What is the preferred antiplatelet therapy, cilostazol (Pletal) or aspirin, for a diabetic patient with peripheral arterial disease (PAD) and a history of foot complications?

Antiplatelet Therapy for PAD with Diabetes and Foot Complications

For a diabetic patient with peripheral arterial disease and foot complications, aspirin (75-100 mg daily) or clopidogrel (75 mg daily) should be the primary antiplatelet therapy, with cilostazol added specifically to improve claudication symptoms and potentially enhance wound healing—not as a replacement for standard antiplatelet therapy. 1

Primary Antiplatelet Therapy: Aspirin or Clopidogrel

Both aspirin (75-325 mg daily) and clopidogrel (75 mg daily) are Class I, Level A recommendations for reducing myocardial infarction, stroke, and vascular death in symptomatic PAD patients. 1, 2 The 2016 AHA/ACC guidelines and 2012 CHEST guidelines establish these as equivalent first-line options for cardiovascular event prevention. 1

• Clopidogrel may have a marginal advantage over aspirin for reducing MI, stroke, and vascular death specifically in PAD patients, though this is a weaker recommendation (Class IIb). 1
• The choice between aspirin and clopidogrel should consider bleeding risk, cost, and patient tolerance. 1

Role of Cilostazol: Symptom Management, Not Primary Prevention

Cilostazol is NOT a substitute for aspirin or clopidogrel—it serves a different purpose. The critical distinction is that cilostazol treats claudication symptoms and improves walking distance, while aspirin/clopidogrel prevent cardiovascular events. 1, 2

When to Add Cilostazol:

• Add cilostazol 100 mg twice daily when intermittent claudication remains refractory to exercise therapy and smoking cessation, in addition to (not instead of) aspirin or clopidogrel. 1, 2
• Cilostazol improves maximal walking distance by 28-100% compared to baseline in clinical trials. 3
• In diabetic PAD patients specifically, cilostazol improved absolute walking distance by 86.4% at 6 weeks and 143% at 24 weeks versus placebo. 4

Emerging Evidence for Diabetic Foot Ulcers:

• A 2025 retrospective study found cilostazol achieved 90% complete wound healing in diabetic foot ulcer patients with PAD, compared to 55% with aspirin alone, with faster healing timelines. 5
• This suggests cilostazol may offer additional benefits beyond claudication in diabetic patients with foot complications, though this requires validation in larger randomized trials. 5

Critical Safety Consideration: Heart Failure Contraindication

Cilostazol is absolutely contraindicated in any patient with congestive heart failure of any severity due to increased mortality risk from its phosphodiesterase III inhibitor properties. 2, 6, 3 This is a Class III (Harm) recommendation. Before prescribing cilostazol, you must exclude heart failure—a common pitfall given the overlap between PAD and cardiac disease.

Common Side Effects Leading to Discontinuation:

• Headache (up to 25%), diarrhea, dizziness, and palpitations are common. 1, 6
• Approximately 20% of patients discontinue cilostazol within 3 months due to side effects. 1, 6
• Evaluate tolerance at 2-4 weeks and assess clinical benefit at 3-6 months; discontinue if no improvement. 6

Safety of Combination Therapy

Cilostazol can be safely combined with aspirin or clopidogrel without significantly increasing bleeding risk. 7, 8 A crossover trial demonstrated that while aspirin and clopidogrel each increased bleeding times, cilostazol alone did not, and adding cilostazol to aspirin/clopidogrel regimens caused no further bleeding time prolongation. 7

The CASTLE study (1,435 patients) found no increase in serious bleeding events with cilostazol (18 events) versus placebo (22 events), even in patients using aspirin, clopidogrel, or anticoagulants. 8

Dual Antiplatelet Therapy: Generally Not Recommended

The combination of aspirin plus clopidogrel is not recommended for routine PAD management (Class IIb, Level B). 1 This combination does not provide established benefit for reducing cardiovascular events in PAD and increases bleeding risk. 1

• Exception: Dual antiplatelet therapy may be reasonable for 1 month after lower extremity revascularization to reduce limb-related events. 1

Alternative: Rivaroxaban Plus Aspirin for High-Risk Patients

For PAD patients with high ischemic risk and non-high bleeding risk, rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily should be considered (Class IIa, Level A). 1 This combination reduces cardiovascular death, MI, or stroke compared to aspirin alone but increases bleeding risk. 1

Practical Algorithm for Your Patient

1. Start with aspirin 75-100 mg daily OR clopidogrel 75 mg daily for cardiovascular event prevention. 1, 2

2. Screen for heart failure before considering cilostazol—echocardiography if clinical suspicion exists. 2, 6

3. If claudication limits function despite exercise therapy and smoking cessation, ADD cilostazol 100 mg twice daily (not as replacement). 1, 2

4. For diabetic foot ulcers with PAD, strongly consider cilostazol given emerging evidence of superior wound healing. 5

5. Reassess at 2-4 weeks for side effects and 3-6 months for efficacy; discontinue cilostazol if no benefit or intolerable side effects. 6

6. Ensure all patients receive statin therapy (Class I, Level A) and appropriate blood pressure control. 1

Common Pitfalls to Avoid

• Do not use cilostazol as monotherapy—it does not prevent cardiovascular events like aspirin/clopidogrel. 1
• Do not prescribe cilostazol without excluding heart failure, even if currently compensated. 2, 6
• Do not routinely use dual antiplatelet therapy (aspirin + clopidogrel) outside the post-revascularization period. 1
• Beta-blockers are NOT contraindicated in PAD—they are effective antihypertensives and should be used when indicated. 2