Advertisement

Journal of Thrombosis and Thrombolysis

, Volume 42, Issue 3, pp 369–375 | Cite as

Prasugrel 5 mg inhibits platelet P-selectin and GPIIb–IIIa expression in very elderly and non elderly: results from the GENERATIONS trial, a pharmacodynamic study in stable CAD patients

  • Henrik WagnerEmail author
  • Christian Lood
  • Catharina Borna
  • Olof Gidlöf
  • Lennart Truedsson
  • Patricia Brown
  • Chunmei Zhou
  • Kenneth Winters
  • Joseph A. Jakubowski
  • David Erlinge
Article

Abstract

Platelet P-selectin and activated glycoprotein IIb–IIIa (GPIIb–IIIa) are markers of platelet activation and mediates platelet aggregation. Prasugrel (Pras) 5 mg may be used in very elderly (VE) acute coronary syndrome (ACS) patients undergoing PCI, but its effect on platelet P-selectin and activated GPIIb–IIIa in those patients is not known. Stable ACS patients, VE (78 ± 5 years, n = 23) and non-elderly (NE) (55 ± 5 years, n = 22) were randomized to Pras (5 or 10 mg) or clopidogrel (Clop) 75 mg during three 12-day periods. Platelet activation markers were measured by flow cytometry on unstimulated or stimulated (adenosine diphosphate (ADP) 20 μM) platelets, before and after each dosing period.Results: At baseline there was no difference in platelet activation markers, either unstimulated or ADP-stimulated, between NE and VE. Pras 5 mg reduced both ADP-stimulated platelet P-selectin and activated GPIIb–IIIa in VE (p < 0.01 for both analyses) and NE (p < 0.001 and p < 0.05, respectively). Clop 75 mg had a similar effect as Pras 5 mg but did not significantly reduce activated GPIIb–IIIa in VE. Prasugrel 10 mg resulted in decreased platelet activation in both age groups compared to Clop 75 mg (p < 0.01).Conclusions: In VE and NE-patients, Pras 5 mg inhibited platelet P-selectin expression similar to Clop 75 mg and Pras 10 mg. Prasugrel 10 mg inhibited platelet P-selectin expression better than Clop 75 mg. Prasugrel 10 mg and 5 mg, but not Clop 75 mg, significantly inhibited activated GPIIb–IIIa in VE. This platelet reactivity data support the use of Pras 5 mg for VE patients.

Keywords

Surface P-selectin Activated GPIIb–IIIa Prasugrel Platelets 

Notes

Acknowledgments

Sponsored by Daiichi Sankyo Company, Ltd. and Eli Lilly and Company.

Compliance with ethical standards

Conflict of interest

DE has received fees for being a speaker from Daiichi Sankyo Company, Ltd. and Eli Lilly and Company, AstraZeneca, Sanofi-Aventis and Accumetrics and for being an advisory board member for AstraZeneca, Eli Lilly and Company, and Merck. HW has received grants from JOLIFE Sweden AB/Physio-Control Inc. and has consulted for Eli Lilly Sweden. JJ, KW, CZ and PB are employees of and minor shareholders of Eli Lilly and Company. CL, OG, CB and LT have no conflicts to declare.

