Pharmacodynamic Effects of Cilostazol Versus Clopidogrel in Stented Patients under Proton Pump Inhibitor Co-administration: The ACCEL-PARAZOL Study

Abstract

Aim: Proton pump inhibitor (PPI) therapy has been shown to attenuate the antiplatelet effects of clopidogrel. The aim of this study was to compare the antiplatelet effects of cilostazol versus clopidogrel in patients co-administered a PPI. Methods: We enrolled PPI-naïve stented patients treated with standard clopidogrel and aspirin therapy for at least six months (n = 100). The patients were randomly assigned to receive either cilostazol at a dose of 100 mg twice daily (CILO group) or clopidogrel at a dose of 75 mg daily (CLPD group) in addition to lansoprazole (30 mg daily). The platelet aggregation (PA) determined using light transmittance aggregometry and the platelet reactivity index (PRI) obtained using a vasodilator-stimulated phosphoprotein phosphorylation assay were measured before randomization and at the 14-day follow-up visit. The primary endpoint was the PRI value at follow-up. Results: At follow-up, the CLPD group showed similar values of PRI as the CILO group (66.9±14.0% vs. 63.1±14.1%; mean difference: 3.9%; 95% confidence interval of difference: −1.7% to 9.4%; p=0.174). However, the 6 μg/mL collagen-and 0.5 mg/mL arachidonic acid-induced PA values in the CLPD group were higher than those observed in the CILO group (mean differences: 9.8% to 11.1%; all p values ＜0.001). CYP2C19 loss-of-function allele carriage was the major contributing factor associated with the PRI level in the absence of lansoprazole treatment (with a gene-dose effect); this association was not observed in the subjects receiving lansoprazole co-administration in the CLPD group. Conclusions: During lansoprazole co-administration, cilostazol treatment achieves a more favorable platelet function profile than clopidogrel therapy. The use of combination treatment with cilostazol and aspirin deserves further attention with respect to the management of stable stented patients requiring PPI co-administration. IntroductionDual antiplatelet therapy (DAPT) with clopidogrel and aspirin has been shown to reduce major cardiovascular events following percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS). However, the risk of gastrointestinal (GI) Park Y and Jung JM contributed equally to this work. cilostazol compared with that of ADP P2Y12 receptor blockers and the findings of a previous report of healthy subjects showing relatively lower inhibitory effects of ADP-mediated platelet aggregation by cilostazol than with clopidogrel 18) may limit its clinical application in stented patients. Since cilostazol is also metabolized by the CYP2C19 enzyme 19) , the CYP2C19 genetic polymorphism and/or concomitant use of a PPI may influence its pharmacodynamic effect.In the current study, we therefore evaluated the influence of lansoprazole administration on the effects of clopidogrel and compared the pharmacodynamic actions of cilostazol vs. clopidogrel treatment during PPI co-administration in patients with a history of coronary stenting. Methods Patient Selection and Study DesignThis ACCEL-PARAZOL (phArmacodynamic effect of Cilos...

Current Antiplatelet Treatment Strategy in Patients with Diabetes Mellitus

“…Cilostazol is a dual inhibitor of PDE3 and adenosine reuptake that may have an important role in reducing ischemic events associated with CAD [ 50 - 53 ]. Cilostazol is a widely used selective and reversible PDE3 inhibitor, which is highly expressed in myocardial and vascular smooth muscle cells (VSMCs) and platelets.…”

“…In the Adjunctive Cilostazol versus double-dose ClopidogrEL in Diabetes Mellitus (ACCEL-DM) trial, adjunctive cilostazol to DAPT showed the greater inhibition of platelet aggregation and the lower prevalence of HPR than double-dose clopidogrel in type 2 diabetic patients undergoing PCI [ 50 ]. More interestingly, compared with clopidogrel (75 mg daily) on top of aspirin, adjunctive cilostazol (100 mg twice daily) to aspirin showed the similar inhibition of ADP-induced platelet aggregation [ 52 , 53 ]. In addition, the cilostazol treatment achieved the lower level of platelet function after the stimuli with collagen and arachidonic acid compared with the clopidogrel treatment, which implicates the unique character of antiplatelet effect by cilostazol.…”

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

“…44 Interestingly, during proton pump inhibitor coadministration (eg, lansoprazole), cilostazol treatment was shown to achieve a more favorable profile in platelet function than clopidogrel treatment. 45 The relative bioavailability of the 100-mg cilostazol tablet vs an oral 100-mg cilostazol suspension is 100%. The 50-mg twice-daily and 100-mg once-daily tablet dosings are deemed bioequivalent.…”

“…Aspirin coadministration does not cause clinically significant changes in the coagulation profile, platelet aggregation, or plasma levels of cilostazol and its 2 active metabolites 44 . Interestingly, during proton pump inhibitor coadministration (eg, lansoprazole), cilostazol treatment was shown to achieve a more favorable profile in platelet function than clopidogrel treatment 45 …”