Atrial Fibrillation, Stroke
Conditions
Brief summary
The primary objective of this trial is to demonstrate the efficacy and safety of dabigatran etexilate in patients with non-valvular atrial fibrillation for the prevention of stroke and systemic embolism.
Interventions
Sponsors
Population Health Research Institute
Uppsala University
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients with non-valvular atrial fibrillation (AF), at moderate to high risk of stroke, or systemic embolism with at least one additional risk factor (i.e. previous ischemic stroke, TIA, or systemic embolism, left ventricular dysfunction, age \>=75 years, age \>=65 with either diabetes mellitus, history of coronary artery disease or hypertension)
Exclusion criteria
1. Prosthetic heart valves requiring anticoagulation per se, or hemodynamically relevant valve disease that is expected to require surgical intervention during the course of the study 2. Severe, disabling stroke within the previous 6 months, or any stroke within the previous 14 days 3. Conditions associated with an increased risk of bleeding 4. Contraindication to warfarin treatment 5. Reversible causes of atrial fibrillation (e.g., cardiac surgery, pulmonary embolism, untreated hyperthyroidism). 6. Plan to perform a pulmonary vein ablation or surgery for cure of the AF 7. Severe renal impairment (estimated creatinine clearance \<=30 mL/min) 8. Active infective endocarditis 9. Active liver disease 10. Women who are pregnant, lactating, or of childbearing potential who refuse to use a medically acceptable form of contraception throughout the study 11. Anaemia (haemoglobin \<100g/L) or thrombocytopenia (platelet count \<100 x 109/L) 12. Patients who have developed transaminase elevations upon exposure to ximelagatran 13. Patients who have received an investigational drug in the past 30 days or are participating in another drug study 14. Patients considered unreliable by the investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration, has a life expectancy less than the expected duration of the trial due to concomitant disease, or has any condition which in the opinion of the investigator, would not allow safe participation in the study (e.g., drug addiction, alcohol abuse) 15. Any known hypersensitivity to galactose if the warfarin used contains galactose.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Yearly Event Rate for Composite Endpoint of Stroke/SEE | 36 months | Time to first occurrence of stroke or systemic embolic event. Yearly event rate (%) = number of subjects with event / subject-years \* 100. Subject years = sum(date of study termination - date of randomization + 1) of all randomized subjects / 365.25 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Yearly Event Rate for Composite Endpoint of Stroke/SEE/All Cause Death | 36 months | Time to first occurrence of stroke, SEE or all cause death. Yearly event rate (%) = number of subjects with event / subject-years \* 100. Subject years = sum(date of study termination - date of randomization + 1) of all randomized subjects / 365.25 |
| Yearly Event Rate: Composite of Stroke/SEE/PE/MI/Vascular Death | 36 months | Time to first occurrence of stroke, systemic embolic event, pulmonary embolism, myocardial infarction including silent myocardial infarction or vascular death. Yearly event rate (%) = number of subjects with event / subject-years \* 100. Subject years = sum(date of study termination - date of randomization + 1) of all randomized subjects / 365.25 |
| Bleeding Events (Major and Minor) | 36 months | Yearly event rate of bleeds. Yearly event rate (%) = number of subjects with event / subject-years \* 100. Subject years = sum(date of study termination - date of randomization + 1) of all randomized subjects / 365.25 Major bleeds are adjudicated, whereas minor bleeds are investigator reported. |
| Clinical Relevant Abnormalities for Intracerebral Hemorrhage and Other Intracranial Hemorrhage (ICH) | 36 months | Patients with clinical relevant abnormalities for intracerebral hemorrhage, other intracranial hemorrhage (ICH) |
| Abnormal Liver Function Test | 36 months | Number of subjects with abnormal liver function test (LFT), i.e., ALT/AST\>3xULN and total bilirubin \> 2 x ULN |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, Norway, Peru, Philippines, Poland, Portugal, Romania, Russia, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dabigatran 110 mg 110 mg twice daily, total daily dose 220 mg | 6,015 |
| Dabigatran 150 mg 150 mg twice daily, total daily dose 300 mg | 6,076 |
| Warfarin Target International Normalized Ratio (INR) of 2.0 to 3.0 | 6,022 |
| Total | 18,113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 17 | 31 | 41 |
| Overall Study | Not Treated | 32 | 17 | 24 |
| Overall Study | Other | 58 | 59 | 62 |
| Overall Study | Withdrawal by Subject | 128 | 145 | 139 |
Baseline characteristics
| Characteristic | Dabigatran 150 mg | Total | Dabigatran 110 mg | Warfarin |
|---|---|---|---|---|
| Age, Continuous | 71.5 years STANDARD_DEVIATION 8.8 | 71.5 years STANDARD_DEVIATION 8.7 | 71.4 years STANDARD_DEVIATION 8.6 | 71.6 years STANDARD_DEVIATION 8.6 |
