Journal of Thrombosis and Thrombolysis

, Volume 35, Issue 2, pp 155–164 | Cite as

Effects of cangrelor in coronary artery disease patients with and without diabetes mellitus: an in vitro pharmacodynamic investigation

  • José L. Ferreiro
  • Masafumi Ueno
  • Antonio Tello-Montoliu
  • Salvatore D. Tomasello
  • Davide Capodanno
  • Piera Capranzano
  • Kodlipet Dharmashankar
  • Andrew Darlington
  • Bhaloo Desai
  • Fabiana Rollini
  • Luis A. Guzman
  • Theodore A. Bass
  • Dominick J. Angiolillo


Platelets from patients with diabetes mellitus (DM) are hyper-reactive and whether cangrelor, a potent intravenous P2Y12 receptor blocker, has differential pharmacodynamic (PD) effects according DM status is unknown. The aim of this investigation was to evaluate the in vitro PD effects of cangrelor in coronary artery disease (CAD) patients with and without DM. This prospective study enrolled 120 clopidogrel-naïve patients with CAD on aspirin therapy. PD assessments using cangrelor (500 nmol/l) in vitro included vasodilator-stimulated phosphoprotein assay to obtain the P2Y12 reactivity index (PRI), and multiple electrode aggregometry (MEA). In a 20 patients subgroup, dose-dependent response was assessed following exposure to escalating concentrations (baseline, 5, 50, 500 and 5,000 nmol/l); thrombin generation processes were evaluated by thromboelastography (TEG). PD data were evaluable in 103 patients. No differences in baseline PD parameters were observed in DM (n = 48) and non-DM (n = 45) subjects. Cangrelor reduced PRI values irrespective of DM status (p < 0.0001), yielding no difference in patients with and without DM (16.1 ± 12.3 vs. 16.8 ± 11.3; p = 0.346). All MEA values were significantly reduced, although this was of greater magnitude with purinergic compared to non-purinergic agonists. A trend analysis showed a dose-dependent effect on platelet inhibition, with no interaction due to DM status, whereas no significant dose-dependent effect was observed for TEG-derived parameters. Therefore, in vitro cangrelor provides potent and dose-dependent blockade of the platelet P2Y12 receptor, with no differential effect in DM and non-DM patients. In addition, in vitro cangrelor exerts moderate inhibitory effects on non-purinergic platelet signaling pathways, without modulating platelet-derived thrombin generation processes.


Cangrelor Diabetes mellitus Platelet inhibition P2Y12 receptor Antiplatelet agents 



Dominick J. Angiolillo (corresponding author) reports receiving: honoraria for lectures from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly Co; Daiichi Sankyo, Inc; Astra Zeneca; consulting fees from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly Co; Daiichi Sankyo, Inc.; The Medicines Company; Portola; Novartis; Medicure; Accumetrics; Arena Pharmaceuticals; Astra Zeneca; Merck; Evolva; Abbott Vascular; research grants from Bristol Myers Squibb; Sanofi-Aventis; GlaxoSmithKline; Otsuka; Eli Lilly Co; Daiichi Sankyo, Inc., The Medicines Company; Portola; Accumetrics; Schering-Plough; Astra-Zeneca; Eisai. José Luis Ferreiro reports honoraria for lectures from Eli Lilly Co; Daiichi Sankyo, Inc.; Astra Zeneca. Davide Capodanno reports honoraria for lectures from Eli Lilly Co; Daiichi Sankyo, Inc.; AstraZeneca; consulting fees from Eli Lilly Co; Daiichi Sankyo. Luis A. Guzman reports honoraria for lectures from AstraZeneca. This investigator-initiated study was funded by Institutional funding with no external financial support. The Medicines Company provided cangrelor for in vitro investigational use.

Conflict of Interest

None of the other authors have conflict of interest to report.


