Education Blog for Healthcare Professionals

Antidotes for the New Oral Anticoagulants: Update

Stephan Moll, MD writes (on Nov 7th, 2014)… A N Engl J Med publication this week [ref 1] reports on a new reversal agent (PER977 = Aripazine = ciraparantag) that may be effective against a number of different new oral anticoagulants.



The publication reports – as a letter-to-the editor – a study in which 80 healthy volunteers received one dose of the new oral anticoagulant edoxaban (Savaysa®; not FDA approved for any indication as of Nov 7th, 2014), followed by an intravenous dose of PER977 (ciraparantag = aripazine; discussion of drug further below) at various doses. Whole-blood clotting times that were expectedly prolonged with edoxaban, markedly shortened (to within 10 % above the pre-Edoxaban baseline value) within 10 minutes after dosing with PER977.



No reversal agent (antidote, neutralizing drug) is presently clinically available if (a) major bleeding occurs or (b) urgent reversal for emergent surgery is needed in patients on one of the new oral anticoagulants (apixaban = Eliquis®; dabigatran = Pradaxa®; edoxaban = Savaysa®; rivaroxaban = Xarelto®). The following three drugs are in development, but are at least 2 years away from being clinically available, should they prove to be beneficial.

1. ARIPAZINE (PER977; ciraparantag)

    • What is it?  This is a synthetic small molecule (D-arginine  compound) which has broad activity against various old (heparin, low molecular weight heparin) and new oral anticoagulants (dabigatran,  rivaroxaban, apixaban and edoxaban). It is being developed by Perosphere.
    • What anticoagulant drugs might it reverse? Apixaban, edoxaban, rivaroxaban, dabigatran, heparin, LMWH.
    • Clinical trial status: A human volunteer study of 80 individuals receiving aripazine published this week in the New England Journal of Medicine [ref 1] shows that clotting assays (whole-blood clotting time) that were prolonged by edoxaban, decreased after the test persons received aripazine.  Another healthy volunteer study is presently ongoing [NCT02207257].

2. ANDEXANET (PRT064445)

    • What is it? Recombinant, modified factor Xa molecule that is being developed as a direct reversal agent for patients receiving a Factor-Xa inhibitor who suffer a major bleeding episode or who require emergency surgery. It sort-of sops up the anti-Xa anticoagulant, making a  patient’s own factor Xa available again to participate in the coagulation process [ref 2]. It is being developed by Portola.
    • What anticoagulant drugs might it reverse?  Apixaban, edoxaban, rivaroxaban.
    • Clinical  trial status: Healthy volunteer studies to (a) evaluate the ability of Andexanet to reverse the effects of several anticoagulant drugs on laboratory tests (NCT01758432) and (b) reverse apixaban [NCT02207725] and rivaroxaban[NCT02220725] are presently ongoing.


    • What is it?  It is a humanized antibody fragment directed against dabigatran; generated from mouse monoclonal antibody against dabigatran; humanized and reduced to a FAb fragment [ref 3]. It is being developed by Boehringer-Ingelheim.
    • What anticoagulant drugs might it reverse?  Dabigatran.
    • Clinical trial status:  (a) A phase 3 study of patients on dabigatran with major bleeding or needing emergency surgery is       ongoing [NCT02104947. (b) Three phase 1 studies to determine the effect of idarucizumab on coagulation tests in dabigatran-treated healthy volunteers have been completed (NCT01688830, NCT01955720; NCT02028780).



  1. Ansell JE et al. use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014(Nov 5).[Epub ahead of print].
  2. Lu G et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nature Medicine 2013;19(4):446-453.
  3. Schiele F et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121(18):3554-3562.


Conflict of interest:  I have been a consultant for Boehringer-Ingelheim, Daiichi, and Janssen.

Last updated: Nov 7th, 2014

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