Semin Thromb Hemost 2007; 33(2): 196-202
DOI: 10.1055/s-2007-969034
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Variable Response to Clopidogrel in Patients with Coronary Artery Disease

Tobias Geisler1 , Meinrad Gawaz1
  • 1Medizinische Klinik III, Universitätsklinikum Tübingen, Eberhard Karls-Universität Tübingen, Tübingen, Germany
Further Information

Publication History

Publication Date:
06 March 2007 (online)

ABSTRACT

Antiplatelet drug resistance is a multifactorial phenomenon that affects a large number of cardiovascular patients with symptomatic coronary artery disease. Although unique definitions for aspirin and clopidogrel resistance are missing, there is growing evidence for a clinical importance of response to antiplatelet therapy. The prevalence for aspirin and clopidogrel resistance has been reported to be between 5 and 30% in literature. Moreover, recent data suggest a high rate of dual antiplatelet drug resistance. Although there are convincing data about an association of aspirin resistance and clinical outcome, little is known about the clinical relevance of clopidogrel hyporesponsiveness. This article reviews the evidence for the clinical impact of antiplatelet drug resistance, with particular attention on the clinical outcome of clopidogrel low response according to current clinical data. Additional systematic studies are needed to evaluate the effects of alternative antiplatelet therapies in patients identified as low responders.

REFERENCES

  • 1 Mehta S R, Yusuf S, Peters R J et al.. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. 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(9281) 527-533
  • 2 Steinhubl S R, Berger P B, Mann III J T et al.. CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.  JAMA. 2002;  288(19) 2411-2420
  • 3 Conley P B, Delaney S M. Scientific and therapeutic insights into the role of the platelet P2Y12 receptor in thrombosis.  Curr Opin Hematol. 2003;  10 333-338
  • 4 Bhatt D L, Bertrand M E, Berger P B et al.. Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting.  J Am Coll Cardiol. 2002;  39 9-14
  • 5 Yusuf S, Zhao F, Mehta S R, Chrolavicius S, Tognoni G, Fox K K. 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
  • 6 Gurbel P A, Bliden K P, Hiatt B L, O'Connor C M. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity.  Circulation. 2003;  107(23) 2908-2913
  • 7 Serebruany V L, Steinhubl S R, Berger P B, Malinin A I, Bhatt D L, Topol E J. Variability in platelet responsiveness to clopidogrel among 544 individuals.  J Am Coll Cardiol. 2005;  45(2) 246-251
  • 8 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(25) 3171-3175
  • 9 Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement.  Thromb Haemost. 2003;  89(5) 783-787
  • 10 Grossmann R, Sokolova O, Schnurr A et al.. Variable extent of clopidogrel responsiveness in patients after coronary stenting.  Thromb Haemost. 2004;  92(6) 1201-1206
  • 11 Mobley J E, Bresee S J, Wortham D C, Craft R M, Snider C C, Carroll R C. Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization.  Am J Cardiol. 2004;  93(4) 456-458
  • 12 Gurbel P A, Cummings C C, Bell C R, Alford A B, Meister A F, Serebruany V L. Onset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective coronary stenting: the Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial.  Am Heart J. 2003;  145(2) 239-247
  • 13 Muller I, Seyfarth M, Rudiger S et al.. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement.  Heart. 2001;  85(1) 92-93
  • 14 von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E, Kastrati A, Schomig A. 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(19) 2946-2950
  • 15 Lau W C, Waskell L A, Watkins P B et al.. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction.  Circulation. 2003;  107 32-37
  • 16 Müller I, Besta F, Schulz C et al.. Effects of statins on platelet inhibition by a high loading dose of clopidogrel.  Circulation. 2003;  108 2195-2197
  • 17 Wienbergen H, Gitt A K, Schiele R et al.. Comparison of clinical benefits of clopidogrel therapy in patients with acute coronary syndromes taking atorvastatin versus other statin therapies.  Am J Cardiol. 2003;  92 285-288
  • 18 Saw J, Steinhubl S R, Berger P B et al. Clopidogrel for the Reduction of Events During Observation Investigators. Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial.  Circulation. 2003;  108(8) 921-924
  • 19 Mukherjee D, Kline-Rogers E, Fang J, Munir K, Eagle K A. Lack of clopidogrel-CYP3A4 statin interaction in patients with acute coronary syndrome.  Heart. 2005;  91(1) 23-26
  • 20 Serebruany V L, Midei M G, Malinin A I et al.. Absence of interaction between atorvastatin or other statins and clopidogrel: results from the interaction study.  Arch Intern Med. 2004;  164 2051-2057
  • 21 Angiolillo D J, Fernandez-Ortiz A, Bernardo E et al.. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment.  Diabetes. 2005;  54(8) 2430-2435
  • 22 Lau W C, Gurbel P A, Watkins P B et al.. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance.  Circulation. 2004;  109(2) 166-171
  • 23 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
  • 24 Fontana P, Gaussem P, Aiach M, Fiessinger J N, Emmerich J, Reny J L. P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study.  Circulation. 2003;  108 2971-2973
  • 25 Suh J W, Koo B K, Zhang S Y et al.. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel.  CMAJ. 2006;  174(12) 1715-1722
  • 26 Ziegler S, Schillinger M, Funk M 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. 2005;  36(7) 1394-1399
  • 27 Lev E I, Patel R T, Maresh K J 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(1) 27-33
  • 28 Wenaweser P, Dörffler-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
  • 29 Gurbel P A, Bliden K P, Guyer K et al.. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE Post-Stenting Study.  J Am Coll Cardiol. 2005;  46(10) 1820-1826
  • 30 Gurbel P A, Bliden K P, 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(10) 1827-1832
  • 31 von Pape K W, Strupp G, Bonzel T, Bohner J. Effect of compliance and dosage adaptation of long term aspirin on platelet function with PFA-100 in patients after myocardial infarction.  Thromb Haemost. 2005;  94(4) 889-891
  • 32 Montalescot G, Sideris G, Meuleman C et al. ALBION Trial Investigators. 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. 2006;  48(5) 931-938
  • 33 Wiviott S D, Antman E M, Winters K J et al. JUMBO-TIMI 26 Investigators. 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(25) 3366-3373
  • 34 Wiviott S D, Antman E M, Gibson C M. for the TRITON-TIMI 38 Investigators. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet Inhibition with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38).  Am Heart J. 2006;  152(4) 627-635
  • 35 Greenbaum A B, Grines C L, Bittl J A et al.. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial.  Am Heart J. 2006;  151(3) 689
  • 36 Husted S, Emanuelsson H, Heptinstall S, Sandset P M, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin.  Eur Heart J. 2006;  27(9) 1038-1047

Meinrad GawazM.D. 

Medizinische Klinik III, Universitätsklinikum Tübingen

Otfried-Müllerstr.10, 72076 Tübingen, Germany

Email: meinrad.gawaz@med.uni-tuebingen.de

    >