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Multicenter research of bleeding risk between prasugrel and clopidogrel in Japanese patients with coronary artery disease undergoing percutaneous coronary intervention

  • Satoshi TokimasaEmail author
  • Hideki Kitahara
  • Takashi Nakayama
  • Yoshihide Fujimoto
  • Taiki Shiba
  • Nobuaki Shikama
  • Mizuo Nameki
  • Toshiharu Himi
  • Ken-ichi Fukushima
  • Yoshio Kobayashi
Original Article
  • 45 Downloads

Abstract

Although it has been reported that prasugrel achieves stronger antiplatelet effect and fewer cardiovascular events compared to clopidogrel in Japanese patients, there are limited data comparing the safety between the 2 dose regimens. Data from 1031 consecutive patients with coronary artery disease undergoing PCI at 5 institutions from May 2014 to April 2016, who received aspirin plus either clopidogrel (619 patients) or prasugrel (412 patients), were retrospectively analyzed. The choice of clopidogrel or prasugrel was left to the operator's discretion. Adverse events were defined as a composite of bleeding, hepatopathy, leukopenia, thrombopenia, exanthema, and major adverse cardiovascular events (MACE). MACE was defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke. The average follow-up period was 143 days in the prasugrel group and 263 days in the clopidogrel group. Adverse events occurred in 34.5% of patients in the prasugrel group and in 28.6% in the clopidogrel group. Although the Kaplan–Meier curves showed lower survival rates from MACE, all-bleeding, major bleeding, minor bleeding, and adverse events, in the prasugrel group compared to the clopidogrel group (log rank test p = 0.009, p = 0.001, p = 0.012, p = 0.018, and p < 0.001, respectively), multivariate Cox-regression analyses determined prasugrel as a significant risk factor for all-bleeding, minor bleeding, and adverse events, but not for MACE and major bleeding events. Dual antiplatelet therapy with prasugrel was independently associated with minor bleeding events, but not with MACE and major bleeding events, compared to clopidogrel, after PCI in common clinical settings.

Keywords

Antiplatelet therapy Hemorrhage Clopidogrel Percutaneous coronary intervention Prasugrel 

Notes

Acknowledgements

I am grateful to Y. K. for suggesting the topic treated in this paper and H. K. for carefully proofreading the manuscript. I would like to thank T. N. and Y. S. for useful discussions. I also thank T. S. for sharing his dataset. One author, S. T., who is independent of the commercial funder, had full access to all the data and takes responsibility for the integrity of the data and analyses.

Compliance with ethical standards

Conflict of interest

Yoshio Kobayashi has received fees from Daiichi-Sankyo and Sanofi. The other auths rept no conflicts.

