CHADS₂ SCORE: A validated measure for assessing stroke risk. It is calculated by assigning 1 point each for a history of congestive heart failure, hypertension, age ≥75 years, or diabetes mellitus and by assigning 2 points for history of stroke or transient ischaemic attack.³

Patients were treated with the 30mg reduced dose of LIXIANA^® if they had one or more of the following clinical factors:
- Renal impairment (CrCl 30 to 50 ml/min)
- Low body weight (≤60 kg/132 lbs)
- Concomitant use of P-gp inhibitors verapamil, dronedarone or quinidine.
The SPC differs from the clinical trial. Hence, no dose adjustment is required for concomitant use of verapamil, amiodarone and quinidine. In patients taking LIXIANA^® and the following P-gp inhibitors; dronedarone, erythromycin, ketoconazole or ciclosporin, the recommended dose is LIXIANA^® 30 mg once daily.

Twenty-three patients in the LIXIANA^® 60/30 mg treatment arm and 24 patients in the warfarin arm did not receive study drug, resulting in 7012 patients included in each arm of the safety analysis, which reflects the modified intention-to-treat population in the on-treatment period.

These patients received a dose reduction of LIXIANA^® (30 mg) if they had one or more of the following factors which put them at risk of bleeding on the 60 mg dose: moderate renal impairment: (CrCI 30–50 ml/min), low body weight (≤60 kg/132 lbs) or concomitant use of P-glycoprotein (P-gp) inhibitors verapamil, dronedarone or quinidine.

The SPC differs from the clinical trial. Hence, no dose adjustment is required for concomitant use of verapamil, amiodarone and quinidine. In patients taking LIXIANA and the following P-gp inhibitors; dronedarone, erythromycin, ketoconazole or ciclosporin, the recommended dose is LIXIANA 30 mg once daily. Patients were excluded from the trial based on the following factors: atrial fibrillation due to a reversible disorder; an estimated CrCl of <30 ml/min; a high risk of bleeding; use of dual antiplatelet therapy; moderate-to-severe mitral stenosis, unresected atrial myxoma, or a mechanical heart valve; other indications for anticoagulation therapy; acute coronary syndromes, coronary revascularisation, or stroke within 30 days before randomisation; history of left atrial appendage exclusion; intracardial mass or left ventricular thrombus; subjects in whom chronic anticoagulation therapy will be discontinued if a planned pharmacologic, electrical, or surgical therapy were to be successful in converting and maintaining normal sinus rhythm; contraindication for anticoagulant agents; chronic ciclosporin therapy, concomitant use of medications that increase the risk of bleeding; active liver disease or persistent elevation of liver enzymes/bilirubin, alanine transaminase or aspartate transaminase ≥2 times the ULN, total bilirubin ≥1.5 times the ULN; known positive hepatitis B antigen or hepatitis C antibody before randomisation; known positive test for HIV; haemoglobin <10 g/dL or platelet count <100,000 cells/mL or white blood cell count <3000 cells/mL; any other clinically relevant laboratory abnormality; preplanned invasive procedures (other than routine endoscopy) or surgeries in which bleeding is anticipated during the study period; subjects who received any investigational drug or device within 30 days before randomisation, or plan to receive such therapy during the study period; subjects previously randomised in a study of edoxaban; women of childbearing potential including women with a history of tubal ligation and women <2 years postmenopausal; subjects with the following diagnoses or situations: active malignancy (diagnosed within 5 years) except for adequately treated nonmelanoma skin cancer or other noninvasive or in situ neoplasm; treatment with anticancer therapy (drugs, radiation, and/or surgery) within the last 5 years; significant active concurrent medical illness or infection; life expectancy <12 months; known drug or alcohol dependence within the past 12 months; any condition that, in the opinion of the investigator, would place the subject at increased risk of harm if he/she participated in the study; and an inability to adhere to study procedures.^1,2

The primary safety endpoint of ENGAGE AF-TIMI 48 was the incidence of adjudicated major bleeding, defined by the International Society on Thrombosis and Haemostasis (ISTH) as (i) fatal bleeding; and/or (ii) symptomatic bleeding in critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or intramuscular with compartment syndrome, and/or (iii) bleeding causing a fall in haemoglobin level of 2.0 g/dL or more, or leading to transfusion of two or more units of whole blood or red cells.