Prevalence of poor biological response to clopidogrel

Summary

The existence of poor biological response to clopidogrel has been shown in some patients. Despite the increasing number of studies, this phenomenon remains difficult to quantify. We performed a systematic review to estimate the prevalence of poor biological response to clopidogrel and investigate the factors known to modulate this. An exhaustive search was performed. Altogether 171 publications were identified, providing data for a total of 45,664 subjects. The estimated prevalence of poor biological response to clopidogrel ranged from 15.9% to 49.5% according to the platelet function assay employed. The assays most frequently used were light transmittance aggregometry (LTA), the vasodilator-stimulated phosphoprotein (VASP) assay and the Verify -now^® assay. For all these assays, higher cut-off values were associated with a lower prevalence of poor biological response to clopidogrel. However, when choosing a fixed cut-off point for each assay, the prevalence of poor biological response to clopidogrel was highly variable suggesting that other factors could modulate poor biological response to clopidogrel. Finally, none of the studied factors could apparently explain the variability of poor biological response to clopidogrel. This meta-analysis shows that the prevalence of poor biological response depends on the assay employed, the cut-off value and on various unidentified additional factors.

Keywords

Meta-analysis - antiplatelet agents - ischaemic heart disease

• References

• 1 Ford NF. Clopidogrel resistance: pharmacokinetic or pharmacogenetic?. J Clin Pharmacol 2009; 49: 506-512.
• 2 De Miguel A, Ibanez B, Badimon JJ. Clinical implications of clopidogrel resistance. Thromb Haemost 2008; 100: 196-203.
• 3 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.
• 4 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.
• 5 Harrison P. Platelet function analysis. Blood Rev 2005; 19: 111-123.
• 6 Bonvini RF, Reny JL, Mach F. et al. Acute coronary syndrome and its antithrombotic treatment: focus on aspirin and clopidogrel resistance. Curr Vasc Pharmacol 2009; 07: 198-208.
• 7 Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 2007; 05 (Suppl. 01) 230-237.
• 8 Kumar S, Saran RK, Puri A, Gupta N, Sethi R, Surin WR. et al. Profile and prevalence of clopidogrel resistance in patients of acute coronary syndrome. Indian Heart J 2007; 59: 152-156.
• 9 Martin-Toutain I. Comparison of two whole blood platelet function assays: PFA-100® and a new multiple electrode aggregometry (Multiplate®) for control of aspirin and/or clopidogrel effect. J Thromb Haemost 2007; 05 (Suppl. 02) P-M-323.
• 10 Golanski J, Pluta J, Baraniak J. et al. Limited usefulness of the PFA-100 for the monitoring of ADP receptor antagonists--in vitro experience. Clin Chem Lab Med 2004; 42: 25-29.
• 11 Geiger J, Teichmann L, Grossmann R. et al. Monitoring of clopidogrel action: comparison of methods. Clin Chem 2005; 51: 957-965.
• 12 Kotzailias N, Elwischger K, Sycha T. et al. Clopidogrel-induced platelet inhibition cannot be detected by the platelet function analyzer-100 system in stroke patients. J Stroke Cerebrovasc Dis 2007; 16: 199-202.
• 13 Dyszkiewicz-Korpanty A, Olteanu H, Frenkel EP. et al. Clopidogrel anti-platelet effect: an evaluation by optical aggregometry, impedance aggregometry, and the platelet function analyzer (PFA-100). Platelets 2007; 18: 491-496.
• 14 Weerakkody GJ, Brandt JT, Payne CD. et al. Clopidogrel poor responders: an objective definition based on Bayesian classification. Platelets 2007; 18: 428-435.
• 15 Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance. Arterioscler Thromb Vasc Biol 2004; 24: 1980-1987.
• 16 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.
• 17 Polack B, Schved JF, Boneu B. Preanalytical recommendations of the ‘Groupe d’Et ud e sur l’Hemostase et la Thrombose’ (GEHT) for venous blood testingin he-mostasis laboratories. Haemostasis 2001; 31: 61-68.
• 18 Aradi D, Komocsi A, Vorobcsuk A. et al. Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: Systematic review and meta-analysis. Am Heart J 2010; 160: 543-551.
• 19 Gremmel T, Panzer S. Clinical, genetic and confounding factors determine the dynamics of the in vitro response/non response to clopidogrel. Thromb Haemost 2011; 106: 211-218.
• 20 Tentzeris I, Siller-Matula J, Farhan S. et al. Platelet function variability and non-genetic causes. Thromb Haemost 2011; 105 (Suppl. 01) S60-66.
• 21 Fernando H, Dart AM, Peter K. et al. Proton pump inhibitors, genetic polymorphisms and response to clopidogrel therapy. Thromb Haemost 2011; 105: 933-944.
• 22 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.
• 23 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.
