Circulation. 2004;109:166-171
Published online before print January 5, 2004, doi: 10.1161/01.CIR.0000112378.09325.F9
Published online before print January 5, 2004, doi: 10.1161/01.CIR.0000112378.09325.F9
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2004;109:166-171.)
© 2004 American Heart Association, Inc.
Clinical Investigation and Reports |
Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance
From the Department of Anesthesiology (W.C.L., C.J.N., A.S.H., A.R.T.), University of Michigan, Ann Arbor, Mich; Sinai Center for Thrombosis Research (P.A.G.), Sinai Hospital of Baltimore, Baltimore, Md; General Clinical Research Center (P.B.W.), University of North Carolina, Chapel Hill, NC; Division of Thrombosis (D.G.M.C., K.E.G.), Department of Chemistry, Indiana University, South Bend, Indiana; and Division of Cardiovascular Diseases (E.R.B.), Department of Internal Medicine, University of Michigan, Ann Arbor, Mich.
Correspondence to Wei C. Lau, MD, Department of Anesthesiology, University of Michigan Health System, 1G323 University Hospital, Box 0048, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0048. E-mail weiclau{at}umich.edu
Received August 29, 2003; de novo received October 9, 2003; revision received November 10, 2003; accepted November 25, 2003.
Background— Interindividual variability of platelet inhibition after aspirin or clopidogrel administration has been described. Additionally, aspirin resistance and clopidogrel resistance occur in some individuals. Because the prodrug clopidogrel is activated by hepatic cytochrome P450 (CYP) 3A4, we hypothesized that interindividual variability in clopidogrel efficacy might be related to interindividual differences in CYP3A4 metabolic activity.
Methods and Results— Platelet aggregation was measured before and after clopidogrel treatment in 32 patients undergoing coronary artery stent implantation and in 35 healthy volunteers. The erythromycin breath test was used to measure CYP3A4 activity in vivo in 25 of the healthy volunteers. Individual platelet aggregation was studied in 10 healthy volunteers after the coadministration of clopidogrel and rifampin (a CYP3A4 inducer). Clopidogrel nonresponders, low responders, and responders were defined by a relative inhibition of adenosine diphosphate (20 µmol/L)–induced platelet aggregation of <10%, 10% to 29%, and 
30%, respectively. Among patients, 22% were clopidogrel nonresponders, 32% were low responders, and 47% were responders. Among volunteers, 16% were nonresponders, 12% were low responders, and 72% were responders. Percent platelet aggregation after clopidogrel inversely correlated with CYP3A4 activity (r=-0.6, P=0.003). Improved platelet inhibition in volunteers resistant to clopidogrel was observed with the coadministration of clopidogrel and rifampin.
Conclusions— Clopidogrel administration results in interindividual variability in platelet inhibition, which correlates with CYP3A4 metabolic activity. Measurement of antiplatelet drug efficacy with a point-of-care device and alternative antithrombotic strategies for aspirin or clopidogrel nonresponders and low responders could reduce the incidence of thrombotic events that continue to occur despite oral antiplatelet therapy.
