Issues in Emerging Health Technologies Antidote Treatments for the Reversal of Direct Oral Anticoagulants Issue 138 June 2015 situations such as life-threatening major bleeding or Summary non-elective major surgery.4 Currently, there are three specific reversal drugs for DOACs under clinical There are three intravenous antidotes currently under development for the reversal of direct oral development (see Table 1). anticoagulants. Idarucizumab (aDabi-Fab/BI 655075/Boehringer Idarucizumab is a humanized, monoclonal, Ingelheim, Germany) is a humanized, monoclonal, antibody fragment that reverses the direct antibody fragment that specifically binds with high thrombin inhibitor dabigatran. Andexanet alfa is affinity to dabigatran, an oral direct thrombin inhibitor a modified recombinant factor Xa molecule that (DTI), also developed by Boehringer Ingelheim. It acts reverses oral direct (e.g., apixaban, edoxaban, by competitively displacing dabigatran from thrombin rivaroxaban) and injectable indirect (e.g., 5 enoxaparin, fondaparinux) factor Xa inhibitors. to reverse anticoagulation and restore fibrin formation. Dabigatran has an affinity for idarucizumab that is 350 Aripazine is a small, synthetic molecule with 8 potentially universal anticoagulant reversal times greater than its affinity for thrombin. The dose 9 activity. currently studied in the phase 3 trial is 5 g. Based on pre-marketing information obtained from the Clinical evidence to support the use of individual antidotes is currently limited to phase 1 and manufacturer, idarucizumab will be available as a phase 2 trials in healthy volunteers. All three single package consisting of two 50 mL vials (2 x antidotes were well tolerated during these studies 2.5 g); no reconstitution will be required. The complete and no pro-coagulant activity was observed. dose of 5 g will be administered intravenously as two Phase 3 trials are underway for idarucizumab consecutive infusions over 5 to 10 minutes each, or as and andexanet alfa. bolus injections (Ernie Hampel, Executive Director, Preliminary data shows promising results but Market Access and Healthcare Affairs, Boehringer assessment of long-term safety and efficacy Ingelheim Canada Ltd., Burlington, ON: personal requires more research. Additional research is communication, 2015 Mar 9). also needed to determine impact on clinical practice. Clear guidance should be available at Andexanet alfa (PRT064445 or PRT4445*/Portola the time these reversal drugs are commercialized Pharmaceuticals Inc., US) is a modified recombinant to promote their appropriate use. factor Xa (FXa) molecule intended for intravenous (IV) administration. It was developed as an antidote to reverse anticoagulant activity of oral direct (e.g., The Technology apixaban, edoxaban, and rivaroxaban) and injectable indirect (e.g., enoxaparin and fondaparinux) FXa In the past decade, the use of direct oral anticoagulants inhibitors. Andexanet alfa acts as a decoy to target and (DOACs; apixaban, dabigatran, edoxaban, rivaroxaban) sequester with high specificity both oral and injectable has been approved for a number of conditions such as FXa inhibitors in the blood.10 It lacks a membrane- the prevention of stroke in patients with non-valvular binding gamma-carboxyglutamic acid domain, atrial fibrillation (AF); the prevention of venous rendering it catalytically inactive, but it retains a high thromboembolism (VTE) after hip or knee replacement binding affinity to FXa inhibitors.6 Two doses are surgery; and the treatment of VTE, as well as the currently being studied in phase 3 trials: 400 mg IV prevention of VTE recurrence. [Note: apixaban, bolus followed by continuous infusion at 4 mg per dabigatran, and rivaroxaban are currently available in 11,12 1-3 minute for 120 minutes (reversal of apixaban) and Canada.] Unlike warfarin and other vitamin K 800 mg IV bolus followed by continuous infusion at antagonists, there are no specific antidotes available to 8 mg per minute for 120 minutes (reversal of reverse the anticoagulant effect of DOACs. Although rivaroxaban).11,13 the latter have short half-lives, which suggests reversal drugs may not be needed in non-urgent situations, the Aripazine (PER977/ciraparantag/Perosphere Inc., US) lack of such antidotes is a concern in emergency is a small, synthetic molecule designed with broad reversal activity and administered as a single IV bolus 1 dose. It binds to oral FXa inhibitors and DTIs, as well development program for aripazine is currently at the as to injectable unfractionated heparin (UFH) and low- phase 2 stage, it is not possible to comment on the dose molecular-weight heparin (LMWH) via non-covalent that will be studied in the phase 3 trial and which is bonding and charge-charge interactions to neutralize