  1. 1.
    Geisler T, Anders N, Paterok M et al (2007) Platelet response to clopidogrel is attenuated in diabetic patients undergoing coronary stent implantation. Diabetes Care 30:372–374PubMedCrossRefGoogle Scholar
  2. 2.
    Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al (2005) Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 54:2430–2435PubMedCrossRefGoogle Scholar
  3. 3.
    Serebruany V, Pokov I, Kuliczkowski W, Chesebro J, Badimon J (2008) Baseline platelet activity and response after clopidogrel in 257 diabetics among 822 patients with coronary artery disease. Thromb Haemost 100:76–82PubMedGoogle Scholar
  4. 4.
    Lüscher TF, Creager MA, Beckman JA, Cosentino F (2003) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II. Circulation 108:1655–1661PubMedCrossRefGoogle Scholar
  5. 5.
    Ferreiro JL, Angiolillo DJ (2011) Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation 123:798–813PubMedCrossRefGoogle Scholar
  6. 6.
    Ferreiro JL, Cequier ÁR, Angiolillo DJ (2010) Antithrombotic therapy in patients with diabetes mellitus and coronary artery disease. Diab Vasc Dis Res 7:274–288PubMedCrossRefGoogle Scholar
  7. 7.
    Ueno M, Ferreiro JL, Tomasello SD et al (2011) Functional profile of the platelet P2Y12 receptor signalling pathway in patients with type 2 diabetes mellitus and coronary artery disease. Thromb Haemost 105:730–732PubMedCrossRefGoogle Scholar
  8. 8.
    Gurbel PA, Bliden KP, Guyer K, Aggarwal N, Tantry US (2007) Delayed thrombin-induced platelet-fibrin clot generation by clopidogrel: a new dose-related effect demonstrated by thrombelastography in patients undergoing coronary artery stenting. Thromb Res 119:563–570PubMedCrossRefGoogle Scholar
  9. 9.
    Leon C, Ravanat C, Freund M, Cazenave JP, Gachet C (2003) Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity. Arterioscler Thromb Vasc Biol 23:1941–1947PubMedCrossRefGoogle Scholar
  10. 10.
    van der Meijden PE, Feijge MA, Giesen PL, Huijberts M, van Raak LP, Heemskerk JW (2005) Platelet P2Y12 receptors enhance signalling towards procoagulant activity and thrombin generation. A study with healthy subjects and patients at thrombotic risk. Thromb Haemost 93:1128–1136PubMedGoogle Scholar
  11. 11.
    Angiolillo DJ, Capranzano P, Desai B et al (2009) Impact of P2Y(12) inhibitory effects induced by clopidogrel on platelet procoagulant activity in type 2 diabetes mellitus patients. Thromb Res 124:318–322PubMedCrossRefGoogle Scholar
  12. 12.
    Ferreiro JL, Ueno M, Angiolillo DJ (2009) Cangrelor: a review on its mechanism of action and clinical development. Expert Rev Cardiovasc Ther 7:1195–1201PubMedCrossRefGoogle Scholar
  13. 13.
    Storey RF, Oldroyd KG, Wilcox RG (2001) Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes. Thromb Haemost 85:401–407PubMedGoogle Scholar
  14. 14.
    Storey RF, Wilcox RG, Heptinstall S (2002) Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets 13:407–413PubMedCrossRefGoogle Scholar
  15. 15.
    Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553PubMedCrossRefGoogle Scholar
  16. 16.
    Harrington RA, Stone GW, McNulty S et al (2009) Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 361:2318–2329PubMedCrossRefGoogle Scholar
  17. 17.
    Bhatt DL, Lincoff AM, Gibson CM, CHAMPION PLATFORM Investigators et al (2009) Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 361:2330–2341PubMedCrossRefGoogle Scholar
  18. 18.
    Bouman HJ, van Werkum JW, Hackeng CM, Clappers N, Ten Berg JM (2009) Cangrelor increases the magnitude of platelet inhibition and reduces interindividual variability in clopidogrel-pretreated subjects. Neth Heart J 17:195–198PubMedCrossRefGoogle Scholar
  19. 19.
    Aleil B, Ravanat C, Cazenave JP, Rochoux G, Heitz A, Gachet C (2005) Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost 3:85–92PubMedCrossRefGoogle Scholar
  20. 20.
    Angiolillo DJ, Shoemaker SB, Desai B et al (2007) Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the optimizing antiplatelet therapy in diabetes mellitus (OPTIMUS) study. Circulation 115:708–716PubMedCrossRefGoogle Scholar
  21. 21.
    Sibbing D, Braun S, Jawansky S et al (2008) Assessment of ADP-induced platelet aggregation with light transmission aggregometry and multiple electrode platelet aggregometry before and after clopidogrel treatment. Thromb Haemost 99:121–126PubMedGoogle Scholar
  22. 22.
    Ueno M, Ferreiro JL, Tomasello SD et al (2011) Impact of pentoxifylline on platelet function profiles in patients with type 2 diabetes mellitus and coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel. JACC Cardiovasc Interv 4:905–912PubMedCrossRefGoogle Scholar
  23. 23.
