A Phase 3 interventional study of Edoxaban-based Regimen and VKA-based Regimen in Atrial Fibrillation, sponsored by Daiichi Sankyo. Completed at 230 sites in 14 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-03-24.
Sponsored by Daiichi Sankyo · Phase 3, Interventional, and Treatment
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.
Use of Edoxaban in patients with atrial fibrillation (AF) and indication to chronic oral anticoagulation (OAC) after transcatheter aortic valve implantation (TAVI)
Objective:
3,870 studies on the registry are indexed under Atrial Fibrillation; 924 are open to participants now.
This study's enrollment of 1,426 is above the median of 144 across 2,380 interventional studies indexed under Atrial Fibrillation.
Browse Atrial Fibrillation studies →Daiichi Sankyo is the lead sponsor of 316 studies on the registry; 35 are open to participants now.
Of its 51 completed or terminated interventional studies of FDA-regulated products, 38 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Has signs, symptoms or history of any condition that, per protocol or in the opinion of the investigator, might compromise:
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
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
15 mg, 30 mg and 60 mg film coated tablet for oral use (with anti-platelet therapy pre-declared at randomization if prescribed)
Also known as: Savaysa, Lixiana
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).
Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on ISTH Criteria in Participants Taking Edoxaban vs VKA
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\].
Time frame: Baseline through study completion, up to 36 months post-dose
Number of Participants Who Experienced Major Bleeding (Adjudicated Data) Based on ISTH Criteria in Participants Taking Edoxaban vs VKA
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.
Time frame: Baseline through study completion, up to 36 months post-dose
Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on TIMI Criteria in Participants Taking Edoxaban vs VKA
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.
Time frame: Baseline through study completion, up to 36 months post-dose
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
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
Time frame: Baseline through study completion, up to 36 months post-dose
Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on GUSTO Criteria in Participants Taking Edoxaban vs VKA
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.
Time frame: Baseline through study completion, up to 36 months post-dose
Number of Participants Who Experienced Major Adverse Cardiac Events (MACE) in Participants Taking Edoxaban vs VKA (Adjudicated Data)
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.
Time frame: Baseline through study completion, up to 36 months post-dose
Number of Participants Who Experienced Major Adverse Cardiac and Cerebrovascular Events (MACCE) in Participants Taking Edoxaban vs VKA (Adjudicated Data)
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
Time frame: Baseline through study completion, up to 36 months post-dose
Number of Participants Who Experienced a Composite of Adverse Events in Participants Taking Edoxaban vs VKA (Adjudicated Data)
A composite of clinical adverse events included cardiovascular death, MI ischemic stroke, SEE, valve thrombosis, and major bleeding as defined by ISTH criteria.
Time frame: Baseline through study completion, up to 36 months post-dose
Number of Participants Who Experienced Stroke Events (Ischemic, Hemorrhagic, Undetermined) in Participants Taking Edoxaban vs VKA (Adjudicated Data)
Stroke events are categorized as any stroke, fatal stroke, and non-fatal stroke.
Time frame: Baseline through study completion, up to 36 months post-dose
Number of Participants Who Experienced Systemic Embolic Events in Participants Taking Edoxaban vs VKA (Adjudicated Data)
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).
Time frame: Baseline through study completion, up to 36 months post-dose
Number of Participants Who Experienced Myocardial Infarctions (MI) in Participants Taking Edoxaban vs VKA (Adjudicated Data)
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.
Time frame: Baseline through study completion, up to 36 months post-dose
Number of Participants Who Experienced Valve Thrombosis in Participants Taking Edoxaban vs VKA (Adjudicated Data)
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.
