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Author: Sandeep Devabhakthuni, PharmD, BCPS-AQ Cardiology

Multiple observational trials have assessed the efficacy and safety of warfarin in patients with non-valvular atrial fibrillation (NVAF, or simply AF in this blog) and end stage renal disease (ESRD).1-10 However, these studies have shown conflicting results owing to differences in study design (e.g., different criteria used for patient selection, conflicting definitions for bleeding and stroke outcomes, missing confounders). To date, no randomized controlled trials have been conducted comparing warfarin to no anticoagulation in patients with ESRD and AF. This blog will provide an overview of the available literature and highlight limitations and concerns surrounding the use of apixaban in ESRD.

More Clinical Experience with Warfarin in Renal Disease
In patients with ESRD, a few small prospective studies and numerous retrospective, observational trials have found a net clinical benefit with warfarin, including lower mortality, decreased rates of ischemic stroke, and similar risk of bleeding compared to no anticoagulation.1-5 In contrast, some studies have demonstrated no difference in mortality or ischemic stroke rates but increased incidence of intracranial hemorrhage.6-10 It’s imperative to recognize and appreciate differences in study design which likely account for the discrepant results. First, warfarin was not randomly allocated in these studies and thus selection bias is a potential confounder. Indeed, patients who received warfarin were selectively healthier than those receiving no anticoagulation in at least two of the aforementioned trials.3,4 Second, the selection of patients have considerable issues related to quality and accuracy. Studies that defined chronic kidney disease using International Classification of Diseases 9/10 codes may have been prone to misclassification as validation studies have reported low positive predictive values (<50%).10,11 There may have been a misclassification bias for ischemic stroke too since there is also a variable positive predictive value (range 46-94%).12 Third, many studies are subject to incident/prevalent bias since many studies define onset of AF during a hospital admission and may miss the true onset that may have occurred as outpatient. Patients with ESRD are already at higher risk of bleeding so it is unclear if warfarin alone is the main culprit for this outcome. Finally, none of the included studies account for compliance with warfarin use and maintenance of therapeutic range for international normalized ratio. Other missing confounders included the effect of proteinuria, inclusion of patients requiring peritoneal dialysis and those who received renal transplant, and receipt of heparin with hemodialysis that could potentially increase risk of bleeding.

Clinical Data and Dosing with Apixaban Are Unclear
As highlighted in part II of this blog series, limited data exist for apixaban over warfarin in ESRD.13-15  The primary trial that demonstrated superiority of apixaban over warfarin with a lower risk of bleeding was fraught with limitations.15 This trial was a retrospective, prognostic score-matched analysis of Medicare beneficiaries with ESRD and AF. However, the study had a risk of confounding bias because data were extracted from medical claims. First, the authors did not have information on body weight at time of apixaban prescription, which was an important variable to assess need for dose reduction. Second, due to the nature of the claims, the authors could not examine adherence in the apixaban group or the time in therapeutic range for INR in the warfarin group. Third, there was a high rate of censoring either because of expiration of anticoagulation prescription or > 30-day gap between prescriptions. This likely contributed to the short period of anticoagulant therapy in this study (average time for apixaban and warfarin was 105 days and 157 days, respectively). Fourth, the authors did not characterize the anticoagulation practices for dialysis (e.g., use of parenteral anticoagulants for the circuit, continuation of oral anticoagulant during dialysis session). Finally, this analysis included a small group of patients requiring peritoneal dialysis, and it is unclear if either warfarin or apixaban are safe and effective in this population. These limitations highlight the need for additional clinical studies to assess the net clinical benefit of anticoagulation with either apixaban or warfarin in patients with AF on dialysis.

In addition to limited clinical experience, there are conflicting data on the best dosing regimen for apixaban. The FDA has approved apixaban for use in dialysis patients at a dose of 5 mg twice daily based on a single-dose pharmacokinetic study in eight hemodialysis patients.16 More recently, a steady state pharmacokinetic study in ESRD patients who received 5 mg twice daily had a mean drug concentration approximately 45% higher than that of healthy comparators receiving an equivalent dose, leading to the authors’ conclusion that apixaban 2.5 mg twice daily should be used in dialysis patients.17 Seven patients on dialysis receiving 2.5 mg twice daily had a drug concentration approximately 33% lower than those who received 5 mg twice daily.17 These conflicting data highlight the need for more clinical studies to determine the optimal dosing for apixaban in patients with ESRD and AF.

Another consideration with apixaban is the potential for drug accumulation due to decreased protein binding and reduced metabolism. Patients with ESRD develop uremia, which can impair plasma protein binding; apixaban is highly protein bound at 87%.18,19 Furthermore, patients with ESRD typically have reduced albumin levels due to proteinuria or nutritional deficiency. Renal failure can also impair non-renal drug metabolism by a down regulation of hepatic metabolism.19 So lower protein binding and reduced metabolism may increase levels of free drug. Without appropriate dose adjustment, repeated dosing of a drug that is inadequately cleared could lead to accumulation, resulting in toxicity due to supra-therapeutic levels. This is difficult to assess given the lack of monitoring that is routinely available for apixaban.

Conclusions & Recommendations
Taken altogether, the evidence for warfarin is subject to numerous confounding variables, rendering the results difficult to apply and make firm recommendations. The conflicting data reported from observational trials does not clearly support either warfarin or apixaban. Therefore, clinical judgment is warranted when making recommendations for patients with ESRD and AF. As discussed in part I of this blog series, clinicians should first decide if the benefits of anticoagulation clearly outweighs the risks. If anticoagulation is deemed necessary, warfarin is certainly a reasonable choice until results of ongoing randomized controlled trials are published. Warfarin still has a role in patients with ESRD and AF, especially in those who may not be able to use apixaban. Warfarin may be a preferred option for patients who have major drug-drug interactions with apixaban or if the cost for apixaban is prohibitive.

Sandeep Devabhakthuni, PharmD, BCCP

Sandeep Devabhakthuni is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in advanced heart failure at the University of Maryland Medical Center in Baltimore, MD. Follow him on Twitter @deepdev511

References

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AC in ESRD (Part III): Warfarin Over Apixaban for Patients with Atrial Fibrillation and End Stage Renal Disease

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