The antiplatelet drug cilostazol works at least as well as aspirin for preventing stroke in patients who have had an ischemic stroke, according to the results of a randomized trial published online in the Sept. 11 issue of The Lancet.
At a mean follow-up of 29 months in the aspirin-controlled, double-blind, noninferiority trial, first-time secondary strokes occurred at a yearly rate of 2.76% among patients who received 100 mg cilostazol twice daily and 3.71% in patients who received 81 mg aspirin once daily. This difference resulted in a hazard ratio of 0.743, or a 25.7% relative reduction of the risk of stroke with the use of cilostazol in comparison with aspirin.
The findings are important because few regimens have proven significantly more effective for stroke prevention than aspirin alone, according to Dr. Yukito Shinahara of Tachikawa Hospital, Tokyo, and colleagues from the Japanese Cilostazol for Prevention of Secondary Stroke (CSPS 2) trial group.
Since cilostazol was shown in the original CSPS trial in 2000 to be more effective than placebo for prevention of secondary cerebral infarction, it has been used in Japan for this purpose and is listed in Japanese guidelines for the management of stroke.
The 2,757 patients in the CSPS 2 trial were adults aged 20-79 years who had experienced a noncardioembolic cerebral infarction within the previous 26 weeks. They were enrolled at 278 sites in Japan between December 2003 and October 2006, and underwent treatment for 1-5 years. (Lancet 2010 Sept. 11 [doi:10.1016/S1474-4422(10)70198-8]).
Dr. Yukito Shinahara and colleagues said that they considered cilostazol to be noninferior to aspirin for the prevention of stroke because the upper limit of the 95% confidence interval was lower than the prespecified inferiority margin of 1.33.
In addition to reducing stroke risk, cilostazol significantly reduced the risk of a composite secondary endpoint (cerebral infarction, ischemic cerebrovascular disease, or death from any cause) by 20.1%, compared with aspirin. Cilostazol also was associated with a reduced risk of hemorrhagic events, which occurred at a rate of 0.77% per person-year in cilostazol-treated patients and 1.78% per person-year in aspirin-treated patients.
Dr. Shinahara and associates noted that “because significantly fewer hemorrhagic events were recorded in the cilostazol group than in the aspirin group, cilostazol might be particularly useful in patients with increased risk of hemorrhage.”
Other adverse events, however, occurred significantly more often in cilostazol-treated patients. These included headache, diarrhea, palpitations, dizziness, and tachycardia. None of these were serious, and all resolved after treatment discontinuation or dose tapering, the investigators said.
“The results of CSPS 2 suggest that cilostazol can be recommended as an option for the prevention of stroke in Asian patients with noncardioembolic stroke who can tolerate long-term treatment with this drug,” wrote the authors, noting that previous studies have suggested that cilostazol is effective for patients of other ethnic origins as well.
In a U.S. study, patients with peripheral artery disease who took cilostazol experienced significantly fewer cerebrovascular events, compared with placebo (J. Stroke. Cerebrovasc. Dis. 2008; 17:129-33).
In addition to its antiplatelet effects, cilostazol also has beneficial effects on other factors associated with thrombus formation, including endothelial function and dilation of blood vessels by increased production of nitric oxide, and reduction of intracellular calcium ion concentrations. The drug also inhibits smooth muscle proliferation and inflammation in various vascular beds, according to the researchers.
Otsuka Pharmaceutical funded the study. Dr. Shinohara disclosed providing consultancy for Schering-Plough and Pfizer Japan, and receiving grants from the Japan Ministry of Health, Labour and Welfare, and receiving lecture fees from Otsuka and other companies. Other authors on the study reported various financial relationships with Otsuka and other companies.