What is the effect of Pletal (Cilostazol)?

From the Guidelines

Cilostazol (Pletal) is recommended as a first-line treatment for patients with intermittent claudication due to peripheral artery disease, at a dosage of 100 mg taken twice daily, as it has been shown to improve symptoms and increase walking distance 1.

Key Points

• The medication works by inhibiting phosphodiesterase, which increases cyclic AMP levels, resulting in vasodilation and inhibition of platelet aggregation, thereby improving blood flow in peripheral arteries and reducing symptoms.
• Treatment should continue for at least 12 weeks to determine effectiveness, and patients should avoid grapefruit juice while taking cilostazol as it can increase drug levels.
• Common side effects include headache, diarrhea, and palpitations, and cilostazol is contraindicated in patients with heart failure, as it can worsen this condition.
• Regular walking exercise in combination with cilostazol therapy provides optimal results for improving walking distance in patients with peripheral arterial disease.

Benefits and Risks

• Benefits: improves symptoms of claudication, increases walking distance, and may reduce restenosis after endovascular therapy for femoropopliteal stenosis.
• Risks: headache, diarrhea, palpitations, and increased bleeding risk when taken with other antiplatelet medications.

Clinical Considerations

• Cilostazol should be used cautiously in patients taking other antiplatelet medications due to increased bleeding risk.
• Patients with heart failure should not take cilostazol, as it can worsen this condition.
• The medication has been shown to be effective in reducing symptoms of claudication and improving walking distance in patients with chronic symptomatic PAD, as stated in the 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS guideline for the management of lower extremity peripheral artery disease 1.

From the FDA Drug Label

CLINICAL PHARMACOLOGY Mechanism of Action: The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelet and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress. In humans, heart rate increased in a dose-proportional manner by a mean of 5. 1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with Holter monitors, numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained ventricular tachycardia events than did placebo-treated patients; the increases were not dose-related.

The main effects of cilostazol are:

• Inhibition of platelet aggregation
• Vasodilation
• Increase in heart rate
• Possible increase in ventricular premature beats and non-sustained ventricular tachycardia events 2

From the Research

Treatment of Intermittent Claudication

• Intermittent claudication (IC) is a symptom of peripheral arterial disease (PAD) and is associated with high morbidity and mortality 3.
• The treatment of PAD is aimed at maintaining or improving functional status, reducing or eliminating ischemic symptoms, and preventing disease progression 4.
• Exercise and aggressive risk factor modification represent the cornerstones of treatment for IC 4.
• Medical therapy with an antiplatelet agent and statin is recommended for all patients with PAD, including those with IC 5.
• Regular exercise has been shown to improve walking distance and quality of life in patients with symptomatic PAD and should be incorporated into each patient's treatment plan 5.

Pharmacological Interventions

• Pentoxifylline is one of many drugs used to treat IC, and it acts by decreasing blood viscosity, improving erythrocyte flexibility, and promoting microcirculatory flow and tissue oxygen concentration 3.
• There is low-certainty evidence that pentoxifylline may improve pain-free walking distance (PFWD) and total walking distance (TWD) compared to placebo, but no evidence of a benefit to ankle-brachial pressure index (ABI) or quality of life (QoL) 3.
• Cilostazol, a new antiplatelet, antithrombotic agent, reduces claudication symptoms 4.
• Angiogenic growth factors have shown preliminary success in patients with rest pain and ischemic ulcers and are being investigated for use in patients with IC 4.

Endovascular Revascularization

• Endovascular revascularization is indicated for limb salvage and symptom relief in patients with critical limb ischemia (CLI) and in those with persistent lifestyle-limiting claudication despite optimal medical therapy and an exercise program 5.
• Consensus guidelines currently support an endovascular first approach to revascularization in the majority of cases 5.
• Patients with IC and CLI have significant anatomic, lesion, and treatment differences, with significantly higher mortality and adverse limb outcomes in CLI 6.
• Patients with IC had higher femoropopliteal artery interventions, while below the knee interventions were more frequent in CLI 6.

Modern Therapeutic Approaches

• The efficacy of non-invasive treatment strategies for PAD has been well documented, including smoking cessation, supervised exercise programs, and medical therapy 7.
• Strategies for invasive management of PAD are more controversial due to variability in the manifestations of PAD, including lesion length, location, severity, and clinical presentation 7.
• The current review aims to summarize the most recent clinical research in the field of PAD in patients with IC, with a focus on the latest studies regarding risk factor modification and endovascular revascularization therapies 7.