Abstract
High on-treatment platelet reactivity (HTPR) on clopidogrel correlates with adverse outcomes in patients treated with percutaneous coronary intervention (PCI). Whether HTPR is a modifiable risk factor for future events is not clear. We evaluated the effect of serial clopidogrel dose adjustment based on platelet function testing (PFT) during 12 months of dual antiplatelet therapy (DAPT) using Multiplate® analyzer in patients with HTPR after PCI in acute coronary syndrome on clinical outcome. Eighty-seven patients were randomized to interventional (n = 43) and control group (n = 44). Blood samples for PFT were drawn at day 1, 2, 3, 7, 30 and at month 2, 3, 6, 9 and 12. Clopidogrel dose was modified at each point of PFT in the interventional group with patients taking up to two additional 600 mg loading doses and a range of 75–300 mg maintenance dose to achieve and maintain optimal platelet reactivity (19–46 U). The incidence of the primary endpoint (composite of cardiovascular death, non-fatal myocardial infarction, target vessel revascularization and ischemic stroke) was significantly higher in the control group (36.3 vs 16.2 %; p = 0.034). There were no differences in total bleeding events (6.8 vs 4.6 %, p = ns). Patients in the interventional group maintained better P2Y12 inhibition during follow-up. We hypothesize that targeting the therapeutic window of platelet reactivity continuously throughout DAPT by dose adjustment of P2Y12 inhibitor may lead to better platelet reactivity control, and thus reduce the rate of ischemic complications in this high risk group of patients.
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References
Hamm CW, Bassand JP, Agewall S et al (2011) ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European society of cardiology (ESC). Eur Heart J 32:2999–3054
Steg PG, James SK, Atar D et al (2012) ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 33:2569–2619
O’Gara PT, Kushner FG, Ascheim DD et al (2013) 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 127:e362–e425
Jneid H, Anderson JL, Wright RS et al (2012) 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infaction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 126:875–910
Yusuf S, Zhao F, Mehta SR et al (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494–502
Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ (2005) Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 45:246–251
Wiviott SD, Braunwald E, McCabe CH et al (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Eng J Med 357:2001–2015
Top 20 global products 2012 (2013) IMS Health Midas. http://www.imshealth.com/deployedfiles/ims/Global/Content/Corporate/Press%20Room/Top-Line%20Market%20Data%20&%20Trends/Top_20_Global_Products_2012_2.pdf. Accessed 19 October 2013
Wallentin L, Becker RC, Budaj A et al (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057
Stone GW, Witzenbichler B, Weisz G et al (2013) Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 382:614–623
Aradi D, Storey RF, Komócsi A et al (2014) Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J 35:209–215
Tantry US, Bonello L, Aradi D et al (2013) Consensus and update on the definition of on-treatment platelet reactivity to ADP associated with ischemia and bleeding. J Am Coll Cardiol 62:2261–2273
Mehran R, Rao SV, Bhatt DL et al (2011) Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the BleedingAcademic Research Consortium. Circulation 123:2736–2747
Sibbing D, Braun S, Morath T et al (2009) Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 53:849–856
Sibbing D, Schulz S, Braun S et al (2010) Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 8:250–256
Yusuf S, Mehta SR, Zhao F et al (2003) Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation 107:966–972
Hazarbasanov D, Velchev V, Finkov B et al (2012) Tailoring clopidogrel dose according to multiple electrode aggregometry decreases the rate of ischemic complications after percutaneous coronary intervention. J Thromb Thrombolysis 34:85–90
Giles H, Smith REA, Martin J (1994) Platelet glycoprotein IIb-IIIa and size are increased in acute myocardial infarction. Eur J Clin Invest 24:69–72
Gawaz M, Neumann FJ, Ott I et al (1996) Platelet function in acute myocardial infarction treated with direct angioplasty. Circulation 93:229–237
Muller I, Seyfarth M, Rudiger S et al (2001) Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 85:92–93
Breet NJ, van Werkum JW, Bouman HJ et al (2010) Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 303:754–762
Trenk D, Hochholzer W, Fromm MF et al (2008) 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 51:1925–1934
Price MJ, Nayak KR, Barker CM, Kandzari DE, Teirstein PS (2009) Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention. Am J Cardiol 103:1339–1343
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al (2007) Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 49:1505–1516
Lev EI, Patel RT, Maresh KJ et al (2006) Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 47:27–33
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al (2005) Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 54:2430–2435
Cuisset T, Frere C, Quilici J et al (2009) Relationship between aspirin and clopidogrel responses in acute coronary syndrome and clinical predictors of non response. Thromb Res 123:597–603
Kuchulakanti PK, Chu WW, Torguson R et al (2006) Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 113:1108–1113
Price MJ, Berger PB, Teirstein PS et al (2011) Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 305:1097–1105
Collet JP, Cuisset T, Rangé G et al (2012) Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 367:2100–2109
Campo G, Parrinello G, Ferraresi P et al (2011) 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 57:2474–2483
Parodi G, Marcucci R, Valenti R et al (2011) High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA 306:1215–1223
Brar SS, ten Berg J, Marcucci M et al (2011) Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention: a collaborative meta-analysis of individual participant data. J Am Coll Cardiol 58:1945–1954
Aradi D, Pinter T, Magyari B et al (2014) Optimizing P2Y12-receptor inhibition in acute coronary syndrome after PCI using platelet function testing: impact of prasugrel versus high-dose clopidogrel. J Am Coll Cardiol 63:1061–1070
Arméro S, Camoin Jau L, Omar Aït Mokhtar O et al (2010) Intra-individual variability in clopidogrel responsiveness in coronary artery disease patients under long term therapy. Platelets 21:503–507
Gurbel PA, Bliden KP, Hayes KM et al (2005) 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 45:1392–1396
Mayer K, Schulz S, Bernlochner I et al. (2014) A comparative cohort study on personalised antiplatelet therapy in PCI-treated patients with high on-clopidogrel platelet reactivity. Results of the ISAR-HPR registry. Thromb Haemost 10;112(2)
Siller-Matula JM, Francesconi M, Dechant C et al (2013) Personalized antiplatelet treatment after percutaneous coronary intervention: the MADONNA study. Int J Cardiol 167:2018–2023
Gurbel PA, Erlinge D, Ohman EM et al (2012) Platelet function during extended prasugrel and Clopidogrel therapy for patients with ACS treated without revascularization: the TRILOGY ACS platelet function substudy. JAMA 308:1785–1794
Bonello L, Camoin-Jau L, Armero S et al (2009) Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol 103:5–10
Chirumamilla AP, Maehara A, Mintz GS et al (2012) High platelet reactivity on clopidogrel therapy correlates with increased coronary atherosclerosis and calcification: a volumetric intravascular ultrasound study. JACC Cardiovasc Imaging 5:540–549
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This investigation was funded by the Croatian Ministry of Science, Education and Sports.
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The authors declare that they have no conflict of interest.
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Samardzic, J., Krpan, M., Skoric, B. et al. Serial clopidogrel dose adjustment after platelet function testing improves outcome of acute coronary syndrome patients undergoing percutaneous coronary intervention with high on-treatment platelet reactivity. J Thromb Thrombolysis 38, 459–469 (2014). https://doi.org/10.1007/s11239-014-1087-0
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DOI: https://doi.org/10.1007/s11239-014-1087-0