The results from the global phase 3 Hokusai-VTE study of 8,292 patients with either acute symptomatic deep vein thrombosis ( DVT ), pulmonary embolism ( PE ), or both, were presented at the ESC Congress 2013 in Amsterdam. The study found that the investigational, oral, once-daily direct factor Xa inhibitor Edoxaban ( Lixiana, Savaysa ) met the primary efficacy endpoint of non-inferiority compared to Warfarin, following initial use of Heparin in both arms, for the treatment and prevention of recurrent symptomatic venous thromboembolism ( VTE ).
Once-daily Edoxaban has also demonstrated superiority compared to Warfarin for the principal safety outcome of clinically relevant bleeding ( the composite of major or clinically relevant non-major bleeding ). The Hokusai-VTE study was designed to reflect clinical practice using a flexible treatment duration of three to 12 months, including initial Heparin treatment, in a broad spectrum of venous thromboembolism patients, including those with severe pulmonary embolism.
For the primary efficacy outcome, Edoxaban has demonstrated non-inferiority with a numerically lower incidence of recurrent symptomatic venous thromboembolism compared to Warfarin ( 3.2% vs 3.5%, respectively ) ( hazard ratio, HR=0.89; P less than 0.001 for non-inferiority ).
Edoxaban was also found to be superior to Warfarin for the pre-specified principal safety outcome of clinically relevant bleeding ( 8.5% vs 10.3%, respectively ) ( HR=0.81; P=0.004 for superiority ).
In the Hokusai-VTE study, patient specific dosing was applied according to the study protocol. Edoxaban was dosed at 60 mg once-daily, except for those patients with clinical factors that commonly impact response to oral anticoagulants ( renal impairment, low body weight, or concomitant use of certain p-glycoprotein inhibitors ) who received Edoxaban 30 mg according to the study protocol.
The reduced dose of Edoxaban was found to have an efficacy profile consistent with the overall study cohort, with fewer recurrent VTE events in patients receiving 30 mg Edoxaban ( n=733 ) compared to Warfarin ( n=719 ) ( VTE recurrence of 3.0% vs 4.2%; HR=0.73 ).
Clinically relevant bleeding in patients receiving Edoxaban 30 mg was significantly lower compared to Warfarin ( 7.9% vs 12.8%, respectively ) ( HR=0.62 ).
Among patients with deep vein thrombosis ( n=4,921 ), venous thromboembolism recurrence was similar in the Edoxaban and Warfarin groups ( 3.4% vs 3.3%, respectively ) (HR=1.02 ), while the incidence of recurrent venous thromboembolism among patients with pulmonary embolism ( n=3,319 ) was numerically lower for patients treated with once-daily Edoxaban compared to Warfarin ( 2.8% vs. 3.9%, respectively ) ( HR=0.73 ).
Additionally, in a sub-group analysis, patients with severe pulmonary embolism and evidence of right ventricular dysfunction ( defined as NT pro-BNP greater than or equal to 500 pg/mL, n=938 ) treated with Edoxaban had a 48% lower risk of recurrent symptomatic venous thromboembolism compared to Warfarin ( 3.3% vs. 6.2%, respectively ) ( HR=0.52 ).
Hokusai-VTE was a global, event-driven, randomized, double-blind, 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 symptomatic deep vein thrombosis and/or pulmonary embolism.
Patients were randomized to one of two different treatment groups. Both groups received open-label Enoxaparin or unfractionated Heparin for at least five days, and either Warfarin or placebo ( administered to Edoxaban group ), followed by double-blind Edoxaban 60 mg ( n=4,118 ) ( Edoxaban 30 mg for patients with renal impairment or low body weight or p-glycoprotein inhibitor use ) or Warfarin ( n=4,122 ) for at least three months and up to a maximum of one year ( duration of study treatment was determined by the investigator based on the patient’s clinical features ).
Patients were followed for 12 months regardless of treatment duration to provide investigators with a better understanding of outcomes in clinical practice relative to an on-treatment analysis only.
The primary efficacy outcome was the recurrence of symptomatic venous thromboembolism, defined as the composite of recurrent symptomatic deep vein thrombosis, non-fatal symptomatic pulmonary embolism and fatal pulmonary embolism in patients during the 12-month study period.
The principal safety outcome was clinically relevant bleeding ( major or non-major ) occurring during or within three days of interrupting or stopping study treatment.
Secondary efficacy outcomes included the composite clinical outcome of symptomatic recurrent deep vein thrombosis, non-fatal symptomatic recurrent pulmonary emboslim and all-cause mortality.
Venous thromboembolism is a major cause of morbidity and mortality worldwide with an annual incidence of approximately one per 1,000 in developed countries, including an estimated 430,000 PE events, 680,000 DVT events and 540,000 deaths each year in the EU.
In the U.S., it is currently estimated that more than 950,000 VTE events and approximately 300,000 VTE related deaths occur each year.
Thirty percent of people with venous thromboembolism die within one month of diagnosis and about 20% of those with pulmonary embolism experience sudden death. ( Xagena )
Source: Daiichi Sankyo, 2013