Download PDF
Thromb Haemost 2011; 105(05): 766-773
DOI: 10.1160/TH10-10-0633
Clinical Focus
Schattauer GmbH

Clopidogrel in acute coronary syndromes: Where are we now?

Kevin R. Bainey
1   Department of Medicine, McMaster University and Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada
,
Tony F. Lai
1   Department of Medicine, McMaster University and Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada
,
Shamir R. Mehta
1   Department of Medicine, McMaster University and Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada
› Author Affiliations
Further Information

Publication History

Received: 04 October 2010

Accepted after major revision: 28 January 2011

Publication Date:
28 November 2017 (online)

Also available at
    Permissions and Reprints

 

 

  • References

  • 1 Thom T, Haase N, Rosamond W. et al. Heart disease and stroke statistics--2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2006; 113: e85-151.
    CrossrefPubMedGoogle Scholar
  • 2 Derhaschnig U, Jilma B. Assessment of platelets and the endothelium in patients presenting with acute coronary syndromes--is there a future?. Thromb Haemost 2009; 102: 1144-1148.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Langer HF, Gawaz M. Platelet-vessel wall interactions in atherosclerotic disease. Thromb Haemost 2008; 99: 480-486.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Engelmann B, Luther T, Muller I. Intravascular tissue factor pathway--a model for rapid initiation of coagulation within the blood vessel. Thromb Haemost 2003; 89: 3-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Jennings LK. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost 2009; 102: 248-257.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Becker RC, Gurbel PA. Platelet P2Y12 receptor antagonist pharmacokinetics and pharmacodynamics: A foundation for distinguishing mechanisms of bleeding and anticipated risk for platelet-directed therapies. Thromb Haemost 2010; 103: 535-544.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).. CAPRIE Steering Committee. Lancet 1996; 348: 1329-1339.
    CrossrefPubMedGoogle Scholar
  • 8 Steinhubl SR, Berger PB, Mann JT. 3rd, 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.
    CrossrefPubMedGoogle Scholar
  • 9 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.
    CrossrefPubMedGoogle Scholar
  • 10 Anderson JL, Adams CD, Antman EM. 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/NonST-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 2007; 50: e1-e157.
    CrossrefPubMedGoogle Scholar
  • 11 Bassand JP, Hamm CW, Ardissino D. et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007; 28: 1598-1660.
    CrossrefPubMedGoogle Scholar
  • 12 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.
    CrossrefPubMedGoogle Scholar
  • 13 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 PCI-CLARITY study. J Am Med Assoc 2005; 294: 1224-1232.
    CrossrefPubMedGoogle Scholar
  • 14 Chen ZM, Jiang LX, Chen YP. et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607-1621.
    CrossrefPubMedGoogle Scholar
  • 15 Gurbel PA, Tantry US. Drug insight: Clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med 2006; 3: 387-395.
    CrossrefPubMedGoogle Scholar
  • 16 Jaitner J, Stegherr J, Morath T. et al. Stability of the high on-treatment platelet reactivity phenotype over time in clopidogrel-treated patients. Thromb Haemost 2011; 105: 107-112.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Ferreiro JL, Angiolillo DJ. Clopidogrel response variability: current status and future directions. Thromb Haemost 2009; 102: 7-14.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 De Miguel A, Ibanez B, Badimon JJ. Clinical implications of clopidogrel resistance. Thromb Haemost 2008; 100: 196-203.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Sofi F, Marcucci R, Gori AM. et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost 2010; 103: 841-848.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 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.
    CrossrefPubMedGoogle Scholar
  • 21 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Buonamici P, Marcucci R, Migliorini A. et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 49: 2312-2317.
    CrossrefPubMedGoogle Scholar
  • 23 Price M. GRAVITAS: Primary results of the gauging responsiveness with a VerifyNow assay – impact on thrombosis and safety trial. Presented at American Heart Association Scientific Sessions; November 16, 2010; Chicago, Illinois.
    PubMedGoogle Scholar
  • 24 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: 92-93.
    CrossrefPubMedGoogle Scholar
  • 25 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.
    CrossrefPubMedGoogle Scholar
  • 26 Cuisset T, Frere C, Quilici J. et al. 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 2006; 48: 1339-1345.
    CrossrefPubMedGoogle Scholar
  • 27 Montalescot G, Sideris G, Meuleman C. 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 2006; 48: 931-938.
    CrossrefPubMedGoogle Scholar
