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

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

Pehrsson, S. (author): AstraZeneca AB

Johansson, K. J. (author): AstraZeneca AB

Janefeldt, A. (author): AstraZeneca AB

Sandinge, A. S. (author): AstraZeneca AB

Maqbool, S. (author)

Goodman, J. (author)

Sanchez, J. (author): AstraZeneca AB

Almqvist, Joachim E, 1980 (author): Chalmers tekniska högskola,Chalmers University of Technology

Gennemark, Peter, 1974 (author): AstraZeneca AB

Nylander, S. (author): AstraZeneca AB

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(creator_code:org_t)

Elsevier BV, 2017
2017
English.
In: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7836 .- 1538-7933. ; 15:6, s. 1213-1222

Related links:: http://dx.doi.org/10...; show more...; https://onlinelibrar...; https://research.cha...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Anestesi och intensivvård (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Anesthesiology and Intensive Care (hsv//eng)

Keyword

swine
antidote
hemorrhage
ticagrelor
blood platelets

Publication and Content Type

art (subject category)
ref (subject category)

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By the author/editor: Pehrsson, S.; Johansson, K. J.; Janefeldt, A.; Sandinge, A. S.; Maqbool, S.; Goodman, J.; show more...; Sanchez, J.; Almqvist, Joachi ...; Gennemark, Peter ...; Nylander, S.; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Anesthesiology a ...

Articles in the publication: Journal of Throm ...

By the university: Chalmers University of Technology

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