Atrial Fibrillation, Embolism, Stroke
Conditions
Keywords
Systemic embolic events
Brief summary
This study is to demonstrate the safety and efficacy profile, in two different dose regimens of Edoxaban (DU-176b), (an investigational new drug being tested for the prevention of stroke/systemic embolic events (SEE)), in individuals with atrial fibrillation. Patients will be randomized to one of three treatment groups: High Dose Regimen, Low Dose Regimen, & Warfarin. The expected duration of the study is 24 months.
Interventions
DRUGwarfarin tablets
Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months
DRUGEdoxaban tablets (high dose regimen-60mg)
Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months
DRUGEdoxaban tablets (low dose regimen-30mg)
Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months
DRUGplacebo warfarin
placebo warfarin
DRUGplacebo edoxaban
placebo edoxaban
Sponsors
The TIMI Study Group
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 21 years of age or older; male or female. * Able to provide written informed consent. * History of documented AF within the prior 12 months * A moderate to high risk of stroke, as defined by CHADS2 index score of at least 2
Exclusion criteria
* Transient atrial fibrillation secondary to other reversible disorders * Subjects with moderate or severe mitral stenosis, unresected atrial myxoma, or a mechanical heart valve * Subjects with any contraindication for anticoagulant agents; * Subjects with conditions associated with high risk of bleeding or have known or suspected hereditary or acquired bleeding disorders * Females of childbearing potential including the following: * Females with a history of tubal-ligation * Females less than 2 years post-menopausal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | on-treatment period 2.5 years of median study drug exposure and 2.8 year of median follow-up | The composite of stroke and Systemic Embolic Events (SEE) during the on treatment period in the mITT analysis population with a non-inferiority analysis. |
| Compare Edoxaban to Warfarin for Superiority for Composite of Stroke and Systemic Embolic Events (SEE). | overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up | Compare edoxaban to warfarin for the composite of stroke and Systemic Embolic Events (SEE) during the overall study period in the ITT analysis set with a superiority analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Compare Edoxaban to Warfarin for Composite of Stroke, Systemic Embolic Event (SEE), and Cardiovascular (CV) Mortality | overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up | Compare edoxaban to warfarin for the composite of stroke, Systemic Embolic Events, and Cardiovascular mortality during the overall study period in the ITT analysis set. |
| Compare Edoxaban to Warfarin for Major Adverse Cardiac Event (MACE): a Composite of Non-fatal MI, Non-fatal Stroke, Non-fatal SEE, and Death Due to CV Cause or Bleeding | overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up | Compare edoxaban to warfarin for Major Adverse Cardiac Event (MACE): a composite of non-fatal Myocardial Infarction, non-fatal stroke, non-fatal Systemic Embolic Events, and death due to Cardiovascular cause or bleeding during the overall study period in the ITT analysis set. |
| Compare Edoxaban to Warfarin for Composite of Stroke, SEE, and All-cause Mortality | overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up | Compare Edoxaban to warfarin for Composite of stroke, Systemic Embolic Events, and all-cause mortality during the overall study period in the ITT analysis set. |
| Adjudicated Bleeding Events | on-treatment period 2.5 years of median study drug exposure and 2.8 year of median follow-up | Compare edoxaban versus warfarin for Adjudicated Bleeding Events during the on-treatment period in the Safety Analysis set. Major bleeding was adjudicated by the Clinical Events Committee (CEC) and defined based on published guidance from the International Society on Thrombosis and Haemostasis (ISTH), with minor modifications for Hgb decrease and blood transfusion requirements. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Guatemala, Hungary, India, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Norway, Peru, Philippines, Poland, Portugal, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Warfarin/Placebo Edoxaban Warfarin tablets plus placebo Edoxaban tablets
warfarin tablets: Warfarin tablets plus Edoxaban placebo tablets each taken once daily for 24 months
placebo edoxaban: placebo edoxaban | 7,012 |
