Rachel Forman, MD

Kim BJ, Kwon SU, Park J-H, Kim Y-J, Hong K-S, Wong LKS, et al. Cilostazol Versus Aspirin in Ischemic Stroke Patients With High-Risk Cerebral Hemorrhage: Subgroup Analysis of the PICASSO Trial. Stroke. 2019.

One of the most common discussions on any given stroke service involves the balance of preventing ischemic strokes (IS) and preventing intracranial hemorrhage (ICH). Whether it is about resuming anticoagulation in a hemorrhage patient or resuming aspirin in a patient with cerebral amyloid angiopathy there is always much debate on timing and decisions.  The decision to resume aspirin in a patient with an MRI full of cerebral microbleeds (CMBs) is often difficult. This paper looks into an alternative agent, cilostazol, for reducing hemorrhage risk in patients who warrant anti-platelet therapy. The background of the study is that cilostazol has shown to have less hemorrhagic events than aspirin among patients with ischemic stroke. 

The PICASSO trial (Prevention of Cardiovascular Events in Asian Ischemic Stroke Patients with High Risk of Cerebral Hemorrhage) was an Asian trial that aimed to determine which antiplatelet agent is more effective and safe in patients with prior hemorrhagic stroke or multiple CMBs. Cilostazol is an antiplatelet agent with additional vasodilatory effects. The trial, published in 2018, showed that cilostazol was noninferior to aspirin in preventing a composite of major vascular events; however, it failed to reduce ICH. This paper reviews the subgroup analysis to identify patients who would show greater benefit with cilostazol. 

The PICASSO trial was performed at multiple centers throughout Asia; patients were randomized to the antiplatelet arm (cilostazol 100mg BID or aspirin 100mg daily) or to the probucol arm (probucol 500mg daily or none). The study included patients >20 years old who had a history of non-cardioembolic IS or TIA within 180 days and were at high risk for ICH (clinical or radiographic history of ICH or >2 CMBs). The primary outcome was the occurrence of composite of major vascular events (any stroke, MI, and vascular death). Primary safety outcome was occurrence of ICH or SAH. 

During the study 1534 patients were enrolled: 766 to cilostazol and 768 to aspirin. To briefly review risk factor profiles: 89.1% of patients had hypertension, 32.1% had diabetes, and 57.6% were >65 years old. The authors also classified the patients’ Fazekas score (quantified degree of white matter changes): 27.5% had a score of 1, 41.9% with score of 2, and 17.3% with score of 3 (higher score indicates worse white matter changes). Additionally, 59.8% of patients had multiple CMBs, 21.4% had radiographic ICH, and 18.8% had history of ICH. 

Cilostazol failed to reduce ICH in the overall population, but in the subgroup analysis, there was less ICH in patients with multiple CMBs. One of the proposed reasons for this is that cilostazol protects the security of the blood brain barrier, especially in patients with diffuse fragile perforators. Cilostazol significantly reduced the incidence of stroke in patients with mild-moderate white matter changes, but not those with severe changes (possibly due to the ceiling effect in patients with severe white matter changes). Additionally, cilostazol was associated with greater increase in heart rate and lower reduction in HDL cholesterol than aspirin. 

An additional point that is discussed is about the background of cilostazol: In the past, it has shown greater benefit than aspirin in diabetic IS patients. However, subgroup analysis in this study failed to show that cilostazol improved outcomes in patients with diabetes. Some limitations of the paper include that the trial was performed in only Asian countries, it was a subgroup analysis, and that CMB location was not taken into consideration. 

To conclude, cilostazol may be a more reasonable choice than aspirin in select patients with multiple CMBs and also may be more effective for patients with diffuse fragile small vessel disease.