Hemostatic effects of the ticagrelor antidote MEDI2452 in pigs treated with ticagrelor on a background of aspirin

Abstract

Background Ticagrelor, a P2Y antagonist, is approved for the prevention of thromboembolic events. However, antiplatelet therapies carry a risk of bleeding. Objective To explore the hemostatic effects of MEDI2452, 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 MEDI2452 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 MEDI2452 eliminated the free concentrations of ticagrelor and its active metabolite AR-C124910XX within 5 min. ADP-induced platelet 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 (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 MEDI2452 eliminated free ticagrelor and AR-C124910XX 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.

Quantification of unbound concentration of ticagrelor in plasma as a proof of mechanism biomarker of the reversal agent, MEDI2452

“…To evaluate sample preparation further, four in vivo plasma samples from a study in pigs [ 15 ] dosed with ticagrelor and MEDI2452 were subjected to ED. After sample collection, formic acid was added to the final concentration of either 0.17% or 1.7% to retentate sample prior to protein precipitation.…”

“… Addition of 0.17% or 1.7% formic acid (final concentrations) to pig plasma samples were made 10 minutes prior to protein precipitation. Aspirin pre-treated pigs were infused with ticagrelor (3 mg/kg/h) for 60 minutes followed by a MEDI2452 bolus (600 mg/kg) [ 15 ]. Samples were collected 15 minutes after MEDI2452 bolus.…”

“…The study was performed in accordance with relevant guidelines and regulations, the animal work was approved by the Local Animal Research Ethics Board of Gothenburg, Sweden. As described previously [ 15 ], three groups of Swedish landrace pigs were given either ASA (acetylsalicylic acid) alone, ASA + ticagrelor or ASA + ticagrelor + MEDI2452.…”

Management of Bleeding Events Associated with Antiplatelet Therapy: Evidence, Uncertainties and Pitfalls

“…MEDI2452, a specific antidote for ticagrelor, is in advanced development. MEDI2452 binds to circulating ticagrelor and ticagrelor-active metabolite with an affinity 100-fold higher than the affinity of ticagrelor for the P2Y 12 receptor [ 15 , 16 ]. After promising results in animal studies suggesting efficacy and safety, this antidote provided immediate and sustained reversal of the antiplatelet effects of ticagrelor in healthy volunteers, as measured by multiple assays [ 17 ].…”

Bleeding risk of ticagrelor compared to clopidogrel in intensive care unit patients with acute coronary syndrome: A propensity-score matching analysis

“…Platelet transfusion, which is normally performed to reverse the effects of antiplatelet drugs, has been found to be inefficient in the first 24 hours in ticagrelor-treated patients, likely because circulating ticagrelor and its active metabolite (whose half-lives are 9 and 12 hours, respectively) inhibit fresh platelets [24][25][26][27]. A specific antidote to ticagrelor is currently being researched to address this problem [28]. Finally, the transition from clopidogrel to ticagrelor is the only switch between P2Y12 inhibitors that has been investigated in a trial powered for clinical endpoint; efficacy and safety of ticagrelor were not affected by previous clopidogrel https://doi.org/10.1371/journal.pone.0232768.t002…”