Subscribe to RSS
DOI: 10.1160/TH12-01-0039
Translational platelet research in patients with coronary artery disease: What are the major knowledge gaps?
Publication History
Received:
23 January 2012
Accepted after major revision:
03 April 2012
Publication Date:
22 November 2017 (online)
Summary
Translational platelet function investigations performed in the percutaneous coronary intervention (PCI)-treated population receiving clopidogrel have identified high platelet reactivity to ADP (HPR) as a major risk factor for both acute as well as long-term ischaemic event occurrence, including stent thrombosis. Recent studies have highlighted the relation of single nucleotide polymorphisms of genes involved in clopidogrel absorption and metabolism to reduced pharmacokinetic and pharmacodynamic responses to clopidogrel. CYP 2C19 loss-of-function (LoF) allele carriage has been associated with increased thrombotic risk in the PCI population. However, there is no information regarding the utility of platelet function testing to predict outcomes in patients with stable coronary artery disease and in medically managed patients with acute coronary syndromes. Additionally, few studies have included longitudinal assessment of platelet function to assess a potential time-dependent relation to ischaemic event occurrence and no phase-III antiplatelet-therapy trial has included a large enough platelet function sub-study to examine the relation between on-treatment platelet reactivity, bleeding, and ischaemic event occurrence. Therefore, futher studies are needed to delineate the role of platelet function testing across the spectrum of symptomatic coronary artery disease.
-
References
- 1 Gurbel PA, Bliden KP, Hayes KM. et al. Platelet activation in myocardial ischemic syndromes. Expert Rev Cardiovasc Ther 2004; 02: 535-545.
- 2 Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J Clin Invest 2004; 113: 340-345.
- 3 Helton TJ, Bavry AA, Kumbhani DJ. et al. Incremental effect of clopidogrel on important outcomes in patients with cardiovascular disease: a meta-analysis of randomized trials. Am J Cardiovasc Drugs 2007; 07: 289-297.
- 4 Bonello L, Tantry US, Marcucci R. et al. Working Group on High On-Treatment Platelet Reactivity. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
- 5 Gurbel PA, Antonino MJ, Tantry US. Recent developments in clopidogrel pharmacology and their relation to clinical outcomes. Expert Opin Drug Metab Toxicol 2009; 05: 989-1004.
- 6 Brandt JT, Close SL, Iturria SJ. et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 05: 2429-2436.
- 7 Mega JL, Close SL, Wiviott SD. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-362.
- 8 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.
- 9 Mega JL, Simon T, Collet JP. et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. J Am Med Assoc 2010; 304: 1821-1830.
- 10 Pare G, Mehta SR, Yusuf S. et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010; 363: 1704-1714.
- 11 Wallentin L, James S, Storey RF. et al. Effect of CYP2C19and 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.
- 12 Price MJ, Tantry US, Gurbel PA. The influence of CYP2C19 polymorphisms on the pharmacokinetics, pharmacodynamics, and clinical effectiveness of P2Y(12) inhibitors. Rev Cardiovasc Med 2011; 12: 1-12.
- 13 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 pharmacogenetic analysis. Lancet 2010; 376: 1312-1319.
- 14 Bouman HJ, Schömig E, van Werkum JW. et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 2011; 17: 110-116.
- 15 Price MJ, Murray SS, Angiolillo DJ. et al. Primary Results From Genotype Information and Functional Testing A Prospective pharmacogenomic Analysis of Clopidogrel Therapy. Presented at American College of Cardiology Meeting 2011 at New Orleans, USA (late braking presentation.
- 16 Lewis JP, Fisch AS, Ryan K. et al. Paraoxonase 1 (PON1) Gene Variants Are Not Associated With Clopidogrel Response. Clin Pharmacol Ther 2011; 90: 568-574.
- 17 FDA Drug Safety Communication: reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. Available at: http://www.fda.gov/Drugs/DrugSafety/Postmarket DrugSafetyInformationfor-PatientsandProviders/ucm203888.htm Accessed April 28, 2011
- 18 Jeong YH, Kim IS, Park Y. et al. Carriage of cytochrome 2C19 polymorphism is associated with risk of high post-treatment platelet reactivity on high m aintenancedose clopidogrel of 150 mg/day: Results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) study. JACC Cardiovasc Interv 2010; 03: 731-741.
- 19 Bonello L, Armero S, Ait Mokhtar O. et al. Clopidogrel loading dose adjustment according to platelet reactivity monitoring in patients carrying the 2C19*2 loss of function polymorphism. J Am Coll Cardiol 2010; 56: 1630-1636.
- 20 Mega JL, Hochholzer W, Frelinger 3rd AL. et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. J Am Med Assoc 2012; 306: 2221-2228.
