Arthroplasty, Replacement, Knee, Thromboembolism
Conditions
Brief summary
To determine the comparative efficacy and safety of two different doses (75mg day 1 followed by 150 mg day 2-completion, and 110 mg day 1 followed by 220 mg day 2-completion) of dabigatran administered orally (capsules), compared to enoxaparin 30 mg twice a day subcutaneous, in prevention of venous thromboembolism in patients with primary elective total knee replacement surgery
Interventions
DRUGDabigatran Dose 1 - day 2 to completion
low dose regimen taken once daily
DRUGDabigatran Dose 1 - day 1
low dose regimen taken once daily
DRUGDabigatran Dose 2 - day 2 to completion
high dose regimen taken once daily
DRUGDabigatran Dose 2 - day 1
high dose regimen taken once daily
DRUGEnoxaparin
30 mg subcutaneously twice daily
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
INCLUSION CRITERIA 1. Patients scheduled to undergo a primary, unilateral elective total knee repla cement. 2. Male or female 18 years of age or older. 3. Patients weighing at least 40 kg. 4. Written informed consent prior to the start of study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period | First administration until 12-15 days | Total Venous Thromboembolic Event (VTE) includes both proximal and distal deep vein thrombosis (DVT) (detected by routine bilateral venography), symptomatic DVT (confirmed by venous compression ultrasound, venography or autopsy) and pulmonary embolism (PE) (confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy). All of these components and all deaths were centrally adjudicated by the VTE events committee, which was not aware of the treatment allocation of the patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period | First administration until 12-15 days | Proximal Deep Vein Thrombosis as adjudicated by the VTE events committee |
| Number of Participants With Total Deep Vein Thrombosis During Treatment Period | First administration until 12-15 days | Total Deep Vein Thrombosis as adjudicated by the VTE events committee |
| Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period | First administration until 12-15 days | Symptomatic Deep Vein Thrombosis, confirmed by venous compression ultrasound, venography or autopsy, and as adjudicated by the VTE events committee |
| Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period | First administration until 12-15 days | Major Venous Thromboembolic Event (VTE) is defined as proximal DVT and PE, as adjudicated by the VTE events committee |
| Number of Participants Who Died During Treatment Period | First administration until 12-15 days | All cause death, as adjudicated by the VTE events committee |
| Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | 3 months | Total Venous Thromboembolic Event (VTE) includes both proximal and distal deep vein thrombosis (DVT) (detected by routine bilateral venography), symptomatic DVT (confirmed by venous compression ultrasound, venography or autopsy) and pulmonary embolism (PE) (confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy). |
| Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | First administration until 12-15 days | Major bleeding events were defined as * fatal * clinically overt associated with loss of haemoglobin \>=20g/L in excess of what was expected * clinically overt leading to the transfusion of \>=2 units packed cells or whole blood in excess of what was expected * symptomatic retroperitoneal, intracranial, intraocular or intraspinal * requiring treatment cessation * leading to re-operation Clinically-relevant was defined as * spontaneous skin hematoma greater than or equal to 25 cm² * wound hematoma greater than or equal to 100 cm² * spontaneous nose bleed lasting longer than 5 min * macroscopic hematuria spontaneous or lasting longer than 24 hours if associated with an intervention * spontaneous rectal bleeding (more than a spot on toilet paper) * gingival bleeding lasting longer than 5 min * any other bleeding event considered clinically relevant by the investigator Minor bleeding events were defined as all other bleeding events that did not fulfil the criteria from above. |
| Number of Participants With Pulmonary Embolism During Treatment Period | First administration until 12-15 days | Pulmonary embolism confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy, and as adjudicated by the VTE events committee |
Countries
Canada, Mexico, United Kingdom, United States
Participant flow
Recruitment details
The treatment period is from first administration of study medication, until 3 days after last administration of study medication. Treatment duration is planned for 12 - 15 days. The study period is from first administration of study medication until day 84 - 91.
Pre-assignment details
Whilst 2615 patients were enrolled/randomised to treatment post surgery in this trial, only 2596 started treatment. Therefore, 19 patients were randomised but not treated (treatment was planned to start post surgery).
