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Thromb Haemost 2015; 114(01): 198-205
DOI: 10.1160/TH15-03-0192
Trial Protocol Design Paper
Schattauer GmbH

Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran

Charles V. Pollack Jr.
1   Pennsylvania Hospital, Philadelphia, Pennsylvania, USA
,
Paul A. Reilly
2   Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conneticut, USA
,
Richard Bernstein
3   Northwestern University, Chicago, Illinois, USA
,
Robert Dubiel
2   Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conneticut, USA
,
John Eikelboom
4   McMaster University, Hamilton, Ontario, Canada
,
Stephan Glund
5   Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
,
Menno V. Huisman
6   Leiden University Medical Center, Leiden, Netherlands
,
Elaine Hylek
7   Boston University School of Medicine, Boston, Massachusetts, USA
,
Chak-Wah Kam
8   Tuen Mun Hospital, Tuen Mun, NT, Hong Kong
,
Pieter W. Kamphuisen
9   University Medical Center, Groningen, Netherlands
,
Joerg Kreuzer
10   Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
,
Jerrold H. Levy
11   Duke University Medical Center, Durham, North Carolina, USA
,
Frank Sellke
12   Brown Medical School, Providence, Rhode Island, USA
,
Joachim Stangier
5   Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
,
Thorsten Steiner
13   University of Heidelberg, Heidelberg, Germany
,
Bushi Wang
2   Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conneticut, USA
,
Jeffrey I. Weitz
4   McMaster University, Hamilton, Ontario, Canada
› Author Affiliations
Further Information

Publication History

Received: 03 March 2015

Accepted after major revision: 19 May 2015

Publication Date:
22 November 2017 (online)

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Summary

Idarucizumab, a Fab fragment directed against dabigatran, produced rapid and complete reversal of the anticoagulation effect of dabigatran in animals and in healthy volunteers. The Study of the REVERS al E ffects of Idarucizumab in Patients on A ctive D abigatran (RE-VERSE AD™) is a global phase 3 prospective cohort study aimed at investigating idarucizumab in dabigatran-treated patients who present with uncontrollable or life-threatening bleeding, and in those requiring urgent surgery or intervention. We describe the rationale for, and design of the trial (clinicaltrials.gov NCT02104947).

 

