Dabigatran Etexilate Compared With Enoxaparin in Prevention of Venous Thromboembolism (VTE) Following Total Hip Arthroplasty

Study Overview
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Brief Summary
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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.

Official Title
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A Phase III Randomised, Parallel Group, Double-blind, Active Controlled Study to Investigate the Efficacy and Safety of Orally Administered 220 mg Dabigatran Etexilate Capsules (110 mg Administered on the Day of Surgery Followed by 220 mg Once Daily) Compared to Subcutaneous 40 mg Enoxaparin Once Daily for 28-35 Days, in Prevention of Venous Thromboembolism in Patients With Primary Elective Total Hip Arthroplasty Surgery. (RE-NOVATE II)

Conditions
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Venous Thromboembolism

Intervention / Treatment
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* Drug: Enoxaparin
* Drug: Dabigatran etexilate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabigatran etexilate<br>220 mg once daily | Drug: Dabigatran etexilate<br>* 220 mg once daily<br>|
| Active Comparator: Enoxaparin<br>40 mg once daily | Drug: Enoxaparin<br>* 40 mg once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 28-35 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 28-35 days | 
| Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period | Proximal Deep Vein Thrombosis as adjudicated by the VTE events committee | 28-35 days | 
| Number of Participants With Total Deep Vein Thrombosis During Treatment Period | Total Deep Vein Thrombosis as adjudicated by the VTE events committee | 28-35 days | 
| 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 | 28-35 days | 
| 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 | 28-35 days | 
| Number of Participants Who Died During Treatment Period | All cause death, as adjudicated by the VTE events committee | 28-35 days | 
| 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). | 3 months | 
| 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. | 28-35 days | 
| Blood Transfusion | Number of treated and operated patients with required blood transfusion on day of surgery. | Day 1 | 
| Volume of Blood Loss | Volume of blood loss for treated and operated patients during surgery. | Day 1 | 
| Laboratory Analyses | Frequency of patients with possible clinically significant abnormalities. | First administration to end of study |