The European Committee for Medicinal Products for Human Use ( CHMP ) has recommended approval of Lixiana ( Edoxaban ), an oral, once-daily selective factor Xa inhibitor, for the prevention of stroke and systemic embolism ( SE ) in adult patients with non-valvular atrial fibrillation ( NVAF ) with one or more risk factors.
The CHMP also recommended approval of Lixiana for the treatment of deep vein thrombosis ( DVT ) and pulmonary embolism ( PE ), and prevention of recurrent DVT and PE in adults.
The two related conditions deep vein thrombosis and pulmonary embolism are collectively referred to as venous thromboembolism ( VTE ).
The European regulatory committee has recognised the positive benefit-risk profile of the 60 mg dosing regimen [ with a dose reduction to 30 mg in selected patients with creatinine clearance ( CrCL ) 15-50 mL/min, body weight less than or equal to 60 kg, or concomitant use of certain P-glycoprotein ( P-gp ) inhibitors ].
The CHMP opinion to approve once-daily Edoxaban for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors and for the treatment and prevention of recurrent venous thromboembolism is based on the data of the phase 3 ENGAGE AF-TIMI 48 and Hokusai-VTE studies, respectively.
In the ENGAGE AF-TIMI 48 study, once-daily Edoxaban 60 mg demonstrated non-inferiority to well-managed Warfarin for the primary efficacy endpoint of occurrence of stroke or systemic embolism in patients with non-valvular atrial fibrillation ( 1.18% vs. 1.50% per year, respectively; hazard ratio [ HR ], 0.79; 97.5% confidence interval [CI], 0.63 to 0.99, p less than 0.001 ).
In addition, once-daily Edoxaban 60 mg demonstrated a significant 20% risk reduction of major bleeding in patients with non-valvular atrial fibrillation compared to Warfarin ( 2.75% vs. 3.43% per year, respectively; HR, 0.80; 95% CI, 0.71 to 0.91, p less than 0.001 ).
In the Hokusai-VTE study, once-daily Edoxaban 60 mg was non-inferior to Warfarin for the primary efficacy endpoint of recurrence of symptomatic venous thromboembolism ( 3.2% vs. 3.5% of patients, respectively; HR, 0.89; 95% CI, 0.70 to 1.13, p less than 0.001 ).
In addition, Edoxaban demonstrated a significant 19% risk reduction of clinically relevant bleeding in patients with venous thromboembolism compared to Warfarin ( 8.5% vs. 10.3% of patients, respectively; HR, 0.81; 95% CI, 0.71 to 0.94, p=0.004 ).
ENGAGE AF-TIMI 48 ( Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation ) was a three-arm, randomized, double-blind, double-dummy, global phase 3 clinical trial comparing once-daily Edoxaban with well-managed Warfarin in 21,105 patients with non-valvular atrial fibrillation at moderate-to-high risk of thromboembolic events at 1,393 centers in 46 countries.
ENGAGE AF-TIMI 48 compared two Edoxaban treatment strategies, a higher dose arm ( 60 mg or 30 mg dose reduced ) once-daily and a lower dose arm ( 30 mg or 15 mg dose reduced ) once-daily, with Warfarin in patients with non-valvular atrial fibrillation for a median of 2.8 years follow-up.
Patients were dose reduced for CrCL 30 to 50 mL/min, body weight of 60 kg or less or certain P-gp inhibitor use.
Hokusai-VTE was a global, event-driven, randomized, double-blind, double-dummy, parallel-group phase 3 clinical study involving 8,292 patients in 439 clinical sites across 37 countries to evaluate once-daily Edoxaban in patients with either acute symptomatic deep vein thrombosis, pulmonary embolism or both.
The Hokusai-VTE study was designed to reflect clinical practice using a flexible treatment duration of 3-12 months in a broad spectrum of VTE patients, including initial use of parenteral anticoagulant ( Heparin ) for 5-10 days, the proven global standard of care.
Patients were randomized to receive Edoxaban 60 mg once-daily ( dose reduced to 30 mg for CrCL 30 to 50 mL/min, body weight of 60 kg or less, or certain P-gp inhibitor use ) or the comparator, Warfarin, following initial open-label Enoxaparin or unfractionated Heparin therapy.
In the comparator arm, patients received initial Heparin therapy concurrently with Warfarin, titrated to a target INR of 2.0 to 3.0, followed by Warfarin alone.
The treatment duration was from 3 months and up to a maximum of one year. The duration of study treatment was determined by the investigator based on the patient’s clinical features. ( Xagena )
Source: Daiichi-Sankyo, 2015