Download PDF
Thromb Haemost 2013; 110(01): 110-117
DOI: 10.1160/TH13-01-0057
Platelets and Blood Cells
Schattauer GmbH

Clopidogrel pretreatment in primary percutaneous coronary intervention: Prevalence of high on-treatment platelet reactivity and impact on preprocedural patency of the infarct-related artery

José Luis Ferreiro   *
1   Heart Diseases Institute, Bellvitge University Hospital – IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
,
Sílvia Homs   *
1   Heart Diseases Institute, Bellvitge University Hospital – IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
,
Javier Berdejo
1   Heart Diseases Institute, Bellvitge University Hospital – IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
,
Gerard Roura
1   Heart Diseases Institute, Bellvitge University Hospital – IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
,
Josep Gómez-Lara
1   Heart Diseases Institute, Bellvitge University Hospital – IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
,
Rafael Romaguera
1   Heart Diseases Institute, Bellvitge University Hospital – IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
,
Luis Teruel
1   Heart Diseases Institute, Bellvitge University Hospital – IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
,
Guillermo Sánchez-Elvira
1   Heart Diseases Institute, Bellvitge University Hospital – IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
,
Ana Lucrecia Marcano
1   Heart Diseases Institute, Bellvitge University Hospital – IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
,
Joan Antoni Gómez-Hospital
1   Heart Diseases Institute, Bellvitge University Hospital – IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
,
Dominick J. Angiolillo
2   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
,
Ángel Cequier
1   Heart Diseases Institute, Bellvitge University Hospital – IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain
› Author Affiliations Financial support: Silvia Homs is recipient of a Grant of the Interventional Cardiology Section of the Spanish Society of Cardiology for Post-Residency Training in Research.
Further Information

Publication History

Received: 23 January 2013

Accepted after major revision: 08 April 2013

Publication Date:
30 November 2017 (online)

    Permissions and Reprints

Summary

To date, there is limited data on levels of platelet inhibition achieved in patients with ST-elevation myocardial infarction (STEMI) who are loaded with clopidogrel and aspirin (ASA) prior to undergoing primary percutaneous coronary intervention (P-PCI). The aim of this investigation was to evaluate the percentage of STEMI patients with high on-treatment platelet reactivity (HPR) to clopidogrel at the time of initiating P-PCI and its association with the initial patency of the infarct-related artery (IRA). This prospective pharmacodynamic study included 50 STEMI patients, previously naïve to oral antiplatelet agents, who received 500-mg ASA and 600-mg clopidogrel loading doses prior to P-PCI. Platelet function assessment was performed at the beginning of the procedure using various assays, including VerifyNow™ system (primary endpoint), light transmission aggregometry and multiple electrode aggregometry. The percentage of patients with suboptimal response to clopidogrel and ASA assessed with the VerifyNow™ system was 88.0% and 28.6%, respectively. Similar results were obtained with the other assays used. A higher percentage of patients with initial patency of the IRA was observed among those patients without HPR compared with those with HPR to clopidogrel (66.7% vs 15.9%; p=0.013), while no differences were observed regarding postprocedural angiographic or electrocardiographic outcomes. In conclusion, this study shows that a high percentage of STEMI patients have inadequate levels of clopidogrel-induced and, to a lesser extent, aspirin-mediated platelet inhibition when starting a P-PCI procedure, and suggests that a poor response to clopidogrel might be associated with impaired initial TIMI flow in the IRA.

Keywords

Clopidogrel responsiveness - ST-elevation myocardial infarction - antiplatelet therapy

* JLF and SH contributed equally as first authors to this manuscript.


 

