Chronic Ischemic Stroke Reduced With Dual Antiplatelet Therapy for Lacunar Stroke

In patients with lacunar stroke, long-term cilostazol therapy decreases rates of recurrent ischemic stroke without increased risk for severe bleeding.

Long-term dual antiplatelet therapy (DAPT) using cilostazol significantly reduces the rate of recurrent ischemic stroke without increasing risk for severe or life-threatening bleeding in patients with lacunar stroke, according to study findings published in Stroke.

Researchers sought to compare the efficacy and safety of DAPT vs single antiplatelet therapy (SAPT) in preventing recurrence of stroke in patients with chronic lacunar stroke. The primary efficacy endpoint was the first recurrence of ischemic stroke. The primary safety endpoints were severe or life-threatening bleeding.

Researchers in Japan conducted a prespecified subanalysis ( Identifier: NCT01995370) of (Cilostazol Stroke Prevention Study for Antiplatelet Combination), a multicenter, open-label, randomized, prospective, controlled trial that included 1884 patients with history of high-risk noncardioembolic stroke enrolled in the trial 8 to 180 days following stroke. Patients were recruited from 292 hospitals across Japan. Patients were aged 20 to 85 years, had noncardioembolic ischemic stroke identified on magnetic resonance imaging between 8 and 180 days before treatment, and were taking either clopidogrel or aspirin alone when the study was initiated. Patients with atherothrombotic stroke or stroke of unknown embolic source were excluded.

All patients had at least 1 high risk factor for stroke recurrence, including at least 50% stenosis in a major intracranial artery or of an extracranial artery, or at least 2 risk factors including being a current smoker, having hypertension, diabetes, chronic kidney disease, peripheral artery disease, being aged 65 years or older, having history of ischemic stroke other than the qualifying episode for this trial, and ischemic heart disease history.

Using data from the trial subgroup, DAPT using cilostazol had remarkable benefits for patients with lacunar infarction in reducing the incidence of recurrent ischemic stroke by half compared with SAP.

In the subanalysis, 925 patients (mean age, 69.5 years; 30.6% women; 100% Asian ethnicity) with lacunar stroke were randomly assigned to receive DAPT or SAPT. Of these patients, 464 patients (29% current smokers; 88% with hypertension; 36% with diabetes) received DAPT (cilostazol [100 mg] and either aspirin [81 or 100 mg] or clopidogrel [50 or 75 mg]) and 461 patients (30% current smokers; 87% hypertension; 38% diabetes) received SAPT (aspirin or clopidogrel alone). Patients were then followed for 0.5 to 3.5 years. Patients were well-matched except for modified Rankin Scale scores with patients in DAPT having a significantly higher prevalence of score 0 to 1.

During follow-up, researchers found ischemic stroke occurred in 12 patients in the DAPT group (1.84 per 100 patient-years) and in 31 patients in the SAPT group (4.42 per 100 patient-years). Ischemic stroke risk was significantly lower in the DAPT group vs SAPT group (hazard ratio [HR], 0.43; 95% CI, 0.22-0.84) after adjusting for multiple potential confounding factors.

There was significantly lower risk of composite vascular events (HR, 0.41; 95% CI, 0.23-0.75; P =.004) and all vascular events (HR, 0.50; 95% CI, 0.29-0.85; P =.011) in the DAPT group vs SAPT group. The significance remained after excluding patients with extracranial or intracranial artery stenosis of more than 50% and adjusting for potential confounding factors.

There was no significant difference in the rate of severe or life-threatening bleeding in DAPT (2 patients; 0.31 per 100 patient-years) vs SAPT (6 patients; 0.86 per 100 patient-years; HR, 0.36; 95% CI, 0.07-1.81).

Study limitations include the lack of statistical power and generalizability. Additionally, the planned sample size was never reached and there was a relatively short follow-up period.

”Using data from the trial subgroup, DAPT using cilostazol had remarkable benefits for patients with lacunar infarction in reducing the incidence of recurrent ischemic stroke by half compared with SAPT,” the study authors wrote. “Moreover, it did not significantly increase the risk of severe or life-threatening bleeding.”

Disclosure: This research was supported by Otsuka Pharmaceutical Co, Ltd. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Nishiyama Y, Kimura K, Otsuka T, et al.; on behalf of the Trial Investigators. Dual antiplatelet therapy with cilostazol for secondary prevention in lacunar stroke: subanalysis of the trial. Stroke. Published online February 3, 2023. doi:10.1161/STROKEAHA.122.039900