Reversal of Anticoagulation in a True Emergency – An Update

Author: Erica Simon, DO, MHA (EM Resident Physician, SAUSHEC) // Edited by: Alex Koyfman, MD (EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital, @EMHighAK) & Justin Bright, MD (@JBright2021)

Please see prior post here: http://www.emdocs.net/reversal-of-anticoagulation/

On October 16, 2015 the FDA granted accelerated approval of idarucizumab (Praxbind), a novel reversal agent of the direct thrombin inhibitor Dabigatran (Pradaxa), for utilization in life-threatening bleeding emergencies.1

Idarucizumab is a humanized monoclonal antibody (Fab) fragment designed specifically to bind dabigatran.  It has an affinity for dabigatran that is approximately 350 times greater than that of thrombin.2,3

Human Studies

Glund, et al. performed a phase 1, single-rising-dose, randomized, double-blinded, placebo-controlled trial of 110 healthy male volunteers (ages 18-45) to assess the pharmacokinetics and safety of idarucizumab.4  Randomization (designed to occur in a 3:1 ratio) assigned 27 participants to receive placebo and 83 to receive idarucizumab.  For those enrolled in the idarucizumab study arm, dosing was randomly assigned with individuals receiving between 20 mg – 8 g of idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, versus 1, 2 or 4 g of idarucizumab as a 5-minute infusion.  Results of the phase 1 trial revealed that idarucizumab attained peak plasma levels rapidly, but that its concentration decreased to 5 % or less of the peak level within 4 h secondary to renal elimination.  It was noted that idarucizumab required a 1:1 dosing ratio with dabigatran for complete efficacy, and of significance, idarucizumab demonstrated no impact on the coagulation profile of subjects who received placebo.4

Pollack et al. are currently conducting a phase 3 prospective cohort study to determine the safety of 5 g of IV idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patient with serious bleeding (Group A) or requiring an urgent procedure (Group B).  A preliminary report including data from 90 patients (51 Group A, 39 Group B) assessed the primary end point of maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours of idarucizumab administration (utilizing dilute thrombin time or ecarin clotting time).  Among patients with an elevated dilute thrombin time and or an elevated ecarin clotting time, the median maximum percentage reversal was 100% (95% confidence interval, 100-100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes.  Concentrations of unbound dabigatran remained below 20 ng per milliliter (steady-state) at 24 hours in 79% of the patients.   Preliminary data on the secondary end point of hemostasis was also published: among 35 patients in Group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours.  Among 36 patients in Group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively.  One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.5,6

Administration

Praxbind is currently marketed as an IV formulated solution for injection, with dosing recommendations of 5 g (administered as 2 separate 2.5 g doses no more than 15 minutes apart).  Per the manufacturer (Boehringer Ingelheim Pharmaceuticals, Inc), if coagulation parameters (eg, aPTT) re-elevate and clinically relevant bleeding occurs, or if a second emergency surgery/urgent procedure is required and patient has elevated coagulation parameters, the physician may consider administration of an additional 5 g (few studies to support).5,7

Additional Up and Coming Novel Reversal Agents for Factor Xa Inhibitors

Andexanet Alfa (PRT064445) – Previously introduced in the Factor Xa Inhibitor Section

Andexanet alfa (PRT064445, r-Antidote; Portola Pharmaceuticals) is a recombinant modified human factor Xa decoy protein designed to reverse the effects of direct and indirect factor Xa inhibitors.  Andexanet binds and sequesters factor Xa inhibitors within the vascular space, thereby restoring the activity of endogenous factor Xa and reducing levels of anticoagulant activity.2,9

Human Studies

In phase 2 proof-of-concept and dose-ranging studies, Crowther et al. demonstrated that the administration of andexanet resulted in dose-dependent, reproducible reversal of anticoagulation in cohorts of healthy volunteers receiving one of four factor Xa inhibitors (apixaban, rivaroxaban, edoxaban, or enoxaparin).  Reversal was assessed as the reduction in anti–factor Xa activity and unbound factor Xa inhibitor concentrations, as well as the restoration of thrombin generation.11-13 No serious adverse reactions were reported, and no antibodies against factor Xa or factor X were detected.11-13

ANNEXA-A (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors – Apixaban) and ANNEXA-R (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors – Rivaroxaban) – Results published November 11, 2015:

ANNEXA-A and ANNEXA-R were conducted as parallel, randomized, double-blind, placebo-controlled studies to evaluate the ability of andexanet to reverse anticoagulation with apixaban or rivaroxaban and to evaluate the safety of andexanet in healthy older volunteers (ages 50-75).  To review study methods, reference the Siegel article cited below.