References

  1. 1.
    Wiviott SD et al (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357(20):2001–2015CrossRefPubMedGoogle Scholar
  2. 2.
    Hamm CW et al (2011) ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 32(23):2999–3054CrossRefPubMedGoogle Scholar
  3. 3.
    Calver AL et al (2000) Clopidogrel for prevention of major cardiac events after coronary stent implantation: 30-day and 6-month results in patients with smaller stents. Am Heart J 140(3):483–491CrossRefPubMedGoogle Scholar
  4. 4.
    Kolansky DM et al (2000) Combination therapy with clopidogrel and aspirin after coronary stenting. Catheter Cardiovasc Interv 50(3):276–279CrossRefPubMedGoogle Scholar
  5. 5.
    Gurbel PA et al (2003) Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 107(23):2908–2913CrossRefPubMedGoogle Scholar
  6. 6.
    Angiolillo DJ et al (2005) Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thromb Res 115(1–2):101–108CrossRefPubMedGoogle Scholar
  7. 7.
    Cuisset T et al (2006) High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 4(3):542–549CrossRefPubMedGoogle Scholar
  8. 8.
    Matetzky S et al (2004) Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 109(25):3171–3175CrossRefPubMedGoogle Scholar
  9. 9.
    Erlinge D et al (2013) Prasugrel 5 mg in the very elderly attenuates platelet inhibition but maintains noninferiority to prasugrel 10 mg in nonelderly patients: the GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable coronary artery disease patients. J Am Coll Cardiol 62(7):577–583CrossRefPubMedGoogle Scholar
  10. 10.
    Erlinge D et al (2012) Reduction in platelet reactivity with prasugrel 5 mg in low-body-weight patients is noninferior to prasugrel 10 mg in higher-body-weight patients: results from the FEATHER trial. J Am Coll Cardiol 60(20):2032–2040CrossRefPubMedGoogle Scholar
  11. 11.
    Company ELa (2012) Efient (prasugrel) Eurepean Union summary of product characteristicsGoogle Scholar
  12. 12.
    McEver RP (2001) Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inflammation. Thromb Haemost 86(3):746–756PubMedGoogle Scholar
  13. 13.
    McEver RP, Cummings RD (1997) Role of PSGL-1 binding to selectins in leukocyte recruitment. J Clin Invest 100(11 Suppl):S97–S103PubMedGoogle Scholar
  14. 14.
    Kansas GS (1996) Selectins and their ligands: current concepts and controversies. Blood 88(9):3259–3287PubMedGoogle Scholar
  15. 15.
    Bigalke B et al (2010) High plasma levels of adipocytokines are associated with platelet activation in patients with coronary artery disease. Platelets 21(1):11–19CrossRefPubMedGoogle Scholar
  16. 16.
    Braun OO et al (2008) Greater reduction of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease. Thromb Haemost 100(4):626–633PubMedGoogle Scholar
  17. 17.
    Merten M, Thiagarajan P (2000) P-selectin expression on platelets determines size and stability of platelet aggregates. Circulation 102(16):1931–1936CrossRefPubMedGoogle Scholar
  18. 18.
    Angiolillo DJ et al (2007) Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 49(14):1505–1516CrossRefPubMedGoogle Scholar
  19. 19.
    Gremmel T et al (2013) Prasugrel reduces agonists’ inducible platelet activation and leukocyte-platelet interaction more efficiently than clopidogrel. Cardiovasc Ther 31(9):e40–e45CrossRefPubMedGoogle Scholar
  20. 20.
    Kuzniatsova N et al (2012) No effect of clopidogrel activity or cessation on vascular function or markers of inflammation. Int J Angiol 21(4):195–200CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Dorr G et al (2002) Effects of combined therapy with clopidogrel and acetylsalicylic acid on platelet glycoprotein expression and aggregation. J Cardiovasc Pharmacol 39(4):523–532CrossRefPubMedGoogle Scholar
  22. 22.
    van der Zee PM et al (2006) P-selectin- and CD63-exposing platelet microparticles reflect platelet activation in peripheral arterial disease and myocardial infarction. Clin Chem 52(4):657–664CrossRefPubMedGoogle Scholar
  23. 23.
    Gilstad JR, Gurbel PA, Andersen RE (2009) Relationship between age and platelet activation in patients with stable and unstable angina. Arch Gerontol Geriatr 48(2):155–159CrossRefPubMedGoogle Scholar
  24. 24.
    Scalone G et al (2011) Evidence of increased platelet reactivity in the first six months after acute ST segment elevation myocardial infarction. Thromb Res 128(2):174–178CrossRefPubMedGoogle Scholar
  25. 25.
    Bernlochner I et al (2015) Impact of immature platelets on platelet response to ticagrelor and prasugrel in patients with acute coronary syndrome. Eur Heart J 36(45):3202–3210CrossRefPubMedGoogle Scholar
  26. 26.
    Gremmel T et al (2013) Preserved thrombin-inducible platelet activation in thienopyridine-treated patients. Eur J Clin Invest 43(7):689–697CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Henrik Wagner
    • 1
    Email author
  • Christian Lood
    • 2
  • Catharina Borna
    • 1
  • Olof Gidlöf
    • 1
  • Lennart Truedsson
    • 3
  • Patricia Brown
    • 4
  • Chunmei Zhou
    • 4
  • Kenneth Winters
    • 4
  • Joseph A. Jakubowski
    • 4
  • David Erlinge
    • 1
  1. 1.Department of Cardiology, Clinical SciencesLund UniversityLundSweden
  2. 2.Department of Reumatology, Clinical SciencesLund UniversityLundSweden
  3. 3.Section of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine LundLund UniversityLundSweden
  4. 4.Eli Lilly and CompanyIndianapolisUSA

Personalised recommendations