Treatment of Patients Undergoing Primary Unilateral Elective Total Knee or Hip Replacement With Dabigatran Etexilate

An Open Label, Non-comparative, Pharmacokinetic and Pharmacodynamic Study to Evaluate the Effect of Dabigatran Etexilate on Coagulation Parameters Including a Calibrated Thrombin Time Test in Patients With Moderate Renal Impairment (Creatinine Clearance 30-50 ml/Min) Undergoing Primary Unilateral Elective Total Knee or Hip Replacement Surgery

To supplement the current evidence of the effect of Pradaxa® (dabigatran etexilate) on coagulation parameters, including a calibrated thrombin time test, in patients with moderate renal impairment undergoing elective total hip- or knee-replacement surgery, this PK/PD study will be conducted.

Inclusion criteria:

1. Patients scheduled for primary unilateral elective total knee or hip replacement, male or female being 18 years or older
2. Moderate renal impairment (CrCl 30-50 mL/min)
3. Written informed consent
4. Caucasian patients

Exclusion criteria:

1. Patients weighing less than 40 kg.

2. Patients requiring chronic treatment with anticoagulants (e.g. vitamin K antagonists; e.g. patients with atrial fibrillation, patients with artificial heart valves, etc.).

3. Patients who in the investigator's judgment were perceived as having an excessive risk of bleeding, for example:

   Constitutional or acquired coagulation disorders

   History of bleeding diathesis

   Clinically relevant bleeding (gastrointestinal, pulmonary, intraocular or urogenital bleeding) within 3 months of enrolment

   Major surgery or trauma (e.g. hip fracture) within 3 months of enrolment

   History of thrombocytopenia, including heparin-induced thrombocytopenia, or a platelet count <100 000 cells/microliter at randomization

   Any history of hemorrhagic stroke or any of the following intracranial pathologies: bleeding, neoplasm

   Any arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities

   Presence of malignant neoplasms at higher risk of bleeding

   Known or suspected oesophageal varices

   Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days

   Treatment with anticoagulants, clopidogrel, ticlopidine, abciximab, aspirin >162.5 mg/day or non-steroidal anti-inflammatory drug (NSAID) with t1/2>12 hours within 7 days prior to hip or knee replacement surgery OR anticipated need while the patient was receiving study medication and prior to 24 hours after the last administration of study medication (COX-2 selective inhibitors are allowed) because of anticipated need of quinidine, verapamil or other restricted medication during the treatment period

4. Recent unstable cardiovascular disease (in the investigator's opinion) such as uncontrolled hypertension, that was ongoing at the time of enrolment or history of myocardial infarction within 3 months of enrolment.

5. Ongoing treatment for VTE.

6. Liver disease expected to have any potential impact on survival (i.e. hepatitis B or C, cirrhosis) or ALT/AST >3x upper limit of normal range (ULN). This did not include Gilbert's syndrome or hepatitis A with complete recovery.

7. Known severe renal insufficiency (CrCl <30 mL/min) and patients with mild renal insufficiency (CrCl >50 mL/min) or normal renal function.

8. Planned anaesthesia with post-operative indwelling epidural catheters.

9. Pre-menopausal women (last menstruation <=1 year prior to signing informed consent), who were:

   Pregnant

   Nursing

   Of child-bearing potential and were NOT practicing acceptable methods of birth control, or did NOT plan to continue practicing an acceptable method throughout the study. Acceptable methods of birth control included intrauterine device; oral, implantable or injectable contraceptives and surgical sterility

10. Hypersensitivity to dabigatran etexilate or to any of excipients.

11. Participation in a clinical trial within 30 days of enrolment.

12. Known alcohol or drug abuse which would interfere with completion of the study; patients considered unreliable by the investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration.

13. Previous participation in this study.