10,000 patient-years 2
• The trade-off includes 12 additional life-threatening bleeding events per 10,000 patient-years, yielding a favorable benefit-risk ratio 2

Moderate or Low Ischemic Risk:

• Single antiplatelet therapy (aspirin 75-325 mg daily OR clopidogrel 75 mg daily) is recommended 1
• Clopidogrel may be preferred over aspirin based on superior efficacy in the CAPRIE trial 1

After Lower Extremity Revascularization (Endovascular or Surgical)

Immediate Post-Revascularization Period (1-6 months):

• Dual antiplatelet therapy with aspirin plus clopidogrel is reasonable for at least 1-6 months 1
• Alternatively, rivaroxaban 2.5 mg twice daily + aspirin 100 mg daily should be considered in patients with non-high bleeding risk 1
• This combination prevents an estimated 181 primary outcome events (MI, stroke, CV death, acute limb ischemia, major amputation) per 10,000 patient-years compared to aspirin alone 2

Beyond 6 Months Post-Revascularization:

• Transition to rivaroxaban 2.5 mg twice daily + aspirin 100 mg daily for patients at high ischemic risk with non-high bleeding risk 1
• Otherwise, continue single antiplatelet therapy 1

For Asymptomatic PAD

Without Diabetes:

• Single antiplatelet therapy is reasonable but evidence is less robust 1
• Antiplatelet therapy may be considered to reduce MACE risk 1

With Diabetes:

• Aspirin 75-100 mg daily for primary prevention may be considered in the absence of contraindications 1

Critical Exclusion Criteria for Rivaroxaban + Aspirin

Do NOT use rivaroxaban plus aspirin in patients with: 2

• High bleeding risk (history of intracranial hemorrhage, hemorrhagic or lacunar stroke)
• Severe kidney disease (eGFR <15 mL/min)
• Need for dual antiplatelet therapy beyond 6 months
• Need for full-intensity oral anticoagulation for another indication
• Active gastroduodenal ulcer or bleeding in previous 3 months
• Bronchiectasis with pulmonary cavitation
• Active cancer requiring dual antiplatelet therapy

What NOT to Do

Full-intensity oral anticoagulation (e.g., rivaroxaban 20 mg daily, apixaban 5 mg twice daily) should NOT be used in PAD without another indication such as atrial fibrillation, as it may be harmful. 1

The COMPASS trial demonstrated that rivaroxaban 5 mg twice daily alone was not superior to aspirin alone and is therefore not recommended 2

Defining High Ischemic Risk

Patients are considered at high ischemic risk if they have: 1

• Polyvascular disease (CAD plus PAD)
• Diabetes mellitus with PAD
• Recent revascularization procedure
• History of acute limb ischemia or major amputation
• Multiple cardiovascular risk factors

Monitoring Considerations

Bleeding Risk Assessment:

• Major bleeding increases with rivaroxaban plus aspirin (HR 1.51) but severe/fatal bleeding does not significantly increase (HR 1.18) 3
• The excess bleeding is largely driven by nonfatal, non-intracranial hemorrhage 4

Follow-up Requirements:

• Assess patients at least annually for recurrence of symptoms, medication adherence, and bleeding complications 1, 5
• If claudication recurs or new vascular symptoms develop, reassess with ankle-brachial index and consider vascular imaging 5

Special Populations

Patients Requiring Anticoagulation for Atrial Fibrillation:

• After endovascular or surgical revascularization, adding single antiplatelet therapy to full-intensity anticoagulation is reasonable if not at high bleeding risk 1
• After 6-12 months of dual therapy, transition to oral anticoagulant monotherapy is preferred 1
• NOACs (dabigatran, rivaroxaban, apixaban, edoxaban) are preferred over warfarin 1

Post-Surgical Revascularization with Prosthetic Graft:

• Dual antiplatelet therapy with P2Y12 antagonist plus low-dose aspirin may be reasonable for at least 1 month 1

Common Pitfalls to Avoid

• Do not confuse low-dose rivaroxaban (2.5 mg twice daily) with therapeutic anticoagulation doses - they serve different purposes and have different risk-benefit profiles 2
• Do not use dual antiplatelet therapy long-term in symptomatic PAD without recent revascularization - the benefit is uncertain and bleeding risk increases 1
• Do not use vorapaxar routinely - its benefit added to existing antiplatelet therapy is uncertain 1
• Do not assume all PAD patients need intensive antithrombotic therapy - asymptomatic PAD does not warrant aggressive treatment 6