Efficacy and safety of ticagrelor: A reversible P2Y12 receptor antagonist

Annals of Pharmacotherapy

Volumn 44, Issue 3, 2010, Pages 524-537

  Anderson, Shawn D ^a,b   Shah, Niren K ^c   Yim, Juwon ^c   Epstein, Benjamin J ^b  

^a DEPARTMENT OF VETERANS AFFAIRS   (United States)

^b UNIVERSITY OF FLORIDA   (United States)

^c UNIVERSITY OF FLORIDA HEALTH   (United States)

Author keywords

ACS; Atherothrombosis; AZD6140; Cardiovascular disease; P2Y12 receptor antagonist; Platelets; Ticagrelor

Indexed keywords

CLOPIDOGREL; PRASUGREL; PURINERGIC P2Y12 RECEPTOR; PURINERGIC RECEPTOR BLOCKING AGENT; TICAGRELOR;

ACUTE CORONARY SYNDROME; BLEEDING; BRAIN HEMORRHAGE; CARDIOVASCULAR RISK; CAUSE OF DEATH; CLINICAL TRIAL; CONTROLLED STUDY; DIARRHEA; DIZZINESS; DRUG EFFICACY; DRUG ERUPTION; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSPEPSIA; DYSPNEA; ELECTROCARDIOGRAPHY MONITORING; EMBASE; FATALITY; FIBRINOLYTIC THERAPY; HEADACHE; HEART ARRHYTHMIA; HEART INFARCTION; HEART VENTRICLE TACHYCARDIA; HOLTER MONITORING; HUMAN; HYPOTENSION; INFORMATION RETRIEVAL; INSOMNIA; LABORATORY TEST; LOADING DRUG DOSE; MAINTENANCE DRUG DOSE; MEDLINE; NAUSEA; NONHUMAN; PRIORITY JOURNAL; PROPHYLAXIS; REVIEW; RISK REDUCTION; STENT THROMBOSIS; STROKE; SYNCOPE; THORAX PAIN; THROMBOCYTE ACTIVATION; THROMBOCYTE AGGREGATION INHIBITION;

ACUTE CORONARY SYNDROME; ADENOSINE; ANIMALS; CARDIOVASCULAR DISEASES; HUMANS; PLATELET AGGREGATION INHIBITORS; RECEPTORS, PURINERGIC P2; TICLOPIDINE;

EID: 77749345735     PISSN: 10600280     EISSN: None     Source Type: Journal    
DOI: 10.1345/aph.1M548     Document Type: Review

References (48)