Time frame: Baseline through study completion, up to 36 months post-dose
A total of 1426 participants who met all inclusion criteria and no exclusion criteria were randomized to treatment at 173 clinic sites in Europe, Asia, and North America.
| Milestone | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Started | 713 | 713 |
| Completed | 431 | 350 |
| Not completed | 282 | 363 |
| Withdrew: Adverse event | 112 | 97 |
| Withdrew: Withdrawal by subject | 63 | 126 |
| Withdrew: Physician decision | 23 | 47 |
| Withdrew: Death | 46 | 46 |
| Withdrew: Lost to follow-up | 1 | 0 |
| Withdrew: Other | 16 | 19 |
| Withdrew: Did not receive any study medication | 21 | 28 |
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\].
| Participants | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Number of Participants Who Experienced Net Adverse Clinical Events (Adjudicated Data) Based on ISTH Criteria in Participants Taking Edoxaban vs VKA | 170 | 157 |
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.
| Participants | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Number of Participants Who Experienced Major Bleeding (Adjudicated Data) Based on ISTH Criteria in Participants Taking Edoxaban vs VKA | 98 | 68 |
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.
| Participants | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Composite endpoint NACE (TIMI) | 154 | 141 |
| Composite of major and minor bleeding (TIMI) | 72 | 42 |
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
| Participants | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Composite endpoint NACE (BARC Type 3 or 5) | 164 | 151 |
| Major bleeding (BARC Type 3 or 5) | 89 | 57 |
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.
| Participants | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Composite endpoint NACE (GUSTO) | 160 | 146 |
| Severe or life threatening and moderate bleeding (GUSTO) | 82 | 51 |
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.
| Participants | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Number of Participants Who Experienced Major Adverse Cardiac Events (MACE) in Participants Taking Edoxaban vs VKA (Adjudicated Data) | 61 | 53 |
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
| Participants | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Number of Participants Who Experienced Major Adverse Cardiac and Cerebrovascular Events (MACCE) in Participants Taking Edoxaban vs VKA (Adjudicated Data) | 86 | 80 |
A composite of clinical adverse events included cardiovascular death, MI ischemic stroke, SEE, valve thrombosis, and major bleeding as defined by ISTH criteria.
| Participants | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Number of Participants Who Experienced a Composite of Adverse Events in Participants Taking Edoxaban vs VKA (Adjudicated Data) | 151 | 123 |
Stroke events are categorized as any stroke, fatal stroke, and non-fatal stroke.
| Participants | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Any stroke (ischemic, hemorrhagic, or undetermined) | 29 | 35 |
| Fatal stroke (ischemic, hemorrhagic, or undetermined) | 4 | 3 |
| Non-fatal stroke (ischemic, hemorrhagic, or undetermined) | 25 | 32 |
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).
| Participants | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Number of Participants Who Experienced Systemic Embolic Events in Participants Taking Edoxaban vs VKA (Adjudicated Data) | 2 | 3 |
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.
| Participants | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Number of Participants Who Experienced Myocardial Infarctions (MI) in Participants Taking Edoxaban vs VKA (Adjudicated Data) | 12 | 7 |
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.
| Participants | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Number of Participants Who Experienced Valve Thrombosis in Participants Taking Edoxaban vs VKA (Adjudicated Data) | 0 | 0 |
Collected over Treatment-emergent adverse events were collected from the Safety Analysis Set from baseline up 4 weeks post-discontinuation of study treatment or through study completion, up to 36 months post-dose.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Edoxaban | 83/693 (12%) | 388/693 (56%) | 522/693 (75.3%) |
| Vitamin K Antagonist (VKA) | 78/684 (11.4%) | 372/684 (54.4%) | 429/684 (62.7%) |
| Event | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Cardiac failureCardiac disorders | 57/693 | 64/684 |
| PneumoniaInfections and infestations | 39/693 | 37/684 |
| AnemiaBlood and lymphatic system disorders | 31/693 | 11/684 |
| Cardiac failure congestiveCardiac disorders | 23/693 | 12/684 |
| Urinary tract infectionInfections and infestations | 21/693 | 17/684 |
| Atrial fibrillationCardiac disorders | 17/693 | 18/684 |
| Acute kidney injuryRenal and urinary disorders | 18/693 | 17/684 |
| Lower gastrointestinal haemorrhageGastrointestinal disorders | 16/693 | 7/684 |
| EndocarditisInfections and infestations | 14/693 | 7/684 |
| Respiratory tract infectionInfections and infestations | 7/693 | 13/684 |
| Event | Edoxaban | Vitamin K Antagonist (VKA) |
|---|---|---|
| Cardiac failureCardiac disorders | 78/693 | 85/684 |
| EpistaxisRespiratory, thoracic and mediastinal disorders | 64/693 | 30/684 |
| Urinary tract infectionInfections and infestations | 63/693 | 45/684 |
| AnaemiaBlood and lymphatic system disorders | 62/693 | 40/684 |
| DizzinessNervous system disorders | 47/693 | 33/684 |
| PneumoniaInfections and infestations | 45/693 | 43/684 |
| HaematomaVascular disorders | 26/693 | 41/684 |
| HaematuriaRenal and urinary disorders | 40/693 | 18/684 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 39/693 | 35/684 |
| Atrial fibrillationCardiac disorders | 23/693 | 36/684 |
Patient demographics were assessed in the Intent-to-Treat Analysis Set.
