Andexanet Alfa (Andexxa) Formulary Review

Abstract

Andexanet alfa, a recombinant modified human “decoy” factor Xa (FXa) protein, is the first and only available antidote approved by the Food and Drug Administration to manage life-threatening or uncontrolled bleeding associated with the anti-Xa agents. It binds to direct and indirect anti-Xa oral anticoagulants with high specificity to reverse their inhibitory effects and restore the activity of FXa. Andexanet alfa is administered via two different dosing regimens, standard and high dose, based on the specific FXa inhibitor, dose, and time since the patient’s last dose of FXa inhibitor. The approval for andexanet alfa is supported by data from two phase 3 studies (ANNEXA-A, ANNEXA-R) and preliminary data from the phase 3b/4 ANNEXA-4 trial. The first study found that andexanet alfa rapidly reduced anti-Xa activity by 92%–94% in healthy volunteers taking apixaban or rivaroxaban. The ANNEXA-4 study found that the median anti-Xa activity decreased by 89%–93% in patients with major bleeding taking apixaban or rivaroxaban. However, thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up in ANNEXA-4. Additionally, only 40% of patients had restarted anticoagulation and, in this group, the rate of thrombotic events was 12%. Four patients had a thrombotic event within 3 days after andexanet alfa treatment. The wholesale acquisition cost of the standard dose regimen is $24,750, and the high-dose regimen is $49,500. The estimated annual drug budget of treating 10–100 patients ranges from $248K to $495M. Effective October 1, 2018, Medicare will provide an add-on payment for andexanet alfa of up to $14,063 per qualifying case to Inpatient Prospective Payment System-participating acute care hospitals. In this formulary review for a health system’s pharmacy and therapeutics committee, andexanet alfa clinical trials and medication package insert were summarized and, after consulting with clinical experts from our institutions, practical recommendations for use were generated to ensure appropriate and safe use of this agent.

Major bleed costs of atrial fibrillation patients treated with factor Xa inhibitor anticoagulants

“…9,10 Because of such increased utilization, it is important to have targeted treatment options available that can rapidly reverse the anticoagulation effects of FXaIs when a life-threatening or severe MB event occurs. 14 In this study, approximately 10% of the AF patients treated with FXaIs who were hospitalized with an MB had an ICH. Although lower in prevalence than GI MBs, ICHs account for the majority of stroke-related deaths with approximately half of fatalities occurring within 48 h of the onset of an ICH.…”

The Use of Prothrombin Complex Concentrates: Results of a Nationwide Survey of Critical Care Pharmacists

“…Several studies demonstrate that PCCs act more rapidly than standard blood products to reverse coagulopathy which isn't surprising since PCCs may be administered rapidly and possess concentrated clotting factors. [8][9][10][11][12][13][14][15]18 While the overall estimated cost of each unit of PCCs is approximately $1.30 and each 250 mL unit of fresh frozen plasma is $70-350, the cost of PCCs relative to standard blood products/procoagulants must account for costs associated with their adverse event profiles and the collection, storage, and administration of blood products. 14,18 Both PCCs and standard blood products are associated with thromboembolic events but PCCs are far less likely to cause hypervolemia and immune reactions.…”

“…10 Since the time this survey was conducted, antidotes are now available for anti-Xa reversal; however, their availabilities were initially limited, the costs prohibitive, and limited data are available regarding their efficacy and safety. 12 A recent retrospective comparison of 4-factor PCCs and andexanet alfa for the treatment of intracranial hemorrhage related to apixaban or rivaroxaban showed that excellent or good hemostasis favored andexanet alfa (88.9% vs. 60%) although thrombosis (16.7% vs. 9.1%) and cost/patient ($29,970 vs. $6925) were higher. 13 A systems analysis of hospital usage demonstrated higher rates of excellent to good hemostasis with andexanet alfa but 4-factor PCCs were significantly less expensive and had lower rates of thrombosis.…”

Intracranial Hemorrhage following Lumbar Puncture in a Patient on Apixaban

“…If an LP is crucial to patient care, providers should consider rapid reversal of the DOAC in emergent situations in order to minimize bleeding risk [8]. Unfortunately, the current cost of andexanet alfa, the direct reversal agent for apixaban, is quite high, running USD 25,000–50,000 per patient treatment [9]. This excessive cost may deter providers from using andexanet alfa prior to LP.…”