This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (118) Citing Articles via Google Scholar Google Scholar Articles by Nguyen, T. A. Articles by Pharand, C. Search for Related Content PubMed PubMed Citation Articles by Nguyen, T. A. Articles by Pharand, C.

STATE-OF-THE-ART PAPER

Resistance to clopidogrel: A review of the evidence

Thuy Anh Nguyen, MSc, Pharm^_*, Jean G. Diodati, MD^,,|| and Chantal Pharand, PharmD^_*,,,_*

^_* Pharmacy Department, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada
Service of Cardiology, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada
Research Centre, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada
Faculty of Pharmacy, Université de Montréal, Montreal, Canada.
^|| Faculty of Medicine, Université de Montréal, Montreal, Canada.

Manuscript received December 8, 2004; revised manuscript received January 19, 2005, accepted January 25, 2005.

^_* Reprint requests and correspondence: Dr. Chantal Pharand, Research Centre, Hôpital du Sacré-Coeur de Montréal, 5400, Gouin Boulevard West, Montreal, Quebec, Canada H4J 1C5. (Email: chantal.pharand{at}umontreal.ca).

Current available data show that about 4% to 30% of patients treated with conventional doses of clopidogrel do not display adequate antiplatelet response. Clopidogrel resistance is a widely used term that remains to be clearly defined. So far, it has been used to reflect failure of clopidogrel to achieve its antiaggregatory effect. The interpatient variability in clopidogrel response is multifactorial. It can be due to extrinsic or intrinsic mechanisms. Among extrinsic mechanisms are the possibility of clopidogrel underdosing in patients undergoing stenting or with acute coronary syndrome, and drug-drug interactions involving CYP3A4. Intrinsic mechanisms include genetic polymorphisms of the P2Y₁₂ receptor and of the CYP3As, accrued release of adenosine diphosphate, or up-regulation of other platelet activation pathways. Presently, there is no definite demonstration of an association between low responsiveness to clopidogrel and thrombotic events. The optimal level of clopidogrel-induced platelet inhibition, which will correlate quantitatively with clopidogrel’s ability to prevent atherothrombotic events is still lacking. Furthermore, because there is no single and validated platelet function assay to measure clopidogrel’s antiplatelet effect, it is not justified to routinely look for clopidogrel resistance in the clinical setting. This review discusses currently available evidence surrounding the variability in the antiplatelet response to clopidogrel.

Abbreviations and Acronyms   ACS = acute coronary syndromes   ADP = adenosine diphosphate   cAMP = cyclic adenosine monophosphate   CYP450 = cytochrome P450   GPIIb/IIIa = glycoprotein IIb/IIIa   PCI = percutaneous coronary intervention   PGE1 = prostaglandin E1   SAT = subacute stent thrombosis   VASP = vasodilator-stimulated phosphoprotein

This article has been cited by other articles:

				J. A. Rassen, N. K. Choudhry, J. Avorn, and S. Schneeweiss Cardiovascular Outcomes and Mortality in Patients Using Clopidogrel With Proton Pump Inhibitors After Percutaneous Coronary Intervention or Acute Coronary Syndrome Circulation, December 8, 2009; 120(23): 2322 - 2329. [Abstract] [Full Text] [PDF]

				C. W. Hamm Current practice and limitations of dual antiplatelet therapy in acute coronary syndrome Eur. Heart J. Suppl., December 1, 2009; 11(suppl_G): G4 - G8. [Abstract] [Full Text] [PDF]

				D. R. Holmes Jr, D. J. Kereiakes, N. S. Kleiman, D. J. Moliterno, G. Patti, and C. L. Grines Combining Antiplatelet and Anticoagulant Therapies. J. Am. Coll. Cardiol., July 7, 2009; 54(2): 95 - 109. [Abstract] [Full Text] [PDF]

				C. Gao, C. Ren, D. Li, and L. Li Clopidogrel and aspirin versus clopidogrel alone on graft patency after coronary artery bypass grafting. Ann. Thorac. Surg., July 1, 2009; 88(1): 59 - 62. [Abstract] [Full Text] [PDF]

				J. Smout and G. Stansby Surgery and antiplatelet agents: what are the risks? Clin Risk, May 1, 2009; 15(3): 101 - 105. [Full Text] [PDF]

				N. F. Ford Clopidogrel Resistance: Pharmacokinetic or Pharmacogenetic? J. Clin. Pharmacol., May 1, 2009; 49(5): 506 - 512. [Abstract] [Full Text] [PDF]

				D. M. Scott, R. M Norwood, and D. Parra P2Y12 Inhibitors in Cardiovascular Disease: Focus on Prasugrel Ann. Pharmacother., January 1, 2009; 43(1): 64 - 76. [Abstract] [Full Text] [PDF]

				C. W. Hamm, H. Möllmann, J.-P. Bassand, and F. van de Werf CHAPTER 16 Acute Coronary Syndromes ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]

				L. Ang and E. Mahmud Monitoring oral antiplatelet therapy: is it justified? Therapeutic Advances in Cardiovascular Disease, December 1, 2008; 2(6): 485 - 496. [Abstract] [PDF]

				M. Lordkipanidze, C. Pharand, T. A. Nguyen, E. Schampaert, D. A. Palisaitis, and J. G. Diodati Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Eur. Heart J., December 1, 2008; 29(23): 2877 - 2885. [Abstract] [Full Text] [PDF]

