Hemostatic effects of the ticagrelor antidote MEDI2452 in pigs treated with ticagrelor on a background of aspirin
Artikel i vetenskaplig tidskrift, 2017

Background: Ticagrelor, a P2Y12 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, pretreated 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: bodyweight- 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% 0.1350.148) (ticagrelor and aspirin) vs. 0.04 (CI 95% 0.030.05) 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% 94136) mmHg (aspirin alone). Conclusion: MEDI2452 eliminated free ticagrelor and AR-C124910XX within 5 min. This translated into a gradual normalization of ADPinduced platelet aggregation and significant improvement in blood pressure and numerical but non-significant improvements in blood-loss and survival.

swine

antidote

hemorrhage

ticagrelor

blood platelets

Författare

S. Pehrsson

AstraZeneca AB

K. J. Johansson

AstraZeneca AB

A. Janefeldt

AstraZeneca AB

A. S. Sandinge

AstraZeneca AB

S. Maqbool

Clinical Pharmacology and DMPK

J. Goodman

Clinical Pharmacology and DMPK

J. Sanchez

AstraZeneca AB

Joachim E Almqvist

Chalmers, Biologi och bioteknik, Systembiologi

Peter Gennemark

AstraZeneca AB

S. Nylander

AstraZeneca AB

Journal of Thrombosis and Haemostasis

1538-7933 (ISSN) 1538-7836 (eISSN)

Vol. 15 1213-1222

Ämneskategorier

Anestesi och intensivvård

DOI

10.1111/jth.13680

PubMed

28322016