Coronary Disease
Conditions
Brief summary
The purpose of this trial is to evaluate the safety and indicators of efficacy of up to 4 doses of orally administered dabigatran etexilate, administered twice daily, compared to placebo when given in addition to dual antiplatelet treatment in patients with an index event (MI) at high risk for new ischaemic cardiovascular events.
Interventions
DRUGplacebo
matched placebo
DRUGdabigatran etexilate
capsules, twice daily, 26 weeks treatment
Sponsors
Uppsala University
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients with acute coronary syndromes with at least one additional risk factor for cardiovascular complications.
Exclusion criteria
1. Long term treatment with any other oral anticoagulant 2. Severe/disabling stroke within last 6 months 3. Conditions associated with increased bleeding risk 4. Anaemia or thrombocytopenia 5. Severe renal impairment 6. Liver disease 7. Positive pregnancy test
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Displaying the Composite of Major and Clinically Relevant Minor Bleeding Events During Total Observation Time | 6 month treatment period + 2 week post treatment follow up | International Society Thrombosis and Haemostasis (ISTH) definition of a major bleed, and clinically relevant minor bleed. A bleeding event was considered as major if it was fatal, was a symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome), or caused a fall in haemoglobin level of ≥2 g/dL (≥1.24 mmol/L), or led to transfusion of ≥2 units of whole blood or red cells. All non major bleeding events were classified as minor bleeds; minor bleeds were subdivided in clinically relevant minor bleeds and not clinically relevant minor bleeds. A CRBE was defined as an acute or subacute clinically overt bleed that did not meet the criteria of a major bleed but either lead to hospital admission and/or a physician guided medical or surgical treatment and/or a change in antithrombotic therapy (including interruption or discontinuation of study drug). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | 6 month treatment period + 2 week post treatment follow up | Number of Participants with individual occurrence of death (cardiovascular and all-cause), non-fatal MI, severe recurrent ischaemia and non-haemorrhagic stroke during six months of treatment. |
| Number of Participants With Any Reduction of D-dimer Concentration | at 1 week and 4 weeks | — |
| Composite of Cardiovascular Death (CVD) With Non Fatal Myocardial Infarction (MI) and Non Haemorrhagic Stroke and All Cause Death (ACD), Non Fatal MI, Severe Recurrent Ischaemia (SRI) and Non Haemorrhagic Stroke During Six Months Treatment | 6 month treatment period + 2 week post treatment follow up | Number of Participants with Composite of Cardiovascular death (CVD) with non fatal myocardial infarction (MI) and non haemorrhagic stroke and All cause death (ACD), non fatal MI, severe recurrent ischaemia (SRI) and non haemorrhagic stroke during six months treatment |
| Number of Participants With Bleeding Events During Total Observation Time | 6 month treatment period + 2 week post treatment follow up | International Society Thrombosis and Haemostasis (ISTH) definition of a major bleed, and clinically relevant minor bleed. A bleeding event was considered as major if it was fatal, was a symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome), or caused a fall in haemoglobin level of ≥2 g/dL (≥1.24 mmol/L), or led to transfusion of ≥2 units of whole blood or red cells. All non major bleeding events were classified as minor bleeds; minor bleeds were subdivided in clinically relevant minor bleeds (CRBE) and not clinically relevant minor bleeds. A CRBE was defined as an acute or subacute clinically overt bleed that did not meet the criteria of a major bleed but either lead to hospital admission and/or a physician guided medical or surgical treatment and/or a change in antithrombotic therapy (including interruption or discontinuation of study drug). |
| Laboratory Analyses | 6 month treatment period + 2 week post treatment follow up | Number of patients with possible clinically significant abnormalities. Clinically significant abnormalities refers to the increase or decrease from baseline. |
| Change From Baseline in log10 D-dimer After 1 and 4 Weeks | Baseline and at 1 week and 4 weeks | Change from baseline in log10 D-dimer concentration after 1 and 4 weeks of dabigatran etexilate treatment compared to placebo. The standard deviation is the geometric standard deviation. |
Countries
Belgium, Bulgaria, Canada, Czechia, Denmark, Finland, France, Georgia, Germany, Hungary, India, Ireland, Italy, Netherlands, Norway, Poland, Romania, Russia, South Korea, Spain, Sweden, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
International multi-centre trial with 161 trial sites in 24 countries recruiting patients with acute coronary syndromes with increased troponin levels within 14 days post index myocardial infarction (ST or non-ST elevation between March 2008 and March 2009.