| High Dose Edoxaban/Placebo Warfarin Edoxaban tablets plus warfarin placebo tablets
60mg Edoxaban tablets (high dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months
placebo warfarin: placebo warfarin | 7,012 |
| Low Dose Edoxaban/Placebo Warfarin Edoxaban tablets plus warfarin placebo tablets
30mg Edoxaban tablets (low dose regimen): Edoxaban tablets plus warfarin placebo tablets each taken once daily for 24 months
placebo warfarin: placebo warfarin | 7,002 |
| Total | 21,026 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 789 | 730 | 706 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | never received study drug | 24 | 23 | 32 |
| Overall Study | Protocol Violation | 19 | 17 | 20 |
| Overall Study | Withdrawal by Subject | 47 | 37 | 25 |
Baseline characteristics
| Characteristic | Low Dose Edoxaban/Placebo Warfarin | Total | High Dose Edoxaban/Placebo Warfarin | Warfarin/Placebo Edoxaban |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5218 Participants | 15543 Participants | 5182 Participants | 5143 Participants |
| Age, Categorical Between 18 and 65 years | 1784 Participants | 5483 Participants | 1830 Participants | 1869 Participants |
| Age, Continuous | 70.6 years STANDARD_DEVIATION 9.31 | 70.6 years STANDARD_DEVIATION 9.42 | 70.6 years STANDARD_DEVIATION 9.51 | 70.5 years STANDARD_DEVIATION 9.44 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 975 Participants | 2894 Participants | 956 Participants | 963 Participants |
| Race (NIH/OMB) Black or African American | 94 Participants | 278 Participants | 96 Participants | 88 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 283 Participants | 846 Participants | 281 Participants | 282 Participants |
| Race (NIH/OMB) White | 5650 Participants | 17008 Participants | 5679 Participants | 5679 Participants |
| Region of Enrollment Argentina | 362 participants | 1059 participants | 345 participants | 352 participants |
| Region of Enrollment Australia | 32 participants | 102 participants | 40 participants | 30 participants |
| Region of Enrollment Belgium | 64 participants | 149 participants | 44 participants | 41 participants |
| Region of Enrollment Brazil | 225 participants | 703 participants | 242 participants | 236 participants |
| Region of Enrollment Bulgaria | 165 participants | 518 participants | 174 participants | 179 participants |
| Region of Enrollment Canada | 242 participants | 772 participants | 271 participants | 259 participants |
| Region of Enrollment Chile | 88 participants | 253 participants | 91 participants | 74 participants |
| Region of Enrollment China | 152 participants | 465 participants | 150 participants | 163 participants |
| Region of Enrollment Colombia | 48 participants | 141 participants | 42 participants | 51 participants |
| Region of Enrollment Croatia | 39 participants | 125 participants | 33 participants | 53 participants |
| Region of Enrollment Czech Republic | 386 participants | 1165 participants | 369 participants | 410 participants |
| Region of Enrollment Denmark | 70 participants | 218 participants | 80 participants | 68 participants |
| Region of Enrollment Estonia | 60 participants | 191 participants | 55 participants | 76 participants |
| Region of Enrollment Finland | 15 participants | 42 participants | 18 participants | 9 participants |
| Region of Enrollment France | 32 participants | 110 participants | 38 participants | 40 participants |
| Region of Enrollment Germany | 307 participants | 908 participants | 293 participants | 308 participants |
| Region of Enrollment Greece | 9 participants | 50 participants | 27 participants | 14 participants |
| Region of Enrollment Guatemala | 39 participants | 135 participants | 48 participants | 48 participants |
| Region of Enrollment Hungary | 167 participants | 461 participants | 143 participants | 151 participants |
| Region of Enrollment India | 234 participants | 686 participants | 220 participants | 232 participants |
| Region of Enrollment Israel | 88 participants | 280 participants | 88 participants | 104 participants |
| Region of Enrollment Italy | 54 participants | 169 participants | 55 participants | 60 participants |
| Region of Enrollment Japan | 337 participants | 1010 participants | 336 participants | 337 participants |
| Region of Enrollment Korea, Republic of | 78 participants | 226 participants | 84 participants | 64 participants |
| Region of Enrollment Mexico | 60 participants | 190 participants | 70 participants | 60 participants |
| Region of Enrollment Netherlands | 40 participants | 153 participants | 49 participants | 64 participants |
