Is cilostazol (Phosphodiesterase 3 inhibitor) an adequate treatment for Peripheral Artery Disease (PAD)?

Is Cilostazol Adequate Treatment for PAD?

Yes, cilostazol 100 mg twice daily is adequate and recommended as first-line pharmacotherapy for patients with peripheral artery disease and lifestyle-limiting intermittent claudication, provided they do not have heart failure of any severity. 1, 2

Evidence-Based Recommendation

The ACC/AHA guidelines give cilostazol a Class I recommendation (Level of Evidence: A) for improving symptoms and increasing walking distance in PAD patients with intermittent claudication. 1

Efficacy Data

• Cilostazol improves maximal walking distance by 40-60% compared to placebo after 12-24 weeks of therapy, based on five prospective randomized trials. 1, 3

• The medication produces a 50.7% improvement from baseline in maximal walking distance compared to 24.3% with placebo, representing an absolute improvement of 42.1 meters greater than placebo. 4

• Benefits are sustained over 24 weeks and continue to increase throughout the treatment period. 4

• Cilostazol improves not only walking distance but also health-related quality of life according to meta-analyses. 1

Dosing Algorithm

• Start with 100 mg orally twice daily, which is significantly more effective than 50 mg twice daily. 1, 3

• If side effects occur, dose may be reduced to 50 mg twice daily temporarily, but 91.3% of physicians increase back to full dose within 4 weeks. 5

• Treatment should continue for at least 12-24 weeks to achieve maximal benefit. 1, 3

Critical Absolute Contraindication

Cilostazol is absolutely contraindicated in patients with heart failure of any severity due to FDA black-box warning. 1, 6

• Other phosphodiesterase III inhibitors (milrinone, vesnarinone) have demonstrated increased mortality in heart failure patients. 1, 6

• The mechanism involves increased cyclic AMP levels that can trigger ventricular tachycardia in heart failure patients. 6

• You must screen every patient for any history or symptoms of heart failure before prescribing cilostazol. 6

Safety Profile

• Long-term safety data from 1435 patients showed no increased mortality risk: 18 deaths on cilostazol versus 19 on placebo (hazard ratio 0.99,95% CI 0.52-1.88). 7

• Cardiovascular deaths were identical: 14 patients on cilostazol and 14 on placebo. 7

• Serious bleeding events were not increased: 18 patients on cilostazol versus 22 on placebo, even with concurrent aspirin, clopidogrel, or anticoagulants. 7

• A pooled analysis of nine trials (1258 subjects) demonstrated no increased risk of all-cause mortality (RR 0.95% CI 0.68-1.35). 4

Common Side Effects

• Approximately 50% of patients experience minor adverse effects, and about 20% discontinue within 3 months due to side effects. 3, 8

• Most common: headache, diarrhea, abnormal stools, palpitations, and dizziness. 1

• Cilostazol increases heart rate by mean of 7.4 beats per minute at 100 mg twice daily dose. 9

Treatment Algorithm for PAD with Claudication

1. Screen for heart failure (absolute contraindication). 1, 6

2. Initiate supervised exercise therapy (30-45 minutes, at least 3 times weekly for minimum 12 weeks) as first-line therapy. 3

3. Start cilostazol 100 mg twice daily simultaneously for all patients with lifestyle-limiting claudication without heart failure. 2, 3

4. If cilostazol is contraindicated or not tolerated, consider pentoxifylline 400 mg three times daily as second-line alternative, though its efficacy is marginal. 1, 2

5. Reassess at 12-24 weeks: If inadequate response to optimal medical therapy, consider endovascular intervention. 2

Efficacy Across Patient Subgroups

• Benefits are observed irrespective of age, sex, smoking status, duration of PAD, diabetes, hypertension, prior myocardial infarction, or beta-blocker use. 4

• The medication produces modest increases in ankle-brachial index (ABI), but hemodynamic effects cannot fully account for the improvement in claudication symptoms. 1, 3

Additional Mechanisms Beyond Symptom Relief

• Cilostazol increases HDL cholesterol by approximately 10% and reduces triglycerides by 15% (29.3 mg/dL reduction). 1, 9

• The drug inhibits vascular smooth muscle cell proliferation and may prevent restenosis, making it potentially useful after revascularization procedures. 1, 10

• 30% of physicians prescribe cilostazol in patients who have undergone revascularization for its anti-restenotic properties. 5

Common Pitfall to Avoid

The most critical error is prescribing cilostazol to patients with any degree of heart failure. Always verify absence of heart failure before initiating therapy, as the FDA black-box warning exists due to class effect concerns with phosphodiesterase III inhibitors. 1, 6