Pre-assignment details
Patients receiving aspirin and clopidogrel at randomisation were included. They also had at least 1 additional risk factor (for e.g. age ≥65 years, diabetes previous myocardial infarction, peripheral arterial disease). Moderate renal impairment at screening resulted in dose adjustment.
Participants by arm
| Arm | Count |
|---|---|
| 50mg Dabigatran Etexilate 26 week blinded treatment | 372 |
| 75mg Dabigatran Etexilate 26 week blinded treatment | 371 |
| 110mg Dabigatran Etexilate 26 week blinded treatment | 411 |
| 150mg Dabigatran Etexilate 26 week blinded treatment | 351 |
| Placebo 26 week blinded treatment | 373 |
| Total | 1,878 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 32 | 31 | 48 | 34 | 31 |
| Overall Study | Lost to Follow-up | 0 | 1 | 3 | 4 | 1 |
| Overall Study | Other | 9 | 7 | 6 | 5 | 4 |
| Overall Study | Patients did not receive study drug | 3 | 3 | 5 | 4 | 2 |
| Overall Study | Protocol Violation | 16 | 8 | 6 | 7 | 8 |
| Overall Study | Withdrawal by Subject | 16 | 11 | 13 | 13 | 9 |
Baseline characteristics
| Characteristic | 75mg Dabigatran Etexilate | Total | Placebo | 150mg Dabigatran Etexilate | 50mg Dabigatran Etexilate | 110mg Dabigatran Etexilate |
|---|---|---|---|---|---|---|
| Age, Continuous | 60.7 Years STANDARD_DEVIATION 11.7 | 61.8 Years STANDARD_DEVIATION 11.4 | 61.5 Years STANDARD_DEVIATION 11.3 | 62.3 Years STANDARD_DEVIATION 10.8 | 61.9 Years STANDARD_DEVIATION 12.2 | 62.3 Years STANDARD_DEVIATION 11.1 |
| Creatinine Clearance N=(372;371;411;350;373;1877) | 88.7 mL/min STANDARD_DEVIATION 32.4 | 86.3 mL/min STANDARD_DEVIATION 31.6 | 86.6 mL/min STANDARD_DEVIATION 34.8 | 86.3 mL/min STANDARD_DEVIATION 28.1 | 85.4 mL/min STANDARD_DEVIATION 30.2 | 84.7 mL/min STANDARD_DEVIATION 32 |
| Race (NIH/OMB) Asian | 102 participants | 424 participants | 105 participants | 51 participants | 84 participants | 82 participants |
| Race (NIH/OMB) Black | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race (NIH/OMB) Other | 1 participants | 6 participants | 0 participants | 0 participants | 0 participants | 5 participants |
| Race (NIH/OMB) White | 267 participants | 1447 participants | 268 participants | 300 participants | 288 participants | 324 participants |
| Region of Enrollment Asia | 99 participants | 419 participants | 104 participants | 51 participants | 84 participants | 81 participants |
| Region of Enrollment Central Europe | 155 participants | 932 participants | 165 participants | 217 participants | 165 participants | 230 participants |
| Region of Enrollment North America | 24 participants | 101 participants | 20 participants | 11 participants | 25 participants | 21 participants |
| Region of Enrollment Western Europe | 93 participants | 426 participants | 84 participants | 72 participants | 98 participants | 79 participants |
| Sex: Female, Male Female | 75 Participants | 450 Participants | 81 Participants | 93 Participants | 84 Participants | 117 Participants |
| Sex: Female, Male Male | 296 Participants | 1428 Participants | 292 Participants | 258 Participants | 288 Participants | 294 Participants |
| Type of Index Event Non ST elevation myocardial infarction (NSTEMI) | 144 participants | 752 participants | 143 participants | 147 participants | 161 participants | 157 participants |
| Type of Index Event ST elevation myocardial infarction (STEMI) | 227 participants | 1126 participants | 230 participants | 204 participants | 211 participants | 254 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 369 | 0 / 368 | 0 / 406 | 0 / 347 | 0 / 371 |
| serious Total, serious adverse events | 33 / 369 | 31 / 368 | 35 / 406 | 21 / 347 | 32 / 371 |
Outcome results
Primary
Number of Participants Displaying the Composite of Major and Clinically Relevant Minor Bleeding Events During Total Observation Time
International Society Thrombosis and Haemostasis (ISTH) definition of a major bleed, and clinically relevant minor bleed. A bleeding event was considered as major if it was fatal, was a symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome), or caused a fall in haemoglobin level of ≥2 g/dL (≥1.24 mmol/L), or led to transfusion of ≥2 units of whole blood or red cells. All non major bleeding events were classified as minor bleeds; minor bleeds were subdivided in clinically relevant minor bleeds and not clinically relevant minor bleeds. A CRBE was defined as an acute or subacute clinically overt bleed that did not meet the criteria of a major bleed but either lead to hospital admission and/or a physician guided medical or surgical treatment and/or a change in antithrombotic therapy (including interruption or discontinuation of study drug).
