Trial to Evaluate Anticoagulation Therapy in Hemodialysis Patients With Atrial Fibrillation

Study Overview
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Brief Summary
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This is a prospective, randomized, open-label, blinded end-point evaluation trial. The patient population consists of patients on hemodialysis who have atrial fibrillation (AF) and end-stage renal disease (ESRD) .

Detailed Description
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This is a multicenter study in adult patients with AF and ESRD who are on hemodialysis and who have stroke risk factors making them candidates for oral anticoagulation. Patients will be randomized to apixaban versus warfarin, and will be treated for up to 15 months.

Official Title
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RENal Hemodialysis Patients ALlocated Apixaban Versus Warfarin in Atrial Fibrillation (RENAL-AF) Randomized Clinical Trial

Conditions
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Atrial Fibrillation, End Stage Renal Disease

Intervention / Treatment
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* Drug: apixaban
* Drug: warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, age at least 18 years, or the local age of consent, whichever is greater. Patients with AF defined as AF on ECG at enrollment or two or more reports of AF from separate monitoring events at least 2 weeks apart (report of ECG, Holter monitor, event monitor or implantable loop recorder). CHA2DS2-VASc score of ≥ 2. End-stage renal disease treated with hemodialysis for ≥ 3 months. Considered by the treating physician(s) to be candidate for oral anticoagulation. If of childbearing potential, be willing to avoid pregnancy during the study. Exclusion Criteria: Not considered by the treating physician(s) to be candidates for oral anticoagulation (for example, hemoglobin < 8.5g/dL, history of intracranial hemorrhage, active bleeding, recent gastrointestinal bleed or retroperitoneal bleed, severe hepatic impairment, or anaphylactic reaction to apixaban) Moderate or severe mitral stenosis Conditions other than AF that require anticoagulation such as mechanical prosthetic valve, deep venous thrombosis, or pulmonary embolism Need for aspirin at a dose > 81 mg a day or need for P2Y12 antagonist therapy (for example clopidogrel, prasugrel, or ticagrelor) Life expectancy < 3 months Anticipated kidney transplant within the next 3 months Prisoners or others who are involuntarily incarcerated or detained Pregnant, breastfeeding, or considering pregnancy. Participation in a clinical trial of an experimental treatment within the past 30 days

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: apixaban<br>apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients) | Drug: apixaban<br>* oral anticoagulant<br>* Other names: Eliquis;|
| Experimental: warfarin<br>warfarin daily dose adjusted to target International Normalized Ration(INR) of 2-3 | Drug: warfarin<br>* oral anticoagulant<br>* Other names: Jantoven;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing ISTH (International Society on Thrombosis and Haemostasis) Major or Clinically Relevant Non-major Bleeding | Assess the safety of apixaban versus warfarin regarding ISTH major bleeding or clinically relevant non-major bleeding events in patients with NVAF (nonvalvular atrial fibrillation) and ESRD (end-stage renal disease) on hemodialysis. Major bleeding event is defined as:Acute clinically overt bleeding (including access site related bleeding) accompanied by 1 or more of the following: Decrease in Hgb of 2g/dL or more with overt bleeding; Transfusion of 2 or more units of packed RBCs in the setting of an overt bleeding event; Bleeding within a critical site. Hemorrhagic stroke (primary or infarction with hemorrhagic conversion) were classified as major bleeds. Non-major bleeding event is defined as: Acute or sub-acute clinically overt bleeding (including access site related bleeding) that does not meet criteria for major bleeding & results in Hospital admission for bleeding, physician guided medical or surgical treatment for bleeding, or change in antithrombotic therapy | Randomization up to Month 15/Final Visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Stroke or Systemic Embolism | Number of participants experiencing adjudicated stroke or systemic embolism. | Randomization up to Month 15/Final Visit | 
| Number of Participants Experiencing Mortality | Evaluate mortality rates for those participants randomized to warfarin and apixaban in patients with NVAF and ESRD on hemodialysis | Randomization up to Month 15/Final Visit | 
| Persistence of Therapy | Evaluate days between time from initiation to discontinuation of randomized therapy. | Randomization up to Month 15/Final Visit | 
| Apixaban Plasma Concentration, Cmax | Evaluate the pharmacokinetics of apixaban in ESRD NVAF patients on hemodialysis. The measurement was done from 0-12 hours after the dose was given on Day 1. | 0-12 hours post-dose | 
| Apixaban Plasma Concentration, Cmin | Evaluate the pharmacokinetics of apixaban in ESRD NVAF patients on hemodialysis. The measurement was done from 0-12 hours after the dose was given on Day 1. | 0-12 hours post-dose | 
| Area Under the Plasma Apixaban Concentration Curve From 0 to 12 Hours After Dose (AUCO-12) | Evaluate the pharmacokinetics of apixaban in ESRD NVAF patients on hemodialysis. The measurement was done from 0 to 12 hours after dose was given on Day 1. | 0-12 hours post-dose | 
| Apixaban Pharmacodynamics, Chromogenic Factor Xa Assay | Evaluate the pharmacodynamics of apixaban in ESRD NVAF patients on hemodialysis | Baseline: Day 3, 4, or 5; Day 28 | 
| Adherence to Treatment With Apixaban or With Warfarin | Measured by self-reported days of medication compliance over the last 30 days. | Month 15/Final Visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal dialysis