The Danish Warfarin-Dialysis Study - Safety and Efficacy of Warfarin in Patients With Atrial Fibrillation on Dialysis (DANWARD)

The Danish Warfarin-Dialysis Study: Safety and Efficacy of Warfarin in Patients With Atrial Fibrillation on Dialysis - A Nationwide Parallel-group Open Randomized Clinical Trial

The study aims to evaluate the appropriateness of initiating oral anticoagulation for stroke risk reduction in dialysis populations with atrial fibrillation. Specifically, the study will assess the overall safety, tolerability, and efficacy of initiating treatment with Warfarin in patients with end-stage renal disease on dialysis and atrial fibrillation.

Study Overview

• Status: Recruiting
• Conditions: Stroke; End-stage Renal Disease; Atrial Fibrillation and Flutter; Major Bleed
• Intervention / Treatment: Drug: Warfarin

Detailed Description

Data pertaining to the tolerability, safety, and benefit of initiating anticoagulation for stroke risk reduction in patients with end-stage renal disease and atrial fibrillation remains conflicting and insufficient. Patients on dialysis continue to be routinely excluded from randomized controlled trials, and evidence from observational studies is plausibly biased. The main objective of the following parallel-group open randomized clinical trial presents a nationwide study aimed at investigating the benefit, tolerability, and safety of initiating warfarin versus no treatment in patients with atrial fibrillation on dialysis. The anticipated results from this project will provide conclusive evidence as to the appropriateness of initiating oral anticoagulation for stroke risk reduction in dialysis populations with atrial fibrillation with direct effects on clinical management and international guidelines pertaining to these patients.

The study is planned as a multicentre, randomized, open label, parallel group trial with planned inclusion of a total of 718 patients (359 patients per arm). Dialysis-treated patients with end-stage renal disease with paroxysmal, persistent, or permanent atrial fibrillation will be enrolled and randomized to either treatment with warfarin or no treatment. Randomization with be attained using a 1:1 allocation as per a computer-generated randomization schedule stratified by gender, age by decade, and center using permuted blocks of random sizes. Study participants will be allocated to treatment in accordance with the randomization for the full duration of the trial i.e. at a minimum one year following randomization, and followed with regular monitoring for the the primary efficacy outcome of ischemic stroke or death due to ischemic or unspecified stroke and the primary safety outcome of major bleeding defined in accordance with the International Society on Thrombosis and Hemostasis definition.

• Study Type: Interventional
• Enrollment (Estimated): 718
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Nicholas Carlson, MD PhD; Phone Number: +45 35455827; Email: nicholas.carlson.01@regionh.dk
• Study Contact Backup: Name: Gunnar H Gislason, Prof MD PhD; Phone Number: +45 70 25 00 00; Email: Gunnar.Gislason@regionh.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9100
    • Recruiting
    • Aalborg University Hosptial
    • Contact: Jesper M Rantanen, MD PhD; Email: jemr@rn.dk
  • Aarhus, Denmark, 8200
    • Recruiting
    • Aarhus University Hospital
    • Contact: Christian D Peters, MD PhD; Email: chipte@rm.dk
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Department of Nephrology, Copenhagen University Hospital Rigshospitalet
    • Contact: Nicholas Carlson, MD PhD; Phone Number: +45 35455927; Email: nicholas.carlson.01@regionh.dk
    • Principal Investigator: Nicholas Carlson, MD PhD
  • Esbjerg, Denmark, 6700
    • Recruiting
    • Esbjerg and Grindsted Hospital
    • Contact: Alice S Nielsen, MD; Email: alice.skovhede.nielsen@rsyd.dk
    • Contact: Johanne K Breinholt, MD; Email: johanne.kodal.breinholt@rsyd.dk
  • Herlev, Denmark, 2730
    • Recruiting
    • Department of Nephrology, Herlev Hospital
    • Contact: Kristine Lindhard Rasmussen, MD; Email: kristine.lindhard.rasmussen@regionh.dk
    • Principal Investigator: Kristine Lindhard Rasmussen, MD
  • Hillerød, Denmark, 3400
    • Recruiting
    • Department of nephrology, Nordsjaellands Hospital
    • Contact: Marianne Bertelsen, MD; Email: marianne.camilla.bertelsen@regionh.dk
    • Principal Investigator: Marianne Bertelsen, MD
  • Holbæk, Denmark, 4300
    • Recruiting
    • Holbaek Hospital
    • Contact: Morten Lindhardt, MD PhD; Email: moli@regionsjaelland.dk
  • Holstebro, Denmark, 7500
    • Recruiting
    • Holstebro Hospital
    • Contact: Frank H Mose, MD PhD; Email: frank.holden.christensen@vest.rm.dk
  • Kolding, Denmark
    • Recruiting
    • Lillebælt Hospital
    • Contact: Donata Cibulskyte-Ninkovic, MD; Email: donata.cibulskyte-ninkovic@rsyd.dk
  • Roskilde, Denmark, 4000
    • Recruiting
    • Zealand University Hospital
    • Contact: Rikke Borg, MD PhD; Email: rbor@regionsjaelland.dk
    • Sub-Investigator: Lene Boesby, MD PhD
  • Rønne, Denmark, 3700
    • Recruiting
    • Bornholms Hospital
    • Contact: Finn T Nielsen, MD; Email: finnthomsen.nielsen@regionh.dk
  • Sønderborg, Denmark, 6400
    • Recruiting
    • Hospital Sønderjylland
    • Contact: Jan D Kampmann, MD; Email: jdk@rsyd.dk
  • Viborg, Denmark, 8800
    • Recruiting
    • Viborg Regional Hospital
    • Contact: Ida Tietze, MD PhD; Email: ida@tietze.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients ≥18 years on chronic dialysis due to end-stage renal disease
• Non-valvular paroxysmal, persistent, or permanent atrial fibrillation OR non-treated (for >2 months) prevalent paroxysmal, persistent or permanent atrial fibrillation as documented by an electrocardiogram or an episode of ≥30 seconds on Holter monitor, or episodes ≥ 6 minutes on event recorders or any other recording device.
• Competence to understand the study rationale, including potential risks and benefits associated with treatment, necessary for written informed consent.

