Atrial Fibrillation
Conditions
Keywords
Nonvalvular atrial fibrillation (NVAF), anti-coagulant, warfarin, edoxaban, electrical cardioversion
Brief summary
The purpose of this study is to compare edoxaban to warfarin (with enoxaparin, if needed). It will see if edoxaban prevents stroke and other blood clotting problems as well and as safely as warfarin. People with atrial fibrillation (irregular heartbeat) might be able to join. Their doctors must plan to use shock to make their hearts beat normally. About 2200 people from different countries will join. They will have an equal chance of receiving either treatment. They are anticipated to be in the study for around 82 days. Tests will include physicals and finger-pricks. Participants will provide blood and urine samples.
Detailed description
The purpose of this study is to compare edoxaban (investigational drug) with warfarin and enoxaparin, to see if it is safe and effective in preventing stroke and other blood clot complications in subjects with atrial fibrillation whose doctors plan to treat them with an electrical cardioversion. It is expected that 284 sites will recruit 2200 subjects from North America, EU, Russia, Ukraine and Israel. Participants will be randomly allocated to receive either treatment with edoxaban, or treatment with warfarin, plus enoxaparin if required. Participants will have an equal chance of receiving either treatment. Participants will be in the study for a maximum of 82 days. Study procedures will include physical examinations, vital signs (pulse and sitting blood pressure), ECG (electrocardiogram), finger prick blood clotting tests, blood samples and urine samples. The study is expected to show that edoxaban will provide comparable incidence rates to warfarin plus enoxaparin, the current standard treatment for both efficacy and bleeding.
Interventions
DRUGEdoxaban
Edoxaban 30 mg tablets for oral administration
DRUGWarfarin
Warfarin tablet, 1.0 or 2.5 mg, for oral administration
DRUGEnoxaparin
Enoxaparin per label, at prescribed dose until PT INR at least 2.0
Sponsors
Daiichi Sankyo
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
* Has signed informed consent * Is older than minimum legal adult age (country specific) * Has had ongoing AF lasting at least 48 hrs but \<= 12 months (with or without valvular heart disease) * Has treatment plan that includes for electrical cardioversion * Has NVAF or other specific valvular heart diseases (eg, mitral valve prolapse, mitral valve regurgitation, and aortic valve disease)
Exclusion criteria
* Has AF that is transient or reversible * Has contraindicated condition, ie, conditions considered to be formal indication for conventional anticoagulation * Has a history of left atrial appendage (LAA) closure * Has a known thrombus in LAA, the left atrial, left ventricle or aorta - or an intracardial mass * Has had myocardial infarction (MI), stroke, acute coronary syndrome (ACS), or percutaneous coronary intervention (PCI) within the past 30 days * Has any contraindication to anticoagulant agents * Has had protocol-defined signs of bleeding or conditions associated with high risk of bleeding that would preclude participation * Is receiving, or plans to receive during the study period, dual antiplatelet therapy (DAPT) or invasive procedures (other than routine endoscopy) in which bleeding would be anticipated * Has received prohibited concomitant medication or therapy * Has had protocol-defined signs of bleeding or high * Has inadequate liver, kidney, and blood test results * Received any investigational drug or device within the past 30 days or plans to during the study period * Has reproductive potential and does not agree to take proper contraceptive measures * Has active cancer requiring chemotherapy/radiation/major surgery within the next 3 months * Has significant active concurrent medical illness or infection or life expectancy less than 6 months * In the opinion of the investigator, is unlikely to comply with the protocol or complete the study, has had drug or alcohol dependence within the past year, or has any other condition that might place the participant at increased risk of harm * Is a participant in the United States after January 2015 with creatinine clearance (CrCL) greater than 95 mL/minute
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Composite Endpoint of Stroke, Systemic Embolic Stroke (SEE), Myocardial Infarction (MI) and Cardiovascular (CV) Mortality From Randomization to End of Follow up | Randomization to end of follow-up (within 2 years) |
| Percentage of Participants With Composite Endpoints of Major and Clinically-relevant Non-major (CRNM) Bleeding | During treatment period (within 2 years) |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Composite Endpoints of Stroke, SEE, MI, CV Mortality, and Major Bleeding | From randomization to the end of follow-up (within 2 years) |
Countries
Austria, Belgium, Bulgaria, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Netherlands, Poland, Romania, Russia, Spain, Sweden, Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Edoxaban Participants randomized to receive Edoxaban | 1,095 |
