Diagnosis and Management of High Platelet Reactivity on Treatment with Clopidogrel

Abstract

Clopidogrel is an antithrombotic drug that inhibits the P2Y₁₂ platelet receptor for adenosine diphosphate. Wide interindividual variability of responses to clopidogrel were reported in several studies: about one-third of treated patients exhibit high on-treatment platelet reactivity. Genetic and environmental factors influence the absorption and/or the extent of metabolism of clopidogrel (which is a prodrug) to its active metabolite and this contributes to the observed variability of response. Tailored treatment based on the results of laboratory tests of platelet function was proposed as a solution to this problem. However, we still need to identify the ideal laboratory test and to answer basic questions on its clinical utility and cost-effectiveness, before monitoring clopidogrel therapy can be recommended in clinical practice. When possible, the use of alternative drugs with more uniform and predictable bioavailability and with favorable profiles in terms of risk/benefit and cost/benefit ratios should be preferred.

Keywords

clopidogrel - P2Y12 - prasugrel - ticagrelor - acute coronary syndromes

• References

• 1 Cattaneo M. The platelet P2Y₁₂ receptor for adenosine diphosphate: congenital and drug-induced defects. Blood 2011; 117 (7) 2102-2112
• 2 Bonello L, Tantry US, Marcucci R , et al; Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56 (12) 919-933
• 3 Bouman HJ, Schömig E, van Werkum JW , et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 2011; 17 (1) 110-116
• 4 Hulot JS, Collet JP, Cayla G , et al. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv 2011; 4 (5) 422-428
• 5 Camps J, Joven J, Mackness B , et al. Paraoxonase-1 and clopidogrel efficacy. Nat Med 2011; 17 (9) 1041-1042 , author reply 1042–1044
• 6 Dansette PM, Rosi J, Bertho G, Mansuy D. Paraoxonase-1 and clopidogrel efficacy. Nat Med 2011; 17 (9) 1040-1041 , author reply 1042–1044
• 7 Cuisset T, Morange PE, Quilici J, Bonnet JL, Gachet C, Alessi MC. Paraoxonase-1 and clopidogrel efficacy. Nat Med 2011; 17 (9) 1039 , author reply 1042–1044
• 8 Fontana P, James R, Barazer I , et al. Relationship between paraoxonase-1 activity, its Q192R genetic variant and clopidogrel responsiveness in the ADRIE study. J Thromb Haemost 2011; 9 (8) 1664-1666
• 9 Trenk D, Hochholzer W, Fromm MF , et al. Paraoxonase-1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement. Circ Cardiovasc Genet 2011; 4 (4) 429-436
• 10 Sibbing D, Koch W, Massberg S , et al. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur Heart J 2011; 32 (13) 1605-1613
• 11 Cattaneo M. New P2Y(12) inhibitors. Circulation 2010; 121 (1) 171-179
• 12 Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance. Arterioscler Thromb Vasc Biol 2004; 24 (11) 1980-1987
• 13 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 (19) 1945-1954
• 14 Cattaneo M. Response variability to clopidogrel: is tailored treatment, based on laboratory testing, the right solution?. J Thromb Haemost 2012; 10 (3) 327-336
• 15 Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 2007; 5 (Suppl 1) 230-237
• 16 Cuisset T, Frere C, Poyet R , et al. Clopidogrel response: head-to-head comparison of different platelet assays to identify clopidogrel non responder patients after coronary stenting. Arch Cardiovasc Dis 2010; 103 (1) 39-45
• 17 Lordkipanidzé M, Pharand C, Nguyen TA, Schampaert E, Palisaitis DA, Diodati JG. Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients. Eur Heart J 2008; 29: 2877-2885
• 18 Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW. Comparison of methods to evaluate clopidogrel-mediated platelet inhibition after percutaneous intervention with stent implantation. Thromb Haemost 2009; 101 (2) 333-339
• 19 Paniccia R, Antonucci E, Gori AM , et al. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. J Thromb Haemost 2007; 5 (9) 1839-1847
• 20 Paniccia R, Antonucci E, Maggini N , et al. Comparison of methods for monitoring residual platelet reactivity after clopidogrel by point-of-care tests on whole blood in high-risk patients. Thromb Haemost 2010; 104 (2) 287-292
• 21 Breet NJ, van Werkum JW, Bouman HJ , et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 2010; 303 (8) 754-762
• 22 Madsen EH, Saw J, Kristensen SR, Schmidt EB, Pittendreigh C, Maurer-Spurej E. Long-term aspirin and clopidogrel response evaluated by light transmission aggregometry, VerifyNow, and thrombelastography in patients undergoing percutaneous coronary intervention. Clin Chem 2010; 56 (5) 839-847
