Secondary Prevention, Stroke
Conditions
Brief summary
This trial will enroll approximately 6,000 patients with recent embolic stroke of unknown source (ESUS). Patients will be randomized to dabigatran or acetylsalicyclic acid (ASA) (1:1 ratio) and have visits every three months. The study doctor may prescribe blinded concomitant ASA for pts with coronary artery disease but this is not mandatory. All Adverse Events (AEs), Serious Adverse Events (SAEs), outcome events will be recorded. The trial will conclude when the required number of stroke events are positively adjudicated which is estimated to take 3 years (including 2.5 years of enrollment).
Interventions
DRUGoptional ASA as comedication
optional concomitant treatment which can be used for patients with coronary artery disease. It is not required for these pts.
DRUGplacebo to ASA
placebo to comparator drug
DRUGplacebo to optional ASA as comedication
optional concomitant treatment which can be used for patients with coronary artery disease. It is not required for these pts.
DRUGplacebo to dabigatran etexilate
placebo
DRUGASA 100 mg
active comparator drug
DRUGdabigatran etexilate
active drug
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 150 Years
Healthy volunteers
No
Inclusion criteria
* Ischemic stroke with a brain lesion visualized by neuroimaging (either brain Computed Tomography (CT) or Magnetic Resonance Image (MRI)). The visualized stroke is a non-lacunar infarct , e.g. involving the cortex or \>1.5 cm (\>2.0 cm if measured on MRI diffusion-weighted images) in largest diameter if exclusively subcortical.Visualization by CT usually requires delayed imaging \>24-48 hours after stroke onset. * The index stroke must have occurred either up to 3 months before randomization (Modified Rankin Scale(mRS) \<=3 at randomization) or up to 6 months before randomization (mRS \<=3 at randomization) in selected patients that are \>= 60 years plus at least one additional risk factor for recurrent stroke. * Arterial imaging or cervical plus Transcranial Doppler (TCD) ultrasonography does not show extra-cranial or intracranial atherosclerosis with \>= 50% luminal stenosis in artery supplying the area of acute ischemia. * As evidenced by cardiac monitoring for \>= 20 hours with automated rhythm detection, there is absence of AF \> 6 minutes in duration (within a 20 hour period, either as single episode or cumulative time of multiple episodes). Further inclusion criteria apply.
Exclusion criteria
* Modified Rankin Scale of \>=4 at time of randomization or inability to swallow medications. * Major risk cardioembolic source of embolism such as: a) intracardiac thrombus as evidenced by transthoracic or transesophageal echocardiography, b) paroxysmal, persistent or permanent Atrial fibrillation (AF), c) atrial flutter, d) prosthetic cardiac valve (mitral or aortic, bioprosthetic or mechanical), e) atrial myxoma, f) other cardiac tumors, g) moderate or severe mitral stenosis, h) recent (\< 4weeks) myocardial infarction, i) valvular vegetations, or j) infective endocarditis. * Any indication that requires treatment with an anticoagulant as per Investigator's judgment. * History of atrial fibrillation (unless it was due to reversible causes such as hyperthyroidism or binge drinking, and has been permanently resolved). * Other specific stroke etiology (i.e. cerebral arteritis or arterial dissection, migraine with aura/vasospasm, drug abuse). * Renal impairment with estimated creatinine clearance (as calculated by Cockcroft-Gault equation) \<30mL/min at screening, or where Investigator expects creatinine clearance is likely to drop below 30mL/min during the course of the study. Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjudicated Recurrent Stroke | From randomisation until full follow up period, approximately 43 months. | Adjudicated recurrent stroke (ischemic, hemorrhagic, or unspecified) is presented. The annualised event rate represents the average number of events per patient during a 1-year period. |
| First Major Bleed (Adjudicated) | Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months. | First major bleed is primary safety endpoint. Major bleeds were defined according to the International Society of Thrombosis and Haemostasis (ISTH) definition as follows: * Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or, * Bleeding (which should be overt) associated with a reduction in haemoglobin of at least 2 grams/ decilitre (g/dL) (1.24 millimoles Per Litre (mmol/L)), or leading to transfusion of ≥2 units of blood or packed cells (equivalent to ≥4.5 units in Japan); the haemoglobin drop should be considered to be due to and temporally related to the bleeding event and/or, * Fatal bleed. The annualised event rate represents the average number of events per patient during a 1-year period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disabling Stroke | From randomisation until full follow up period, up to 43 months | Disabling stroke (modified Rankin Scale greater than or equal to 4, as determined 3 months after recurrent stroke) is presented. The annualised event rate represents the average number of events per patient during a 1-year period. |
| All-cause Death | From randomisation until full follow up period, up to 43 months | All-cause death is presented. The annualised event rate represents the average number of events per patient during a 1-year period. |
| Adjudicated Intracranial Hemorrhage | Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months. | Adjudicated intracranial haemorrhage comprised the subtypes of intracerebral bleeds, intraventricular bleeds, subdural bleeds, epidural bleeds, and subarachnoid bleeds. Microbleeds did not qualify as intracranial haemorrhage, except when they were symptomatic. The annualised event rate represents the average number of events per patient during a 1-year period. |