  • References

  • 1 Ferreiro JL, Angiolillo DJ. New directions in antiplatelet therapy. Circ Cardiovasc Interv 2012; 05: 433-445.
    CrossrefPubMedGoogle Scholar
  • 2 Gómez-Hospital JA, Dallaglio PD, Sánchez-Salado JC. et al. Impact on Delay Times and Characteristics of Patients Undergoing Primary Percutaneous Coronary Intervention in the Southern Metropolitan Area of Barcelona After Implementation of the Infarction Code Program. Rev Esp Cardiol 2012; 65: 911-918.
    CrossrefPubMedGoogle Scholar
  • 3 Bellemain-Appaix A, O’Connor SA, Silvain J. et al; for the ACTION group. Association of Clopidogrel Pretreatment With Mortality, Cardiovascular Events, and Major Bleeding Among Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-analysis. J Am Med Assoc 2012; 308: 2507-2516.
    CrossrefPubMedGoogle Scholar
  • 4 Vlaar PJ, Svilaas T, Damman K. et al. Impact of pretreatment with clopidogrel on initial patency and outcome in patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: a systematic review. Circulation 2008; 118: 1828-1836.
    CrossrefPubMedGoogle Scholar
  • 5 Dörler J, Edlinger M, Alber HF. et al; Austrian Acute PCI Investigators. Clopidogrel pre-treatment is associated with reduced in-hospital mortality in primary percutaneous coronary intervention for acute ST-elevation myocardial infarction. Eur Heart J 2011; 32: 2954-2961.
    CrossrefPubMedGoogle Scholar
  • 6 Fefer P, Hod H, Hammerman H. et al. Usefulness of pretreatment with highdose clopidogrel in patients undergoing primary angioplasty for ST-elevation myocardial infarction. Am J Cardiol 2009; 104: 514-518.
    CrossrefPubMedGoogle Scholar
  • 7 Ferreiro JL, Angiolillo DJ. Clopidogrel response variability: current status and future directions. Thromb Haemost 2009; 102: 7-14.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Bonello L, Berbis J, Laine M. et al. Biological efficacy of a 600 mg loading dose of clopidogrel in ST-elevation myocardial infarction. Thromb Haemost 2012; 108: 101-106.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Alexopoulos D, Theodoropoulos KC, Stavrou EF. et al. Prasugrel versus high dose clopidogrel to overcome early high on clopidogrel platelet reactivity in patients with ST elevation myocardial infarction. Cardiovasc Drugs Ther 2012; 26: 393-400.
    CrossrefPubMedGoogle Scholar
  • 10 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
  • 11 Ariza A, Ferreiro JL, Sánchez-Salado JC. et al. Early Anticoagulation May Improve Preprocedural Patency of the Infarct-related Artery in Primary Percutaneous Coronary Intervention. Rev Esp Cardiol. 2012 Epub ahead of print.
    PubMedGoogle Scholar
  • 12 TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. N Engl J Med 1985; 312: 932-936.
    PubMedGoogle Scholar
  • 13 van 't Hof AW, Liem A, Suryapranata H. et al. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Zwolle Myocardial Infarction Study Group. Circulation 1998; 97: 2302-2306.
    CrossrefPubMedGoogle Scholar
  • 14 van 't Hof AW, Liem A, de Boer MJ. et al. Clinical value of 12-lead electrocardiogram after successful reperfusion therapy for acute myocardial infarction. Zwolle Myocardial infarction Study Group. Lancet 1997; 350: 615-619.
    CrossrefPubMedGoogle Scholar
  • 15 Malinin A, Pokov A, Spergling M. et al. Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12(R) rapid analyzer: the VERIfy Thrombosis risk ASsessment (VERITAS) study. Thromb Res 2007; 119: 277-284.
    CrossrefPubMedGoogle Scholar
  • 16 Fox SC, Behan MW, Heptinstall S. Inhibition of ADP-induced intracellular Ca2+ responses and platelet aggregation by the P2Y12 receptor antagonists ARC69931MX and clopidogrel is enhanced by prostaglandin E1. Cell Calcium 2004; 35: 39-46.
    CrossrefPubMedGoogle Scholar
  • 17 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
  • 18 Sibbing D, Braun S, Jawansky S. et al. Assessment of ADP-induced platelet aggregation with light transmission aggregometry and multiple electrode platelet aggregometry before and after clopidogrel treatment. Thromb Haemost 2008; 99: 121-126.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Ueno M, Ferreiro JL, Tomasello SD. et al. Impact of pentoxifylline on platelet function profiles in patients with type 2 diabetes mellitus and coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel. JACC Cardiovasc Interv 2011; 04: 905-912.
    PubMedGoogle Scholar
  • 20 Ferreiro JL, Angiolillo DJ. Clopidogrel response variability: current status and future directions. Thromb Haemost 2009; 102: 7-14.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 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