  • References

  • 1 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
    CrossrefPubMedSearch in Google Scholar
  • 2 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
    CrossrefPubMedSearch in Google Scholar
  • 3 Schulman S, Kakkar AK, Goldhaber SZ. et al. the RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129: 764-772.
    CrossrefPubMedSearch in Google Scholar
  • 4 Desai J, Kolb JM, Weitz JI. et al. Gastrointestinal bleeding with the new oral anticoagulants--defining the issues and the management strategies. Thromb Hae-most 2013; 110: 205-212.
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Eikelboom JW, Wallentin L, Connolly SJ. et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation. Circulation 2011; 123: 2363-2372.
    CrossrefPubMedSearch in Google Scholar
  • 6 Graham DJ, Reichman ME, Wernecke M. et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for non-valvular atrial fibrillation. Circulation 2015; 131: 157-164.
    CrossrefPubMedSearch in Google Scholar
  • 7 Majeed A, Hwang HG, Connolly SJ. et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013; 128: 2325-2332.
    CrossrefPubMedSearch in Google Scholar
  • 8 Abbas S, Ihle P, Harder S. et al. Risk of bleeding and antibiotic use in patients receiving continuous phenprocoumon therapy. A case-control study nested in a large insurance- and population-based German cohort. Thromb Haemost 2014; 111: 912-922.
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Seeger JD, Bartels DB, Huybrechts K. et al. Safety and effectiveness of dabigatran relative to warfarin in routine care. Circulation. 2014 Epub ahead of print.
    PubMedSearch in Google Scholar
  • 10 Villines TC, Schnee J, Fraeman K. et al. The comparative safety and effectiveness of the oral anticoagulant (OAC) dabigatran versus warfarin utilized in a large healthcare system in non-valvular atrial fibrillation (NVAF) patients. Circulation. 2014 Epub ahead of print.
    PubMedSearch in Google Scholar
  • 11 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Schiele F, van Ryn J, Canada K. et al. A specific antidote for dabigatran: functional and structural characterisation. Blood 2013; 121: 3554-3562.
    CrossrefPubMedSearch in Google Scholar
  • 13 Honickel M, Grottke O, van Ryn J. et al. Use of a specific antidote to dabigatran (idarucizumab) reduces blood loss and mortality in dabigatran-induced and trauma-induced bleeding in pigs. Crit Care 2014; 18 (Suppl. 01) P99.
    CrossrefPubMedSearch in Google Scholar
  • 14 van Ryn J, Litzenburger T, Schurer J. Reversal of anticoagulant activity of dabigatran and dabigatran-induced bleeding in rats by a specific antidote (antibody fragment). Circulation 2012; 126: A9928.
    PubMedSearch in Google Scholar
  • 15 Glund S, Moschetti V, Norris S. et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015; 113: 943-951.
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Glund S, Stangier J, Schmohl M. et al. Idarucizumab, a specific antidote for dabigatran: Immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects. 56th Ann Mtg of the American Society of Hematology (ASH),. San Francisco. 6–9 Dec 2014 (Oral Presentation) Blood 2014 124 Abstract 344.
    PubMedSearch in Google Scholar
  • 17 http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2014/30_june_2014_dabigatranetexilate.html accessed May 14, 2015.
    PubMed
  • 18 Reilly PA, Lehr T, Haertter S. et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). Am Coll Cardiol 2014; 63: 321-328.
    CrossrefPubMedSearch in Google Scholar
  • 19 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285-295.
    CrossrefPubMedSearch in Google Scholar
  • 20 Stangier J, Feuring M. Using the HAEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23: 138-143.
    CrossrefPubMedSearch in Google Scholar
  • 21 Blech S, Ebner T, Ludwig-Schwellinger E. et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36: 386-399.
    CrossrefPubMedSearch in Google Scholar
  • 22 Schulman S, Angerås U, Bergqvist D. et al. Definition of major bleeding in clinical investigations of antihaemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 08: 202-204.
    CrossrefPubMedSearch in Google Scholar
  • 23 Chesebro JH, Knatterud G, Roberts R. et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase: clinical findings through hospital discharge. Circulation 1987; 76: 142-154.
    CrossrefPubMedSearch in Google Scholar
  • 24 GUSTO Investigators.. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673-682.
    CrossrefPubMedSearch in Google Scholar
  • 25 Wilson JL, Hareendran A, Grant M. et al. Improving the assessment of outcomes in stroke: Use of a structured interview to assign grades on the Modified Rankin Scale. Stroke 2002; 33: 2243-2246.
    CrossrefPubMedSearch in Google Scholar
  • 26 Dennis M, Mead G, Doubal F. et al. Determining the modified Rankin score after stroke by postal and telephone questionnaires. Stroke 2012; 43: 851-853.
    CrossrefPubMedSearch in Google Scholar
  • 27 Pragst I, Zeitler SH, Doerr B. et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost 2012; 10: 1841-1848.
    CrossrefPubMedSearch in Google Scholar
  • 28 Grottke O, Honickel M, van Ryn J. et al. Blood loss in dabiagtran-anticoagulated pigs with polytraumna is significantly reduced by early therapy with activated and nonactivated prothrombin complex concentrates. 87th Scientific Session 2014 of the American Heart Association (AHA), Chicago, November 15–19, 2014. Circulation. 2014 130. (Suppl 2): Abstract 18544.
    PubMedSearch in Google Scholar
  • 29 Pragst I, Kaspereit F, Dörr B. et al. Prothrombin complex concentrate (Beriplex P/N) for control of bleeding after kidney trauma in a rabbit dilutional coagulopathy model. Thromb Res 2010; 125: 272-277.
    CrossrefPubMedSearch in Google Scholar
  • 30 Heidbuchel H, Verhamme P, Alings M. et al. European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with nonvalvular atrial fibrillation. Europace 2013; 15: 625-651.
    CrossrefPubMedSearch in Google Scholar
  • 31 Holbrook A, Schulman S, Witt DM. et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141 (Suppl) e152S-e184S.
    CrossrefPubMedSearch in Google Scholar
  • 32 Steiner T, Bohm M, Dichgans M. et al. Recommendations for the emergency management of complications associated with new direct oral anticoagulants (DOAC) Apixaban, dabigatran, and Rivaroxaban. Clin Res Cardiol 2013; 102: 399-412.
    CrossrefPubMedSearch in Google Scholar
  • 33 Kyrle P, Binder K, Eichinger S. et al. Dabigatran: Patient management in specific clinical settings. Wien Klin Wochenschr 2014; 126: 503-508.
    CrossrefPubMedSearch in Google Scholar
  • 34 Awad NI, Brunetti L, Juurlink DN. Enhanced elimination of dabigatran through extracorporeal methods. J Med Toxicol. 2014 Epub ahead of print.
    PubMedSearch in Google Scholar
  • 35 Miesbach W, Seifried E. New direct oral anticoagulants: Current therapeutic options and treatment recommendations for bleeding complications. Thromb Haemost 2012; 108: 625-632.
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Lazo-Langner A, Lang ES, Douketis J. Clinical review: Clinical management of new oral anticoagulants: A structured review with emphasis on the reversal of bleeding complications. Crit Care 2013; 17: 230-241.
    CrossrefPubMedSearch in Google Scholar
  • 37 Franchini M, Lippi G. Prothrombin complex concentrates: An update. Blood Transfus 2010; 08: 149-154.
    PubMedSearch in Google Scholar
  • 38 Cabral KP, Fraser GL, Duprey J. et al. Prothrombin complex concentrates to reverse warfarin-induced coagulopathy in patients with intracranial bleeding. Clin Neurol Neurosurg 2013; 115: 77074.
    PubMedSearch in Google Scholar
  • 39 Bauer KA. Reversal of antithrombotic agents. Am J Hematol 2012; 87: S119-126.
    CrossrefPubMedSearch in Google Scholar
  • 40 Sarich TC, Seltzer JH, Berkowitz SD. et al. Novel oral anticoagulants (NOAC) and reversal agents: Considerations for clinical development. Am Heart J. 2015 In press (available online).
    PubMedSearch in Google Scholar
  • 41 Siegal DM, Garcia DA, Crowther MA. How I treat: Target specific oral anticoagulant related bleeding. Blood 2014; 123: 1152-1158.
    CrossrefPubMedSearch in Google Scholar
  • 42 Gold AM, Crowther M, Levy G. et al. Annexa-R: A pahse 3, randomized, double-blind, placebo-controlled triall demonstratring reversal of rivaroxaban-induced anticoagulation in older subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (FXa) inhibitors. J Am Coll Cardiol. 2015 Epub ahead of print.
    PubMedSearch in Google Scholar
  • 43 Ansell JE, Bakhry SH, Laulicht BE. et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; 371: 2141-2142.
    CrossrefPubMedSearch in Google Scholar