Thienopyridines in cardiovascular disease: Focus on Clopidogrel resistance
01 August 2006
Accepted after revision 15 January 2007
28 November 2017 (online)
Platelets play an important role in atherothrombotic disease, as well as in the pathogenesis of atherosclerosis and in complications. Antiplatelet therapy with Clopidogrel represents at present an important treatment of coronary artery disease (CAD), especially in and after acute coronary syndromes (ACS), and after coronary interventions when stents are used. Clopidogrel is a potent and specific inhibitor of platelet ADP receptor (P2Y12 receptor) with high antithrombotic activity. Emerging data suggest that a significant percentage of individuals treated with Clopidogrel do not receive the expected therapeutic benefit because of a decreased responsiveness of their platelets, which is caused by several extrinsic and/or intrinsic mechanisms. As long as Clopidogrel is the “gold standard” in combination with aspirin in the treatment of patients undergoing percutaneous coronary intervention and stent implantation, the overall challenge is to develop a fast “point-of-care” assay to detect Clopidogrel resistance early and to enable alternative antithrombotic strategies in non-responders or low-responders. This test should be easily performed (bedside) and reproducible, with a standardized definition of response, which is known to correlate with clinical outcomes. Unfortunately, such a test does not exist at present. As an alternative, new ADP receptor antagonists with better bioavailability and improved pharmacokinetics, e.g. intestinal reabsorption as an active drug or 1:1 conversion into an active metabolite thus reducing individual variations, are in development and have already found their way into clinical use in phase-3 trials. Prasugrel is one of the incoming new drugs with high expectations, but other agents might follow in the near future.
- 1 McNicol A, Israels SJ. Platelets and anti-platelet therapy. J Pharmacol Sci 2003; 93: 381-396.
- 2 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8: 1227-1234.
- 3 Massberg S, Gawaz M, Gruner S. et al. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. J Exp Med 2003; 197: 41-49.
- 4 Arya M, Lopez JA, Romo GM. et al. Glycoprotein Ib-IX-mediated activation of integrin alpha(IIb)beta(3): effects of receptor clustering and von Willebrand factor adhesion. J Thromb Haemost 2003; 1: 1150-1157.
- 5 Gachet C. ADP receptors of platelets and their inhibition. Thromb Haemost 2001; 86: 222-232.
- 6 Nasu-Tada K, Koizumi S, Inoue K. Involvement of beta1 integrin in microglial chemotaxis and proliferation on fibronectin: different regulations by ADP through PKA. Glia 2005; 52: 98-107.
- 7 Reigada D, Lu W, Zhang X. et al. Degradation of extracellular ATP by the retinal pigment epithelium. Am J Physiol Cell Physiol 2005; 289: C617-624.
- 8 Ennion SJ, Powell AD, Seward EP. Identification of the P2Y(12) receptor in nucleotide inhibition of exocytosis from bovine chromaffin cells. Mol Pharmacol 2004; 66: 601-611.
- 9 Hollopeter G, Jantzen HM, Vincent D. et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-207.
- 10 Falker K, Lange D, Presek P. ADP secretion and subsequent P2Y12 receptor signalling play a crucial role in thrombin-induced ERK2 activation in human platelets. Thromb Haemost 2004; 92: 114-123.
- 11 Matsuno H, Tokuda H, Ishisaki A. et al. P2Y12 receptors play a significant role in the development of platelet microaggregation in patients with diabetes. J Clin Endocrinol Metab 2005; 90: 920-927.
- 12 Wang L, Erling P, Bengtsson AA. et al. Transcriptional down-regulation of the platelet ADP receptor P2Y(12) and clusterin in patients with systemic lupus erythematosus. J Thromb Haemost 2004; 2: 1436-1442.
- 13 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Identification of low responders to a 300-mg clopi- dogrel loading dose in patients undergoing coronary stenting. Thromb Res 2005; 115: 101-108.
- 14 Savi P, Herbert JM. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost 2005; 31: 174-183.
- 15 Wiviott SD, Antman EM, Winters KJ. et al. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation 2005; 111: 3366-3373.
- 16 Kauffenstein G, Hechler B, Cazenave JP. et al. Adenine triphosphate nucleotides are antagonists at the P2Y receptor. J Thromb Haemost 2004; 2: 1980-1988.
- 17 Claes P, Van Kolen K, Roymans D. et al. Reactive blue 2 inhibition of cyclic AMP-dependent differentiation of rat C6 glioma cells by purinergic receptor-independent inactivation of phosphatidylinositol 3-kinase. Biochem Pharmacol 2004; 67: 1489-1498.
