Patient Education Blog

Major Bleeding on the New Oral Blood Thinners: Update on Reversal Drugs

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



The publication reports a study in which 80 healthy volunteers received one dose of the new oral blood thinner edoxaban (Savaysa®; not FDA approved as of Nov 7th, 2014), followed by an intravenous dose of the investigational drug PER977 (ciraparantag = aripazine; discussion of drug further below) at various doses [ref 1].  The results showed that PER977 reversed the blood thinning effect of edoxaban within 10 minutes of dosing as judged by a near-normalization of a clotting test (called “whole-blood clotting time”).



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 blood thinners (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, i.e. enoxaparin = Lovenox®, dalteparin = Frgamin®, tinzaparin = Innohep®) and new oral blood thinners (dabigatran = Pradaxa®,  rivaroxaban = Xarelto®, apixaban = Eliquis® and edoxaban = Savaysa®). It is being developed by the company Perosphere.
    • What blood thinners might it reverse? Eliquis®, Pradaxa®, Xarelto®, Savaysa®, heparin, LMWH.
    • Clinical trial status: As discussed above, 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 blood thinner who suffer a major bleeding episode or who require emergency surgery. It sort-of sops up the anti-Xa blood thinner, making a  patient’s own clotting factor Xa available again to participate in the clotting process [ref 2]. It is being developed by the company Portola.
    • What anticoagulant drugs might it reverse?  Eliquis®, Xarleto®, Savaysa®.
    • Clinical  trial status: Healthy volunteer studies to (a) evaluate the ability of Andexanet to reverse the effects of several blood thinners on laboratory tests (NCT01758432) and (b) reverse Eliquis® [NCT02207725] and Xarelto®[NCT02220725] are presently ongoing.


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