Time frame: 6 month treatment period + 2 week post treatment follow up
Population: Treated set - The treated set includes all patients who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50mg Dabigatran Etexilate | Number of Participants Displaying the Composite of Major and Clinically Relevant Minor Bleeding Events During Total Observation Time | Major and clinically relevant minor bleed events | 13 participants |
| 50mg Dabigatran Etexilate | Number of Participants Displaying the Composite of Major and Clinically Relevant Minor Bleeding Events During Total Observation Time | No major or clinically relevant minor bleed events | 356 participants |
| 75mg Dabigatran Etexilate | Number of Participants Displaying the Composite of Major and Clinically Relevant Minor Bleeding Events During Total Observation Time | No major or clinically relevant minor bleed events | 352 participants |
| 75mg Dabigatran Etexilate | Number of Participants Displaying the Composite of Major and Clinically Relevant Minor Bleeding Events During Total Observation Time | Major and clinically relevant minor bleed events | 16 participants |
| 110mg Dabigatran Etexilate | Number of Participants Displaying the Composite of Major and Clinically Relevant Minor Bleeding Events During Total Observation Time | Major and clinically relevant minor bleed events | 32 participants |
| 110mg Dabigatran Etexilate | Number of Participants Displaying the Composite of Major and Clinically Relevant Minor Bleeding Events During Total Observation Time | No major or clinically relevant minor bleed events | 374 participants |
| 150mg Dabigatran Etexilate | Number of Participants Displaying the Composite of Major and Clinically Relevant Minor Bleeding Events During Total Observation Time | No major or clinically relevant minor bleed events | 320 participants |
| 150mg Dabigatran Etexilate | Number of Participants Displaying the Composite of Major and Clinically Relevant Minor Bleeding Events During Total Observation Time | Major and clinically relevant minor bleed events | 27 participants |
| Placebo | Number of Participants Displaying the Composite of Major and Clinically Relevant Minor Bleeding Events During Total Observation Time | No major or clinically relevant minor bleed events | 363 participants |
| Placebo | Number of Participants Displaying the Composite of Major and Clinically Relevant Minor Bleeding Events During Total Observation Time | Major and clinically relevant minor bleed events | 8 participants |
Comparison: The proportion of patients who reach this endpoint were analysed by a logistic model for linear trend (dose response).~The null hypothesis is that the relationship between dose level (0mg, 50mg, 75mg, 110mg and 150mg) and the proportions of patients with major and clinically relevant minor bleeding is not linear (slope parameter = 0)p-value: <0.001Cochran-Armitage test for linear trend
Secondary
Change From Baseline in log10 D-dimer After 1 and 4 Weeks
Change from baseline in log10 D-dimer concentration after 1 and 4 weeks of dabigatran etexilate treatment compared to placebo. The standard deviation is the geometric standard deviation.