- 18 Vasiljev KS, Uri A, Laitinen JT. 2-Alkylthio-substituted platelet P2Y12 receptor antagonists reveal pharmacological identity between the rat brain Gi-linked ADP receptors and P2Y12 . Neuropharmacology 2003; 45: 145-154.
- 19 Van Kolen K, Slegers H. P2Y12 receptor stimulation inhibits beta-adrenergic receptor-induced differentiation by reversing the cyclic AMP-dependent inhibition of protein kinase B. J Neurochem 2004; 89: 442-453.
- 20 Defreyn G, Bernat A, Delebassee D. et al. Pharmacology of ticlopidine: a review. Semin Thromb Hemost 1989; 15: 159-166.
- 21 Arrebola MM, De la Cruz JP, Villalobos MA. et al. In vitro effects of clopidogrel on the platelet-subendothelium interaction, platelet thromboxane and endothelial prostacyclin production, and nitric oxide synthesis. J Cardiovasc Pharmacol 2004; 43: 74-82.
- 22 Hayakawa M, Kuzuya F. Effects of ticlopidine on erythrocyte aggregation in thrombotic disorders. Angiology 1991; 42: 747-753.
- 23 Mazoyer E, Ripoll L, Boisseau MR. et al. How does ticlopidine treatment lower plasma fibrinogen?. Thromb Res 1994; 75: 361-370.
- 24 Hermann A, Rauch BH, Braun M. et al. Platelet CD40 ligand (CD40L)--subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets 2001; 12: 74-82.
- 25 Klinkhardt U, Bauersachs R, Adams J. et al. Clopidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with atherosclerotic vascular disease. Clin Pharmacol Ther 2003; 73: 232-241.
- 26 Savi P, Pereillo JM, Uzabiaga MF. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-896.
- 27 Yoneda K, Iwamura R, Kishi H. et al. Identification of the active metabolite of ticlopidine from rat in vitro metabolites. Br J Pharmacol 2004; 142: 551-557.
- 28 Pereillo JM, Maftouh M, Andrieu A. et al. Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos 2002; 30: 1288-1295.
- 29 Hasegawa M, Sugidachi A, Ogawa T. et al. Stereoselective inhibition of human platelet aggregation by R-138727, the active metabolite of CS-747 (prasugrel, LY640315), a novel P2Y12 receptor inhibitor. Thromb Haemost 2005; 94: 593-598.
- 30 Ding Z, Kim S, Dorsam RT. et al. Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270. Blood 2003; 101: 3908-3914.
- 31 Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100: 1667-1672.
- 32 Cattaneo M. P2Y12 receptor antagonists: a rapidly expanding group of antiplatelet agents. Eur Heart J 2006; 27: 1010-1012.
- 33 Desager JP. Clinical pharmacokinetics of ticlopidine. Clin Pharmacokinet 1994; 26: 347-355.
- 34 Balsano F, Rizzon P, Violi F. et al. Antiplatelet treatment with ticlopidine in unstable angina. A controlled multicenter clinical trial. The Studio della Ticlopidina nell'Angina Instabile Group. Circulation 1990; 82: 17-26.
- 35 Leon MB, Baim DS, Popma JJ. et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998; 339: 1665-1671.
- 36 Green D. CAPRIE trial. Lancet 1997; 349: 354-355. author reply 356
- 37 Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324: 71-86.
- 38 Bhatt DL, Chew DP, Hirsch AT. et al. Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001; 103: 363-368.
- 39 Ringleb PA, Bhatt DL, Hirsch AT. et al. Benefit of clopidogrel over aspirin is amplified in patients with a history of ischemic events. Stroke 2004; 35: 528-532.
- 40 Bhatt DL, Marso SP, Hirsch AT. et al. Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 2002; 90: 625-628.
- 41 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: 494-502.
- 42 Yusuf S, Mehta SR, Zhao F. et al. Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation 2003; 107: 966-972.
- 43 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: 527-533.
- 44 Steinhubl SR, Berger PB, Mann 3rd JT. et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2002; 288: 2411-2420.
- 45 Sabatine MS, Cannon CP, Gibson CM. et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-1189.
- 46 Sabatine MS, Cannon CP, Gibson CM. et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCICLARITY study. J Am Med Assoc 2005; 294: 1224-1232.
- 47 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: 1706-1717.
- 48 Jernberg T, Payne CD, Winters KJ. et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 2006; 27: 1166-1173.
- 49 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
- 50 Gurbel PA, Bliden KP, Hayes KM. et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005; 45: 1392-1396.
- 51 Jaremo P, Lindahl TL, Fransson SG, Richter A. Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002; 252: 233-238.
