Up to 20 percent of older adults have occlusive vascular disease of the lower extremities, and intermittent claudication may represent a major reason for a decline in physical functioning in older persons. Effective drug therapy for intermittent claudication is limited. Beebe and associates evaluated the safety and efficacy of a new agent, cilostazol, in relieving intermittent claudication.

Cilostazol is a type III phosphodiesterase inhibitor with vasodilatory properties. Its mechanism of action is thought to involve inhibition of cyclic adenosine monophosphate phosphodiesterase and enhancement of the effect of prostaglandin I₂. Prostaglandin I₂ inhibits platelet aggregation and relaxes vascular smooth muscle.

The double-blind, placebo-controlled study was conducted at 37 hospitals. The 516 men and women in the study were at least 40 years of age and had a six-month or longer history of intermittent claudication secondary to occlusive vascular disease. Patients had stable, symptomatic claudication and had to terminate treadmill testing because of claudication-related pain. Patients with ischemic pain at rest were excluded.

A history of cigarette smoking was noted in 93.4 percent of the patients (482 of the 516 patients), and more than one third of the patients were current smokers. Diabetes was present in 28.1 percent of the patients (145 of the 516 patients).

Patients were randomly assigned to receive cilostazol in twice-daily doses of 50 mg (171 patients) or 100 mg (175 patients), or placebo (170 patients). In addition to baseline assessment, patients were evaluated after four, eight, 16, 20 and 24 weeks of therapy. Efficacy was assessed by the pain-free walking distance in meters and the maximal walking distance at week 24. Secondary variables included quality-of-life functioning.

At week 24, pain-free and maximal walking distances were statistically significantly greater in both cilostazol groups compared with the placebo group. Improvement in pain-free walking distance increased by 59 percent in the 100-mg group and by 48 percent in the 50-mg group, compared with a 20 percent increase in the placebo group. The mean pain-free walking distance after 24 weeks of therapy was 137.9 m in patients who received 100 mg of cilostazol twice daily, 115.1 m in those who received 50 mg twice daily and 95.5 m in those who received placebo. The superiority of active treatment over placebo was observed as early as the fourth week and was maintained in all subsequent time points up to 24 weeks.

Patients who received 100 mg of cilostazol twice daily nearly doubled their maximal walking distance on the treadmill, from a mean of 129.7 m at baseline to a mean of 258.8 m after 24 weeks of therapy. Patients who received 50 mg twice a day increased their maximal walking distances from a mean of 131.5 m at baseline to a mean of 198.8 m at 24 weeks, representing an increase of greater than 1.5-fold in walking distance.

Compared with the placebo group, patients in both cilostazol groups had significantly superior scores in physical function and bodily pain scales at the end of the study. There was no significant difference between the active drug groups and the placebo group in the mental health domain. Significantly more patients in the active drug groups rated their condition as “better” or “much better” than their condition before treatment.

The most common adverse events in the cilostazol-treated patients were headache, loose or soft stools, dizziness and palpitations. Significant positive changes were observed in high-density lipoprotein cholesterol and triglyceride levels in the cilostazol-treated patients compared with patients who received placebo. All three groups showed a trend toward reduced triglyceride and low-density lipoprotein cholesterol levels, but greater and more immediate reductions were observed in the two cilostazol groups.

The authors conclude that cilostazol, in a dosage of 50 or 100 mg twice daily, is more effective than placebo in improving walking distances in patients with stable intermittent claudication. While severe incapacitating intermittent claudication may be treated surgically, there have thus far been few medical treatment options for patients with moderate claudication. Cilostazol may offer such patients a means of reducing ischemic pain and improving quality of life.