#Enoxaparin antidote trial#

It binds to oral FXa inhibitors and DTIs, as well as to injectable unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) via non-covalent bonding and charge-charge interactions to neutralize anticoagulation and bleeding. 11,13Īripazine (PER977/ciraparantag/Perosphere Inc., US) is a small, synthetic molecule designed with broad reversal activity and administered as a single IV bolusĭose. 6 Two doses are currently being studied in phase 3 trials: 400 mg IV bolus followed by continuous infusion at 4 mg per minute for 120 minutes (reversal of apixaban) 11,12 and 800 mg IV bolus followed by continuous infusion at 8 mg per minute for 120 minutes (reversal of rivaroxaban). 10 It lacks a membrane-binding gamma-carboxyglutamic acid domain, rendering it catalytically inactive, but it retains a high binding affinity to FXa inhibitors. Andexanet alfa acts as a decoy to target and sequester with high specificity both oral and injectable FXa inhibitors in the blood. It was developed as an antidote to reverse anticoagulant activity of oral direct (e.g., apixaban, edoxaban, and rivaroxaban) and injectable indirect (e.g., enoxaparin and fondaparinux) FXa inhibitors. The complete dose of 5 g will be administered intravenously as two consecutive infusions over 5 to 10 minutes each, or as bolus injections (Ernie Hampel, Executive Director, Market Access and Healthcare Affairs, Boehringer Ingelheim Canada Ltd., Burlington, ON: personal communication, 2015 Mar 9).Īndexanet alfa (PRT064445 or PRT4445*/Portola Pharmaceuticals Inc., US) is a modified recombinant factor Xa (FXa) molecule intended for intravenous (IV) administration. 9 Based on pre-marketing information obtained from the manufacturer, idarucizumab will be available as a single package consisting of two 50 mL vials (2 x 2.5 g) no reconstitution will be required.

#Enoxaparin antidote trial#

8 The dose currently studied in the phase 3 trial is 5 g. 5 Dabigatran has an affinity for idarucizumab that is 350 times greater than its affinity for thrombin. It acts by competitively displacing dabigatran from thrombin to reverse anticoagulation and restore fibrin formation. Idarucizumab (aDabi-Fab/BI 655075/Boehringer Ingelheim, Germany) is a humanized, monoclonal, antibody fragment that specifically binds with high affinity to dabigatran, an oral direct thrombin inhibitor (DTI), also developed by Boehringer Ingelheim. 4 Currently, there are three specific reversal drugs for DOACs under clinical development (see Table 1). Although the latter have short half-lives, which suggests reversal drugs may not be needed in non-urgent situations, the lack of such antidotes is a concern in emergency situations such as life-threatening major bleeding or non-elective major surgery. 1-3 Unlike warfarin and other vitamin K antagonists, there are no specific antidotes available to reverse the anticoagulant effect of DOACs. In the past decade, the use of direct oral anticoagulants (DOACs apixaban, dabigatran, edoxaban, rivaroxaban) has been approved for a number of conditions such as the prevention of stroke in patients with non-valvular atrial fibrillation (AF) the prevention of venous thromboembolism (VTE) after hip or knee replacement surgery and the treatment of VTE, as well as the prevention of VTE recurrence. Clear guidance should be available at the time these reversal drugs are commercialized to promote their appropriate use. Additional research is also needed to determine impact on clinical practice.

Preliminary data shows promising results but assessment of long-term safety and efficacy requires more research.

Phase 3 trials are underway for idarucizumab and andexanet alfa.

All three antidotes were well tolerated during these studies and no pro-coagulant activity was observed. Clinical evidence to support the use of individual antidotes is currently limited to phase 1 and phase 2 trials in healthy volunteers.Aripazine is a small, synthetic molecule with potentially universal anticoagulant reversal activity. Andexanet alfa is a modified recombinant factor Xa molecule that reverses oral direct (e.g., apixaban, edoxaban, rivaroxaban) and injectable indirect (e.g., enoxaparin, fondaparinux) factor Xa inhibitors.

Idarucizumab is a humanized, monoclonal, antibody fragment that reverses the direct thrombin inhibitor dabigatran.

There are three intravenous antidotes currently under development for the reversal of direct oral anticoagulants.