• 24 Gaglia Jr MA, Torguson R, Hanna N. et al. Relation of proton pump inhibitor use after percutaneous coronary intervention with drug-eluting stents to outcomes. Am J Cardiol 2010; 105: 833-838.
• 25 Sarafoff N, Sibbing D, Sonntag U. et al. Risk of drug-eluting stent thrombosis in patients receiving proton pump inhibitors. Thromb Haemost 2010; 104: 626-632.
• 26 Tentzeris I, Jarai R, Farhan S. et al. Impact of concomitant treatment with proton pump inhibitors and clopidogrel on clinical outcome in patients after coronary stent implantation. Thromb Haemost 2010; 104: 1211-1218.
• 27 Simon T, Steg PG, Gilard M. et al. Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) registry. Circulation 2011; 123: 474-482.
• 28 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: 919-933.
• 29 Snoep JD, Hovens MM, Eikenboom JC. et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and metaanalysis. Am Heart J 2007; 154: 221-231.
• 30 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.
• 31 Combescure C, Fontana P, Mallouk N. et al. Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost 2010; 08: 923-933.
• 32 King 3rd SB, Smith Jr SC, Hirshfeld Jr JW. et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol 2008; 51: 172-209.
• 33 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/Non-ST-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.
• 34 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.
• 35 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; 01: 631-638.
• 36 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.
• 37 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.
• 38 Angiolillo DJ, 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: 2430-2435.
• 39 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.
• 40 Angiolillo DJ, Bernardo E, Sabate M. et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2007; 50: 1541-1547.
• 41 Angiolillo DJ, Bernardo E, Capodanno D. et al. Impact of chronic kidney disease on platelet function profiles in diabetes mellitus patients with coronary artery disease taking dual antiplatelet therapy. J Am Coll Cardiol 2010; 55: 1139-1146.
• 42 Angiolillo DJ, Badimon JJ, Saucedo JF. et al. A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial. Eur Heart J 2011; 32: 838-846.
• 43 Aradi D, Vorobcsuk A, Lenkey Z. et al. Low platelet disaggregation predicts poor response to 150 mg clopidogrel in patients with elevated platelet reactivity. Platelets 2010; 21: 1-10.
• 44 Aradi D, Magyarlaki T, Tokes-Fuzesi M. et al. Comparison of conventional aggregometry with VASP for monitoring P2Y12-specific platelet inhibition. Platelets 2010; 21: 563-570.
• 45 Behr T, Kuch B, Behr W. et al. Optimizing of thienopyridine therapy by multiple electrode platelet aggregometry in clopidogrel low responders undergoing PCI. Clin Res Cardiol 2011; 100: 907-914.
• 46 Bellemain-Appaix A, Montalescot G, Silvain J. et al. Slow response to clopidogrel predicts low response. J Am Coll Cardiol 2010; 55: 815-822.
• 47 Bernlochner I, Steinhubl S, Braun S. et al. Association between inflammatory biomarkers and platelet aggregation in patients under chronic clopidogrel treatment. Thromb Haemost 2010; 104: 1193-1200.
• 48 Bjelland TW, Hjertner O, Klepstad P. et al. Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation 2010; 81: 1627-1631.
• 49 Bonello L, Paganelli F, Dignat-George F. et al. Two strategies of clopidogrel loading dose to decrease the frequency of clopidogrel resistance in patients undergoing percutaneous coronary intervention. Thromb Res 2008; 122: 285-288.
• 50 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.
• 51 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.
• 52 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.
• 53 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.
• 54 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.
• 55 Campo G, Valgimigli M, Gemmati D. et al. Poor responsiveness to clopidogrel: drug-specific or class-effect mechanism?. Evidence from a clopidogrel-to-ticlopidine crossover study. J Am Coll Cardiol 2007; 50: 1132-1137.
• 56 Cayla G, Macia JC, Rabesandratana H. et al. Flow cytometric assessment of vasodilator-stimulated phosphoprotein: prognostic value of recurrent cardiovascular events after acute coronary syndromes. Arch Cardiovasc Dis 2008; 101: 743-751.
• 57 Cecchi E, Marcucci R, Paniccia R. et al. Effect of blood hematocrit and erythrocyte deformability on adenosine 5’-diphosphate platelet reactivity in patients with acute coronary syndromes on dual antiplatelet therapy. Am J Cardiol 2009; 104: 764-768.
• 58 Cesari F, Marcucci R, Caporale R. et al. Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb Haemost 2008; 99: 930-935.
• 59 Chen H, Yan W, Wu XY. Relationships of blood stasis syndrome, CYP2C19 gene polymorphism with clopidogrel resistance and post-PCI prognosis. Zhongguo Zhong Xi Yi Jie He Za Zhi 2010; 30: 1245-1249.
