Similar Efficacy, Less Bleeding With Cilostazol vs Aspirin for Recurrent Stroke Prevention: CSPS 2 Published

September 28, 2010 — Results of a randomized trial suggest that cilostazol (Pletal, Otsuka Pharmaceutical) may provide an alternative to aspirin for secondary stroke prevention.

"Cilostazol seems to be noninferior, and might be superior, to aspirin for prevention of stroke after an ischemic stroke and was associated with fewer hemorrhagic events," lead study author Yukito Shinohara, MD, from the Federation of National Public Service Personnel Mutual Aid Associations Tachikawa Hospital in Tokyo, Japan, and colleagues conclude.

"Based on these findings, we believe cilostazol should be considered as a potential treatment option for secondary stroke prevention in patients who can tolerate long-term administration of this drug," Dr. Shinohara said in an interview with Medscape Medical News when the study was first presented earlier this year at the International Stroke Conference.

Final results from the Cilostazol Stroke Prevention Study 2 (CSPS 2) trial were published online September 11 in Lancet Neurology. The trial was supported by Otsuka Pharmaceutical.

Multiple Mechanisms

Cilostazol is an antiplatelet drug that works by inhibiting phosphodiesterase 3, which in turn increases cyclic adenosine monophosphate concentrations and consequently inhibits platelet aggregation, the study authors write. However, it also has vasodilatory activity, inhibits vascular smooth muscle cell proliferation, and protects the vascular wall and endothelium. It is already approved in the United States for the treatment of intermittent claudication in the setting of peripheral artery disease.

The CSPS reported a decade ago by Dr. Shinohara and colleagues in Japan showed that compared with placebo, cilostazol significantly reduced cerebral infarction without increasing cerebral hemorrhage (J Stroke Cerebrovasc Dis. 2000;9:147-157).

CSPS 2 was a direct comparison of cilostazol and aspirin in 2757 patients with noncardioembolic ischemic stroke. The double-blind, multicenter study randomized patients to receive 100 mg of cilostazol twice daily or 81 mg of aspirin once a day. Treatment duration ranged from 1 to 5 years.

The study's primary endpoint was first occurrence of symptomatic stroke, including cerebral infarction or intracerebral or subarachnoid hemorrhage, during the treatment period.

Stroke occurred in 119 of the 1335 aspirin-treated patients, and 3 of these events were fatal during 3203.6 person-years. Among 1337 subjects in the cilostazol group, there were 82 strokes, including 2 deaths, during 2965.9 person-years, meeting the predefined margin for noninferiority, an upper 95% confidence interval for the hazard ratio of 1.33.

Table 1. CSPS 2: Primary Endpoint

Endpoint	Cilostazol	Aspirin	Hazard Ratio (95% CI)	P
Yearly rate of first occurrence of stroke, %	2.76	3.71	0.743 (0.564 – 0.981)	.0357

CI = confidence interval; CSPS 2 = Cilostazol Stroke Prevention Study 2

Hemorrhagic events, defined as cerebral hemorrhage, subarachnoid hemorrhage, or hemorrhage requiring hospitalization, were highly significantly less frequent among those taking cilostazol.

Table 2. CSPS 2: Hemorrhagic Events

Endpoint	Cilostazol	Aspirin	Hazard Ratio (95% CI)	P
Yearly rate of hemorrhagic events, No. (%)	23 (0.77)	57 (1.78)	0.458 (0.296 – 0.711)	.0004

CI = confidence interval; CSPS 2 = Cilostazol Stroke Prevention Study 2

Although the rate of bleeding was lower in the cilostazol group, the drug fared worse compared with aspirin with respect to adverse events other than bleeding, with higher rates of headache, diarrhea, palpitations, dizziness, and tachycardia. However, those in the aspirin group had greater rates of hypertension and constipation.

Cilostazol was also associated with a lower rate of a composite of secondary endpoints, including stroke, transient ischemic attack, angina pectoris, myocardial infarction, heart failure, and hemorrhage requiring hospitalization.

"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," the researchers conclude, although they point to previous trials showing cilostazol was effective for peripheral artery disease in other ethnic groups, including US populations.

A Promising Pathway

In a Reflection and Reaction article accompanying the publication, Dharam J. Kumbhani, MD, and Deepak Bhatt, MD, both from the VA Boston Healthcare System, Brigham and Women's Hospital, and Harvard Medical School in Boston, Massachusetts, point out that the censoring of patients at discontinuation of study drug in this trial makes the efficacy and bleeding results "difficult to interpret.

"That an antiplatelet drug could simultaneously reduce ischemic stroke and bleeding compared with aspirin seems paradoxical," they write. "To date, antiplatelet agents that are more potent than aspirin in reducing ischemic events have invariably increased rates of bleeding."

One limitation of the study was that it included only East Asian patients, they note, because differences in pharmacodynamics and pharmacokinetics have been seen among ethnic groups that could have changed the outcome. Adverse effects have also been a practical problem with this drug, as was seen in this trial, and the costs will clearly be higher than those associated with aspirin, the editorialists add.

Still, they conclude, the results of CSPS 2 are interesting and should be validated in larger and more diverse populations. "The choice of the best antiplatelet drug for the secondary prevention of ischemic stroke remains challenging, but the CSPS 2 trial shows that there might be another promising pathway for secondary stroke prevention beyond the protection provided by aspirin."

Replication Required

Asked for comment on these findings, Philip B. Gorelick, MD, MPH, John S. Garvin professor and head of the Department of Neurology and Rehabilitation and director of the Center for Stroke Research at the University of Illinois College of Medicine at Chicago, pointed out that cilostazol was at least noninferior to aspirin for recurrent stroke prevention, and hemorrhagic events were less with cilostazol.

"However," he added, "other side effects, such as headache, diarrhea, palpitations, dizziness, and tachycardia, were more frequent with cilostazol than aspirin and led to more participant discontinuations," Dr. Gorelick said.

The findings are very important in relation to Asian countries, where brain hemorrhage rates have traditionally been high but may be reduced with careful control of blood pressure, he said.

"Additional study in more diverse populations might be useful to determine if the efficacy findings of CSPS 2 can be replicated, whereby cilostazol would be a welcome addition to our recurrent stroke prevention armamentarium," Dr. Gorelick concluded.

The study was supported by Otsuka Pharmaceutical. Dr. Shinohara has provided consultancy for Schering-Plough and Pfizer Japan; has received grants from the Japan Ministry of Health, Labor, and Welfare; and has received lecture fees from Sanofi-Aventis, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Bayer HealthCare, Kyorin Pharmaceutical, and Daiichi-Sankyo. Dr. Bhatt has received institutional research support from AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and The Medicines Company and has received honoraria from Duke Clinical Research Institute.

Lancet Neurol. Published online September 11, 2010.

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