Key Words: drugs • platelets • pharmacology
This article has been cited by other articles:
 |
|
 |
|
  T. Geisler, C. Zurn, M. Paterok, K. Gohring-Frischholz, B. Bigalke, K. Stellos, P. Seizer, B. F. Kraemer, J. Dippon, A. E. May, et al. Statins do not adversely affect post-interventional residual platelet aggregation and outcomes in patients undergoing coronary stenting treated by dual antiplatelet therapy Eur. Heart J., July 1, 2008; 29(13): 1635 - 1643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Alvarez Jr. For better or for worse: The future of antiplatelet therapy Am. J. Health Syst. Pharm., June 1, 2008; 65(11): 1017 - 1017. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Patrono, C. Baigent, J. Hirsh, and G. Roth Antiplatelet Drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 199S - 233S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. I. Weitz, J. Hirsh, and M. M. Samama New Antithrombotic Drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 234S - 256S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-P. Bassand Unmet needs in antiplatelet therapy Eur. Heart J. Suppl., May 1, 2008; 10(suppl_D): D3 - D11. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Kereiakes and P. A. Gurbel Peri-Procedural Platelet Function and Platelet Inhibition in Percutaneous Coronary Intervention J. Am. Coll. Cardiol. Intv., April 1, 2008; 1(2): 111 - 121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Srinivasan and D Smith Drug interaction with anti-mycobacterial treatment as a cause of clopidogrel resistance Postgrad. Med. J., April 1, 2008; 84(990): 217 - 219. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Michelson P2Y12 Antagonism: Promises and Challenges Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): s33 - s38. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Prabhakaran, K.R Wells, V.H. Lee, C.A. Flaherty, and D.K. Lopes Prevalence and Risk Factors for Aspirin and Clopidogrel Resistance in Cerebrovascular Stenting AJNR Am. J. Neuroradiol., February 1, 2008; 29(2): 281 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gilard, B. Arnaud, J.-C. Cornily, G. Le Gal, K. Lacut, G. Le Calvez, J. Mansourati, D. Mottier, J.-F. Abgrall, and J. Boschat Influence of Omeprazole on the Antiplatelet Action of Clopidogrel Associated With Aspirin: The Randomized, Double-Blind OCLA (Omeprazole CLopidogrel Aspirin) Study J. Am. Coll. Cardiol., January 22, 2008; 51(3): 256 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Gurbel, W. C. Lau, and U. S. Tantry Omeprazole: A Possible New Candidate Influencing the Antiplatelet Effect of Clopidogrel J. Am. Coll. Cardiol., January 22, 2008; 51(3): 261 - 263. [Full Text] [PDF]
|
|
|
|
|
|
R. F. Storey Variability of response to antiplatelet therapy Eur. Heart J. Suppl., January 1, 2008; 10(suppl_A): A21 - A27. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. I. Simon and A. H. Schmaier Sweet and Sticky: Diabetic Platelets, Enhanced Reactivity, and Cardiovascular Risk J. Am. Coll. Cardiol., October 16, 2007; 50(16): 1548 - 1550. [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Weerakkody, J. A. Jakubowski, J. T. Brandt, C. D. Payne, H. Naganuma, and K. J. Winters Greater Inhibition of Platelet Aggregation and Reduced Response Variability With Prasugrel Versus Clopidogrel: An Integrated Analysis Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2007; 12(3): 205 - 212. [Abstract] [PDF]
|
|
|
|
|
|
D. J. Angiolillo and F. Alfonso Clopidogrel Statin Interaction: Myth or Reality? J. Am. Coll. Cardiol., July 24, 2007; 50(4): 296 - 298. [Full Text] [PDF]
|
|
|
|
|
|
J. Saw, D. M. Brennan, S. R. Steinhubl, D. L. Bhatt, K.-H. Mak, K. Fox, E. J. Topol, and on behalf of the CHARISMA Investigators Lack of Evidence of a Clopidogrel Statin Interaction in the CHARISMA Trial J. Am. Coll. Cardiol., July 24, 2007; 50(4): 291 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Buonamici, R. Marcucci, A. Migliorini, G. F. Gensini, A. Santini, R. Paniccia, G. Moschi, A. M. Gori, R. Abbate, and D. Antoniucci Impact of Platelet Reactivity After Clopidogrel Administration on Drug-Eluting Stent Thrombosis J. Am. Coll. Cardiol., June 19, 2007; 49(24): 2312 - 2317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Howard-Alpe, J. de Bono, L. Hudsmith, W. P. Orr, P. Foex, and J. W. Sear Coronary artery stents and non-cardiac surgery Br. J. Anaesth., May 1, 2007; 98(5): 560 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. O. Maree and D. J. Fitzgerald Variable Platelet Response to Aspirin and Clopidogrel in Atherothrombotic Disease Circulation, April 24, 2007; 115(16): 2196 - 2207. [Full Text] [PDF]