• 60 Chin SP, Liew CK, Tay SP. et al. Platelet non-responsiveness to dual antiplatelet therapy and relation to coronary disease among diabetes patients. Int J Cardiol 2007; 118: 418-420.
• 61 Collet JP, Silvain J, Landivier A. et al. Dose effect of clopidogrel reloading in patients already on 75-mg maintenance dose: the Reload with Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term with Dual Antiplatelet Therapy (RELOAD) study. Circulation 2008; 118: 1225-1233.
• 62 Cotton JM, Worrall AM, Hobson AR. et al. Individualised assessment of response to clopidogrel in patients presenting with acute coronary syndromes: a role for short thrombelastography?. Cardiovasc Ther 2010; 28: 139-146.
• 63 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.
• 64 Cuisset T, Frere C, Quilici J, Poyet R, Gaborit B, Bali L. et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol 2009; 54: 1149-1153.
• 65 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: 39-45.
• 66 de Miguel Castro A, Cuellas Ramon C, Diego Nieto A. et al. Post-treatment platelet reactivity predicts long-term adverse events better than the response to clopidogrel in patients with non-ST-segment elevation acute coronary syndrome. Rev Esp Cardiol 2009; 62: 126-135.
• 67 Djukanovic N, Todorovic Z, Grdinic A. et al. Thienopyridine resistance among patients undergoing intracoronary stent implantation and treated with dual antiplatelet therapy: assessment of some modifying factors. J Pharmacol Sci 2008; 107: 451-455.
• 68 Dropinski J, Jakiela B, Sanak M. et al. The additive antiplatelet action of clopidogrel in patients with coronary artery disease treated with aspirin. Thromb Haemost 2007; 98: 201-209.
• 69 Drosch T, Brodoefel H, Geisler T. et al. Plaque distribution in clopidogrel responders and low responders as determined by multislice computed tomography. Tex Heart Inst J 2010; 37: 547-552.
• 70 Dziewierz A, Dudek D, Heba G. et al. Inter-individual variability in response to clopidogrel in patients with coronary artery disease. Kardiol Pol 2005; 62: 108-117.
• 71 El Ghannudi S, Ohlmann P, Meyer N. et al. Impact of P2Y12 inhibition by clopidogrel on cardiovascular mortality in unselected patients treated by percutaneous coronary angioplasty: a prospective registry. JACC Cardiovasc Interv 2010; 03: 648-656.
• 72 Erlinge D, Varenhorst C, Braun OO. et al. Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo. J Am Coll Cardiol 2008; 52: 1968-1977.
• 73 Eshtehardi P, Windecker S, Cook S. et al. Dual low response to acetylsalicylic acid and clopidogrel is associated with myonecrosis and stent thrombosis after coronary stent implantation. Am Heart J 2010; 159: 891-898. e1.
• 74 Feher G, Koltai K, Alkonyi B. et al. Clopidogrel resistance: role of body mass and concomitant medications. Int J Cardiol 2007; 120: 188-192.
• 75 Fontana P, Senouf D, Mach F. Biological effect of increased maintenance dose of clopidogrel in cardiovascular outpatients and influence of the cytochrome P450 2C19*2 allele on clopidogrel responsiveness. Thromb Res 2008; 121: 463-468.
• 76 Fontana P, Berdague P, Castelli C. et al. Clinical predictors of dual aspirin and clopidogrel poor responsiveness in stable cardiovascular patients from the ADRIE study. J Thromb Haemost 2010; 08: 2614-2623.
• 77 Frere C, Cuisset T, Quilici J. et al. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome. Thromb Haemost 2007; 98: 838-8343.
• 78 Freynhofer MK, Brozovic I, Bruno V. et al. Multiple electrode aggregometry and vasodilator stimulated phosphoprotein-phosphorylation assay in clinical routine for prediction of postprocedural major adverse cardiovascular events. Thromb Haemost 2011; 106: 230-239.
• 79 Frolova NS, Shakhnovich RM, Sirotkina OV. et al. Clopidogrel resistance in patients with acute coronary syndrome. Ter Arkh 2010; 82: 14-20.
• 80 Fu Q, Yokoyama N, Takada K. et al. Comparison of platelet P2Y(12) ADP receptor-mediated pathway inhibition in triple versus dual antiplatelet therapy as assessed by VASP-phosphorylation in Japanese patients undergoing coronary stenting. Int Heart J 2010; 51: 303-307.
• 81 Fukuoka T, Furuya D, Takeda H. et al. Evaluation of clopidogrel resistance in ischemic stroke patients. Intern Med 2011; 50: 31-35.
• 82 Furuta T, Iwaki T, Umemura K. [13C]pantoprazole breath test as a predictor of the antiplatelet function of clopidogrel. Eur J Clin Pharmacol 2010; 66: 457-463.
