Venous Thromboembolism
Conditions
Brief summary
The primary objective of the trial is to demonstrate non-inferiority of 220 mg oral dabigatran etexilate compared to 40 mg subcutaneous enoxaparin administered once daily. Safety and efficacy will be compared between the treatment groups.
Interventions
DRUGEnoxaparin
40 mg once daily
DRUGDabigatran etexilate
220 mg once 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
* Patients scheduled to undergo primary, unilateral, elective total hip arthroplasty. * Male or female 18 years of age or older. * Patients giving written informed consent for study participation.
Exclusion criteria
* Patients weighing less than 40 kg. * History of bleeding diathesis. * Patients who in the investigators judgement are perceived as having an excessive risk of bleeding, for example, constitutional or acquired coagulation disorders or because of anticipated need of quinidine, verapamil or other restricted medication during the treatment period (see Section 4.2.2). * Major surgery or trauma (e.g., hip fracture) within 3 months of enrolment. * Recent unstable cardiovascular disease (in the investigators opinion) such as uncontrolled hypertension, that is ongoing at the time of enrolment or history of myocardial infarction within 3 months of enrolment. * Any history of haemorrhagic stroke or any of the following intracranial pathologies: bleeding, neoplasm, Atriovenous (AV) malformation or aneurysm. * Ongoing treatment for Venous Thromboembolism (VTE). * Clinically relevant bleeding (gastrointestinal, pulmonary, intraocular or urogenital bleeding) within 6 months of enrolment. * Gastric or duodenal ulcer within one year of enrolment. * Liver disease expected to have any potential impact on survival (ie, hepatitis B or C, cirrhosis). This does not include Gilberts syndrome or hepatitis A with complete recovery. * Active liver disease or liver disease decreasing survival (e.g, acute hepatitis, chronic active hepatitis, cirrhosis) or Alanine Aminotransferase (ALT) \>3 x ULN. * Known severe renal insufficiency (CrCl \<30 ml/min). Note: CrCl should be calculated only if serum creatinine is elevated or renal insufficiency is suspected. See Appendix 10.1 for calculation. * Elevated creatinine that, in the investigators opinion, contraindicates venography. * Treatment with anticoagulants, clopidogrel, ticlopidine, abciximab, aspirin \>162.5 mg/day or NSAID with t 1/2 \>12 hours within 7 days prior to hip replacement surgery OR anticipated need while the patient is receiving study medication and prior to 24 hours after the last administration of any blinded study medication (COX-2 selective inhibitors are allowed). * Anticipated required use of intermittent pneumatic compression and electric stimulation of lower limb. * Pre-menopausal women (last menstruation within 1 year prior to signing informed consent) who: * Are pregnant. * Are nursing. * Are of child-bearing potential and are NOT practicing acceptable methods of birth control, or do NOT plan to continue practicing an acceptable method throughout the study. Acceptable methods of birth control include intrauterine device; oral, implantable or injectable contraceptives and surgical sterility. * Known allergy to radio opaque contrast media. * History of thrombocytopenia, including heparin-induced thrombocytopenia, or a platelet count \<100,000 cells/microliter at randomisation. * Allergy to heparins or dabigatran etexilate. * Active malignant disease or current cytostatic treatment. Patients should be disease free for at least 5 years. * Participation in a clinical trial within 30 days of randomisation. * Leg amputee. * Known alcohol or drug abuse which would interfere with completion of the study. * Contraindications to enoxaparin. * Previous participation in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period | 28-35 days | Total Venous Thromboembolic Event (VTE) includes both proximal and distal deep vein thrombosis (DVT) (detected by routine venography), symptomatic DVT (confirmed by venous duplex, 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 | 28-35 days | Proximal Deep Vein Thrombosis as adjudicated by the VTE events committee |
| Number of Participants With Total Deep Vein Thrombosis During Treatment Period | 28-35 days | Total Deep Vein Thrombosis as adjudicated by the VTE events committee |
| Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period | 28-35 days | Symptomatic Deep Vein Thrombosis, confirmed by venous duplex, ultrasound, venography or autopsy, and as adjudicated by the VTE events committee |
