Elsevier

The Lancet Neurology

Volume 7, Issue 6, June 2008, Pages 494-499
The Lancet Neurology

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Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study

https://doi.org/10.1016/S1474-4422(08)70094-2Get rights and content

Summary

Background

Most patients who have had a stroke are given aspirin; however, aspirin-related cerebral haemorrhage is a complication that is currently of concern, particularly in China where there is a high incidence of cerebral haemorrhage in secondary prevention programmes and within the community. Cilostazol, a phosphodiesterase 3 (PDE3) inhibitor, is an alternative to aspirin that works through a different mechanism. This trial aimed to compare the efficacy and safety of cilostazol with that of aspirin for the long-term prevention of the recurrence of ischaemic stroke.

Methods

720 patients (mean age 60·2 years, SD 9·86) who had had an ischaemic stroke within the previous 1–6 months were enrolled consecutively in a prospective, multicentre, double-blind, randomised trial. 360 patients were randomly assigned to receive cilostazol and 360 patients to receive aspirin. Analysis was by intention to treat. Patients in both groups took the medication for 12–18 months. The primary endpoint was any recurrence of stroke (ischaemic stroke, haemorrhagic stroke, or subarachnoid haemorrhage) during the trial period. All patients had MRI with T1 MRI, T2 MRI, diffusion-weighted imaging (DWI), T2 fluid-attenuated inversion recovery (FLAIR), and T2 gradient echo imaging (T2*) at the beginning and the end of the study. This trial is registered with ClinicalTrials.gov, number NCT00202020.

Findings

The average duration of treatment was 740 person-years, and 719 patients were analysed (360 in the cilostazol group and 359 in the aspirin group). The primary endpoint was reported in 12 patients in the cilostazol group and in 20 patients in the aspirin group. The estimated hazard ratio, calculated with Kaplan–Meier curves (risk of primary endpoint in cilostazol group vs aspirin group), was 0·62 (95% CI 0·30–1·26; p=0·185). Symptomatic cerebral haemorrhage was reported in six patients: one in the cilostazol group and five in the aspirin group. Asymptomatic cerebral haematoma was found in four patients in the aspirin group and one patient in the cilostazol group. Brain bleeding events were significantly more common in the aspirin group than in the cilostazol group (7 vs 1, p=0·034). All of the six patients with symptomatic haemorrhage had previous cerebral microbleeds in the area where the haematoma was located.

Interpretation

The results of this pilot study showed no significant difference in the rate of recurrence of stroke between patients with ischaemic stroke who were randomly assigned to take either cilostazol or aspirin. The lower rates of ischaemic and haemorrhagic stroke in the cilostazol group suggest that cilostazol might be a more effective and safer alternative to aspirin for Chinese patients with ischaemic stroke; however, a larger phase III trial is required to confirm this.

Funding

National Health Ministry of the People's Republic of China; Otsuka Pharmaceutical.

Introduction

Stroke is the second leading cause of mortality in China, with about 7 million people affected countrywide.1 Aspirin is effective for the prevention of secondary stroke and has been used in up to 89% of patients in China (REACH registry, unpublished data). However, although recurrent stroke is controlled by this treatment, the incidence of cerebral haemorrhage and other bleeding events is higher in China than in high-income countries.2 To overcome the risk of haemorrhage, combinations of antiplatelet drugs that act on different pathways have been used; these compounds were used effectively and safely in patients with unstable coronary heart disease, with the most benefits seen during the first few weeks of treatment.3 The results of recent studies have shown that the combination of two antiplatelet drugs failed to improve stroke prevention rates owing to the increased risk of bleeding events associated with their long-term use.4, 5 Bleeding due to antiplatelet drugs is an important clinical problem in primary6 and secondary stroke prevention, particularly in the Chinese population, which has a higher incidence of cerebral haemorrhage than other ethnic groups.7, 8

Cilostazol, a selective inhibitor of phosphodiesterase 3 (PDE3), prevents inactivation of the intracellular second messenger cyclic AMP and irreversibly inhibits platelet aggregation and vasodilation. In addition, cilostazol delays the onset of atherosclerosis,9 protects the vessel endothelium, inhibits the proliferation of arterial smooth-muscle cells,10, 11 and has shown efficacy in the prevention of ischaemic stroke in a group of patients from Japan.12 However, no studies have compared the efficacy of cilostazol with that of aspirin, which continues to be widely used to prevent secondary ischaemic stroke. 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 III trial.

Section snippets

Participants

720 patients (495 male and 225 female, mean age 60·2 years) were enrolled consecutively between May 1, 2004, and Dec 31, 2004. Follow-up was concluded on Dec 31, 2005. Patients were eligible for inclusion if they had had an ischaemic stroke within the preceding 1 to 6 months, their diagnosis had been confirmed with neuroimaging, and they had a modified Rankin scale score of less than 4 at enrolment. Exclusion criteria were one or more from a history of intracranial or subarachnoid haemorrhage,

Results

Treatment was given for a total of 740 person-years. The trial profile is shown in figure 1.

569 patients (79%) had vascular risk factors, including hypertension, diabetes, and high lipid concentrations. The profiles of the cilostazol patients and aspirin patients were similar (table 1), although baseline systolic blood pressure was significantly higher in the control group than in the cilostazol group (p=0·03) but this resolved after 1 month's treatment with antihypertensive drugs. 223 patients

Discussion

Cilostazol has similar effects to those of aspirin in the prevention of recurrent ischemic stroke during the first 6 months after starting treatment. By contrast, after 6 months, cilostazol was more effective than aspirin, and at the end of the study there was a 38·1% reduction in the relative risk of a primary endpoint in the cilostazol group compared with the aspirin group. However, this did not reach statistical significance, which, we feel, is due to the small sample size and the short

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