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

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ClinicalTrials.gov Identifier: NCT03862859
Recruitment Status : Recruiting
First Posted : March 5, 2019
Last Update Posted : October 17, 2019
Sponsor:
Collaborator:
Danish Heart Foundation
Information provided by (Responsible Party):
Nicholas Carlson, Rigshospitalet, Denmark

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 de novo atrial fibrillation.

Condition or disease Intervention/treatment Phase
Atrial Fibrillation and Flutter Stroke Major Bleed End-stage Renal Disease Drug: Warfarin Phase 4

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 de novo diagnosis of 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 718 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A multicentre, randomized, open label, parallel group study.
Masking: None (Open Label)
Masking Description: None (Open Label
Primary Purpose: Prevention
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
Actual Study Start Date : October 9, 2019
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2024

Resource links provided by the National Library of Medicine


Arm Intervention/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:
  • Coumadin
  • Marevan
  • Jantoven

No Intervention: No treatment
No treatment



Primary Outcome Measures :
  1. Primary efficacy outcome - Number of participants with transient ischemic attack, fatal and non-fatal ischaemic or unspecific stroke [ Time Frame: From randomization to end of observation - up to 4 years ]
    Any transient ischemic attack, fatal and non-fatal ischaemic or unspecific stroke or death attributable to either ischemic or undefined stroke

  2. Primary safety outcome - Number of participants with fatal or non-fatal major bleeding [ Time Frame: From randomization to end of observation - up to 4 years ]
    Any major bleeding as defined in accordance with the International Society on Thrombosis and Hemostasis definition pertaining to major bleeding in non-surgical patients


Secondary Outcome Measures :
  1. Number of participants with ischemic or unspecified stroke [ Time Frame: From time of randomization to end of observation - up to 4 years ]
    Any non-fatal or fatal ischemic stroke or unspecified stroke event

  2. Number of participants with ischemic stroke [ Time Frame: From time of randomization to end of observation - up to 4 years ]
    Any non-fatal or fatal ischemic stroke event

  3. Number of participants with hemorrhagic stroke [ Time Frame: From time of randomization to end of observation - up to 4 years ]
    Any non-fatal or fatal hemorrhagic stroke event

  4. Number of participants with ischemic or hemorrhagic stroke [ Time Frame: From time of randomization to end of observation - up to 4 years ]
    Any non-fatal or fatal ischemic or hemorrhagic stroke event

  5. Number of deaths [ Time Frame: From time of randomization to end of observation - up to 4 years ]
    All-cause mortality

  6. The combination of any non-fatal stroke and all-cause mortality [ Time Frame: From time of randomization to end of observation - up to 4 years ]
    Number of participants with either non-fatal ischemic or hemorrhagic stroke of death due to any cause

  7. The combination of any non-fatal stroke, any non-fatal major bleeding, and all-cause mortality [ Time Frame: From time of randomization to end of observation - up to 4 years ]
    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


Other Outcome Measures:
  1. Discontinuation of the allocated randomized therapy [ Time Frame: From time of randomization to end of observation - up to 4 years ]
    Number of participants discontinuing the allocated randomized therapy irrespective of cause

  2. Number of participants with peripheral artery disease [ Time Frame: From time of randomization to end of observation - up to 4 years ]
    Any diagnosis of previously unverified peripheral artery disease

  3. Number of participants with fatal or non-fatal acute myocardial infarction [ Time Frame: From randomization to end of observation - up to 4 years ]
    Any non-fatal or fatal acute myocardial infarction event

  4. Number of participants with calciphylaxis [ Time Frame: From time of randomization to end of observation - up to 4 years ]
    Development of calciphylaxis as defined by clinical diagnosis

  5. Number of participants hospitalized due to left-sided heart failure [ Time Frame: From time of randomization to end of observation - up to 4 years ]
    Any hospitalization due to left-sided heart failure as defined by de novo LVEF <30% with echocardiographic verification

  6. Percentage of participants with arteriovenous fistula thrombosis [ Time Frame: From randomization to end of observation - up to 4 years ]
    Arteriovenous fistula thrombosis in participants dialyzed via an arteriovenous fistula

  7. Number of participants with osteoporotic fractures [ Time Frame: From randomization to end of observation - up to 4 years ]
    Osteoporotic fractures as defined by low energy fractures of the proximal femur, distal radius, humerus, pelvis, and vertebrae



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients ≥18 years on chronic dialysis due to end-stage renal disease with de novo diagnosis of non-valvular 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03862859


Contacts
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Contact: Nicholas Carlson, MD PhD +45 35455827 nicholas.carlson.01@regionh.dk
Contact: Gunnar H Gislason, Prof MD PhD +45 70 25 00 00 Gunnar.Gislason@regionh.dk

Locations
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Denmark
Department of Nephrology, Copenhagen University Hospital Rigshospitalet Recruiting
Copenhagen, Denmark, 2100
Contact: Nicholas Carlson, MD PhD    +45 35455927    nicholas.carlson.01@regionh.dk   
Principal Investigator: Nicholas Carlson, MD PhD         
Department of Nephrology, Herlev Hospital Not yet recruiting
Herlev, Denmark, 2730
Contact: Kristine Lindhard Rasmussen, MD       kristine.lindhard.rasmussen@regionh.dk   
Principal Investigator: Kristine Lindhard Rasmussen, MD         
Department of nephrology, Nordsjaellands Hospital Not yet recruiting
Hillerød, Denmark, 3400
Contact: Lisbet Brandi, MD DMSc       lisbet.brandi@regionh.dk   
Principal Investigator: Lisbet Brandi, MD DMSc         
Sponsors and Collaborators
Nicholas Carlson
Danish Heart Foundation
Investigators
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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

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Responsible Party: Nicholas Carlson, Principal Investigator, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT03862859     History of Changes
Other Study ID Numbers: DANWARD 1.21
2018-000484-86 ( EudraCT Number )
First Posted: March 5, 2019    Key Record Dates
Last Update Posted: October 17, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data for primary and secondary outcomes measures will be made available
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Data will be available within 12 months of study completion
Access Criteria: Data access requests will be reviewed, requestors will be required to sign a Data Access Agreement.

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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
Additional relevant MeSH terms:
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Kidney Failure, Chronic
Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Kidney Diseases
Urologic Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Warfarin
Anticoagulants