How does cilostazol help patients with Peripheral Vascular Disease (PVD)?

Cilostazol's Mechanism of Action and Benefits in Peripheral Vascular Disease

Cilostazol is a phosphodiesterase type 3 inhibitor that improves walking distance by 40-60% in patients with peripheral arterial disease through vasodilation, platelet inhibition, and vascular effects. 1, 2

Mechanism of Action

• Cilostazol increases cyclic adenosine monophosphate (cAMP) by inhibiting phosphodiesterase type 3, which produces both vasodilator and platelet inhibitory effects 3
• It causes non-homogeneous dilation of vascular beds, with greater dilation in femoral arteries than in vertebral, carotid, or superior mesenteric arteries 3
• Cilostazol has been shown to increase plasma HDL cholesterol and decrease triglyceride concentrations, providing additional cardiovascular benefits 1, 4
• It inhibits vascular smooth muscle cell proliferation and prevents restenosis in patients with vascular disease 1, 2

Clinical Benefits in PVD

• Cilostazol significantly improves maximal walking distance by 40-60% compared to placebo after 12-24 weeks of therapy 1, 3
• It increases both pain-free walking distance and maximal walking distance in patients with intermittent claudication 2, 5
• Cilostazol produces a modest increase in ankle-brachial index (ABI), though this hemodynamic effect alone cannot fully account for the improvement in claudication symptoms 1, 4
• It improves quality of life measures in patients with intermittent claudication, as demonstrated by improvements in Walking Impairment Questionnaire scores and SF-36 physical summary scores 3, 5

Dosing and Administration

• The recommended dose is 100 mg orally twice daily, which is more effective than 50 mg twice daily 1, 2
• Improvements in walking distance can be seen as early as 2-4 weeks after starting therapy 3, 4
• A therapeutic trial of cilostazol should be considered in all patients with lifestyle-limiting claudication (in the absence of heart failure) 1

Important Contraindications and Safety Considerations

• Cilostazol is absolutely contraindicated in patients with heart failure of any severity 1, 2
• The FDA has mandated a black box warning against use in heart failure patients due to concerns about increased mortality risk associated with phosphodiesterase III inhibitors 1, 4
• Common side effects include headache, diarrhea, abnormal stools, palpitations, and dizziness 1, 2
• Approximately 20% of patients discontinue cilostazol within 3 months due to side effects 2, 4
• Long-term safety studies have not shown increased mortality risk in patients without heart failure 6

Comparative Efficacy

• Cilostazol is superior to pentoxifylline for improving walking distance in patients with intermittent claudication 1, 4
• Pentoxifylline may be considered as a second-line alternative therapy, but its clinical effectiveness is marginal and not well established 1
• Recent data suggests cilostazol may be associated with improved amputation-free survival in patients undergoing peripheral vascular interventions 7

Treatment Algorithm for PVD

1. First-line therapy: Supervised exercise training (30-45 minutes, at least 3 times weekly for minimum 12 weeks) 1, 2
2. Add cilostazol 100 mg twice daily for all patients with lifestyle-limiting claudication without heart failure 1
3. Assess patient tolerance at 2-4 weeks and evaluate benefit within 3-6 months 4
4. Consider pentoxifylline only as a second-line alternative if cilostazol is not tolerated or contraindicated 1
5. Consider endovascular procedures for patients with inadequate response to exercise and pharmacological therapy 1

Clinical Pearls and Pitfalls

• Always assess for heart failure before prescribing cilostazol, as it is absolutely contraindicated in these patients 2, 4
• Combination therapy with supervised exercise and cilostazol may provide additive benefits for patients with claudication 2
• Cilostazol appears to be underutilized in clinical practice despite its proven benefits 7
• Cilostazol does not appear to increase serious bleeding events, even in patients using aspirin, aspirin plus clopidogrel, or anticoagulants 6