- 21 Tantry US, Bliden KP, Wei C. et al. First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies. Circ Cardiovasc Genet 2010; 03: 556-566.
- 22 Alexopoulos D, Dimitropoulos G, Davlouros P. et al. Prasugrel overcomes high on-clopidogrel platelet reactivity post-stenting more effectively than high-dose (150-mg) clopidogrel: the importance of CYP2C19*2 genotyping. JACC Cardiovasc Interv 2011; 04: 403-410.
- 23 Wiviott SD, Braunwald E, McCabe CH. et al. TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
- 24 Varenhorst C, James S, Erlinge D. et al. Genetic variation of cyp2c19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Eur Heart J 2009; 30: 1744-1752.
- 25 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.
- 26 Tentzeris I, Siller-Matula J, Farhan S. et al. Platelet function variability and non-genetic causes. Thromb Haemost 2011; 105 (Suppl. 01) S60-66.
- 27 Gurbel PA, Ohman EM, Jeong YH. et al. Toward a therapeutic window for antiplatelet therapy in the elderly. Eur Heart J. 2012 Epub ahead of print.
- 28 Bliden KP, DiChiara J, Lookman L. et al. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol 2008; 52: 531-533.
- 29 Berger JS, Bhatt DL, Steinhubl SR. et al. CHARISMA Investigators. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation 2009; 120: 2337-2344.
- 30 Desai NR, Mega JL, Jiang S. et al. Interaction between cigarette smoking and clinical benefit of clopidogrel. J Am Coll Cardiol 2009; 53: 1273-1278.
- 31 Wright RS, Anderson JL, Adams CD. et al. 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/ Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 123: 2022-2060.
- 32 Bhatt DL, Paré G, Eikelboom JW. et al. The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study. Eur Heart J. 2012 Epub ahead of print.
- 33 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
- 34 Price MJ, Berger PB, Teirstein PS. et al. GRAVITAS Investigators. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. J Am Med Assoc 2011; 305: 1097-1105.
- 35 Campo G, Parrinello G, Ferraresi P. et al. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol 2011; 57: 2474-2483.
- 36 Gurbel PA, Tantry US. Clopidogrel response variability and the advent of personalised antiplatelet therapy. A bench to bedside journey. Thromb Haemost 2011; 106: 265-271.
- 37 Sibbing D, Byrne RA, Bernlochner I, Kastrati A. High platelet reactivity and clinical outcome - fact and fiction. Thromb Haemost 2011; 106: 191-202.
- 38 Price MJ, Endemann S, Gollapudi RR. et al. 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 2008; 29: 992-1000.
- 39 Gurbel PA, Antonino MJ, Bliden KP. et al. Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target. Platelets 2008; 19: 595-604.
- 40 Bonello L, Paganelli F, Arpin-Bornet M. et al. Vasodilatorstimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 2007; 05: 1630-1636.
- 41 Sibbing D, Braun S, Morath T. et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849-856.
- 42 Brar SS, Ten Berg J, Marcucci R. et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention a collaborative meta-analysis of individual participant data. J Am Coll Cardiol 2011; 58: 1945-1954.
- 43 Stone GW. Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents A Large-Scale, Prospective, Multicenter Registry Examining the Relationship Between Platelet Responsiveness and Stent Thrombosis After DES Implantation. Presented at TCT 2011 (late braking presentation).
- 44 Cattaneo M. Bleeding manifestations of congenital and drug-induced defects of the platelet P2Y12 receptor for adenosine diphosphate. Thromb Haemost 2011; 105 (Suppl. 01) S67-74.
- 45 Gurbel PA, Mahla E, Tantry US. Peri-operative platelet function testing: the potential for reducing ischaemic and bleeding risks. Thromb Haemost 2011; 106: 248-252.
- 46 Peter K, Myles PS. Perioperative antiplatelet therapy: a knife-edged choice between thrombosis and bleeding still based on consensus rather than evidence. Thromb Haemost 2011; 105: 750-751.
- 47 Chen L, Bracey AW, Radovancevic R. et al. Clopidogrel and bleeding in patients undergoing elective coronary artery bypass grafting. J Thorac Cardiovasc Surg 2004; 128: 425-431.
- 48 Mahla E, Suarez TA, Bliden KP. et al. Platelet Function Measurement-Based Strategy to Reduce Bleeding and Waiting Time in Clopidogrel-Treated Patients Undergoing Coronary Artery Bypass Graft Surgery: The Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG (TAR-GET-CABG) Study. Circ Cardiovasc Interv 2012; 05: 261-269.
- 49 Reece MJ, Klein AA, Salviz EA. et al. Near-patient platelet function testing in patients undergoing coronary artery surgery: a pilot study*. Anaesthesia 2011; 66: 97-103.
