Circulation. 2004;109:3171-3175
Published online before print June 7, 2004, doi: 10.1161/01.CIR.0000130846.46168.03
Published online before print June 7, 2004, doi: 10.1161/01.CIR.0000130846.46168.03
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2004;109:3171-3175.)
© 2004 American Heart Association, Inc.
Clinical Investigation and Reports |
Clopidogrel Resistance Is Associated With Increased Risk of Recurrent Atherothrombotic Events in Patients With Acute Myocardial Infarction
From the Heart Institute (S.M., V.G., M.S., R.B., I.G., I.N., H.P., H.H.), Institute of Thrombosis and Hemostasis (B.S., D.V.), and Goldschleger Eye Research Institute (N.S.), Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Israel.
Correspondence to Hanoch Hod, MD, Director, ICCU, Heart Institute, Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail hod{at}netvision.net.il
Received October 20, 2003; de novo received December 14, 2003; revision received February 24, 2004; accepted March 16, 2004.
Background— Although clopidogrel reduces the risk of cardiovascular episodes after coronary events and stenting, a substantial number of incidents continue to occur.
Methods and Results— The antiplatelet effect of clopidogrel was studied prospectively in 60 consecutive patients who underwent primary angioplasty (percutaneous coronary intervention [PCI]) with stenting for acute ST-segment–elevation myocardial infarction (STEMI) to determine whether variability in response to clopidogrel affects clinical outcomes. Patients were stratified into 4 quartiles according to the percentage reduction of ADP-induced platelet aggregation. Although patients in the first quartile were resistant to the effects of clopidogrel (ADP-induced platelet aggregation at day 6, 103±8% of baseline), ADP-induced aggregation was reduced to 69±3%, 58±7%, and 33±12% of baseline, respectively, in patients in quartiles 2 through 4 (P<0.01 for all). In addition, epinephrine-induced platelet aggregation and platelet aggregation under flow conditions, assessed by the cone-and-plate(let) analyzer method, were reduced significantly less in the first quartile than in quartiles 2 through 4. Whereas 40% of patients in the first quartile sustained a recurrent cardiovascular event during a 6-month follow-up, only 1 patient (6.7%) in the second quartile and none in the third and fourth quartiles suffered a cardiovascular event (P=0.007).
Conclusions— Up to 25% of STEMI patients undergoing primary PCI with stenting are resistant to clopidogrel and therefore may be at increased risk for recurrent cardiovascular events.
Key Words: platelets • myocardial infarction • clopidogrel
Related Article:
Circulation 2004 109: 3064-3067.
This article has been cited by other articles:
 |
|
 |
|
  Y. Yano, T. Ohmori, S. Hoshide, S. Madoiwa, K. Yamamoto, T. Katsuki, T. Mitsuhashi, J. Mimuro, K. Shimada, K. Kario, et al. Determinants of thrombin generation, fibrinolytic activity, and endothelial dysfunction in patients on dual antiplatelet therapy: involvement of factors other than platelet aggregability in Virchow's triad Eur. Heart J., July 2, 2008; 29(14): 1729 - 1738. [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. S. Rihal Drug-Eluting Stents for ST-Segment Elevation Myocardial Infarction: Treatment of Choice or Is Discretion the Better Part of Valor? J. Am. Coll. Cardiol. Intv., June 1, 2008; 1(3): 233 - 235. [Full Text] [PDF]
|
|
|
|
 |
|
 T Geisler, M Kapp, K Gohring-Frischholz, K Daub, C Dosch, B Bigalke, H Langer, C Herdeg, and M Gawaz Residual platelet activity is increased in clopidogrel- and ASA-treated patients with coronary stenting for acute coronary syndromes compared with stable coronary artery disease Heart, June 1, 2008; 94(6): 743 - 747. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Aradi, A. Konyi, L. Palinkas, T. Berki, T. Pinter, T. Tahin, I. Horvath, L. Papp, and A. Komocsi Thienopyridine Therapy Influences Late Outcome After Coronary Stent Implantation Angiology, May 1, 2008; 59(2): 172 - 178. [Abstract] [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]
|
|
|
|
|
|
