Cilostazol Alleviates Delayed Cerebral Ischemia After Subarachnoid Hemorrhage by Attenuating Microcirculatory Dysfunction

Abstract

Cilostazol, a phosphodiesterase 3 (PDE3) inhibitor that exerts antiplatelet effects, has therapeutic potential for delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, its mechanism of action remains unclear. We hypothesized that cilostazol alleviates DCI by improving cerebral microcirculatory dysfunction, which is a component of early brain injury. To test this hypothesis, we analyzed the intracerebral circulation time (iCCT) in 256 patients with aSAH from two randomized controlled trials (74 received cilostazol, 54 received pitavastatin, and 128 were controls). A minority of patients (n = 72, 28%) developed severe angiographic vasospasm (aVS) and DCI (n = 42, 16%) and had poor outcomes (n = 35, 14%). We measured iCCT as the time to peak in the ultraearly phase (baseline) and the subacute phase or at DCI onset (follow-up). The cilostazol group had shorter follow-up iCCT and larger iCCT differences than the other groups, indicating improved microcirculatory function, particularly in patients with DCI and poor outcomes. Multivariate analysis revealed that cilostazol treatment is a significant predictor of favorable outcomes, whereas DCI occurrence, a decrease in iCCT differences, and high clinical severity (Hunt & Hess grades 3-4) were associated with poor outcomes. Diminished microcirculatory dysfunction may alleviate DCI and improve outcomes among patients with aSAH following cilostazol treatment. Further research is warranted to confirm these findings and explore the dose-dependent effects of cilostazol on the microcirculatory function.

Keywords: Aneurysmal subarachnoid hemorrhage; Delayed cerebral ischemia; Early brain injury; Intracerebral circulation time; Microcirculatory dysfunction.