Clinical trial NCT03862859: The Danish Warfarin-Dialysis Study - Safety and Efficacy of Warfarin in Patients With Atrial Fibrillation on Dialysis
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Atrial Fibrillation and Flutter
Stroke
Major Bleed
End-stage Renal Disease
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Danish Heart Foundation
First posted: 2019-03-05
Enrollment: 718
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A multicentre, randomized, open label, parallel group study.
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Primary efficacy outcome - Number of participants with transient ischemic attack, fatal and non-fatal ischaemic or unspecific stroke
timeFrame: From randomization to end of observation - up to 4 years
measure: Primary safety outcome - Number of participants with fatal or non-fatal major bleeding
timeFrame: From randomization to end of observation - up to 4 years
Secondary outcomes:
measure: Number of participants with ischemic or unspecified stroke
timeFrame: From time of randomization to end of observation - up to 4 years
measure: Number of participants with ischemic stroke
timeFrame: From time of randomization to end of observation - up to 4 years
measure: Number of participants with hemorrhagic stroke
timeFrame: From time of randomization to end of observation - up to 4 years
measure: Number of participants with ischemic or hemorrhagic stroke
timeFrame: From time of randomization to end of observation - up to 4 years
measure: Number of deaths
timeFrame: From time of randomization to end of observation - up to 4 years
measure: The combination of any non-fatal stroke and all-cause mortality
timeFrame: From time of randomization to end of observation - up to 4 years
measure: The combination of any non-fatal stroke, any non-fatal major bleeding, and all-cause mortality
timeFrame: From time of randomization to end of observation - up to 4 years
Other outcomes:
measure: Discontinuation of the allocated randomized therapy
timeFrame: From time of randomization to end of observation - up to 4 years
measure: Number of participants with peripheral artery disease
timeFrame: From time of randomization to end of observation - up to 4 years
measure: Number of participants with fatal or non-fatal acute myocardial infarction
timeFrame: From randomization to end of observation - up to 4 years
measure: Number of participants with calciphylaxis
timeFrame: From time of randomization to end of observation - up to 4 years
measure: Number of participants hospitalized due to left-sided heart failure
timeFrame: From time of randomization to end of observation - up to 4 years
measure: Percentage of participants with arteriovenous fistula thrombosis
timeFrame: From randomization to end of observation - up to 4 years
measure: Number of participants with osteoporotic fractures
timeFrame: From randomization to end of observation - up to 4 years
Locations:
city: Aalborg
country: Denmark
facility: Aalborg University Hosptial
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Department of Nephrology, Copenhagen University Hospital Rigshospitalet
city: Esbjerg
country: Denmark
facility: Esbjerg and Grindsted Hospital
city: Herlev
country: Denmark
facility: Department of Nephrology, Herlev Hospital
city: Hillerød
country: Denmark
facility: Department of nephrology, Nordsjaellands Hospital
city: Holbæk
country: Denmark
facility: Holbaek Hospital
city: Holstebro
country: Denmark
facility: Holstebro Hospital
city: Kolding
country: Denmark
facility: Lillebælt Hospital
city: Roskilde
country: Denmark
facility: Zealand University Hospital
city: Rønne
country: Denmark
facility: Bornholms Hospital
city: Sønderborg
country: Denmark
facility: Hospital Sønderjylland
city: Viborg
country: Denmark
facility: Viborg Regional Hospital
Study officials:
affiliation: Department of Nephrology, Copenhagen University Hospital Rigshospitalet
name: Nicholas Carlson, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Danish Heart Foundation
name: Gunnar H Gislason, Prof MD PhD
role: STUDY_CHAIR
affiliation: Department of Nephrology, Copenhagen University Hospital Rigshospitalet
name: Anne-Lise Kamper, MD DMSc
role: STUDY_CHAIR
affiliation: Department of Cardiology, North Zealand Hospital
name: Christian Torp-Pedersen, Prof MD DMSc
role: STUDY_CHAIR
affiliation: Department of Cardiology, Copenhagen University Hospital Gentofte
name: Jonas B Olesen, MD PhD
role: STUDY_CHAIR
affiliation: Department of Cardiology, Frederiksberg and Bispebjerg Hospital
name: Casper Bang, MD PhD
role: STUDY_CHAIR
affiliation: Danish Heart Foundation
name: Thomas A Gerds, Prof
role: STUDY_CHAIR
affiliation: Department of Nephrology, Copenhagen University Hospital Herlev
name: Ditte Hansen, MD PhD
role: STUDY_CHAIR
affiliation: Department of Cardiology, Copenhagen University Hospital Herlev
name: Morten Schou, Prof MD PhD
role: STUDY_CHAIR
affiliation: Department of Nephrology, Copenhagen University Hospital Rigshospitalet
name: Mads Hornum, Prof MD PhD
role: STUDY_CHAIR
affiliation: Department of Cardiology, Aarhus University Hospital
name: Erik Grove, MD PhD
role: STUDY_CHAIR
affiliation: Department of Nephrology, Aarhus University Hospital
name: Jens D Jensen, MD PhD
role: STUDY_CHAIR
affiliation: Department of Nephrology, Copenhagen University Hospital Rigshospitalet
name: Ellen Linnea F Ballegaard, MD
role: STUDY_CHAIR
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