Participants by arm
| Arm | Count |
|---|---|
| Dabigatran 220mg qd (once daily) oral | 857 |
| Dabigatran 150mg qd (once daily) oral | 871 |
| Enoxaparin 30mg bid (twice daily) subcutaneous | 868 |
| Total | 2,596 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 12 | 10 | 9 |
| Overall Study | Lost to Follow-up | 17 | 14 | 13 |
| Overall Study | Other | 3 | 5 | 5 |
| Overall Study | Protocol Violation | 10 | 11 | 8 |
| Overall Study | Withdrawal by Subject | 9 | 8 | 14 |
| Treatment | Adverse Event | 49 | 40 | 54 |
| Treatment | Lost to Follow-up | 1 | 2 | 1 |
| Treatment | Other | 9 | 11 | 10 |
| Treatment | Protocol Violation | 8 | 6 | 10 |
| Treatment | Withdrawal by Subject | 4 | 4 | 5 |
Baseline characteristics
| Characteristic | Dabigatran 220mg | Dabigatran 150mg | Enoxaparin | Total |
|---|---|---|---|---|
| Age, Continuous | 66.2 Years STANDARD_DEVIATION 9.5 | 65.9 Years STANDARD_DEVIATION 9.5 | 66.3 Years STANDARD_DEVIATION 9.6 | 66.1 Years STANDARD_DEVIATION 9.5 |
| Body Mass Index | 31.6 kg/m^2 STANDARD_DEVIATION 6 | 31.4 kg/m^2 STANDARD_DEVIATION 6.1 | 31.4 kg/m^2 STANDARD_DEVIATION 6 | 31.5 kg/m^2 STANDARD_DEVIATION 6.1 |
| Sex: Female, Male Female | 486 Participants | 507 Participants | 504 Participants | 1497 Participants |
| Sex: Female, Male Male | 371 Participants | 364 Participants | 364 Participants | 1099 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 | 718 / 857 | 724 / 871 | 711 / 868 |
| serious Total, serious adverse events | 59 / 857 | 57 / 871 | 45 / 868 |
Outcome results
Primary
Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period
Total Venous Thromboembolic Event (VTE) includes both proximal and distal deep vein thrombosis (DVT) (detected by routine bilateral venography), symptomatic DVT (confirmed by venous compression ultrasound, venography or autopsy) and pulmonary embolism (PE) (confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy). All of these components and all deaths were centrally adjudicated by the VTE events committee, which was not aware of the treatment allocation of the patients.
Time frame: First administration until 12-15 days
Population: Full Analysis Set (all patients who had surgery and were randomised, received treatment, had an evaluable venogram for distal and proximal Deep Vein Thrombosis, or had confirmed symptomatic Deep Vein Thrombosis, Pulmonary Embolism, or had died)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period | 188 Participants |
| Dabigatran 150mg | Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period | 219 Participants |
| Enoxaparin | Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period | 163 Participants |
Comparison: Risk difference versus Enoxaparinp-value: 0.023495% CI: [0.8, 10.8]Normal approximation
Comparison: Risk difference versus Enoxaparinp-value: 0.000995% CI: [3.4, 13.3]Normal approximation
Secondary
Number of Participants Who Died During Treatment Period
All cause death, as adjudicated by the VTE events committee
Time frame: First administration until 12-15 days
Population: Full Analysis Set - op
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants Who Died During Treatment Period | 1 Participants |
| Dabigatran 150mg | Number of Participants Who Died During Treatment Period | 1 Participants |
| Enoxaparin | Number of Participants Who Died During Treatment Period | 0 Participants |
Comparison: Comparison versus Enoxaparinp-value: 0.4968Fisher Exact
Comparison: Comparison versus Enoxaparinp-value: 1Fisher Exact
Secondary
Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period
Major bleeding events were defined as * fatal * clinically overt associated with loss of haemoglobin \>=20g/L in excess of what was expected * clinically overt leading to the transfusion of \>=2 units packed cells or whole blood in excess of what was expected * symptomatic retroperitoneal, intracranial, intraocular or intraspinal * requiring treatment cessation * leading to re-operation Clinically-relevant was defined as * spontaneous skin hematoma greater than or equal to 25 cm² * wound hematoma greater than or equal to 100 cm² * spontaneous nose bleed lasting longer than 5 min * macroscopic hematuria spontaneous or lasting longer than 24 hours if associated with an intervention * spontaneous rectal bleeding (more than a spot on toilet paper) * gingival bleeding lasting longer than 5 min * any other bleeding event considered clinically relevant by the investigator Minor bleeding events were defined as all other bleeding events that did not fulfil the criteria from above.
