Cilostazol

Placebo-controlled studies

The efficacy and safety data of cilostazol in placebo-controlled clinical trials have been repeatedly subjected to meta-analysis, with the same conclusion [ , ]. Cilostazol is well tolerated; headache, bowel complaints, and palpitation are the most common but mild adverse effects.

Six multicenter placebo-controlled trials have been conducted in the USA [ , ]. They involved more than 2000 patients with intermittent claudication and established the efficacy of cilostazol in improving walking distance in these patients.

Cilostazol was approved by the FDA in January 1999 for the treatment of symptoms of intermittent claudication; from 1984 to 1999 pentoxifylline was the only drug approved in the USA for this indication. The two drugs have been compared with placebo in a large, randomized, double-blind, placebo-controlled trial [ ]. After 24 weeks of treatment the mean increase in maximal walking distance was 54% with cilostazol and only 30% with pentoxifylline and 34% with placebo. Headache, diarrhea, abnormal stools, and bouts of palpitation were significantly more common with cilostazol. They were reported as generally mild to moderate and self-limiting and have been previously recognized as being related to cilostazol.

The efficacy of antithrombotic prophylaxis with cilostazol for the secondary prevention of cerebral infarction has been studied in a Japanese, placebo-controlled trial in 1095 patients [ ]. There was a 42% relative risk reduction compared with placebo. As in the trials in patients with peripheral arterial disease, mild to moderate headache and palpitation were the most commonly observed symptomatic adverse events attributed to cilostazol; they respectively occurred in 13 and 5.3%. Headache with cilostazol is attributed to cerebral vasodilatation induced by relaxation of vascular smooth muscle.

In another placebo-controlled trial, there were gastrointestinal complaints in 44% of the cilostazol-treated patients and in 15% of the placebo group. The most commonly reported adverse effects included diarrhea, loose stools, flatulence, and nausea; they were usually mild and transient but persisted in some patients. Headache occurred in 20% of cilostazol-treated patients but also in 15% of those given placebo [ ].

Safety data relating to the use of cilostazol in 2702 patients who participated in eight USA–UK placebo-controlled trials have been re-analysed [ ]. The most frequently recorded adverse events were headache (32%), diarrhea (17%), and abnormal stools (14%). Palpitation, tachycardia, and dizziness were additional events that occurred more often in cilostazol-treated patients and were considered to be probably related to treatment. Headache led to withdrawal of cilostazol in 3.5% of patients, and palpitation and diarrhea led to withdrawal in another 1%. All adverse events quickly resolved after withdrawal. Cardiovascular and all-cause mortality were similar with cilostazol and placebo.