What medications are used to treat peripheral arterial disease (PAD)?

Medications for Peripheral Arterial Disease

All patients with symptomatic PAD should receive single antiplatelet therapy (aspirin 75-325 mg daily OR clopidogrel 75 mg daily), high-intensity statin therapy targeting LDL-C <70 mg/dL, and antihypertensive therapy if indicated, with clopidogrel preferred over aspirin based on superior cardiovascular event reduction. 1, 2, 3

Antiplatelet Therapy: The Foundation

Single antiplatelet therapy is mandatory for all symptomatic PAD patients to reduce myocardial infarction, stroke, and vascular death. 4, 1

First-Line Options:

• Clopidogrel 75 mg daily is the preferred agent based on the CAPRIE trial demonstrating 24% relative risk reduction in cardiovascular events compared to aspirin in PAD patients specifically. 4, 2, 5
• Aspirin 75-325 mg daily is an acceptable alternative if clopidogrel is contraindicated or unavailable. 4, 1
• Both agents are equally recommended as Class I evidence for symptomatic PAD, including those with intermittent claudication, critical limb ischemia, or prior revascularization. 4

Important Caveats:

• Avoid dual antiplatelet therapy (aspirin + clopidogrel) in stable PAD as it increases major bleeding risk without additional cardiovascular benefit (Grade 2B). 1
• Never combine antiplatelet agents with warfarin in symptomatic PAD (Grade 1B). 1
• Clopidogrel effectiveness depends on CYP2C19 metabolism—consider alternative P2Y12 inhibitors in poor metabolizers. 3

Asymptomatic PAD:

• Antiplatelet therapy is reasonable for asymptomatic patients with ABI ≤0.90 (Class IIa). 4, 1
• Evidence is weaker for borderline ABI (0.91-0.99). 4

Advanced Antiplatelet Strategy: Dual Pathway Inhibition

For symptomatic PAD patients without high bleeding risk, consider adding rivaroxaban 2.5 mg twice daily to aspirin 75-100 mg daily (Class 2a recommendation). 2, 6

Evidence Base:

• The COMPASS trial demonstrated 24% reduction in major adverse cardiovascular events, 47% reduction in major adverse limb events, and 18% reduction in mortality compared to aspirin alone. 6
• Greatest benefit in patients with polyvascular disease, type 2 diabetes, heart failure, or chronic kidney disease. 6
• This dual pathway inhibition (DPI) targets both platelet aggregation and coagulation cascade. 6

When to Use:

• Symptomatic PAD patients at high cardiovascular risk without recent major bleeding. 6
• After lower extremity revascularization once hemostasis is established (within 10 days post-procedure). 6

Lipid-Lowering Therapy

All PAD patients require high-intensity statin therapy regardless of baseline cholesterol levels, targeting LDL-C <70 mg/dL. 1, 2

• Statins reduce intermittent claudication incidence and improve exercise duration. 7
• This is a Class I recommendation for cardiovascular risk reduction. 1

Antihypertensive Therapy

Administer antihypertensive medications to reduce MI, stroke, heart failure, and cardiovascular death. 1, 2

Target Blood Pressure:

• <140/90 mmHg for most patients. 1
• <130/80 mmHg if diabetes or chronic kidney disease present. 1

Agent Selection:

• ACE inhibitors or ARBs are preferred for cardiovascular protection (Class IIa for asymptomatic PAD). 4, 2
• Beta-blockers are NOT contraindicated in PAD and are effective antihypertensives, especially if coronary artery disease coexists (Level of Evidence: A). 4, 2

Symptom Relief: Claudication Management

For persistent claudication despite exercise therapy and smoking cessation, add cilostazol 100 mg twice daily to baseline antiplatelet therapy (Grade 2C). 1, 7

• Cilostazol improves walking distance and quality of life. 1
• This is added to, not substituted for, antiplatelet therapy. 1

Alternative Agent:

• Pentoxifylline has been used historically but is less effective than cilostazol and not strongly recommended. 8

Diabetes Management

Optimize glycemic control with target hemoglobin A1C <7% to reduce microvascular complications and potentially improve cardiovascular outcomes (Class IIa). 4, 2

• GLP-1 receptor agonists and SGLT-2 inhibitors are preferred antidiabetic agents for cardiovascular benefit. 9
• Proper foot care is mandatory (Class I): appropriate footwear, daily inspection, skin cleansing, topical moisturizers, and urgent treatment of lesions. 4

Smoking Cessation Pharmacotherapy

All smokers with PAD must be offered pharmacological therapy (Class I, Level A). 4, 2

Options (all equally effective):

• Varenicline
• Bupropion
• Nicotine replacement therapy 4, 2

Post-Revascularization Management

After Endovascular Intervention:

• Dual antiplatelet therapy (aspirin + clopidogrel) for 1-6 months is reasonable (Class IIa). 2
• Long-term single antiplatelet therapy (aspirin 75-100 mg OR clopidogrel 75 mg daily) thereafter (Grade 1A). 1
• Alternative: Rivaroxaban 2.5 mg twice daily + aspirin based on VOYAGER PAD trial. 2, 6

After Bypass Surgery:

• Continue aspirin 75-100 mg daily OR clopidogrel 75 mg daily long-term (Grade 1A). 1

Acute Limb Ischemia

Immediate systemic anticoagulation with unfractionated heparin is recommended over no anticoagulation (Grade 2C). 1

• Surgery is preferred over intra-arterial thrombolysis for definitive management (Grade 1B). 1

What NOT to Use

• Homocysteine-lowering therapy (folic acid, B12) is not well established even with elevated homocysteine >14 micromoles/L (Class IIb). 4
• Dual antiplatelet therapy without recent revascularization increases bleeding without clear benefit. 1
• Warfarin plus antiplatelet therapy is contraindicated. 1

Common Pitfalls

• Underutilization of clopidogrel: Many clinicians default to aspirin despite superior PAD-specific evidence for clopidogrel. 5
• Forgetting statin therapy: PAD patients are very high cardiovascular risk—statins are mandatory regardless of cholesterol levels. 1
• Avoiding beta-blockers unnecessarily: Historical concerns about worsening claudication are unfounded; beta-blockers are safe and effective. 4
• Premature discontinuation of antiplatelet therapy: Stopping increases cardiovascular event risk; restart as soon as possible if interrupted. 3