  • 28 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 (Intra-coronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 2005; 112: 2946-2950.
    PubMedGoogle Scholar
  • 29 Angiolillo DJ, Shoemaker SB, Desai B. et al. 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 2007; 115: 708-716.
    CrossrefPubMedGoogle Scholar
  • 30 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J 2004; 25: 1903-1910.
    CrossrefPubMedGoogle Scholar
  • 31 von Beckerath N, Kastrati A, Wieczorek A. et al. 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 2007; 28: 1814-1819.
    CrossrefPubMedGoogle Scholar
  • 32 Mehta SR, Bassand JP, Chrolavicius S. et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010; 363: 930-942.
    CrossrefPubMedGoogle Scholar
  • 33 Mehta SR, Tanguay JF, Eikelboom JW. et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010; 376: 1233-1243.
    CrossrefPubMedGoogle Scholar
  • 34 Cutlip DE, Windecker S, Mehran R. et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115: 2344-2351.
    CrossrefPubMedGoogle Scholar
  • 35 Kazui M, Nishiya Y, Ishizuka T. et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 2010; 38: 92-99.
    CrossrefPubMedGoogle Scholar
  • 36 Collet JP, Hulot JS, Pena A. et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373: 309-317.
    CrossrefPubMedGoogle Scholar
  • 37 Mega JL, Close SL, Wiviott SD. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-362.
    CrossrefPubMedGoogle Scholar
  • 38 Mega JL, Close SL, Wiviott SD. et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009; 119: 2553-2560.
    CrossrefPubMedGoogle Scholar
  • 39 Simon T, Verstuyft C, Mary-Krause M. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-375.
    CrossrefPubMedGoogle Scholar
  • 40 Shuldiner AR, O’Connell JR, Bliden KP. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. J Am Med Assoc 2009; 302: 849-857.
    CrossrefPubMedGoogle Scholar
  • 41 Paré G, Mehta SR, Yusuf S. et al. Effects of CYP2C19 genotype on clopidogrel treatment. N Eng J Med 2010; 363: 1704-1714.
    CrossrefPubMedGoogle Scholar
  • 42 Wallentin L, James S, Storey RF. et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010; 376: 1320-1328.
    CrossrefPubMedGoogle Scholar
  • 43 Taubert D, von Beckerath N, Grimberg G. et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006; 80: 486-501.
    CrossrefPubMedGoogle Scholar
  • 44 Mega JL, Close SL, Wiviott SD. et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmaco-genetic analysis. Lancet 2010; 376: 1312-1319.
    CrossrefPubMedGoogle Scholar
  • 45 Gilard M, Arnaud B, Cornily JC. et al. 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 2008; 51: 256-260.
    CrossrefPubMedGoogle Scholar
  • 46 Sibbing D, Morath T, Stegherr J. et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101: 714-719.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. J Am Coll Cardiol 2008; 52: 1038-1039 author reply 1039.
    PubMedGoogle Scholar
  • 48 Juurlink DN, Gomes T, Ko DT. et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009; 180: 713-718.
    CrossrefPubMedGoogle Scholar
  • 49 Ho PM, Maddox TM, Wang L. et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. J Am Med Assoc 2009; 301: 937-944.
    CrossrefPubMedGoogle Scholar
  • 50 O’Donoghue ML, Braunwald E, Antman EM. et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 2009; 374: 989-997.
    CrossrefPubMedGoogle Scholar
  • 51 Charlot M, Ahlehoff O, Norgaard ML. et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med 2010; 153: 378-386.
    CrossrefPubMedGoogle Scholar
  • 52 Siller-Matula JM, Jilma B, Schror K. et al. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. J Thromb Haemost 2010; 8: 2624-2641.
    CrossrefPubMedGoogle Scholar
  • 53 Bhatt DL, Cryer BL, Contant CF. et al. Clopidogrel with or without Omeprazole in Coronary Artery Disease. N Engl J Med 2010; 363: 1909-1917.
    CrossrefPubMedGoogle Scholar
  • 54 Serebruany VL. The TRITON versus PLATO trials: differences beyond platelet inhibition. Thromb Haemost 2010; 103: 259-261.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 55 Wiviott SD, Braunwald E, McCabe CH. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
    CrossrefPubMedGoogle Scholar
  • 56 Mehta SR, Yusuf S, Peters RJ. et al. Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
    CrossrefPubMedGoogle Scholar
  • 57 Montalescot G, Wiviott SD, Braunwald E. et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373: 723-731.
    CrossrefPubMedGoogle Scholar
  • 58 Dangas G, Mehran R, Guagliumi G. et al. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol 2009; 54: 1438-1446.
    CrossrefPubMedGoogle Scholar
  • 59 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
    CrossrefPubMedGoogle Scholar
  • 60 Steg PG, James S, Harrington RA. et al. Ticagrelor Versus Clopidogrel in Patients With ST-Elevation Acute Coronary Syndromes Intended for Reper-fusion With Primary Percutaneous Coronary Intervention: A Platelet Inhibition and Patient Outcomes (PLATO) Trial Subgroup Analysis. Circulation 2010; 122: 2131-2141.
    CrossrefPubMedGoogle Scholar