Cangrelor: A novel P2Y12 receptor antagonist

Expert Opinion on Investigational Drugs

Volumn 18, Issue 8, 2009, Pages 1219-1230

  Norgard, Nicholas B ^a  

^a UNIVERSITY AT BUFFALO   (United States)

Author keywords

Antiplatelet; AR C69931MX; Cangrelor; P2Y12 inhibitor

Indexed keywords

ABCIXIMAB; ACETYLSALICYLIC ACID; CANGRELOR; CLOPIDOGREL; FIBRINOGEN RECEPTOR ANTAGONIST; PLACEBO; PRASUGREL; PURINERGIC P2Y12 RECEPTOR; PURINERGIC RECEPTOR BLOCKING AGENT; TICAGRELOR; TICLOPIDINE; TISSUE PLASMINOGEN ACTIVATOR; ADENOSINE PHOSPHATE; ANTITHROMBOCYTIC AGENT; DRUG DERIVATIVE; PURINERGIC P2 RECEPTOR;

ACUTE CORONARY SYNDROME; ANGINA PECTORIS; BLEEDING; CONTINUOUS INFUSION; DRUG CLEARANCE; DRUG HALF LIFE; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG TOLERABILITY; HEART INFARCTION; HUMAN; INJECTION SITE BLEEDING; LOADING DRUG DOSE; PERCUTANEOUS CORONARY INTERVENTION; REVIEW; STENT THROMBOSIS; THROMBOCYTE AGGREGATION INHIBITION; THROMBOCYTE FUNCTION; THROMBOCYTOPENIA; THROMBOSIS; UNSTABLE ANGINA PECTORIS; ANIMAL; BLOOD; CHEMICAL STRUCTURE; CLINICAL TRIAL; CORONARY ARTERY THROMBOSIS; DRUG ANTAGONISM; DRUG SCREENING; METABOLISM;

ACUTE CORONARY SYNDROME; ADENOSINE MONOPHOSPHATE; ANIMALS; CLINICAL TRIALS AS TOPIC; CORONARY THROMBOSIS; DRUG EVALUATION, PRECLINICAL; HUMANS; MOLECULAR STRUCTURE; PLATELET AGGREGATION INHIBITORS; RECEPTORS, PURINERGIC P2;

EID: 68049138035     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543780903136708     Document Type: Review

References (76)

1. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357(24):2482-94
2. King SB 3rd, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol 2008;51(2):172-209
3. Collaborative overview of randomised trials of antiplatelet therapy - I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ 1994;308(6921):81-106
4. Frelinger AL 3rd, Furman MI, Linden MD, et al. Residual arachidonic acid-induced platelet activation via an adenosine diphosphate-dependent but cyclooxygenase-1- and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance. Circulation 2006;113(25):2888-96
5. Ohmori T, Yatomi Y, Nonaka T, et al. Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity: involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients. J Thromb Haemost 2006;4(6):1271-8
6. Brener SJ. The benefits of platelet glycoprotein IIb/IIIa receptor inhibition during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: drug-specific or class effect? J Am Coll Cardiol 2009;53(18):1674-6
7. Madan M, Blankenship JC, Berkowitz SD. Bleeding complications with platelet glycoprotein IIb/IIIa receptor antagonists. Curr Opin Hematol 1999;6(5):334-41
8. Stone GW, Moliterno DJ, Bertrand M, et al. Impact of clinical syndrome acuity on the differential response to 2 glycoprotein IIb/IIIa inhibitors in patients undergoing coronary stenting: the TARGET Trial. Circulation 2002;105(20):2347-54
9. Savi P, Herbert JM. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost 2005;31(2):174-83
10. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345(7):494-502
11. Norgard NB, Abu-Fadel M. Future prospects in antiplatelet therapy: a review of potential P2Y12 and thrombin receptor antagonists. Recent patents Cardiovasc Drug Discov 2008;3(3):194-200
12. Purkayastha S, Athanasiou T, Malinovski V, et al. Does clopidogrel affect outcome after coronary artery bypass grafting? A meta-analysis. Heart 2006;92(4):531-2
13. Ascione R, Ghosh A, Rogers CA, et al. In-hospital patients exposed to clopidogrel before coronary artery bypass graft surgery: a word of caution. Ann Thorac Surg 2005;79(4):1210-6
14. Chu MW, Wilson SR, Novick RJ, et al. Does clopidogrel increase blood loss following coronary artery bypass surgery? Ann Thorac Surg 2004;78(5):1536-41
15. Leong JY, Baker RA, Shah PJ, et al. Clopidogrel and bleeding after coronary artery bypass graft surgery. Ann Thorac Surg 2005;80(3):928-33
16. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107(23):2908-13
17. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109(25):3171-5
18. Hagihara K, Nishiya Y, Kurihara A, et al. Comparison of human cytochrome p450 inhibition by the thienopyridines prasugrel, clopidogrel, and ticlopidine. Drug Metab Pharmacokinet 2008;23(6):412-20
19. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-62
20. Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004;109(2):166-71
21. Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006;108:2244-7
22. von Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 2005;112(19):2946-50
23. Niitsu Y, Jakubowski JA, Sugidachi A, Asai F. Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb Hemost 2005;31(2):184-94
24. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357(20):2001-15
25. Lieu HD, Conley PB, Andre P, et al. Initial intravenous experience with PRT060128 (PRT128), an orally-available, direct-acting, and reversible P2Y12 inhibitor [abstract]. J Thromb Haemost 2007;5(Suppl 2):P-T-292
26. 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(19):1844-51
27. Humphries RG. Pharmacology of AR-C69931MX and related compounds: from pharmacological tools to clinical trials. Haematologica 2000;85(Suppl):1-100
28. Gachet C. P2 receptors, platelet function and pharmacological implications. Thromb Haemost 2008;99(3):466-72
29. Gachet C. Identification, characterization, and inhibition of the platelet ADP receptors. Int J Hematol 2001;74(4):375-81
30. Gachet C. ADP receptors of platelets and their inhibition. Thromb Haemost 2001;86(1):222-32
31. Leon C, Freund M, Ravanat C, et al. Key role of the P2Y(1) receptor in tissue factor-induced thrombin-dependent acute thromboembolism: studies in P2Y(1)-knockout mice and mice treated with a P2Y(1) antagonist. Circulation 2001;103(5):718-23
32. Leon C, Ravanat C, Freund M, et al. Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity. Arterioscler Thromb Vasc Biol 2003;23(10):1941-7