J.J.J. van Giezen Optimizing platelet inhibition Eur. Heart J. Suppl., May 1, 2008; 10(suppl_D): D23 - D29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wallentin Dual antiplatelet therapy in the drug-eluting stent era Eur. Heart J. Suppl., May 1, 2008; 10(suppl_D): D38 - D44. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Bonello, L. Camoin-Jau, S. Arques, C. Boyer, D. Panagides, O. Wittenberg, M.-C. Simeoni, P. Barragan, F. Dignat-George, and F. Paganelli Adjusted Clopidogrel Loading Doses According to Vasodilator-Stimulated Phosphoprotein Phosphorylation Index Decrease Rate of Major Adverse Cardiovascular Events in Patients With Clopidogrel Resistance: A Multicenter Randomized Prospective Study J. Am. Coll. Cardiol., April 8, 2008; 51(14): 1404 - 1411. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Price, S. Endemann, R. R. Gollapudi, R. Valencia, C. T. Stinis, J. P. Levisay, A. Ernst, N. S. Sawhney, R. A. Schatz, and P. S. Teirstein Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation Eur. Heart J., April 2, 2008; 29(8): 992 - 1000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Holmes Jr Resistance to what, does it matter? How do we study it? Eur. Heart J., April 2, 2008; 29(8): 957 - 958. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
P. L. L'Allier, G. Ducrocq, N. Pranno, S. Noble, R. Ibrahim, J. C. Gregoire, F. Azzari, A. Nozza, C. Berry, S. Doucet, et al. Clopidogrel 600-mg double loading dose achieves stronger platelet inhibition than conventional regimens: results from the PREPAIR randomized study. J. Am. Coll. Cardiol., March 18, 2008; 51(11): 1066 - 1072. [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]
|
|
|
|
|
|
L. Wallentin, C. Varenhorst, S. James, D. Erlinge, O. O Braun, J. A. Jakubowski, A. Sugidachi, K. J. Winters, and A. Siegbahn Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease Eur. Heart J., January 1, 2008; 29(1): 21 - 30. [Abstract] [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]
|
|
|
|
|
|
C. Gachet and B. Aleil Testing antiplatelet therapy Eur. Heart J. Suppl., January 1, 2008; 10(suppl_A): A28 - A34. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Wiviott, D. Trenk, A. L. Frelinger, M. O'Donoghue, F.-J. Neumann, A. D. Michelson, D. J. Angiolillo, H. Hod, G. Montalescot, D. L. Miller, et al. Prasugrel Compared With High Loading- and Maintenance-Dose Clopidogrel in Patients With Planned Percutaneous Coronary Intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation Thrombolysis in Myocardial Infarction 44 Trial Circulation, December 18, 2007; 116(25): 2923 - 2932. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Wiviott, E. Braunwald, C. H. McCabe, G. Montalescot, W. Ruzyllo, S. Gottlieb, F.-J. Neumann, D. Ardissino, S. De Servi, S. A. Murphy, et al. Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes N. Engl. J. Med., November 15, 2007; 357(20): 2001 - 2015. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Gurbel, R. C. Becker, K. G. Mann, S. R. Steinhubl, and A. D. Michelson Platelet Function Monitoring in Patients With Coronary Artery Disease J. Am. Coll. Cardiol., November 6, 2007; 50(19): 1822 - 1834. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Cannon, S. Husted, R. A. Harrington, B. M. Scirica, H. Emanuelsson, G. Peters, R. F. Storey, and for the DISPERSE-2 Investigators 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., November 6, 2007; 50(19): 1844 - 1851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. F. Storey, S. Husted, R. A. Harrington, S. Heptinstall, R. G. Wilcox, G. Peters, M. Wickens, H. Emanuelsson, P. Gurbel, P. Grande, et al. Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y12 Receptor Antagonist, Compared With Clopidogrel in Patients With Acute Coronary Syndromes J. Am. Coll. Cardiol., November 6, 2007; 50(19): 1852 - 1856. [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]
|
|
|
|
|
|
D. J. Angiolillo, E. Bernardo, M. Sabate, P. Jimenez-Quevedo, M. A. Costa, J. Palazuelos, R. Hernandez-Antolin, R. Moreno, J. Escaned, F. Alfonso, et al. Impact of Platelet Reactivity on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease J. Am. Coll. Cardiol., October 16, 2007; 50(16): 1541 - 1547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Campo, M. Valgimigli, D. Gemmati, G. Percoco, L. Catozzi, A. Frangione, F. Federici, F. Ferrari, M. Tebaldi, S. Luccarelli, et al. Poor Responsiveness to Clopidogrel: Drug-Specific or Class-Effect Mechanism?: Evidence From a Clopidogrel-to-Ticlopidine Crossover Study J. Am. Coll. Cardiol., September 18, 2007; 50(12): 1132 - 1137. [Abstract] [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]