				L. Ang, V. Palakodeti, A. Khalid, S. Tsimikas, Z. Idrees, P. Tran, P. Clopton, N. Zafar, G. Bromberg-Marin, S. Keramati, et al. Elevated Plasma Fibrinogen and Diabetes Mellitus Are Associated With Lower Inhibition of Platelet Reactivity With Clopidogrel J. Am. Coll. Cardiol., September 23, 2008; 52(13): 1052 - 1059. [Abstract] [Full Text] [PDF]

				L. T. Newsome, M. A. Kutcher, and R. L. Royster Coronary Artery Stents: Part I. Evolution of Percutaneous Coronary Intervention Anesth. Analg., August 1, 2008; 107(2): 552 - 569. [Abstract] [Full Text] [PDF]

				S. Muller-Schunk, J. Linn, N. Peters, M. Spannagl, M. Deisenberg, H. Bruckmann, and T.E. Mayer Monitoring of Clopidogrel-Related Platelet Inhibition: Correlation of Nonresponse with Clinical Outcome in Supra-Aortic Stenting AJNR Am. J. Neuroradiol., April 1, 2008; 29(4): 786 - 791. [Abstract] [Full Text] [PDF]

				C. Gachet and B. Aleil Testing antiplatelet therapy Eur. Heart J. Suppl., January 1, 2008; 10(suppl_A): A28 - A34. [Abstract] [Full Text] [PDF]

				R. J. Jaumdally, C. Varma, A. D. Blann, R. J. MacFadyen, and G. Y. H. Lip Platelet Activation in Coronary Artery Disease: Intracardiac vs Peripheral Venous Levels and the Effects of Angioplasty Chest, November 1, 2007; 132(5): 1532 - 1539. [Abstract] [Full Text] [PDF]

				R. Jaffe and B. H. Strauss Late and Very Late Thrombosis of Drug-Eluting Stents: Evolving Concepts and Perspectives J. Am. Coll. Cardiol., July 10, 2007; 50(2): 119 - 127. [Abstract] [Full Text] [PDF]

				W. A. Schumacher, J. S. Bostwick, M. L. Ogletree, A. B. Stewart, T. E. Steinbacher, J. Hua, L. A. Price, P. C. Wong, and R. P. Rehfuss Biomarker Optimization to Track the Antithrombotic and Hemostatic Effects of Clopidogrel in Rats J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 369 - 377. [Abstract] [Full Text] [PDF]

				Authors/Task Force Members, J.-P. Bassand, C. W. Hamm, D. Ardissino, E. Boersma, A. Budaj, F. Fernandez-Aviles, K. A.A. Fox, D. Hasdai, E. M. Ohman, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology Eur. Heart J., July 1, 2007; 28(13): 1598 - 1660. [Full Text] [PDF]

				A. Ouattara, H. Bouzguenda, Y. Le Manach, P. Leger, A. Mercadier, P. Leprince, N. Bonnet, G. Montalescot, B. Riou, and P. Coriat Impact of aspirin with or without clopidogrel on postoperative bleeding and blood transfusion in coronary surgical patients treated prophylactically with a low-dose of aprotinin Eur. Heart J., April 12, 2007; (2007) ehm049v1. [Abstract] [Full Text] [PDF]

				J.-S. Hulot, A. Bura, E. Villard, M. Azizi, V. Remones, C. Goyenvalle, M. Aiach, P. Lechat, and P. Gaussem Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects Blood, October 1, 2006; 108(7): 2244 - 2247. [Abstract] [Full Text] [PDF]

				G. Montalescot, G. Sideris, C. Meuleman, C. Bal-dit-Sollier, N. Lellouche, Ph. G. Steg, M. Slama, O. Milleron, J.-P. Collet, P. Henry, et al. A Randomized Comparison of High Clopidogrel Loading Doses in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes: The ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) Trial J. Am. Coll. Cardiol., September 5, 2006; 48(5): 931 - 938. [Abstract] [Full Text] [PDF]

				R. A. Chaer, J. A. Graham, and L. Mureebe Platelet Function and Pharmacologic Inhibition Vascular and Endovascular Surgery, August 1, 2006; 40(4): 261 - 267. [Abstract] [PDF]

				D. J. Angiolillo, A. Fernandez-Ortiz, E. Bernardo, C. Ramirez, U. Cavallari, E. Trabetti, M. Sabate, R. Hernandez, R. Moreno, J. Escaned, 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, August 1, 2006; 26(8): 1895 - 1900. [Abstract] [Full Text] [PDF]

				G. W. Stone and H. D. Aronow Long-term Care After Percutaneous Coronary Intervention: Focus on the Role of Antiplatelet Therapy Mayo Clin. Proc., May 1, 2006; 81(5): 641 - 652. [Abstract] [Full Text] [PDF]

				E. D. Michos, R. Ardehali, R. S. Blumenthal, R. A. Lange, and H. Ardehali Aspirin and Clopidogrel Resistance Mayo Clin. Proc., April 1, 2006; 81(4): 518 - 526. [Abstract] [Full Text] [PDF]

				B. T. Ivandic, P. Schlick, P. Staritz, K. Kurz, H. A. Katus, and E. Giannitsis Determination of Clopidogrel Resistance by Whole Blood Platelet Aggregometry and Inhibitors of the P2Y12 Receptor Clin. Chem., March 1, 2006; 52(3): 383 - 388. [Abstract] [Full Text] [PDF]

				A Blann Antiplatelet therapy and the vascular tree Heart, January 1, 2006; 92(1): 3 - 4. [Full Text] [PDF]

				R. P. Giugliano and E. Braunwald The Year in Non--ST-Segment Elevation Acute Coronary Syndromes J. Am. Coll. Cardiol., September 6, 2005; 46(5): 906 - 919. [Full Text] [PDF]