What is the preferred treatment between cilostazol (phosphodiesterase inhibitor) and sulodexide (glycosaminoglycan) for a patient with peripheral artery disease (PAD) and intermittent claudication?

Cilostazol is Strongly Preferred Over Sulodexide for Peripheral Artery Disease

Cilostazol 100 mg twice daily is the evidence-based first-line pharmacotherapy for intermittent claudication in PAD patients without heart failure, while sulodexide has no established role in current treatment guidelines. 1, 2

Primary Recommendation

The American College of Cardiology explicitly recommends cilostazol 100 mg orally twice daily as the pharmacologic treatment of choice for all patients with lifestyle-limiting intermittent claudication from PAD, provided they do not have heart failure of any severity. 1, 2 Sulodexide is notably absent from all major PAD treatment guidelines and lacks the robust evidence base that supports cilostazol use.

Evidence Supporting Cilostazol

Walking Distance Improvements

• Cilostazol improves maximal walking distance by 40-60% after 12-24 weeks of therapy compared to placebo 1, 2, 3
• Pain-free walking distance increases by 59% with the 100 mg twice daily dose 1, 3
• These improvements translate to clinically meaningful increases: from approximately 130 meters at baseline to 259 meters at 24 weeks 3
• Benefits become evident as early as 4 weeks and continue improving through 24 weeks 3

Mechanism and Effects

• Cilostazol is a phosphodiesterase type 3 inhibitor with antiplatelet, vasodilatory, and antiproliferative properties 1, 4
• The drug produces modest improvements in ankle-brachial index, though hemodynamic effects alone don't fully explain symptom improvement 1

Quality of Life

• Multiple studies demonstrate improvements in quality of life measures and functional status with cilostazol therapy 4, 3, 5

Treatment Algorithm

First-Line Approach

1. Initiate supervised exercise training (30-45 minutes, at least 3 times weekly for minimum 12 weeks) 1
2. Start cilostazol 100 mg twice daily simultaneously or if exercise proves inadequate 1, 2
3. Screen for heart failure before prescribing - this is an absolute contraindication 1, 2, 6

Dosing Strategy

• Standard dose: 100 mg orally twice daily (significantly more effective than 50 mg twice daily) 1, 2, 6
• May reduce to 50 mg twice daily temporarily if early side effects occur, then uptitrate to 100 mg within 4 weeks 7
• Evaluate tolerance at 2-4 weeks and clinical benefit at 3-6 months 6

Alternative Only When Cilostazol Fails

• Pentoxifylline 400 mg three times daily is second-line therapy only when cilostazol is contraindicated or not tolerated 2
• Pentoxifylline has marginal and poorly established clinical effectiveness 1, 2

Critical Contraindication

Cilostazol is absolutely contraindicated in patients with heart failure of any severity due to increased mortality risk associated with phosphodiesterase III inhibitors. 1, 2, 6 The FDA issued a black box warning for this contraindication 6. Always assess cardiac function before prescribing.

Safety Profile

Common Adverse Effects

• Headache (most common - occurs 2.83 times more frequently than placebo) 6, 5
• Diarrhea and abnormal stools 6, 3
• Dizziness and palpitations 6, 3
• Approximately 20% of patients discontinue within 3 months due to side effects 1

Long-Term Safety

• No increased mortality signal in long-term studies (hazard ratio 0.99,95% CI 0.52-1.88) 8
• No increased serious bleeding events, even with concurrent antiplatelet or anticoagulant therapy 8
• Cardiovascular deaths were equivalent to placebo 8

Why Sulodexide Is Not Recommended

Sulodexide (a glycosaminoglycan) is conspicuously absent from:

• American College of Cardiology guidelines for PAD management 1, 2
• Cochrane systematic reviews of claudication treatments 5
• FDA-approved therapies for intermittent claudication 6

The lack of guideline support and high-quality evidence for sulodexide in PAD makes cilostazol the clear choice based on established efficacy, safety data, and guideline endorsement.

Clinical Pearls

• Combination of supervised exercise plus cilostazol may provide additive benefits 1
• Most physicians prescribe cilostazol for 4 months continuously, though 17.6% advocate lifelong treatment 7
• Consider revascularization if inadequate response after 12-24 weeks of optimal medical therapy 2
• Some clinicians use cilostazol after revascularization for potential anti-restenotic properties 7