    Rivard GE, Brummel-Ziedins KE, Mann KG, Fan L, Hofer A, Cohen E (2005) Evaluation of the profile of thrombin generation during the process of whole blood clotting as assessed by thrombelastography. J Thromb Haemost 3:2039–2043PubMedCrossRefGoogle Scholar
  24. 24.
    Ferreiro JL, Angiolillo DJ (2012) New directions in antiplatelet therapy. Circ Cardiovasc Interv 5:433–445PubMedCrossRefGoogle Scholar
  25. 25.
    James S, Angiolillo DJ, Cornel JH, PLATO Study Group et al (2010) Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient outcomes (PLATO) trial. Eur Heart J 31:3006–3016PubMedCrossRefGoogle Scholar
  26. 26.
    Wiviott SD, Braunwald E, Angiolillo DJ, TRITON-TIMI 38 Investigators et al (2008) Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation 118:1626–1636PubMedCrossRefGoogle Scholar
  27. 27.
    Angiolillo DJ, Badimon JJ, Saucedo JF et al (2011) A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the optimizing anti-platelet therapy in diabetes mellitus (OPTIMUS)-3 trial. Eur Heart J 32:838–846PubMedCrossRefGoogle Scholar
  28. 28.
    Storey RF, Sanderson HM, White AE, May JA, Cameron KE, Heptinstall S (2000) The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol 110:925–934PubMedCrossRefGoogle Scholar
  29. 29.
    Holinstat M, Voss B, Bilodeau ML, McLaughlin JN, Cleator J, Hamm HE (2006) PAR4, but not PAR1, signals human platelet aggregation via Ca2 + mobilization and synergistic P2Y12 receptor activation. J Biol Chem 281:26665–26674PubMedCrossRefGoogle Scholar
  30. 30.
    Srinivasan S, Mir F, Huang JS, Khasawneh FT, Lam SC, Le Breton GC (2009) The P2Y12 antagonists, 2-methylthioadenosine 5′-monophosphate triethylammonium salt and cangrelor (ARC69931MX), can inhibit human platelet aggregation through a Gi-independent increase in cAMP levels. J Biol Chem 284:16108–16117PubMedCrossRefGoogle Scholar
  31. 31.
    Kirkby NS, Leadbeater PD, Chan MV, Nylander S, Mitchell JA, Warner TD (2011) Antiplatelet effects of aspirin vary with level of P2Y12 receptor blockade supplied by either ticagrelor or prasugrel. J Thromb Haemost 9:2103–2105PubMedCrossRefGoogle Scholar
  32. 32.
    Armstrong PC, Leadbeater PD, Chan MV et al (2011) In the presence of strong P2Y12 receptor blockade, aspirin provides little additional inhibition of platelet aggregation. J Thromb Haemost 9:552–561PubMedCrossRefGoogle Scholar
  33. 33.
    Angiolillo DJ, Capranzano P, Ferreiro JL et al (2011) Impact of adjunctive cilostazol therapy on platelet function profiles in patients with and without diabetes mellitus on aspirin and clopidogrel therapy. Thromb Haemost 106:253–262PubMedCrossRefGoogle Scholar
  34. 34.
    Hayashi H, Sudo T (2009) Effects of the cAMP-elevating agents cilostamide, cilostazol and forskolin on the phosphorylation of Akt and GSK-3beta in platelets. Thromb Haemost 102:327–335PubMedGoogle Scholar
  35. 35.
    Gachet C, Léon C, Hechler B (2006) The platelet P2 receptors in arterial thrombosis. Blood Cells Mol Dis 36:223–227PubMedCrossRefGoogle Scholar
  36. 36.
    White H, Chew DP, Dauerman HL et al (2012) Reduced immediate ischemic events with cangrelor in PCI: a pooled analysis of the CHAMPION trials using the universal definition of myocardial infarction. Am Heart J 163:182–190PubMedCrossRefGoogle Scholar
  37. 37.
    Angiolillo DJ, Firstenberg MS, Price MJ et al (2012) Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA 307:265–274PubMedCrossRefGoogle Scholar
  38. 38.
    Angiolillo DJ, Schneider DJ, Bhatt DL et al (2012) Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis 34:44–55PubMedCrossRefGoogle Scholar
  39. 39.
    Leonardi S, Mahaffey KW, White HD et al (2012) Rationale and design of the Cangrelor versus standard therapy to acHieve optimal Management of Platelet InhibitiON PHOENIX trial. Am Heart J 163(768–776):e2PubMedGoogle Scholar
  40. 40.
    Roberts HR, Hoffman M, Monroe DM (2006) A cell-based model of thrombin generation. Semin Thromb Hemost 32(Suppl 1):32–38PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • José L. Ferreiro
    • 1
    • 2
  • Masafumi Ueno
    • 1
  • Antonio Tello-Montoliu
    • 1
  • Salvatore D. Tomasello
    • 1
  • Davide Capodanno
    • 1
  • Piera Capranzano
    • 1
  • Kodlipet Dharmashankar
    • 1
  • Andrew Darlington
    • 1
  • Bhaloo Desai
    • 1
  • Fabiana Rollini
    • 1
  • Luis A. Guzman
    • 1
  • Theodore A. Bass
    • 1
  • Dominick J. Angiolillo
    • 1
  1. 1.University of Florida College of Medicine-JacksonvilleJacksonvilleUSA
  2. 2.Heart Diseases Institute, Hospital Universitari de Bellvitge-IDIBELLUniversity of BarcelonaBarcelonaSpain

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