Clopidogrel response status assessed with Multiplate point-of-care analysis and the incidence and timing of stent thrombosis over six months following coronary stenting

Summary

Clopidogrel low-responsiveness assessed with multiple electrode platelet aggregometry (MEA) has been shown to be a strong and independent predictor of early stent thrombosis (ST) after coronary stenting. The relation of clopidogrel response status, as assessed with MEA, with incidence and timing of ST during an extended follow-up period has never been reported. Here, we report the six-month follow-up results of a prospective trial assessing clopidogrel responsiveness with MEA in patients undergoing percutaneous coronary intervention (PCI). A total of 1,608 consecutive patients with planned drug-eluting stent placement were enrolled in this study. Before PCI patients uniformly received 600 mg clopidogrel and blood was taken directly before PCI to measure ADP-induced platelet aggregation with MEA. The upper quin-tile (20%) of patients according to MEA measurements (n=323) was defined as clopidogrel low responders. Compared with normal responders (n=1,285), the cumulative incidence of definite ST within six months was significantly higher in low responders [2.5% vs. 0.4%; OR 6.5; 95% CI, 2.4–17.0; P<0.001]. The combined incidence of definite or probable ST was higher as well in low vs. normal responders [4.1% vs. 0.7%; OR 5.8; 95% CI, 2.8–12.3; P<0.0001]. A significant inverse correlation of MEA values and the timing of definite or probable ST (in days) was observed (Spearman coefficient = –0.45; P=0.04) with events occurring earlier in the low-responder group. MEA measurements are highly predictive for the occurrence of ST during the first six months following coronary stenting. In the majority of clopidogrel low responders suffering ST, the ischaemic event occurs early in the course after the procedure.

Keywords

Clopidogrel - stent thrombosis - platelet aggregation - whole blood aggregometry

• References

• 1 Smith Jr SC, Feldman TE, Hirshfeld Jr, JW. et al. ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006; 113: 156-175.
• 2 Kastrati A, Mehilli J, Neumann FJ. et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. J Am Med Assoc 2006; 295: 1531-1538.
• 3 Kastrati A, Mehilli J, Schuhlen H. et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004; 350: 232-238.
• 4 Kastrati A, Neumann FJ, Mehilli J. et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008; 359: 688-696.
• 5 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.
• 6 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007; 49: 1505-1516.
• 7 Siller-Matula J, Schror K, Wojta J. et al. Thienopyridines in cardiovascular disease: focus on clopidogrel resistance. Thromb Haemost 2007; 97: 385-393.
• 8 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.
• 9 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.
• 10 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48: 1742-1750.
• 11 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.
• 12 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.
• 13 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.
• 14 Bonello L, Paganelli F, Arpin-Bornet M. et al. Vasodilator-stimulated phospho-protein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 2007; 05: 1630-1636.
• 15 Müller 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.
• 16 Harrison P. Assessment of platelet function in the laboratory. Hamostaseologie 2009; 29: 25-31.
• 17 Gremmel T, Steiner S, Seidinger D. et al. Comparison of methods to evaluate clopidogrel-mediated platelet inhibition after percutaneous intervention with stent implantation. Thromb Haemost 2009; 101: 333-339.
• 18 Oestreich JH, Smyth SS, Campbell CL. Platelet function analysis: at the edge of meaning. Thromb Haemost 2009; 101: 217-219.
• 19 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.
• 20 Rahe-Meyer N, Winterhalter M, Boden A. et al. Platelet concentrates transfusion in cardiac surgery and platelet function assessment by multiple electrode aggregometry. Acta Anaesthesiol Scand 2009; 53: 168-175.
• 21 Gorlinger K, Jambor C, Dirkmann D. et al. [Platelet function analysis with pointof-care methods]. Herz 2008; 33: 297-305.
• 22 Johnson A, Dovlatova N, Heptinstall S. Multiple electrode aggregometry and P2Y(12) antagonists. Thromb Haemost 2008; 99: 1127-1129.
• 23 Toth O, Calatzis A, Penz S. et al. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006; 96: 781-788.
• 24 Paniccia R, Antonucci E, Maggini N. et al. Assessment of platelet function on whole blood by multiple electrode aggregometry in high-risk patients with coronary artery disease receiving antiplatelet therapy. Am J Clin Pathol 2009; 131: 834-842.
• 25 Dynabyte Informationssysteme GmbH, Homepage. Available at: www.multi/plate.net. Accessed May 3rd, 2009.
• 26 Sibbing D, Morath T, Stegherr J. et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101: 714-719.
• 27 Cutlip DE, Windecker S, Mehran R. et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115: 2344-2351.
• 28 TIMI Study Group.. Definitions used in TIMI trials. Available at: http://www.timi. org. Accessed May 3rd, 2009.
• 29 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.
• 30 Wenaweser P, Daemen J, Zwahlen M. et al. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice. 4-year results from a large 2-institutional cohort study. J Am Coll Cardiol 2008; 52: 1134-1140.
• 31 Nikolsky E, Grines CL, Cox DA. et al. Impact of baseline platelet count in patients undergoing primary percutaneous coronary intervention in acute myocardial infarction (from the CADILLAC trial). Am J Cardiol 2007; 99: 1055-1061.
• 32 Iakovou I, Schmidt T, Bonizzoni E. et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. J Am Med Assoc 2005; 293: 2126-2130.
• 33 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.
• 34 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.
• 35 Price MJ, Berger PB, Angiolillo DJ. et al. Evaluation of individualized clopidogrel therapy after drug-eluting stent implantation in patients with high residual platelet reactivity: design and rationale of the GRAVITAS trial. Am Heart J 2009; 157: 818-824.
• 36 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.
• 37 Sibbing D, von Beckerath O, Schömig A. et al. Impact of body mass index on platelet aggregation after administration of a high loading dose of 600 mg of clopidogrel before percutaneous coronary intervention. Am J Cardiol 2007; 100: 203-205.
• 38 Ang L, Palakodeti V, Khalid A. et al. Elevated plasma fibrinogen and diabetes mellitus are associated with lower inhibition of platelet reactivity with clopidogrel. J Am Coll Cardiol 2008; 52: 1052-1059. Text_Literatur