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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Atrial Fibrillation and Flutter, Stroke, Major Bleed, End-stage Renal Disease

Intervention / Treatment
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* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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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, prior atrial fibrillation, 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A multicentre, randomized, open label, parallel group study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment with Warfarin<br>Warfarin with dosing targeting an international normalized ratio of 2-3. | Drug: Warfarin<br>* Dose adjusted Warfarin targeting an international normalized ratio of 2-3.<br>* Other names: Jantoven;|
| No Intervention: No treatment<br>No treatment | |

What is the study measuring?
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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 |