- 50 Kwak YL, Kim JC, Choi YS. et al. Clopidogrel responsiveness regardless of the discontinuation date predicts increased blood loss and transfusion requirement after off-pump coronary artery bypass graft surgery. J Am Coll Cardiol 2010; 56: 1994-2002.
- 51 Ranucci M, Baryshnikova E, Soro G. et al. Surgical and Clinical Outcome Research (SCORE) Group. Multiple electrode whole-blood aggregometry and bleeding in cardiac surgery patients receiving thienopyridines. Ann Thorac Surg 2011; 91: 123-129.
- 52 Sibbing D, Schulz S, Braun S. et al. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 2010; 08: 250-256.
- 53 Gurbel PA, Bliden KP, Navickas IA. et al. Adenosine diphosphate-induced platelet-fibrin clot strength: a new thrombelastographic indicator of long-term post-stenting ischemic events. Am Heart J 2010; 160: 346-354.
- 54 Mokhtar OA, Lemesle G, Armero S. et al. Relationship between platelet reactivity inhibition and non-CABG related major bleeding in patients undergoing percutaneous coronary intervention. Thromb Res 2010; 126: e147-149.
- 55 Patti G, Pasceri V, Vizzi V. et al. Usefulness of platelet response to clopidogrel by point-of-care testing to predict bleeding outcomes in patients undergoing percutaneous coronary intervention (from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty-Bleeding Study). Am J Cardiol 2011; 107: 995-1000.
- 56 Cuisset T, Cayla G, Frere C. et al. Predictive value of post-treatment platelet reactivity for occurrence of post-discharge bleeding after non-ST elevation acute coronary syndrome. Shifting from antiplatelet resistance to bleeding risk assessment? Euro Interv 2009; 05: 325-329.
- 57 Gurbel PA, Becker RC, Mann KG. et al. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007; 50: 1822-1834.
- 58 Bonello L, Camoin-Jau L, Arques S. et al. 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 2008; 51: 1404-1411.
- 59 Bonello L, Camoin-Jau L, Armero S. et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol 2009; 103: 5-10.
- 60 Campo G, Fileti L, de Cesare N. et al. 3T/2R Investigators. Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy. J Am Coll Cardiol 2010; 56: 1447-1455.
- 61 Cuisset T, Frere C, Quilici J. et al. Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders: a prospective, randomized study. J Am Coll Cardiol Intv 2008; 01: 649-653.
- 62 Gurbel PA, Tantry US. An initial experiment with personalized antiplatelet therapy: the GRAVITAS trial. J Am Med Assoc 2011; 305: 1136-1137.
- 63 Price MJ, Angiolillo DJ, Teirstein PS. et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention. A time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation 2011; 124: 1132-1137.
- 64 Trenk D, Stone GW, Gawaz M. et al. A Randomized Trial of Prasugrel Versus Clopidogrel in Patients With High Platelet Reactivity on Clopidogrel After Elective Percutaneous Coronary Intervention With Implantation of Drug-Eluting Stents: Results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) Study. J Am Coll Cardiol. 2012 Epub ahead of print.
- 65 Gurbel PA, Tantry US, Bliden KP, Jeong YH. Immunity to thrombotic events is achievable if we stop the guessing game: is this the major hidden message from GRAVITAS?. Thromb Haemost 2011; 106: 263-264.
- 66 Breet NJ, van Werkum JW, Bouman HJ. et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. J Am Med Assoc 2010; 303: 754-762.
- 67 Geisler T, Grass D, Bigalke B. et al. The Residual Platelet Aggregation after Deployment of Intracoronary Stent (PREDICT) score. J Thromb Haemost 2008; 06: 54-61.
- 68 Jeong YH, Tantry US, Kim IS. et al. Effect of CYP2C19*2 and *3 Loss-of-Function Alleles on Platelet Reactivity and Adverse Clinical Events in East Asian Acute Myocardial Infarction Survivors Treated With Clopidogrel and Aspirin. Circ Cardiovasc Interv. 2011 Epub ahead of print.
- 69 Singla A, Antonino MJ, Bliden KP. et al. The relation between platelet reactivity and glycemic control in diabetic patients with cardiovascular disease on maintenance aspirin and clopidogrel therapy. Am Heart J 2009; 158 784 e1-6.
- 70 Mangiacapra F, Patti G, Peace A. et al. Comparison of platelet reactivity and periprocedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention. Am J Cardiol 2010; 106: 619-623.
- 71 Chin CT, Roe MT, Fox KA. et al. TRILOGY ACS Steering Committee. Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial. Am Heart J 2010; 160: 16-22. e1.