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Neurology Today At the Meetings: International Stroke Conference

Access daily, concise peer-reviewed reports from the International Stroke Conference selected by the Neurology Today editors.

Tuesday, February 12, 2019

Cilostazol Prevents Recurrent Strokes in Japanese Study


HONOLULU—Dual antiplatelet therapy that includes cilostazol appears to reduce strokes in patients who have had a previous stroke and are at high risk of experiencing another, researchers reported here at the 2019 International Stroke Conference.

In a late breaker presentation, Kazunori Toyoda, MD, PhD, deputy director general of the Hospital of the National Cerebral and Cardiovascular Center in Suita, Osaka, Japan, said that the combination of cilostazol plus either aspirin or clopidogrel was superior in preventing another stroke than either clopidogrel or aspirin alone.

Although aspirin and clopidogrel have been shown to reduce early recurrence of ischemic stroke, the benefits seem to be short and are offset by a risk of major bleeding in long-term use, Dr. Toyoda said. Since cilostazol has been shown to prevent stroke recurrence without increasing serious bleeding as compared with aspirin, researchers wanted to determine if dual antiplatelet therapy involving cilostazol would be safe and fit for long-term use.

Dr. Toyoda and researchers from 292 sites in Japan enrolled 1,839 patients who were at least 65 years old, including 756 taking aspirin and 1,083 taking clopidogrel who had experienced an ischemic stroke up to six months earlier. That group who were taking 81–100 mg of aspirin daily or 50–75 mg of clopidogrel daily were randomly assigned to receive cilostazol 100 mg plus aspirin or cilostazol plus clopidogrel and were compared with the patients who continued on their aspirin or clopidogrel regimen. They also had to have at least a 50 percent stenosis of a major intracranial artery or at least a 50 percent stenosis of a extracranial artery and a history of cardiovascular disease.

Ischemic stroke recurred in 11.4 percent of patients who were taking monotherapy compared with 4.7 percent of patients on dual therapy, a relative risk reduction of 51 percent (HR 0.49 [95% CI 0.31-0.76], p=0.0010), over four years of follow-up, Dr. Toyoda said.

Treatment with cilostazol also similarly reduced the risk of the composite of stroke, myocardial infarction, and vascular death, (HR 0.52 [95% CI 0.35-0.77] p=0.0008), he said, in describing the results of the multicenter, open-label, Cilostazol Stroke Prevention Study for Antiplatelet Combination (

Importantly, he said, there did not appear to be any major risk of bleeding with the cilostazol combination when compared with the monotherapy. The rate of severe or life-threatening bleeds was 0.6 percent a year among patients on the cilostazol combination and 0.9 percent a year for patients on monotherapy (p=0.3539).

"In patients with high-risk stroke recurrence, the combination of cilostazol with aspirin or clopidogrel had a lower risk of ischemic stroke and a similar risk of bleeding compared with aspirin or clopidogrel alone," Dr. Toyoda said. 

"The addition of cilostazol to aspirin or clopidogrel is recommended for long-term use in high-risk, non-cardioembolic strokes for patients who are tolerable to headache and palpitation," he suggested.

Nervous system adverse events occurred among 8.9 percent of the combination patients and among 9.6 percent of the monotherapy patients: 8.4 percent of the patients taking combination therapy experienced cardiac palpitations compared with 1.8 percent of those taking monotherapy, Dr. Toyoda said. He added that 26 patients experienced headache in the combination treatment group.

Despite the findings, Karen Furie, MD, MPH, chairman of neurology at the Warren Alpert Medical School at Brown University in Providence, RI, said she didn't believe the study would change clinical practice. "The study design was a bit flexible in that they combined cilostazol with either aspirin or clopidogrel, and they used two different doses of clopidogrel in the monotherapy group, so when I look at the data, it is not entirely clear what was being compared."

"There is a trend to use dual platelet therapy in a number of conditions, so there may be something there," Dr. Furie told Neurology Today At the Meetings. "But because of some of the variability in the study design, it is hard to know exactly how to interpret the results and how to implement this in practice," she said.

Dr. Furie suggested that the researchers have identified a high-risk population, so a trial designed with a fixed dose in the monotherapy group might produce more generalizable results that could move the needle in practice.

The study was funded by Otsuka Pharmaceutical Co. Ltd. Dr. Toyoda disclosed he has served on the speakers' bureau for Bayer Yakuhin, Daichi Sankyo, Bristol Meyers Squibb, and Nippon Boerhringer Ingelheim.


ISC Abstract LB3: Toyoda K, Uchiyama S, Hoshino H, et al, for the Study Investigators. Dual antiplatelet therapy using cilostazol for secondary stroke prevention in high-risk patients: The Cilostazol Stroke Prevention Study for Antiplatelet Combination (