Atrial Fibrillation
Conditions
Brief summary
There are insufficient data on the safety and efficacy of edoxaban therapy in subjects with AF following catheter ablation. This phase 3b study is designed to evaluate the safety and to explore the efficacy of an edoxaban-based antithrombotic regimen versus a VKA-based antithrombotic regimen in subjects with AF following catheter ablation. Bleeding is a central safety outcome in cardiovascular clinical trials, especially for antithrombotic strategies and invasive procedures.
Interventions
DRUGEdoxaban
Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects.
Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, United Kingdom (UK), Taiwan and Korea.
Sponsors
Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female at least 18 years of age with documented history of paroxysmal (lasting ≤7 days), persistent (lasting \>7 days but ≤12 months) or long-standing \[long-lasting\] persistent (\>12 months) non-valvular AF. Duration of AF can be confirmed by any electrical tracing or a recording in the subject's medical records (e.g., medical chart, hospital discharge summary). * Subject is eligible and is scheduled for either radio frequency (RF) or cryoballoon catheter ablation (both first and repeated procedure included). * Signed informed consent form (ICF).
Exclusion criteria
* AF considered to be of a transient or reversible nature (such as in myocarditis, post-surgery, ionic disturbances, thyrotoxicosis, pneumonia, severe anemia etc.). * Subject post stroke, or with a systemic thromboembolic event within the past 6 months prior to randomization. * Subject has a thrombus in the left atrial appendage (LAA), left atrium (LA), left ventricle (LV), or aorta, or an intracardial mass. * Subject had a myocardial infarction (MI) within the 2 months prior to randomization or coronary artery bypass graft (CABG) surgery within 3 months prior to the randomization. * Subject has signs of bleeding, history of clinically-relevant bleeding according to International Society on Thrombosis and Hemostasis (ISTH), or conditions associated with high risk of bleeding * Subjects with any contraindication for anticoagulant agents.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced the Composite of All-cause Death, Stroke (VARC-2), and Major Bleeding (ISTH) in the Edoxaban Group Compared With Vitamin K Antagonist (VKA) Group in Participants Undergoing Catheter Ablation (Adjudicated Data) | Day 1 to Day 90 | Stroke (ischemic, hemorrhagic, or undetermined) was defined by Valve Academic Research Consortium-2 (VARC-2) as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury following hemorrhage or infarction. A stroke event was based on any of the following: duration of neurological dysfunction \>24 hours (h), duration of neurological dysfunction \<24 h in case of imaging-documented new hemorrhage or infarction, and a neurological dysfunction resulting in death. Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of \>2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability. |
| Number of Participants Who Experienced Major Bleeding (International Society on Thrombosis and Hemostasis [ISTH]) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data) | Day 1 to Day 90 | Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of \>2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced the Composite of All-cause Death, Stroke (Alternative), and Major Bleeding (ISTH) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data) | Day 1 to Day 90 | An alternative definition characterized stroke (ischemic, hemorrhagic, or undetermined) as an abrupt onset, over minutes to hours, of a focal neurological deficit in the distribution of a single brain artery that was not due to an identifiable nonvascular cause (ie, brain tumor or trauma), and that either lasted at least 24 hours or resulted in death within 24 hours of onset. Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of \>2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability. |
| Number of Participants Who Experienced the Composite of Stroke (VARC-2), Systemic Embolic Events (SEE), and Cardiovascular (CV) Mortality in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data) | Day 1 to Day 90 | Stroke (ischemic, hemorrhagic, or undetermined) was defined by Valve Academic Research Consortium-2 (VARC-2) as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury following hemorrhage or infarction. A stroke event was based on any of the following: duration of neurological dysfunction \>24 hours (h), duration of neurological dysfunction \<24 h in case of imaging-documented new hemorrhage or infarction, and a neurological dysfunction resulting in death. SEE was defined as an arterial embolism resulting in clinical ischemia, excluding the central nervous system, coronary, and pulmonary arterial circulation. CV mortality was defined as cardiac or vascular death according to Academic Research Consortium. |
Countries
Belgium, Canada, Czechia, Germany, Hungary, Italy, Poland, South Korea, Spain, Taiwan, United Kingdom
Participant flow
Recruitment details
A total of 614 participants who met the inclusion and none of the exclusion criteria were randomized; 602 received study drug.
Pre-assignment details
Participants were required to have completed between 21 to 28 days of anticoagulation with study treatment prior to the catheter ablation visit/periprocedural visit (Day 0).
Participants by arm
| Arm | Count |
|---|---|
| Edoxaban-based Regimen Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period.
Edoxaban: Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects. | 405 |
| VKA-based Regimen VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen)
VKA-Based Regimen: Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, United Kingdon (UK), Taiwan and Korea.
VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Germany, Belgium, and the Netherlands.
VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in France.
VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Spain. | 197 |
| Total | 602 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 28 | 6 |
| Overall Study | Other | 10 | 8 |
| Overall Study | Physician Decision | 1 | 4 |
| Overall Study | Withdrawal by Subject | 7 | 5 |
Baseline characteristics
| Characteristic | Edoxaban-based Regimen | VKA-based Regimen | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 143 Participants | 67 Participants | 210 Participants |
| Age, Categorical Between 18 and 65 years | 262 Participants | 130 Participants | 392 Participants |
| Age, Continuous | 59.5 years STANDARD_DEVIATION 10.2 | 59.6 years STANDARD_DEVIATION 10 | 59.5 years STANDARD_DEVIATION 10.1 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Belgium | 5 participants | 4 participants | 9 participants |
| Region of Enrollment Canada | 35 participants | 18 participants | 53 participants |
| Region of Enrollment Czechia | 74 participants | 35 participants | 109 participants |
| Region of Enrollment Germany | 28 participants | 16 participants | 44 participants |
| Region of Enrollment Hungary | 52 participants | 23 participants | 75 participants |
| Region of Enrollment Italy | 42 participants | 21 participants | 63 participants |
| Region of Enrollment Poland | 54 participants | 24 participants | 78 participants |
| Region of Enrollment South Korea | 28 participants | 11 participants | 39 participants |
| Region of Enrollment Spain | 22 participants | 11 participants | 33 participants |
| Region of Enrollment Taiwan | 25 participants | 14 participants | 39 participants |
| Region of Enrollment United Kingdom | 40 participants | 20 participants | 60 participants |
| Sex: Female, Male Female | 118 Participants | 51 Participants | 169 Participants |
| Sex: Female, Male Male | 287 Participants | 146 Participants | 433 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 405 | 0 / 197 |
| other Total, other adverse events | 210 / 405 | 99 / 197 |
| serious Total, serious adverse events | 40 / 405 | 15 / 197 |
Outcome results
Primary
Number of Participants Who Experienced Major Bleeding (International Society on Thrombosis and Hemostasis [ISTH]) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data)
Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of \>2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability.
Time frame: Day 1 to Day 90
Population: Major bleeding was assessed in the modified Intent-to-Treat (mITT) Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban-based Regimen | Number of Participants Who Experienced Major Bleeding (International Society on Thrombosis and Hemostasis [ISTH]) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data) | 10 Participants |
| VKA-based Regimen | Number of Participants Who Experienced Major Bleeding (International Society on Thrombosis and Hemostasis [ISTH]) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data) | 3 Participants |
Primary
Number of Participants Who Experienced the Composite of All-cause Death, Stroke (VARC-2), and Major Bleeding (ISTH) in the Edoxaban Group Compared With Vitamin K Antagonist (VKA) Group in Participants Undergoing Catheter Ablation (Adjudicated Data)
Stroke (ischemic, hemorrhagic, or undetermined) was defined by Valve Academic Research Consortium-2 (VARC-2) as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury following hemorrhage or infarction. A stroke event was based on any of the following: duration of neurological dysfunction \>24 hours (h), duration of neurological dysfunction \<24 h in case of imaging-documented new hemorrhage or infarction, and a neurological dysfunction resulting in death. Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of \>2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability.
Time frame: Day 1 to Day 90
Population: The composite of all-cause death, stroke (VARC-2), and major bleeding (ISTH) was assessed in the Per Protocol (PP) Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban-based Regimen | Number of Participants Who Experienced the Composite of All-cause Death, Stroke (VARC-2), and Major Bleeding (ISTH) in the Edoxaban Group Compared With Vitamin K Antagonist (VKA) Group in Participants Undergoing Catheter Ablation (Adjudicated Data) | 1 Participants |
| VKA-based Regimen | Number of Participants Who Experienced the Composite of All-cause Death, Stroke (VARC-2), and Major Bleeding (ISTH) in the Edoxaban Group Compared With Vitamin K Antagonist (VKA) Group in Participants Undergoing Catheter Ablation (Adjudicated Data) | 2 Participants |
Secondary
Number of Participants Who Experienced the Composite of All-cause Death, Stroke (Alternative), and Major Bleeding (ISTH) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data)
An alternative definition characterized stroke (ischemic, hemorrhagic, or undetermined) as an abrupt onset, over minutes to hours, of a focal neurological deficit in the distribution of a single brain artery that was not due to an identifiable nonvascular cause (ie, brain tumor or trauma), and that either lasted at least 24 hours or resulted in death within 24 hours of onset. Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of \>2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability.
Time frame: Day 1 to Day 90
Population: The composite of all-cause death, stroke (alternative), and major bleeding (ISTH) was assessed in the PP Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban-based Regimen | Number of Participants Who Experienced the Composite of All-cause Death, Stroke (Alternative), and Major Bleeding (ISTH) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data) | 1 Participants |
| VKA-based Regimen | Number of Participants Who Experienced the Composite of All-cause Death, Stroke (Alternative), and Major Bleeding (ISTH) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data) | 2 Participants |
Secondary
Number of Participants Who Experienced the Composite of Stroke (VARC-2), Systemic Embolic Events (SEE), and Cardiovascular (CV) Mortality in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data)
Stroke (ischemic, hemorrhagic, or undetermined) was defined by Valve Academic Research Consortium-2 (VARC-2) as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury following hemorrhage or infarction. A stroke event was based on any of the following: duration of neurological dysfunction \>24 hours (h), duration of neurological dysfunction \<24 h in case of imaging-documented new hemorrhage or infarction, and a neurological dysfunction resulting in death. SEE was defined as an arterial embolism resulting in clinical ischemia, excluding the central nervous system, coronary, and pulmonary arterial circulation. CV mortality was defined as cardiac or vascular death according to Academic Research Consortium.
Time frame: Day 1 to Day 90
Population: The composite of stroke (VARC-2), systemic embolic events (SEE), and cardiovascular (CV) mortality was assessed in the PP Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Edoxaban-based Regimen | Number of Participants Who Experienced the Composite of Stroke (VARC-2), Systemic Embolic Events (SEE), and Cardiovascular (CV) Mortality in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data) | 1 Participants |
| VKA-based Regimen | Number of Participants Who Experienced the Composite of Stroke (VARC-2), Systemic Embolic Events (SEE), and Cardiovascular (CV) Mortality in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data) | 0 Participants |