What is the recommended anticoagulation therapy for patients with severe Peripheral Arterial Disease (PAD)?

Anticoagulation in Severe PAD

For patients with severe (symptomatic) PAD at high ischemic risk and without high bleeding risk, combination therapy with low-dose rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily is the preferred strategy to reduce both major adverse cardiovascular events (MACE) and major adverse limb events (MALE). 1

Risk Stratification Framework

Before selecting antithrombotic therapy, assess the patient's ischemic and bleeding risk profiles:

High Ischemic Risk Features:

• Previous amputation 1
• Chronic limb-threatening ischemia (CLTI) 1
• Previous revascularization 1
• Heart failure 1
• Diabetes mellitus 1
• Vascular disease in two or more vascular beds 1
• Moderate kidney dysfunction (eGFR <60 mL/min/1.73 m²) 1

High Bleeding Risk (Contraindications to Dual Pathway):

• History of hemorrhagic or lacunar stroke 1
• Severe kidney disease 1
• Need for dual antiplatelet therapy or full anticoagulation for another indication 1

Treatment Algorithm by Clinical Scenario

Severe PAD WITHOUT High Ischemic Risk Features

Single antiplatelet therapy (SAPT) is recommended: 1

• Clopidogrel 75 mg once daily (Class I, Level A) 1
  • Preferred over aspirin based on superior MACE reduction in the CAPRIE trial 1, 2
• OR Aspirin 75-160 mg once daily (Class I, Level A) 1

Severe PAD WITH High Ischemic Risk Features AND Non-High Bleeding Risk

Dual pathway inhibition (DPI) should be considered: 1

• Rivaroxaban 2.5 mg twice daily PLUS aspirin 100 mg once daily (Class IIa, Level A) 1, 3
• This combination reduces MACE by 24% and MALE significantly compared to aspirin alone 1, 4
• Increases major bleeding risk, but predominantly nonfatal, non-intracranial hemorrhage 5
• FDA-approved for this indication 3

After Lower Extremity Revascularization (Endovascular or Surgical)

Immediate post-procedure (once hemostasis established):

• Rivaroxaban 2.5 mg twice daily PLUS aspirin 100 mg once daily (Class I, Level A for rivaroxaban combination; Class IIa for general post-revascularization) 1, 3
• The VOYAGER PAD trial demonstrated this reduces total vascular events by 14% and prevents an estimated 12.5 vascular events per 100 participants over 3 years 6

Alternative for endovascular revascularization:

• Dual antiplatelet therapy (DAPT) with clopidogrel 75 mg plus aspirin 75-100 mg daily for at least 1-6 months is reasonable (Class IIa, Level C-LD) 1

For prosthetic below-knee bypass grafts:

• DAPT with clopidogrel 75 mg plus aspirin 75-100 mg daily may be reasonable for at least 1 month (Class IIb, Level B-R) 1

Patients Requiring Full-Intensity Anticoagulation for Another Indication

If patient has atrial fibrillation, mechanical valve, or other indication for oral anticoagulation:

• Single oral anticoagulant (OAC) monotherapy (Class IIb) 1
• Adding single antiplatelet therapy is reasonable if not at high bleeding risk (Class IIa, Level C-LD) 1
• Do NOT use full-intensity OAC for PAD alone (Class III: Harm, Level A) 1

Critical Pitfalls to Avoid

Long-term dual antiplatelet therapy (aspirin + clopidogrel) is NOT recommended for chronic PAD without recent revascularization (within 6 months), as bleeding risk outweighs uncertain benefits 1

Full-intensity oral anticoagulation monotherapy should NOT be used for PAD without another indication (e.g., atrial fibrillation), as it increases bleeding without reducing MACE or MALE 1

Ticagrelor is NOT routinely recommended for PAD patients, as the EUCLID trial showed similar efficacy to clopidogrel but higher adverse event rates 1

Vorapaxar benefit is uncertain in symptomatic PAD and should generally be avoided due to bleeding concerns 1

Monitoring and Follow-Up

• Assess clinical and functional status, medication adherence, and limb symptoms at least annually 1
• Reassess ischemic and bleeding risk at every follow-up visit 1
• Monitor for bleeding complications, particularly in the first 3 months of dual pathway therapy 1
• Calculate creatinine clearance based on actual weight; avoid rivaroxaban if CrCl <15 mL/min 3

Evidence Strength Considerations

The 2024 ESC and ACC/AHA guidelines both provide Class I, Level A recommendations for SAPT in symptomatic PAD 1. The rivaroxaban plus aspirin combination receives Class IIa, Level A recommendations from ESC and Class I, Level A from ACC/AHA specifically for post-revascularization patients 1. The COMPASS and VOYAGER PAD trials provide the highest-quality evidence supporting dual pathway inhibition in high-risk PAD populations 1, 4, 6.