BETHESDA, MA — The US Food and Drug Administration (FDA) has approved edoxaban (Savaysa, Daiichi-Sankyo), a factor Xa inhibitor, for the prevention of stroke and non–central-nervous-system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF)^[1].

The FDA also approved edoxaban for treating deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5 to 10 days.

Edoxaban is the third factor Xa inhibitor approved for the nonvalvular AF indication, following approvals for rivaroxaban(Xarelto, Bayer) and apixaban (Eliquis, Bristol Myers-Squibb). In addition to these novel oral anticoagulants, dabigatran(Pradaxa, Boehringer Ingelheim), a direct-thrombin inhibitor, is also available for stroke prevention in AF patients.

The US approval follows a mostly positive review of theEffective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48(ENGAGE-TIMI 48) trial by a recent FDA advisory panel.

Led by Dr Robert Giugliano (Brigham and Women's Hospital, Boston, MA), and reported by heartwire when it was presented at the American Heart Association 2013 Scientific Sessions, the ENGAGE-TIMI 48 investigators showed that 30 mg and 60 mg of edoxaban was noninferior to warfarin for preventing stroke and systemic embolism in more than 20 000 patients with AF. Both doses were also associated with significantly less major bleeding than warfarin.

As part of its label, though, edoxaban will carry a boxed warning stating the novel anticoagulant is less effective in AF patients with a creatinine clearance >95 mL/min and that kidney function should be assessed prior to starting treatment. Patients with a creatinine clearance >95 mL/min have a greater risk of stroke compared with similar patients treated with warfarin, according to the FDA.

The boxed warning is partly the result of a subgroup analysis suggesting patients with normal renal function fared worse when treated with edoxaban vs warfarin. In ENGAGE-TIMI 48, individuals with a creatinine clearance >80 mL/min fared significantly worse on the primary efficacy end point—time to the first adjudicated ischemic or hemorrhagic stroke or systemic embolic event—when treated with the 30-mg dose of edoxaban. In patients treated with the 60-mg dose, the results showed the same trend. Overall, the hazard ratio for the primary end point vs warfarin was 1.41 (95% CI 0.97–2.05) for individuals with normal renal function treated with 60 mg of edoxaban

It was noted at the time that 50% to 60% of edoxaban is excreted by the kidneys, so it's possible patients with normal renal function might have less circulating levels of the drug and be underexposed to treatment.

In October, the Cardiovascular and Renal Drugs Advisory Committee voted 9 to 1 in favor of approving edoxaban. Despite voting overwhelmingly in favor of approval, panel members did express concerns, namely about treating patients with normal kidney function with edoxaban. Given the subgroup analysis, which most panel members believed to be a real finding, the experts floated the idea of limiting edoxaban to patients with impaired renal function or even sending a "Dear Doctor" letter warning about the lack of efficacy in the group with normal kidney function.

The edoxaban approval for DVT/PE prophylaxis is based on the results of the Hokusai-Venous Thromboembolism (VTE) study, a trial that showed edoxaban was as effective as warfarin in preventing recurrences in patients with acute VTE. Rivaroxaban, apixaban, and dabigatran also have indications for preventing DVT/PE recurrences.