Atrial Fibrillation and Flutter, End-stage Renal Disease, Major Bleed, Stroke
Conditions
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.
Interventions
DRUGWarfarin
Dose adjusted Warfarin targeting an international normalized ratio of 2-3.
Sponsors
Nicholas Carlson
Danish Heart Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Masking description
None (Open Label
Intervention model description
A multicentre, randomized, open label, parallel group study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary efficacy outcome - Number of participants with transient ischemic attack, fatal and non-fatal ischaemic or unspecific stroke | 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 |
| Primary safety outcome - Number of participants with fatal or non-fatal major bleeding | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with ischemic or unspecified stroke | From time of randomization to end of observation - up to 4 years | Any non-fatal or fatal ischemic stroke or unspecified stroke event |
| Number of participants with ischemic stroke | From time of randomization to end of observation - up to 4 years | Any non-fatal or fatal ischemic stroke event |
| Number of participants with hemorrhagic stroke | From time of randomization to end of observation - up to 4 years | Any non-fatal or fatal hemorrhagic stroke event |
| Number of participants with ischemic or hemorrhagic stroke | From time of randomization to end of observation - up to 4 years | Any non-fatal or fatal ischemic or hemorrhagic stroke event |
| Number of deaths | From time of randomization to end of observation - up to 4 years | All-cause mortality |
| The combination of any non-fatal stroke and all-cause mortality | 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 |
| The combination of any non-fatal stroke, any non-fatal major bleeding, and all-cause mortality | 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 |
Countries
Denmark
Contacts
CONTACTNicholas Carlson, MD PhD Ass. Prof
CONTACTEllen LF Ballegaard, MD PhD
PRINCIPAL_INVESTIGATORNicholas Carlson, MD PhD
Department of Nephrology, Copenhagen University Hospital Rigshospitalet
STUDY_CHAIRAnne-Lise Kamper, MD DMSc
Department of Nephrology, Copenhagen University Hospital Rigshospitalet
STUDY_CHAIRChristian Torp-Pedersen, Prof MD DMSc
Department of Cardiology, North Zealand Hospital
STUDY_CHAIRDitte Hansen, MD PhD
Department of Nephrology, Copenhagen University Hospital Herlev
STUDY_CHAIRMads Hornum, Prof MD PhD
Department of Nephrology, Copenhagen University Hospital Rigshospitalet
STUDY_CHAIRErik Grove, MD PhD
Department of Cardiology, Aarhus University Hospital
STUDY_CHAIREllen Linnea F Ballegaard, MD
Department of Nephrology, Copenhagen University Hospital Rigshospitalet
STUDY_CHAIRChristian D Peters, MD PhD
Department of Nephrology, Aarhus University Hospital
Outcome results
None listed