| Warfarin Participants randomized to receive Warfarin | 1,104 |
| Total | 2,199 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 6 |
| Overall Study | Adverse event, serious fatal | 1 | 6 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 14 | 29 |
| Overall Study | Physician Decision | 5 | 10 |
| Overall Study | Protocol Violation | 10 | 9 |
| Overall Study | Withdrawal by Subject | 17 | 29 |
Baseline characteristics
| Characteristic | Edoxaban | Total | Warfarin |
|---|---|---|---|
| Age, Continuous | 64.3 years STANDARD_DEVIATION 10.34 | 64.2 years STANDARD_DEVIATION 10.54 | 64.2 years STANDARD_DEVIATION 10.75 |
| Age, Customized Age, Categorical <75 years | 923 Participants | 1840 Participants | 917 Participants |
| Age, Customized Age, Categorical ≥75 years | 172 Participants | 359 Participants | 187 Participants |
| Region of Enrollment Austria | 19 participants | 32 participants | 13 participants |
| Region of Enrollment Belgium | 19 participants | 41 participants | 22 participants |
| Region of Enrollment Bulgaria | 70 participants | 125 participants | 55 participants |
| Region of Enrollment Czechia | 86 participants | 173 participants | 87 participants |
| Region of Enrollment Denmark | 26 participants | 57 participants | 31 participants |
| Region of Enrollment France | 26 participants | 39 participants | 13 participants |
| Region of Enrollment Germany | 56 participants | 123 participants | 67 participants |
| Region of Enrollment Hungary | 89 participants | 179 participants | 90 participants |
| Region of Enrollment Israel | 39 participants | 82 participants | 43 participants |
| Region of Enrollment Italy | 34 participants | 69 participants | 35 participants |
| Region of Enrollment Netherlands | 24 participants | 47 participants | 23 participants |
| Region of Enrollment Poland | 21 participants | 54 participants | 33 participants |
| Region of Enrollment Romania | 68 participants | 122 participants | 54 participants |
| Region of Enrollment Russia | 110 participants | 216 participants | 106 participants |
| Region of Enrollment Spain | 73 participants | 142 participants | 69 participants |
| Region of Enrollment Sweden | 7 participants | 14 participants | 7 participants |
| Region of Enrollment Ukraine | 206 participants | 430 participants | 224 participants |
| Region of Enrollment United Kingdom | 76 participants | 159 participants | 83 participants |
| Region of Enrollment United States | 46 participants | 95 participants | 49 participants |
| Sex: Female, Male Female | 374 Participants | 756 Participants | 382 Participants |
| Sex: Female, Male Male | 721 Participants | 1443 Participants | 722 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 1,067 | 5 / 1,082 |
| other Total, other adverse events | 53 / 1,067 | 53 / 1,082 |
| serious Total, serious adverse events | 85 / 1,067 | 83 / 1,082 |
Outcome results
Primary
Percentage of Participants With Composite Endpoint of Stroke, Systemic Embolic Stroke (SEE), Myocardial Infarction (MI) and Cardiovascular (CV) Mortality From Randomization to End of Follow up
Time frame: Randomization to end of follow-up (within 2 years)
Population: This outcome was assessed in the Intent-to-Treat (ITT) Analysis Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Edoxaban | Percentage of Participants With Composite Endpoint of Stroke, Systemic Embolic Stroke (SEE), Myocardial Infarction (MI) and Cardiovascular (CV) Mortality From Randomization to End of Follow up | 0.5 Percentage of participants |
| Warfarin | Percentage of Participants With Composite Endpoint of Stroke, Systemic Embolic Stroke (SEE), Myocardial Infarction (MI) and Cardiovascular (CV) Mortality From Randomization to End of Follow up | 1 Percentage of participants |
95% CI: [0.12, 1.43]
Primary
Percentage of Participants With Composite Endpoints of Major and Clinically-relevant Non-major (CRNM) Bleeding
Time frame: During treatment period (within 2 years)
Population: This outcome was assessed in the Safety Analysis Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Edoxaban | Percentage of Participants With Composite Endpoints of Major and Clinically-relevant Non-major (CRNM) Bleeding | 1.5 Percentage of participants |
| Warfarin | Percentage of Participants With Composite Endpoints of Major and Clinically-relevant Non-major (CRNM) Bleeding | 1 Percentage of participants |
95% CI: [0.64, 3.55]
Secondary
Percentage of Participants With Composite Endpoints of Stroke, SEE, MI, CV Mortality, and Major Bleeding
Time frame: From randomization to the end of follow-up (within 2 years)
Population: This outcome was assessed in the ITT Analysis Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Edoxaban | Percentage of Participants With Composite Endpoints of Stroke, SEE, MI, CV Mortality, and Major Bleeding | 0.7 Percentage of participants |
| Warfarin | Percentage of Participants With Composite Endpoints of Stroke, SEE, MI, CV Mortality, and Major Bleeding | 1.4 Percentage of participants |
95% CI: [-1.59, 0.15]