A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry

Joseph A Jakubowski; Christopher D Payne; Ying G Li; Nagy A Farid; John T Brandt; David S Small; Daniel E Salazar; Kenneth J Winters

doi:10.1160/TH07-09-0555

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2008; 99(01): 215-222
DOI: 10.1160/TH07-09-0555

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry

Joseph A Jakubowski

¹Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA

,

Christopher D Payne

²Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, UK

,

Ying G Li

¹Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA

,

Nagy A Farid

¹Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA

,

John T Brandt

¹Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA

,

David S Small

¹Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA

,

Daniel E Salazar

³Daiichi Sankyo, Inc., Parsippany, NJ, USA

,

Kenneth J Winters

¹Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA

› Institutsangaben

Abstract

Summary

Platelet inhibition as measured by vasodilator-stimulated phosphoprotein (VASP) and light transmission aggregometry (LTA) have shown concordance following dosing of clopidogrel. No reports have directly compared theVASP assay and LTA at the levels of P2Y12 blockade after loading doses (LDs) of prasugrel or high dose clopidogrel (600 and 900 mg).The aim was to compare theVASP assay and LTA during the loading dose phase of a comparative study of prasugrel and clopidogrel. Prasugrel 60 mg LD/10 mg maintenance dose (MD) and clopidogrel 300 mg/75 mg and 600 mg/75 mg LD/MD regimens were compared in a 3-way crossover study in 41 healthy, aspirin-free subjects. Each LD was followed by seven daily MDs and a 14-day washout period. P2Y₁₂ receptor blockade was estimated using theVASP assay, expressed as platelet reactivity index (VASP-PRI). Platelet aggregation was assessed by light transmission aggregometry (20 and 5 μM ADP).Twenty-four hoursafter prasgurel 60 mg or clopidogrel 300 mg and 600 mg, respectively, VASP-PRI decreased from ∼80% to 8.9%, 54.7%, and 39.0 %, and maximal platelet aggregation (MPA) decreased from ∼79% to 10.8%, 42.7%, and 31.2%, with an overall VASP:MPA correlation of 0.88 (p<0.01). VASP assay responses after the clopidogrel LDs showed a wider range of values (300 mg: 0–93%; 600 mg: 0–80%) than prasugrel (0–13%); MPA responses followed a similar trend. Pearson’s correlation suggested a strong agreement between VASP and LTA (20 μM ADP) for MPA (r=0.86, p<0.0001).VASP and LTA demonstrated concordance across the response range of P2Y₁₂ receptor blockade following thienopyridine LDs.