- 52 Muller I, Besta F, Schulz C. et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89: 783-787.
- 53 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: 3171-3175.
- 54 Gurbel PA, Samara WM, Bliden KP. Failure of clopidogrel to reduce platelet reactivity and activation following standard dosing in elective stenting: implications for thrombotic events and restenosis. Platelets 2004; 15: 95-99.
- 55 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Is a 300 mg clopidogrel loading dose sufficient to inhibit platelet function early after coronary stenting? A platelet function profile study. J Invasive Cardiol 2004; 16: 325-329.
- 56 Mobley JE, Bresee SJ, Wortham DC. et al. Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization. Am J Cardiol 2004; 93: 456-458.
- 57 Samara WM, Bliden KP, Tantry US. et al. The difference between clopidogrel responsiveness and posttreatment platelet reactivity. Thromb Res 2005; 115: 89-94.
- 58 Gurbel PA, Bliden KP, Samara W. et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827-1832.
- 59 Wenaweser P, Dorffler-Melly J, Imboden K. et al. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol 2005; 45: 1748-1752.
- 60 Cuisset T, Frere C, Quilici J. et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006; 4: 542-549.
- 61 Lev EI, Patel RT, Maresh KJ. et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006; 47: 27-33.
- 62 Gencheva E, Sloan M, Leurgans S. et al. Attrition and non-compliance in secondary stroke prevention trials. Neuroepidemiology 2004; 23: 61-66.
- 63 Heptinstall S. Variable therapeutic effectiveness of clopidogrel in acute coronary syndromes. J Thromb Haemost 2006; 4: 539-541.
- 64 Kastrati A, von Beckerath N, Joost A. et al. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation 2004; 110: 1916-1919.
- 65 Hochholzer W, Trenk D, Frundi D. et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005; 111: 2560-2564.
- 66 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: 2946-2950.
- 67 Taubert D, Kastrati A, Harlfinger S. et al. Pharmacokinetics of clopidogrel after administration of a high loading dose. Thromb Haemost 2004; 92: 311-316.
- 68 Lau WC, Waskell LA, Watkins PB. et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 2003; 107: 32-37.
- 69 Neubauer H, Mugge A. Thienopyridines and statins: assessing a potential drug-drug interaction. Curr Pharm Des 2006; 12: 1271-1280.
- 70 Gorchakova O, von Beckerath N, Gawaz M. et al. Antiplatelet effects of a 600 mg loading dose of clopidogrel are not attenuated in patients receiving atorvastatin or simvastatin for at least 4 weeks prior to coronary artery stenting. Eur Heart J 2004; 25: 1898-1902.
- 71 Mitsios JV, Papathanasiou AI, Rodis FI. et al. Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes. Circulation 2004; 109: 1335-1338.
- 72 Schror K, Weber AA, Hohlfeld T. Clopidogrel „resistance“ and statin cotreatment – significant for cardiocoronary prevention in real life?. Thromb Haemost 2005; 94: 235-237.
- 73 Fontana P, Dupont A, Gandrille S. et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation 2003; 108: 989-995.
- 74 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol 2006; 26: 1681-1683.
- 75 Dai D, Tang J, Rose R, Hodgson E. et al. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther 2001; 299: 825-831.
- 76 Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance. Arterioscler Thromb Vasc Biol 2004; 24: 1980-1987.
- 77 Bretschneider E, Glusa E, Schror K. ADP-, PAFand adrenaline-induced platelet aggregation and thromboxane formation are not affected by a thromboxane receptor antagonist at physiological external Ca++ concentrations. Thromb Res 1994; 75: 233-242.
- 78 Storey RF, Oldroyd KG, Wilcox RG. Open multicentre study of the P2T receptor antagonist ARFor C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes. Thromb Haemost 2001; 85: 401-407.
- 79 Husted S, Emanuelsson H, Heptinstall S. et al. Pharmacodynamics, pharmacokinetics, and safety of hte oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27: 1038-1047.
- 80 Uren NG, Schwarzacher SP, Metz JA. et al. Predictors and outcomes of stent thrombosis: an intravascular ultrasound registry. Eur Heart J 2002; 23: 124-132.
- 81 Balaguer-Malfagon JR, Pomar-Domingo F. et al. Stent thrombosis in the modern era: Incidence, outcome and predictive factors. Rev Esp Cardiol 2006; 59: 842-845.
- 82 Nordmann AJ, Briel M, Bucher HC. Mortality in randomized controlled trials comparing drug-eluting vs. bare metal stents in coronary artery disease: a metaanalysis. Eur Heart J. 2006 doi:101093/euroheartj/ehl282