Randomized Comparison of Ticagrelor versus Prasugrel in Patients with Acute Coronary Syndrome and Planned Invasive Strategy—Design and Rationale of the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 Trial

  • Stefanie Schulz
  • Dominick J. Angiolillo
  • David Antoniucci
  • Isabell Bernlochner
  • Christian Hamm
  • Juliane Jaitner
  • Karl-Ludwig Laugwitz
  • Katharina Mayer
  • Barbara von Merzljak
  • Tanja Morath
  • Franz-Josef Neumann
  • Gert Richardt
  • Judith Ruf
  • Gisela Schömig
  • Helmut Schühlen
  • Heribert Schunkert
  • Adnan Kastrati
  • Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 Trial Investigators
Article

Abstract

In acute coronary syndromes (ACS), a dual antiplatelet regimen with an adenosine diphosphate (ADP) receptor antagonist plus aspirin has become the cornerstone of treatment. The third-generation thienopyridine prasugrel and the cyclopentyl-triazolo-pyrimidine ticagrelor provide a greater, more rapid and consistent platelet inhibition compared to their predecessor clopidogrel. Based on their advantages over clopidogrel in two landmark studies, both drugs received a class I recommendation for their use in ACS patients with and without ST segment elevation. Due to differences in ACS populations and conditions investigated, the relative merits of ticagrelor versus prasugrel in the treatment of ACS patients with planned invasive strategy cannot be reliably estimated from independent trials. To date, no direct head-to-head comparison of ticagrelor and prasugrel in terms of clinical outcome exists. The aim of this multicenter, randomized, open-label trial is to assess whether ticagrelor is superior to prasugrel in ACS patients with planned invasive strategy.