• 83 Furuta T, Iwaki T, Umemura K. Influences of different proton pump inhibitors on the antiplatelet function of clopidogrel in relation to CYP2C19 genotypes. Br J Clin Pharmacol 2010; 70: 383-392.
• 84 Gaborit B, Frere C, Cuisset T. et al. Enhanced post-clopidogrel platelet reactivity in diabetic patients is independently related to plasma fibrinogen level but not to glycemic control. J Thromb Haemost 2009; 07: 1939-1941.
• 85 Gajos G, Rostoff P, Undas A. et al. Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: the OMEGA-PCI (OMEGA-3 fatty acids after pci to modify responsiveness to dual antiplatelet therapy) study. J Am Coll Cardiol 2010; 55: 1671-1678.
• 86 Ge H, Zhou Y, Liu X. et al. Relationship Between Plasma Inflammatory Markers and Platelet Aggregation in Patients With Clopidogrel Resistance After Angioplasty. Angiology 2011; 63: 62-66.
• 87 Geara AS, Ayoub I, Abi Rached J. et al. Does hemodialysis affect clopidogrel resistance as measured by VerifyNow P2Y12 test?. Am J Cardiol 2011; 107: 1103-1104.
• 88 Geisler T, Langer H, Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420-2425.
• 89 Geisler T, Schaeffeler E, Dippon J. et al. CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics 2008; 09: 1251-1259.
• 90 Geisler T, Kapp M, Gohring-Frischholz K. et al. Residual platelet activity is increased in clopidogrel- and ASA-treated patients with coronary stenting for acute coronary syndromes compared with stable coronary artery disease. Heart 2008; 94: 743-747.
• 91 Gladding P, Webster M, Zeng I. et al. The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel: the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv 2008; 01: 612-619.
• 92 Godino C, Mendolicchio L, Figini F. et al. Comparison of VerifyNow-P2Y12 test and Flow Cytometry for monitoring individual platelet response to clopidogrel. What is the cut-off value for identifying patients who are low responders to clopidogrel therapy?. Thromb J 2009; 07: 4.
• 93 Gori AM, Marcucci R, Paniccia R. et al. Thrombotic events in high risk patients are predicted by evaluating different pathways of platelet function. Thromb Haemost 2008; 100: 1136-1145.
• 94 Gremmel T, Steiner S, Seidinger D. et al. Comparison of methods to evaluate clopidogrelmediated platelet inhibition after percutaneous intervention with stent implantation. Thromb Haemost 2009; 101: 333-9.
• 95 Gremmel T, Steiner S, Seidinger D. et al. Smoking promotes clopidogrel-mediated platelet inhibition in patients receiving dual antiplatelet therapy. Thromb Res 2009; 124: 588-591.
• 96 Gremmel T, Steiner S, Seidinger D. et al. The influence of proton pump inhibitors on the antiplatelet potency of clopidogrel evaluated by 5 different platelet function tests. J Cardiovasc Pharmacol 2010; 56: 532-539.
• 97 Grossmann R, Sokolova O, Schnurr A. et al. Variable extent of clopidogrel responsiveness in patients after coronary stenting. Thromb Haemost 2004; 92: 1201-1206.
• 98 Guha S, Mookerjee S, Guha P. et al. Anti platelet drug resistance in patients with recurrent acute coronary syndrome undergoing conservative management. Indian Heart J 2009; 61: 348-352.
• 99 Gurbel PA, Bliden KP, Hayes KM. et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005; 45: 1392-1396.
• 100 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.
• 101 Gurbel PA, Bliden KP, Butler K. et al. Response to ticagrelor in clopidogrel non-responders and responders and effect of switching therapies: the RESPOND study. Circulation 2010; 121: 1188-1199.
• 102 Gurbel PA, Bliden KP, Antonino MJ. et al. The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to CYP2C19*2 genotype: first experience in patients. J Thromb Haemost 2010; 08: 43-53.
• 103 Gurbel PA, Shuldiner AR, Bliden KP. et al. The relation between CYP2C19 genotype and phenotype in stented patients on maintenance dual antiplatelet therapy. Am Heart J 2011; 161: 598-604.
• 104 Hobson AR, Qureshi Z, Banks P. et al. Gender and responses to aspirin and clopidogrel: insights using short thrombelastography. Cardiovasc Ther 2009; 27: 246-252.
• 105 Hoshino K, Horiuchi H, Tada T. et al. Clopidogrel resistance in Japanese patients scheduled for percutaneous coronary intervention. Circ J 2009; 73: 336-342.
• 106 Htun P, Fateh-Moghadam S, Bischofs C. et al. Low responsiveness to clopidogrel increases risk among CKD patients undergoing coronary intervention. J Am Soc Nephrol 2011; 22: 627-633.
