What is the recommended dosage and treatment approach for a patient with intermittent claudication due to peripheral arterial disease using cilostazol?

Cilostazol for Intermittent Claudication

Recommended Dosage

The standard dose of cilostazol is 100 mg orally twice daily, taken 30 minutes before or 2 hours after breakfast and dinner, which improves maximal walking distance by 40-60% after 12-24 weeks of therapy. 1, 2, 3

• The 100 mg twice daily dose is significantly more effective than the 50 mg twice daily dose in comparative studies 1, 2
• The 50 mg twice daily dose may be considered if patients cannot tolerate the higher dose, though efficacy is reduced 1
• Treatment effects become apparent as early as 2-4 weeks after initiation 4, 5

Treatment Algorithm

First-line therapy should be supervised exercise training (30-45 minutes, at least 3 times weekly for minimum 12 weeks), with cilostazol 100 mg twice daily added simultaneously or if exercise alone is inadequate. 1, 3

Step-by-step approach:

1. Screen for heart failure - Cilostazol is absolutely contraindicated in patients with heart failure of any severity due to FDA black box warning regarding increased mortality risk with phosphodiesterase III inhibitors 1, 2, 3

2. Initiate combination therapy - Start supervised exercise plus cilostazol 100 mg twice daily for all patients with lifestyle-limiting claudication without heart failure 1, 3

3. Evaluate tolerance - Assess patient tolerance at 2-4 weeks after initiation 2

4. Determine clinical benefit - Evaluate response at 12-24 weeks to decide whether to continue long-term therapy 2, 4

5. Consider alternatives if needed - If cilostazol is contraindicated or not tolerated, pentoxifylline 400 mg three times daily with meals may be used as second-line therapy, though its clinical effectiveness is marginal 1, 3

Expected Clinical Benefits

Cilostazol produces substantial improvements in both pain-free walking distance (59% increase) and maximal walking distance (40-60% increase). 1, 5

• Initial claudication distance improves by approximately 31 meters compared to placebo 6, 7
• Absolute claudication distance improves by approximately 43 meters compared to placebo 6, 7
• A modest increase in ankle-brachial index occurs, though this hemodynamic effect does not fully account for symptom improvement 1
• The mechanism involves phosphodiesterase type 3 inhibition producing antiplatelet and vasodilatory effects 1

Common Adverse Effects and Discontinuation

Approximately 20% of patients discontinue cilostazol within 3 months due to side effects, most commonly headache, diarrhea, abnormal stools, palpitations, and dizziness. 1, 2

• Headache is the most frequent adverse effect, occurring 2.8 times more often than with placebo 7
• These side effects are generally mild, self-limited, and treatable 6, 5
• Withdrawal rates due to adverse events are similar across treatment and placebo groups (approximately 14.5%) 5

Critical Contraindications and Pitfalls

Always assess for heart failure before prescribing cilostazol - this is an absolute contraindication regardless of severity. 1, 2, 3

• The FDA black box warning prohibits use in any patient with heart failure due to increased mortality risk with type III phosphodiesterase inhibitors 2
• Do not consider pentoxifylline equivalent to cilostazol, as pentoxifylline's benefit is marginal at best 3
• If inadequate response occurs after 12-24 weeks of optimal medical therapy, consider endovascular intervention 3

Cardiovascular Safety

Long-term mortality data from a Phase IV study showed no increased cardiovascular risk with cilostazol, with sufficient data to exclude a 75% increase in mortality risk. 4

• The 36-month Kaplan-Meier event rate for deaths was 5.6% on cilostazol versus 6.8% on placebo 4
• There is no difference in all-cause mortality or cardiovascular events between cilostazol and placebo groups 6, 7, 8
• Current evidence is insufficient to determine effects on amputation or revascularization rates 7