Keywords

Ticagrelor Prasugrel Acute coronary syndrome PCI 

Abbreviations

ACS

Acute coronary syndrome

ADP

Adenosine diphosphate

ASA

Acetylsalicylic acid

CABG

Coronary artery bypass graft

ISAR-REACT

Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment

LBBB

Left bundle branch block

MRI

Magnetic resonance imaging

NSTE–ACS

Non-ST segment elevation acute coronary syndrome

NSTEMI

Non-ST segment elevation myocardial infarction

PCI

Percutaneous coronary intervention

STEMI

ST segment elevation myocardial infarction

URL

Upper reference limit

References

  1. 1.
    Schomig, A., Neumann, F. J., Kastrati, A., et al. (1996). A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. The New England Journal of Medicine, 334, 1084–1089.PubMedCrossRefGoogle Scholar
  2. 2.
    Hamm, C. W., Bassand, J. P., Agewall, S., 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). European Heart Journal, 32, 2999–3054.PubMedCrossRefGoogle Scholar
  3. 3.
    Task Force on the management of STseamiotESoC, Steg, P. G., James, S. K., et al. (2012). ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. European Heart Journal, 33, 2569–2619.PubMedCrossRefGoogle Scholar
  4. 4.
    Kushner, F. G., Hand, M., Smith, S. C., Jr., et al. (2009). 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology, 54, 2205–2241.PubMedCrossRefGoogle Scholar
  5. 5.
    Levine, G. N., Bates, E. R., Blankenship, J. C., et al. (2011). 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Journal of the American College of Cardiology, 58, e44–e122.PubMedCrossRefGoogle Scholar
  6. 6.
    Gurbel, P. A., Bliden, K. P., Hiatt, B. L., & O'Connor, C. M. (2003). Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation, 107, 2908–2913.PubMedCrossRefGoogle Scholar
  7. 7.
    Serebruany, V. L., Steinhubl, S. R., Berger, P. B., Malinin, A. I., Bhatt, D. L., & Topol, E. J. (2005). Variability in platelet responsiveness to clopidogrel among 544 individuals. Journal of the American College of Cardiology, 45, 246–251.PubMedCrossRefGoogle Scholar
  8. 8.
    Bonello, L., Tantry, U. S., Marcucci, R., et al. (2010). Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. Journal of the American College of Cardiology, 56, 919–933.PubMedCrossRefGoogle Scholar
  9. 9.
    Wiviott, S. D., Braunwald, E., McCabe, C. H., et al. (2007). Prasugrel versus clopidogrel in patients with acute coronary syndromes. New England Journal of Medicine, 357, 2001–2015.PubMedCrossRefGoogle Scholar
  10. 10.
    Wallentin, L., Becker, R. C., Budaj, A., et al. (2009). Ticagrelor versus clopidogrel in patients with acute coronary syndromes. The New England Journal of Medicine, 361, 1045–1057.PubMedCrossRefGoogle Scholar
  11. 11.
    Brandt, J. T., Payne, C. D., Wiviott, S. D., et al. (2007). A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. American Heart Journal, 153(66), 9–16.Google Scholar
  12. 12.
    Gurbel, P. A., Bliden, K. P., Butler, K., et al. (2009). Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation, 120, 2577–2585.PubMedCrossRefGoogle Scholar
  13. 13.
    Sugidachi, A., Asai, F., Ogawa, T., Inoue, T., & Koike, H. (2000). The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. British Journal of Pharmacology, 129, 1439–1446.PubMedCrossRefGoogle Scholar
  14. 14.
    Husted, S., Emanuelsson, H., Heptinstall, S., Sandset, P. M., Wickens, M., & Peters, G. (2006). Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. European Heart Journal, 27, 1038–1047.PubMedCrossRefGoogle Scholar
  15. 15.
    Wallentin, L. (2009). P2Y(12) inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. European Heart Journal, 30, 1964–1977.PubMedCrossRefGoogle Scholar
  16. 16.
    Schomig, A. (2009). Ticagrelor—is there need for a new player in the antiplatelet-therapy field? The New England Journal of Medicine, 361, 1108–1111.PubMedCrossRefGoogle Scholar
  17. 17.
    Steg, P. G., James, S., Harrington, R. A., et al. (2010). Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a platelet inhibition and patient outcomes (PLATO) trial subgroup analysis. Circulation, 122, 2131–2141.PubMedCrossRefGoogle Scholar
  18. 18.
    Montalescot, G., Wiviott, S. D., Braunwald, E., et al. (2009). Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet, 373, 723–731.PubMedCrossRefGoogle Scholar
  19. 19.
    Montalescot, G., Bolognese, L., Dudek, D., et al. (2011). A comparison of prasugrel at the time of percutaneous coronary intervention or as pretreatment at the time of diagnosis in patients with non-ST-segment elevation myocardial infarction: design and rationale for the ACCOAST study. American Heart Journal, 161, 650–656. e1.PubMedCrossRefGoogle Scholar
  20. 20.
