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Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation (ENVISAGE-TAVI AF)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02943785
Recruitment Status : Completed
First Posted : October 25, 2016
Results First Posted : March 24, 2022
Last Update Posted : March 24, 2022
Sponsor:
Collaborator:
Chiltern International Inc.
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

Brief Summary:

When the upper chambers of a person's heart receive or generate irregular electrical signals, it causes abnormal rhythm in the heartbeat. This is called atrial fibrillation.

Atrial fibrillation goes along with blood clots that may cause mainly strokes and less often other diseases, such as a heart attack. Some patients with atrial fibrillation have other heart disease, such as heart valves that may need to be replaced using catheters.

Often doctors give patients drugs that reduce those blood clots. These are either vitamin K antagonist (VKA) or direct anticoagulants, such as edoxaban. In these patients, it is unclear which of the drugs is better for reducing stroke without increasing severe bleedings.


Condition or disease Intervention/treatment Phase
Atrial Fibrillation Drug: Edoxaban-based Regimen Drug: VKA-based Regimen Phase 3

Detailed Description:

Use of Edoxaban in patients with atrial fibrillation (AF) and indication to chronic oral anticoagulation (OAC) after transcatheter aortic valve implantation (TAVI)

Objective:

  • To assess the effect of Edoxaban versus vitamin K antagonist (VKA) on net adverse clinical events (NACE), i.e., the composite of all-cause death, myocardial infarction (MI), ischemic stroke, systemic thromboembolism (SEE), valve thrombosis, and major bleeding (International Society on Thrombosis and Haemostasis [ISTH] definition).
  • To assess the effect of Edoxaban versus VKA on major bleeding (ISTH definition).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1426 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Edoxaban Versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation (TAVI) - in Atrial Fibrillation
Actual Study Start Date : March 21, 2017
Actual Primary Completion Date : February 28, 2021
Actual Study Completion Date : February 28, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Edoxaban

Arm Intervention/treatment
Experimental: Edoxaban-based Regimen
Edoxaban-based regimen 60 mg and 30 mg film coated tablet for once-daily oral use, and 15 mg film coated tablet in case of transitioning at the end of treatment. Dosing must follow the locally approved label.
Drug: Edoxaban-based Regimen
15 mg, 30 mg and 60 mg film coated tablet for oral use (with anti-platelet therapy pre-declared at randomization if prescribed)
Other Names:
  • Savaysa
  • Lixiana

Active Comparator: VKA-based Regimen
VKA-based regimen oral VKA tablets as selected and provided by the site and used in accordance with the local label. The Investigator will monitor the patient and adjust the VKA dose to maintain the dose within target.
Drug: VKA-based Regimen
Dosed at International Normalized Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in the country location (with anti-platelet therapy pre-declared at randomization if prescribed).




Primary Outcome Measures :
  1. Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on ISTH Criteria in Participants Taking Edoxaban vs VKA [ Time Frame: Baseline through study completion, up to 36 months post-dose ]
    The composite endpoint net adverse clinical events (NACE) included all-cause death, myocardial infarction (MI), ischemic stroke, systemic embolic events (SEE), valve thrombosis, and major bleeding per definition of the International Society on Thrombosis and Haemostasis (ISTH].

  2. Number of Participants Who Experienced Major Bleeding (Adjudicated Data) Based on ISTH Criteria in Participants Taking Edoxaban vs VKA [ Time Frame: Baseline through study completion, up to 36 months post-dose ]
    ISTH Bleeding Criteria for Major Bleeding are defined as clinically overt bleeding that is associated with: a fall in hemoglobin of 2 g/dL (1.24 mmol/L) or more, or a transfusion of 2 or more units of whole blood or packed red blood cells, or symptomatic bleeding into a critical site or organ such as intracranial, intraspinal, intraocular, retroperitoneal, pericardial, intra-articular, or intramuscular with compartment syndrome, or a fatal outcome.


Secondary Outcome Measures :
  1. Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on TIMI Criteria in Participants Taking Edoxaban vs VKA [ Time Frame: Baseline through study completion, up to 36 months post-dose ]
    The composite endpoint of net adverse event clinical events (NACE) included all-cause death, myocardial infarction (MI), ischemic stroke, systemic embolic events (SEE), valve thrombosis, and major bleeding based on Thrombolysis in Myocardial Infarction (TIMI) criteria. Bleeding by TIMI criteria was defined as the following: (1) Major, any intracranial hemorrhage or any clinically overt bleeding, (including bleeding evident in imaging studies) associated with a fall of hemoglobin (Hb) of ≥ 5g/dL or fatal bleeding and (2) Minor, any clinically overt bleeding associated with a fall in Hb ≥ 3g/dL but < 5 g/dL.

  2. Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on BARC Type 3 or 5 Criteria in Participants Taking Edoxaban vs VKA [ Time Frame: Baseline through study completion, up to 36 months post-dose ]
    The composite endpoint of net adverse event clinical events (NACE) included all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major bleeding based on Bleeding Academic Research Consortium (BARC) Type 3 or 5 criteria. Major bleeding by BARC criteria was defined as Type 3: clinical, laboratory, and/or imaging evidence of bleeding with provider responses; Type 3a: any transfusion with overt bleeding; overt bleeding plus Hb drop of 3 to < 5 g/dL; Type 3b: overt bleeding plus Hb drop ≥ 5 g/dL; cardiac tamponade; bleeding requiring surgical intervention; bleeding requiring intravenous vasoactive drugs; Type 3c: intracranial hemorrhage; subcategories confirmed by autopsy, imaging, or lumbar puncture; intraocular bleed compromising vision; Type 5: fatal bleeding; Type 5a: probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious; Type 5b: definite fatal bleeding; overt bleeding or autopsy or imaging confirmation

  3. Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on GUSTO Criteria in Participants Taking Edoxaban vs VKA [ Time Frame: Baseline through study completion, up to 36 months post-dose ]
    The composite endpoint of net adverse event clinical events (NACE) included all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major bleeding based on Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO). GUSTO criteria was defined as the following: severe or life threatening: intracerebral hemorrhage or resulting in substantial hemodynamic compromise requiring treatment and moderate: requiring blood transfusion but not resulting in hemodynamic compromise.