Exclusion Criteria:

• CHA2DS2-VASc Score ≤1
• Other indications for oral anticoagulation treatment (pulmonary embolism < 6 months, deep vein thrombosis <3 months, mechanical heart valve prosthesis) irrespective of whether treatment is implemented
• Ongoing dual antiplatelet treatment
• Malignancy (with exception of non-melanoma skin cancer) with recent < 1 year, ongoing, or planned curative, or palliative chemo- , radiation-, and/or scheduled surgical therapy
• Endoscopy with gastrointestinal ulcer <1 month
• Esophageal varices
• Autoimmune og genetic coagulation disorders
• Congenital alactasia, Lapp Lactase deficiency or glucose-galactose malabsorption
• Pending spinal tap
• Cerebrovascular malformations
• Arterial aneurysms
• Ulcers or wounds (Wagner grad >1)
• Bacterial endocarditis < 3 months
• Active bleeding contraindicating anticoagulation
• Any non-elective and/or non-ambulant surgery <7 days
• Cerebral hemorrhage <4 weeks
• Thrombocytopenia (platelet count <100 × 109/L) <30 days.
• Severe liver insufficiency (spontaneous international normalized ratio >1.5) <30 days.
• Known intolerance to warfarin
• Use of hypericum perforatum / St. John's Wort
• Uncontrolled hypertension (repeat blood pressure >180/110 mmhg) < 30 days
• Uncontrolled hyperthyroidism (thyroid-stimulating hormone <0.1μIU/mL) <30 days
• Pregnancy or lactation
• Participation in other ongoing intervention trials adjudged to influence study outcomes

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: No treatment
Active Comparator: Treatment with Warfarin; Warfarin with dosing targeting an international normalized ratio of 2-3.	Drug: Warfarin; Dose adjusted Warfarin targeting an international normalized ratio of 2-3.; Other Names: Marevan; Coumadin; Jantoven

