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

Summary

Variability in response to antiplatelet agents has prompted the development of point-of-care (POC) technology. In this study, we compared theVerifyNow^TM P2Y12 (VN-P2Y12) POC device with light transmission aggregometry (LTA) in subjects switched directly from clopidogrel to prasugrel. Healthy subjects on aspirin were administered a clopidogrel 600 mg loading dose (LD) followed by a 75 mg/d maintenance dose (MD) for 10 days. Subjects were then switched to a prasugrel 60 mg LD and then 10 mg/d MD for 10 days (n=16), or to a prasugrel 10 mg/d MD for 11 days (n=19). Platelet function was measured by LTA andVN-P2Y12 at baseline and after dosing. Clopidogrel 600 mg LD/75 mg MD treatment led to a reduction in P2Y₁₂ reaction units (PRU) from baseline. A switch from clopidogrel MD to prasugrel 60 mg LD/10 mg MD produced an immediate decrease in PRU, while a switch to prasugrel 10 mg MD resulted in a more gradual decline. Consistent with the reduction in PRU, device-reported percent inhibition increased during both clopidogrel and prasugrel regimens. Inhibition of platelet aggregation as measured by LTA showed a very similar pattern to that found with VN-P2Y12 measurement, irrespective of treatment regimens. The dynamic range of VN-P2Y12 appeared to be narrower than that of LTA. With two different thienopyridines, the VN-P2Y12 device, within a somewhat more limited range, reflected the overall magnitude of change in aggregation response determined by LTA. The determination of the clinical utility of such POC devices will require their use in clinical outcome studies.

Keywords

VerifyNow^TM P2Y12 - light transmission aggregometry - prasugrel - clopidogrel - platelet aggregation

• References

• 1 Harrison P, Frelinger AL, III Furman MI. et al. Measuring antiplatelet drug effects in the laboratory. Thromb Res 2007; 120: 323-336.
• 2 Michelson AD, Frelinger AL III, Furman MI. et al. Current options in platelet function testing. Am J Cardiol 2006; 98 10A 4N-10N.
• 3 Brandt JT, Payne CD, Wiviott SD. et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007; 153: 66.e9-66.e16.
• 4 Jakubowski JA, Matsushima N, Asai F. et al. A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans. Br J Clin Pharmacol 2007; 63: 421-430.
• 5 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.
• 6 Sugidachi A, Asai F, Ogawa T. et al. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol 2000; 129: 1439-1446.
• 7 Jakubowski JA, Winters KJ, Naganuma H. et al. Prasugrel: A Novel Thienopyridine Antiplatelet Agent. A Review of Preclinical and Clinical Studies and the Mechanistic Basis for its Distinct Antiplatelet Profile. Cardiovasc Drug Rev 2007; 25: 357-374.
• 8 Wiviott SD, Braunwald E, McCabe C. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
• 9 Malinin A, Pokov A, Swaim L. et al. Validation of a VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with clopidogrel. Methods Find Exp Clin Pharmacol 2006; 28: 315-322.
• 10 Malinin A, Pokov A, Spergling M. et al. Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12^® rapid analyzer: the VERIfy Thrombosis risk ASsessment (VERITAS) study. Thromb Res 2007; 119: 277-284.
• 11 Van Werkum JW, van der Stelt CA, Seesing TH. et al. A head-to-head comparison between the VerifyNow P2Y12 assay and light transmittance aggregometry for monitoring the individual platelet response to clopidogrel in patients undergoing elective percutaneous coronary intervention. J Thromb Haemost 2006; 4: 2516-2518.
• 12 von Beckerath N, Pogatsa-Murray G, Wieczorek A. et al. Correlation between platelet response units measured with a point-of-care test and ADP-induced platelet aggregation assessed with conventional optical aggregometry. Eur Heart J. 2001 26. 01 SEP.
• 13 Price MJ, Coleman JL, Steinhubl SR. et al. Onset and offset of platelet inhibition after high-dose clopidogrel loading and standard daily therapy measured by a point-of-care assay in healthy volunteers. Am J Cardiol 2006; 98: 681-684.
• 14 Jakubowski JA, Payne CD, Li GY. et al. Effect of prasugrel and high-dose clopidogrel on platelet function as assessed by point of care and optical aggregometry. J Thromb Haemost 2007; 5 (Suppl. 02) P-S-346.
• 15 VerifyNow P2Y12 Assay. Accumetrics.. 2007. San Diego, CA.: Instructions for use.
• 16 Jakubowski JA, Stampfer MJ, Vaillancourt R. et al. Cumulative antiplatelet effect of low-dose enteric coated aspirin. Br J Haematol 1985; 60: 635-642.
• 17 Payne CD, Li YG, Brandt JT. et al. Switching directly to prasugrel from clopidogrel results in greater inhibition of platelet aggregation in aspirin-treated subjects. Platelets. 2008 in press.
• 18 von Beckerath N, Pogatsa-Murray G, Wieczorek A. et al. Correlation of a new point-of-care test with conventional optical aggregometry for the assessment of clopidogrel responsiveness. Thromb Haemost 2006; 95: 910-911.
• 19 Husted S, Emanuelsson H, Heptinstall S. et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27: 1038-1047.
• 20 Wiviott SD, Antman EM, Gibson CM. et al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the Trial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis. In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J 2006; 152: 627-635.
• 21 Dombrowski KE, Trevillyan JM, Cone JC. et al. Identification and partial characterization of an ectoATPase expressed by human natural killer cells. Biochemistry 1993; 32: 6515-6522.
• 22 El-Omar MM, Islam N, Broekman MJ. et al. The ratio of ADP- to ATP-ectonucleotidase activity is reduced in patients with coronary artery disease. Thromb Res 2005; 116: 199-206.
• 23 Glenn JR, White AE, Johnson A. et al. Leukocyte count and leukocyte ecto-nucleotidase are major determinants of the effects of adenosine triphosphate and adenosine diphosphate on platelet aggregation in human blood. Platelets 2005; 16: 159-170.
• 24 Koziak K, Sevigny J, Robson SC. et al. Analysis of CD39/ATP diphosphohydrolase (ATPDase) expression in endothelial cells, platelets and leukocytes. Thromb Haemost 1999; 82: 1538-1544.
• 25 Leal DB, Streher CA, Neu TN. et al. Characterization of NTPDase (NTPDasel; ecto-apyrase; ecto-diphosphohydrolase; CD39; EC 3.6.1.5) activity in human lymphocytes. Biochim Biophys Acta 2005; 1721: 9-15.
• 26 Jin RC, Voetsch B, Loscalzo J. Endogenous mechanisms of inhibition of platelet function. Microcirculation 2005; 12: 247-258.
• 27 Jakubowski JA, Payne CD, Weerakkody GJ. et al. Dose-dependent inhibition of human platelet aggregation by prasugrel and its interaction with aspirin in healthy subjects. J Cardiovasc Pharmacol 2007; 49: 167-173.