• 107 Hulot JS, Wuerzner G, Bachelot-Loza C. et al. Effect of an increased clopidogrel maintenance dose or lansoprazole co-administration on the antiplatelet response to clopidogrel in CYP2C19-genotyped healthy subjects. J Thromb Haemost 2010; 08: 610-613.
• 108 Ivandic BT, Schlick P, Staritz P. et al. Determination of clopidogrel resistance by whole blood platelet aggregometry and inhibitors of the P2Y12 receptor. Clin Chem 2006; 52: 383-388.
• 109 Ivandic BT, Sausemuth M, Ibrahim H. et al. Dual antiplatelet drug resistance is a risk factor for cardiovascular events after percutaneous coronary intervention. Clin Chem 2009; 55: 1171-1176.
• 110 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.
• 111 Jakubowski JA, Payne CD, Li YG. et al. A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry. Thromb Haemost 2008; 99: 215-222.
• 112 Jang S. Clinical experience with platelet aggregation testing for aspirin and clopidogrel. J Thromb Haemost 2007; 05 (Suppl. 02) P-M-308.
• 113 Jeong YH, Lee SW, Choi BR. et al. Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study. J Am Coll Cardiol 2009; 53: 1101-1109.
• 114 Jernberg T, Payne CD, Winters KJ. et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 2006; 27: 1166-1173.
• 115 Kang HS, Kwon BJ, Kim JE. et al. Preinterventional clopidogrel response variability for coil embolization of intracranial aneurysms: clinical implications. Am J Neuroradiol 2010; 31: 1206-1210.
• 116 Kim H, Lee HK, Han K. et al. Prevalence and risk factors for aspirin and clopidogrel resistance in patients with coronary artery disease or ischemic cerebrovascular disease. Ann Clin Lab Sci 2009; 39: 289-294.
• 117 Kim IS, Jeong YH, Park Y. et al. Platelet inhibition by adjunctive cilostazol versus high maintenance-dose clopidogrel in patients with acute myocardial infarction according to cytochrome P450 2C19 genotype. JACC Cardiovasc Interv 2011; 04: 381-391.
• 118 Ko YG, Suh JW, Kim BH. et al. Comparison of 2 point-of-care platelet function tests, VerifyNow Assay and Multiple Electrode Platelet Aggregometry, for predicting early clinical outcomes in patients undergoing percutaneous coronary intervention. Am Heart J 2011; 161: 383-390.
• 119 Koessler J, Kobsar AL, Rajkovic MS. et al. The new INNOVANCE(R) PFA P2Y cartridge is sensitive to the detection of the P2Y receptor inhibition. Platelets 2011; 22: 19-25.
• 120 Labarthe B, Theroux P, Angioi M. et al. Matching the evaluation of the clinical efficacy of clopidogrel to platelet function tests relevant to the biological properties of the drug. J Am Coll Cardiol 2005; 46: 638-645.
• 121 Lau WC, Gurbel PA, Watkins PB. et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004; 109: 166-171.
• 122 Lau WC, Welch TD, Shields T. et al. The effect of St John’s Wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity. J Cardiovasc Pharmacol 2011; 57: 86-93.
• 123 Lee DH, Arat A, Morsi H. et al. Dual antiplatelet therapy monitoring for neuroin-terventional procedures using a point-of-care platelet function test: a singlecenter experience. Am J Neuroradiol 2008; 29: 1389-1394.
• 124 Lee JM, Park S, Shin DJ. et al. Relation of genetic polymorphisms in the cytochrome P450 gene with clopidogrel resistance after drug-eluting stent implantation in Koreans. Am J Cardiol 2009; 104: 46-51.
• 125 Lee K, Kim JY, Yoo BS. et al. Cilostazol augments the inhibition of platelet aggregation in clopidogrel low-responders. J Thromb Haemost 2010; 08: 2577-2579.
• 126 Lee Y. Monitoring of platelet function after clopidogrel treatment. J Thromb Haemost 2007; 05 (Suppl. 02) P-M-315.
• 127 Lepantalo A, Virtanen KS, Heikkila J. et al. Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions. Eur Heart J 2004; 25: 476-483.
• 128 Lepantalo A, Virtanen KS, Resendiz JC. et al. Antiplatelet effect of clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions--limited inhibition of the P2Y12 receptor. Thromb Res 2009; 124: 193-198.
• 129 Lev EI, Patel RT, Maresh KJ. 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: 27-33.
• 130 Lev EI, Ramchandani M, Garg R. et al. Response to aspirin and clopidogrel in patients scheduled to undergo cardiovascular surgery. J Thromb Thrombolysis 2007; 24: 15-21.
• 131 Lindvall G, Sartipy U, Bjessmo S. et al. Aprotinin reduces the antiplatelet effect of clopidogrel. Interact Cardiovasc Thorac Surg 2009; 09: 178-181.
