Antiplatelet Effects Of Different Loading Doses Of Ticagrelor In Patients With NSTE-ACS Undergoing PCI And Validation Of A New ELISA-based VASP Assay To Assess Platelet Reactivity Index

[Background]Dual antiplatelet therapy consisting of aspirin and clopidogrel is conventional treatment in patients with acute coronary syndromes (ACS) or undering percutaneous coronary intervention (PCI) for prevention thrombotic events. Even if it is so, there are considerable number of patients who would recurrent thrombotic events.Ticagrelor, a new P2Y12 receptor antagonist which reversibly binds the P2Y12 receptor has been approved for clinical use. It has been demonstrated that ticagrelor has more marked antiplatelet effect compared with clopidogrel, and overall better clinical outcomes.In DISPERSE1 study, the first to investigate ticagrelor in patients with atherosclerosis, ticagrelor 100 mg bid, 200 mg bid, and 400 mg qd rapidly and nearly completely inhibited P2Y12 -mediated platelet aggregation as measured by optical aggregometry. However, loading dose of ticagrelor was not administered in this study.DISPERSE2 trial demonstrated that ticagrelor inhibited platelet aggregation in a dose dependent fashion. Dimitrios Alexopoulos et al found that a delay in action during the first 2 hours postloading dose with ticagrelor in ST-segment elevation acute coronary syndromes (STEMI) patients. A higher loading dose in patients with STEMI could theoretically achieve a faster platelet inhibition. However, the inhibition of platelet aggregation (IPA) of higher loading dose of ticagrelor in patients with NSTE-ACS is still unknown.[Objective]This is to compare the antiplatelet effects and clinical outcomes using high loading dose(360mg) with conventional loading dose (180 mg) of ticagrelor in patients with NSTE-ACS undergoing percutaneous coronary intervention (PCI).[Methods]In this interventional, multicenter, and open-label trial, 278 NSTE-ACS patients were randomized to receive a high LD (360 mg) or conventional LD (180 mg) of ticagrelor, and then a maintenance dose of 90 mg bid was started 12 hours after the LD. The primary endpoint was platelet reactivity index (PRI) 2 hours after the LD.The secondary endpoints included the PRI at 0.5, 1, 8, and 24 hours after the LD,occurrence of periprocedural myocardial infarction and bleeding events.[Results]PRI at 2h was significantly lower in high LD group (12.2%, 4.3% to 21.3%)compared with conventional LD group (16.7%, 9.3% to 32.3%) (p =0.023). PRI least squares mean difference (95% CI) between groups at 0.5, 1, 8, and 24 h post-loading was -13.2 (-22.05 to -4.36), -11.2 (-19.07 to -3.23), -6.4 (-9.98 to -2.89), and -4.8(-9.30 to -0.25) with p = 0.004, 0.006, 0.0004, and 0.039, respectively. No significant difference with regard to the rates of bleeding was found between the two groups(14% vs. 14.3%, p = 0.43). The high LD group had a lower HPR rate than the conventional LD group at 0.5, 1h post LD. Four cases of periprocedural myocardial infarctions and one death in each group, and one acute myocardial infarction occurring in the conventional LD group were found. There was no stroke, target lesion revascularization or target vessel revascularization.[Conclusion]High LD of ticagrelor produced a significantly faster onset of antiplatelet action and higher platelet inhibition compared with the traditional ticagrelor LD in NSTE-ACS without an increase in the rate of bleeding.[Background]The level of platelet reactivity inhibition obtained after administration of a P2Y12-ADP receptor antagonist is associated with ischemic and bleeding risks following percutaneous coronary intervention in acute coronary syndrome.Determination of platelet reactivity inhibition may be valuable to confirm effective platelet inhibition for individual patients and identify patients at risk of bleeding.Several platelet function tests have been developed to measure antiplatelet effects during antiplatelet therapy to facilitate an optimal clinical outcome.. However, which test can be best to measure platelet reactivity specifically and predict clincial outcomes was still uncertain. The enzyme-linked immunosorbent assay(ELISA)-based vasodilator-stimulated phosphoprotein (VASP) assay offers unique advantages over other methods. It has not been used in the Chinese population.[Objective]The objectives of the present study were to compare the performance of the ELISA and FC methods and to describe the relative flexibility of the ELISA-based assay.[Methods]We enrolled 10 healthy volunteers and 54 patients with acute coronary syndrome. The volunteers received no treatment, and patients were administered a loading dose of clopidogrel or ticagrelor. The platelet reactivity index(PRI) was measured using flow cytometry (FC)-VASP and ELISA-VASP at baseline and 8 hours post-loading dose.Healthy volunteer and patient blood samples were frozen and stored for 1, 2, and 4 weeks after initial activation. All frozen samples were tested using ELISA-VASP.[Results]The platelet reactivity index assessed by FC-VASP and ELISA-VASP correlated well showing a high degree of consistency in identifying high on-treatment platelet reactivity or low on-treatment platelet reactivity. No time-dependent changes in platelet reactivity index results were observed in frozen samples stored up to 4 weeks compared to non-frozen samples. The platelet reactivity index of ticagrelor-treated patients was lower than that of clopidogrel-treated patients.[Conclusion]ELISA-VASP effctively assesses the platelet reactivity index, and results in frozen specimens are unaffected by storage and shipment prior to assay. Ticagrelor was superior to clopidogrel in decreasing the platelet reactivity index.