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary efficacy outcome - Number of participants with transient ischemic attack, fatal and non-fatal ischaemic or unspecific stroke	Any transient ischemic attack, fatal and non-fatal ischaemic or unspecific stroke or death attributable to either ischemic or undefined stroke	From randomization to end of observation - up to 4 years
Primary safety outcome - Number of participants with fatal or non-fatal major bleeding	Any major bleeding as defined in accordance with the International Society on Thrombosis and Hemostasis definition pertaining to major bleeding in non-surgical patients	From randomization to end of observation - up to 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with ischemic or unspecified stroke	Any non-fatal or fatal ischemic stroke or unspecified stroke event	From time of randomization to end of observation - up to 4 years
Number of participants with ischemic stroke	Any non-fatal or fatal ischemic stroke event	From time of randomization to end of observation - up to 4 years
Number of participants with hemorrhagic stroke	Any non-fatal or fatal hemorrhagic stroke event	From time of randomization to end of observation - up to 4 years
Number of participants with ischemic or hemorrhagic stroke	Any non-fatal or fatal ischemic or hemorrhagic stroke event	From time of randomization to end of observation - up to 4 years
Number of deaths	All-cause mortality	From time of randomization to end of observation - up to 4 years
The combination of any non-fatal stroke and all-cause mortality	Number of participants with either non-fatal ischemic or hemorrhagic stroke of death due to any cause	From time of randomization to end of observation - up to 4 years
The combination of any non-fatal stroke, any non-fatal major bleeding, and all-cause mortality	Number of participants with either non-fatal ischemic or hemorrhagic stroke, any non-fatal major bleeding as defined in accordance with the International Society on Thrombosis and Hemostasis definition pertaining to major bleeding in non-surgical patients, or death due to any cause	From time of randomization to end of observation - up to 4 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Discontinuation of the allocated randomized therapy	Number of participants discontinuing the allocated randomized therapy irrespective of cause	From time of randomization to end of observation - up to 4 years
Number of participants with peripheral artery disease	Any diagnosis of previously unverified peripheral artery disease	From time of randomization to end of observation - up to 4 years
Number of participants with fatal or non-fatal acute myocardial infarction	Any non-fatal or fatal acute myocardial infarction event	From randomization to end of observation - up to 4 years
Number of participants with calciphylaxis	Development of calciphylaxis as defined by clinical diagnosis	From time of randomization to end of observation - up to 4 years
Number of participants hospitalized due to left-sided heart failure	Any hospitalization due to left-sided heart failure as defined by de novo LVEF <30% with echocardiographic verification	From time of randomization to end of observation - up to 4 years
Percentage of participants with arteriovenous fistula thrombosis	Arteriovenous fistula thrombosis in participants dialyzed via an arteriovenous fistula	From randomization to end of observation - up to 4 years
Number of participants with osteoporotic fractures	Osteoporotic fractures as defined by low energy fractures of the proximal femur, distal radius, humerus, pelvis, and vertebrae	From randomization to end of observation - up to 4 years

Collaborators and Investigators

• Sponsor: Nicholas Carlson
• Collaborators: Danish Heart Foundation
• Investigators: Principal Investigator: Nicholas Carlson, MD PhD, Department of Nephrology, Copenhagen University Hospital Rigshospitalet; Study Chair: Gunnar H Gislason, Prof MD PhD, Danish Heart Foundation; Study Chair: Anne-Lise Kamper, MD DMSc, Department of Nephrology, Copenhagen University Hospital Rigshospitalet; Study Chair: Christian Torp-Pedersen, Prof MD DMSc, Department of Cardiology, North Zealand Hospital; Study Chair: Jonas B Olesen, MD PhD, Department of Cardiology, Copenhagen University Hospital Gentofte; Study Chair: Casper Bang, MD PhD, Department of Cardiology, Frederiksberg and Bispebjerg Hospital; Study Chair: Thomas A Gerds, Prof, Danish Heart Foundation; Study Chair: Ditte Hansen, MD PhD, Department of Nephrology, Copenhagen University Hospital Herlev; Study Chair: Morten Schou, Prof MD PhD, Department of Cardiology, Copenhagen University Hospital Herlev; Study Chair: Mads Hornum, Prof MD PhD, Department of Nephrology, Copenhagen University Hospital Rigshospitalet; Study Chair: Erik Grove, MD PhD, Department of Cardiology, Aarhus University Hospital; Study Chair: Jens D Jensen, MD PhD, Department of Nephrology, Aarhus University Hospital; Study Chair: Ellen Linnea F Ballegaard, MD, Department of Nephrology, Copenhagen University Hospital Rigshospitalet

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2019
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: February 22, 2019
• First Submitted That Met QC Criteria: March 1, 2019
• First Posted (Actual): March 5, 2019

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 23, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Disease Attributes; Renal Insufficiency; Arrhythmias, Cardiac; Renal Insufficiency, Chronic; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Atrial Fibrillation; Kidney Failure, Chronic; Anticoagulants; Warfarin
• Other Study ID Numbers: DANWARD 1.26; 2018-000484-86 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data for primary and secondary outcomes measures will be made available
• IPD Sharing Time Frame: Data will be available within 12 months of study completion
• IPD Sharing Access Criteria: Data access requests will be reviewed, requestors will be required to sign a Data Access Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No