1. Jennings LK. Role of platelets in atherothrombosis. Am J Cardiol 2009;103(3 suppl):4A-10A. DOI 10.1016/j.amjcard.2008.11.017
2. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008;51:210-47. DOI 10.1016/j.jacc.2007.10.001
3. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 Guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2007;50:e1-e157. DOI 10.1016/j.jacc.2007.02.013
4. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics - 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009;119:e21-e181. DOI 10.1161/CIRCULATIONAHA 108.191261
5. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358:527-33. DOI 10.1016/S0140-6736(01)05701-4
6. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1607-21. DOI 10.1016/S0140-6736(05)67660-X
7. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17. DOI 10.1056/NEJMoa060989
8. Jakubowski JA, Payne CD, Li YG, et al. A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry. Thromb Haemost 2008;99:215-22. DOI 10.1160/TH07-09-0555
9. Angiolillo DJ. Variability in responsiveness to oral antiplatelet therapy. Am J Cardiol 2009;103 (3 suppl):27A-34A. DOI 10.1016/j.amjcard.2008.11. 020
10. Lau WC, Gurbel PA. Antiplatelet drug resistance and drug-drug interactions: role of cytochrome P450 3A4. Pharm Res 2006;23:2691-708. DOI 10.1007/s11095-006-9084-4
11. Gibson CM. Antiplatelet therapy: anti-ischemic benefits versus bleeding risk. J Interv Cardiol 2008;21(suppl 1):S3-9. DOI 10.1111/j.1540-8183.2008. 00407.x
12. Ben-Dor I, Kleiman NS, Lev E. Assessment, mechanisms, and clinical implication of variability in platelet response to aspirin and clopidogrel therapy. Am J Cardiol 2009;104:227-33. DOI 10.1016/j.amjcard.2009.03.022
13. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301:937-44. DOI 10.1001/jama.2009.261
14. Ang L, Mahmud E. Monitoring oral antiplatelet therapy: is it justified? Ther Adv Cardiovasc Dis 2008;2:485-96. DOI 10.1177/1753944708094736
15. Geiger J, Brich J, Honig-Liedl P, et al. Specific impairment of human platelet P2Y(AC) ADP receptor mediated signaling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol 1999;19:2007-11.
16. Trumel C, Payrastre B, Plantavid M, et al. A key role of adenosine diphosphate in the irreversible platelet aggregation induced by the PAR1-activating peptide through the late activation of phosphoinositide 3-kinase. Blood 1999;94:4156-65.
17. Wihlborg AK, Wang L, Braun OO, et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol 2004;24:1810-5. DOI 10.1161/01.ATV.0000142376. 30582.ed
18. Bjorkman JA, Kirk I, van Giezen JJ. AZD6140 inhibits adenosine uptake into erythrocytes and enhances coronary blood flow after local ischemia or intracoronary adenosine infusion (abstract 245). Circulation 2007;116: II-28.
19. Van Giezen JJ, Nilsson L, Berntsson P, et al. Ticagrelor binds to the human P2Y(12) receptor independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost 2009;7:1556-65. DOI 10.1111/j.1538-7836.2009.03527.x
20. Springthorpe B, Bailey A, Barton P, et al. From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorg Med Chem Lett 2007;17:6013-8. DOI 10.1016/j.bmcl.2007.07.057
21. van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost 2005;31:195-204. DOI 10.1055/s-2005-869525
22. Storey RF, Husted S, Harrington RA, et al. 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. DOI 10.1016/j.jacc.2007.07.058
23. Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006;27:1038-47. DOI 10.1093/eurheartj/ehi754
24. Husted S, van Giezen JJ. Ticagrelor: the first reversibly binding oral P2Y receptor antagonist. Cardiovasc Ther 2009;27(4):259-74.
25. Peters G, Robbie G. Single-dose pharmacokinetics and pharmacodynamics of AZD6140 - an oral reversible ADP receptor antagonist (abstract). Haematologica 2004;989(suppl 7):14.
26. Peters G, Buter K, Winter HE, et al. Multiple dose pharmacokinetics and pharmacodynamics of the reversible, orally active ADP receptor antagonist AZD6140 (abstract P4556). Eur Heart J 2006;27(suppl 1):758.
27. Butler K, Mitchell PD, Teng R. No significant food effect on the pharmacokinetics of AZD6140, the first reversible oral P2Y12 receptor antagonist, in healthy subjects (abstract P1-39). Clin Pharmacol Ther 2009;85:S9-36. DOI 10.1038/sj.clpt.2008.283
28. Cannon CP, Husted S, Harrington RA, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 2007;50:1844-51. DOI 10.1016/j.jacc.2007.07.053
29. James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J 2009;157:599-605. DOI 10.1016/j.ahj.2009.01.003
30. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361. DOI 10.1056/NEJMoa0904327
31. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2005;111:2099-106. DOI 10.1161/01.CIR.0000161383.06692.D4
32. Bhatt DL. Intensifying platelet inhibition-navigating between Scylla and Charybdis. N Engl J Med 2007;357:2078-81. DOI 10.1056/NEJMe0706859
33. Serebruany VL, Stebbing J, Atar D. Dyspnoea after antiplatelet agents: the AZD6140 controversy. Int J Clin Pract 2007;61:529-33. DOI 10.1111/j.1742-1241.2007.01294.x
34. Reynolds SM, Docherty R, Robbins J, Spina D, Page CP. Adenosine induces a cholinergic tracheal reflex contraction in guinea pigs in vivo via an adenosine A1 receptor - dependent mechanism. J Appl Physiol 2008; 105:187-96. DOI. 10.1152/japplphysiol.01048.2007
35. Jacobson KA, Gao ZG. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 2006;5:247-64. DOI 10.1038/nrd1983
36. Picard-Fraire C. Ticlopidine hydrochloride: relationship between dose, kinetics, plasma concentration and effect on platelet function. Thromb Res Suppl 1983;4:119-28.
37. Kurihara A, Hagihara K, Kazui M, Ozeki T, Farid NA, Ikeda T. In vitro metabolism of antiplatelet agent clopidogrel: cytochrome P450 isoforms responsible for two oxidation steps involved in the active metabolite formation. Drug Metab Rev 2005;37(suppl 2):99.
38. Rehmel JL, Eckstein JA, Farid NA, et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos 2006;34:600-7. DOI 10.1124/dmd.105.007989
39. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-62. DOI 10.1056/NEJMoa0809171
40. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360:363-75. DOI 10.1056/NEJMoa0808227
41. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009;119: 2553-60. DOI10.1161/CIRCULATIONAHA.109.851949
42. von Beckerath N, Taubert D, Pogatsa-Murray G, Schömig E, Kastrati A, Schömig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISARCHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 2005;112:2946-50. DOI 10.1161/CIRCULATIONAHA.105.559088
43. Douketis JD, Berger PB, Dunn AS, et al; American College of Chest Physicians. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133 (6 suppl):299S-339S. DOI 10.1378/chest.08-0675
44. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15. DOI 10.1056/NEJMoa0706482
45. van Giezen JJ, Berntsson P, Zachrisson H, Björkman JA. Comparison of ticagrelor and thienopyridine P2Y(12) binding characteristics and antithrombotic and bleeding effects in rat and dog models of thrombosis/hemostasis. Thromb Res 2009;124(5):565-71. DOI 10.1016/j.thromres. 2009.06.029
46. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in unstable angina to prevent recurrent events trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
47. Shryock JC, Belardinelli L. Adenosine and adenosine receptors in the cardiovascular system: biochemistry, physiology, and pharmacology. Am J Cardiol 1997;79:2-10.
48. Cohen MV, Downey JM. Adenosine: trigger and mediator of cardioprotection. Basic Res Cardiol 2008;103:203-15. DOI 10.1007/s00395-007-0687-7