therefore more likely to be approved for clinical use. anticoagulation and bleeding.7,14 As the clinical 5-7 TABLE 1: ANTIDOTES UNDER DEVELOPMENT FOR DIRECT ORAL ANTICOAGULANTS Antidote Target Structure Route Storage Idarucizumab Oral DTI Humanized IV Refrigerated (BI 655075) monoclonal antibody fragment Andexanet alfa Oral FXa inhibitors; Modified IV Refrigerated (PRT064445 or injectable LMWH recombinant FXa PRT4445*) and fondaparinux protein Aripazine Oral FXa inhibitors Synthetic small IV Room temperature (PER977) and DTI; molecule injectable UFH, LMWH, and fondaparinux DTI = direct thrombin inhibitor; FXa = factor Xa; IV = intravenous; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin. reversal of the anticoagulant effect. At this time, it is Regulatory Status anticipated that the targeted population for these drugs will be patients in emergency situations such as those Currently, idarucizumab, andexanet alfa, and aripazine with major bleeding or who require non-elective major are not approved for use in Canada, the US, the United 4,9,24 15-17 surgery. Although the definition for major bleeding Kingdom, or European Union (EU) countries. may vary across clinical trials, the International Society Andexanet alfa and idarucizumab were granted on Thrombosis and Haemostasis (ISTH) developed a breakthrough therapy designation by the US Food and classification commonly used in research and that Drug Administration (FDA) in November 2013 and 18-20 provides a good description of these serious adverse June 2014, respectively. On February 26, 2015, the events (AEs). Overall, major bleeds are those that result FDA also granted orphan drug designation to andexanet in death, are life-threatening, cause chronic sequelae, or alfa for reversing the anticoagulant effect of direct or consume major health care resources. Types of major indirect FXa inhibitors in patients experiencing a bleeding events defined by ISTH’s classification serious, uncontrolled bleeding event or who require 10 include fatal bleedings and bleedings occurring in urgent or emergency surgery. On March 3, 2015, critical anatomical sites such as the brain, spine, eyes, Boehringer Ingelheim, the manufacturer of abdominal cavity, joints, or pericardium, or in muscle if idarucizumab, announced that submission for approval compartment syndrome is present. Other types of major was filed in the US, the EU, and Canada for use in 21 bleeding events under ISTH’s definition include a fall patients requiring an antidote to dabigatran. On April in hemoglobin levels of at least 2 g/dL or the need for 24, 2015, the FDA granted priority review/accelerated 25 22 transfusing at least two red cell packs. Of interest, approval status to idarucizumab. Of note, final results other potential conditions where reversal of DOACs from phase 3 clinical studies for both idarucizumab and 9,18,23 may be considered have been identified in a recent andexanet alfa are pending. Aripazine was granted review. These include clinical conditions at high risk of fast-track status in the US on April 15, 2015; phase 3 14 bleeding such as major head injury in patients treated trials are planned. with DOACs, DOAC overdose in patients with coagulation or platelet disorders or in patients also Patient Group taking antithrombotic drugs at the same time.26 Of note, Pending confirmation of their efficacy and safety, these these conditions are not specifically included in antidote treatments will fulfill an unmet need in currently ongoing phase 3 clinical trials. patients using a DOAC and who need immediate 2 or require emergency surgery or procedures (see Table Current Practice 2). A dose of 5 g idarucizumab will be administered intravenously to reverse the effect of dabigatran. The In patients experiencing a DOAC-induced major trial will measure plasma-diluted thrombin time and bleeding event, current consensus-based guidelines ecarin clotting time as primary outcome measures. recommend withdrawing the anticoagulant and Time to cessation of bleeding will be a secondary administering oral charcoal (if within two hours of outcome. Results from the trial are anticipated in July DOAC ingestion). The use of prothrombin complex 2017.9 concentrate (PCC, Octaplex) at a dose of 25 U/kg (which may be repeated once or twice), activated Andexanet alfa prothrombin complex concentrate (aPCC, FEIBA) at a Two phase 2 trials evaluated the safety and efficacy of dose of 50 IE/kg (max 200 IE/kg/day) or recombinant andexanet alfa in healthy volunteers receiving apixaban factor VIIa (rFVIIa, NiaStase) may be considered.26-30 or rivaroxaban, which are two DOACs available in Overall, there appears to be relatively limited available Canada. Patients in one study by Crowther et al.34 data supporting the efficacy