The major adverse effect of all anticoagulant medications is bleeding. In May 2018, the FDA approved andexanet alfa as the first and only antidote for patients treated with rivaroxaban and apixaban who require reversal of anticoagulation owing to life-threatening or uncontrolled bleeding. Further investigation of the benefits and risks of emergency andexanet alfa administration in patients with acute bleeding is underway. Rivaroxaban and apixaban are eliminated by hepatic metabolism (about ) and by renal excretion (about ) and the AUC (area under the curve) is increased in renal impairment. 80-83 In addition, there are insufficient data to recommend the use of andexanet for the reversal of FXa inhibitors other than apixaban or rivaroxaban. Due to the premarketing study design constraints, it also remains unknown if FXa inhibitor reversal by andexanet alfa will equate to a clinically meaningful reduction in bleeding.
80 The drug is labeled with warnings regarding the possible development of thromboembolic events, ischemic stroke, myocardial infarction, cardiac arrest, and sudden death, but the occurrence of these outcomes attributable to drug administration is unknown. 11 In these premarket studies, andexanet alfa appeared to be well tolerated and the accumulated data did not signal excess immunogenic or prothrombotic safety concerns. 11 The effect on anti-FXa lasted ~2 hours, thrombin production remained elevated for ≥22 hours, and TFPI inhibition was judged to last ~96 hours. 11 These studies demonstrated that andexanet alfa reduced anti–factor Xa activity by >90% and increased tissue factor–initiated thrombin generation within 2–5 minutes of the start of administration.
The pharmacodynamic and pharmacokinetic effects of andexanet alfa were measured in volunteers age 50–75 years using assays to detect changes in anti-factor Xa activity and thrombin generation following administration of either apixaban or rivaroxaban.
Due to logistical difficulties and ethical concerns associated with studying patients in need of rapid FXa inhibitor reversal, FDA allowed randomized, placebo-controlled clinical trials in healthy volunteers as the basis for andexanet alfa’s approval. EMA’s human medicines committee has recommended granting a conditional marketing authorisation in the European Union for Ondexxya (andexanet alfa).
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