Time frame: Baseline and at 1 week and 4 weeks
Population: Full Analysis Set (FAS)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50mg Dabigatran Etexilate | Change From Baseline in log10 D-dimer After 1 and 4 Weeks | Ratio of week 4 to baseline | 0.33 ratio | Standard Deviation 3.04 |
| 50mg Dabigatran Etexilate | Change From Baseline in log10 D-dimer After 1 and 4 Weeks | Ratio of week 1 to baseline | 0.58 ratio | Standard Deviation 2.6 |
| 75mg Dabigatran Etexilate | Change From Baseline in log10 D-dimer After 1 and 4 Weeks | Ratio of week 1 to baseline | 0.52 ratio | Standard Deviation 2.81 |
| 75mg Dabigatran Etexilate | Change From Baseline in log10 D-dimer After 1 and 4 Weeks | Ratio of week 4 to baseline | 0.31 ratio | Standard Deviation 3.3 |
| 110mg Dabigatran Etexilate | Change From Baseline in log10 D-dimer After 1 and 4 Weeks | Ratio of week 4 to baseline | 0.29 ratio | Standard Deviation 3.14 |
| 110mg Dabigatran Etexilate | Change From Baseline in log10 D-dimer After 1 and 4 Weeks | Ratio of week 1 to baseline | 0.52 ratio | Standard Deviation 2.54 |
| 150mg Dabigatran Etexilate | Change From Baseline in log10 D-dimer After 1 and 4 Weeks | Ratio of week 1 to baseline | 0.55 ratio | Standard Deviation 2.58 |
| 150mg Dabigatran Etexilate | Change From Baseline in log10 D-dimer After 1 and 4 Weeks | Ratio of week 4 to baseline | 0.31 ratio | Standard Deviation 3.02 |
| Placebo | Change From Baseline in log10 D-dimer After 1 and 4 Weeks | Ratio of week 1 to baseline | 0.87 ratio | Standard Deviation 2.45 |
| Placebo | Change From Baseline in log10 D-dimer After 1 and 4 Weeks | Ratio of week 4 to baseline | 0.57 ratio | Standard Deviation 3.01 |
Secondary
Composite of Cardiovascular Death (CVD) With Non Fatal Myocardial Infarction (MI) and Non Haemorrhagic Stroke and All Cause Death (ACD), Non Fatal MI, Severe Recurrent Ischaemia (SRI) and Non Haemorrhagic Stroke During Six Months Treatment
Number of Participants with Composite of Cardiovascular death (CVD) with non fatal myocardial infarction (MI) and non haemorrhagic stroke and All cause death (ACD), non fatal MI, severe recurrent ischaemia (SRI) and non haemorrhagic stroke during six months treatment
Time frame: 6 month treatment period + 2 week post treatment follow up
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50mg Dabigatran Etexilate | Composite of Cardiovascular Death (CVD) With Non Fatal Myocardial Infarction (MI) and Non Haemorrhagic Stroke and All Cause Death (ACD), Non Fatal MI, Severe Recurrent Ischaemia (SRI) and Non Haemorrhagic Stroke During Six Months Treatment | ACD, non-fatal MI, SRI, non-haemorrhagic stroke | 25 participants |
| 50mg Dabigatran Etexilate | Composite of Cardiovascular Death (CVD) With Non Fatal Myocardial Infarction (MI) and Non Haemorrhagic Stroke and All Cause Death (ACD), Non Fatal MI, Severe Recurrent Ischaemia (SRI) and Non Haemorrhagic Stroke During Six Months Treatment | CVD, non-fatal MI, non-haemorrhagic stroke | 17 participants |
| 75mg Dabigatran Etexilate | Composite of Cardiovascular Death (CVD) With Non Fatal Myocardial Infarction (MI) and Non Haemorrhagic Stroke and All Cause Death (ACD), Non Fatal MI, Severe Recurrent Ischaemia (SRI) and Non Haemorrhagic Stroke During Six Months Treatment | ACD, non-fatal MI, SRI, non-haemorrhagic stroke | 27 participants |
| 75mg Dabigatran Etexilate | Composite of Cardiovascular Death (CVD) With Non Fatal Myocardial Infarction (MI) and Non Haemorrhagic Stroke and All Cause Death (ACD), Non Fatal MI, Severe Recurrent Ischaemia (SRI) and Non Haemorrhagic Stroke During Six Months Treatment | CVD, non-fatal MI, non-haemorrhagic stroke | 18 participants |
| 110mg Dabigatran Etexilate | Composite of Cardiovascular Death (CVD) With Non Fatal Myocardial Infarction (MI) and Non Haemorrhagic Stroke and All Cause Death (ACD), Non Fatal MI, Severe Recurrent Ischaemia (SRI) and Non Haemorrhagic Stroke During Six Months Treatment | ACD, non-fatal MI, SRI, non-haemorrhagic stroke | 21 participants |
| 110mg Dabigatran Etexilate | Composite of Cardiovascular Death (CVD) With Non Fatal Myocardial Infarction (MI) and Non Haemorrhagic Stroke and All Cause Death (ACD), Non Fatal MI, Severe Recurrent Ischaemia (SRI) and Non Haemorrhagic Stroke During Six Months Treatment | CVD, non-fatal MI, non-haemorrhagic stroke | 12 participants |