| Region of Enrollment New Zealand | 40 participants | 130 participants | 50 participants | 40 participants |
| Region of Enrollment Norway | 15 participants | 34 participants | 8 participants | 11 participants |
| Region of Enrollment Peru | 60 participants | 170 participants | 46 participants | 64 participants |
| Region of Enrollment Philippines | 45 participants | 124 participants | 36 participants | 43 participants |
| Region of Enrollment Poland | 454 participants | 1273 participants | 424 participants | 395 participants |
| Region of Enrollment Portugal | 61 participants | 178 participants | 71 participants | 46 participants |
| Region of Enrollment Romania | 124 participants | 409 participants | 144 participants | 141 participants |
| Region of Enrollment Russian Federation | 369 participants | 1150 participants | 406 participants | 375 participants |
| Region of Enrollment Serbia | 74 participants | 276 participants | 107 participants | 95 participants |
| Region of Enrollment Slovakia | 129 participants | 405 participants | 133 participants | 143 participants |
| Region of Enrollment South Africa | 90 participants | 279 participants | 92 participants | 97 participants |
| Region of Enrollment Spain | 54 participants | 163 participants | 65 participants | 44 participants |
| Region of Enrollment Sweden | 86 participants | 253 participants | 78 participants | 89 participants |
| Region of Enrollment Switzerland | 4 participants | 5 participants | 1 participants | 0 participants |
| Region of Enrollment Taiwan | 85 participants | 234 participants | 72 participants | 77 participants |
| Region of Enrollment Thailand | 33 participants | 113 participants | 40 participants | 40 participants |
| Region of Enrollment Turkey | 31 participants | 110 participants | 39 participants | 40 participants |
| Region of Enrollment Ukraine | 402 participants | 1148 participants | 386 participants | 360 participants |
| Region of Enrollment United Kingdom | 145 participants | 398 participants | 121 participants | 132 participants |
| Region of Enrollment United States | 1308 participants | 3893 participants | 1288 participants | 1297 participants |
| Sex: Female, Male Female | 2718 Participants | 8006 Participants | 2659 Participants | 2629 Participants |
| Sex: Female, Male Male | 4284 Participants | 13020 Participants | 4353 Participants | 4383 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4,200 / 7,012 | 4,201 / 7,012 | 4,057 / 7,002 |
| serious Total, serious adverse events | 3,581 / 7,012 | 3,393 / 7,012 | 3,448 / 7,002 |
Outcome results
Primary
Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE).
The composite of stroke and Systemic Embolic Events (SEE) during the on treatment period in the mITT analysis population with a non-inferiority analysis.
Time frame: on-treatment period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Population: mITT (modified Intent To Treat) Analysis set; which included randomized subjects who received 1 or more dose of study drug. The time period included the subject was taking study drug and up to 3 days after their last dose (On-Treatment ).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | 253 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | 182 number of participants with event |
| Warfarin/Placebo Edoxaban | Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | 232 number of participants with event |
Comparison: The primary efficacy endpoint, time to the first occurrence of stroke/SEE, was first compared concurrently between each of the 2 edoxaban groups and warfarin group using the mITT Analysis Set in the on-treatment period for non-inferiority. In order to control the study-wise type-I error rate of two-sided α=0.05 for non-inferiority, each of these 2 comparisons were performed at the statistical significance level of two-sided α=0.025, respectively.p-value: <0.000197.5% CI: [0.632, 0.985]Cox proportional hazards model
Comparison: The primary efficacy endpoint, time to the first occurrence of stroke/SEE, was first compared concurrently between each of the 2 edoxaban groups and warfarin group using the mITT Analysis Set in the on-treatment period for non-inferiority. In order to control the study-wise type-I error rate of two-sided α=0.05 for non-inferiority, each of these 2 comparisons were performed at the statistical significance level of two-sided α=0.025, respectively.p-value: 0.005597.5% CI: [0.874, 1.314]Cox proportional hazards model
Primary
Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE).