| Age, Customized <65 | 1030 Participants | 2981 Participants | 998 Participants | 953 Participants |
| Age, Customized 65<= and <75 | 2580 Participants | 7894 Participants | 2668 Participants | 2646 Participants |
| Age, Customized >=75 | 2466 Participants | 7238 Participants | 2349 Participants | 2423 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 416 Participants | 1244 Participants | 421 Participants | 407 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5660 Participants | 16868 Participants | 5593 Participants | 5615 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 965 participants | 2875 participants | 955 participants | 955 participants |
| Race/Ethnicity, Customized Black | 57 participants | 176 participants | 52 participants | 67 participants |
| Race/Ethnicity, Customized Missing | 0 participants | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Other | 786 participants | 2382 participants | 799 participants | 797 participants |
| Race/Ethnicity, Customized White | 4268 participants | 12679 participants | 4208 participants | 4203 participants |
| Region of Enrollment Asia | 933 participants | 2782 participants | 923 participants | 926 participants |
| Region of Enrollment Central Europe | 706 participants | 2119 participants | 707 participants | 706 participants |
| Region of Enrollment Latin America | 320 participants | 956 participants | 320 participants | 316 participants |
| Region of Enrollment Other | 362 participants | 1072 participants | 355 participants | 355 participants |
| Region of Enrollment USA, Canada | 2200 participants | 6533 participants | 2166 participants | 2167 participants |
| Region of Enrollment Western Europe | 1555 participants | 4651 participants | 1544 participants | 1552 participants |
| Regular Alcohol Consumption Missing | 0 participants | 3 participants | 2 participants | 1 participants |
| Regular Alcohol Consumption No | 4077 participants | 12134 participants | 4017 participants | 4040 participants |
| Regular Alcohol Consumption Yes | 1999 participants | 5976 participants | 1996 participants | 1981 participants |
| Sex/Gender, Customized Female | 2236 participants | 6598 participants | 2149 participants | 2213 participants |
| Sex/Gender, Customized Male | 3840 participants | 11514 participants | 3865 participants | 3809 participants |
| Sex/Gender, Customized Missing | 0 participants | 1 participants | 1 participants | 0 participants |
| Smoking history Ex-smoker | 2636 participants | 7836 participants | 2633 participants | 2567 participants |
| Smoking history Missing | 0 participants | 2 participants | 1 participants | 1 participants |
| Smoking history Non-smoker | 2993 participants | 8940 participants | 2941 participants | 3006 participants |
| Smoking history Smoker | 447 participants | 1335 participants | 440 participants | 448 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 | 2,286 / 5,983 | 2,273 / 6,059 | 2,118 / 5,998 |
| serious Total, serious adverse events | 1,263 / 5,983 | 1,289 / 6,059 | 1,357 / 5,998 |
Outcome results
Primary
Yearly Event Rate for Composite Endpoint of Stroke/SEE
Time to first occurrence of stroke or systemic embolic event. Yearly event rate (%) = number of subjects with event / subject-years \* 100. Subject years = sum(date of study termination - date of randomization + 1) of all randomized subjects / 365.25
Time frame: 36 months
Population: Randomized set - The randomized set includes all randomized subjects in the treatment groups to which they were randomized, regardless of whether the subjects took randomized study medication or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Yearly Event Rate for Composite Endpoint of Stroke/SEE | 1.54 yearly event rate (percentage) |
| Dabigatran 150 mg | Yearly Event Rate for Composite Endpoint of Stroke/SEE | 1.11 yearly event rate (percentage) |
| Warfarin | Yearly Event Rate for Composite Endpoint of Stroke/SEE | 1.71 yearly event rate (percentage) |
Comparison: Non-inferiority comparison of dabigatran 110 mg to warfarinp-value: <0.000195% CI: [0.74, 1.1]Regression, Cox
Comparison: Non-inferiority comparison of dabigatran 150 mg to warfarinp-value: <0.000195% CI: [0.52, 0.81]Regression, Cox
Secondary
Abnormal Liver Function Test
Number of subjects with abnormal liver function test (LFT), i.e., ALT/AST\>3xULN and total bilirubin \> 2 x ULN
Time frame: 36 months
Population: Safety set - all subjects who were randomized and received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Abnormal Liver Function Test | 11 participants |
| Dabigatran 150 mg | Abnormal Liver Function Test | 14 participants |
| Warfarin | Abnormal Liver Function Test | 21 participants |
Secondary
Bleeding Events (Major and Minor)
Yearly event rate of bleeds. Yearly event rate (%) = number of subjects with event / subject-years \* 100. Subject years = sum(date of study termination - date of randomization + 1) of all randomized subjects / 365.25 Major bleeds are adjudicated, whereas minor bleeds are investigator reported.
