What is the role of Cilostazol in Peripheral Arterial Occlusive Disease (PAOD)?

From the Guidelines

Cilostazol is recommended for patients with peripheral arterial occlusive disease (PAOD) to improve walking distance and reduce claudication symptoms, as evidenced by the most recent guidelines from 2024 1. The standard dosage is 100 mg taken orally twice daily, at least 30 minutes before or 2 hours after meals due to improved absorption on an empty stomach. Patients should expect to take cilostazol for at least 12 weeks before determining its full effectiveness, though some may notice improvements earlier. Cilostazol works by inhibiting phosphodiesterase type III, which leads to vasodilation and inhibition of platelet aggregation, thereby improving blood flow in the affected limbs. Common side effects include headache, diarrhea, palpitations, and dizziness, which often diminish over time. Cilostazol is contraindicated in patients with heart failure, as it can worsen this condition, and should be used cautiously with CYP3A4 and CYP2C19 inhibitors which may increase its concentration. Some key points to consider when prescribing cilostazol include:

• Potential benefits in preventing in-stent restenosis in patients who have undergone stenting of the femoropopliteal segment 1
• Importance of assessing patient tolerance of cilostazol at 2 to 4 weeks and evaluating benefit within 3 to 6 months to determine whether long-term therapy will be beneficial 1
• Need for comprehensive management of PAOD, including smoking cessation, regular exercise, blood pressure control, and statin therapy to address cardiovascular risk factors 1 For optimal management of PAOD, cilostazol should be combined with other interventions including smoking cessation, regular exercise, blood pressure control, and statin therapy to comprehensively address cardiovascular risk factors. It is also important to note that cilostazol has been shown to improve Peripheral Artery Questionnaire (PAQ) outcomes and physical limitation score in a longitudinal prospective registry, and to improve maximal walking distance and ABI in a network meta-analysis 1. Overall, the use of cilostazol in patients with PAOD should be guided by the most recent clinical guidelines and should take into account the individual patient's risk factors, medical history, and potential for benefit.

From the FDA Drug Label

CLINICAL STUDIES: The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i. d. (n=998), and placebo (n=973). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers, or gangrene.

The primary role of Cilostazol in Peripheral Arterial Occlusive Disease (PAOD) is to improve walking distance in patients with stable intermittent claudication.

• Cilostazol has been shown to statistically significantly improve walking distances, with improvements seen as early as 2-4 weeks after starting treatment.
• The improvement in maximal walking distance with cilostazol 100 mg b.i.d. ranged from 28% to 100% across eight clinical trials.
• However, cilostazol has not been studied in patients with more severe forms of PAOD, such as rapidly progressing claudication, leg pain at rest, ischemic leg ulcers, or gangrene 2.

From the Research

Role of Cilostazol in Peripheral Arterial Occlusive Disease (PAOD)

• Cilostazol is a potent inhibitor of platelet aggregation with vasodilation effects, used to treat intermittent claudication, a common manifestation of arterial occlusive disease 3.
• The medication has been shown to improve walking distances in patients with intermittent claudication, with a 51% geometric mean improvement in maximal walking distance at a dose of 100 mg twice daily 3.
• Long-term use of cilostazol has been demonstrated to be safe, with no significant increase in mortality or cardiovascular events 4.

Efficacy of Cilostazol

• Cilostazol has been shown to improve initial and absolute claudication distances in patients with stable intermittent claudication, with a weighted mean difference of 31.41 meters for initial claudication distance and 43.12 meters for absolute claudication distance 5.
• The medication has also been shown to improve quality of life in patients with intermittent claudication, although the evidence is largely descriptive and not statistically significant 5.
• A real-world study has demonstrated the effectiveness of controlled-release cilostazol in patients with symptomatic peripheral artery disease, with 78.93% of patients experiencing improvement in intermittent claudication 6.

Safety of Cilostazol

• Cilostazol has been associated with adverse events such as headache, diarrhea, and palpitations, although these are generally mild and treatable 3, 5, 6.
• Long-term safety studies have demonstrated no significant increase in mortality or cardiovascular events with cilostazol use 4.
• The controlled-release formulation of cilostazol has been associated with a lower prevalence of adverse events compared to the immediate-release formulation 6.