  4. Number of Participants Who Experienced Major Adverse Cardiac Events (MACE) in Participants Taking Edoxaban vs VKA (Adjudicated Data) [ Time Frame: Baseline through study completion, up to 36 months post-dose ]
    Major adverse cardiac events (MACE) is defined as the composite of all-cause death (excluding adjudicated non-cardiac death), MI, or repeat coronary revascularization of the target lesion.

  5. Number of Participants Who Experienced Major Adverse Cardiac and Cerebrovascular Events (MACCE) in Participants Taking Edoxaban vs VKA (Adjudicated Data) [ Time Frame: Baseline through study completion, up to 36 months post-dose ]
    Major adverse cardiac and cerebrovascular events (MACCE) is defined as the composite of all-cause death (excluding adjudicated non-cardiac death), MI, stroke (ischemic, hemorrhagic, or undetermined), or repeat coronary revascularization of the target lesion

  6. Number of Participants Who Experienced a Composite of Adverse Events in Participants Taking Edoxaban vs VKA (Adjudicated Data) [ Time Frame: Baseline through study completion, up to 36 months post-dose ]
    A composite of clinical adverse events included cardiovascular death, MI ischemic stroke, SEE, valve thrombosis, and major bleeding as defined by ISTH criteria.

  7. Number of Participants Who Experienced Stroke Events (Ischemic, Hemorrhagic, Undetermined) in Participants Taking Edoxaban vs VKA (Adjudicated Data) [ Time Frame: Baseline through study completion, up to 36 months post-dose ]
    Stroke events are categorized as any stroke, fatal stroke, and non-fatal stroke.

  8. Number of Participants Who Experienced Systemic Embolic Events in Participants Taking Edoxaban vs VKA (Adjudicated Data) [ Time Frame: Baseline through study completion, up to 36 months post-dose ]
    Systemic thromboembolism [non-central nervous system] is defined as abrupt vascular insufficiency of an extremity or organ associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms, (e.g., trauma, atherosclerosis, instrumentation).

  9. Number of Participants Who Experienced Myocardial Infarctions (MI) in Participants Taking Edoxaban vs VKA (Adjudicated Data) [ Time Frame: Baseline through study completion, up to 36 months post-dose ]
    Peri-procedural MI was defined as new ischemic symptoms or signs and elevated cardiac biomarkers within 72 hours after index procedure, consisting of at least one sample post-procedure with a peak value exceeding 15x as the upper reference limit (URL) for troponin or 5x for CK-MB. Spontaneous MI is defined as any one of the following: Detection of rise and/or fall of cardiac biomarkers with at least one value above the 99th percentile URL, together with the evidence of myocardial ischemia with at least one of the following: Symptoms of ischemia; ECG changes indicative of new ischemia; New pathological Q-waves in at least two contiguous leads; Imaging evidence of a new loss of viable myocardium or new wall motion abnormality; Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive of myocardial ischemia, and accompanied by new ST elevation or new left bundle branch block, and/or evidence of fresh thrombus; Pathological findings of an acute MI.

  10. Number of Participants Who Experienced Valve Thrombosis in Participants Taking Edoxaban vs VKA (Adjudicated Data) [ Time Frame: Baseline through study completion, up to 36 months post-dose ]
    Valve thrombosis was defined as any thrombus attached to or near an implanted valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently large to warrant treatment.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Meets protocol-specified criteria for qualification and contraception
  • Is willing and able to comply with any restrictions related food, drink and medications
  • Voluntarily consents to participate and provides written informed consent prior to any protocol-specific procedures

Exclusion Criteria:

  • Has history or current use of over-the-counter medications, dietary supplements, or drugs (including nicotine and alcohol) outside protocol-specified parameters
  • Has signs, symptoms or history of any condition that, per protocol or in the opinion of the investigator, might compromise:

    1. the safety or well-being of the participant or study staff
    2. the safety or well-being of the participant's offspring (such as through pregnancy or breast-feeding)
    3. the analysis of results

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02943785


Locations
Show Show 230 study locations
Sponsors and Collaborators
Daiichi Sankyo, Inc.
Chiltern International Inc.
Investigators
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Study Director: Global Clinical Leader Daiichi Sankyo, Inc.
  Study Documents (Full-Text)

Documents provided by Daiichi Sankyo, Inc.:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT02943785    
Other Study ID Numbers: DU176B-C-U4001
2016-003930-26 ( EudraCT Number )
First Posted: October 25, 2016    Key Record Dates
Results First Posted: March 24, 2022
Last Update Posted: March 24, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
URL: https://vivli.org/ourmember/daiichi-sankyo/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Daiichi Sankyo, Inc.:
Transcatheter Aortic Valve Implantation -- TAVI
Anticoagulation
Atrial Fibrillation
ENVISAGE-TAVI-AF
Additional relevant MeSH terms:
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Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Edoxaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants