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According to current guidelines, duration of anticoagulant treatment after a venous thromboembolic event varies from 3 months to indefinite treatment depending on the estimated risks of venous thromboembolism (VTE) recurrence and bleeding. Current data for edoxaban are limited to a maximum treatment duration of 12 months (Hokusai-VTE; N Engl J Med. 2013; 369:1406-15).
Therefore, this study aims to gather further insight into efficacy (i.e. symptomatic recurrent VTE) and safety (i.e. bleeding events, liver adverse events, all-cause mortality and other drug related adverse events) of extended treatment with edoxaban up to 18 months in an unselected patient population in routine clinical practice.
Real-world evidence data in routine clinical practice use of edoxaban up to 18 months will be collected in 2,700 patients, treated by specialized as well as non-specialized physicians in hospitals and office based centres in 8 European countries. Patients from different countries and care settings (primary care and secondary care, different specialties) will be enrolled in this post-authorization safety study. Documentation of baseline and follow up information at 1, 3, 6, 12, and 18 months (only when available) will be collected. In addition, recurrence of symptomatic VTE and death will be captured retrospectively at time point of Last Patient Out per country.
Patients who discontinue permanently edoxaban during the observational period will be followed up according to the same scheme.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients treated with Edoxaban | Patients with established initial or recurrent acute symptomatic VTE treated with edoxaban according to the Summary of Product Characteristics (SmPC). Physician's prescribing behaviour will not be influenced, patients may only be included after the treating physician has made the clinical decision to prescribe edoxaban. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Edoxaban | Drug | Prescribed according to approved label |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants With At Least 1 Symptomatic Venous Thromboembolism Recurrence - Overall | Descriptive statistics were used to report the number of participants with at least 1 symptomatic VTE recurrence. Recurrent VTE events were based on adjudicated events. For the overall symptomatic VTE, precentage of participants (including 95% confidence intervals) were calculated. | Baseline up to end of observation period (18 months) |
| Number of Participants With Bleeding Events (Adjudicated) While On Edoxaban Treatment | Descriptive statistics were used to report the number of participants with bleeding events. For the analysis of bleeding events, absolute number of participants were calculated. | Baseline up to end of observation period (18 months) |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants Experiencing At Least 1 Real World Safety Event - Overall | Descriptive statistics were used to report the number of participants experiencing recurrent VTE and at least 1 real world safety event. VTE recurrence data were reported by recurrent deep vein thrombosis (DVT), recurrent pulmonary embolism (PE) with DVT, and recurrent PE only. Recurrent VTE events were based on adjudicated events. Real world safety events included all-cause death, cardiovascular (CV)-related death, VTE-related death, stroke, systemic embolic event, and hospitalization related to CV. For recurrent VTE and real world safety events, absolute and relative frequencies (including 95% confidence intervals) were calculated. |
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Inclusion Criteria:
Exclusion Criteria:
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All patients with established initial or recurrent acute symptomatic VTE (distal or proximal deep vein thrombosis/pulmonary embolism) treated with edoxaban according to the Summary of Product Characteristics (SmPC). To ensure that the physician's prescribing behaviour will not be influenced, patients may only be included after the treating physician has made the clinical decision to prescribe edoxaban. Patients must have provided written informed consent for participation in the study (ICF) and should not participate simultaneously in any interventional study.
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| Name | Affiliation | Role |
|---|---|---|
| Global Clinical Leader | Daiichi Sankyo | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| International Clinical Research GmbH | Germering | 82110 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24251359 | Background | Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19. | |
| 23991658 |
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A total of 2809 participants were included in the All Documented Patient Set defined as participants with a signed ICF and trustworthy data at sites in Germany, Austria, Switzerland, Belgium, The Netherlands, United Kingdom, Ireland, and Italy; a total of 2655 participants were included in the Baseline Analysis Set and a total of 2644 participants were included in the Full Analysis Set.
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| ID | Title | Description |
|---|---|---|
| FG000 | ETNA-VTE | Participants with established initial or recurrent acute symptomatic venous thromboembolism (VTE) who were treated with edoxaban according to the Summary of Product Characteristics (SmPC) based on the clinical decision of the treating physician. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Demographic and baseline characteristics were assessed in the Full Analysis Set.