| 150mg Dabigatran Etexilate | Composite of Cardiovascular Death (CVD) With Non Fatal Myocardial Infarction (MI) and Non Haemorrhagic Stroke and All Cause Death (ACD), Non Fatal MI, Severe Recurrent Ischaemia (SRI) and Non Haemorrhagic Stroke During Six Months Treatment | CVD, non-fatal MI, non-haemorrhagic stroke | 12 participants |
| 150mg Dabigatran Etexilate | Composite of Cardiovascular Death (CVD) With Non Fatal Myocardial Infarction (MI) and Non Haemorrhagic Stroke and All Cause Death (ACD), Non Fatal MI, Severe Recurrent Ischaemia (SRI) and Non Haemorrhagic Stroke During Six Months Treatment | ACD, non-fatal MI, SRI, non-haemorrhagic stroke | 25 participants |
| Placebo | Composite of Cardiovascular Death (CVD) With Non Fatal Myocardial Infarction (MI) and Non Haemorrhagic Stroke and All Cause Death (ACD), Non Fatal MI, Severe Recurrent Ischaemia (SRI) and Non Haemorrhagic Stroke During Six Months Treatment | ACD, non-fatal MI, SRI, non-haemorrhagic stroke | 26 participants |
| Placebo | Composite of Cardiovascular Death (CVD) With Non Fatal Myocardial Infarction (MI) and Non Haemorrhagic Stroke and All Cause Death (ACD), Non Fatal MI, Severe Recurrent Ischaemia (SRI) and Non Haemorrhagic Stroke During Six Months Treatment | CVD, non-fatal MI, non-haemorrhagic stroke | 14 participants |
Secondary
Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment
Number of Participants with individual occurrence of death (cardiovascular and all-cause), non-fatal MI, severe recurrent ischaemia and non-haemorrhagic stroke during six months of treatment.
Time frame: 6 month treatment period + 2 week post treatment follow up
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Non-haemorrhagic stroke | 0 participants |
| 50mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Cardiovascular death | 8 participants |
| 50mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | All cause death | 8 participants |
| 50mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Non-fatal myocardial infarction | 9 participants |
| 50mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Severe recurrent ischaemia | 9 participants |
| 75mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Non-haemorrhagic stroke | 1 participants |
| 75mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Severe recurrent ischaemia | 11 participants |
| 75mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Non-fatal myocardial infarction | 8 participants |
| 75mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | All cause death | 10 participants |
| 75mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Cardiovascular death | 9 participants |
| 110mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Severe recurrent ischaemia | 9 participants |
| 110mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Cardiovascular death | 5 participants |
| 110mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Non-fatal myocardial infarction | 7 participants |
| 110mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Non-haemorrhagic stroke | 0 participants |
| 110mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | All cause death | 7 participants |
| 150mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | All cause death | 7 participants |
| 150mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Cardiovascular death | 4 participants |
| 150mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Non-haemorrhagic stroke | 0 participants |
| 150mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Severe recurrent ischaemia | 11 participants |
| 150mg Dabigatran Etexilate | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Non-fatal myocardial infarction | 8 participants |
| Placebo | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Severe recurrent ischaemia | 9 participants |
| Placebo | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Non-haemorrhagic stroke | 3 participants |
| Placebo | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Cardiovascular death | 9 participants |
| Placebo | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | All cause death | 14 participants |
| Placebo | Individual Occurrence of Death (Cardiovascular and All-cause), Non-fatal MI, Severe Recurrent Ischaemia and Non-haemorrhagic Stroke During Six Months of Treatment | Non-fatal myocardial infarction | 4 participants |
Secondary
Laboratory Analyses
Number of patients with possible clinically significant abnormalities. Clinically significant abnormalities refers to the increase or decrease from baseline.