  • 22 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 (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 2005; 112: 2946-2950.
    PubMedGoogle Scholar
  • 23 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
  • 24 Soffer D, Moussa I, Harjai KJ. et al. Impact of angina class on inhibition of platelet aggregation following clopidogrel loading in patients undergoing coronary intervention: do we need more aggressive dosing regimens in unstable angina?. Catheter Cardiovasc Interv 2003; 59: 21-25.
    CrossrefPubMedGoogle Scholar
  • 25 Sibbing D, von Beckerath O, Schömig A. et al. Platelet function in clopidogreltreated patients with acute coronary syndrome. Blood Coagul Fibrinolysis 2007; 18: 335-339.
    CrossrefPubMedGoogle Scholar
  • 26 Biscaglia S, Tebaldi M, Vranckx P. et al. Effects of pre-hospital clopidogrel administration on early and late residual platelet reactivity in ST-segment elevation myocardial infarction patients undergoing primary intervention. J Thromb Haemost 2013; 11: 192-194.
    PubMedGoogle Scholar
  • 27 Heestermans AA, van Werkum JW, Taubert D. et al. Impaired bioavailability of clopidogrel in patients with a ST-segment elevation myocardial infarction. Thromb Res 2008; 122: 776-781.
    CrossrefPubMedGoogle Scholar
  • 28 Bailey RW, Bulkley GB, Hamilton SR. et al. Protection of the small intestine from nonocclusivemesenteric ischemic injury due to cardiogenic shock. Am J Surg 1987; 153: 108-116.
    CrossrefPubMedGoogle Scholar
  • 29 Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J Med 1999; 341: 577-585.
    CrossrefPubMedGoogle Scholar
  • 30 Taubert D, Kastrati A, Harlfinger S. et al. Pharmacokinetics of clopidogrel after administration of high loading dose. Thromb Haemost 2004; 92: 311-316.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Alexopoulos D, Theodoropoulos KC, Stavrou EF. et al. Prasugrel versus high dose clopidogrel to overcome early high on clopidogrel platelet reactivity in patients with ST elevation myocardial infarction. Cardiovasc Drugs Ther 2012; 26: 393-400.
    CrossrefPubMedGoogle Scholar
  • 32 Bliden KP, Tantry US, Storey RF. et al. The effect of ticagrelor versus clopidogrel on high on-treatment platelet reactivity: combined analysis of the ONSET/OFFSET and RESPOND studies. Am Heart J 2011; 162: 160-165.
    CrossrefPubMedGoogle Scholar
  • 33 Montalescot G, Wiviott SD, Braunwald E. et al. TRITON-TIMI 38 investigators. 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
  • 34 Steg PG, James S, Harrington RA. et al; PLATO Study Group. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation 2010; 122: 2131-2141.
    CrossrefPubMedGoogle Scholar
  • 35 Nührenberg TG, Trenk D, Leggewie S. et al. Clopidogrel pretreatment of patients with ST-elevation myocardial infarction does not affect platelet reactivity after subsequent prasugrel-loading: Platelet reactivity in an observational study. Platelets. 2012 Epub ahead of print.
    PubMedGoogle Scholar
  • 36 Alexopoulos D, Galati A, Xanthopoulou I. et al. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. J Am Coll Cardiol 2012; 60: 193-199.
    CrossrefPubMedGoogle Scholar
  • 37 Alexopoulos D, Xanthopoulou I, Gkizas V. et al. Randomized Assessment of Ticagrelor Versus Prasugrel Antiplatelet Effects in Patients with ST-Segment-Elevation Myocardial Infarction. Circ Cardiovasc Interv 2012; 05: 797-804.
    CrossrefPubMedGoogle Scholar
  • 38 Heestermans AA, van Werkum JW, Zwart B. et al. Acute and subacute stent thrombosis after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: incidence, predictors and clinical outcome. J Thromb Haemost 2010; 08: 2385-2393.
    CrossrefPubMedGoogle Scholar
  • 39 Valgimigli M, Tebaldi M, Campo G. et al.; FABOLUS PRO Investigators. Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial. JACC Cardiovasc Interv 2012; 05: 268-277.
    CrossrefPubMedGoogle Scholar
  • 40 Angiolillo DJ, Schneider DJ, Bhatt DL. et al. Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis 2012; 34: 44-55.
    CrossrefPubMedGoogle Scholar
  • 41 Ferreiro JL, Ueno M, Tello-Montoliu A. et al. Effects of cangrelor in coronary artery disease patients with and without diabetes mellitus: an in vitro pharmacodynamic investigation. J Thromb Thrombolysis. 2012 Epub ahead of print.
    PubMedGoogle Scholar
  • 42 Bhatt DL, Stone GW, Mahaffey KW. et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013 Epub ahead of print.
    PubMedGoogle Scholar