33. Rolf MG, Brearley CA, Mahaut-Smith MP. Platelet shape change evoked by selective activation of P2X1 purinoceptors with alpha,beta-methylene ATP. Thromb Haemost 2001;85(2):303-8
34. Macfarlane DE, Mills DC. The effects of ATP on platelets: evidence against the central role of released ADP in primary aggregation. Blood 1975;46(3):309-20
35. Mustard JF, Packham MA. Factors influencing platelet function: adhesion, release, and aggregation. Pharmacol Rev 1970;22(2):97-187
36. Gordon JL. Extracellular ATP: effects, sources and fate. Biochem J 1986;233(2):309-19
37. Ingall AH, Dixon J, Bailey A, et al. Antagonists of the platelet P-2T receptor: a novel approach to antithrombotic therapy. J Med Chem 1999;213-20
38. van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost 2005;31(2):195-204
39. Storey R, Judge HM, Wilcox R, Heptinstall S. Inhibition of ADP-induced P-selectin expression and platelet-leukocyte conjugate formation by clopidogrel and the P2Y12 receptor antagonist AR-C69931MX but not aspirin. Thromb Haemost 2002;88(3):488-94
40. Storey RF, Sanderson HM, White AE, et al. The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol 2000;110(4):925-34
41. Norgard NB, Hann CL, Dale GL. Cangrelor attenuates coated-platelet formation. Clin Appl Thromb Hemost 2008;15(2):177-82
42. Huang J, Driscoll EM, Gonzales ML, et al. Prevention of arterial thrombosis by intravenously administered platelet P2T receptor antagonist AR-C69931MX in a canine model. J Pharmacol Exp Ther 2000;295(2):492-9
43. van Gestel MA, Heemskerk JW, Slaaf DW, et al. In vivo blockade of platelet ADP receptor P2Y12 reduces embolus and thrombus formation but not thrombus stability. Arterioscler Thromb Vasc Biol 2003;23(3):518-23
44. Wang K, Zhou X, Zhou Z, et al. Blockade of the platelet P2Y12 receptor by AR-C69931MX sustains coronary artery recanalization and improves the myocardial tissue perfusion in a canine thrombosis model. Arterioscler Thromb Vasc Biol 2003;23(2):357-62
45. Nassim MASJ, Clarke C, et al. Investigation of the novel P2T receptor antagonist AR-C69931MX on ex vivo adenosine diphosphate-induced platelet aggregation and bleeding time in healthy volunteers [abstract]. J Am Coll Cardiol 1999;33(Suppl 2A):255A
46. Storey RF, Wilcox RG, Heptinstall S. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets 2002;407-13 • This study showed that substantially greater P2Y12 receptor blockade can be achieved with cangrelor compared to clopidogrel administration.
47. Jacobsson F, Swahn E, Wallentin L, Dellborg M. Safety profile and tolerability of intravenous AR-C69931MX, a new antiplatelet drug, in unstable angina pectoris and non-Q-wave myocardial infarction. Clin Ther 2002;752-65 • As adjunctive therapy to aspirin and low-molecular-weight heparin in patients with non-ST elevated ACS, intravenous cangrelor was well tolerated, with no difference in the incidence of serious adverse events compared with placebo.
48. Storey RF, Oldroyd KG, Wilcox RG. Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes. Thromb Haemost 2001;85(3):401-7 • In this study, cangrelor displayed rapid platelet inhibition and was shown to be safe as adjunctive therapy to aspirin and heparin in patients with ACS.
49. Greenbaum AB, Ohman EM, Gibson CM, et al. Preliminary experience with intravenous P2Y12 platelet receptor inhibition as an adjunct to reduced-dose alteplase during acute myocardial infarction: results of the Safety, Tolerability and Effect on Patency in Acute Myocardial Infarction (STEP-AMI) angiographic trial. Am Heart J 2007;154(4):702-9 •• This first experience with the intravenous P2Y12 receptor inhibitor, cangrelor, suggests the potential of this compound as an adjunct to fibrinolysis during treatment of AMI.
50. Greenbaum AB, Grines CL, Bittl JA, et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J 2006;151(3):689.e1-e10 •• This initial experience with intravenous cangrelor during PCI suggests an acceptable risk of bleeding and adverse cardiac events while achieving rapid, reversible inhibition of platelet aggregation through competitive binding to the ADP P2Y12 platelet receptor with less prolongation of bleeding time than the glycoprotein IIb/IIIa receptor antagonist abciximab.