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| ID | Title | Description |
|---|---|---|
| BG000 | ETNA-VTE | Participants with established acute initial or recurrent VTE who were treated with edoxaban according to Summary of Product Characteristics (SmPC) based on the clinical decision of the treating physician. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percentage of Participants With At Least 1 Symptomatic Venous Thromboembolism Recurrence - Overall | Descriptive statistics were used to report the number of participants with at least 1 symptomatic VTE recurrence. Recurrent VTE events were based on adjudicated events. For the overall symptomatic VTE, precentage of participants (including 95% confidence intervals) were calculated. | VTE recurrence was assessed in the Full Analysis Set. | Posted | Number | 95% Confidence Interval | Percentage of VTE recurrence | Baseline up to end of observation period (18 months) |
|
Treatment-emergent adverse events were not assessed in this non-interventional (observational) study.
Treatment-emergent adverse events were not assessed in this non-interventional (observational) study. Adverse drug reactions were reported as a secondary outcome measure.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | ETNA-VTE | Participants with established acute initial or recurrent VTE who were treated with edoxaban according to Summary of Product Characteristics (SmPC) based on the clinical decision of the treating physician. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Contact for Clinical Trial Information | Daiichi Sankyo | 908-992-6400 | CTRinfo@dsi.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 12, 2016 | Dec 16, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D054556 | Venous Thromboembolism |
| ID | Term |
|---|---|
| D013923 | Thromboembolism |
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C552171 | edoxaban |
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| Baseline up to end of observation period (18 months) |
| Percentage of Participants With At Least 1 Symptomatic Venous Thromboembolism Recurrence - On Edoxaban Treatment | Descriptive statistics were used to report the number of participants with overall symptomatic VTE recurrence. VTE recurrence data were further reported by recurrent deep venous thrombosis (DVT), recurrent pulmonary embolism (PE) with deep venous thrombosis (DVT), and recurrent PE only. Recurrent VTE events were based on adjudicated events. For symptomatic VTE recurrence, percentage of participants (95% confidence intervals) were calculated. | Baseline up to end of observation period (18 months) |
| Total Number of Venous Thromboembolism Recurrences By Type - Overall | Descriptive statistics were used to describe the number of VTE events reported by the patient. For VTE recurrences, absolute number of VTE events were calculated. | Baseline up to end of observation period (18 months) |
| Duration of Venous Thromboembolism Recurrences, by Type - Overall | Descriptive statistics were used to assess the duration of VTE events reported by the patient. For VTE recurrences, median duration of VTE events (interquartile range) were calculated. | Baseline up to end of observation period (18 months) |
| Total Number of Venous Thromboembolism Recurrences (On Edoxaban Treatment) | Descriptive statistics were used to assess the number of recurrent VTE events reported by the patient. For VTE recurrences, absolute number of VTE recurrences were calculated. | Baseline up to end of observation period (18 months) |
| Duration of Venous Thromboembolism Events (On Edoxaban Treatment) | Descriptive statistics were used to assess the duration of VTE events reported by the patient. For VTE events, median duration of VTE events (interquartile range) were calculated. | Baseline up to end of observation period (18 months) |
| Number of Participants With Risk Factors for Thromboembolic Events at Baseline | Descriptive statistics were used to assess the number of participants with risk factors for thromboembolic events. For risk factors for thromboembolic events, absolute number of participants with risk factors (percentage) were calculated. | at Baseline |
| Duration of Edoxaban Treatment | Descriptive statistics were used to report the duration of edoxaban treatment. | Baseline up to end of observational period (18 months) |
| Number of Stroke Events | Descriptive statistics were used to report the number of stroke events. For stroke events, absolute number of stroke events were calculated. | Baseline up to end of observation period (18 months) |
| Number of Systemic Embolic Events - Overall | Descriptive statistics were used to report the number of systemic embolic events (SEE). For SEE, absolute SEEs were calculated. | Baseline up to end of observation period (18 months) |
| Overview of Participants With Adverse Drug Reactions | Descriptive statistics were used to report an overview of participants with adverse drug reactions (ADR). ADRs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1. | Baseline up to end of observation period (18 months) |
