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

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)

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.

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.