The composite of stroke and Systemic Embolic Events (SEE) during the overall study period in the mITT analysis population.
Time frame: overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Population: mITT (modified Intent To Treat) Analysis set; which included randomized subjects who received 1 or more dose of study drug. The time frame included overall study period (first dose to end of study).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | 382 Number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | 292 Number of participants with event |
| Warfarin/Placebo Edoxaban | Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | 336 Number of participants with event |
Comparison: Non-inferiority or equivalence analysis; Non-inferiority analysis. The non-inferiority analysis included the mITT and PP analysis sets for both the on treatment and overall study period, although mITT on-treatment was considered primary.p-value: <0.000197.5% CI: [0.719, 1.029]Cox proportional hazards model
Comparison: Non-inferiority or equivalence analysis; Non-inferiority analysis. The non-inferiority analysis included the mITT and PP analysis sets for both the on treatment and overall study period, although mITT on-treatment was considered primary.p-value: 0.007497.5% CI: [0.955, 1.336]Cox proportional hazards model
Primary
Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE).
The composite of stroke and Systemic Embolic Events (SEE) during the on treatment period in the PP (per protocol) analysis set population.
Time frame: on-treatment period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Population: PP (Per Protocol) Analysis set; which included all randomized subjects who received at least 1 dose of randomized study drug and did not have any major protocol violations. The time period included the time the subject was taking study drug and up to 3 days after their last dose (On Treatment Period).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | 253 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | 182 number of participants with event |
| Warfarin/Placebo Edoxaban | Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | 231 number of participants with event |
Comparison: The non-inferiority analysis included the mITT and PP analysis sets for both the on treatment and overall study period, although mITT on-treatment was considered primary.p-value: <0.000197.5% CI: [0.634, 0.989]Cox proportional hazards model
Comparison: The non-inferiority analysis included the mITT and PP analysis sets for both the on treatment and overall study period, although mITT on-treatment was considered primary.p-value: 0.006497.5% CI: [0.878, 1.32]Cox proportional hazards model
Primary
Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE).
The composite of stroke and Systemic Embolic Events (SEE) during the overall study period in the PP (per protocol) analysis set population.
Time frame: overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Population: PP (per Protocol) Analysis set; which included all randomized subjects who received 1 or more dose of study drug for the overall study period (first dose to end of study) and did not have any major protocol violations. The time period included from the reference date (initial dose of study drug date) to the common study end date (CSED) Visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | 382 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | 292 number of participants with event |
| Warfarin/Placebo Edoxaban | Compare Edoxaban to Warfarin for Composite of Stroke and Systemic Embolic Events (SEE). | 335 number of participants with event |
Comparison: The non-inferiority analysis included the mITT and PP analysis sets for both the on-treatment and overall study period, although mITT on-treatment was considered primary.p-value: <0.000197.5% CI: [0.72, 1.032]Cox proportional hazards model
Comparison: The non-inferiority analysis included the mITT and PP analysis sets for both the on-treatment and overall study period, although mITT on-treatment was considered primary.p-value: 0.008497.5% CI: [0.958, 1.34]Cox proportional hazards model
Primary
Compare Edoxaban to Warfarin for Superiority for Composite of Stroke and Systemic Embolic Events (SEE).
Compare edoxaban to warfarin for the composite of stroke and Systemic Embolic Events (SEE) during the overall study period in the ITT analysis set with a superiority analysis.