Time frame: 6 month treatment period + 2 week post treatment follow up
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50mg Dabigatran Etexilate | Laboratory Analyses | Bilirubin increase N=(359;360;388;329;355) | 1 participants |
| 50mg Dabigatran Etexilate | Laboratory Analyses | AST decrease N=(359;359;388;329;356) | 0 participants |
| 50mg Dabigatran Etexilate | Laboratory Analyses | ALT increase N=(359;359;388;329;356) | 10 participants |
| 50mg Dabigatran Etexilate | Laboratory Analyses | Bilirubin decrease N=(359;360;388;329;355) | 0 participants |
| 50mg Dabigatran Etexilate | Laboratory Analyses | AST increase N=(359;359;388;329;356) | 8 participants |
| 50mg Dabigatran Etexilate | Laboratory Analyses | ALT decrease N=(359;359;388;329;356) | 0 participants |
| 75mg Dabigatran Etexilate | Laboratory Analyses | ALT decrease N=(359;359;388;329;356) | 0 participants |
| 75mg Dabigatran Etexilate | Laboratory Analyses | AST decrease N=(359;359;388;329;356) | 0 participants |
| 75mg Dabigatran Etexilate | Laboratory Analyses | AST increase N=(359;359;388;329;356) | 5 participants |
| 75mg Dabigatran Etexilate | Laboratory Analyses | Bilirubin increase N=(359;360;388;329;355) | 1 participants |
| 75mg Dabigatran Etexilate | Laboratory Analyses | ALT increase N=(359;359;388;329;356) | 4 participants |
| 75mg Dabigatran Etexilate | Laboratory Analyses | Bilirubin decrease N=(359;360;388;329;355) | 0 participants |
| 110mg Dabigatran Etexilate | Laboratory Analyses | ALT decrease N=(359;359;388;329;356) | 0 participants |
| 110mg Dabigatran Etexilate | Laboratory Analyses | AST increase N=(359;359;388;329;356) | 5 participants |
| 110mg Dabigatran Etexilate | Laboratory Analyses | ALT increase N=(359;359;388;329;356) | 4 participants |
| 110mg Dabigatran Etexilate | Laboratory Analyses | Bilirubin decrease N=(359;360;388;329;355) | 0 participants |
| 110mg Dabigatran Etexilate | Laboratory Analyses | Bilirubin increase N=(359;360;388;329;355) | 2 participants |
| 110mg Dabigatran Etexilate | Laboratory Analyses | AST decrease N=(359;359;388;329;356) | 0 participants |
| 150mg Dabigatran Etexilate | Laboratory Analyses | Bilirubin increase N=(359;360;388;329;355) | 0 participants |
| 150mg Dabigatran Etexilate | Laboratory Analyses | Bilirubin decrease N=(359;360;388;329;355) | 0 participants |
| 150mg Dabigatran Etexilate | Laboratory Analyses | AST decrease N=(359;359;388;329;356) | 0 participants |
| 150mg Dabigatran Etexilate | Laboratory Analyses | ALT increase N=(359;359;388;329;356) | 7 participants |
| 150mg Dabigatran Etexilate | Laboratory Analyses | ALT decrease N=(359;359;388;329;356) | 0 participants |
| 150mg Dabigatran Etexilate | Laboratory Analyses | AST increase N=(359;359;388;329;356) | 2 participants |
| Placebo | Laboratory Analyses | Bilirubin decrease N=(359;360;388;329;355) | 0 participants |
| Placebo | Laboratory Analyses | AST increase N=(359;359;388;329;356) | 4 participants |
| Placebo | Laboratory Analyses | AST decrease N=(359;359;388;329;356) | 0 participants |
| Placebo | Laboratory Analyses | ALT decrease N=(359;359;388;329;356) | 0 participants |
| Placebo | Laboratory Analyses | ALT increase N=(359;359;388;329;356) | 4 participants |
| Placebo | Laboratory Analyses | Bilirubin increase N=(359;360;388;329;355) | 0 participants |
Secondary
Number of Participants With Any Reduction of D-dimer Concentration
Time frame: at 1 week and 4 weeks
Population: Full analysis set - The full analysis set includes all randomised and treated patients who had at least one post-dose assessment of D-dimer available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50mg Dabigatran Etexilate | Number of Participants With Any Reduction of D-dimer Concentration | Missing data | 20 participants |
| 50mg Dabigatran Etexilate | Number of Participants With Any Reduction of D-dimer Concentration | Number of Patients with no reduction | 48 participants |
| 50mg Dabigatran Etexilate | Number of Participants With Any Reduction of D-dimer Concentration | Number of Patients with any reduction | 290 participants |
| 75mg Dabigatran Etexilate | Number of Participants With Any Reduction of D-dimer Concentration | Number of Patients with no reduction | 49 participants |
| 75mg Dabigatran Etexilate | Number of Participants With Any Reduction of D-dimer Concentration | Missing data | 16 participants |
| 75mg Dabigatran Etexilate | Number of Participants With Any Reduction of D-dimer Concentration | Number of Patients with any reduction | 293 participants |
| 110mg Dabigatran Etexilate | Number of Participants With Any Reduction of D-dimer Concentration | Missing data | 14 participants |
| 110mg Dabigatran Etexilate | Number of Participants With Any Reduction of D-dimer Concentration | Number of Patients with no reduction | 41 participants |
