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The promise of a specific reversal agent for Factor Xa inhibitors
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In recent years, medicine has witnessed the arrival of the direct oral anticoagulants, which include the direct thrombin inhibitor dabigatran and the Factor Xa inhibitors apixaban, edoxaban and rivaroxaban. To some, the direct oral anticoagulants are an attractive alternative to warfarin because they do not require therapeutic monitoring or individualized dosing. However, a major limitation to the direct oral anticoagulants is the absence of a specific antidote.
The Institute of Safe Medication Practices recently acknowledged 10,674 reports of fatal or serious adverse events due to rivaroxaban (Xarelto, Janssen) use in 2015 — the highest number of adverse drug reports for any one drug that year — with the majority (n = 8,643) being reports of rivaroxaban-induced bleeding. Overall, in 2015, there were 16,222 reports of hemorrhage associated with all oral anticoagulants combined, including warfarin and the direct oral anticoagulants.
Examining need for an antidote
The need for an antidote for the direct oral anticoagulants was partially met in 2015 with the release of idarucizumab (Praxbind, Boehringer Ingelheim), a monoclonal antibody that inactivates dabigatran (Pradaxa, Boehringer Ingelheim). However, there is still no specific antidote on the market for the oral Factor Xa inhibitors. Andexanet alfa (AndexXa, Portola Pharmaceuticals) is in development as a reversal agent for Factor Xa inhibitors in the event of life-threatening bleeding or the need for emergent surgery.
Andexanet alfa is a recombinant Factor Xa decoy protein that is missing two active sites that normally interact with prothrombin and Factor Va in the clotting cascade. Andexanet alfa binds to and sequesters Factor Xa inhibitors while allowing endogenous Factor Xa to return to normal levels and achieve hemostasis. Andexanet alfa can bind to direct Factor Xa inhibitors — apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), edoxaban (Savaysa, Daiichi Sankyo) and rivaroxaban — and indirect Factor Xa inhibitors — unfractionated heparin and low–molecular-weight heparins.
Clinical trials of andexanet alfa
Two theoretical concerns exist with andexanet alfa — that it could induce a rebound hypercoagulable state and/or stimulate the production of antibodies to endogenous Factor Xa. In phase 2 trials, andexanet alfa was shown to reduce levels of Factor Xa inhibitors in a dose-dependent fashion while avoiding both thrombosis and the development of anti-Factor Xa antibodies.
Two phase 3 studies explored the safety and efficacy of andexanet alfa in healthy volunteers. ANNEXA-A and ANNEXA-R were randomized, double blind, placebo-controlled trials that recruited nonbleeding older adults. In ANNEXA-A, participants received apixaban 5 mg twice daily for 3.5 days, and then were given andexanet alfa 400 mg as an IV bolus alone (part 1) or 400 mg, followed by an infusion of 4 mg per minute for 2 hours (part 2). In ANNEXA-R, participants received rivaroxaban 20 mg daily for 4 days, and then were given andexanet alfa 800 mg as an IV bolus alone (part 1) or 800 mg, followed by 8 mg per minute for 2 hours (part 2).
In both studies, administration of andexanet alfa reduced anti-Factor Xa activity (ie, reduced anticoagulant activity) by at least 80% in all participants and restored thrombin generation to normal in all but one participant who did not receive the full dose of andexanet alfa. Reduction of anti-Factor Xa activity and thrombin generation was present within minutes of andexanet alfa administration and persisted for 2 hours and 12 hours, respectively. In both ANNEXA-A and ANNEXA-R, adverse events were mild (gastrointestinal upset, flushing, urticaria), and anti-Factor Xa antibodies were not detected. Although there were no reports of thrombosis, the investigators noted early elevations in D-dimer and prothrombin fragments 1 and 2, which returned to baseline at 24 and 48 hours.
ANNEXA-4 is an actively recruiting, open-label, single-group, cohort study of andexanet alfa in participants who present with acute major bleeding due to apixaban, edoxaban, enoxaparin or rivaroxaban. ANNEXA-4 includes only patients with active bleeding, unlike the REVERSE-AD trial of idarucizumab, which also recruited nonbleeding patients requiring dabigatran reversal for an emergent procedure.