Time frame: overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Population: ITT (Intent To Treat) Analysis set; which included all randomized subjects whether or not they received a single dose of randomized study drug. The time frame included from reference date (randomization date) to the common study end date (CSED) Visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Superiority for Composite of Stroke and Systemic Embolic Events (SEE). | 383 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Superiority for Composite of Stroke and Systemic Embolic Events (SEE). | 296 number of participants with event |
| Warfarin/Placebo Edoxaban | Compare Edoxaban to Warfarin for Superiority for Composite of Stroke and Systemic Embolic Events (SEE). | 337 number of participants with event |
Comparison: The superiority analysis included the ITT analysis setp-value: 0.08199% CI: [0.709, 1.068]Log Rank
Secondary
Adjudicated Bleeding Events
Compare edoxaban versus warfarin for Adjudicated Bleeding Events during the on-treatment period in the Safety Analysis set. Major bleeding was adjudicated by the Clinical Events Committee (CEC) and defined based on published guidance from the International Society on Thrombosis and Haemostasis (ISTH), with minor modifications for Hgb decrease and blood transfusion requirements.
Time frame: on-treatment period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Population: Safety-analysis set, on-treatment period
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | Non-ICH Major bleed | 214 number of participants with event |
| Low Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | Major bleed | 254 number of participants with event |
| Low Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | ICH Major bleed | 41 number of participants with event |
| Low Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | Fatal bleed | 21 number of participants with event |
| Low Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | non-fatal (Major) bleed | 234 number of participants with event |
| Low Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | life-threatening bleed | 40 number of participants with event |
| Low Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | clinically relevant non-major bleed | 969 number of participants with event |
| Low Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | major or clinically relevant non-major | 1161 number of participants with event |
| Low Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | minor | 533 number of participants with event |
| Low Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | any confirmed bleed | 1499 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | life-threatening bleed | 62 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | Non-ICH Major bleed | 359 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | ICH Major bleed | 61 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | non-fatal (Major) bleed | 386 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | any confirmed bleed | 1865 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | Major bleed | 418 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | minor | 604 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | major or clinically relevant non-major | 1528 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | clinically relevant non-major bleed | 1214 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Adjudicated Bleeding Events | Fatal bleed | 32 number of participants with event |
| Warfarin/Placebo Edoxaban | Adjudicated Bleeding Events | major or clinically relevant non-major | 1761 number of participants with event |
| Warfarin/Placebo Edoxaban | Adjudicated Bleeding Events | Fatal bleed | 59 number of participants with event |
| Warfarin/Placebo Edoxaban | Adjudicated Bleeding Events | any confirmed bleed | 2114 number of participants with event |
| Warfarin/Placebo Edoxaban | Adjudicated Bleeding Events | non-fatal (Major) bleed | 466 number of participants with event |
| Warfarin/Placebo Edoxaban | Adjudicated Bleeding Events | minor | 714 number of participants with event |
| Warfarin/Placebo Edoxaban | Adjudicated Bleeding Events | life-threatening bleed | 122 number of participants with event |
| Warfarin/Placebo Edoxaban | Adjudicated Bleeding Events | clinically relevant non-major bleed | 1396 number of participants with event |
| Warfarin/Placebo Edoxaban | Adjudicated Bleeding Events | ICH Major bleed | 132 number of participants with event |
| Warfarin/Placebo Edoxaban | Adjudicated Bleeding Events | Major bleed | 524 number of participants with event |
| Warfarin/Placebo Edoxaban | Adjudicated Bleeding Events | Non-ICH Major bleed | 398 number of participants with event |
Comparison: All Major Adjudicated Bleeding Events, Safety Analysis Set On-treatment periodp-value: 0.000995% CI: [0.707, 0.914]Regression, Cox
Comparison: All Major Adjudicated Bleeding Events, Safety Analysis Set On-treatment period.~The HR, two-sided CI, and p-value for pairwise comparisons versus Warfarin are based on the Cox regression model with counting process approach for on-treatment including treatment and the two stratification factors as covariates: the dichotomized CHADS2 score and the dichotomized dose-adjustment factorp-value: <0.000195% CI: [0.406, 0.548]Regression, Cox
Comparison: Major or Clinically Relevant Non-Major, high dose vs. warfarinp-value: <0.000195% CI: [0.8, 0.918]Regression, Cox
Comparison: Major or Clinically Relevant Non-Major, low dose vs. warfarinp-value: <0.000195% CI: [0.575, 0.666]Regression, Cox
Secondary
Compare Edoxaban to Warfarin for Composite of Stroke, SEE, and All-cause Mortality
Compare Edoxaban to warfarin for Composite of stroke, Systemic Embolic Events, and all-cause mortality during the overall study period in the ITT analysis set.
