Greater reduction of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease

Oscar Ö. Braun; Matilda Johnell; Christoph arenhorst; Stefan James; John T. Brandt; Joseph A. Jakubowski; Kenneth J. Winters; Lars Wallentin; David Erlinge; Agneta Siegbahn

doi:10.1160/TH08-05-0313

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 100(04): 626-633
DOI: 10.1160/TH08-05-0313

Platelets and Blood Cells

Schattauer GmbH

Greater reduction of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease

Oscar Ö. Braun^*

¹Department of Cardiology, Lund University, Sweden

,

Matilda Johnell^*

²Coagulation Laboratory, Department of Medical Sciences, Clinical Chemistry, Uppsala, Sweden

,

Christoph arenhorst

³Uppsala Clinical Research Centre and Department of Medical Sciences, Uppsala University, Sweden

,

Stefan James

³Uppsala Clinical Research Centre and Department of Medical Sciences, Uppsala University, Sweden

,

John T. Brandt

⁴Lilly Research Laboratories, Indianapolis, Indiana, USA

,

Joseph A. Jakubowski

⁴Lilly Research Laboratories, Indianapolis, Indiana, USA

,

Kenneth J. Winters

⁴Lilly Research Laboratories, Indianapolis, Indiana, USA

,

Lars Wallentin

³Uppsala Clinical Research Centre and Department of Medical Sciences, Uppsala University, Sweden

,

David Erlinge

¹Department of Cardiology, Lund University, Sweden

,

Agneta Siegbahn

²Coagulation Laboratory, Department of Medical Sciences, Clinical Chemistry, Uppsala, Sweden

› Author Affiliations

Abstract

Summary

Prasugrel, a novel P2Y₁₂ ADP-receptor antagonist, has been reported to achieve greater inhibition of platelet aggregation compared to clopidogrel as assessed by light transmission aggregometry. It was the objective of this study to investigate the effect of prasugrel on alternative markers of platelet activation in comparison to a high loading dose and the approved maintenance dose of clopidogrel. One hundred ten aspirintreated patients with stable coronary artery disease were randomized to a loading dose (LD, day 1)/ maintenance dose (MD, days 2–29) of prasugrel 60 mg/10 mg or clopidogrel 600 mg/75 mg. Platelet activation markers were analyzed by whole blood flow cytometry pre-dose and at 2 and 24 hours after LD and pre-dose at 14 and 29 days. After stimulation with 20 µM ADP, 2 hours after LD, significantly lower expression of activated GPIIb/IIIa (4.3 vs. 21.8 [mean fluorescent intensity (MFI)], p < 0.001) and P-selectin (2.0 vs. 11.7 MFI, p < 0.001) along with decreased formation of platelet-monocyte aggregates (16.4% vs.29.6% positive cells, p < 0.001) was observed with prasugrel versus clopidogrel. All these effects were maintained through 24 hours and during the MD period. In conclusion, prasugrel 60 mg LD and 10 mg MD inhibit several markers of platelet activation and the formation of platelet-monocyte aggregates more effectively than a 600 mg LD and 75 mg MD of clopidogrel. Attenuated platelet aggregation and reduced expression of platelet procoagulant and pro-inflammatory markers with prasugrel suggest the potential to reduce cardiovascular events both in the acute setting and in longterm treatment.