| Adjudicated Ischaemic Stroke | From randomisation until full follow up period, up to 43 months | Adjudicated ischaemic stroke is a key secondary endpoint. The annualised event rate represents the average number of events per patient during a 1-year period. |
| Adjudicated Life-threatening Bleed | Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months. | Major bleeds were to be classified as life-threatening if they met one or more of the following criteria: fatal bleed, symptomatic intracranial bleed, reduction in haemoglobin of at least 5 grams/ deciliter (g/dL), transfusion of at least 4 units of packed red blood cells (equivalent to 9 units in Japan), associated with hypotension requiring the use of intravenous inotropic agents, or necessitated surgical intervention. The annualised event rate represents the average number of events per patient during a 1-year period. |
| Any Bleed (Investigator-reported) | Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months. | This was the sum of all major and minor bleeds (Minor bleeds were clinical bleeds that did not fulfil the criteria for major bleeds), regardless of severity. The annualised event rate represents the average number of events per patient during a 1-year period. |
| Adjudicated Fatal Bleed | Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months. | Adjudicated fatal bleeding was defined as a bleeding event which the Independent Event Adjudication Committee (IAC) determined as the primary cause of death or contributed directly to death. The annualised event rate represents the average number of events per patient during a 1-year period. Because there were 0 events in one treatment group, the hazard ratio is unable to be calculated. |
| Adjudicated Composite of Non-fatal Stroke, Non-fatal Myocardial Infarction, or Cardiovascular Death | From randomisation until full follow up period, up to 43 months | Adjudicated composite of non-fatal stroke, non-fatal myocardial infarction (MI), or cardiovascular death is a key secondary endpoint. The annualised event rate represents the average number of events per patient during a 1-year period. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, Colombia, Croatia, Czechia, Estonia, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Japan, Malaysia, Mexico, New Zealand, Peru, Poland, Portugal, Russia, Serbia, Singapore, Slovakia, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
This was randomised, active comparator, double-blind, 2 arms (1:1 ratio) event-driven Phase III trial in participants with embolic stroke of undetermined source (ESUS). Study was conducted at multiple centers in 42 countries between 3 Dec 2014 (first participant enrollment) and 14 August 2018 (last participant visit).
Pre-assignment details
All participants were screened for eligibility to participate in the trial. Participants attended specialist sites which would then ensured that all participants met all inclusion/exclusion criteria. Participants were not to be randomized to trial treatment if any one of the specific entry criteria were not met.
Participants by arm
| Arm | Count |
|---|---|
| Dabigatran Etexilate 110 or 150 Milligram (mg) Participants were orally administered one 110 mg (for participants aged ≥75 years or with a creatinine clearance (CrCl) of 30 to \<50 millilitre/ minute (mL/min)) or one 150 mg (for participants aged \<75 years and with a CrCl of ≥50 mL/minute) Dabigatran etexilate (DE) capsule twice daily. | 2,695 |
| Acetylsalicylic Acid, Aspirin (ASA) 100 mg Participants were orally administered one 100 mg Aspirin non-enteric coated tablet once daily. | 2,695 |
| Total | 5,390 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 56 | 58 |
| Overall Study | Lost to Follow-up | 19 | 14 |
Baseline characteristics
| Characteristic | Acetylsalicylic Acid, Aspirin (ASA) 100 mg | Total | Dabigatran Etexilate 110 or 150 Milligram (mg) |
|---|---|---|---|
| Age, Continuous | 63.9 Years STANDARD_DEVIATION 11.39 | 64.2 Years STANDARD_DEVIATION 11.42 | 64.5 Years STANDARD_DEVIATION 11.44 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 268 Participants | 549 Participants | 281 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2371 Participants | 4725 Participants | 2354 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 56 Participants | 116 Participants | 60 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 20 Participants | 31 Participants | 11 Participants |
| Race (NIH/OMB) Asian | 597 Participants | 1228 Participants | 631 Participants |
| Race (NIH/OMB) Black or African American | 40 Participants | 94 Participants | 54 Participants |
| Race (NIH/OMB) More than one race | 12 Participants | 22 Participants | 10 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 56 Participants | 117 Participants | 61 Participants |
| Race (NIH/OMB) White | 1966 Participants | 3892 Participants | 1926 Participants |
| Sex: Female, Male Female | 986 Participants | 1987 Participants | 1001 Participants |
| Sex: Female, Male Male | 1709 Participants | 3403 Participants | 1694 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 56 / 2,695 | 58 / 2,695 |
| other Total, other adverse events | 306 / 2,676 | 295 / 2,674 |
| serious Total, serious adverse events | 724 / 2,676 | 740 / 2,674 |
Outcome results
Primary
Adjudicated Recurrent Stroke
Adjudicated recurrent stroke (ischemic, hemorrhagic, or unspecified) is presented. The annualised event rate represents the average number of events per patient during a 1-year period.
