BACKGROUND: Pentoxifylline and cilostazol are the only 2 prescription drugs labeled for treatment of intermittent claudication. No studies have compared the relative benefit of these agents. The only other therapy demonstrated to be effective is active exercise intervention, usually in the form of a walking program.
POPULATION STUDIED: The investigators enrolled 698 patients with stable moderate to severe symptoms of intermittent claudication and confirmed peripheral vascular disease. These patients had symptoms present for at least 6 months but without substantial change in the last 3 months. All patients had peripheral vascular disease confirmed by either a resting ankle/brachial index of 0.90 or lower and a 10-mm Hg or higher decrease in ankle pressure measured 1 minute after walking to maximal walking distance, or a 20-mm Hg or higher decrease in postexercise ankle pressure in the symptomatic extremity. To qualify for study inclusion, the patients needed a baseline pain-free walking distance between 53.5 meters (1 minute on treadmill protocol) and 537.7 meters (10 minutes). The study subjects were 76% men and had an average age of 66 years. Patients were ineligible who had critical lower extremity ischemia, arterial reconstruction, or sympathectomy within the previous 3 months, as were patients with an exercise capacity limited by conditions other than intermittent claudication. The 3 groups were similar in age, sex, race, smoking status, diabetes, hypercholesterolemia, hypertension, and baseline disease severity.
STUDY DESIGN AND VALIDITY: The study was a double-blind multicenter trial with patients randomized using concealed allocation to receive either cilostazol (100 mg orally twice daily), pentoxifylline (400 mg orally 3 times daily), or placebo for a 24-week period. No specific counseling about diet, smoking cessation, or exercise was offered to the patients during the study period. At baseline and every 4 weeks afterward, study participants underwent evaluation including medical history, physical examination, treadmill testing, Doppler limb pressure measurements, and assessment of adverse events.
OUTCOMES MEASURED: The primary study end point was a comparison of the relative effects of cilostazol and pentoxifylline on walking ability, as measured by maximal walking distance on a standardized treadmill test. Secondary end points included pain-free walking distance and resting Doppler limb pressures. Perception of functional ability and quality of life was measured with the Medical Outcomes Scale Short Form-36 (SF-36) and the Walking Impairment Questionnaire. In addition, physicians and patients were asked for their subjective assessment of benefit at the end of treatment.
RESULTS: Using a treadmill protocol and assessed by intention-to treat analysis, cilostazol increased the maximal walking distance by 54% over baseline (average=107 m), compared with a 30% increase with pentoxifylline (P <.001) and a 34% increase in the placebo group (P <.001). The improvement with pentoxifylline was similar to that in the placebo group (average=65 m). Walking distances progressively increased in all 3 groups and did not plateau within the 24-week study. Side effects including headache, diarrhea, and abnormal stools occurred more commonly in the cilostazol group, yet the withdrawal rate was similar between the 2 active drug treatment groups (16%-19%). Scores on the SF-36 and the Walking Impairment Questionnaire revealed no significant differences in general health perception or patient-reported walking distance. In subjective assessment by patients, 51% of the cilostazol group judged their outcome to be successful compared with 39% in the pentoxifylline group (P=.004) and 34% in the placebo group (P <.001).
For patients with moderate to severe intermittent claudication, cilostazol results in longer walking distances than pentoxifylline. Future studies will need to address the symptomatic improvement gained over longer durations of therapy with cilostazol and in combination with a directed exercise program.