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Anti-Clotting Drug Savaysa (Edoxaban) Wins FDA Nod
The FDA has approved Savaysa (edoxaban, Daiichi Sankyo Company), an oral, once-daily selective factor-Xa inhibitor, to reduce the risk of stroke and systemic embolism (SE) in patients with non-valvular atrial fibrillation (NVAF). The drug is also indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.
The approved indications are based on data from the ENGAGE AF-TIMI 48 and Hokusai-VTE studies.
The ENGAGE AF-TIMI 48 (Effective ANticoaGulation With Factor XA Next-GEneration in Atrial Fibrillation) trial was a global, randomized, double-blind, double-dummy, phase III study comparing once-daily edoxaban with warfarin in 21,105 patients with NVAF at moderate-to-high risk of thromboembolic events. The trial compared two edoxaban treatment strategies –– a higher-dose arm (60 mg or 30 mg reduced dose) once-daily and a lower-dose arm (30 mg or 15 mg reduced dose) once-daily –– with warfarin in patients with NVAF for a median period of 2.8 years. The patients received reduced doses if they had creatinine clearance (CrCl) of 30 to 50 mL/min or a body weight of less than 60 kg, or if they used certain p-glycoprotein inhibitors. The lower-dose arm is not an approved treatment regimen in the U.S.
In this study, edoxaban was associated with significantly fewer major bleeding events in patients with NVAF, both in the overall study population (hazard ratio [HR], 0.80; P <0.001) and in patients with CrCL of less than or equal to 95 mL/min (HR, 0.84), compared with warfarin. In addition, in the approved population, lower rates of intracranial hemorrhage were observed in the edoxaban groups compared with the warfarin group in patients with NVAF (0.5% vs. 1.0% per year, respectively; HR, 0.44). The approved population showed a significant increase in gastrointestinal bleeding events with edoxaban compared with warfarin (1.8% vs. 1.3% per year, respectively; HR, 1.4).
The Hokusai-VTE trial was a global, event-driven, randomized, double-blind, parallel-group, phase III study evaluating once-daily edoxaban in 8,292 patients with acute symptomatic DVT, PE, or both. The study was designed to reflect clinical practice, using a flexible treatment duration of 3 to 12 months in a broad spectrum of VTE patients. The study protocol also included the initial use of a parenteral anticoagulant (heparin) for 5 to 10 days (the global standard of care) in both treatment arms.
After treatment with open-label enoxaparin or unfractionated heparin for at least 5 days, and with either warfarin or placebo (administered to the edoxaban group), the patients were randomly assigned to receive either edoxaban 60 mg (reduced to 30 mg for patients with CrCL of 30 to 50 mL/min, body weight of less than 60 kg, or the use of certain p-glycoprotein inhibitors) or warfarin for 3 to 12 months. The duration of treatment was determined by the investigator based on the patient’s clinical features.
Once-daily enoxaparin 60 mg was non-inferior to warfarin for the primary efficacy endpoint of the recurrence of symptomatic VTE (3.2% vs. 3.5%, respectively; HR, 0.89). In addition, enoxaparin demonstrated a significant 19% lower rate of clinically relevant bleeding in patients with VTE compared with warfarin (8.5% vs. 10.3%, respectively; HR, 0.81; P = 0.004).
The most common adverse events observed in study participants treated with enoxaparin were bleeding and anemia. Enoxaparin increases the risk of bleeding and can cause serious and potentially fatal bleeding.
Source: Daiichi Sankyo Company; January 9, 2015.