• 132 Linnemann B, Schwonberg J, Rechner AR. et al. Assessment of clopidogrel non-response by the PFA-100 system using the new test cartridge INNOVANCE PFA P2Y. Ann Hematol 2010; 89: 597-605.
• 133 Liu XL, Wang ZJ, Yang Q. et al. Impact of CYP2C19 polymorphism and smoking on response to clopidogrel in patients with stable coronary artery disease. Chin Med J (Engl) 2010; 123: 3178-3183.
• 134 Liu Y, Liu N, Li W. et al. Clopidogrel response variability and its correlation with early recurrent cardiovascular events in chinese patients undergoing percutaneous coronary intervention. Pharmacology 2011; 87: 321-330.
• 135 Lordkipanidze M, Diodati JG, Schampaert E. et al. Prevalence of unresponsive-ness to aspirin and/or clopidogrel in patients with stable coronary heart disease. Am J Cardiol 2009; 104: 1189-1193.
• 136 Madsen EH, Schmidt EB, Maurer-Spurej E. et al. Effects of aspirin and clopidogrel in healthy men measured by platelet aggregation and PFA-100. Platelets 2008; 19: 335-341.
• 137 Madsen EH, Saw J, Kristensen SR. et al. Long-term aspirin and clopidogrel response evaluated by light transmission aggregometry, VerifyNow, and thrombelastography in patients undergoing percutaneous coronary intervention. Clin Chem 2010; 56: 839-847.
• 138 Madsen EH, Gehr NR, Johannesen NL. et al. Platelet response to aspirin and clopidogrel in patients with peripheral atherosclerosis. Platelets 2011; 22: 537-546.
• 139 Malek LA, Grabowski M, Spiewak M. et al. Relation between impaired antiplatelet response to clopidogrel and possible pleiotropic effects. J Thromb Thrombolysis 2007; 24: 301-305.
• 140 Mangiacapra F, Barbato E, Patti G. et al. Point-of-care assessment of platelet reactivity after clopidogrel to predict myonecrosis in patients undergoing percutaneous coronary intervention. JACC Cardiovasc Interv 2010; 03: 318-323.
• 141 Mangiacapra F, De Bruyne B, Muller O. et al. High residual platelet reactivity after clopidogrel: extent of coronary atherosclerosis and periprocedural myocardial infarction in patients with stable angina undergoing percutaneous coronary intervention. JACC Cardiovasc Interv 2010; 03: 35-40.
• 142 Marcucci R, Gori AM, Paniccia R. et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation 2009; 119: 237-242.
• 143 Maruyama H, Takeda H, Dembo T. et al. Clopidogrel resistance and the effect of combination cilostazol in patients with ischemic stroke or carotid artery stenting using the VerifyNow P2Y12 Assay. Intern Med 2011; 50: 695-698.
• 144 Matetzky S, Fefer P, Shenkman B. et al. Effectiveness of reloading to overcome clopidogrel nonresponsiveness in patients with acute myocardial infarction. Am J Cardiol 2008; 102: 524-529.
• 145 Michelson AD, Frelinger 3rd AL, Braunwald E. et al. Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial. Eur Heart J 2009; 30: 1753-1763.
• 146 Migliorini A, Valenti R, Marcucci R. et al. High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease. Circulation 2009; 120: 2214-2221.
• 147 Mobley JE, Bresee SJ, Wortham DC. et al. Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization. Am J Cardiol 2004; 93: 456-458.
• 148 Moerenhout CM, Claeys MJ, Haine S. et al. Clinical relevance of clopidogrel un-responsiveness during elective coronary stenting: experience with the point-of-care platelet function assay-100 C/ADP. Am Heart J 2010; 159: 434-438.
• 149 Morel O, Bernhard N, Desprez D. et al. Residual prothrombotic status in low responder patients to clopidogrel identified by Vasodilator-Stimulated Phosphoprotein Phosphorylation (VASP) analysis?. Thromb Haemost 2008; 99: 448-451.
• 150 Morris A, Aliprandi-Costa B, Brieger D. Platelet function analysis: a comparison of methods. Int J Cardiol 2009; 145: 167-168.
• 151 Motovska Z, Widimsky P, Petr R. et al. Optimal pretreatment timing for high load dosing (600 mg) of clopidogrel before planned percutaneous coronary intervention for maximal antiplatelet effectiveness. Int J Cardiol 2009; 144: 255-257.
• 152 Mueller T, Dieplinger B, Poelz W. et al. Utility of whole blood impedance aggregometry for the assessment of clopidogrel action using the novel Multiplate analyzer--comparison with two flow cytometric methods. Thromb Res 2007; 121: 249-258.
• 153 Muller-Schunk S, Linn J, Peters N. et al. Monitoring of clopidogrel-related platelet inhibition: correlation of nonresponse with clinical outcome in supra-aortic stenting. Am J Neuroradiol 2008; 29: 786-791.