| 110mg Dabigatran Etexilate | Number of Participants With Any Reduction of D-dimer Concentration | Number of Patients with any reduction | 333 participants |
| 150mg Dabigatran Etexilate | Number of Participants With Any Reduction of D-dimer Concentration | Number of Patients with no reduction | 28 participants |
| 150mg Dabigatran Etexilate | Number of Participants With Any Reduction of D-dimer Concentration | Number of Patients with any reduction | 296 participants |
| 150mg Dabigatran Etexilate | Number of Participants With Any Reduction of D-dimer Concentration | Missing data | 8 participants |
| Placebo | Number of Participants With Any Reduction of D-dimer Concentration | Number of Patients with no reduction | 77 participants |
| Placebo | Number of Participants With Any Reduction of D-dimer Concentration | Number of Patients with any reduction | 264 participants |
| Placebo | Number of Participants With Any Reduction of D-dimer Concentration | Missing data | 15 participants |
Comparison: The proportion of patients who reach this endpoint were analysed by a logistic model for linear trend (dose response).~The null hypothesis is that the relationship between dose level (0mg, 50mg, 75mg, 110mg and 150mg) and the proportions of patients with major and clinically relevant minor bleeding is not linear (slope parameter = 0)p-value: <0.001Cochran-Armitage test for linear trend
Secondary
Number of Participants With Bleeding Events During Total Observation Time
International Society Thrombosis and Haemostasis (ISTH) definition of a major bleed, and clinically relevant minor bleed. A bleeding event was considered as major if it was fatal, was a symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome), or caused a fall in haemoglobin level of ≥2 g/dL (≥1.24 mmol/L), or led to transfusion of ≥2 units of whole blood or red cells. All non major bleeding events were classified as minor bleeds; minor bleeds were subdivided in clinically relevant minor bleeds (CRBE) and not clinically relevant minor bleeds. A CRBE was defined as an acute or subacute clinically overt bleed that did not meet the criteria of a major bleed but either lead to hospital admission and/or a physician guided medical or surgical treatment and/or a change in antithrombotic therapy (including interruption or discontinuation of study drug).
Time frame: 6 month treatment period + 2 week post treatment follow up
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Major bleeding events | 3 participants |
| 50mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Clinically relevant bleeding events | 10 participants |
| 50mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Not clinically relevant bleeding events | 32 participants |
| 50mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Any bleeding events | 42 participants |
| 75mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Clinically relevant bleeding events | 16 participants |
| 75mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Any bleeding events | 45 participants |
| 75mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Major bleeding events | 1 participants |
| 75mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Not clinically relevant bleeding events | 29 participants |
| 110mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Clinically relevant bleeding events | 24 participants |
| 110mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Not clinically relevant bleeding events | 35 participants |
| 110mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Any bleeding events | 60 participants |
| 110mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Major bleeding events | 8 participants |
| 150mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Clinically relevant bleeding events | 23 participants |
| 150mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Any bleeding events | 42 participants |
| 150mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Not clinically relevant bleeding events | 20 participants |
| 150mg Dabigatran Etexilate | Number of Participants With Bleeding Events During Total Observation Time | Major bleeding events | 4 participants |
| Placebo | Number of Participants With Bleeding Events During Total Observation Time | Not clinically relevant bleeding events | 17 participants |
| Placebo | Number of Participants With Bleeding Events During Total Observation Time | Clinically relevant bleeding events | 6 participants |
| Placebo | Number of Participants With Bleeding Events During Total Observation Time | Any bleeding events | 25 participants |
| Placebo | Number of Participants With Bleeding Events During Total Observation Time | Major bleeding events | 2 participants |