Keywords

CAD - thienopyridines - platelet markers - tissue factor - flow cyto metry

Full Text

References

References
1 Fuster V, Stein B, Ambrose JA. et al. Atherosclerotic plaque rupture and thrombosis. Evolving concepts. Circulation 1990; 82 (Suppl. 03) II47-59.
2 Bassand JP, Hamm CW, Ardissino D. et al. Guidelines for the diagnosis and treatment of non-ST - segment elevation acute coronary syndromes. European Heart J 2007; 28: 1598-1660.
3 Jaremo P, Lindahl TL, Fransson SG. et al. Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002; 252: 233-238.
4 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
5 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thromb Res 2005; 115: 101-108.
6 Braun OÖ, Amisten S, Wihlborg A-K. et al. Residual platelet ADP reactivity after clopidogrel treatment is dependent on activation of both the unblocked P2Y1 and the P2Y12 receptor and is correlated with protein expression of P2Y12. Purinergic Signalling 2007; 03: 195-201.
7 Gurbel PA, Bliden KP, Guyer K. et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST- STENTING Study. J Am Coll Cardiol 2005; 46: 1820-1826.
8 Cuisset T, Frere C, Quilici J. et al. High post-treatment platelet reactivity identified lowresponders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006; 04: 542-549.
9 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.
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 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.
12 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. European Heart J 2006; 27: 1166-1173.
13 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. Cardiovascular Drug Rev 2007; 25: 357-374.
14 Wiviott SD, Braunwald E, McCabe CH. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
15 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 08: 1227-1234.
16 Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest 2005; 115: 3378-3384.
17 Furman MI, Benoit SE, Barnard MR. et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 1998; 31: 352-358.
18 Michelson AD, Barnard MR, Krueger LA. et al. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001; 104: 1533-1537.
19 Furman MI, Barnard MR, Krueger LA. et al. Circulating monocyte-platelet aggregates are an early marker of acute myocardial infarction. J Am Coll Cardiol 2001; 38: 1002-1006.
20 Lindmark E, Wallentin L, Siegbahn A. Blood cell activation, coagulation, and inflammation in men and women with coronary artery disease. Thromb Res 2001; 103: 249-259.
21 Lindmark E, Tenno T, Siegbahn A. Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression. Arterioscler Thromb Vasc Biol 2000; 20: 2322-2328.
22 Matzdorff A. Platelet function tests and flow cytometry to monitor antiplatelet therapy. Semin Thromb Hemost 2005; 31: 393-399.
23 Quinn MJ, Bhatt DL, Zidar F. et al. Effect of clopidogrel pretreatment on inflammatory marker expression in patients undergoing percutaneous coronary intervention. Am J Cardiol 2004; 93: 679-684.
24 Klinkhardt U, Bauersachs R, Adams J. et al. Clopidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with atherosclerotic vascular disease. Clin Pharmacol Therap 2003; 73: 232-241.
25 Frelinger 3rd AL, Jakubowski JA, Li Y. et al. The active metabolite of prasugrel inhibits ADP-stimulated thrombo-inflammatory markers of platelet activation: Influence of other blood cells, calcium, and aspirin. Thromb Haemost 2007; 98: 192-200.
26 Wallentin L, Varenhorst C, James S. et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirintreated patients with coronary artery disease. European Heart J 2008; 29: 21-30.
27 Li N, Goodall AH, Hjemdahl P. Efficient flow cytometric assay for platelet-leukocyte aggregates in whole blood using fluorescence signal triggering. Cytometry 1999; 35: 154-161.
28 Armitage P, Berry G. Statistical Methods in Medical Research. 3rd edition. Blackwell Scientific Publications; Oxford: 1994: 154-174.
29 Ley K. The role of selectins in inflammation and disease. Trends Mol Med 2003; 09: 263-268.
30 Rao LV, Pendurthi UR. Tissue factor-factor VIIa signaling. Arterioscler Thromb Vasc Biol 2005; 25: 47-56.
31 Siegbahn A, Johnell M, Nordin A. et al. TF/FVIIa transactivate PDGFRbeta to regulate PDGF-BB-induced chemotaxis in different cell types: involvement of Src and PLC. Arterioscler Thromb Vasc Biol 2008; 28: 135-141.
32 McEver RP. Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inflammation. Thromb Haemost 2001; 86: 746-756.
33 Huo Y, Schober A, Forlow SB. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 09: 61-67.
34 Burger PC, Wagner DD. Platelet P-selectin facilitates atherosclerotic lesion development. Blood 2003; 101: 2661-2666.
35 von Hundelshausen P, Weber KS, Huo Y. et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 2001; 103: 1772-1777.
36 Schober A, Manka D, von Hundelshausen P. et al. Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury. Circulation 2002; 106: 1523-1529.
37 Polgar J, Matuskova J, Wagner DD. The P-selectin, tissue factor, coagulation triad. J Thromb Haemost 2005; 03: 1590-1596.
38 Hrachovinova I, Cambien B, Hafezi-Moghadam A. et al. Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med 2003; 09: 1020-1025.
39 Massberg S, Brand K, Gruner S. et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med 2002; 196: 887-896.