| Age, Continuous(years) | Edoxaban | Vitamin K Antagonist (VKA) | Total |
|---|---|---|---|
| Mean | 82.1 ± 5.4 | 82.1 ± 5.5 | 82.1 ± 5.5 |
| Age, Customized(Participants) | Edoxaban | Vitamin K Antagonist (VKA) | Total |
|---|---|---|---|
| <65 years | 5 | 5 | 10 |
| ≥65 to <75 years | 53 | 55 | 108 |
| ≥75 to <80 years | 131 | 122 | 253 |
| ≥80 to <85 years | 289 | 298 | 587 |
| ≥85 to <90 years | 191 | 183 | 374 |
| ≥90 years | 44 | 50 | 94 |
| Sex: Female, Male(Participants) | Edoxaban | Vitamin K Antagonist (VKA) | Total |
|---|---|---|---|
| Female | 347 | 331 | 678 |
| Male | 366 | 382 | 748 |
| Race (NIH/OMB)(Participants) | Edoxaban | Vitamin K Antagonist (VKA) | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 92 | 89 | 181 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 1 | 4 | 5 |
| White | 593 | 594 | 1187 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 27 | 26 | 53 |
| Region of Enrollment(participants) | Edoxaban | Vitamin K Antagonist (VKA) | Total |
|---|---|---|---|
| United States | 77 | 77 | 154 |
| Japan | 82 | 77 | 159 |
| United Kingdom | 7 | 10 | 17 |
| Switzerland | 17 | 17 | 34 |
| Spain | 172 | 172 | 344 |
| Canada | 8 | 6 | 14 |
| Austria | 30 | 32 | 62 |
| Netherlands | 28 | 27 | 55 |
| South Korea | 9 | 10 | 19 |
| Belgium | 17 | 17 | 34 |
| Poland | 10 | 10 | 20 |
| Italy | 65 | 67 | 132 |
| France | 22 | 24 | 46 |
| Germany | 169 | 167 | 336 |
| Weight(kg) | Edoxaban | Vitamin K Antagonist (VKA) | Total |
|---|---|---|---|
| Mean | 74.6 ± 17.9 | 76.0 ± 17.3 | 75.3 ± 17.6 |
| Body mass index(kg/m^2) | Edoxaban | Vitamin K Antagonist (VKA) | Total |
|---|---|---|---|
| Mean | 27.5 ± 5.7 | 27.9 ± 5.4 | 27.7 ± 5.5 |
| Creatinine Clearance (Cockcroft-Gault formula)(mL/min) | Edoxaban | Vitamin K Antagonist (VKA) | Total |
|---|---|---|---|
| Mean | 57.9 ± 24.0 | 58.6 ± 24.3 | 58.2 ± 24.1 |
6 further baseline measures are reported on the registry.
Showing the first 100 of 230 sites across 14 countries.
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — 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 information: Study protocol, Sap, Csr
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