Adjunctive Cilostazol to Dual Antiplatelet Therapy to Enhance Mobilization of Endothelial Progenitor Cell in Patients with Acute Myocardial Infarction: A Randomized, Placebo-Controlled EPISODE Trial

Abstract

Background: Endothelial progenitor cells (EPCs) have the potential to protect against atherothrombotic event occurrences. There are no data to evaluate the impact of cilostazol on EPC levels in high-risk patients. Methods: We conducted a randomized, double-blind, placebo-controlled trial to assess the effect of adjunctive cilostazol on EPC mobilization and platelet reactivity in patients with acute myocardial infarction (AMI). Before discharge, patients undergoing percutaneous coronary intervention (PCI) were randomly assigned to receive cilostazol SR capsule (200-mg) a day (n = 30) or placebo (n = 30) on top of dual antiplatelet therapy (DAPT) with clopidogrel and aspirin. Before randomization (baseline) and at 30-day follow-up, circulating EPC levels were analyzed using flow cytometry and hemostatic measurements were evaluated by VerifyNow and thromboelastography assays. The primary endpoint was the relative change in EPC levels between baseline and 30-day. Results: At baseline, there were similar levels of EPC counts between treatments, whereas patients with cilostazol showed higher levels of EPC counts compared with placebo after 30 days. Cilostazol versus placebo treatment displayed significantly higher changes in EPC levels between baseline and follow-up (ΔCD133+/KDR+: difference 216%, 95% confidence interval (CI) 44~388%, p = 0.015; ΔCD34+/KDR+: difference 183%, 95% CI 25~342%, p = 0.024). At 30-day follow-up, platelet reactivity was lower in the cilostazol group compared with the placebo group (130 ± 45 versus 169 ± 62 P2Y12 Reaction Unit, p = 0.009). However, there were no significant correlations between the changes of EPC levels and platelet reactivity. Conclusion: Adjunctive cilostazol on top of clopidogrel and aspirin versus DAPT alone is associated with increased EPC mobilization and decreased platelet reactivity in AMI patients, suggesting its pleiotropic effects against atherothrombotic events (NCT04407312).

Update on Cilostazol: A Critical Review of Its Antithrombotic and Cardiovascular Actions and Its Clinical Applications

“…58 A randomized controlled trial (RCT) in patients with acute myocardial infarction (MI) undergoing PCI, randomized to cilostazol SR (200 mg/day; n = 30) or placebo (n = 30) added to DAPT with clopidogrel and aspirin, indicated that patients with cilostazol had higher endothelial progenitor cell counts vs the placebo after 1 month. 59 Furthermore, the cilostazol group had decreased platelet reactivity. These findings attest to cilostazol's pleiotropic effects against atherothrombotic events.…”

“…Cilostazol also enhanced the mobilization of endothelial progenitor cells contributing to endothelial repair and improved endothelium‐dependent function by altering some metabolic and angiogenic markers in 71 patients at increased risk of CVD 58 . A randomized controlled trial (RCT) in patients with acute myocardial infarction (MI) undergoing PCI, randomized to cilostazol SR (200 mg/day; n = 30) or placebo (n = 30) added to DAPT with clopidogrel and aspirin, indicated that patients with cilostazol had higher endothelial progenitor cell counts vs the placebo after 1 month 59 . Furthermore, the cilostazol group had decreased platelet reactivity.…”

Long-acting cilostazol versus isosorbide mononitrate for patients with vasospastic angina: a randomized controlled trial

“…Cilostazol may be beneficial in patients with VSA by virtue of its action of reducing the cytosolic calcium concentration, leading to vasodilation [7]. Cilostazol has antiplatelet properties which reduce the atherothrombotic burden in patient with coronary artery disease [8,9]. Previous data suggest that cilostazol is effective in patients with VSA who cannot tolerate conventional treatment [10,11].…”