Second Strokes Less Common With Cilostazol

The antiplatelet agent cilostazol (Pletal) appeared significantly more effective than aspirin for secondary prevention of strokes and was associated with fewer major bleeding events in a Japanese study.

In a large randomized trial with mean follow-up of 29 months, ischemic or hemorrhagic strokes were observed in 2.76% of patient-years in the cilostazol group compared with 3.71% of patient-years in the aspirin group (P=0.0357), researchers reported online in Lancet Neurology.

Also, rates of cranial or other serious hemorrhages in the cilostazol group were less than half those seen with aspirin (0.77% versus 1.78% of patient-years, P=0.0004), according to Yukito Shinohara, MD, of the Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, in Tokyo, and colleagues.

Although the trial was structured as a noninferiority study, the efficacy advantage for cilostazol met prespecified criteria for a finding of superiority, the researchers indicated.

But they stopped short of advocating a wholesale switch from aspirin to cilostazol. “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,” Shinohara and colleagues wrote, with perhaps the most benefit in patients at increased risk for bleeding events.

Shinohara had earlier reported topline results from the trial, called CSPS-2, at the American Stroke Association meeting last February, which compared 100 mg of cilostazol twice daily with 81 mg/day of aspirin in 2,757 Japanese patients.

Cilostazol, a phosphodiesterase 3A inhibitor, is currently approved in the U.S. for treating intermittent claudication.

The study enrolled patients at nearly 300 centers from 2003 to 2008. To be eligible, patients had to be 20 to 79 years of age and have had a noncardioembolic stroke in the previous six months rated as class III under NINDS criteria.

Exclusions included previous or planned cerebral revascularization, high risk for hemorrhage, peptic ulcer, congestive heart failure, or other conditions associated with cardioembolism. Other “blood thinners” and NSAIDs were not permitted.

One noteworthy finding was that the risk of ischemic strokes during follow-up did not differ significantly between the two treatments, although there was a trend toward reduction with cilostazol. Shinohara and colleagues found the hazard ratio for this class of stroke was 0.88 (95% CI 0.65 to 1.20) for cilostazol relative to aspirin.

There was a similar nonsignificant trend for lower rates of cerebral infarctions combined with transient ischemic attacks with cilostazol (HR 0.90, 95% CI 0.68 to 1.19).

On the other hand, a composite safety endpoint that included cerebral and subarachnoid hemorrhage as well as any hemorrhage requiring hospitalization clearly favored cilostazol (HR 0.46, 95% CI 0.30 to 0.71).

The drug was more likely to cause some less severe adverse effects, however. Shinohara and colleagues reported that rates of tachycardia, headache, diarrhea, palpitations, and dizziness were significantly more common with cilostazol than with aspirin.

Some 5% of patients assigned to cilostazol dropped out because of headache. Overall discontinuations because of adverse effects were more common with cilostazol (267 versus 166 for aspirin). The disparity was even more pronounced for dropouts not related to bleeding events (124 for cilostazol, 12 for aspirin).

In an accompanying editorial, two Boston-area researchers expressed surprise that an antiplatelet drug could simultaneously reduce rates of ischemic stroke, by even a small number, while also reducing bleeding events substantially.

“To date, antiplatelet agents that are more potent than aspirin in reducing ischemic events have invariably increased rates of bleeding,” wrote Dharam J. Kumbhani, MD, of the VA Boston Healthcare System, and Deepak L. Bhatt, MD, of Brigham and Women’s Hospital.

They suggested that Shinohara and colleagues’ decision to censor data following study drug discontinuation may have influenced the findings.

Kumbhani and Bhatt noted that CSPS-2’s location in Japan and its exclusion of patients with severe strokes limited its generalizability.

They also cited other reasons for restraining their enthusiasm for cilostazol, including its high cost relative to aspirin and the high rate of side effects.

Nevertheless, they concluded that cilostazol deserves more trials in “larger and more diverse” samples.

source: The Lancet Neurology

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