Time frame: From randomisation until full follow up period, approximately 43 months.
Population: Randomised set (RS): RS consisted of all participants who were randomised, regardless of whether they took trial medication. The start date of the observation period for this population was the date of randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 110 or 150 Milligram (mg) | Adjudicated Recurrent Stroke | 4.09 Annualised event rate (%/ year) |
| Acetylsalicylic Acid, Aspirin (ASA) 100 mg | Adjudicated Recurrent Stroke | 4.80 Annualised event rate (%/ year) |
p-value: 0.102895% CI: [0.69, 1.03]Regression, Cox
Primary
First Major Bleed (Adjudicated)
First major bleed is primary safety endpoint. Major bleeds were defined according to the International Society of Thrombosis and Haemostasis (ISTH) definition as follows: * Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or, * Bleeding (which should be overt) associated with a reduction in haemoglobin of at least 2 grams/ decilitre (g/dL) (1.24 millimoles Per Litre (mmol/L)), or leading to transfusion of ≥2 units of blood or packed cells (equivalent to ≥4.5 units in Japan); the haemoglobin drop should be considered to be due to and temporally related to the bleeding event and/or, * Fatal bleed. The annualised event rate represents the average number of events per patient during a 1-year period.
Time frame: Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months.
Population: Treated set (TS): TS consisted of all patients who were treated with at least 1 dose of trial medication. The start date of the observation period for this population was the date of first intake of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 110 or 150 Milligram (mg) | First Major Bleed (Adjudicated) | 1.84 Annualised event rate (%/ year) |
| Acetylsalicylic Acid, Aspirin (ASA) 100 mg | First Major Bleed (Adjudicated) | 1.33 Annualised event rate (%/ year) |
p-value: 0.107695% CI: [0.94, 1.97]Regression, Cox
Secondary
Adjudicated Composite of Non-fatal Stroke, Non-fatal Myocardial Infarction, or Cardiovascular Death
Adjudicated composite of non-fatal stroke, non-fatal myocardial infarction (MI), or cardiovascular death is a key secondary endpoint. The annualised event rate represents the average number of events per patient during a 1-year period.
Time frame: From randomisation until full follow up period, up to 43 months
Population: RS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 110 or 150 Milligram (mg) | Adjudicated Composite of Non-fatal Stroke, Non-fatal Myocardial Infarction, or Cardiovascular Death | 4.80 Annualised event rate (%/ year) |
| Acetylsalicylic Acid, Aspirin (ASA) 100 mg | Adjudicated Composite of Non-fatal Stroke, Non-fatal Myocardial Infarction, or Cardiovascular Death | 5.40 Annualised event rate (%/ year) |
p-value: 0.191195% CI: [0.73, 1.06]Regression, Cox
Secondary
Adjudicated Fatal Bleed
Adjudicated fatal bleeding was defined as a bleeding event which the Independent Event Adjudication Committee (IAC) determined as the primary cause of death or contributed directly to death. The annualised event rate represents the average number of events per patient during a 1-year period. Because there were 0 events in one treatment group, the hazard ratio is unable to be calculated.
Time frame: Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months.