Time frame: 36 months
Population: Randomized set - The randomized set includes all randomized subjects in the treatment groups to which they were randomized, regardless of whether the subjects took randomized study medication or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabigatran 110 mg | Bleeding Events (Major and Minor) | Major bleeds | 2.99 yearly event rate (percentage) |
| Dabigatran 110 mg | Bleeding Events (Major and Minor) | Minor bleeds | 13.16 yearly event rate (percentage) |
| Dabigatran 150 mg | Bleeding Events (Major and Minor) | Major bleeds | 3.55 yearly event rate (percentage) |
| Dabigatran 150 mg | Bleeding Events (Major and Minor) | Minor bleeds | 14.85 yearly event rate (percentage) |
| Warfarin | Bleeding Events (Major and Minor) | Minor bleeds | 16.37 yearly event rate (percentage) |
| Warfarin | Bleeding Events (Major and Minor) | Major bleeds | 3.81 yearly event rate (percentage) |
Comparison: Analysis is for adjudicated major bleedsp-value: 0.002695% CI: [0.7, 0.93]Regression, Cox
Comparison: Analysis is for adjudicated major bleedsp-value: 0.314695% CI: [0.81, 1.07]Regression, Cox
Secondary
Clinical Relevant Abnormalities for Intracerebral Hemorrhage and Other Intracranial Hemorrhage (ICH)
Patients with clinical relevant abnormalities for intracerebral hemorrhage, other intracranial hemorrhage (ICH)
Time frame: 36 months
Population: Randomized set - The randomized set includes all randomized subjects in the treatment groups to which they were randomized, regardless of whether the subjects took randomized study medication or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabigatran 110 mg | Clinical Relevant Abnormalities for Intracerebral Hemorrhage and Other Intracranial Hemorrhage (ICH) | intracerebral hemorrhage | 0.12 yearly event rate (percentage)] |
| Dabigatran 110 mg | Clinical Relevant Abnormalities for Intracerebral Hemorrhage and Other Intracranial Hemorrhage (ICH) | intracranial hemorrhage (ICH) | 0.23 yearly event rate (percentage)] |
| Dabigatran 150 mg | Clinical Relevant Abnormalities for Intracerebral Hemorrhage and Other Intracranial Hemorrhage (ICH) | intracerebral hemorrhage | 0.10 yearly event rate (percentage)] |
| Dabigatran 150 mg | Clinical Relevant Abnormalities for Intracerebral Hemorrhage and Other Intracranial Hemorrhage (ICH) | intracranial hemorrhage (ICH) | 0.32 yearly event rate (percentage)] |
| Warfarin | Clinical Relevant Abnormalities for Intracerebral Hemorrhage and Other Intracranial Hemorrhage (ICH) | intracerebral hemorrhage | 0.38 yearly event rate (percentage)] |
| Warfarin | Clinical Relevant Abnormalities for Intracerebral Hemorrhage and Other Intracranial Hemorrhage (ICH) | intracranial hemorrhage (ICH) | 0.76 yearly event rate (percentage)] |
Comparison: Analysis of ICHp-value: <0.000195% CI: [0.19, 0.45]Regression, Cox
Comparison: Analysis of ICHp-value: <0.000195% CI: [0.28, 0.6]Regression, Cox
Secondary
Yearly Event Rate: Composite of Stroke/SEE/PE/MI/Vascular Death
Time to first occurrence of stroke, systemic embolic event, pulmonary embolism, myocardial infarction including silent myocardial infarction or vascular death. Yearly event rate (%) = number of subjects with event / subject-years \* 100. Subject years = sum(date of study termination - date of randomization + 1) of all randomized subjects / 365.25
Time frame: 36 months
Population: Randomized set - The randomized set includes all randomized subjects in the treatment groups to which they were randomized, regardless of whether the subjects took randomized study medication or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Yearly Event Rate: Composite of Stroke/SEE/PE/MI/Vascular Death | 4.26 yearly event rate (percentage) |
| Dabigatran 150 mg | Yearly Event Rate: Composite of Stroke/SEE/PE/MI/Vascular Death | 3.68 yearly event rate (percentage) |
| Warfarin | Yearly Event Rate: Composite of Stroke/SEE/PE/MI/Vascular Death | 4.35 yearly event rate (percentage) |
p-value: 0.750895% CI: [0.87, 1.11]Regression, Cox
p-value: 0.009395% CI: [0.74, 0.96]Regression, Cox
Secondary
Yearly Event Rate for Composite Endpoint of Stroke/SEE/All Cause Death
Time to first occurrence of stroke, SEE or all cause death. Yearly event rate (%) = number of subjects with event / subject-years \* 100. Subject years = sum(date of study termination - date of randomization + 1) of all randomized subjects / 365.25
Time frame: 36 months
Population: Randomized set - The randomized set includes all randomized subjects in the treatment groups to which they were randomized, regardless of whether the subjects took randomized study medication or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Yearly Event Rate for Composite Endpoint of Stroke/SEE/All Cause Death | 4.85 yearly event rate (percentage) |
| Dabigatran 150 mg | Yearly Event Rate for Composite Endpoint of Stroke/SEE/All Cause Death | 4.32 yearly event rate (percentage) |
| Warfarin | Yearly Event Rate for Composite Endpoint of Stroke/SEE/All Cause Death | 5.20 yearly event rate (percentage) |
p-value: 0.220695% CI: [0.83, 1.04]Regression, Cox
p-value: 0.001595% CI: [0.74, 0.93]Regression, Cox