Time frame: overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Population: ITT overall study period, which included all randomized subjects whether or not they received a single dose of randomized study drug. The time frame included from the reference date (randomization date) to the common study end date (CSED) Visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Composite of Stroke, SEE, and All-cause Mortality | 985 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Composite of Stroke, SEE, and All-cause Mortality | 949 number of participants with event |
| Warfarin/Placebo Edoxaban | Compare Edoxaban to Warfarin for Composite of Stroke, SEE, and All-cause Mortality | 1046 number of participants with event |
Comparison: the time to first event was estimated by a KM estimate and was compared between the edoxaban 60 mg group and the warfarin group using a log-rank test at a pairwise comparison significance level of α=0.01.p-value: 0.016895% CI: [0.823, 0.981]Log Rank
Secondary
Compare Edoxaban to Warfarin for Composite of Stroke, Systemic Embolic Event (SEE), and Cardiovascular (CV) Mortality
Compare edoxaban to warfarin for the composite of stroke, Systemic Embolic Events, and Cardiovascular mortality during the overall study period in the ITT analysis set.
Time frame: overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Population: ITT (Intent To Treat) Analysis set; overall study period, which included all randomized subjects whether or not they received a single dose of randomized study drug. The time frame included from reference date (randomization date) to the common study end date (CSED) Visit..
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Composite of Stroke, Systemic Embolic Event (SEE), and Cardiovascular (CV) Mortality | 796 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Composite of Stroke, Systemic Embolic Event (SEE), and Cardiovascular (CV) Mortality | 728 number of participants with event |
| Warfarin/Placebo Edoxaban | Compare Edoxaban to Warfarin for Composite of Stroke, Systemic Embolic Event (SEE), and Cardiovascular (CV) Mortality | 831 number of participants with event |
Comparison: the time to first event was estimated by a KM estimate and was compared between the edoxaban 60 mg group and the warfarin group using a log-rank test at a pairwise comparison significance level of α=0.01.p-value: 0.005395% CI: [0.786, 0.959]Log Rank
Secondary
Compare Edoxaban to Warfarin for Major Adverse Cardiac Event (MACE): a Composite of Non-fatal MI, Non-fatal Stroke, Non-fatal SEE, and Death Due to CV Cause or Bleeding
Compare edoxaban to warfarin for Major Adverse Cardiac Event (MACE): a composite of non-fatal Myocardial Infarction, non-fatal stroke, non-fatal Systemic Embolic Events, and death due to Cardiovascular cause or bleeding during the overall study period in the ITT analysis set.
Time frame: overall study period 2.5 years of median study drug exposure and 2.8 year of median follow-up
Population: ITT overall study period, which included all randomized subjects whether or not they received a single dose of randomized study drug. The time frame included from the reference date (randomization date) to the common study end date (CSED) Visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Major Adverse Cardiac Event (MACE): a Composite of Non-fatal MI, Non-fatal Stroke, Non-fatal SEE, and Death Due to CV Cause or Bleeding | 913 number of participants with event |
| High Dose Edoxaban/Placebo Warfarin | Compare Edoxaban to Warfarin for Major Adverse Cardiac Event (MACE): a Composite of Non-fatal MI, Non-fatal Stroke, Non-fatal SEE, and Death Due to CV Cause or Bleeding | 827 number of participants with event |
| Warfarin/Placebo Edoxaban | Compare Edoxaban to Warfarin for Major Adverse Cardiac Event (MACE): a Composite of Non-fatal MI, Non-fatal Stroke, Non-fatal SEE, and Death Due to CV Cause or Bleeding | 926 number of participants with event |
Comparison: the time to first event was estimated by a KM estimate and was compared between the edoxaban 60 mg group and the warfarin group using a log-rank test at a pairwise comparison significance level of α=0.01.p-value: 0.010995% CI: [0.806, 0.972]Log Rank