Hemostatic effects of the ticagrelor antidote MEDI MEDI 2452 in pigs treated with ticagrelor on a background of aspirin

摘要

Essentials MEDI2452 is a specific antidote of the platelet P2Y 12 receptor antagonist ticagrelor. Hemostatic effects of MEDI2452 were evaluated in pigs treated with ticagrelor and aspirin. MEDI2452 eliminated free ticagrelor within 5 min and gradually normalized platelet aggregation. Improvements in blood pressure (significant) and in blood‐loss and survival (non‐significant) were observed. Summary Background Ticagrelor, a P2Y 12 antagonist, is approved for the prevention of thromboembolic events. However, antiplatelet therapies carry a risk of bleeding. Objective To explore the hemostatic effects of MEDI 2452, an antidote for ticagrelor. Methods Pigs, pre‐treated with aspirin, were given an intravenous infusion of ticagrelor or vehicle. At the end of the infusion, a piece of a liver lobe was cut off and a bolus of MEDI 2452 or vehicle was administered intravenously. Blood was collected to monitor blood loss, mean arterial blood pressure ( MAP ) was recorded and survival time was observed over 4 h. Blood samples for drug plasma exposures and platelet aggregation were collected. Results MEDI 2452 eliminated the free concentrations of ticagrelor and its active metabolite AR ‐C124910 XX within 5 min. ADP ‐induced pla t elet aggregation was close to normal at 60 min, which was not significantly different from aspirin alone. MEDI2452 numerically reduced ticagrelor‐mediated effects: body‐weight‐adjusted blood loss in the 15‐ to 90‐min interval, 12 (confidence interval [CI] 95% 7–28] vs. 17 (CI 95% 5–31) (ticagrelor and aspirin) vs. 5 (CI 95% 3–9) mL kg ?1 (aspirin alone), survival 70% (CI 95% 47–100) vs. 45% (CI 95% 21–92) (ticagrelor and aspirin) vs. 100% (CI 95% 100–100) (aspirin alone), and median survival time, 240 (CI 95% 180–240) vs. 169 (CI 95% 64–240) (ticagrelor and aspirin) vs. 240 (CI 95% 240–240) min (aspirin alone). Finally, MEDI2452 significantly attenuated the decline in MAP, 0.08 (CI 95% 0.07–0.09) vs. 0.141 (CI 95% 0.135–0.148) (ticagrelor and aspirin) vs. 0.04 (CI 95% 0.03–0.05) mmHg per min (aspirin alone) and maintained MAP at a significantly higher level, 73 (CI 95% 51–95) vs. 48 (CI 95% 25–70) (ticagrelor and aspirin) vs. 115 (CI 95% 94–136) mmHg (aspirin alone). Conclusion MEDI 2452 eliminated free ticagrelor and AR ‐C124910 XX within 5 min. This translated into a gradual normalization of ADP ‐induced platelet aggregation and significant improvement in blood pressure and numerical but non‐significant improvements in blood‐loss and survival.