Strategies for the Management of Atrial Fibrillation in patiEnts Receiving Dialysis

Study Overview
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Brief Summary
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The prevention of atrial fibrillation related thromboembolism in the dialysis population is unclear. While the practice of anticoagulation appears favorable in patients with mild-to-moderate chronic kidney disease, no patients with severe chronic kidney disease (estimated glomerular filtration rate <25 ml/min), and specifically those receiving dialysis, have been included in randomized trials.Moreover, the effect of anticoagulation in the dialysis population may fundamentally differ from those studied in clinical trials. Accordingly, characterization of the optimal management strategy to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation receiving dialysis is a priority. The overall goal of this pilot trial is to evaluate the feasibility of conducting a randomized controlled trial comparing anticoagulation strategies in patients with atrial fibrillation receiving dialysis (either hemodialysis or peritoneal dialysis).

Official Title
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Strategies for the Management of Atrial Fibrillation in patiEnts Receiving Dialysis (SAFE-D)

Conditions
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Atrial Fibrillation, End Stage Renal Failure on Dialysis

Intervention / Treatment
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* Drug: Warfarin
* Drug: Apixaban
* Other: No oral anticoagulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Receiving maintenance hemodialysis or peritoneal dialysis for > 90 days. History of AF or atrial flutter as defined by: (i) AF or atrial flutter on a 12 lead ECG at enrollment, and not due to a reversible cause, or (ii) AF or atrial flutter documented on two separate occasions, not due to a reversible cause, at least 1 day apart prior to enrollment. AF or atrial flutter may be documented by ECG, or as an episode lasting at least 30 seconds on a rhythm strip or Holter recording, or more than 30 minutes if using pacemaker or implantable cardioverter defibrillator (ICD) recordings, or (iii) AF or atrial flutter documented on one occasion, not due to a reversible cause, prior to enrollment and being treated with an oral anticoagulant for AF or atrial flutter at enrollment. [AF or atrial flutter may be documented by ECG, or as an episode lasting at least 30 seconds on a rhythm strip or Holter recording, or more than 30 minutes if using pacemaker or implantable cardioverter defibrillator (ICD) recordings, or mentioned in the medical record], or (iv) AF or atrial flutter documented on one occasion on ECG, not due to a reversible cause, prior to enrollment and at least one more episode of AF or atrial flutter mentioned in the medical record, or (v) AF or atrial flutter documented on one occasion in a cardiologist report, not due to a reversible condition, prior to enrollment. Satisfying CHADS-65 criteria: i) Age ≥65 or ii) Age <65 and one of: hypertension, diabetes mellitus, congestive heart failure, stroke/transient ischemic attack or peripheral embolism. Exclusion Criteria: Moderate or severe mitral stenosis. Conditions other than non-valvular atrial fibrillation that require oral anticoagulation, such as mechanical prosthetic valve, deep venous thrombosis, or pulmonary embolism. Need for aspirin at a dose > 165 mg a day, or need for aspirin in combination with P2Y12 antagonist therapy. Need for an interacting drug which precludes the safe use of apixaban. Life expectancy < 6 months. Scheduled live-donor kidney transplant in the next 6 months. A woman who is pregnant or breastfeeding or unwilling to pursue methods of contraception if < 12 months since the last menstrual period. Co-enrollment in a clinical trial where the intervention is deemed to interfere with the adherence, safety or efficacy of the intervention provided herein. Patient's attending physician(s) (e.g., nephrologist and/or cardiologist and/or neurologist) believes that oral anticoagulation is absolutely mandated. Patient's attending physician(s) (e.g., nephrologist and/or cardiologist and/or neurologist) believes that oral anticoagulation is absolutely contraindicated.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Warfarin<br>Individuals randomized to this arm will be exposed to dose-adjusted daily warfarin targeting an international normalized ratio (INR) of 2.0-3.0. | Drug: Warfarin<br>* Individuals randomized to this arm will be exposed to dose-adjusted daily warfarin targeting an international normalized ratio (INR) of 2.0-3.0.<br>* Other names: Coumadin;|
| Active Comparator: Apixaban<br>Individuals randomized to this arm will receive apixaban 5 mg twice daily (a reduced dose of 2.5 mg twice daily will be given to selected participants). | Drug: Apixaban<br>* Individuals randomized to this arm will receive apixaban 5 mg twice daily (a reduced dose of 2.5 mg twice daily will be given to selected participants).<br>* Other names: Eliquis;|
| Active Comparator: No oral anticoagulation<br>Individuals in this arm will be exposed to a treatment strategy in which no oral anticoagulation is prescribed. | Other: No oral anticoagulation<br>* No oral anticoagulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment of the target population within 2 years |  | 2 years from start of trial | 
| At least 80% of randomized participants remain in the trial and on the allocated study treatment at the end of the 26-week study period. |  | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients randomized to warfarin achieving a Time in the Therapeutic Range (TTR) >65%. |  | 26 weeks | 
| >95% of randomized patients adhere to the enrollment criteria with respect to atrial fibrillation or atrial flutter | Through adjudication of ECGs or other cardiac diagnostics | End of trial | 
| Major bleeding | As defined by the International Society of Thrombosis and Haemostasis (ISTH) | 26 weeks | 
| Clinically relevant non-major bleeding | As defined by the International Society of Thrombosis and Haemostasis (ISTH) | 26 weeks | 
| Stroke and systemic embolism |  | 26 weeks | 
| All cause mortality |  | 26 weeks | 
| Non-fatal myocardial infarction |  | 26 weeks | 
| Vascular events not related to dialysis access |  | 26 weeks | 
| Events of special interest related to dialysis access, the dialysis procedure or the oral anticoagulants | Thrombosis of fistula or graft; fistula or graft abandonment; thrombosis of dialysis catheter; red blood cell transfusions; calciphylaxis | 26 weeks |