Bleeding risk with AZD6140, a reversible P2Y12 receptor antagonist, vs. clopidogrel in patients undergoing coronary artery bypass grafting in the DISPERSE2 trial

AZD6140, the first reversible oral P2Y(12) receptor antagonist, exhibits greater and more consistent inhibition of platelet aggregation than the irreversible thienopyridine clopidogrel. As a result of its reversible effect, AZD6140 may pose less risk for bleeding when antiplatelet treatment cannot be stopped at least 5 days before coronary artery bypass graft (CABG) surgery or other invasive procedures. The Dose conflrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in NSTEMI (DISPERSE2) trial showed overall comparable bleeding rates with antiplatelet treatment with AZD6140 90 mg twice daily or 180 mg twice daily vs. clopidogrel 75 mg once daily in 984 patients with non-ST-elevation acute coronary syndromes. A post hoc exploratory analysis of bleeding outcomes in the subset of 84 patients undergoing CABG in DISPERSE2 suggests reduced risk for total bleeding (41% and 58% vs. 62%), all major bleeding (38% and 50% vs. 62%), and life-threatening bleeding (22% and 38% vs. 54%) with AZD6140 90 mg (n = 32) and 180 mg (n = 26) vs. clopidogrel (n = 26) respectively. Trends suggested that major bleeding rates were reduced with AZD6140 (combined groups) vs. clopidogrel when treatment was stopped <= 5 days prior to surgery (39% vs. 63%, p = 0.15) but not when treatment was stopped > 5 days before surgery (50% vs. 60%). This observation is consistent with the reversible binding of AZD6140 to the P2Y(12) receptor. Further prospective studies are planned to assess the relationship between this potential clinical benefit of AZD6140 and the reversibility of its antiplatelet effects.