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

Journal of Thrombosis and Haemostasis

Volumn 15, Issue 6, 2017, Pages 1213-1222

  Pehrsson, S ^a   Johansson, K J ^a   Janefeldt, A ^a   Sandinge, A S ^a   Maqbool, S ^b   Goodman, J ^b   Sanchez, J ^a   Almquist, J ^a,c,d   Gennemark, P ^a   Nylander, S ^a  

^a ASTRAZENECA R AND D   (Sweden)

^b MEDIMMUNE LTD   (United Kingdom)

^c FRAUNHOFER CHALMERS CENTRE   (Sweden)

^d CHALMERS UNIVERSITY OF TECHNOLOGY   (Sweden)

Author keywords

antidote; blood platelets; hemorrhage; swine; ticagrelor

Indexed keywords

ACETYLSALICYLIC ACID; AR C124910XX; HEMOSTATIC AGENT; MEDI 2452; PURINERGIC P2Y RECEPTOR ANTAGONIST; TICAGRELOR; UNCLASSIFIED DRUG; ADENOSINE; ADENOSINE DIPHOSPHATE; ANTIDOTE; ANTITHROMBOCYTIC AGENT; MEDI2452; NEUTRALIZING ANTIBODY;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BLEEDING; BLOOD PRESSURE MEASUREMENT; BODY TEMPERATURE; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG HALF LIFE; HEMOSTASIS; LANDRACE PIG; LIMIT OF QUANTITATION; MEAN ARTERIAL PRESSURE; NONHUMAN; PRIORITY JOURNAL; SURVIVAL RATE; SURVIVAL TIME; THROMBOCYTE AGGREGATION; ANALOGS AND DERIVATIVES; ANIMAL; BIOTINYLATION; BLOOD CLOTTING PARAMETERS; BLOOD PRESSURE; CHEMICALLY INDUCED; CHEMISTRY; DRUG EFFECTS; HUMAN; PIG; TIME FACTOR;

ADENOSINE; ADENOSINE DIPHOSPHATE; ANIMALS; ANTIBODIES, NEUTRALIZING; ANTIDOTES; ASPIRIN; BIOTINYLATION; BLOOD PRESSURE; HEMORRHAGE; HEMOSTASIS; HUMANS; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; PLATELET FUNCTION TESTS; SWINE; TIME FACTORS;

EID: 85019168476     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1111/jth.13680     Document Type: Article

References (23)

1. Van Giezen JJJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost 2005; 31: 195–204.
2. Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, Wickens M, Emanuelsson H, Gurbel P, Grande P, Cannon CP. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 2007; 50: 1852–6.
3. Nylander S, Schulz R. Effects of P2Y(12) receptor antagonists beyond platelet inhibition - comparison of ticagrelor with thienopyridines. Br J Pharmacol 2016; 173: 1163–78.
4. Armstrong D, Summers C, Ewart L, Nylander S, Sidaway JE, van Giezen JJ. Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J Cardiovasc Pharmacol Ther 2014; 19: 209–19.
5. Cattaneo M, Schulz R, Nylander S. Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance. J Am Coll Cardiol 2014; 63: 2503–9.
6. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045–57.
7. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsoon O, Oude Ophis T, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, et al.; for the PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372: 1791–800.
8. Storey RF. New P2Y12 inhibitors. Heart 2011; 97: 1262–7.
9. Bell AD, Roussin A, Cartier R, Chan WS, Douketis JD, Gupta A, Kraw ME, Lindsay TF, Love MP, Pannu N, Rabasa-Lhoret R, Shuaib A, Teal P, Théroux P, Turpie AG, Welsh RC, Tanguay JF. The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society guidelines. Can J Cardiol 2011; 27 (Suppl. A): S1–59.
10. Fitchett DH, Theroux P, Brophy JM, Cantor WJ, Cox JL, Gupta M, Kertland H, Mehta SR, Welsh RC, Goodman SG. Assessment and management of acute coronary syndromes (ACS): a Canadian perspective on current guideline-recommended treatment- part 1: non-ST-segment elevation ACS. Can J Cardiol 2011; 27 (Suppl. A): S387–401.
11. Becker RC, Bassand JP, Budaj A, Wojdyla DM, James SK, Cornel JH, French J, Held C, Horrow J, Husted S, Lopez-Sendon J, Lassila R, Mahaffey KW, Storey RF, Harrington RA, Wallentin L. Bleeding complications with the P2Y12 receptor antagonist clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2011; 32: 2933–44.
12. Held C, Asenblad N, Bassand JP, Becker RC, Cannon CP, Claeys MJ, Harrington RA, Horrow J, Husted S, James SK, Mahaffey KW, Nicolau JC, Scirica BM, Storey RF, Vintila M, Ycas J, Wallentin L. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol 2011; 57: 672–84.
13. Taylor G, Osinski D, Thevenin A, Devys JM. Is platelet transfusion efficient to restore platelet reactivity in patients who are responders to aspirin and/or clopidogrel before emergency surgery? J Trauma Acute Care Surg 2013; 74: 1367–9.
14. Teng R, Carlson GF, Nylander S, Andersson TL. Effects of autologous platelet transfusion on platelet inhibition in ticagrelor- and clopidogrel-treated subjects. J Thromb Haemost 2016; 12: 2342–52.
15. Godier A, Taylor G, Gaussem P. Inefficacy of platelet transfusion to reverse ticagrelor. N Engl J Med 2015; 372: 196–7.
16. Dalén M, Ivert T, Lindvall G, van der Linden J. Ticagrelor-associated bleeding in a patient undergoing surgery for acute type A aortic dissection. J Cardiothorac Vasc Anesth 2013; 27: e55–7.
17. Martin A-C, Berndt C, Calmette L, Philip I, Decouture B, Gaussem P, Gouin-Thibault I, Samama C-M, Bachelot-Loza C, Godier A. The effectiveness of platelet supplementation for the reversal of ticagrelor-induced inhibition of platelet aggregation: an in vitro study. Eur J Anaesthesiol 2015; 32: 1–7.
18. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, de Gans K, Koopman MM, Brand A, Majoie CB, Beenen LF, Marquering HA, Vermeulen M, Nederkoorn PJ, de Haan RJ, Roos YB; PATCH Investigators. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet 2016; 387: 2605–13.
19. Buchanan A, Newton P, Pehrsson S, Inghardt T, Antonsson T, Svensson P, Sjögren T, Öster L, Janefeldt A, Sandinge AS, Keyes F, Austin M, Spooner J, Gennemark P, Penney M, Howells G, Vaughan T, Nylander S. Structural and functional characterization of a specific antidote for ticagrelor. Blood 2015; 125: 3484–90.
20. Almquist J, Penney M, Pehrsson S, Sandinge AS, Janefeldt A, Maqbool S, Madalli S, Goodman J, Nylander S, Gennemark P. Unraveling the pharmacokinetic interaction of ticagrelor and MEDI2452 (Ticagrelor antidote) by mathematical modeling. CPT Pharmacometrics Syst Pharmacol 2016; 5: 313–23.
21. ™ platform to ligand-binding assays: a user's perspective. Bioanalysis 2010; 2: 1711–5.
22. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with severe renal impairment. J Clin Pharmacol 2012; 52: 1388–98.
23. Teng R, Oliver S, Hayes MA, Butler K. Absorption, distribution, metabolism and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 2010; 38: 1514–21.