| Number of Participants With Pulmonary Embolism During Treatment Period | 28-35 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 |
| Number of Participants Who Died During Treatment Period | 28-35 days | All cause death, as adjudicated by the VTE events committee |
| Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period | 28-35 days | Major Venous Thromboembolic Event (VTE) is defined as proximal DVT and PE, as adjudicated by the VTE events committee |
| Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | 28-35 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 \>=25 cm² * wound hematoma \>=100 cm² * spontaneous nose bleed \>5 min * macroscopic hematuria spontaneous or \>24 hours if associated with an intervention * spontaneous rectal bleeding * gingival bleeding \>5 min * any other bleeding event considered clinically relevant by the investigator Any bleeding events were defined as major, clinically-relevant and minor bleeding events. Minor bleeding events were defined as all other bleeding events that did not fulfil the criteria from above. |
| Blood Transfusion | Day 1 | Number of treated and operated patients with required blood transfusion on day of surgery. |
| Volume of Blood Loss | Day 1 | Volume of blood loss for treated and operated patients during surgery. |
| Laboratory Analyses | First administration to end of study | Frequency of patients with possible clinically significant abnormalities. |
| 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 venography), symptomatic DVT (confirmed by venous duplex, ultrasound, venography or autopsy) and pulmonary embolism (PE) (confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy). |
Countries
Australia, Austria, Belgium, Canada, Czechia, Denmark, Finland, Germany, Hungary, India, Italy, Netherlands, New Zealand, Norway, Poland, South Africa, Spain, Sweden, 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 28 - 35 days. The study period is from first administration of study medication until day 84 - 91.
Pre-assignment details
Whilst 2055 patients were randomised to treatment prior to surgery in this trial, only 2013 started treatment. Therefore, 42 patients were randomised but not treated.
Participants by arm
| Arm | Count |
|---|---|
| Dabigatran 220mg qd (once daily) oral | 1,010 |
| Enoxaparin 40mg qd (once daily) subcutaneous | 1,003 |
| Total | 2,013 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 19 | 10 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Non-compliant with protocol | 5 | 9 |
| Overall Study | Other | 38 | 38 |
| Overall Study | Withdrawal by Subject | 51 | 36 |
| Treatment | Adverse Event | 60 | 53 |
| Treatment | Lost to Follow-up | 1 | 0 |
| Treatment | Non-compliant with protocol | 10 | 9 |
| Treatment | Other | 13 | 15 |
| Treatment | Withdrawal by Subject | 23 | 20 |
Baseline characteristics
| Characteristic | Dabigatran 220mg | Enoxaparin | Total |
|---|---|---|---|
| Age, Continuous | 61.9 Years STANDARD_DEVIATION 11.5 | 62.0 Years STANDARD_DEVIATION 11.3 | 62.0 Years STANDARD_DEVIATION 11.4 |
| Body Mass Index N=(1003;992;1995) | 27.8 kg/m^2 STANDARD_DEVIATION 4.8 | 27.8 kg/m^2 STANDARD_DEVIATION 4.8 | 27.8 kg/m^2 STANDARD_DEVIATION 4.8 |
| Sex: Female, Male Female | 541 Participants | 501 Participants | 1042 Participants |
| Sex: Female, Male Male | 469 Participants | 502 Participants | 971 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 389 / 1,010 | 389 / 1,003 |
| serious Total, serious adverse events | 57 / 1,010 | 59 / 1,003 |
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 venography), symptomatic DVT (confirmed by venous duplex, 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: 28-35 days
Population: Full Analysis Set (randomised, had taken at least 1 dose of oral or subcutaneous trial medication, had undergone surgery, had evaluable negative venogram for both distal and proximal DVT in both legs or positive venography in any 1 segment of 1 or both legs, or confirmed symptomatic DVT, PE or death during the treatment period.)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period | 61 Participants |
| Enoxaparin | Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period | 69 Participants |
Comparison: Risk difference versus Enoxaparinp-value: <0.000195% CI: [-3.79, 1.64]Normal approximation
Secondary
Blood Transfusion
Number of treated and operated patients with required blood transfusion on day of surgery.
