American Heart Journal
Volume 153, Issue 1 , Pages 66.e9-66.e16 , January 2007

A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation

  • John T. Brandt, MD

      Affiliations

    • Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN
    • Corresponding Author InformationReprint requests: John T. Brandt, MD, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center DC 2133, Indianapolis, IN 46285.
    • ,
  • Christopher D. Payne, MS

      Affiliations

    • Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN
    • ,
  • Stephen D. Wiviott, MD

      Affiliations

    • TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    • ,
  • Govinda Weerakkody, PhD

      Affiliations

    • Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN
    • ,
  • Nagy A. Farid, PhD

      Affiliations

    • Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN
    • ,
  • David S. Small, PhD

      Affiliations

    • Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN
    • ,
  • Joseph A. Jakubowski, PhD

      Affiliations

    • Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN
    • ,
  • Hideo Naganuma, PhD

      Affiliations

    • Sankyo Co, Ltd, Tokyo, Japan
    • ,
  • Kenneth J. Winters, MD

      Affiliations

    • Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN

Received 20 April 2006 ,Accepted 9 October 2006.

References 

  1. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the management of patients with unstable angina). J Am Coll Cardiol. 2000;36:970–1056
  2. Schulman SP. Antiplatelet therapy in non–ST-segment elevation acute coronary syndromes. JAMA. 2004;292:1875–1882
  3. Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study. Circulation. 1998;98:1597–1603
  4. Cutlip DE, Leon MB, Ho KK, et al. Acute and nine-month clinical outcomes after “suboptimal” coronary stenting: results from the STent Anti-thrombotic Regimen Study (STARS) registry. J Am Coll Cardiol. 1999;34:698–706
  5. Kastrati A, Mehilli J, Schuhlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med. 2004;350:232–238
  6. Mehta SR, Yusuf S, Peters RJG, 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
  7. Urban P, Macaya C, Rupprecht HJ, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS). Circulation. 1998;98:2126–2132
  8. Niitsu Y, Jakubowski JA, Sugidachi A, et al. Pharmacology of CS-747 (Prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y(12) receptor antagonist activity. Semin Thromb Hemost. 2005;31:184–194
  9. Savi P, Herbert JM. Clopidogrel and ticlopidine: P2Y(12) adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost. 2005;31:174–183
  10. Coukell AJ, Markham A. Clopidogrel. Drugs. 1997;54:745–750
  11. Bertrand ME, Rupprecht H-J, Urban P, et al. 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
  12. Aleil B, Gachet C. The inter-individual variability of the response to clopidogrel. Arch Mal Coeur Vaiss. 2005;98:216–225
  13. 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
  14. 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
  15. Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation. 2004;109:166–171
  16. Lepantaloa A, Virtanen KS, Heikkila J, et al. Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions. Eur Heart J. 2004;25:476–483
  17. Mobley JE, Bresee SJ, Wortham DC, et al. Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization. Am J Cardiol. 2004;93:456–458
  18. Muller I, Besta F, Schulz C, et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost. 2003;89:783–787
  19. Serebruany VL, Steinhubl SR, Berger PB, et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol. 2005;45:246–251
  20. 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
  21. Barragan P, Bouvier JL, Roquebert PO, et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv. 2003;59:295–302
  22. Cuisset T, Frere C, Quilici J, et al. 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. 2006;4:542–549
  23. 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
  24. 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
  25. Pang H, Kawabata K, Takahashi M, et al. Stabilization of R-138727, the active metabolite of prasugrel (CS747/LY640315), in whole blood and its assay in human plasma by LC-MS/MS (abstract). J Am Soc Mass Spectrom. 2005;16:98S;Abstract 127
  26. Fontana P, Dupont A, Gandrille S, et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation. 2003;108:989–995
  27. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol. 2005;45:1157–1164
  28. Wiviott SD, Antman EM, Wiviott SD, et al. Clopidogrel resistance: a new chapter in a fast-moving story. Circulation. 2004;109:3064–3067
  29. Labarthe B, Theroux P, Angioi M, et al. Matching the evaluation of the clinical efficacy of clopidogrel to platelet function tests relevant to the biological properties of the drug. J Am Coll Cardiol. 2005;46:638–645
  30. Sugidachi A, Ogawa T, Asai F. Active metabolites of CS-747 (Prasugrel, LY640315) and clopidogrel show similar in vitro P2Y12 receptor blockade but greater in vivo potency of CS-747 (abstract). J Thromb Haemost. 2005;1:P1109
  31. 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
  32. Gorchakova O, von Beckerath N, Gawaz M, et al. Antiplatelet effects of a 600 mg loading dose of clopidogrel are not attenuated in patients receiving atorvastatin or simvastatin for at least 4 weeks prior to coronary artery stenting. Eur Heart J. 2004;25:1898–1902
  33. Hochholzer W, Trenk D, Frundi D, 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
  34. Kastrati A, von Beckerath N, Joost 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
  35. Taubert D, Kastrati A, Harlfinger S, et al. Pharmacokinetics of clopidogrel after administration of a high loading dose. Thromb Haemost. 2004;92:311–316
  36. von Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation. 2005;112:2946–2950
  37. 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
  38. 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

 This study was funded by Eli Lilly and Company and Sankyo Co, Ltd., Tokyo, Japan.

PII: S0002-8703(06)00902-1

doi: 10.1016/j.ahj.2006.10.010

American Heart Journal
Volume 153, Issue 1 , Pages 66.e9-66.e16 , January 2007

Article Tools

* Image Usage & Resolution