What is Cilostazol?
Cilostazol is a phosphodiesterase type 3 (PDE III) inhibitor medication used primarily to treat intermittent claudication in patients with peripheral arterial disease (PAD). 1, 2
Mechanism of Action
Cilostazol works by inhibiting phosphodiesterase type 3, which increases cyclic adenosine monophosphate (cAMP) levels in platelets and blood vessels 1, 2. This produces several key effects:
- Vasodilation: Dilates blood vessels, particularly in the femoral arteries
- Antiplatelet activity: Reversibly inhibits platelet aggregation induced by multiple stimuli (thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress)
- Antiproliferative effects: Inhibits vascular smooth muscle cell proliferation and migration
- Metabolic benefits: Increases HDL cholesterol by approximately 10% and decreases triglycerides by 15% 3, 1, 2
The precise mechanism by which these effects improve claudication symptoms is not fully understood 2.
Clinical Efficacy
Cilostazol 100 mg twice daily improves maximal walking distance by 40-60% after 12-24 weeks of therapy 3. The drug also:
- Improves pain-free walking distance by approximately 24 meters compared to placebo 4
- Modestly increases ankle-brachial index (ABI), though this hemodynamic effect does not fully account for symptom improvement 3
- Improves quality of life and walking ability based on meta-analyses 3, 5
- The 100 mg twice daily dose is more effective than 50 mg twice daily 3
FDA-Approved Indication
Cilostazol is FDA-approved for reducing symptoms of intermittent claudication, as indicated by increased walking distance 2.
Guideline Recommendations
The ACC/AHA guidelines provide Class I recommendations (strongest level):
- Cilostazol 100 mg orally twice daily is indicated as effective therapy to improve symptoms and increase walking distance in patients with lower extremity PAD and intermittent claudication (in the absence of heart failure) 3, 1, 5
- A therapeutic trial should be considered in all patients with lifestyle-limiting claudication (in the absence of heart failure) 3, 1, 5
Additional Clinical Uses
Beyond claudication, cilostazol has shown benefit in:
- Reducing restenosis after femoropopliteal stenting: Improves primary patency and reduces target lesion revascularization 5
- Secondary stroke prevention: Investigated in cerebrovascular disease 6, 7
- Adjunct to coronary interventions: May reduce restenosis after percutaneous coronary angioplasty 1
Common Side Effects
The most frequently reported adverse effects include 1, 5:
- Headache (most common - approximately 2.8 times more likely than placebo)
- Diarrhea
- Abnormal stools
- Palpitations
- Dizziness
- Pain
Approximately 20% of patients discontinue cilostazol within 3 months due to side effects 5. It is valuable to assess patient tolerance at 2-4 weeks and evaluate benefit within 3-6 months to determine whether long-term therapy is warranted 5.
Critical Contraindication
Cilostazol carries an FDA black-box warning and is absolutely contraindicated in patients with heart failure of any severity 1, 5. This stems from concerns about a class effect, as other PDE III inhibitors (milrinone, vesnarinone) have been associated with increased mortality in heart failure patients 1. While trials have not shown increased cardiovascular mortality with cilostazol specifically (0.6% vs 0.5% with placebo), the contraindication remains in place 1.
Pharmacokinetics
- Half-life: approximately 10 hours, resulting in 2-fold accumulation with repeated dosing 8
- Undergoes complete hepatic metabolism via cytochrome P450 systems
- Potential drug interactions with erythromycin and omeprazole 8
Cardiovascular Effects
Cilostazol increases heart rate in a dose-proportional manner (mean increase of 5.1 beats/minute at 50 mg twice daily and 7.4 beats/minute at 100 mg twice daily) 2. It also increases myocardial contractility, coronary blood flow, and ventricular automaticity 2.