*This is commentary for cover 2
Cilostazol is an antiplatelet agent now used extensively in the US in patients with peripheral vascular occlusive disease. It is a member of a different class of agents than either aspirin or clopidogrel—the two most widely prescribed antiplatelet agents in North America. Cilostazol is a phosphodiesterase (PDE) inhibitor, a class of compounds with important protective effects and actions related to the vascular endothelium. Studies on the most prominent PDE inhibitors, dipyridamole and cilostazol, indicate that each has some direct effect on blood platelets, but their predominant mode of action is to inhibit platelet attachment to the vascular endothelium, and in so doing prevent development of white platelet-fibrin thrombi. These agents are not known to cause important bleeding. Cilostazol has been studied extensively in Asia for secondary prevention of stroke. To date, it has not been extensively studied in the US in patients with coronary artery disease or stroke. The Cilostazol Stroke Prevention Study (CSPS I) was carried out in Japan and reported in 2000. This study was a secondary prevention study that enrolled 526 patients treated with cilostazol and 526 placebo-treated controls. Cilostazol showed a relative risk reduction of 41.7% (95% CI 9.2% to 62.5%). Analysis of the results showed that cilostazol was especially effective among hypertensive and diabetic patients and in those who had penetrating artery disease as the cause of their presenting strokes (see Matsumoto; and Shinohara, Gotoh, Tohgi, et al). A study in Korea included 135 patients with intracranial stenotic lesions involving the middle cerebral or basilar arteries. Patients were randomized to aspirin alone or aspirin with 200 mg cilostazol a day (see Kwon, Cho, Koo, et al). There were no stroke recurrences in either group. In the cilostazol plus aspirin group, three out of 45 (6.7%) lesions progressed and 11 (24.4%) regressed, compared with 28.8% progression and 15.4% regression in the aspirin alone group. Progression of symptomatic intracranial stenotic lesions was significantly lower in the cilostazol plus aspirin group. In a Chinese study (CASISP) of secondary stroke prevention, among 720 patients, 360 were given cilostazol and 360 aspirin (see Huang, Cheng, Wu, et al). The primary end point (ischemic or hemorrhagic stroke or subarachnoid hemorrhage) occurred in 12 patients in the cilostazol group and 20 in the aspirin group, an insignificant difference. A larger trial in China is planned. At the recent International Stroke Conference sponsored by the American Heart and American Stroke Associations in San Antonio, Texas, Professor Yukito Shinohara, MD, presented the results of the CSPS II study. This randomized, double-blind therapeutic trial differed from the CSPS I study, since it included many more patients and compared cilostazol with aspirin rather than with placebo. Fully 2,757 patients who had had an ischemic stroke within the 26 preceding weeks were randomized to aspirin (81 mg/day) or cilostazol (100 mg twice a day). Stroke developed in 82 of 1,337 patients (6%) in the cilostazol group, compared with 119 of 1,335 (8.9%) in the aspirin group showing a noninferiority and possible superiority of cilostazol over aspirin in secondary stroke prevention. Intracranial hemorrhage requiring hospitalization developed in 23 patients (1.7%) in the cilostazol group and 57 (4.3%) in the aspirin group. In a handful of cilostazol studies performed in the last five years, the rate of bleeding reported with cilostazol was quite low and there were no important safety issues. Headache was a prominent symptom, reflecting vasodilatation and augmented cerebral blood flow. The stroke prevention studies to date have included Asian patients from China, Korea, and Japan. In these countries penetrating artery disease and intracranial occlusive lesions are the most common cause of ischemic stroke. Patients with hypertension and diabetes, two conditions that predispose to penetrating artery disease, seem to especially benefit with cilostazol. To date, no trials have compared the two phosphodiesterase inhibitors. Cilostazol has been shown to be an effective agent for secondary stroke prevention in Asia. We all look forward to future studies—especially those including Caucasian patients with well-defined stroke subtypes to determine the generalizability of these promising results. |