Time frame: First administration until 12-15 days
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabigatran 220mg | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Major | 5 Participants |
| Dabigatran 220mg | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Clinically relevant | 23 Participants |
| Dabigatran 220mg | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Minor | 46 Participants |
| Dabigatran 220mg | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | None | 783 Participants |
| Dabigatran 150mg | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | None | 799 Participants |
| Dabigatran 150mg | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Major | 5 Participants |
| Dabigatran 150mg | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Minor | 45 Participants |
| Dabigatran 150mg | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Clinically relevant | 22 Participants |
| Enoxaparin | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | None | 784 Participants |
| Enoxaparin | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Clinically relevant | 21 Participants |
| Enoxaparin | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Minor | 51 Participants |
| Enoxaparin | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Major | 12 Participants |
Comparison: Comparison versus Enoxaparinp-value: 0.1416Fisher Exact
Comparison: Comparison versus Enoxaparinp-value: 0.0942Fisher Exact
Secondary
Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period
Major Venous Thromboembolic Event (VTE) is defined as proximal DVT and PE, as adjudicated by the VTE events committee
Time frame: First administration until 12-15 days
Population: Full Analysis Set - major (all patients who had surgery and were randomised, received treatment, had an evaluable venogram for proximal Deep Vein Thrombosis, or had confirmed symptomatic Deep Vein Thrombosis, Pulmonary Embolism, or had died by a Venous Thromboembolic Event-related death)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period | 21 Participants |
| Dabigatran 150mg | Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period | 20 Participants |
| Enoxaparin | Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period | 15 Participants |
Comparison: Risk difference versus Enoxaparinp-value: 0.213995% CI: [-0.7, 3]Normal approximation
Comparison: Risk difference versus Enoxaparinp-value: 0.362895% CI: [-0.9, 2.5]Normal approximation
Secondary
Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period
Proximal Deep Vein Thrombosis as adjudicated by the VTE events committee
Time frame: First administration until 12-15 days
Population: Full Analysis Set - pDVT (all patients who had surgery and were randomised, received treatment, had an evaluable venogram for proximal Deep Vein Thrombosis, or had confirmed symptomatic Deep Vein Thrombosis)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period | 15 Participants |
| Dabigatran 150mg | Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period | 20 Participants |
| Enoxaparin | Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period | 10 Participants |
Comparison: Risk difference versus Enoxaparinp-value: 0.230995% CI: [-0.6, 2.5]Normal approximation
Comparison: Risk difference versus Enoxaparinp-value: 0.060295% CI: [-0.1, 3.2]Normal approximation
Secondary
Number of Participants With Pulmonary Embolism During Treatment Period
Pulmonary embolism confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy, and as adjudicated by the VTE events committee
Time frame: First administration until 12-15 days
Population: Full Analysis Set - op
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants With Pulmonary Embolism During Treatment Period | 6 Participants |
| Dabigatran 150mg | Number of Participants With Pulmonary Embolism During Treatment Period | 0 Participants |
| Enoxaparin | Number of Participants With Pulmonary Embolism During Treatment Period | 5 Participants |
Comparison: Comparison versus Enoxaparinp-value: 0.7724Fisher Exact
Comparison: Comparison versus Enoxaparinp-value: 0.0308Fisher Exact
Secondary
Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period
Symptomatic Deep Vein Thrombosis, confirmed by venous compression ultrasound, venography or autopsy, and as adjudicated by the VTE events committee
Time frame: First administration until 12-15 days
Population: Full Analysis Set - op (all patients who are treated and operated)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period | 7 Participants |
| Dabigatran 150mg | Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period | 6 Participants |
| Enoxaparin | Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period | 5 Participants |
Comparison: Comparison versus Enoxaparinp-value: 0.5774Fisher Exact
Comparison: Comparison versus Enoxaparinp-value: 1Fisher Exact
Secondary
Number of Participants With Total Deep Vein Thrombosis During Treatment Period
Total Deep Vein Thrombosis as adjudicated by the VTE events committee
Time frame: First administration until 12-15 days
Population: Full Analysis Set - tDVT (all patients who had surgery and were randomised, received treatment, had an evaluable venogram, or had confirmed symptomatic Deep Vein Thrombosis)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants With Total Deep Vein Thrombosis During Treatment Period | 184 Participants |
| Dabigatran 150mg | Number of Participants With Total Deep Vein Thrombosis During Treatment Period | 218 Participants |
| Enoxaparin | Number of Participants With Total Deep Vein Thrombosis During Treatment Period | 158 Participants |
Comparison: Risk difference versus Enoxaparinp-value: 0.019495% CI: [1, 10.9]Normal approximation
Comparison: Risk difference versus Enoxaparinp-value: 0.000495% CI: [4, 13.9]Normal approximation
Secondary
Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period
Total Venous Thromboembolic Event (VTE) includes both proximal and distal deep vein thrombosis (DVT) (detected by routine bilateral venography), symptomatic DVT (confirmed by venous compression ultrasound, venography or autopsy) and pulmonary embolism (PE) (confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy).
Time frame: 3 months
Population: Patients with any data available during follow-up
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabigatran 220mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | Total VTE and all-cause mortality | 7 Participants |
| Dabigatran 220mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | Pulmonary Embolism | 2 Participants |
| Dabigatran 220mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | symptotic Deep Vein Thrombosis | 2 Participants |
| Dabigatran 220mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | death | 1 Participants |
| Dabigatran 220mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | asymptotic Deep Vein Thrombosis | 2 Participants |
| Dabigatran 150mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | death | 2 Participants |
| Dabigatran 150mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | Total VTE and all-cause mortality | 7 Participants |
| Dabigatran 150mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | asymptotic Deep Vein Thrombosis | 1 Participants |
| Dabigatran 150mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | symptotic Deep Vein Thrombosis | 4 Participants |
| Dabigatran 150mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | Pulmonary Embolism | 0 Participants |
| Enoxaparin | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | asymptotic Deep Vein Thrombosis | 4 Participants |
| Enoxaparin | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | death | 2 Participants |
| Enoxaparin | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | Pulmonary Embolism | 2 Participants |
| Enoxaparin | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | Total VTE and all-cause mortality | 10 Participants |
| Enoxaparin | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | symptotic Deep Vein Thrombosis | 2 Participants |