Time frame: Day 1
Population: Treated and operated patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabigatran 220mg | Blood Transfusion | Transfusions required | 246 participants |
| Dabigatran 220mg | Blood Transfusion | Missing | 4 participants |
| Enoxaparin | Blood Transfusion | Transfusions required | 237 participants |
| Enoxaparin | Blood Transfusion | Missing | 7 participants |
Secondary
Laboratory Analyses
Frequency of patients with possible clinically significant abnormalities.
Time frame: First administration to end of study
Population: Treated patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabigatran 220mg | Laboratory Analyses | AST increase N=(964;962) | 28 participants |
| Dabigatran 220mg | Laboratory Analyses | AST decrease N=(964;962) | 0 participants |
| Dabigatran 220mg | Laboratory Analyses | ALT increase N=(966;962) | 34 participants |
| Dabigatran 220mg | Laboratory Analyses | ALT decrease N=(966;962) | 0 participants |
| Dabigatran 220mg | Laboratory Analyses | Bilirubin increase N=(966;962) | 3 participants |
| Dabigatran 220mg | Laboratory Analyses | Bilirubin decrease N=(966;962) | 0 participants |
| Enoxaparin | Laboratory Analyses | Bilirubin increase N=(966;962) | 1 participants |
| Enoxaparin | Laboratory Analyses | AST increase N=(964;962) | 44 participants |
| Enoxaparin | Laboratory Analyses | ALT decrease N=(966;962) | 0 participants |
| Enoxaparin | Laboratory Analyses | AST decrease N=(964;962) | 0 participants |
| Enoxaparin | Laboratory Analyses | Bilirubin decrease N=(966;962) | 0 participants |
| Enoxaparin | Laboratory Analyses | ALT increase N=(966;962) | 67 participants |
Secondary
Number of Participants Who Died During Treatment Period
All cause death, as adjudicated by the VTE events committee
Time frame: 28-35 days
Population: Full Analysis Set - op (all patients who had been randomised, had taken at least 1 dose of oral or subcutaneous trial medication or had undergone surgery (i.e. a date of surgery was reported)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants Who Died During Treatment Period | 0 Participants |
| Enoxaparin | Number of Participants Who Died During Treatment Period | 1 Participants |
Comparison: Comparison versus Enoxaparinp-value: 0.4977Fisher 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 \>=25 cm² * wound hematoma \>=100 cm² * spontaneous nose bleed \>5 min * macroscopic hematuria spontaneous or \>24 hours if associated with an intervention * spontaneous rectal bleeding * gingival bleeding \>5 min * any other bleeding event considered clinically relevant by the investigator Any bleeding events were defined as major, clinically-relevant and minor bleeding events. Minor bleeding events were defined as all other bleeding events that did not fulfil the criteria from above.