|
|
|
|
|
|
D. J. Angiolillo, A. Fernandez-Ortiz, E. Bernardo, F. Alfonso, C. Macaya, T. A. Bass, and M. A. Costa Variability in Individual Responsiveness to Clopidogrel: Clinical Implications, Management, and Future Perspectives J. Am. Coll. Cardiol., April 10, 2007; 49(14): 1505 - 1516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tang, M. Mukundan, J. Yang, N. Charpentier, E. L. LeCluyse, C. Black, D. Yang, D. Shi, and B. Yan Antiplatelet Agents Aspirin and Clopidogrel Are Hydrolyzed by Distinct Carboxylesterases, and Clopidogrel Is Transesterificated in the Presence of Ethyl Alcohol J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1467 - 1476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. O'Donoghue and S. D. Wiviott Clopidogrel Response Variability and Future Therapies: Clopidogrel: Does One Size Fit All? Circulation, November 28, 2006; 114(22): e600 - e606. [Full Text] [PDF]
|
|
|
|
|
|
M. Pfisterer, H. P. Brunner-La Rocca, P. T. Buser, P. Rickenbacher, P. Hunziker, C. Mueller, R. Jeger, F. Bader, S. Osswald, C. Kaiser, et al. Late Clinical Events After Clopidogrel Discontinuation May Limit the Benefit of Drug-Eluting Stents: An Observational Study of Drug-Eluting Versus Bare-Metal Stents J. Am. Coll. Cardiol., November 1, 2006; (2006) j.jacc.2006.10.026v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Michelson, A. L. Frelinger, and M. I. Furman Resistance to antiplatelet drugs Eur. Heart J. Suppl., October 1, 2006; 8(suppl_G): G53 - G58. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 J.-W. Suh, B.-K. Koo, S.-Y. Zhang, K.-W. Park, J.-Y. Cho, I.-J. Jang, D.-S. Lee, D.-W. Sohn, M.-M. Lee, and H.-S. Kim Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel Can. Med. Assoc. J., June 6, 2006; 174(12): 1715 - 1722. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Turgeon, C. Pharand, and V. Michaud Understanding clopidogrel efficacy in the presence of cytochrome P450 polymorphism Can. Med. Assoc. J., June 6, 2006; 174(12): 1729 - 1729. [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. F. Rehmel, J. A. Eckstein, N. A. Farid, J. B. Heim, S. C. Kasper, A. Kurihara, S. A. Wrighton, and B. J. Ring INTERACTIONS OF TWO MAJOR METABOLITES OF PRASUGREL, A THIENOPYRIDINE ANTIPLATELET AGENT, WITH THE CYTOCHROMES P450 Drug Metab. Dispos., April 1, 2006; 34(4): 600 - 607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. H. Wang, D. L. Bhatt, and E. J. Topol Aspirin and clopidogrel resistance: an emerging clinical entity Eur. Heart J., March 2, 2006; 27(6): 647 - 654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Barsky and R. R. Arora Clopidogrel Resistance: Myth or Reality? Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2006; 11(1): 47 - 53. [Abstract] [PDF]
|
|
|
|
 |
|
 S J Walsh, M S Spence, D Crossman, and A A J Adgey Clopidogrel in non-ST segment elevation acute coronary syndromes: an overview of the submission by the British Cardiac Society and the Royal College of Physicians of London to the National Institute for Clinical Excellence, and beyond Heart, September 1, 2005; 91(9): 1135 - 1140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Labarthe, P. Theroux, M. Angioi, and M. Ghitescu Matching the Evaluation of the Clinical Efficacy of Clopidogrel to Platelet Function Tests Relevant to the Biological Properties of the Drug J. Am. Coll. Cardiol., August 16, 2005; 46(4): 638 - 645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Frelinger III and A. D. Michelson Clopidogrel: Linking Evaluation of Platelet Response Variability to Mechanism of Action J. Am. Coll. Cardiol., August 16, 2005; 46(4): 646 - 647. [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Angiolillo, A. Fernandez-Ortiz, E. Bernardo, C. Ramirez, M. Sabate, P. Jimenez-Quevedo, R. Hernandez, R. Moreno, J. Escaned, F. Alfonso, et al. Platelet Function Profiles in Patients With Type 2 Diabetes and Coronary Artery Disease on Combined Aspirin and Clopidogrel Treatment Diabetes, August 1, 2005; 54(8): 2430 - 2435. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ziegler, M. Schillinger, M. Funk, K. Felber, M. Exner, W. Mlekusch, S. Sabeti, J. Amighi, E. Minar, M. Brunner, et al. Association of a Functional Polymorphism in the Clopidogrel Target Receptor Gene, P2Y12, and the Risk for Ischemic Cerebrovascular Events in Patients With Peripheral Artery Disease Stroke, July 1, 2005; 36(7): 1394 - 1399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ajzenberg, P. Aubry, M.-G. Huisse, A. Cachier, W. El Amara, L. J. Feldman, D. Himbert, D. Baruch, M.-C. Guillin, and Ph. G. Steg Enhanced Shear-Induced Platelet Aggregation in Patients Who Experience Subacute Stent Thrombosis: A Case-Control Study J. Am. Coll. Cardiol., June 7, 2005; 45(11): 1753 - 1756. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Geiger, L. Teichmann, R. Grossmann, B. Aktas, U. Steigerwald, U. Walter, and R. Schinzel Monitoring of Clopidogrel Action: Comparison of Methods Clin. Chem., June 1, 2005; 51(6): 957 - 965. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Bates, W. C. Lau, and B. E. Bleske Loading, Pretreatment, and Interindividual Variability Issues With Clopidogrel Dosing Circulation, May 24, 2005; 111(20): 2557 - 2559. [Full Text] [PDF]
|
|
|
|
|
|
P. A. Gurbel, K. P. Bliden, K. M. Hayes, J. A. Yoho, W. R. Herzog, and U. S. Tantry 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., May 3, 2005; 45(9): 1392 - 1396. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Bates and W. C. Lau Controversies in Antiplatelet Therapy for Patients With Cardiovascular Disease Circulation, May 3, 2005; 111(17): e267 - e271. [Full Text] [PDF]
|
|
|
|
|
|
T. A. Nguyen, J. G. Diodati, and C. Pharand Resistance to clopidogrel: A review of the evidence J. Am. Coll. Cardiol., April 19, 2005; 45(8): 1157 - 1164. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. T.L. Ong, A. Hoye, J. Aoki, C. A.G. van Mieghem, G. A. Rodriguez Granillo, K. Sonnenschein, E. Regar, E. P. McFadden, G. Sianos, W. J. van der Giessen, et al. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation J. Am. Coll. Cardiol., March 15, 2005; 45(6): 947 - 953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Raja Reasons for inability of clopidogrel to inhibit platelet aggregation early after coronary artery bypass surgery J. Thorac. Cardiovasc. Surg., February 1, 2005; 129(2): 475 - 475. [Full Text] [PDF]
|
|
|
|
|
|
D. J. Angiolillo, A. Fernandez-Ortiz, E. Bernardo, C. Ramirez, M. Sabate, C. Banuelos, R. Hernandez-Antolin, J. Escaned, R. Moreno, F. Alfonso, et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability Eur. Heart J., November 1, 2004; 25(21): 1903 - 1910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cattaneo Aspirin and Clopidogrel: Efficacy, Safety, and the Issue of Drug Resistance Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 1980 - 1987. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Schulman Antiplatelet Therapy in Non-ST-Segment Elevation Acute Coronary Syndromes JAMA, October 20, 2004; 292(15): 1875 - 1882. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Wiviott and E. M. Antman Clopidogrel Resistance: A New Chapter in a Fast-Moving Story Circulation, June 29, 2004; 109(25): 3064 - 3067. [Full Text] [PDF]
|
|
|
|
|
|
S. Matetzky, B. Shenkman, V. Guetta, M. Shechter, R. Bienart, I. Goldenberg, I. Novikov, H. Pres, N. Savion, D. Varon, et al. Clopidogrel Resistance Is Associated With Increased Risk of Recurrent Atherothrombotic Events in Patients With Acute Myocardial Infarction Circulation, June 29, 2004; 109(25): 3171 - 3175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Kastrati, A Schomig, and E Schomig Are we making efficient use of clopidogrel? Eur. Heart J., March 2, 2004; 25(6): 454 - 456. [Full Text] [PDF]
|
|