Andexanet alfa—The first 150 days
Authors: Sarah E. Culbreth, Jessica Rimsans, Katelyn Sylvester, Daniel J. Pallin, Jean M. Connors
Journal: American Journal of Hematology (2018)

Andexanet alfa, the first FDA approved (May 2018) targeted reversal agent for the oral factor Xa inhibitors (Xai), is a recombinant factor Xa modified to lack catalytic activity that binds, sequesters, and neutralizes unbound Xai.1 Approval was based on results in healthy volunteers (ANNEXA-A, ANNEXA-R)2 and data from the interim analysis of the ANNEXA-4 trial,3, 4 a Phase 3b/4 single arm study of use in bleeding patients. Inclusion criteria required that patients have life threatening bleeding or bleeding at a critical site with the last dose of Xai ingested within 18 hours of administration. Exclusions included planned surgery within 12 hours of administration (except minimally invasive diagnostic or therapeutic procedures), intracranial hemorrhage (ICH) with Glasgow coma scores (GCS) <7, estimated intracerebral hematoma volume >60 mL, expected survival <1 month, major thrombotic event within 2 weeks before enrollment, or use of vitamin k antagonists, dabigatran, prothrombin complex concentrate (PCC), whole blood or plasma within 7 days before screening. Institutions need to decide whether to add andexanet alfa to their formulary and how to oversee its use. We describe our approach to the commercial use of andexanet alfa, share our interdisciplinary guideline for use (Table 1), and discuss operational challenges. Criteria for use Coagulation factor Xa (recombinant/inactivated, Andexxa) is currently only FDA approved for the reversal of apixaban and rivaroxaban in the setting of life threatening or uncontrolled major bleeding. Not FDA approved for patients requiring urgent/emergent procedures. Consider use of 4F-PCC The decision to add andexanet alfa to formulary was based on the lack of robust data to support the use of alternative reversal strategies.5 Data from the interim analysis of ANNEXA-4 demonstrated rapid reversal of the anti-Xa activity of both apixaban and rivaroxaban with excellent or good hemostasis in 83% of treated patients 12 hours after treatment.3, 4 Guideline (Table 1) development involved a collaborative effort between physicians, pharmacists, and nurses from various specialties including emergency medicine and hematology; it was approved by the P&T committee. Ordering decision support was provided in our electronic medical record. The guideline is based on criteria from the ANNEXA-4 trial and adapted to allow for "real-world" considerations. Requests for andexanet alfa to treat patients falling outside the trial criteria or FDA label frequently occur. Many patients present with bleeding more than 18 hours since last Xai dose, have poor prognosis with large volume ICH and poor GCS, received PCC, require reversal for use with a nonapproved Xai, or require urgent surgery. Our guidelines have been revised to eliminate unnecessary barriers which might increase time to administration yet also limit use to appropriate patients. There are no restrictions or need for approval for life-threatening bleeds in patients believed to have clinically relevant apixaban or rivaroxaban activity, defined as last dose within 18 hours. We use the standard definition of life-threatening bleeding as bleeding causing hemodynamic compromise, threatens a vital organ or may result in disability, or not responding to conventional measures. Andexanet alfa is not approved for use in patients with less severe bleeding. We require hematology attending approval for life-threatening bleeding in patients in whom the last dose of apixaban or rivaroxaban was more than 18 hours, and for patients treated with alternative reversal agents at outside hospitals. Hematology approval is also required prior to use for reversal of betrixaban, edoxaban, or enoxaparin.4, 6 Andexanet alfa is not FDA approved for reversal of anticoagulation prior to emergency surgery/procedures. Requests for such use require hematology review. The guideline also provides recommendations for laboratory monitoring where appropriate.7 As of October 8, 2018, we have administered andexanet alfa to 15 patients (Table 2). Fourteen presented with ICH, with mean age of 82 years. Atrial fibrillation was the indication for anticoagulation in 73%. Seven of the treated patients were taking apixaban and eight rivaroxaban. Eleven had taken anticoagulants within 18 hours of presentation. Eleven received the standard dose of andexanet alfa. Many patients would not have been eligible for participation in ANNEXA-4; one had had a pulmonary embolism in the preceding 2 weeks, 7 received PCC prior to transfer to our institution (25-50 U/kg), and 3 had surgery within 12 hours of administration although plans for surgery were not known at the time of administration. Seven of eight antiXa activity UFH/LMWH (unfractionated heparin/low-molecular weight heparin calibrated) levels drawn prior to andexanet alfa administration were elevated; 3 of 4 drawn post administration demonstrated decreased activity. Time from order placement to bedside-delivery averaged 43 minutes; time from order to bolus administration averaged 66 minutes. Five patients had procedures within 12 hours of andexanet alfa administration (2 external ventricular drain placements considered minimally invasive, 1 had craniotomy for hematoma evacuation, 1 laparotomy after trauma, 1 laminectomy for c-spine fracture causing paralysis). Despite combined use of PCC and andexanet alfa in 7 patients, we have not observed thrombotic events. Inpatient mortality was 40%. Five patients died within 4 days of presentation as a result of initial bleeds, one patient died after 13 days from infection. Mortality correlated with poor scores on the ICH score (Intracerebral Hemorrhage score, a severity score) and the FUNC score (Functional Outcome in Patients with Primary Intracerebral Hemorrhage prognostic score). These patients would not have been eligible for ANNEXA-4. Mortality at Discharge mRS 3 NIHSS 5 ICH 0 FUNC 8 ICH 5 FUNC 3 NIHSS 7 FUNC 8 mRS 0 ICH 3 FUNC 3 15, ? pt not taking mRS 0 ICH 2 FUNC 6 mRS 0 ICH 3 ICH 4 GCS 15 mRS 0 We have encountered challenges with the use of andexanet alfa including (1) limited availability via the early supply program leading to complicated patient transfers to us for administration; (2) need to determine use in patients who received PCC prior to transfer; (3) lack of approved anti-Xa assays for assessment of anticoagulant levels; (4) drug preparation time requiring reconstitution of multiple vials; (5) small volume administration via smart pump programming requiring planning to ensure all drug is administered; (6) requests for preprocedural use; and (7) requests for use for nonFDA approved Xai. Requests for andexanet alfa have been denied for reasons including preprocedural use in nonbleeding patients with normal renal function and expected normal drug clearance with last ingestion of drug >24 hours earlier, no expectation for survival, and nonlife-threatening bleeds. Andexanet alfa is the first approved specific reversal agent for Xai. Hematology, emergency room, pharmacy, and nursing staff need to work together to determine how to use andexanet alfa at their institutions, particularly in clinical situations that fall outside the label indications. As new data become available we expect that our criteria for use of andexanet alfa in clinical practice will continue to evolve. Jean M Connors is a consultant for Bristol-Myers Squibb, and has participated in scientific advisory boards for Pfizer and Portola. Katelyn Sylvester has participated on scientific advisory board for Bristol-Meyers Squibb, Pfizer. Daniel Pallin has chaired a Medical Advisory Panel for Portola Pharmaceuticals, Inc. The remaining authors have no conflicts of interest to disclose.