Training Example: LIXIANA (Daiichi Sankyo) – Review the Data, Give Your Score & Compare to the Real AI Evaluation

[H2] Nonvalvular atrial fibrillation (NVAF)
Once-daily LIXIANA® was superior to warfarin in reducing the risk of major bleeding across a broad range of NVAF patients2*
Continue to know more about LIXIANA® for NVAF

[H3] LIXIANA® demonstrated superior reduction in major bleeding vs. well managed warfarin in ENGAGE AF-TIMI 48 study2*

In the safety-on-treatment population, the annualised rate of major bleeding events with once-daily LIXIANA® vs. well-controlled warfarin was:
2.75% vs 3.43%2*
HR 0.80; 95% CI, 0.71 to 0.91; P<0.001
Read about the ENGAGE AF-TIMI 48 trial. The longest DOAC trial to date in NVAF
FIND OUT MORE
[H2] LIXIANA® – simple and convenient once-daily dosing in NVAF1

60 mg Standard doseThe recommended dose of LIXIANA® is 60 mg in a once-daily tablet. It can be taken with water, with or without food. To aid compliance, patients should be encouraged to take their dose at the same time every day.
30 mg Standard doseA dose of 30 mg once daily is required for certain patients with one or more of the clinical factors.

Can be taken with or without food1

Not significantly affected by CYP450 inducers/inhibitors (<10% is metabolised by CYP3A4/5)1

Rapid onset of anticoagulant therapeutic effect (1-2 hours)1

No routine anticoagulation level monitoring required1

Can be coadministered with other commonly used cardiovascular agents and proton pump inhibitors3

Lactose not listed as an excipient1***

Renal function in NVAF

In patients with NVAF and high CrCl, there is a trend towards decreasing efficacy with increasing CrCl for edoxaban vs. well-managed warfarin, therefore careful evaluation of thromboembolic and bleeding risk is necessary before initiation.1

Clinical factors

A dose of 30 mg is recommended for patients with one or more of the following factors that increase risks of bleeding:1

Moderate or severe renal impairment (CrCl 15−50 ml/min)

Low body weight (≤60 kg)

Concomitant use of potent P-gp inhibitors (ciclosporin, dronedarone, erythromycin, or ketoconazole)

Footnotes

* The primary safety endpoint of ENGAGE AF-TIMI 48 was the incidence of adjudicated major bleeding2, defined by the International Society of 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.4
*** We cannot guarantee that there has been no contact with lactose during manufacture. Use with caution in patients that have had severe anaphylaxis with lactose products.1
CrCl, creatinine clearance; CYP, cytochrome P450; DOAC, direct oral anticoagulant; P-gp, P‑glycoprotein; VTE, venous thromboembolism.

References

LIXIANA® Summary of Product Characteristics.
Giugliano RP et al. NEJM 2013;369(22):2093–2104 and supplementary appendix.
The Hokusai-VTE Investigators. NEJM 2013;369(15):1406-1415 and supplementary appendix.
Schulman S and Kearon C. J Thromb Haemost 2005;3(4):692–694

[H3] For more information on how to use LIXIANA® please download our practical guide
DOWNLOAD OUR PRACTICAL GUIDE

[H2] Venous thromboembolism (VTE)
Once-daily LIXIANA® was superior to warfarin in reducing the risk of clinically relevant bleeding (the composite of major and clinically relevant nonmajor [CRNM] bleeding**) across a broad range of VTE patients
Continue to know more about LIXIANA® for VTE

[H3] LIXIANA® was superior to warfarin in reducing the risk of clinically relevant bleeding across a broad range of eligible VTE patients in Hokusai-VTE study3,*
In the safety-on-treatment population, the composite of major and clinically relevant nonmajor bleeding events with once-daily LIXIANA® vs. warfarin was: 8.5% vs. 10.3%3,*
HR 0.81; 95% CI, 0.71 to 0.91; p=0.004
Read about the Hokusai-VTE trial. The VTE—the largest single VTE (DVT and/or PE) trial to date.
FIND OUT MORE
[H2] LIXIANA® – simple and convenient once-daily dosing in VTE1

60 mg Standard doseThe recommended dose of LIXIANA® is 60 mg in a once-daily tablet. It can be taken with water, with or without food. To aid compliance, patients should be encouraged to take their dose at the same time every day.
30 mg Standard doseA dose of 30 mg once daily is required for certain patients with one or more of the clinical factors.

Can be taken with or without food1

Not significantly affected by CYP450 inducers/inhibitors (<10% is metabolised by CYP3A4/5)1

Rapid onset of anticoagulant therapeutic effect (1-2 hours)1

No routine anticoagulation level monitoring required1

Can be coadministered with other commonly used cardiovascular agents and proton pump inhibitors3

Lactose not listed as an excipient1***

Renal function in VTE

In patients with VTE, the duration of therapy for treatment of DVT and PE, and prevention of recurrent VTE should be individualised after careful assessment of the treatment benefit against the risk for bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.1

Clinical factors

A dose of 30 mg is recommended for patients with one or more of the following factors that increase risks of bleeding:1

Moderate or severe renal impairment (CrCl 15−50 ml/min)

Low body weight (≤60 kg)

Concomitant use of potent P-gp inhibitors (ciclosporin, dronedarone, erythromycin, or ketoconazole)

Footnotes

* The primary safety endpoint of Hokusai- VTE was the incidence of adjudicated clinically relevant bleeding3, 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.4
*** We cannot guarantee that there has been no contact with lactose during manufacture. Use with caution in patients that have had severe anaphylaxis with lactose products.1
CrCl, creatinine clearance; CYP, cytochrome P450; DOAC, direct oral anticoagulant; P-gp, P‑glycoprotein; VTE, venous thromboembolism.

References

LIXIANA® Summary of Product Characteristics.
Giugliano RP et al. NEJM 2013;369(22):2093–2104 and supplementary appendix.
The Hokusai-VTE Investigators. NEJM 2013;369(15):1406-1415 and supplementary appendix.
Schulman S and Kearon C. J Thromb Haemost 2005;3(4):692–694

[H3] For more information on how to use LIXIANA® please download our practical guide
DOWNLOAD OUR PRACTICAL GUIDE

[H2] Study design1,2

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

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

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

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)

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

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

[H2] ENGAGE AF-TIMI 48: Studied NVAF patients you may see in your daily clinical practice

[H3] ENGAGE AF-TIMI 48 enrolled a high percentage of patients who also had comorbidities or other risk factors1

[H4] Baseline characteristics (% of LIXIANA® 60 mg/30 mg and warfarin patients with comorbidities or other risk factors) in ENGAGE AF-TIMI 481

[H2] Study design1,2

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.

[H2] Hokusai-VTE: Designed to reflect a broad range of VTE patients you may treat in your daily clinical practice

[H3] Hokusai-VTE enrolled a broad range of patients, including a high percentage of patients with varying severities or other risk factors1

[H4] 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

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