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 110 or 150 Milligram (mg) | Adjudicated Fatal Bleed | 0.00 Annualised event rate (%/ year) |
| Acetylsalicylic Acid, Aspirin (ASA) 100 mg | Adjudicated Fatal Bleed | 0.05 Annualised event rate (%/ year) |
Secondary
Adjudicated Intracranial Hemorrhage
Adjudicated intracranial haemorrhage comprised the subtypes of intracerebral bleeds, intraventricular bleeds, subdural bleeds, epidural bleeds, and subarachnoid bleeds. Microbleeds did not qualify as intracranial haemorrhage, except when they were symptomatic. The annualised event rate represents the average number of events per patient during a 1-year period.
Time frame: Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months.
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 110 or 150 Milligram (mg) | Adjudicated Intracranial Hemorrhage | 0.67 Annualised event rate (%/ year) |
| Acetylsalicylic Acid, Aspirin (ASA) 100 mg | Adjudicated Intracranial Hemorrhage | 0.63 Annualised event rate (%/ year) |
p-value: 0.906495% CI: [0.58, 1.83]Regression, Cox
Secondary
Adjudicated Ischaemic Stroke
Adjudicated ischaemic stroke is a key secondary endpoint. The annualised event rate represents the average number of events per patient during a 1-year period.
Time frame: From randomisation until full follow up period, up to 43 months
Population: RS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 110 or 150 Milligram (mg) | Adjudicated Ischaemic Stroke | 3.97 Annualised event rate (%/ year) |
| Acetylsalicylic Acid, Aspirin (ASA) 100 mg | Adjudicated Ischaemic Stroke | 4.71 Annualised event rate (%/ year) |
p-value: 0.089295% CI: [0.68, 1.03]Regression, Cox
Secondary
Adjudicated Life-threatening Bleed
Major bleeds were to be classified as life-threatening if they met one or more of the following criteria: fatal bleed, symptomatic intracranial bleed, reduction in haemoglobin of at least 5 grams/ deciliter (g/dL), transfusion of at least 4 units of packed red blood cells (equivalent to 9 units in Japan), associated with hypotension requiring the use of intravenous inotropic agents, or necessitated surgical intervention. The annualised event rate represents the average number of events per patient during a 1-year period.
Time frame: Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months.
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 110 or 150 Milligram (mg) | Adjudicated Life-threatening Bleed | 0.76 Annualised event rate (%/ year) |
| Acetylsalicylic Acid, Aspirin (ASA) 100 mg | Adjudicated Life-threatening Bleed | 0.91 Annualised event rate (%/ year) |
p-value: 0.435295% CI: [0.49, 1.36]Regression, Cox
Secondary
All-cause Death
All-cause death is presented. The annualised event rate represents the average number of events per patient during a 1-year period.
Time frame: From randomisation until full follow up period, up to 43 months
Population: RS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 110 or 150 Milligram (mg) | All-cause Death | 1.24 Annualised event rate (%/ year) |
| Acetylsalicylic Acid, Aspirin (ASA) 100 mg | All-cause Death | 1.28 Annualised event rate (%/ year) |
p-value: 0.807495% CI: [0.66, 1.38]Regression, Cox
Secondary
Any Bleed (Investigator-reported)
This was the sum of all major and minor bleeds (Minor bleeds were clinical bleeds that did not fulfil the criteria for major bleeds), regardless of severity. The annualised event rate represents the average number of events per patient during a 1-year period.
Time frame: Between the first trial medication intake up to 6 days after the last trial medication intake, approximately 42 months.
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 110 or 150 Milligram (mg) | Any Bleed (Investigator-reported) | 15.21 Annualised event rate (%/ year) |
| Acetylsalicylic Acid, Aspirin (ASA) 100 mg | Any Bleed (Investigator-reported) | 11.64 Annualised event rate (%/ year) |
p-value: 0.000395% CI: [1.12, 1.47]Regression, Cox
Secondary
Disabling Stroke
Disabling stroke (modified Rankin Scale greater than or equal to 4, as determined 3 months after recurrent stroke) is presented. The annualised event rate represents the average number of events per patient during a 1-year period.
Time frame: From randomisation until full follow up period, up to 43 months
Population: RS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 110 or 150 Milligram (mg) | Disabling Stroke | 0.55 Annualised event rate (%/ year) |
| Acetylsalicylic Acid, Aspirin (ASA) 100 mg | Disabling Stroke | 0.93 Annualised event rate (%/ year) |
p-value: 0.035495% CI: [0.36, 0.96]Regression, Cox