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

NCT01431456 | Completed Phase 3 DMC

• 1 other identifier: DARINA
• Study Type: interventional
• Target: 148
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Venous Thromboembolism

Keywords

Prevention; venous thromboembolism after knee arthroplasty

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (3)

Dabigatran

ACTIVE COMPARATOR

Dabigatran

Drug: Dabigatran

Rivaroxaban

ACTIVE COMPARATOR

Rivaroxaban

Drug: Rivaroxaban

Nadroparin

ACTIVE COMPARATOR

Nadroparin

Drug: Nadroparin

Interventions

Dabigatran DRUG

Dabigatran

Dabigatran

Rivaroxaban DRUG

Rivaroxaban

Rivaroxaban

Nadroparin DRUG

Nadroparin

Nadroparin

Eligibility Criteria

• Age: 18 Years - 110 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Martini Hospital Groningen: lead

Study Sites (1)

Martini Ziekenhuis

Groningen, Netherlands

Location

Related Publications (2)

• 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.

  PMID: 33462096 DERIVED

• 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.

  PMID: 23355673 DERIVED

MeSH Terms

Conditions

Venous Thromboembolism

Interventions

Dabigatran; Rivaroxaban; Nadroparin

Condition Hierarchy (Ancestors)

Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Heparin, Low-Molecular-Weight; Heparin; Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Hospital Pharmacist

Study Record Dates

• First Submitted: September 7, 2011
• First Posted: September 9, 2011
• Study Start: September 1, 2013
• Primary Completion: October 1, 2014
• Study Completion: October 1, 2014
• Last Updated: June 7, 2018

Record last verified: 2018-06

Locations

NL (1)