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Am Fam Physician. 2022;105(4):366-367

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial relationships.

Clinical Question

Is cilostazol (Pletal) therapy safe and effective for improving walking distance in patients with intermittent claudication due to peripheral artery disease (PAD)?

Evidence-Based Answer

Cilostazol improves initial and absolute walking distances in patients with intermittent claudication secondary to PAD and appears to be equivalent in effect to pentoxifylline (Trental). Adverse effects of cilostazol include headache, diarrhea, dizziness, and palpitations.1 (Strength of Recommendation: A, meta-analysis with consistent results.)

Practice Pointers

PAD affects up to 12% of people 55 to 69 years of age and 20% of people older than 70 years.1 A sensation of heaviness and fatigue in the leg muscles, known as vascular claudication, is present in 60% of patients with PAD.2,3 Intermittent claudication secondary to PAD is an indicator of increased systemic atherosclerosis. Compared with age-matched controls, patients who experience intermittent claudication have a higher risk of amputation and cardiovascular mortality over five years.4

Medications used to treat intermittent claudication include pentoxifylline (a hemorheologic agent that helps improve blood flow through narrow arteries), antiplatelet agents, and anticoagulants. Cilostazol is a phosphodiesterase-3 inhibitor with antiplatelet and antithrombotic properties that works on smooth muscle as a vasodilator; it also helps to create a more favorable lipid profile by decreasing triglyceride and increasing high-density lipoprotein levels. The authors of this Cochrane review attempted to determine the effects of cilostazol on initial claudication distance (distance walked before pain onset), absolute claudication distance (total distance walked before needing to stop due to pain), mortality, and vascular events in patients with intermittent claudication.

This Cochrane review included 16 randomized controlled trials with 3,972 participants from five countries (United States, Brazil, Ireland, Russia, and Taiwan).1 Follow-up ranged from six weeks to 26 weeks. All studies compared cilostazol (50 to 150 mg, twice daily) with placebo; five of these studies also compared cilostazol (100 mg twice daily) with pentoxifylline (400 mg two to three times daily or 600 mg twice daily). Because of differing methods in treadmill protocols between the studies, the authors standardized comparison groups by calculating walking distances for each participant and then determined the mean change from baseline. Initial and absolute claudication distance outcomes were dependent on each participant’s perception of calf pain (vascular claudication symptoms) and their ability to communicate the onset of pain or discomfort.

Patients taking cilostazol demonstrated an increased initial claudication distance vs. those taking placebo (mean difference = 26 m; 95% CI, 19 to 34 m; low-certainty evidence). Patients taking cilostazol also had an increased absolute claudication distance compared with placebo (mean difference = 40 m; 95% CI, 22 to 57 m; very low-certainty evidence). There were no significant differences in initial and absolute claudication distance when comparing the use of cilostazol and pentoxifylline.

The evidence was insufficient to draw conclusions about the effect of cilostazol on quality of life or other outcomes such as rates of revascularization, cardiovascular events, or amputation. Patients taking cilostazol had increased odds of experiencing headache compared with those using placebo (number needed to harm = 7; 95% CI, 5 to 10; moderate-certainty evidence) and pentoxifylline (number needed to harm = 10; 95% CI, 4 to 63; low-certainty evidence). Other adverse effects of cilostazol included diarrhea, dizziness, and palpitations.

The 2016 American Heart Association/American College of Cardiology guideline on the management of patients with lower extremity PAD recommends structured exercise therapy, risk factor modification, and smoking cessation as the initial approaches to therapy.4 More research is needed to assess the impact of pharmacologic treatment of PAD sequelae, including vascular claudication and the subsequent need for surgical intervention. Until then, family physicians may want to offer pharmacotherapy as an option when symptoms persist despite lifestyle interventions for patients with intermittent claudication.

The practice recommendations in this activity are available at https://www.cochrane.org/CD003748.

The views expressed in this article are the authors’ and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences, the Department of Defense, or the U.S. government.

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