• 23 von Beckerath N, Sibbing D, Jawansky S , et al. Assessment of platelet response to clopidogrel with multiple electrode aggregometry, the VerifyNow P2Y12 analyzer and platelet Vasodilator-Stimulated Phosphoprotein flow cytometry. Blood Coagul Fibrinolysis 2010; 21 (1) 46-52
• 24 Gaglia MA, Torguson R, Pakala R , et al. Correlation between light transmission aggregometry, VerifyNow P2Y12, and VASP-P platelet reactivity assays following percutaneous coronary intervention. J Interv Cardiol 2011; 24 (6) 529-534
• 25 Duxbury BM, Poller L. The oral anticoagulant saga: past, present, and future. Clin Appl Thromb Hemost 2001; 7 (4) 269-275
• 26 Cattaneo M, Hayward CP, Moffat KA, Pugliano MT, Liu Y, Michelson AD. Results of a worldwide survey on the assessment of platelet function by light transmission aggregometry: a report from the platelet physiology subcommittee of the SSC of the ISTH. J Thromb Haemost 2009; 7 (6) 1029
• 27 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 (18) 1447-1455
• 28 Arméro S, Camoin-Jau L, Omar Aït Mokhtar O , et al. Intra-individual variability in clopidogrel responsiveness in coronary artery disease patients under long term therapy. Platelets 2010; 21 (7) 503-507
• 29 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 (1) 107-112
• 30 Aleil B, Jacquemin L, De Poli F , et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study. JACC Cardiovasc Interv 2008; 1 (6) 631-638
• 31 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 (25) 2474-2483
• 32 Tofler GH, Brezinski D, Schafer AI , et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 1987; 316 (24) 1514-1518
• 33 Kozinski M, Bielis L, Wisniewska-Szmyt J , et al. Diurnal variation in platelet inhibition by clopidogrel. Platelets 2011; 22 (8) 579-587
• 34 Mehran R, Pocock SJ, Nikolsky E , et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 2010; 55 (23) 2556-2566
• 35 Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114 (8) 774-782
• 36 Pocock SJ, Mehran R, Clayton TC , et al. Prognostic modeling of individual patient risk and mortality impact of ischemic and hemorrhagic complications: assessment from the Acute Catheterization and Urgent Intervention Triage Strategy trial. Circulation 2010; 121 (1) 43-51
• 37 Sibbing D, Steinhubl SR, Schulz S, Schömig A, Kastrati A. Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: initial evidence of a therapeutic window. J Am Coll Cardiol 2010; 56 (4) 317-318
• 38 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 (14) 1404-1411
• 39 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 (1) 5-10
• 40 Pena A, Collet JP, Hulot JS , et al. Can we override clopidogrel resistance?. Circulation 2009; 119 (21) 2854-2857
• 41 Price MJ, Berger PB, Teirstein PS , et al; Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011; 305 (11) 1097-1105
• 42 Gurbel PA, Tantry US. An initial experiment with personalized antiplatelet therapy: the GRAVITAS trial. JAMA 2011; 305 (11) 1136-1137
• 43 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 (10) 1132-1137
• 44 Parodi G, Marcucci R, Valenti R , et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA 2011; 306 (11) 1215-1223
• 45 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; 59 (24) 2159-2164
• 46 FDA Drug Safety Communication: reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm190836.htm (accessed Aug 3, 2010)
• 47 Holmes Jr DR, Dehmer GJ, Kaul S, Leifer D, O'Gara PT, Stein CM. ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2010; 56 (4) 321-341
• 48 Hochholzer W, Trenk D, Fromm MF , et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol 2010; 55 (22) 2427-2434
• 49 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. JAMA 2009; 302 (8) 849-857
• 50 Bouman HJ, Harmsze AM, van Werkum JW , et al. Variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest in clopidogrel pretreated patients undergoing coronary stenting. Heart 2011; 97 (15) 1239-1244
• 51 Aleil B, Léon C, Cazenave JP, Gachet C. CYP2C19*2 polymorphism is not the sole determinant of the response to clopidogrel: implications for its monitoring. J Thromb Haemost 2009; 7 (10) 1747-1749
• 52 Mega JL, Hochholzer W, Frelinger III AL , et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 2011; 306 (20) 2221-2228
• 53 Roberts JD, Wells GA, Le May MR , et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 2012; 379 (9827) 1705-1711