A recurrent symptomatic VTE prevention trial
8,292 VTE PATIENTS RANDOMISED1
Initial heparin therapy*. Standard dose LIXIANA® (60 mg). Including patients on a 30 mg dose** for patients at higher risk of bleeding (n=4,143)†
Warfarin (administered concurrently with heparin until INR of 2.0 to 3.0 was achieved) (n=4,149)‡
Flexible 3- to 12-month treatment duration1 (all patients were followed for 12 months)
A phase 3, randomised, double-blind, double-dummy, event-driven trial that evaluated the efficacy and safety of LIXIANA® compared with warfarin for noninferiority across a broad range of patients with VTE.
A broad range of patients with varying severities of VTE or other risk factors:
60% of patients had DVT (~42% of whom had extensive DVT [proximal with a clot involving the common femoral or iliac vein]).
40% had PE with or without DVT (~1/3 of whom also had right ventricular dysfunction [examined by CT and NT-pro-BNP in a random sample of 1002 patients]).
To evaluate whether LIXIANA® can be an alternative to warfarin in patients with venous thromboembolism.
Efficacy: The incidence of adjudicated symptomatic recurrent VTE.
Safety: The incidence of adjudicated clinically relevant bleeding.§
18 years of age or older
Had objectively diagnosed, acute, symptomatic DVT involving the popliteal, femoral, or iliac veins; or acute, symptomatic PE (with or without DVT).
All patients provided written informed consent
Contraindications to heparin or warfarin; received treatment for more than 48 hours with therapeutic doses of heparin
Received more than one dose of a vitamin K antagonist
Cancer for which long-term treatment with low molecular-weight heparin was anticipated
Another indication for warfarin therapy
Continued to receive treatment with aspirin at a dose of more than 100 mg daily or dual antiplatelet therapy
Had CrCl < 30 ml/min.
Hokusai-VTE: Designed to reflect a broad range of VTE patients you may treat in your daily clinical practice
Hokusai-VTE enrolled a broad range of patients, including a high percentage of patients with varying severities or other risk factors1
Baseline characteristics (% of LIXIANA® 60 mg/30 mg flexible 3- to 12-month treatment duration and heparin lead-in, including patients with one or more of the listed comorbidities / risk factors) in Hokusai-VTE1
Primary efficacy endpoint
LIXIANA® was proven comparable to well-managed warfarin in reducing symptomatic recurrent VTE risk1
During the overall study period1
The first symptomatic recurrent venous thromboembolism event with once-daily LIXIANA® compared with well-managed warfarin was: 3.2% vs. 3.5%
HR 0.89; 95.0% CI, 0.70 to 1.13; P<0.001 for non-inferiority
Primary safety endpoint
LIXIANA® demonstrated superior reduction in clinically relevant bleedingƗ vs. well-managed warfarin1§
In the safety-on-treatment population1
The rate of clinically relevant bleeding events with once-daily LIXIANA® vs. well‑controlled warfarin efficacy in patients with high bleeding risk was: 8.5% vs. 10.3%§
HR 0.81; 95% Cl, 0.71 to 0.94; P=0.004 for superiority
*Enoxaparin or unfractionated heparin.
**Patients were treated with the 30 mg reduced dose of LIXIANA® if they had one or more of the following clinical factors:1
– Renal impairment (CrCl 30 to 50 ml/min)
– Low body weight (≤60 kg/132 lbs)
– Concomitant use of P-gp inhibitors verapamil, dronedarone or quinidine1
The SmPC differs from the clinical trial. No dose adjustment is required for concomitant use of verapamil, amiodarone and quinidine. In patients concomitantly taking LIXIANA® and the following P-gp inhibitors: ciclosporin, dronedarone, erythromycin or ketoconazole, the recommended dose is 30 mg LIXIANA® once daily.1,3
** 60>30 mg: 60 mg is the recommended dose for most patients (~82%, n=3,385). ~18% (n=733) of patients received a dose reduction from 60 mg to 30 mg if they had one or more of the following factors: moderate renal impairment (CrCl 30–50 mL/min), low body weight (≤60 kg/132 lbs) or concomitant use of P-glycoprotein (P-gp) inhibitors verapamil, dronedarone or quinidine (please note the SmPC differs from the trial. No dose adjustment is required for verapamil, amiodarone and quinidine).1
§ **The primary safety endpoint of Hokusai- VTE was the incidence of adjudicated clinically relevant bleeding1, which was defined as a composite of major or clinically relevant nonmajor bleeding. Bleeding was defined as major if it was overt and was associated with a decrease in haemoglobin of 2 .0 g/dl or more or required a transfusion of 2 or more units of blood, occurred in a critical site, or contributed to death. Clinically relevant nonmajor bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, contact with a physician, or interruption of the study drug or with discomfort or impairment of activities of daily life.1
† Twenty-five patients did not receive study drug, resulting in 4, 118 patients included in the efficacy and safety analysis.
‡ Twenty-seven patients did not receive study drug, resulting in 4, 122 patients included in the efficacy and safety analysis.
AF, atrial fibrillation; B.D., twice-daily; CI, confidence interval; CrCI, creatinine clearance; CYP, cytochrome p450; DOAC, direct oral anticoagulant; HR, hazard ratio; INR, international normalised ratio; IQR, interquartile range; Ml, myocardial infarction; NVAF, nonvalvular atrial fibrillation; O.D., once-daily; SD, standard deviation; SEE, systemic embolic event; TIA, transient ischaemic attack; TTR, time-in-therapeutic range; ULN, upper limit of normal range.