Comparison of methods for monitoring residual platelet reactivity after clopidogrel by point-of-care tests on whole blood in high-risk patients

Summary

Cardiovascular events are more frequent in high-risk coronary artery disease (CAD) patients on dual antiplatelet therapy with a residual platelet reactivity (RPR) than in those showing inhibition of ADP-inducible platelet activation. It is known that post-interventional RPR is a clinically important entity confirming it as a risk factor for thrombo-is-chaemic events. Multiple electrode platelet aggregometry (MEA) on whole blood has been recently proposed as a rapid tool to evaluate RPR in high-risk CAD patients on clopidogrel therapy. It was the aim of this study to detect RPR in 801 high-risk CAD patients on dual antiplatelet therapy comparing MEA with the VerifyNow P2Y12 assay on whole blood and classical light transmission aggregation (LTA) on plateletrich plasma. ADP (10 μM) was employed as agonist for MEA and LTA. The prevalence of RPR was 20.6% by MEA, 16.1% by LTA and 30.8% by VerifyNow. MEA showed a significant correlation (rho=0.62, p<0.0001) with VerifyNow and a moderate agreement (k=0.52, p<0.001) with 81.5% of concordant values. A significant correlation was found between MEA and LTA (rho=0.71, p<0.001) with a good agreement (k=0.63, p<0.001) and 88.8% of concordant values. MEA in relation to LTA showed a sensitivity of 80% and a specificity of 91%. MEA might represent a reliable method and valid alternative in comparison with other available platelet function assays. It might help to guide antiplatelet therapy and thus improve clinical outcome of high-risk CAD patients.

Keywords

Clopidogrel therapy - light transmission aggregometry - multiple elec-trode aggregometry - point-of-care testing - residual platelet reactivity

• References

• 1 De Miguel A, Ibanez B, Badimón JJ. Clinical implications of clopidogrel resistance. Thromb Haemost 2008; 100: 196-203.
• 2 Wallentin L. P2Y(12) inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. Eur Heart J 2009; 30: 1964-1977.
• 3 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.
• 4 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.
• 5 Gurbel PA, Bliden KP, Samara W. et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827-1832.
• 6 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.
• 7 Snoep JD, Hovens MM, Eikenboom JC. et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007; 154: 221-231.
• 8 Buonamici P, Marcucci R, Migliorini A. et al. Impact of platelet reactivity following clopidogrel adminstration on drugeluting. J Am Coll Cardiol 2007; 49: 2312-2317.
• 9 Marcucci R, Paniccia R, Antonucci E. et al. Usefulness of aspirin resistance after percutaneous coronary intervention for acute myocardial infarction in predicting one-year major adverse coronary events. Am J Cardiol 2006; 98: 1156-1159.
• 10 Gianetti J, Parri MS, Sbrana S. et al. Platelet activation predicts recurrent ischemic events after percutaneous coronary angioplasty: a 6 months prospective study. Thromb Res 2006; 118: 487-493.
• 11 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.
• 12 Paniccia R, Antonucci E, Gori AM. et al. Comparison of different methods to evaluate the effect of aspirin on platelet function in high-risk patients with ischemic heart disease receiving dual antiplatelet treatment. Am J Clin Pathol 2007; 128: 143-149.
• 13 Harrison P, Frelinger AL, Furman MI. et al. Measuring antiplatelet drug effects in the laboratory. Thromb Res 2007; 120: 323-336.
• 14 Jakubowski JA, Payne CD, Li YG. et al. The use of the VerifyNow P2Y12 point-of-care device to monitor platelet function across a range of P2Y12 inhibition levels following prasugrel and clopidogrel administration. Thromb Haemost 2008; 99: 409-415.
• 15 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.
• 16 Williams CD, Cherala G, Serebruany V. Application of platelet function testing to the bedside. Thromb Haemost 2010; 103: 29-33.
• 17 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.
• 18 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.
• 19 Siller-Matula JM, Gouya G, Wolzt M. et al. Cross validation of the Multiple Electrode Aggregometry. A prospective trial in healthy volunteers. Thromb Haemost 2009; 102: 397-403.
• 20 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.
• 21 Sibbing D, Braun S, Morath T. et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drugeluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849-856.
• 22 Sibbing D, Morath T, Braun S. et al. Clopidogrel response status assessed with Multiplate point-of-care analysis and the incidence and timing of stent thrombosis over six months following coronary stenting. Thromb Haemost 2010; 103: 151-159.
• 23 Buiatti E, Barchielli A, Marchionni N. et al. Determinants of treatment strategies and survival in acute myocardial infarction: a population-based study in the Florence district, Italy: results of the acute myocardial infarction Florence registry (AMI-Florence). Eur Heart J 2003; 24: 1195-1203.
• 24 Expert committee on the diagnosis, classification of diabetes mellitus Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26: 5-20.
• 25 Cifkova R, Erdine S, Fagard R. et al. Practice guidelines for primary care physicians: 2003 ESH/ESC hypertension guidelines. J Hypertens 2003; 21: 1779-1786.
• 26 Ouriel K. Peripheral arterial disease. Lancet 2001; 358: 1257-1264.
• 27 National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143-3421.
• 28 Tóth 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.
• 29 Born GV. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962; 194: 927-929.
• 30 Smith JW, Steinhubl SR, Lincoff AM. et al. Rapid platelet-function assay: an automated and quantitative cartridge-based method. Circulation 1999; 99: 620-625.
• 31 Breugelmans J, Vertessen F, Mertens G. et al. Multiplate whole blood impedance aggregometry: a recent experience. Thromb Haemost 2008; 100: 725-726.
• 32 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.
• 33 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 Coagulation and Fibrinolysis 2010; 21: 46-52.
• 34 Johnson A, Dovlatova N, Heptinstall S. Multiple electrode aggregometry and P2Y(12) antagonists. Thromb Haemost 2008; 99: 1127-1129.
• 35 Kalb ML, Potura L, Scharbert G. et al. The effect of ex vivo anticoagulants on whole blood platelet aggregation. Platelets 2009; 20: 7-11.
• 36 Paniccia R, Antonucci E, Maggini N. et al. Platelet aggregation in whole blood: sodium citrate or hirudin as anticoagulant? [Abstract]. J Thromb Haemost 2009; 07 (Suppl. 02) PP-WE-746.
• 37 Braun S, von Beckerath N, Ellert J. et al. Assessment of platelet function in whole blood by multiple electrode aggregometry: transport of samples using a pneumatic tube system. Am J Clin Pathol 2009; 132: 802-803. author reply 803–804
• 38 Gawaz M, Geisler T. Coronary artery disease: Platelet activity: an obstacle for successful PCI. Nat Rev Cardiol 2009; 06: 391-392.