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    • Andexanet alfa works as a decoy for the FXa

    2021-09-22

    Andexanet alfa works as a decoy for the FXa inhibitor to bind to irreversibly. The recently completed ANDEXA-4 trial, which was a prospective, open-label, single group study, found that patients achieved good or excellent hemostasis in 82% of subjects [, , ]. There was an overall 10% thromboembolic event rate, Picroside II australia in anti-Xa activity by 92%, and 14% mortality associated with andexanet alfa use. Some concerns were raised during and after the trial however, primarily as it pertained to the overall acuity of the patients enrolled, lack of correlation between anti-Xa activity reduction and hemostasis, and complicated dosing scheme. Another major concern with the use of andexanet alfa is its price point. The low dose and high dose regimens cost approximately $25,000–$50,000, respectively. In comparison, a max dose regimen of PCC would be approximately $8000–$10,000 depending on the final dosage. Lastly, there were concerns on the actual logistics of getting the medication to the patient secondary to the prolonged administration times noted in the ANDEXA-4 trial; however, it must be noted that some of this would be expected secondary to the determination of high vs. low dose regimen arms. Ultimately, andexanet alfa is currently the only FDA approved agent for the reversal of FXa inhibitors and should at minimum facilitate discussions amongst facilities on whether or not to add to their institutional formulary.
    Introduction The use of direct oral anticoagulants has increased since dabigatran was made available in 2010, with an estimated 3.8 million patient-years of exposure by the end of 2016. Dabigatran is a direct thrombin inhibitor, whereas other direct oral anticoagulants work by inhibiting factor Xa (FXa; Table 1). These agents have demonstrated either superiority or noninferiority for thromboembolic outcomes and a similar or statistically reduced risk for major bleeding compared with traditional anticoagulation in clinical trials for various indications. However, harm from all oral anticoagulants remains a significant drug safety problem because of a high rate of injury, causing bleeding in 8%-19% of patients treated for a year.1, 2, 3 In 1 study, anticoagulants that predominantly included warfarin, rivaroxaban, dabigatran, and enoxaparin accounted for 17.6% of all emergency department visits for adverse drug events, which led to a 48.8% hospitalization rate. It is significant that patients with atrial fibrillation experiencing a major bleed from an FXa inhibitor have a 15%-20% 30-day mortality rate, with up to 48% mortality for those experiencing an intracranial hemorrhage.5, 6, 7, 8 In the event of extensive bleeding, an effective, widely available antidote for the anticoagulant is desired. In 2015, the U.S. Food and Drug Administration (FDA) approved idarucizumab (Praxbind) for the reversal of the direct thrombin inhibitor dabigatran. Because of differing mechanisms of action, idarucizumab is not effective for reversing the FXa inhibitors rivaroxaban, apixaban, edoxaban, or betrixaban (Table 1). After several delays due to manufacturing concerns as well as requests for data that included all of the oral FXa inhibitors plus enoxaparin, the FDA granted approval of andexanet alfa in May 2018, under the brand name ANDEXXA, for the reversal of 2 of the FXa inhibitors, apixaban and rivaroxaban, when life-threatening or uncontrolled bleeding occurs. This accelerated approval was based on change in anti-FXa activity from baseline that indicated a reversal of anticoagulation. Any expanded FDA indication will be contingent on results demonstrating improved hemostasis and the ability of andexanet alfa to reverse other FXa inhibitors.10, 11, 12
    Pharmacology Andexanet alfa is a modified FXa decoy protein, engineered to bind to and reverse the anticoagulant effects of both direct and indirect FXa inhibitors, including subcutaneous enoxaparin. It binds FXa inhibitors with strong affinity and overcomes competition with native FXa, thereby reversing the anticoagulant effect of the FXa inhibitor. FXa is then able to resume its normal enzymatic activity of prothrombin activation.10, 13