Drug Therapy for Peripheral Arterial Disease
Antiplatelet Therapy (Cardiovascular Protection)
All symptomatic PAD patients must receive single antiplatelet therapy—either clopidogrel 75 mg daily (preferred) or aspirin 75–100 mg daily—to reduce myocardial infarction, stroke, and vascular death. 1, 2
- Clopidogrel 75 mg daily is the preferred agent based on 24% relative risk reduction in cardiovascular events compared to aspirin in PAD-specific populations 2
- Aspirin 75–100 mg daily is an acceptable alternative when clopidogrel is contraindicated or unavailable 1, 2
- For asymptomatic PAD patients with ABI ≤0.90, aspirin 75–100 mg daily may be considered for primary prevention, though bleeding risk offsets some cardiovascular benefit 2
Critical Pitfalls to Avoid
- Do NOT use dual antiplatelet therapy (aspirin + clopidogrel) routinely—it increases major bleeding without improving outcomes in stable PAD (Grade 2B) 1, 2
- Do NOT combine antiplatelet agents with warfarin unless a separate indication exists (e.g., atrial fibrillation)—this increases bleeding risk without cardiovascular benefit (Grade 1B) 1
Low-Dose Rivaroxaban Plus Aspirin (High-Risk Patients)
For symptomatic PAD patients at high ischemic risk and non-high bleeding risk, rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily should be considered to reduce both major adverse cardiovascular events (MACE) and major adverse limb events (MALE). 1, 3
- This is the ONLY antithrombotic combination proven to reduce limb events and cardiovascular events in PAD 3
- Specifically recommended after lower-limb revascularization to prevent both cardiovascular and limb complications 1, 3
- This regimen is distinct from full-dose anticoagulation and should not be confused with apixaban or other DOACs 3
When NOT to Use Rivaroxaban
- Do NOT use full-dose rivaroxaban (or any full-dose DOAC) for PAD alone—it increases bleeding without proven benefit 3
- Do NOT use apixaban for PAD unless the patient has a separate anticoagulation indication (e.g., atrial fibrillation); in that case, use apixaban monotherapy without adding antiplatelet agents 3
High-Intensity Statin Therapy (Cardiovascular Risk Reduction)
All PAD patients should receive high-intensity statin therapy regardless of baseline cholesterol levels, targeting LDL-C <70 mg/dL. 2
- Statins reduce cardiovascular events, improve exercise duration, and decrease the incidence of intermittent claudication 4, 5
- Lipid-lowering therapy also reduces major limb events in PAD patients 6
ACE Inhibitors or ARBs (Cardiovascular Protection)
ACE inhibitors or ARBs are preferred antihypertensive agents for PAD patients due to cardiovascular protective effects. 2
- Target blood pressure <140/90 mmHg (or <130/80 mmHg if diabetes or chronic kidney disease present) 2
- Beta-blockers are NOT contraindicated in PAD—they are safe and effective, especially when coronary artery disease coexists 2
Cilostazol (Symptom Relief for Claudication)
Cilostazol 100 mg twice daily is indicated for lifestyle-limiting intermittent claudication after a 3-month trial of supervised exercise therapy and smoking cessation. 1
- Cilostazol improves maximal walking distance by 40–60% and increases the proportion of patients experiencing meaningful functional benefit (79 more per 1,000 patients) 1, 2
- Cilostazol does NOT reduce cardiovascular mortality or major cardiovascular events—patients still require clopidogrel or aspirin for cardiovascular protection 2
- Absolute contraindication: heart failure of any severity—discontinue immediately if heart failure develops due to increased mortality risk from phosphodiesterase III inhibition 1, 7
Cilostazol Monitoring and Discontinuation
- Evaluate tolerance at 2–4 weeks; assess clinical benefit at 3–6 months 7
- Discontinue if severe persistent headache (affects 25% of patients), thrombocytopenia, leukopenia, or no symptom improvement after 3–6 months 7
- Approximately 20% of patients discontinue within 3 months due to side effects 7
Pentoxifylline (NOT Recommended)
Pentoxifylline should NOT be prescribed for intermittent claudication—it is marginally better than placebo and inferior to cilostazol. 1, 2
- The clinical effectiveness of pentoxifylline is not well established (Level of Evidence: C) 1
Post-Revascularization Antithrombotic Management
After any lower-extremity revascularization (endovascular or surgical), continue long-term single antiplatelet therapy (clopidogrel 75 mg daily or aspirin 75–100 mg daily). 2
- Alternatively, rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily is recommended to reduce both cardiovascular and limb events post-revascularization 1, 3
- For below-knee bypass using prosthetic grafts, a 12-month course of dual antiplatelet therapy (clopidogrel + aspirin) may be considered (Grade 2C) 2
Acute Limb Ischemia (Emergency Protocol)
Immediate systemic anticoagulation with unfractionated heparin is recommended over no anticoagulation (Grade 2C). 2
- Surgery is preferred over intra-arterial thrombolysis for definitive management (Grade 1B) 2
- If thrombolysis is chosen, use recombinant tissue-type plasminogen activator (rt-PA) or urokinase rather than streptokinase (Grade 2C) 2
Therapies NOT Recommended
- Chelation therapy (e.g., EDTA) is NOT indicated and may have harmful adverse effects 1
- L-arginine, propionyl-L-carnitine, and ginkgo biloba have marginal or unestablished effectiveness for claudication 1
- Triple therapy (anticoagulant + dual antiplatelet) should be avoided except briefly after acute coronary syndrome due to prohibitive bleeding risk 3
Supervised Exercise Therapy (Adjunct to Pharmacotherapy)
Supervised exercise training (SET) is recommended as first-line therapy for symptomatic PAD, performed 30–45 minutes per session, at least 3 times per week for a minimum of 12 weeks. 1