Keywords

Clopidogrel - prasugrel - P2Y₁₂ - thienopyridine - VASP

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Referenzen

References
1 Jennings LK. et al. Platelet aggregation.. Michelson AD. Platelets.. 2^nd ed. San Diego, CA: Elsevier/Academic Press; 2006
2 Michelson AD. et al. Current options in platelet function testing. Am J Cardiol 2006; 98 10A 4N-10N.
3 Geiger J. et al. Specific impairment of human platelet P2Y_ac ADP receptor-mediated signaling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol 1999; 19: 2007-2011.
4 Savi P. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-896.
5 Hollopeter G. et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-207.
6 Kauffenstein G. et al. The P2Y₁₂ receptor induces platelet aggregation through weak activation of the α_IIbβ₃ integrin – a phosphoinositide 3-kinase-depend- ent mechanism. FEBS Letters 2001; 505: 281-290.
7 Jakubowski JA. 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.
8 Gurbel PA. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
9 Bates ER. et al. Loading, pretreatment, and interindividual variability issues with clopidogrel dosing. Circulation 2005; 111: 2557-2559.
10 Gurbel PA. 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.
11 von Beckerath N. et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel. Circulation 2005; 112: 2946-2950.
12 Born G. et al. Antiplatelet drugs. Br J Pharmacol 2006; 147 (Suppl. 01) S241-S251.
13 Michelson AD. et al. Evidence that pre-existent variability in platelet response to ADP accounts for ‘clopidogrel resistance’. J Thromb Haemost 2007; 5: 75-81.
14 Hochholzer W. 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.
15 Jernberg T. et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirintreated patients with stable coronary artery disease. Eur Heart J 2006; 27: 1166-1173.
16 Payne CD. et al. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol 2007; 50: 555-562.
17 Gachet C. ADP receptors of platelets and their inhibition. Thromb Haemost 2001; 86: 222-232.
18 Storey RF. The P2Y12 receptor as a therapeutic target in cardiovascular disease. Platelets 2001; 12: 197-209.
19 Gachet C. Regulation of platelet functions by P2 receptors. Ann Rev Pharmacol Toxicol 2006; 46: 277-300.
20 Storey RF. Biology and pharmacology of the platelet P2Y₁₂ receptor. Curr Pharm Des 2006; 12: 1255-1259.
21 Horstrup K. et al. Phosphorylation of focal adhesion vasodilator-stimulated phosphoprotein at SER 157 in intact human platelets correlates with fibrinogen receptor inhibition. Eur J Biochem 1994; 225: 21-27.
22 Schwarz UR. et al. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets. Thromb Haemost 1999; 82: 1145-1152.
23 Hauser W. et al. Megakaryocyte hyperplasia and enhanced agonist-induced platelet activation in vasodilatator-stimulated phosphoprotein knockout mice. Proc Natl Acad Sci USA 1999; 96: 8120-8125.
24 Hezard N. et al. Platelet VASP phosphorylation assessment in clopidogrel-treated patients: Lack of agreement between Western blot and flow cytometry. Platelets 2005; 16: 474-481.
25 Pampuch A. et al. Comparison of VASP-phosphorylation assay to light-transmission aggregometry in assessing inhibition of the platelet ADP P2Y₁₂ receptor. Thromb Haemost 2006; 96: 767-773.
26 Barragan P. et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Cathet Cardiovasc Intervent 2003; 59: 295-302.
27 Aleil B. et al. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost 2005; 3: 85-92.
28 Package Insert, PLT VASP/P2Y₁₂ Kit, Reference 7014, April 2005, Biocytex, 140 ch. De L’Armee D’Afrique, 13010 Marseille. France.: ;
29 Aleil B. et al. High stability of blood samples for flow cytometric analysis of VASP phosphorylation to measure the clopidogrel responsiveness in patients with coronary artery disease. Thromb Haemost 2005; 94: 886-887.
30 Gurbel PA. et al. Failure of clopidogrel to reduce platelet reactivity and activation following standard dosing in elective stenting: implications for thrombotic events and restenosis. Platelets 2004; 15: 95-99.
31 Kastrati A. et al. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation 2004; 110: 1916-1919.
32 Hochholzer W. et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005; 111: 2560-2564.
33 Montalescot G. et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes. J Am Coll Cardiol 2006; 48: 931-938.
34 Cuisset T. 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.
35 Sugidachi A. et al. The greater in vivo antiplatelet effects of prasugrel compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to prasugrel’s active metabolite. J Thromb Haemost 2007; 5: 1545-1551.
36 Kurihara A. et al. Potent inhibition of platelet aggregation by prasugrel (CS-747, LY640315), a novel thienopyridine antiplatelet agent, is associated with co-valent binding of active metabolite to ADP receptor. Eur Heart J 2005; 26 (Suppl. 01) 485 [abstract].
37 Niitsu Y. et al. Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y₁₂ receptor antagonist activity. Semin Thromb Hemost 2005; 31: 184-194.
38 Brandt JT. 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-e16.
39 Jakubowski JA. et al. Cumulative antiplatelet effect of low-dose enteric coated aspirin. Br J Haematol 1985; 60: 635-642.
40 Armitage P. et al. 1994. Statistical Methods in Medical Research (3rd edition).. Oxford: Blackwell Scientific Publications; : 154-174.
41 Weerakkody G. et al. Clopidogrel nonresponders: an objective definition based on Bayesian classification. Platelets 2007; 18: 428-35.
42 Matetzky S. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175.
43 Buonamici P. et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 49: 2312-2317.
44 Bonello L. et al. VASP phosphorylation analysis prior to percutaneous coronary intervention for exclusion of post-procedural major adverse cardiovascular events. J Thrombos Haemost 2007; 5: 1630-1636.
45 Blindt R. et al. The significance of vasodilator- stimulated phosphoprotein for risk stratification of stent thrombosis. Clin Res Cardiol. 2007 96. 01 P280[abstract].
46 Frere C. 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: 838-843.