Bottom Line: In participants anticoagulated with apixaban, anti–factor Xa activity was reduced by 94% among those who received andexanet (24 individuals), as compared with 21% among those who received placebo (9 individuals) (P<0.001).  As a secondary end point, thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. In study subjects anticoagulated with rivaroxaban, anti–factor Xa activity was reduced by 92% among those who received andexanet (27 individuals), as compared with 18% among those who received placebo (14 individuals) (P<0.001), and thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours, and no serious adverse or thrombotic events were reported.8

Arapazine/Cirapantag (PER977)

PER977 is a synthetic water-soluble molecule that binds to direct inhibitors of factor Xa and IIa as well as to heparin-based anticoagulants through non-covalent hydrogen bonding and charge interactions.

Human Studies

In the first double-blinded, placebo controlled trial of PER977 (NCT01826266), pharmacokinetics and pharmacodynamics were evaluated in 80 healthy volunteers utilizing escalating doses of PER977 (100–300 mg) administered alone and after a 60mg PO dose of edoxaban.  Whole-blood clotting time was employed to assess the anticoagulant effect of edoxaban and its reversal by PER977.

Bottom Line:  After the administration of edoxaban, the mean whole-blood clotting time increased by 37% over the baseline value in study participants.  In patients receiving a single intravenous dose of PER977 three hours after the administration of edoxaban, the whole-blood clotting time decreased to within 10% above the baseline value in 10 minutes or less, whereas in patients receiving placebo, the time to reach that level was approximately 12 to 15 h. The whole-blood clotting time remained within 10% above or below the baseline value for 24 hours after the administration of a single dose of PER977.  Researchers discovered no evidence of pro-coagulant activity after administration of PER977, as assessed by measurement of levels of D-dimer, prothrombin fragments 1 and 2, and tissue factor pathway inhibitor, and by whole-blood clotting time.  Additional phase 2 clinical studies are ongoing.14

 

References / Further Reading

  1. “Press Announcements: FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa.” FDA News Release. U.S. Food and Drug Administration, 2015. Web. 16 Nov. 2015 <http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm>.
  2. Das A, Liu D. Novel antidotes for target specific oral anticoagulants. Exp Hematol Oncol. 2015;4:25.
  3. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121(18):3554-3562.
  4. Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet. 2015;386(9994):680-690.
  5. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511-520.
  6. Pollack CV, Reilly PA, Bernstein R, Dubiel R, Eikelboom J, Glund S, et al. Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost. 2015;114(1):198–205.
  7. Praxbind injection (idarucizumab) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2015.
  8. Siegal D, Curnutte J, Connolly S, et al. Andexanet alpha for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015
  9. Gomez-Outes A, Suarez-Gea ML, Lecumberri R, Terleira-Fernandez AI, Vargas-Castrillon E. Specific antidotes in development for reversal of novel anticoagulants: a review. Recent Pat Cardiovasc Drug Discov. 2014;9(1):2–10
  10. Crowther M KM, Lorenz T, Mathur V, Lu G, Hutchaleelaha A, et al. A phase 2 randomized, double-blind, placebo-controlled trial of PRT064445, a novel, universal antidote for direct and indirect factor Xa inhibitors. J Thromb Haemost. 2013;11(Suppl 2): AS20.1.
  11. Crowther M LG, Lu G, Conley PB, Castillo J, Hollenbach S, et al. Reversal of enoxaparin-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for direct and indirect FXa inhibitors—a phase 2 randomized, double-blind, placebo- controlled trial. J Thromb Haemost. 2014;12(Suppl 1): COA01 (abstract).
  12. Crowther M LG, Conley P, Hollenbach S, Castillo J, Lawrence, J, et al. Sustained reversal of apixaban anticoagulation with andexanet alfa using a bolus plus infusion regimen in a phase 2 placebo controlled trial. Eur Heart J. 2014;35(Suppl.1): P738 (abstract).
  13. Crowther MMV, Kitt M, Lu G, Conley PB, Hollenbach S, et al. A phase 2 randomized, double blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for FXa inhibitors. Blood. 2013;122(21):3636.
  14. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371(22):2141–2142.

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