| Number of Participants With Adverse Drug Reactions by Preferred Term (≥0.2%) | Adverse drug reactions were reported and coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1. | Baseline up to end of observational period (18 months) |
| Number of Participants With Pre-defined Adverse Drug Reactions | Descriptive statistics were used to report the number of participants with pre-defined adverse drug reactions (ADR). ADRs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1. | Baseline up to end of observation period (18 months) |
| Background |
| Hokusai-VTE Investigators; Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. doi: 10.1056/NEJMoa1306638. Epub 2013 Aug 31. |
| 32826158 | Derived | Cohen AT, Hoffmann U, Hainaut P, Gaine S, Ay C, Coppens M, Schindewolf M, Jimenez D, Bruggenjurgen B, Levy P, Laeis P, Fronk EM, Zierhut W, Malzer T, Manu MC, Reimitz PE, Bramlage P, Agnelli G; ETNA-VTE-Europe investigators. ETNA VTE Europe: A contemporary snapshot of patients treated with edoxaban in clinical practice across eight European countries. Eur J Intern Med. 2020 Dec;82:48-55. doi: 10.1016/j.ejim.2020.08.014. Epub 2020 Aug 18. |
| 29719492 | Derived | Cohen AT, Ay C, Hainaut P, Decousus H, Hoffmann U, Gaine S, Coppens M, da Silva PM, Castro DJ, Amann-Vesti B, Bruggenjurgen B, Levy P, Bastida JL, Vicaut E, Laeis P, Fronk EM, Zierhut W, Malzer T, Bramlage P, Agnelli G; ETNA-VTE-Europe investigators. Design and rationale of the non-interventional, edoxaban treatment in routiNe clinical prActice in patients with venous ThromboEmbolism in Europe (ETNA-VTE-Europe) study. Thromb J. 2018 May 1;16:9. doi: 10.1186/s12959-018-0163-7. eCollection 2018. |
| Death |
|
| Other reason for premature termination |
|
| Missing reason for termination |
|
| years |
|
| Age, Customized | Count of Participants | Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Primary | Number of Participants With Bleeding Events (Adjudicated) While On Edoxaban Treatment | Descriptive statistics were used to report the number of participants with bleeding events. For the analysis of bleeding events, absolute number of participants were calculated. | Bleeding events were assessed in the Full Analysis Set. | Posted | Number | participants | Baseline up to end of observation period (18 months) |
|
|
|
| Secondary | Percentage of Participants Experiencing At Least 1 Real World Safety Event - Overall | Descriptive statistics were used to report the number of participants experiencing recurrent VTE and at least 1 real world safety event. VTE recurrence data were reported by recurrent deep vein thrombosis (DVT), recurrent pulmonary embolism (PE) with DVT, and recurrent PE only. Recurrent VTE events were based on adjudicated events. Real world safety events included all-cause death, cardiovascular (CV)-related death, VTE-related death, stroke, systemic embolic event, and hospitalization related to CV. For recurrent VTE and real world safety events, absolute and relative frequencies (including 95% confidence intervals) were calculated. | Real word safety events were assessed in the Full Analysis Set. | Posted | Number | 95% Confidence Interval | Percentage of real world safety events | Baseline up to end of observation period (18 months) |
|
|
|
| Secondary | Percentage of Participants With At Least 1 Symptomatic Venous Thromboembolism Recurrence - On Edoxaban Treatment | Descriptive statistics were used to report the number of participants with overall symptomatic VTE recurrence. VTE recurrence data were further reported by recurrent deep venous thrombosis (DVT), recurrent pulmonary embolism (PE) with deep venous thrombosis (DVT), and recurrent PE only. Recurrent VTE events were based on adjudicated events. For symptomatic VTE recurrence, percentage of participants (95% confidence intervals) were calculated. | VTE recurrence was assessed in the Full Analysis Set. | Posted | Number | 95% Confidence Interval | Percentage of VTE recurrence | Baseline up to end of observation period (18 months) |
|
|
|
| Secondary | Total Number of Venous Thromboembolism Recurrences By Type - Overall | Descriptive statistics were used to describe the number of VTE events reported by the patient. For VTE recurrences, absolute number of VTE events were calculated. | Number of VTE recurrences were assessed in the Full Analysis Set. | Posted | Number | VTE recurrences | Baseline up to end of observation period (18 months) |
|
|
|
| Secondary | Duration of Venous Thromboembolism Recurrences, by Type - Overall | Descriptive statistics were used to assess the duration of VTE events reported by the patient. For VTE recurrences, median duration of VTE events (interquartile range) were calculated. | Duration of VTE recurrences was assessed in patients with available start and stop data in the Full Analysis Set. | Posted | Median | Inter-Quartile Range | days | Baseline up to end of observation period (18 months) |
|
|
|
| Secondary | Total Number of Venous Thromboembolism Recurrences (On Edoxaban Treatment) | Descriptive statistics were used to assess the number of recurrent VTE events reported by the patient. For VTE recurrences, absolute number of VTE recurrences were calculated. | Number of VTE recurrences were assessed in the Full Analysis Set. | Posted | Number | VTE recurrences | Baseline up to end of observation period (18 months) |
