In Asian patients with ischemic stroke or transient ischemic attack with extensive small-vessel disease, cilostazol is noninferior to aspirin in reducing a composite of cardiovascular events, but it is not superior in reducing hemorrhagic stroke, according to results of the multicenter, randomized, controlled, 2×2 factorial PICASSO trial (ClinicalTrials.gov Identifier: NCT01013532), which were published in the Lancet Neurology.
The investigators sought to evaluate the efficacy and safety of cilostazol vs aspirin, with and without probucol, in patients with ischemic stroke at high risk for cerebral hemorrhage. Patients with ischemic stroke who had a history of or imaging findings of intracerebral hemorrhage or at least 2 microbleeds were enrolled from 67 hospitals in 3 Asian countries (South Korea, China [Hong Kong], and the Philippines). All participants were randomly assigned in a 1:1:1:1 ratio to 1 of 4 treatment groups: (1) oral cilostazol 100 mg twice daily (with aspirin placebo); (2) aspirin 100 mg once daily (with cilostazol placebo); (3) cilostazol 100 mg plus probucol 250 mg twice daily (with aspirin placebo); or (4) aspirin 100 mg once daily plus probucol 250 mg twice daily (with cilostazol placebo). Comparison of cilostazol vs aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to the assignment.
The coprimary outcomes were incidence of the composite end point including stroke, myocardial infarction, or vascular death (efficacy outcome), and time to first occurrence of imaging-confirmed cerebral hemorrhage (safety outcome). From August 1, 2009, through August 31, 2015, a total of 1534 patients were randomly assigned to 1 of the 4 treatment arms, of whom 1512 were assessed for the coprimary outcomes.
Over a median follow-up of 1.9 years (range, 1.0 to 3.0 years), the incidence of composite vascular events was 4.27 per 100 person-years in cilostazol-treated patients vs 5.33 per
100 person-years in aspirin-treated patients (hazard ratio [HR], 0.80; 95% CI, 0.57-1.11; noninferiority P =.0077; superiority P =.18). Moreover, the incidence of vascular events was 3.91 per 100 person-years in the probucol group vs 5.75 per 100 person-years in the nonprobucol group (HR, 0.69; 95% CI, 0.50-0.97; superiority P =.0316).
The incidence of cerebral hemorrhage was 0.72 per 100 person-years in the probucol arm vs 1.11 per 100 person-years in the nonprobucol arm (HR, 0.65; 97.5% CI, 0.27-1.57;
P =.55). Adverse events were similar across the 4 study groups, with dizziness, headache, diarrhea, and constipation being the most frequently reported.
The investigators concluded that based on the results of this study, the addition of probucol to aspirin or cilostazol might be beneficial in reducing the incidence of cardiovascular events in patients with ischemic stroke at high risk for cerebral hemorrhage.
Kim BJ, Lee E-J, Kwon SU, et al; on behalf of the PICASSO investigators. Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial. Lancet Neurol. 2018;17(6):509-518.