Time frame: 28-35 days
Population: All patients who had been randomised, had taken at least 1 dose of oral or subcutaneous trial medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabigatran 220mg | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Major bleeding events | 14 Participants |
| Dabigatran 220mg | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Major and clinically relevant bleeding events | 37 Participants |
| Dabigatran 220mg | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Any bleeding events | 98 Participants |
| Enoxaparin | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Major bleeding events | 9 Participants |
| Enoxaparin | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Major and clinically relevant bleeding events | 29 Participants |
| Enoxaparin | Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period | Any bleeding events | 83 Participants |
Comparison: Comparison versus Enoxaparin for the category major bleeding eventsp-value: 0.4022Fisher Exact
Comparison: Absolute difference versus Enoxaparin for the category major and clinically relevant bleeding eventsp-value: 0.330595% CI: [-0.8, 2.3]Normal approximation
Comparison: Absolute difference versus Enoxaparin for the category any bleeding eventsp-value: 0.262695% CI: [-1.1, 3.9]Normal approximation
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: 28-35 days
Population: Full Analysis Set-major (randomised, had taken at least 1 dose of oral or subcutaneous trial medication, had undergone surgery, had evaluable negative venogram for proximal DVT in both legs or a positive venogram for proximal DVT in either leg or confirmed symptomatic proximal DVT, PE or death related to VTE during the treatment period.)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period | 18 Participants |
| Enoxaparin | Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period | 33 Participants |
p-value: 0.02995% CI: [-3.64, -0.19]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: 28-35 days
Population: Full Analysis Set - pDVT (all patients who had been randomised, had taken at least 1 dose of oral or subcutaneous trial medication, had undergone surgery (i.e. a date of surgery was reported), evaluable negative venogram for proximal DVT in both legs or positive venogram in either leg or confirmed symptomatic proximal DVT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period | 17 Participants |
| Enoxaparin | Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period | 31 Participants |
Comparison: Risk difference versus Enoxaparinp-value: 0.035895% CI: [-3.47, -0.12]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: 28-35 days
Population: Full Analysis Set - op (all patients who had been randomised, had taken at least 1 dose of oral or subcutaneous trial medication or had undergone surgery (i.e. a date of surgery was reported)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants With Pulmonary Embolism During Treatment Period | 1 Participants |
| Enoxaparin | Number of Participants With Pulmonary Embolism During Treatment Period | 2 Participants |
Comparison: Comparison versus Enoxaparinp-value: 0.6231Fisher Exact
Secondary
Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period
Symptomatic Deep Vein Thrombosis, confirmed by venous duplex, ultrasound, venography or autopsy, and as adjudicated by the VTE events committee
Time frame: 28-35 days
Population: Full Analysis Set - op (all patients who had been randomised, had taken at least 1 dose of oral or subcutaneous trial medication or had undergone surgery (i.e. a date of surgery was reported)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period | 0 Participants |
| Enoxaparin | Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period | 4 Participants |
Comparison: Comparison versus Enoxaparinp-value: 0.0612Fisher 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: 28-35 days
Population: Full Analysis Set-tDVT (randomised, had taken at least 1 dose of oral or subcutaneous trial medication, had undergone surgery, evaluable negative venogram for both distal and proximal DVT in both legs or positive venography in any 1 segment of 1 or both legs, or confirmed symptomatic DVT.)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 220mg | Number of Participants With Total Deep Vein Thrombosis During Treatment Period | 60 Participants |
| Enoxaparin | Number of Participants With Total Deep Vein Thrombosis During Treatment Period | 67 Participants |
Comparison: Risk difference versus Enoxaparinp-value: 0.483995% CI: [-3.65, 1.73]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 venography), symptomatic DVT (confirmed by venous duplex, 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 | asymptomatic Deep Vein Thrombosis | 0 Participants |
| Dabigatran 220mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | Pulmonary Embolism | 1 Participants |
| Dabigatran 220mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | symptomatic Deep Vein Thrombosis | 1 Participants |
| Dabigatran 220mg | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | death | 0 Participants |
| 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 | 2 Participants |
| Enoxaparin | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | death | 1 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 | 4 Participants |
| Enoxaparin | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | asymptomatic Deep Vein Thrombosis | 1 Participants |
| Enoxaparin | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | symptomatic Deep Vein Thrombosis | 0 Participants |
| Enoxaparin | Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period | Pulmonary Embolism | 2 Participants |
Comparison: Comparison versus Enoxaparinp-value: 0.687Fisher Exact
Secondary
Volume of Blood Loss
Volume of blood loss for treated and operated patients during surgery.
Time frame: Day 1
Population: Treated and operated patients
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran 220mg | Volume of Blood Loss | 404.9 mL | Standard Deviation 259.67 |
| Enoxaparin | Volume of Blood Loss | 411.0 mL | Standard Deviation 275.38 |