• 154 Neubauer H, Lask S, Engelhardt A. et al. How to optimise clopidogrel therapy? Reducing the low-response incidence by aggregometry-guided therapy modification. Thromb Haemost 2008; 99: 357-362.
• 155 Neubauer H, Engelhardt A, Kruger JC. et al. Pantoprazole does not influence the antiplatelet effect of clopidogrel-a whole blood aggregometry study after coronary stenting. J Cardiovasc Pharmacol 2010; 56: 91-97.
• 156 Neubauer H, Kaiser AF, Endres HG. et al. Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance--the BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy. BMC Med 2011; 09: 3.
• 157 Nguyen TA, Lordkipanidze M, Diodati JG. et al. Week-long high-maintenance dose clopidogrel regimen achieves better platelet aggregation inhibition than a standard loading dose before percutaneous coronary intervention: results of a double-blind, randomized clinical trial. J Interv Cardiol 2009; 22: 368-377.
• 158 Palmerini T, Barozzi C, Tomasi L. et al. A randomised study comparing the antiplatelet and antiinflammatory effect of clopidogrel 150 mg/day versus 75 mg/day in patients with ST-segment elevation acute myocardial infarction and poor responsiveness to clopidogrel: results from the DOUBLE study. Thromb Res 2010; 125: 309-314.
• 159 Pandya DJ, Fitzsimmons BF, Wolfe TJ. et al. Measurement of antiplatelet inhibition during neurointerventional procedures: the effect of antithrombotic duration and loading dose. J Neuroimaging 2010; 20: 64-69.
• 160 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; 05: 1839-1847.
• 161 Papp E, Havasi V, Bene J. et al. Does glycoprotein IIIa gene (Pl(A)) polymorphism influence clopidogrel resistance? : a study in older patients. Drugs Aging 2007; 24: 345-350.
• 162 Park KW, Park JJ, Jeon KH. et al. Enhanced clopidogrel responsiveness in smokers: smokers’ paradox is dependent on cytochrome P450 CYP1A2 status. Arterioscler Thromb Vasc Biol 2011; 31: 665-671.
• 163 Patti G, Grieco D, Dicuonzo G. et al. High versus standard clopidogrel maintenance dose after percutaneous coronary intervention and effects on platelet inhibition, endothelial function, and inflammation results of the ARMYDA-150 mg (antiplatelet therapy for reduction of myocardial damage during angioplasty) randomized study. J Am Coll Cardiol 2011; 57: 771-778.
• 164 Pettersen AA, Arnesen H, Opstad TB. et al. The influence of CYP 2C19*2 polymorphism on platelet function testing during single antiplatelet treatment with clopidogrel. Thromb J 2011; 09: 4.
• 165 Polena S, Gupta MP, Shaikh H. et al. Platelet aggregation inhibition in patients receiving statins either fully or partially metabolized by CYP3A4. Proc West Pharmacol Soc 2008; 51: 60-62.
• 166 Prabhakaran S, Wells KR, Lee VH. et al. Prevalence and risk factors for aspirin and clopidogrel resistance in cerebrovascular stenting. Am J Neuroradiol 2008; 29: 281-285.
• 167 Preisman S, Kogan A, Itzkovsky K. et al. Modified thromboelastography evaluation of platelet dysfunction in patients undergoing coronary artery surgery. Eur J Cardiothorac Surg 2010; 37: 1367-1374.
• 168 Price MJ, Endemann S, Gollapudi RR. et al. Prognostic significance of postclopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992-1000.
• 169 Price MJ, Nayak KR, Barker CM. et al. Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention. Am J Cardiol 2009; 103: 1339-1343.
• 170 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. J Am Med Assoc 2011; 305: 1097-1105.
• 171 Ryu DS, Hong CK, Sim YS. et al. Anti-platelet drug resistance in the prediction of thromboembolic complications after neurointervention. J Korean Neurosurg Soc 2010; 48: 319-324.
• 172 Saw J, Densem C, Walsh S. et al. The effects of aspirin and clopidogrel response on myonecrosis after percutaneous coronary intervention: a BRIEF-PCI (Brief Infusion of Intravenous Eptifibatide Following Successful Percutaneous Coronary Intervention) trial substudy. JACC Cardiovasc Interv 2008; 01: 654-659.
• 173 Saw J, Madsen EH, Chan S. et al. The ELAPSE (Evaluation of Long-Term Clopidogrel Antiplatelet and Systemic Anti-Inflammatory Effects) study. J Am Coll Cardiol 2008; 52: 1826-1833.
• 174 Schafer A, Weinberger S, Flierl U. et al. ADP-induced platelet aggregation frequently fails to detect impaired clopidogrel-responsiveness in patients with coronary artery disease compared to a P2Y12-specific assay. Thromb Haemost 2008; 100: 618-625.
