LIXIANA® for NVAF

ENGAGE AF-TIMI 48 is the largest and longest comparative stroke prevention in atrial fibrillation (SPAF) trial to date1

A stroke prevention in NVAF trial

Study design1,2

Characteristics
  • A Phase 3, three-arm, randomised, double-blind, double-dummy, event-driven trial comparing two once-daily regimens of LIXIANA® with warfarin in patients with moderate to high risk atrial fibrillation

Participants
  • Enrolled a high percentage of patients who also had comorbidities or other risk factors

Aim
  • To evaluate whether LIXIANA® can be an alternative to warfarin for stroke prevention in patients with atrial fibrillation.

Primary endpoints
  • Efficacy: The time to first stroke (ischaemic or haemorrhagic) or systemic embolism

  • Safety: Major bleeding as defined by the International Society on Thrombosis and Haemostatis (ISTH)

Key inclusion criteria
  • 21 years of age or older

  • Atrial fibrillation documented by means of electrical tracing within the 12 months preceding randomisation

  • Moderate-to-high stroke risk – a score of 2 or higher on the CHADS2 risk assessment

  • Anticoagulation therapy planned for the duration of the trial

  • All patients provided written informed consent

Key exclusion criteria
  • Atrial Fibrillation due to a reversible disorder

  • Estimated CrCl of <30 ml/min

  • 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 pharmalogic, 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 test for HIV, hepatitis B antigen or hepatitis C antibody before randomisation

  • Haemoglobin <10 g/dL or platelet count <100,000 cells/mL

  • 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 recieve 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 non invasive 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

ENGAGE AF-TIMI 48: Studied NVAF patients you may see in your daily clinical practice

ENGAGE AF-TIMI 48 enrolled a high percentage of patients who also had comorbidities or other risk factors1

Baseline characteristics (% of LIXIANA® 60 mg/30 mg and warfarin patients with comorbidities or other risk factors) in ENGAGE AF-TIMI 481

Study Highlights

Primary efficacy endpoint

LIXIANA® demonstrated proven efficacy in preventing stroke and SEE in NVAF patients – comparable to well‑managed warfarin1

In the modified intention-to-treat population1

The annualised rate of stroke/SEE events with once-daily LIXIANA® 60/30 mg compared with well‑managed warfarin was: 1.18% vs. 1.50% HR, 0.79; 97.5% CI, 0.63 to 0.99; P<0.001 for noninferiority

In the intention-to-treat population1

The annualised rate of stroke/SEE events with once-daily LIXIANA® 60/30 mg compared with well‑managed warfarin was: 1.57% vs. 1.80% HR 0.87; 97.5% CI, 0.73 to 1.04; P=0.08 for superiority

Consistent results across subgroups

LIXIANA® demonstrated consistent efficacy in reducing the risk of stroke/SEE when compared with well-managed warfarin in NVAF patients <65 years, 65-74 years, and ≥75 years as well as very elderly patients ≥80 years and ≥85 years3

LIXIANA® demonstrated similar risk reduction in stroke/SEE when compared with well-managed warfarin in NVAF patients by baseline renal function in the pre-specified analysis4

LIXIANA® demonstrated consistent efficacy in reducing the risk of stroke/SEE when compared with well-managed warfarin in NVAF patients who required a dose reduction to 30 mg qd.1

Primary safety endpoint

LIXIANA® demonstrated superior reduction in major bleeding vs. well managed warfarin

In the safety-on-treatment population1

The annualised rate of major bleeding events with once-daily LIXIANA® 60/30 mg vs. well‑controlled warfarin was: 2.75% vs. 3.43%§ HR 0.80; 95% Cl, 0.71 to 0.91; P<0.01

Consistent results across subgroups

LIXIANA® demonstrated consistent and favourable safety in reducing the risk of major bleeding when compared with well-managed warfarin in NVAF patients <65 years, 65-74 years, and ≥75 years as well as very elderly patients ≥80 years and ≥85 years3

LIXIANA® demonstrated consistent and favourable safety in reducing the risk of major bleeding when compared with well-managed warfarin in NVAF patients by baseline renal function in the pre-specified analysis4

FIND OUT MORE ON SUBGROUP ANALYSES

Footnotes

*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. 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.6

** 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.1

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.5

‡‡ The SmPC 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.2,6

§ The primary safety endpoint of ENGAGE AF-TIMI 48 was the incidence of adjudicated major bleeding,1 defined by the International Society on Thrombosis and Haemostasis (ISTH) as (i) fatal bleeding; and/or (ii) symptomatic bleeding in a 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.7

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.