|
|
|
|
|
|
J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): e1 - e157. [Full Text] [PDF]
|
|
|
|
|
|
J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): 652 - 726. [Full Text] [PDF]
|
|
|
|
|
|
N. von Beckerath, A. Kastrati, A. Wieczorek, G. Pogatsa-Murray, D. Sibbing, I. Graf, and A. Schomig A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days Eur. Heart J., August 1, 2007; 28(15): 1814 - 1819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bode and M. Zehender The use of antiplatelet agents following percutaneous coronary intervention: focus on late stent thrombosis Eur. Heart J. Suppl., August 1, 2007; 9(suppl_D): D10 - D19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Holmes Jr, D. J. Kereiakes, W. K. Laskey, A. Colombo, S. G. Ellis, T. D. Henry, J. J. Popma, P. W.J.C. Serruys, T. Kimura, D. O. Williams, et al. Thrombosis and Drug-Eluting Stents: An Objective Appraisal J. Am. Coll. Cardiol., July 10, 2007; 50(2): 109 - 118. [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. El-Khuffash and E. J Molloy Are B-type natriuretic peptide (BNP) and N-terminal-pro-BNP useful in neonates? Arch. Dis. Child. Fetal Neonatal Ed., July 1, 2007; 92(4): F320 - F324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Moliterno and C. L. Campbell Unraveling Questions Surrounding Clopidogrel Resistance and Stent Thrombosis: One Less Snag J. Am. Coll. Cardiol., June 19, 2007; 49(24): 2318 - 2319. [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]
|
|
|
|
 |
|
 T. A. Meadows and D. L. Bhatt Clinical Aspects of Platelet Inhibitors and Thrombus Formation Circ. Res., May 11, 2007; 100(9): 1261 - 1275. [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]
|
|
|
|
 |
|
 S. Eshaghian, S. Kaul, S. Amin, P. K. Shah, and G. A. Diamond Role of Clopidogrel in Managing Atherothrombotic Cardiovascular Disease Ann Intern Med, March 20, 2007; 146(6): 434 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. P. Bliden, J. DiChiara, U. S. Tantry, A. K. Bassi, S. K. Chaganti, and P. A. Gurbel Increased Risk in Patients With High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing Percutaneous Coronary Intervention: Is the Current Antiplatelet Therapy Adequate? J. Am. Coll. Cardiol., February 13, 2007; 49(6): 657 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Angiolillo, S. B. Shoemaker, B. Desai, H. Yuan, R. K. Charlton, E. Bernardo, M. M. Zenni, L. A. Guzman, T. A. Bass, and M. A. Costa 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, February 13, 2007; 115(6): 708 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Fitzgerald and A. Maree Aspirin and Clopidogrel Resistance Hematology, January 1, 2007; 2007(1): 114 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Dalal, S. D'Souza, and M. S. Shulman Brief review: Coronary drug-eluting stents and anesthesia: [Article de synthese court : Les tuteurs coronariens actifs et l'anesthesie] Can J Anesth, December 1, 2006; 53(12): 1230 - 1243. [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]
|
|
|
|
|
|
W. Hochholzer, D. Trenk, H.-P. Bestehorn, B. Fischer, C. M. Valina, M. Ferenc, M. Gick, A. Caputo, H. J. Buttner, and F.-J. Neumann Impact of the Degree of Peri-Interventional Platelet Inhibition After Loading With Clopidogrel on Early Clinical Outcome of Elective Coronary Stent Placement J. Am. Coll. Cardiol., November 7, 2006; 48(9): 1742 - 1750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Cuisset, C. Frere, J. Quilici, P.-E. Morange, L. Nait-Saidi, J. Carvajal, A. Lehmann, M. Lambert, J.-L. Bonnet, and M.-C. Alessi Benefit of a 600-mg Loading Dose of Clopidogrel on Platelet Reactivity and Clinical Outcomes in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome Undergoing Coronary Stenting J. Am. Coll. Cardiol., October 3, 2006; 48(7): 1339 - 1345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Geisler, H. Langer, M. Wydymus, K. Gohring, C. Zurn, B. Bigalke, K. Stellos, A. E. May, and M. Gawaz Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation Eur. Heart J., October 2, 2006; 27(20): 2420 - 2425. [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]
|
|
|
|
 |
|