• 175 Schwonberg J. Non-response to clopidogrel in patients with peripheral arterial occlusive disease (PAOD); a prospective study. J Thromb Haemost 2007; 05 (Suppl. 02) P-T-688.
• 176 Serebruany VL, Steinhubl SR, Berger PB. et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246-251.
• 177 Shenkman B, Matetzky S, Fefer P. et al. Variable responsiveness to clopidogrel and aspirin among patients with acute coronary syndrome as assessed by platelet function tests. Thromb Res 2008; 122: 336-345.
• 178 Shim CY, Yoon SJ, Park S. et al. The clopidogrel resistance can be attenuated with triple antiplatelet therapy in patients undergoing drug-eluting stents implantation. Int J Cardiol 2009; 134: 351-355.
• 179 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.
• 180 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.
• 181 Siller-Matula JM, Haberl K, Prillinger K. et al. The effect of antiplatelet drugs clopidogrel and aspirin is less immediately after stent implantation. Thromb Res 2009; 123: 874-880.
• 182 Siller-Matula JM, Christ G, Lang IM. et al. Multiple electrode aggregometry predicts stent thrombosis better than the vasodilator-stimulated phosphoprotein phosphorylation assay. J Thromb Haemost 2010; 08: 351-359.
• 183 Sirotkina OV, Zabotina AM, Berkovich OA. et al. Genetic variants of platelet ADP receptor P2Y12 associated with changed platelet functional activity and development of cardiovascular diseases. Genetika 2009; 45: 247-253.
• 184 Spiewak M, Malek LA, Kostrzewa G. et al. Influence of C3435T multidrug resistance gene-1 (MDR-1) polymorphism on platelet reactivity and prognosis in patients with acute coronary syndromes. Kardiol Pol 2009; 67: 827-834.
• 185 Staritz P, Kurz K, Stoll M. et al. Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y12-ADP receptor gene. Int J Cardiol 2009; 133: 341-345.
• 186 Storey RF, Angiolillo DJ, Patil SB. et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol 2010; 56: 1456-1462.
• 187 Thomson VS, John B, Pati PK. et al. Nonresponders to clopidogrel therapy among Indian patients undergoing elective/adhoc angioplasty. Indian Heart J 2008; 60: 543-547.
• 188 Trenk D, Hochholzer W, Fromm MF. et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008; 51: 1925-1934.
• 189 Valgimigli M, Campo G, de Cesare N. et al. Intensifying platelet inhibition with tirofiban in poor responders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention: results from the double-blind, prospective, randomized Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/ or Resistance to Clopidogrel study. Circulation 2009; 119: 3215-3222.
• 190 Valgimigli M, Campo G, Tebaldi M. et al. Randomized, double-blind comparison of effects of abiciximab bolus only vs. on-label regimen on ex vivo inhibition of platelet aggregation in responders to clopidogrel undergoing coronary stenting. J Thromb Haemost 2010; 08: 1903-1911.
• 191 van Werkum JW, Bouman HJ, Breet NJ. et al. The Cone-and-Plate(let) analyzer is not suitable to monitor clopidogrel therapy: a comparison with the flowcytometric VASP assay and optical aggregometry. Thromb Res 2010; 126: 44-49.
• 192 von Lewinski F, Riggert J, Paulus W. Towards a rationale of platelet aggregation monitoring in stroke prophylaxis?. J Stroke Cerebrovasc Dis 2009; 18: 111-115.
• 193 Von Pape K. Platelet responsiveness towards antiplatelet medications before and after coronary angiography and percutenous coronary interventions as determined by whole blood aggregometry. J Thromb Haemost 2007; 05 (Suppl. 02) P-T-363.
• 194 Wang L, Wang X, Chen F. Clopidogrel resistance is associated with long-term thrombotic events in patients implanted with drug-eluting stents. Drugs R D 2010; 10: 219-224.
• 195 Woo KS, Kim BR, Kim JE. et al. Determination of the prevalence of aspirin and clopidogrel resistances in patients with coronary artery disease by using various platelet-function tests. Korean J Lab Med 2010; 30: 460-468.
• 196 Ziegler S, Maca T, Alt E. et al. Monitoring of antiplatelet therapy with the PFA-100 in peripheral angioplasty patients. Platelets 2002; 13: 493-497.
• 197 Zuern CS, Geisler T, Lutilsky N, Winter S, Schwab M, Gawaz M. Effect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy. Thromb Res 2010; 125: e51-54.
• 198 Tsukahara K, Kimura K, Morita S. et al. Impact of concomitant use of protonpump inhibitors and thienopyridine derivatives on the antiplatelet effects. J Cardiol 2011; 57: 275-282.