References

  1. 1.
    Schulz-Schüpke S, Byrne RA, Ten Berg JM, Neumann FJ, Han Y, Adriaenssens T, Tölg R, Seyfarth M, Maeng M, Zrenner B, Jacobshagen C, Mudra H, von Hodenberg E, Wöhrle J, Angiolillo DJ, von Merzljak B, Rifatov N, Kufner S, Morath T, Feuchtenberger A, Ibrahim T, Janssen PW, Valina C, Li Y, Desmet W, Abdel-Wahab M, Tiroch K, Hengstenberg C, Bernlochner I, Fischer M, Schunkert H, Laugwitz KL, Schömig A, Mehilli J, Kastrati A, Intracoronary Stenting Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) Trial Investigators (2015) ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J 36:1252–1263CrossRefGoogle Scholar
  2. 2.
    Palmerini T, Sangiorgi D, Valgimigli M, Biondi-Zoccai G, Feres F, Abizaid A, Costa RA, Hong MK, Kim BK, Jang Y, Kim HS, Park KW, Mariani A, Della Riva D, Genereux P, Leon MB, Bhatt DL, Bendetto U, Rapezzi C, Stone GW (2015) Short- versus long-term dual antiplatelet therapy after drug-eluting stent implantation: an individual patient data pairwise and network meta-analysis. J Am Coll Cardiol 65:1092–1102CrossRefGoogle Scholar
  3. 3.
    Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR Jr, Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM, DAPT Study Investigators (2014) Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 371:2155–2166CrossRefGoogle Scholar
  4. 4.
    Ogawa H, Isshiki T, Kimura T, Yokoi H, Nanto S, Takayama M, Kitagawa K, Nishikawa M, Miyazaki S, Ikeda Y, Nakamura M, Tanaka Y, Saito S (2016) Effects of CYP2C19 allelic variants on inhibition of platelet aggregation and major adverse cardiovascular events in Japanese patients with acute coronary syndrome: the PRASFIT-ACS study. J Cardiol 68:29–36CrossRefGoogle Scholar
  5. 5.
    Cuisset T, Loosveld M, Morange PE, Quilici J, Moro PJ, Saut N, Gaborit B, Castelli C, Beguin S, Grosdidier C, Fourcade L, Bonnet JL, Alessi MC (2012) CYP2C19*2 and *17 alleles have a significant impact on platelet response and bleeding risk in patients treated with prasugrel after acute coronary syndrome. JACC Cardiovasc Interv 5:1280–1287CrossRefGoogle Scholar
  6. 6.
    Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354–362CrossRefGoogle Scholar
  7. 7.
    Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT, Darstein C, Jakubowski JA, Salazar DE (2007) Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther 81:735–741CrossRefGoogle Scholar
  8. 8.
    Rehmel JL, Eckstein JA, Farid NA, Heim JB, Kasper SC, Kurihara A, Wrighton SA, Ring BJ (2006) Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos 34:600–607CrossRefGoogle Scholar
  9. 9.
    Gurbel PA, Bergmeijer TO, Tantry US, ten Berg JM, Angiolillo DJ, James S, Lindahl TL, Svensson P, Jakubowski JA, Brown PB, Duvvuru S, Sundseth S, Walker JR, Small D, Moser BA, Winters KJ, Erlinge D (2014) The effect of CYP2C19 gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease. Thromb Haemost 112:589–597CrossRefGoogle Scholar
  10. 10.
    Kimura T, Isshiki T, Ogawa H, Yokoi H, Yamaguchi T, Ikeda Y (2015) Randomized, double-blind, dose-finding, phase ii study of prasugrel in Japanese patients undergoing elective percutaneous coronary intervention. J Atheroscler Thromb 22:557–569CrossRefGoogle Scholar
  11. 11.
    Saito S, Isshiki T, Kimura T, Ogawa H, Yokoi H, Nanto S, Takayama M, Kitagawa K, Nishikawa M, Miyazaki S, Nakamura M (2014) Efficacy and safety of adjusted-dose prasugrel compared with clopidogrel in Japanese patients with acute coronary syndrome: the PRASFIT-ACS study. Circ J 78:1684–1692CrossRefGoogle Scholar
  12. 12.
    Isshiki T, Kimura T, Ogawa H, Yokoi H, Nanto S, Takayama M, Kitagawa K, Nishikawa M, Miyazaki S, Ikeda Y, Nakamura M, Saito S, PRASFIT-Elective Investigators (2014) Prasugrel, a third-generation P2Y12 receptor antagonist, in patients with coronary artery disease undergoing elective percutaneous coronary intervention. Circ J 78:2926–2934CrossRefGoogle Scholar
  13. 13.
    Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H (2011) Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 123:2736–2747CrossRefGoogle Scholar
  14. 14.
    Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transpl 48:452–458CrossRefGoogle Scholar
  15. 15.
    Miyazaki S, Isshiki T, Kimura T, Ogawa H, Yokoi H, Nishikawa M (2015) Re-evaluation of bleeding events in the Japanese PRASFIT-Elective and PRASFIT-ACS clinical trials using the bleeding academic research consortium criteria. Cardiovasc Pharmacol 4:5CrossRefGoogle Scholar
  16. 16.
    Nishikawa M, Isshiki T, Kimura T, Ogawa H, Yokoi H, Miyazaki S, Ikeda Y, Nakamura M, Tanaka Y, Saito S (2017) Risk of bleeding and repeated bleeding events in prasugrel-treated patients: a review of data from the Japanese PRASFIT studies. Cardiovasc Interv Ther 32:93–105CrossRefGoogle Scholar
  17. 17.
    Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, TRITON-TIMI 38 Investigators (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015CrossRefGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  • Satoshi Tokimasa
    • 1
    Email author
  • Hideki Kitahara
    • 1
  • Takashi Nakayama
    • 1
  • Yoshihide Fujimoto
    • 1
    • 4
  • Taiki Shiba
    • 1
    • 2
  • Nobuaki Shikama
    • 2
  • Mizuo Nameki
    • 3
  • Toshiharu Himi
    • 4
  • Ken-ichi Fukushima
    • 5
  • Yoshio Kobayashi
    • 1
  1. 1.Department of Cardiovascular MedicineChiba University Graduate School of MedicineChibaJapan
  2. 2.Department of CardiologyChiba Aoba Municipal HospitalChibaJapan
  3. 3.Department of CardiologyChiba Kaihin Municipal HospitalChibaJapan
  4. 4.Department of CardiologyKimitsu Chuo HospitalChibaJapan
  5. 5.Department of CardiologyMatsudo City HospitalChibaJapan

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