51. Steinhubl SR, Oh JJ, Oestreich JH, et al. Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thrombosis Res 2008;121(4):527-34 •• This study recognized a drug interaction between clopidogrel and cangrelor. To achieve sustained platelet P2Y12 inhibition in patients treated with cangrelor, clopidogrel administration should be started when the cangrelor infusion is terminated.
52. The Medicines Company Discontinues Phase 3 CHAMPION Clinical Trial Program of Cangrelor. The Medicines Company: Press Release. Available from: http://ir.themedicinescompany.com/phoenix.zhtml?c=122204&p= irol-newsArticle&ID=1287788&highlight= [Last accessed 14 May 2009]
53. A Clinical Trial to demonstrate the efficacy of Cangrelor. U.S. National Institute of Health, 2009. Available from: http://clinicaltrials.gov/ct2/show/ NCT00305162?term=cangrelor&rank=4 [Last accessed 9 May 2009]
54. Cangrelor versus standard therapy to achieve optimal management of platelet inhibition. U.S. National Institute of Health, 2009. Available from: http://clinicaltrials.gov/ct2/show/NCT00385138?term=cangrelor&rank=3 [Last accessed 9 May 2009]
55. Maintenance of platelet inhibition with Cangrelor (Bridge). U.S. National Institute of Health, 2009. Available from: http://clinicaltrials.gov/ct2/show/ NCT00767507?term=cangrelor&rank=5 [Last assessed 17 June 2009]
56. Kereiakes DJ, Gurbel PA. Peri-procedural platelet function and platelet inhibition in percutaneous coronary intervention. JACC Interv 2008;1(2):111-21
57. Jarvis GE, Nassim MA, Humphries RG, et al. The P-2t antagonist AR-C69931MX is a more effective inhibitor of ADP-induced platelet aggregation than clopidogrel. Blood 1999;94(10):22A
58. Wilson SH, Fasseas P, Orford JL, et al. Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting. J Am Coll Cardiol 2003;42(2):234-40
59. Vicenzi MN, Meislitzer T, Heitzinger B, et al. Coronary artery stenting and non-cardiac surgery - a prospective outcome study. Br J Anaesth 2006;96(6):686-93
60. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364(9444):1519-21
61. Nasser M, Kapeliovich M, Markiewicz W. Late thrombosis of sirolimus-eluting stents following noncardiac surgery. Catheter Cardiovasc Interv 2005;65(4):516-9
62. Compton PA, Zankar AA, Adesanya AO, et al. Risk of noncardiac surgery after coronary drug-eluting stent implantation. Am J Cardiol 2006;98(9):1212-3
63. Fleron MH, Dupuis M, Mottet P, et al. Non cardiac surgery in patient with coronary stenting: think sirolimus now!. Ann Fr Anesth Reanim 2003;22(8):733-5
64. Collet JP, Montalescot G, Blanchet B, et al. Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 2004;110(16):2361-7
65. Ferrari E, Benhamou M, Cerboni P, Marcel B. Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 2005;45(3):456-9
66. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293(17):2126-30
67. Kaluza GL, Joseph J, Lee JR, et al. Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol 2000;35(5):1288-94
68. Wilson SH, Rihal CS, Bell MR, et al. Timing of coronary stent thrombosis in patients treated with ticlopidine and aspirin. Am J Cardiol 1999;83(7):1006-11
69. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation 2001;103(15):1967-71
70. Schouten O, Bax JJ, Poldermans D. Management of patients with cardiac stents undergoing noncardiac surgery. Curr Opin Anaesthesiol 2007;20(3):274-8
71. Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006;114(8):774-82
72. Lincoff AM, LeNarz LA, Despotis GJ, et al. Abciximab and bleeding during coronary surgery: results from the EPILOG and EPISTENT trials. Improve Long-term Outcome with abciximab GP IIb/IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibition in STENTing. Ann Thorac Surg 2000;70(2):516-26
73. Gammie JS, Zenati M, Kormos RL, et al. Abciximab and excessive bleeding in patients undergoing emergency cardiac operations. Ann Thorac Surg 1998;65(2):465-9
74. Bizzarri F, Scolletta S, Tucci E, et al. Perioperative use of tirofiban hydrochloride (Aggrastat) does not increase surgical bleeding after emergency or urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg 2001;122(6):1181-5
75. Dyke CM, Bhatia D, Lorenz TJ, et al. Immediate coronary artery bypass surgery after platelet inhibition with eptifibatide: results from PURSUIT. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrelin Therapy. Ann Thorac Surg 2000;70(3):866-71; discussion 71-2
76. Broad L, Lee T, Conroy M, et al. Successful management of patients with a drug-eluting coronary stent presenting for elective, non-cardiac surgery. Br J Anaesth 2007;98(1):19-22