CLINICAL STUDIES A Comparison of Cilostazol and Pentoxifylline for Treating Intermittent Claudication David L. Dawson, MD, Bruce S. Cutler, MD, William R. Hiatt, MD, Robert W. Hobson II, MD, John D. Martin, MD, Enoch B. Bortey, PhD, William P. Forbes, PharmD, D. Eugene Strandness, Jr., MD PURPOSE: We performed a randomized, double-blind, place- bo-controlled, multicenter trial to evaluate the relative efficacy and safety of cilostazol and pentoxifylline. PATIENTS AND METHODS: We enrolled patients with moderate-to-severe claudication from 54 outpatient vascular clinics, including sites at Air Force, Veterans Affairs, tertiary care, and university medical centers in the United States. Of 922 consenting patients, 698 met the inclusion criteria and were randomly assigned to blinded treatment with either cilostazol (100 mg orally twice a day), pentoxifylline (400 mg orally 3 times a day), or placebo. We measured maximal walking dis- tance with constant-speed, variable-grade treadmill testing at baseline and at 4, 8, 12, 16, 20, and 24 weeks. RESULTS: Mean maximal walking distance of cilostazol- treated patients (n = 227) was significantly greater at every postbaseline visit compared with patients who received pen- toxifylline (n = 232) or placebo (n = 239). After 24 weeks of treatment, mean maximal walking distance increased by a mean of 107 m (a mean percent increase of 54% from baseline) in the cilostazol group, significantly more than the 64-m improve- ment (a 30% mean percent increase) with pentoxifylline (P 0.001). The improvement with pentoxifylline was similar (P = 0.82) to that in the placebo group (65 m, a 34% mean percent increase). Deaths and serious adverse event rates were similar in each group. Side effects (including headache, palpita- tions, and diarrhea) were more common in the cilostazol- treated patients, but withdrawal rates were similar in the cilosta- zol (16%) and pentoxifylline (19%) groups. CONCLUSION: Cilostazol was significantly better than pen- toxifylline or placebo for increasing walking distances in pa- tients with intermittent claudication, but was associated with a greater frequency of minor side effects. Pentoxifylline and pla- cebo had similar effects. Am J Med. 2000;109:523–530. 2000 by Excerpta Medica, Inc. A bout 5% of men and 3% of women over 60 years of age have intermittent claudication (1). Al- though resting limb blood flow may be adequate in these patients, the exercise-induced increase in blood flow does not meet the increased requirements of the ex- ercising muscle, resulting in lower extremity pain, aching, or muscle fatigue (2). Options are limited for pharmacologic management of intermittent claudication symptoms. From 1984 to 1999, pentoxifylline was the only drug approved by the US Food and Drug Administration for this indication. A new orally administered drug, cilostazol, has been found to be effective for the treatment of intermittent claudication. Compared with placebo, cilostazol improves the distance that patients with intermittent claudication are able to walk on standardized treadmill testing (3– 6). This in- crease in walking ability correlated with patients’ percep- tion of improved physical function and health (3,4,6). This prospective trial was performed to compare the relative efficacy and safety of cilostazol, pentoxifylline, and placebo therapy in patients with moderate-to-severe intermittent claudication. MATERIAL AND METHODS Design of this trial followed the recommendations of the Society for Vascular Surgery for trials of medications treating intermittent claudication (7). The study was con- ducted under an Investigational New Drug Exemption with approval of each of the 54 participating institutions’ human subjects review committees and the written in- formed consent of each participant. Patients with stable, moderate-to-severe symptoms of From the Wilford Hall Medical Center (DLD), Lackland AFB, Texas; the University of Massachusetts (BSC), Worcester, Massachusetts; the University of Colorado Health Sciences Center (WRH), Denver, Colo- rado; the University of Medicine and Dentistry of New Jersey (RWH), New Jersey Medical School, Newark, New Jersey; Annapolis, Maryland (JDM); Otsuka America Pharmaceuticals, Inc. (EBB, WPF), Rockville, Maryland; the University of Washington (DES), Seattle, Washington, for the Claudication Treatment Study Group. Supported by Otsuka America Pharmaceuticals, Inc., a US affiliate of the manufacturer of cilostazol. The views expressed herein are those of the authors and do not reflect the official policy of the Department of Defense, the Department of Veterans Affairs, or other departments of the United States government. Requests for reprints should be addressed to LTC David L. Dawson, USAF, MC, FS, Medical Sciences Division, NASA–Johnson Space Cen- ter, Mail Code SD, 2101 NASA Road 1, Houston, Texas 77058-1406. Manuscript submitted November 8, 1999, and accepted in revised form July 7, 2000. 2000 by Excerpta Medica, Inc. 0002-9343/00/$–see front matter 523 All rights reserved. PII S0002-9343(00)00569-6