Advertisement

Advances in Therapy

, Volume 26, Issue 11, pp 999–1011 | Cite as

Prasugrel: Clinical development and therapeutic application

  • Daniel R. GuerraEmail author
  • James E. Tcheng
Review

Abstract

Dual antiplatelet therapy with aspirin and clopidogrel is a cornerstone of the management of patients with acute coronary syndromes and following percutaneous coronary intervention. Despite the proven benefits, clear limitations of clopidogrel exist. Prasugrel is a third-generation thienopyridine antiplatelet agent with pharmacologic characteristics that overcome some of the limitations of clopidogrel, but at the expense of increased bleeding. The promising results seen with prasugrel in large, randomized trials led to its recent approval by the US Food and Drug Administration for reducing thrombotic cardiovascular events in patients with acute coronary syndromes managed with percutaneous coronary intervention. This article will review the limitations of standard antiplatelet therapy and discuss the clinical application of prasugrel.

Keywords

acute coronary syndrome clopidogrel percutaneous coronary intervention prasugrel 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Fuster V, Stein B, Ambrose JA, Badimon L, Badimon JJ, Chesebro JH. Atherosclerotic plaque rupture and thrombosis. Evolving concepts. Circulation. 1990;82(3 suppl.):II47–II59.PubMedGoogle Scholar
  2. 2.
    Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502.CrossRefPubMedGoogle Scholar
  3. 3.
    Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411–2420.CrossRefPubMedGoogle Scholar
  4. 4.
    Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527–533.CrossRefPubMedGoogle Scholar
  5. 5.
    Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:1179–1189.CrossRefPubMedGoogle Scholar
  6. 6.
    Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:1607–1621.CrossRefPubMedGoogle Scholar
  7. 7.
    Sabatine MS, Cannon CP, Gibson CM, et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA. 2005;294:1224–1232.CrossRefPubMedGoogle Scholar
  8. 8.
    Kuzniar J, Splawinskqa B, Malinga K, et al. Pharmacodynamics of ticlopidine: relationship between dose and time of administration to platelet inhibition. Int J Clin Pharmacol Ther. 1996;34:357–361.PubMedGoogle Scholar
  9. 9.
    Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation. 2000;102:624–629.PubMedGoogle Scholar
  10. 10.
    Angiolillo DJ, Guzman LA, Bass TA. Current anti-platelet therapies: benefits and limitations. Am Heart J. 2008;156(2 suppl.):S 3–9.CrossRefGoogle Scholar
  11. 11.
    Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol. 2005;45:246–251.CrossRefPubMedGoogle Scholar
  12. 12.
    Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. Prevalence of clopidogrel nonresponders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost. 2003;89:783–787.PubMedGoogle Scholar
  13. 13.
    Gurbel PA, Bliden KP, Hayes KM, Yoho JA, Herzog WR, Tantry US. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol. 2005;45:1392–1396.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    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.CrossRefPubMedGoogle Scholar
  16. 16.
    Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events poststenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol. 2005;46:1820–1826.CrossRefPubMedGoogle Scholar
  17. 17.
    Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354–362.CrossRefPubMedGoogle Scholar
  18. 18.
    Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360:363–375.CrossRefPubMedGoogle Scholar
  19. 19.
    Sugidachi A, Ogawa T, Kurihara 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 that of clopidogrel’s active metabolite. J Thromb Haemost. 2007;5:1545–1551.CrossRefPubMedGoogle Scholar
  20. 20.
    Savi P, Combalbert J, Gaich C, et al. The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A. Thromb Haemost. 1994;72:313–317.PubMedGoogle Scholar
  21. 21.
    Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007;49:1505–1516.CrossRefPubMedGoogle Scholar
  22. 22.
    Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J. 2004;25:1903–1910.CrossRefPubMedGoogle Scholar
  23. 23.
    Cuisset T, Frere C, Quilici J, 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.CrossRefPubMedGoogle Scholar
  24. 24.
    Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation. 2005;111:2099–2106.CrossRefPubMedGoogle Scholar
  25. 25.
    Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29:21–30.CrossRefPubMedGoogle Scholar
  26. 26.
    Payne CD, Li YG, Small DS, 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.CrossRefPubMedGoogle Scholar
  27. 27.
    Farid NA, Smith RL, Gillespie TA, et al. The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos. 2007;35:1096–1104.CrossRefPubMedGoogle Scholar
  28. 28.
    Niitsu Y, Jakubowski JA, Sugidachi A, Asai F. 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.CrossRefPubMedGoogle Scholar
  29. 29.
    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 e69–16.CrossRefPubMedGoogle Scholar
  30. 30.
    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.CrossRefPubMedGoogle Scholar
  31. 31.
    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.CrossRefPubMedGoogle Scholar
  32. 32.
    Wiviott SD, Antman EM, Winters KJ, et al. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation. 2005;111:3366–3373.CrossRefPubMedGoogle Scholar
  33. 33.
    Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116:2923–2932.CrossRefPubMedGoogle Scholar
  34. 34.
    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.CrossRefPubMedGoogle Scholar
  35. 35.
    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.CrossRefPubMedGoogle Scholar
  36. 36.
    Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009;373:723–731.CrossRefPubMedGoogle Scholar
  37. 37.
    Morrow DA, Wiviott SD, White HD, et al. Effect of the novel thienopyridine prasugrel compared with clopidogrel on spontaneous and procedural myocardial infarction in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38: an application of the classification system from the universal definition of myocardial infarction. Circulation. 2009;119:2758–2764.CrossRefPubMedGoogle Scholar
  38. 38.
    Murphy SA, Antman EM, Wiviott SD, et al. Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial. Eur Heart J. 2008;29:2473–2479.CrossRefPubMedGoogle Scholar
  39. 39.
    Effient [package insert]. Revised July 2009 Eli Lilly and Company: Indianapolis, IN; 2009.Google Scholar
  40. 40.
    Serebruany VL. Aggressive chronic platelet inhibition with prasugrel and increased cancer risks: revising oral antiplatelet regimens? Fundam Clin Pharmacol. 2009;23:411–417.CrossRefPubMedGoogle Scholar
  41. 41.
    Anonymous. A comparison of prasugrel and clopidogrel in acute coronary syndrome subjects (TRIOLOGY ACS). Available at: http://clinicaltrials.gov/ct2/show/NCT00699998?term=A+Comparison+of+Prasugrel+and+Clopidogrel+in+Acute+Coronary+Syndrome+Subjects+AND+trilogy+ACS&rank=1. Accessed November 22, 2009.
  42. 42.
    O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet. 2009;374:989–997.CrossRefPubMedGoogle Scholar
  43. 43.
    Search results — studies of prasugrel. Available at: http://clinicaltrials.gov/ct2/results?term=studies+of+prasugrel. Accessed November 22, 2009.
  44. 44.
    Sibbing D. Kastrati A. Risk of combining PPIs with thienopyridines: fact or fiction? Lancet. 2009;374:952–954.CrossRefPubMedGoogle Scholar
  45. 45.
    Angiolillo DJ, Bhatt DL, Gurbel PA, Jennings LK. Advances in antiplatelet therapy: agents in clinical development. Am J Cardiol. 2009;103:40A–51A.CrossRefPubMedGoogle Scholar
  46. 46.
    Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. LATO Investigators. N Engl J Med. 2009;361:1045–1057.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Healthcare Communications 2009

Authors and Affiliations

  1. 1.Cardiac Study CenterTacomaUSA
  2. 2.Division of Cardiovascular MedicineDuke University Medical CenterDurhamUSA

Personalised recommendations