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Exploring Indications for the Use of Direct Oral Anticoagulants and the Associated Risks of Major Bleeding
Truman J. Milling Jr, MD, and Jennifer Frontera, MD, FNCS

Exploring Indications for the Use of Direct Oral Anticoagulants and the Associated Risks of Major Bleeding

Truman J. Milling Jr, MD, and Jennifer Frontera, MD, FNCS
This supplement to The American Journal of Managed Care® describes the burden of thrombosis in terms of strokes and venous thromboembolism and highlights indications for the use of direct oral anticoagulants (DOACs) for the treatment of these conditions. The burden of DOAC-associated bleeding and unmet needs regarding reversal agents are also discussed.
Burden of Bleeding
The retrospective chart review study evaluated the burden of disease and resource utilization associated with current strategies for the management of major bleeding.77,78 Among 56 patients treated with an FXa inhibitor and admitted with major bleeding, 24 (43%) received various factor or plasma products and the remainder received supportive care.77,78 The use of healthcare resources was substantial, with patients primarily admitted to intensive inpatient settings and seeing a median of 4 physician specialists. No significant differences in resource utilizations and outcomes were observed between patients receiving factor or plasma products versus supportive care.
An analysis of data from the Marketscan Commercial and Medicare database from January 1, 2011, to December 31, 2014, offered insight into the burden of healthcare costs associated with major bleeding in patients with AF.72,49 Among all hospitalizations for major bleeding events, independent of bleed location, the average patient hospitalization stay lasted 10 days and the mean total healthcare costs for patients with major bleeding was estimated at $58,169. In contrast, the mean hospital payments for ICHs and GI bleeds were $45,447 and $19,819, respectively.72 Total all-cause healthcare costs were higher during the 12 months of follow-up for patients with AF with major bleeding compared with patients without major bleeding ($63,866 vs $37,916; P <.001).72,49
These retrospective analyses show that the burden of bleeding associated with DOAC treatment is substantial and that there is an unmet need for reversal agents for use in the management of patients who receive FXa inhibitors and experience life-threatening bleeding or need emergency surgery.20

Management of Major Bleeding Associated with DOACs
Current Management Strategies 

Specific treatment options are needed for patients taking a DOAC who experience major bleeding. Idarucizumab is a humanized monoclonal antibody indicated for reversal of the anticoagulant effects of dabigatran.47 Among 494 patients with dabigatran-related life threatening or uncontrolled bleeding or those who required urgent procedures, idarucizumab successfully reversed the anticoagulant effect of dabigatran within the first 4 hours (median) after administration.48,82 There are no specific reversal products currently available for the direct oral FXa inhibitors.
Current treatment strategies for patients with life-threatening bleeding associated with oral FXa inhibitors include PCCs or activated prothrombin complex concentrates (aPCC; factor VIII inhibitor bypassing activity [FEIBA]). However, PCCs and aPCCs are potentially prothrombotic agents, are not specific antidotes for oral FXa inhibitors, and are currently not approved for the treatment of FXa inhibitor-associated bleeding. Furthermore, the data supporting their use in this context are limited to animal and healthy volunteer studies that primarily evaluated laboratory parameters; there are no efficacy data in patients with FXa inhibitor-associated bleeding.34,46,51,83

Investigational Reversal Agents for FXa Inhibitors

Although no reversal agent is currently FDA-approved for FXa inhibitors, andexanet alfa and ciraparantag are being evaluated in clinical trials.84-86

Andexanet Alfa
Andexanet alfa is a human recombinant FXa decoy molecule that is catalytically inactive and sequesters FXa inhibitors through high-affinity binding. Based on its mechanism of action, andexanet alfa is a potential antidote for direct and indirect FXa inhibitors. The results of multiple phase 2 studies have demonstrated the ability of andexanet alfa to reverse the anticoagulant effects of rivaroxaban, edoxaban, apixaban, enoxaparin, and betrixaban in healthy subjects.84,87-91 Further, the ANNEXA-A and ANNEXA-R phase 3 clinical trials demonstrated the clinical efficacy of andexanet alfa in 101 healthy volunteers. In these trials, andexanet alfa rapidly reversed the anti-FXa activity of apixaban and rivaroxaban (within 2 to 5 minutes) and restored thrombin generation without serious adverse events or clinical thrombosis. Subjects who received the full dose of andexanet alfa (either as a bolus dose or a bolus plus a 2-hour infusion) had at least 80% reversal of anti-FXa activity.85 Andexanet alfa normalized thrombin generation within 2 to 10 minutes after bolus administration in 100% of apixaban treated subjects and 96% of rivaroxaban treated subjects. Reversal of anti-FXa activity and normalization of coagulation parameters were sustained for the duration of infusion.85

Interim results from the ongoing phase 3b/4 ANNEXA-4 trial have further demonstrated the efficacy and safety of andexanet alfa in the reversal of FXa inhibitor activity. This study evaluated andexanet alfa in 67 patients who experienced acute major bleeding following treatment with FXa inhibitors (apixaban, rivaroxaban, or enoxaparin).86 The administration of andexanet alfa as an intravenous bolus followed by a continuous infusion resulted in rapid reversal of FXa inhibitor activity. Among patients evaluated for efficacy, at 12 hours post infusion, 79% had achieved hemostasis rated as excellent or good; 84% of patients with GI bleeding and 80% of patients with ICH achieved excellent or good hemostatsis.86 At 30 days of follow-up, 18% of the patients in the safety population experienced a thromboembolic event and 15% died.87 In this analysis, anticoagulation was restarted in 27% of patients within 30 days; however, only 1 of 12 patients with a thromboembolic event was restarted on a therapeutic dose of an anticoagulant.86 A recent update to the ongoing ANNEXA-4 trial in 105 patients reported a 12% rate of thromboembolic events; the rate of restarting some form of anticoagulation therapy was 40%.92

Ciraparantag (aripazine, PER977) is an investigational reversal agent that binds several direct FXa inhibitors (apixaban, rivaroxaban, and edoxaban), the direct thrombin inhibitor dabigatran, and low molecular weight heparin. Although the mechanism of action is not well understood, ciraparantag binds to a range of anticoagulants through noncovalent hydrogen bonding and charge-charge interactions; the resulting ciraparantag/anticoagulant complex prevents the anticoagulant from binding endogenous targets and restores coagulation.93-95 The whole blood clotting time assay is used to monitor the activity of ciraparantag in clinical trials, as the agent interferes with the assay reagents in available routine coagulation tests (ie, prothrombin test, anti-FXa assays).93
In a placebo-controlled phase 1/2 study, ciraparantag reversed edoxaban-induced anticoagulation in 80 healthy patients. Edoxaban administration increased the mean whole blood clotting time by a mean of 37% over patient baseline (pre-anticoagulant level). Ciraparantag was administered intravenously at doses from 100 to 300 mg, and within 30 minutes, the mean whole blood clotting time was reduced to less than 10% above baseline value. In comparison, patients treated with placebo required 12 to 15 hours for the whole blood clotting time to reach these levels. Reversal of anticoagulation was sustained for 24 hours following ciraparantag administration.94,95

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