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Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxabanFinancial support: This study was funded by Peropshere, Inc. Danbury CT; Clinicaltrials.gov number NCT01826266.
01 December 2017 (online)
Of the new direct oral anticoagulants, direct factor Xa inhibitors are limited by the absence of a proven reversal agent. We assessed the safety, tolerability and impact on anticoagulation reversal of ciraparantag (PER977) alone and following a 60 mg dose of the FXa inhibitor edoxaban. Escalating, single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind, placebo-controlled fashion to healthy subjects. Serial assessments of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed. Eighty male subjects completed the study. Following edoxaban (60 mg), a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours. Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis. Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag. Renal excretion of ciraparantag metabolite was the main elimination route. There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels. In conclusion, ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10–30 minutes of administration and sustained for at least 24 hours.
Institution where the work was performed: Duke University Clinical Research Unit, Duke University Medical Center, Durham, NC USA
- 1 Weitz JI, Eikelboom JW, Samama MM. New Antithrombotic Drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guideline. Chest 2012; 141 (Suppl. 02) e120S-e151S.
- 2 Kaatz S, Kouides PA, Garcia DA. et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012; 87 (Suppl. 02) S141-S145.
- 3 Laulicht B, Bakhru S, Jiang X. et al. Antidote for new oral anticoagulants: Mechanism of action and binding specificity of PER977. Internat’l Soc Thromb & Haemost 2013 Abstract http://www.eventure-online.com/eventure/publicAbstractView.do?id=226718&congressId=6839 and http://www.perosphere.com/content/presentations/documents/Perosphere_ISTH_Talk.pdf
- 4 Laulicht B, Bakhru S, Lee C. et al. Small molecule antidote for anticoagulants. Circulation 2012; 126 Abstract #11395.
- 5 Didisheim P. Tests of blood coagulation and hemostasis: The coagulation (clotting) tim. J Am Med Assoc 1966; 198: 1299.
- 6 Eerenberg ES, Levi M, Buller HR. Contra: Antidotes for novel anticoagulants? Do we really need the. Thromb Haemost 2012; 108: 623-624.
- 7 Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence. Thromb Haemost 2014; 111: 189-198.
- 8 Schiele F, van Ryn J, Canada K. et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121: 3554-3562.
- 9 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm Accessed March 9, 2016.
- 10 Lu G, DeGuzman FR, Hollenbach SJ. et al. A novel antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19: 446-451.
- 11 Pollack CV, Reilly PA, Eikelboom J. et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373: 511-520.
- 12 Siegal DM, Curnutte JT, Connolly SJ. et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373: 2413-2424.
- 13 Ansell J. Blocking Bleeding: Reversing Anticoagulant Therap. Nat Med 2013; 19: 402-404.