Safety and Efficacy of Apixaban Versus Warfarin in Peritoneal Dialysis Patients With Non Valvular Atrial Fibrillation

Study Overview
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Brief Summary
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Several well conducted randomized controlled trials have established the superiority or non-inferiority of oral anticoagulants (OACs) compared with vitamin K antagonists to treat non valvular atrial fibrillation (AF) for the prevention of thromboembolic events, as well as their safety profile (less major bleeding events with OACs) in the general population. Atrial fibrillation is associated with higher morbidity and mortality in patients with ESKD but there is a lack of randomized data in ESKD on hemodialysis and no data on peritoneal dialysis. Therefore, available evidence comes from retrospective observational studies that are notoriously unreliable to estimate treatment effects. In the population of patients with end stage renal disease (ESRD) on peritoneal dialysis, the investigators hypothesize that apixaban will be safer and as effective than warfarin for the management of non valvular AF, with a robust methodology: a randomized controlled trial. Individually, if the study hypothesis is confirmed during this protocol, the benefit could be direct in the experimental arm with less bleeding than in standard-of-care arm. Moreover, the risk of bleeding with apixaban will be reduced with the use of concordant dosing in peritoneal dialysis condition, known from APIDP1 study. Collectively, the investigators hope for an improvement in scientific knowledge that will allow us to optimize the treatment of atrial fibrillation in subjects on peritoneal dialysis, maybe with the help of pharmacodynamics indicator.

Detailed Description
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Several randomized controlled trials have established the interest of direct oral anticoagulants (OACs) (dabigatran, apixaban, rivaroxaban, and edoxaban) compared to vitamin K antagonists for the treatment of non valvular atrial fibrillation (AF) to prevent thromboembolic events, as well as their safety profile (less major bleeding events with OACs) in the general population. However, studies with OACs did not enroll patients with end-stage renal disease (ESRD) on dialysis, whereas OACs are partly eliminated by the kidneys. The prevalence of AF in the general population is estimated to range around 1% depending on age, reaching 8% in patients over 80 years old. This prevalence is of 20% and 14% in patients on hemodialysis and peritoneal dialysis. In addition, AF is associated with higher morbidity and mortality rates in patients with advanced chronic kidney disease, in contrast with patients with preserved kidney function, with an overall mortality rate up to 40% at 2 years. On the other hand, patients on dialysis are at particularly high risk of hemorrhagic stroke and bleeding, although patients undergoing peritoneal dialysis appear to be less likely to develop hemorrhagic stroke than those undergoing hemodialysis. So the question of the use oral anticoagulants for stroke prevention in patients with AF and ESRD is still being debated. The nephrological guidelines KDIGO (Kidney Disease: Improving Global Outcomes) statements do not recommend any routine OACs anticoagulation, and warfarin is still the first choice. However, OACs could be an alternative to warfarin: INR monitoring or heparin bridging would be no longer be necessary; minimal affect by foods rich in vitamin K; and theoretically less risk of arterial calcification. Apixaban, an oral selective direct reversible inhibitor of the coagulation factor Xa, is the OAC that is less excreted by the kidneys (27%) and is increasingly prescribed at either the full or reduced doses in dialysis patients. Apixaban was introduced to the market in 2012, after the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation Trial (the ARISTOTLE trial). Among 269 patients with CrCl (Creatinine Clearance) 25 to 30 mL/min included in ARISTOTLE trial, apixaban caused less bleeding than warfarin. To date, there are 2 RCT that compared apixaban to warfarin in patients with AF and ESRD on hemodialysis: RENAL-AF and AXADIA-AFNET. The two studies failed to conclude on efficacy and safety; larger randomized trial are needed. There are retrospective studies comparing apixaban to warfarin in patients on dialysis, or comparing apixaban to no coagulation, but subgroup analysis for peritoneal dialysis patients were not carried out. Yet, apixaban is approved by the US FDA label 24 for use in patients with ESRD maintained on intermittent hemodialysis based on Wang's pharmacokinetic study (5 mg twice daily reduced to 2.5 mg twice daily when age>80 years or weight<60 kg). Hemodialysis requires an artificial kidney machine and is performed two or three times a week while peritoneal dialysis acts via natural filters continuously, so pharmacokinetics differences between these two modes of extrarenal purification techniques are to be expected. With the APIDP1 study, the first pharmacokinetics study of apixaban in patients with ESRD on peritoneal dialysis, the investigators demonstrated differences in pharmacokinetic parameters in comparison to a normal renal function population. The investigators then aim to propose the APIDP2 study, a randomized controlled trial that will assess the safety and efficacy of apixaban for stroke prevention in subjects with ESRD on chronic peritoneal dialysis with atrial fibrillation. The APIDP2 trial is a prospective, randomized, open-label, blinded-outcome evaluation of apixaban versus warfarin in patients receiving peritoneal dialysis with AF and a CHA2DS2-VASC2 score ≥2. Patients are randomly assigned 1:1 to 2.5mg of apixaban twice daily or dose-adjusted warfarin. The primary outcome will be the incidence of major or clinically relevant nonmajor bleeding. Secondary outcomes included stroke, mortality, myocardial infarction and apixaban pharmacodynamics. Follow-up will be one year or at least one week after discontinuation of the anticoagulation. Pharmacodynamics measures aim to investigate relation between antiXa activity and toxicity, which may be stronger than relation between dose and toxicity. Indeed, in ApiDP1, interindividual variability in plasmatic concentrations was high (30-50%). If hypothesis is verified, then apixaban antiXa activity could be used for pharmacological therapeutic monitoring in this population.

Official Title
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Safety and Efficacy of Apixaban Versus Warfarin in Peritoneal Dialysis Patients With Non Valvular Atrial Fibrillation: a Randomized Controlled Trial

Conditions
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Atrial Fibrillation, Peritoneal Dialysis Complication

Intervention / Treatment
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* Drug: Anticoagulation Agents


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, age at least 18 years, in ESRD threated with peritoneal dialysis for ≥ 3 months Patients with a history of non valvular AF treated by oral anticoagulation or patients initiating oral anticoagulation for a diagnosis of non valvular AF CHA2DS2-VASc score of ≥ 2. 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 non valvular AF that require anticoagulation such as mechanical prosthetic valve, deep venous thrombosis, or pulmonary embolism Life expectancy < 3 months Anticipated kidney transplant within the next 3 months childbearing potential

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
Interventional Model Description: a Haybittle sequential plan (PROC SEQDESIGN, SAS 9.4) with decision rule for better safety (larger than expected effect)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Warfarin<br>Warfarin (Coumadine): INR target [2.0-3.0] | Drug: Anticoagulation Agents<br>* anticoagulation in peritoneal dialysis patients with non valvular atrial fibrillation during one year<br>|
| Experimental: Apixaban<br>Apixaban (Eliquis) at 2.5mg, per os, twice a day | Drug: Anticoagulation Agents<br>* anticoagulation in peritoneal dialysis patients with non valvular atrial fibrillation during one year<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ISTH major or clinically relevant non-major bleeding | number of participants experiencing ISTH major or clinically relevant non-major bleeding | 0-12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GUSTO bleeding | number of participants experiencing Gusto bleeding | 0-12 months | 
| TIMI bleeding | number of participants experiencing TIMI bleeding | 0-12 months | 
| Number of Participants Experiencing Stroke or Systemic Embolism |  | 0-12 months | 
| Number of Participants Experiencing Myocardial Infarction |  | 0-12 months | 
| Number of Participants Experiencing Mortality |  | 0-12 months |