An interim report of data from ANNEXA-4 based on 67 patients was published in August 2016. Efficacy of andexanet alfa was determined by measuring the reduction of anti-Factor Xa activity and hemostasis. In patients taking rivaroxaban and apixaban, a significant reduction in anti-Factor Xa activity was observed at the end of the andexanet alfa 400-mg or 800-mg bolus and at the end of the 4-mg/min or 8-mg/min 2-hour infusion. The reduction in anti-Factor Xa activity was less profound when measured at 4, 8 and 12 hours. This is owed to andexanet alfa’s short half-life of approximately 1 hour. Seventy-nine percent of patients were deemed as having excellent or good hemostasis 12 hours after andexanet alfa administration. No anti-Factor Xa antibodies were detected.
In the published data from ANNEXA-4, thrombotic events occurred in 12 patients (18%) within 30 days of andexanet alfa administration. It is important to note that, of these 12 patients, only one had therapeutic anticoagulation restarted before the thrombotic event. In correspondence in The New England Journal of Medicine, the authors of ANNEXA-4 report that, among the 105 patients for whom there was complete data as of Oct. 24, 2016, the rate of restarting therapeutic anticoagulation was 40%, and the rate of thrombosis was 12%. Some have questioned whether a higher rate of restarting anticoagulation would lead to less thrombotic events, but restarting anticoagulation after a major bleeding event requires careful consideration of the risks and benefits.
In late 2015, Portola Pharmaceuticals submitted a biologics license application for andexanet alfa. Portola received a complete response letter from the FDA in August 2016 stating that andexanet alfa was not approved, citing a need for further information on the manufacturing of andexanet alfa and data to support including edoxaban and enoxaparin in the labeling. Portola stated in a press release that it intends to resolve these outstanding issues quickly to obtain FDA approval for andexanet alfa.
Future directions
The promise of a specific antidote for Factor Xa inhibitors such as andexanet alfa is exciting, but there are still uncertainties about its use in clinical practice. The most precise way to identify direct oral anticoagulant response and antidote effect is measurement of anti-Factor Xa levels. However, there are currently no FDA-approved, commercially available, agent-specific anti-Xa assays for direct oral anticoagulants in the United States, which limits assessment of antidote response outside of a research setting.
Operationalizing andexanet alfa administration in clinical practice may also be complex. The current formulation of andexanet alfa in 50-mg and 100-mg vials means that as many as eight 100-mg vials may need to be reconstituted before administration. Also, given manufacturing problems, there is concern that a sufficient supply might not be available for widespread distribution. Health care providers may need to develop action plans for attaining the antidote for patients in need.
At this time, serious bleeding with direct oral anticoagulants should be treated with prothrombin complex concentrates and hemodynamic support. Full results on hemostasis and thrombosis from the ongoing ANNEXA-4 trial are awaited.
- References:
- Connolly SJ, et al. N Engl J Med. 2016;doi:10.1056/NEJMc1613270.
- Connolly SJ, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1607887.
- Institute for Safe Medication Practices. QuarterWatch. Monitoring FDA MedWatch Reports. Annual Report Issue. Data from 2015 Q4. June 29, 2016. Available at: www.ismp.org/QuarterWatch/pdfs/2015Q4.pdf. Accessed Jan. 26, 2017.
- Milling TJ Jr, Kaatz S. Am J Emerg Med. 2016;doi:10.1016/j.ajem.2016.09.052.
- Portola Pharmaceuticals receives complete response letter from FDA for biologics license application for AndexXa (andexanet alfa) [press release]. South San Francisco, CA: Portola Pharmaceuticals; Aug. 17, 2016.
- Siegal DM, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1510991.
- For more information:
- Laura Mentzer, PharmD, BCPS, BCCCP, is a clinical pharmacy specialist in critical care at Temple University Health System-Jeanes Hospital, Philadelphia, Pennsylvania.
- Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology Today Pharmacology Consult column editor. She is professor of clinical pharmacy and the residency and industry fellowships coordinator at Philadelphia College of Pharmacy at the University of the Sciences in Philadelphia. She can be reached at Philadelphia College of Pharmacy at University of the Sciences, 600 N. 43rd St., Philadelphia, PA 19104; email: s.spinle@usciences.edu.
Disclosure: Mentzer reports no relevant financial disclosures.