|
|
|
| Secondary | Duration of Venous Thromboembolism Events (On Edoxaban Treatment) | Descriptive statistics were used to assess the duration of VTE events reported by the patient. For VTE events, median duration of VTE events (interquartile range) were calculated. | Duration of VTE recurrences was assessed in patients with available start and stop data in the Full Analysis Set. | Posted | Median | Inter-Quartile Range | days | Baseline up to end of observation period (18 months) |
|
|
|
| Secondary | Number of Participants With Risk Factors for Thromboembolic Events at Baseline | Descriptive statistics were used to assess the number of participants with risk factors for thromboembolic events. For risk factors for thromboembolic events, absolute number of participants with risk factors (percentage) were calculated. | Risk factors were assessed in the Full Analysis Set. | Posted | Count of Participants | Participants | at Baseline |
|
|
|
| Secondary | Duration of Edoxaban Treatment | Descriptive statistics were used to report the duration of edoxaban treatment. | Duration of edoxaban treatment was assessed in the Full Analysis Set. | Posted | Count of Participants | Participants | Baseline up to end of observational period (18 months) |
|
|
|
| Secondary | Number of Stroke Events | Descriptive statistics were used to report the number of stroke events. For stroke events, absolute number of stroke events were calculated. | Stroke events were assessed in the Full Analysis Set. | Posted | Number | events | Baseline up to end of observation period (18 months) |
|
|
|
| Secondary | Number of Systemic Embolic Events - Overall | Descriptive statistics were used to report the number of systemic embolic events (SEE). For SEE, absolute SEEs were calculated. | Systemic embolic events were assessed in the Full Analysis Set. | Posted | Number | Systemic embolic events | Baseline up to end of observation period (18 months) |
|
|
|
| Secondary | Overview of Participants With Adverse Drug Reactions | Descriptive statistics were used to report an overview of participants with adverse drug reactions (ADR). ADRs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1. | Adverse drug reactions were assessed in the Baseline Analysis Set. | Posted | Count of Participants | Participants | Baseline up to end of observation period (18 months) |
|
|
|
| Secondary | Number of Participants With Adverse Drug Reactions by Preferred Term (≥0.2%) | Adverse drug reactions were reported and coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1. | Adverse drug reactions were assessed in the Baseline Analysis Set. | Posted | Count of Participants | Participants | Baseline up to end of observational period (18 months) |
|
|
|
| Secondary | Number of Participants With Pre-defined Adverse Drug Reactions | Descriptive statistics were used to report the number of participants with pre-defined adverse drug reactions (ADR). ADRs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1. | Adverse drug reactions were assessed in the Baseline Analysis Set. | Posted | Count of Participants | Participants | Baseline up to end of observation period (18 months) |
|
|
|
| 98 |
| 2,644 |
| 0 |
| 0 |
| 0 |
| 0 |
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|
| Minor |
|
| Gastrointestinal bleeding event |
|
| Epidural or subdural haematoma bleeding event |
|
| Intra-ocular bleeding event |
|
| Intra-articular bleeding event |
|
| Pleural bleeding event |
|
| Other bleeding event |
|
| Spontaneous bleeding |
|
| Provoked bleeding |
|
| Unknown bleeding |
|
| Title | Measurements |
|---|---|
|
| All-cause death |
|
| Cardiovascular-related death |
|
| Venous thromboembolism-related death |
|
| Stroke |
|
| Systemic embolic event |
|
| Hospitalization related to CV |
|
| Title | Measurements |
|---|---|
|
| Recurrent PE only |
|
| All-cause death |
|
| CV-related death |
|
| VTE-related death |
|
| Stroke |
|
| Systemic embolic event |
|
| Hospitalization-related to cardiovascular |
|
| Title | Measurements |
|---|---|
|
| Pulmonary embolism only |
|
|
| Pulmonary embolism only |
|
| Title | Measurements |
|---|---|
|
| Pulmonary embolism only |
|
|
| Pulmonary embolism only |
|
| Title | Measurements |
|---|---|
|
| History of major surgery trauma |
|
| Known thrombophilic conditions |
|
| Title | Measurements |
|---|---|
|
| Month 12 ongoing |
|
| Month 18 ongoing |
|
| Participants off edoxaban treatment at 18 months |
|
| Title | Measurements |
|---|---|
|
| Overall treatment: Unknown events |
|
| On treatment: Total number of stroke events |
|
| On treatment: Ischemic events |
|
| On treatment: Haemorrhagic events |
|
| On treatment: Unknown events |
|
| Title | Measurements |
|---|---|
|
| Study discontinuation due to ADR |
|
| Title | Measurements |
|---|---|
|
| Epistaxis |
|
| Fatigue |
|
| Nausea |
|
| Dizziness |
|
| Rash |
|
| Headache |
|
| Pruritus |
|
| Title | Measurements |
|---|---|
|
| Non-valvular atrial fibrillation |
|
| Malignancy |
|
| Others |
|