Abstract 5762: A Randomized Double-Blind Study to Assess the Onset and Offset of the Antiplatelet Effects of Ticagrelor versus Clopidogrel in Patients With Stable Coronary Artery Disease

Background: Rapid and consistent inhibition of platelet aggregation (IPA) confers protection against the occurrence of ischemic events, and reversible inhibition may be desirable for patients who require surgery. The ONSET-OFFSET study was conducted in patients with stable coronary artery disease (CAD) to characterize the onset and offset of IPA associated with ticagrelor (T), the first reversibly binding oral P2Y 12 receptor antagonist, and compare them with those associated with clopidogrel (C). Methods: In a multicenter, randomized, double-blind, parallel-group study, 123 patients with stable CAD currently receiving aspirin (75–100mg) were randomized to doses of T (180 mg loading, 90 mg bid maintenance [n=57]), C (600 mg loading, 75 mg qd maintenance [n=54]) or placebo (n=12) for 6 weeks. Curves for T for onset of IPA (final extent, 20 uM ADP) post loading dose and offset of IPA were compared to those for C. Onset treatment effects were analyzed by the Wilcoxon rank sum test; offset treatment effects were analyzed by random coefficients model. Results: After the loading dose, more rapid onset of IPA occurred with T compared with C at 0.5 h (41±33% vs 8±10%, p<0.0001), 1 h (79±25% vs 23±26%, p<0.0001), and 2 h (88±15 % vs 38±32%, p<0.0001). Higher IPA for T was consistently maintained during maintenance therapy (p<0.0001 at all times). More patients in the T group than in the C group achieved >50% IPA (98% vs 31%, p<0.0001) and >70% IPA (90% vs 16%, p<0.0001) at 2 h post loading dose. At 24 h after the last dose of T, mean IPA was 58% for T vs 52% for C (p=NS). A faster offset rate for IPA was observed after the last dose of T than for C from 4 to 72 h [slope (% IPA/h): −1.037 vs. −0.482, p<0.0001]. Mean IPA for T at 72 h postdose (Day 3) was comparable to C at 120 h (Day 5). Mean IPA on Day 5 for T was similar to that for C on Day 7, both of which were not statistically different from placebo (p<0.05). Conclusions: Ticagrelor achieves more rapid and greater sustained IPA than clopidogrel. Moreover, after drug cessation the antiplatelet effect of ticagrelor had a faster offset. These results suggest value of ticagrelor when treatment protocol calls for rapid platelet inhibition or prompt offset of effect.