Safety of DAbigatran and RIvaroxaban Versus NAdroparin in the Prevention of Venous Thromboembolism After Knee Arthroplasty Surgery (DARINA)

A Randomized Pilot Study Comparing the Safety of DAbigatran and RIvaroxaban Versus NAdroparin in the Prevention of Venous Thromboembolism After Knee Arthroplasty Surgery

Rationale:

After total knee arthroplasty (TKA) surgery, patients are at risk to develop venous thromboembolism (VTE) or deep venous thrombosis (DVT) potentially resulting in a fatal pulmonary embolism (PE). Two novel agents, dabigatran and rivaroxaban, recently gained market authorisation for prevention of venous thromboembolism after knee arthroplasty.

However, there are no clinical trials with dabigatran and/or rivaroxaban and the comparator nadroparin.

Nadroparin is used in the most Dutch departments of orthopaedic surgery after total knee arthroplasty. Also safety of the new oral agents with long term use of 42 days is not available for total knee arthroplasty.

Our aim is to compare the long term use of dabigatran and rivaroxaban versus nadroparin on safety after total knee arthroplasty (TKA) in a clinical explorative pilot study by observing the incidence of major bleeding and clinical relevant non-major bleeding using a standardized model of bleeding definitions.

Objective:

The primary objective of this study is to compare the clinical safety with long term use of the oral once daily unmonitored thrombin inhibitors dabigatran and rivaroxaban versus subcutaneous administered nadroparin by observing the incidence of major bleeding and clinical relevant non-major bleeding in patients after knee arthroplasty surgery.

The secondary objectives of this study are effectivity of the agents, compliance, hospital stay, re-hospitalisation, outpatient clinic visits and interventions following complications. Additionally, coagulation monitoring, knee flexion range of motion, Knee injury and Osteoarthritis Outcome Score (KOOS), Knee Society Score (KSS) and relationship between health statuses and surgery parameters will be evaluated.

Study design:

The study is designed as non-inferiority randomized open label controlled pilot study. A total of 150 patients will be included, 50 patients in each treatment group (dabigatran, rivaroxaban and nadroparin).

Study population:

Patients ≥ 18 years and weighing more than 40 kg, participate in the 'joint care program' for primary elective total knee arthroplasty and want to provide signed informed consent are eligible for the study.

Intervention:

Patients receive subcutaneously nadroparin or oral rivaroxaban or oral dabigatran after knee replacement surgery.

Main study parameters/endpoints:

The primary safety outcome is the incidence of bleeding events occurring during the study period of 135 days (including follow-up). Major bleeding events and clinically relevant non-major bleeding events were defined according to accepted guidelines.

Study Overview

• Status: Completed
• Conditions: Venous Thromboembolism
• Intervention / Treatment: Drug: Rivaroxaban; Drug: Dabigatran; Drug: Nadroparin

• Study Type: Interventional
• Enrollment (Actual): 148
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands
    • Martini Ziekenhuis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 110 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients > 18 years and weighing more than 40 kg who are scheduled for primary elective total knee arthroplasty according to the 'joint care program' and want to provided signed informed consent are eligible for the study.

Exclusion Criteria:

• a known inherited or acquired clinically significant active high risk of bleeding or bleeding disorder;
• major surgery, trauma, uncontrolled severe arterial hypertension, or myocardial infarction within the last 3 months;
• history of acute intracranial disease or hemorrhagic stroke;
• gastrointestinal or urogenital bleeding or ulcer disease within the last 6 months;
• cirrhotic patients with moderate hepatic impairment (aspartate or alanine aminotransferase (AST, ALT) levels higher than 2x the upper limit of the normal range (ULN) within the last month);
• severe renal insufficiency (creatinine clearance < 30 mL/min);
• treatment with anticoagulants during study drug treatment;
• active malignant disease;
• pregnancy or breastfeeding;
• and unable to give informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dabigatran	Drug: Dabigatran; Dabigatran
Active Comparator: Rivaroxaban	Drug: Rivaroxaban; Rivaroxaban
Active Comparator: Nadroparin	Drug: Nadroparin; Nadroparin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary safety outcome is the incidence of bleeding events occurring during the study period of 135 days (including follow-up). Major bleeding events and clinically relevant non-major bleeding events were defined according to accepted guidelines	Major and clinically relevant non-major bleeding	135 days

Collaborators and Investigators

• Sponsor: Martini Hospital Groningen

Publications and helpful links

General Publications

• van der Veen L, Segers M, van Raay JJ, Gerritsma-Bleeker CL, Brouwer RW, Veeger NJ, van Hulst M. Bleeding complications of thromboprophylaxis with dabigatran, nadroparin or rivaroxaban for 6 weeks after total knee arthroplasty surgery: a randomised pilot study. BMJ Open. 2021 Jan 18;11(1):e040336. doi: 10.1136/bmjopen-2020-040336.
• Veen Lv, van Raay JJ, Gerritsma-Bleeker CL, Veeger NJ, Hulst Mv. Direct treatment comparison of DAbigatran and RIvaroxaban versus NAdroparin in the prevention of venous thromboembolism after total knee arthroplasty surgery: design of a randomised pilot study (DARINA). BMJ Open. 2013 Jan 24;3(1):e002218. doi: 10.1136/bmjopen-2012-002218.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2013
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: September 7, 2011
• First Submitted That Met QC Criteria: September 8, 2011
• First Posted (Estimate): September 9, 2011

Study Record Updates

• Last Update Posted (Actual): June 7, 2018
• Last Update Submitted That Met QC Criteria: June 5, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Prevention; venous thromboembolism after knee arthroplasty
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thromboembolism; Venous Thromboembolism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Dabigatran; Nadroparin
• Other Study ID Numbers: DARINA