Cilostazol as Effective as Aspirin in Prevention of Recurrent Stroke

Susan Jeffrey

May 09, 2008

May 8, 2008 — Results of a randomized pilot trial suggest that cilostazol (Pletal, Otsuka Pharmaceuticals), a phosphodiesterase 3 (PDE3) inhibitor, is as effective as aspirin in preventing recurrent stroke, with significantly lower rates of bleeding.

There was a trend toward fewer recurrent strokes with cilostazol in this study, carried out in China, than with aspirin, but this did not reach statistical significance.

"The lower rates of ischemic and hemorrhagic stroke in the cilostazol group suggest that cilostazol might be a more effective and safer alternative to aspirin for Chinese patients with ischemic stroke; however, a larger phase 3 trial is required to confirm this," the researchers, with first author Yining Huang, MD, from Peking University First Hospital, in Beijing, China, conclude.

The study, supported by the National Health Ministry of the People's Republic of China and Otsuka Pharmaceuticals, was released online May 5 in advance of publication in the June issue of Lancet Neurology.

Pilot Findings

Most patients are treated with aspirin after a stroke, the authors write, but "aspirin-related cerebral hemorrhage is a complication that is of concern, particularly in China, where there is a high incidence of cerebral hemorrhage in secondary-prevention programs and within the community."

Cilostazol is already approved in the US for the treatment of symptoms of intermittent claudication associated with peripheral vascular disease. It acts by preventing inactivation of the intracellular second messenger cyclic AMP and irreversibly inhibits platelet aggregation and vasodilation, the authors write. It also has been shown to delay the onset of atherosclerosis, protect endothelium, and inhibit the proliferation of arterial smooth-muscle cells, they note.

A previous study in a Japanese population showed efficacy for cilostazol in the prevention of ischemic stroke, they note. "We report the results of a trial to assess the efficacy and safety of cilostazol compared with aspirin in the prevention of secondary stroke in a small sample of patients, which could be a pilot study for a large phase 3 trial," Dr. Huang and colleagues write.

Called the Cilostazol vs Aspirin for Secondary Ischemic Stroke Prevention (CASISP) trial, the multicenter, double-blind study enrolled 720 consecutive patients within 1 to 6 months of an ischemic stroke. Patients were treated for 12 to 18 months and imaged at the beginning and the end of the study with T1 magnetic resonance imaging (MRI), T2 MRI, diffusion-weighted imaging, T2 fluid-attenuated inversion recovery (FLAIR), and T2 gradient echo imaging. The primary end point was any recurrence of stroke, including ischemic and hemorrhagic stroke, or subarachnoid hemorrhage.

A primary end-point event occurred in 12 patients in the cilostazol group and 20 in the aspirin group. The estimated hazard ratio, calculated with Kaplan-Meier curves (risk of primary end point in the cilostazol group vs the aspirin group) was 0.62 (95% CI, 0.30 – 1.26; P = 0.185).

CASISP: End Points with Cilostazol vs Aspirin

End Point Cilostazol Aspirin
Ischemic Stroke (n) 11 15
Symptomatic hemorrhagic stroke (n) 1 5
Stroke recurrence rate (patients/y) 3.26 5.27

During the first 6 months of treatment, the curves were close, but with aspirin more effective than cilostazol during this period, they note. However, after 6 months, the curves crossed and thereafter favored cilostazol. At the end of the study, there was a 38.1% reduction in the relative risk of the primary end point in the cilostazol group vs the aspirin group. "However, this did not reach statistical significance, which, we feel, is due to the small sample size and the short follow-up period," they write.

In addition, the difference in symptomatic hemorrhage, they write, is "an important distinction between the treatments." Asymptomatic cerebral hematoma was found in 4 patients in the aspirin group vs 1 in the cilostazol group. In all, brain bleeding events occurred in 7 patients treated with aspirin vs 1 on cilostazol (the same patient who had a symptomatic hemorrhage), a significant difference (P = .034).

There was no significant difference between the groups in the combined end point, including recurrent stroke, new myocardial infarction, transient ischemic attack, or a vascular event such as pulmonary embolism. The estimated hazard ratio was 0.70 (95% CI, 0.40 – 1.21; P = .200).

Major adverse effects were generally not different between the groups, they report, but mild adverse events, including headache, dizziness, and tachycardia, as well as palpitations, were more common with cilostazol.

They note that all 6 patients with symptomatic hemorrhage were found to have microbleeds on imaging in the area where the hematoma was located.

"To reduce drug-related cerebral hemorrhage, screening for cerebral microbleeds might be helpful before long-term antiplatelet therapy is started, and aspirin should be selected cautiously, particularly in patients with microbleeds at many sites," they conclude. "Phosphodiesterase inhibitors such as dipyridamole and cilostazol can be thought of as candidate drugs to supplement or replace aspirin in these high-risk patients."

Hope for a Safer Antiplatelet Drug

In a Reflection and Reaction article accompanying the paper, Graeme J. Hankey, MD, from Royal Perth Hospital, in Western Australia, writes that the finding on the primary end point in this study was as expected but points out that the confidence intervals were "extremely wide," owing to the small number of patients randomized, their moderate risk profile, and the short follow-up. "Unfortunately the trial design did not include the more robust outcome event — the composite of stroke, myocardial infarction, or vascular death," he writes.

Although the authors are "understandably excited" about the smaller number of symptomatic intracerebral hemorrhages with cilostazol and the possibility that microbleeds might help identify those at risk for hemorrhage, Dr. Hankey urges caution on interpretation of these results, again based on the small number of events seen in this trial.

"The implications of these results for clinicians are that they offer hope for a safer antiplatelet drug that is at least as effective as aspirin for use in patients with ischemic stroke," Dr. Hankey concludes. "The implications of these results for researchers are the need to explore the external validity of these pilot study results in a phase 3 randomized trial that compares cilostazol with aspirin (or with the new gold standard of antiplatelet therapy, pending the results of the [Prevention Regimen for Effectively Avoiding Second Strokes] PROFESS trial) in a large number of high-risk patients with recent ischemic stroke from a wide range of nations and ethnic groups."

The PROFESS trial is an ongoing randomized trial comparing 2 antithrombotic regimens, a fixed-dose combination of extended-release dipyridamole plus aspirin with clopidogrel, and telmisartan vs placebo in a factorial design in patients with strokes. It will be presented May 14, 2008 at the upcoming European Stroke Conference in Nice, France and will be reported by Medscape Neurology & Neurosurgery at that time.

An Important Predictor

Asked for comment on these findings, Philip B Gorelick, MD, 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, told Medscape Neurology & Neurosurgery that these findings should be viewed as preliminary, as the follow-up period was short and the study included a relatively small number of patients.

"Although the findings are encouraging, especially for patients at high risk for brain hemorrhage such as the Chinese subjects exclusively studied in this trial, a large-scale trial of efficacy and safety is needed to prove or disprove the findings more definitively," Dr. Gorelick said. The trial should include careful control of blood pressure and surveillance for any adverse effects of statins in this population, as well as MRI studies, he added, "as they may prove to be an important predictor of bleeds."

The study was supported by the National Health Ministry of the People's Republic of China and Otsuka Pharmaceuticals. Dr. Huang has received lecture fees from Otsuka. Disclosure information for coauthors appears in the paper. Dr. Hankey reports that he has received honoraria from Sanofi-Aventis, Bristol-Myers Squibb, Boehringer Ingelheim, and Pfizer for serving on advisory boards and speaking at sponsored scientific symposia.

Lancet Neurol. Published online May 5, 2008.


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