    Montalescot, G., Bolognese, L., Dudek, D., et al. (2013). Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. New England Journal of Medicine, 369, 999–1010.PubMedCrossRefGoogle Scholar
  21. 21.
    Roe, M. T., Armstrong, P. W., Fox, K. A., et al. (2012). Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. The New England Journal of Medicine, 367, 1297–1309.PubMedCrossRefGoogle Scholar
  22. 22.
    James, S. K., Roe, M. T., Cannon, C. P., et al. (2011). Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. BMJ, 342, d3527.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Held, C., Asenblad, N., Bassand, J. P., et al. (2011). Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. Journal of the American College of Cardiology, 57, 672–684.PubMedCrossRefGoogle Scholar
  24. 24.
    Headrick, J. P., Peart, J. N., Reichelt, M. E., & Haseler, L. J. (1808). Adenosine and its receptors in the heart: regulation, retaliation and adaptation. Biochimica et Biophysica Acta, 2011, 1413–1428.Google Scholar
  25. 25.
    Serebruany, V. L. (2011). Adenosine release: a potential explanation for the benefits of ticagrelor in the PLATelet inhibition and clinical outcomes trial? American Heart Journal, 161, 1–4.PubMedCrossRefGoogle Scholar
  26. 26.
    Ohman, J., Kudira, R., Albinsson, S., Olde, B., & Erlinge, D. (2012). Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochemical and Biophysical Research Communications, 418, 754–758.PubMedCrossRefGoogle Scholar
  27. 27.
    Björkman JA, K. I., & van Giezen, J. J. J. (2007). AZD6140 inhibits adenosine uptake into erythrocytes and enhances coronary blood flow after local ischemia or intracoronary adenosine infusion. Circulation, 116(II), 28. Abstract 245.Google Scholar
  28. 28.
    van Giezen, J. J., Sidaway, J., Glaves, P., Kirk, I., & Bjorkman, J. A. (2012). Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. Journal of Cardiovascular Pharmacology and Therapeutics, 17, 164–172.PubMedCrossRefGoogle Scholar
  29. 29.
    Wittfeldt, A., Emanuelsson, H., Brandrup-Wognsen, G., et al. (2013). Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. Journal of the American College of Cardiology, 61(7), 723–7. doi:10.1016/j.jacc.2012.11.032.PubMedCrossRefGoogle Scholar
  30. 30.
    Mehran, R., Rao, S. V., Bhatt, D. L., et al. (2011). Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation, 123, 2736–2747.PubMedCrossRefGoogle Scholar
  31. 31.
    Cutlip, D. E., Windecker, S., Mehran, R., et al. (2007). Clinical end points in coronary stent trials: a case for standardized definitions. Circulation, 115, 2344–2351.PubMedCrossRefGoogle Scholar
  32. 32.
    Thygesen, K., Alpert, J. S., Jaffe, A. S., et al. (2012). Third universal definition of myocardial infarction. European Heart Journal, 33, 2551–2567.PubMedCrossRefGoogle Scholar
  33. 33.
    Wiviott, S. D., White, H. D., Ohman, E. M., et al. (2013). Prasugrel versus clopidogrel for patients with unstable angina or non-ST-segment elevation myocardial infarction with or without angiography: a secondary, prespecified analysis of the TRILOGY ACS trial. Lancet, 382, 605–613.PubMedCrossRefGoogle Scholar
  34. 34.
    Sarafoff, N., Martischnig, A., Wealer, J., et al. (2013). Triple therapy with aspirin, prasugrel, and vitamin k antagonists in patients with drug-eluting stent implantation and an indication for oral anticoagulation. Journal of the American College of Cardiology, 61, 2060–2066.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Stefanie Schulz
    • 1
    • 11
  • Dominick J. Angiolillo
    • 2
  • David Antoniucci
    • 3
  • Isabell Bernlochner
    • 4
  • Christian Hamm
    • 5
    • 10
  • Juliane Jaitner
    • 4
  • Karl-Ludwig Laugwitz
    • 4
    • 9
  • Katharina Mayer
    • 1
  • Barbara von Merzljak
    • 1
  • Tanja Morath
    • 1
  • Franz-Josef Neumann
    • 6
  • Gert Richardt
    • 7
  • Judith Ruf
    • 1
  • Gisela Schömig
    • 1
  • Helmut Schühlen
    • 8
  • Heribert Schunkert
    • 1
    • 9
  • Adnan Kastrati
    • 1
    • 9
  • Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 Trial Investigators
  1. 1.Deutsches Herzzentrum MünchenTechnische Universität MünchenMunichGermany
  2. 2.University of Florida College of MedicineJacksonvilleUSA
  3. 3.Careggi Hospital FirenzeFlorenceItaly
  4. 4.1. Medizinische Klinik, Klinikum rechts der IsarTechnische Universität MünchenMunichGermany
  5. 5.Kerckhoff KlinikBad NauheimGermany
  6. 6.Herzzentrum Bad KrozingenBad KrozingenGermany
  7. 7.Herzzentrum der Segeberger KlinikenBad SegebergGermany
  8. 8.Vivantes, Auguste-Viktoria-KlinikumBerlinGermany
  9. 9.DZHK, Partner Site Munich Heart AllianceMunichGermany
  10. 10.DZHK, Partner Site Rhine-MainFrankfurtGermany
  11. 11.ISAResearch CenterDeutsches Herzzentrum MünchenMunichGermany

Personalised recommendations