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

Stroke Clinical Trial

— DANWARD  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03862859
• Other study ID #: DANWARD 1.26
• Secondary ID: 2018-000484-86
• Status: Recruiting
• Phase: Phase 4
• Start date: October 9, 2019
• Est. completion date: January 2027

Study information

• Verified date: February 2024
• Source: Rigshospitalet, Denmark
• Contact: Nicholas Carlson, MD PhD
• Phone: +45 35455827
• Email: nicholas.carlson.01[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 718
• Est. completion date: January 2027
• Est. primary completion date: January 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atrial Fibrillation
• Atrial Fibrillation and Flutter
• End-stage Renal Disease
• Kidney Failure, Chronic
• Major Bleed
• Stroke

Intervention

Drug:
• Warfarin
Dose adjusted Warfarin targeting an international normalized ratio of 2-3.

Locations

Country	Name	City	State
Denmark	Aalborg University Hosptial	Aalborg
Denmark	Aarhus University Hospital	Aarhus
Denmark	Department of Nephrology, Copenhagen University Hospital Rigshospitalet	Copenhagen
Denmark	Esbjerg and Grindsted Hospital	Esbjerg
Denmark	Department of Nephrology, Herlev Hospital	Herlev
Denmark	Department of nephrology, Nordsjaellands Hospital	Hillerød
Denmark	Holbaek Hospital	Holbæk
Denmark	Holstebro Hospital	Holstebro
Denmark	Lillebælt Hospital	Kolding
Denmark	Bornholms Hospital	Rønne
Denmark	Zealand University Hospital	Roskilde
Denmark	Hospital Sønderjylland	Sønderborg
Denmark	Viborg Regional Hospital	Viborg

Sponsors (2)

Lead Sponsor	Collaborator
Nicholas Carlson	Danish Heart Foundation

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Number of deaths	All-cause mortality	From time of randomization to end of observation - up to 4 years
Secondary	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
Secondary	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