Abstract
BackgroundIn order to evaluate the impact of cilostazol on endothelial function, we compared the changes of flow-mediated dilation (FMD) between aspirin and cilostazol groups in patients with acute cerebral ischemia.MethodsPatients presenting with acute cerebral ischemic events were randomly assigned into aspirin (n = 40) or cilostazol (n = 40) group in a double-blinded manner. FMD was measured at baseline (T0) and 90 days (T1). We measured L-arginine at baseline (a precursor of biologically active nitric oxides). Serious and non-serious adverse events were described.ResultsDespite no difference in the baseline FMD values (p = 0.363), there was a significant increase of FMD values in cilostazol group (7.9 ± 2.4 to 8.9 ± 2.3%, p = 0.001) and not in aspirin group (8.5 ± 2.6 to 9.3 ± 2.8%, p = 0.108). In the multiple regression analysis performed in cilostazol group, serum L–arginine levels were inversely correlated with FMD at T1 (ß = −0.050, SE: 0.012, p < 0.001) with age, total cholesterol levels, and C-reactive protein as confounders. While T0 FMD values in both aspirin and cilostazol groups did not show any correlation with serum L-arginine levels, the correlation is restored in the cilostazol group at T1 (r = 0.467, p = 0.007), while such is not shown in the aspirin group. There was no difference of serious adverse events between the two groups (p = 0.235). Adverse events were more common in the cilostazol group (35/40 vs. 25/40, p = 0.010), due to frequent headaches (14/40 vs. 3/30, p = 0.003) which was well tolerated.ConclusionCilostazol improved endothelial function in acute cerebral ischemia patients. It also restored an inverse correlation between 3-month FMD and baseline L-arginine levels.Trial registrationNCT03116269, 04/12/2017, retrospectively registered.
Highlights
In order to evaluate the impact of cilostazol on endothelial function, we compared the changes of flow-mediated dilation (FMD) between aspirin and cilostazol groups in patients with acute cerebral ischemia
The progression rate of symptomatic intracranial artery stenosis was significantly lower in the cilostazol aspirin combination group than in the aspirin monotherapy group [6]. These findings suggest antiatherogenic effects of cilostazol, previously known to be through actions on PDE3 in vascular smooth muscle cells [7], lipoprotein metabolism [8], and prevention of endothelial apoptosis [9]
When initial FMD values and mean age of aspirin and cilostazol groups were compared to reference group, there was no statistical difference (FMD values: 8.5 ± 2.6 vs. 7.9 ± 2.4 vs. 8.8 ± 2.7%, p = 0.257, age: 79.5 ± 11.7 vs. 57.4 ± 12.7 vs. 57.7 ± 14.9, p = 0.787)
Summary
In order to evaluate the impact of cilostazol on endothelial function, we compared the changes of flow-mediated dilation (FMD) between aspirin and cilostazol groups in patients with acute cerebral ischemia. Cilostazol is a selective phosphodiesterase (PDE) 3 inhibitor with therapeutic focus on cyclic adenosine monophosphate (cAMP) [1]. It inhibits platelet aggregation and plays a role as a direct arterial vasodilator [2, 3]. Endothelial function can be noninvasively assessed by the ultrasound measurement of brachial artery flow-mediated dilation (FMD), which represents the endothelium-dependent relaxation of an artery in response to reactive hyperemia [12]. Improvement of FMD can be a biomarker for protection against atherogenesis
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