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Authors: Sandeep Devabhakthuni, PharmD, BCCP and Zachary R. Noel, PharmD, BCCP

The prevalence of atrial fibrillation (AF) is significantly higher in patients with end stage renal disease (ESRD) compared to the general population.1-6  This is due to a number of contributing factors, including advancing age, hypertension, and other comorbidities.4  Based on our knowledge of risk factors for stroke in the general population, stroke prevention with anticoagulation seems like a logical and necessary treatment choice in ESRD. Upon further investigation though, available evidence suggests an unclear benefit of anticoagulation in patients with ESRD and AF.2,7-10 In spite of the aforementioned risk factors for stroke,  patients with ESRD also have high risk for bleeding complications.11 This alters the risk-to-benefit profile of anticoagulants and raises the question of whether doing nothing (i.e., choosing not to anticoagulate) is the best treatment. Part 1 of this series will discuss the risks of anticoagulation in patients with ESRD and AF and explain why anticoagulation may not be the preferred option. Parts 2 and 3 will review the benefits and risks of direct oral anticoagulants (DOACs) and warfarin for stroke prevention in patients with ESRD and AF, respectively.

What are the mechanisms that increase both risks of stroke and bleeding in patients with ESRD and AF?
Patients with ESRD have alterations in hemostasis that can predispose them to both thromboembolic and hemorrhagic complications.11 In ESRD, chronic inflammation leads to endothelial and platelet dysfunction, resulting in platelet hyperreactivity. Additionally, patients have increased levels of factor VII and fibrinogen as well as impaired tissue factor-induced protein response. This hypercoagulable state, in combination with endothelial dysfunction and hemostasis in the left atrium, results in a disproportionately high risk of thromboembolism in patients with ESRD and AF.11 The increased risk of bleeding in patients with ESRD is likely due to increased vascular prostaglandin I and altered von Willebrand factor levels.11 In addition, increased parathyroid hormone, increased nitric oxide availability, production of ischemic toxins, and increase in inflammatory cytokines all contribute to abnormal platelet adhesion and aggregation. Ultimately, these pathologic changes result in a predisposition for bleeding.11 Taken altogether, these pathophysiologic alterations unpredictably change the risk of thrombosis and bleeding such that it is difficult to establish whether a patient will experience net benefit or harm from anticoagulation. Of note, traditional risk scores such as CHADS-VASc and HAS-BLED have not been validated in this population and are of relatively limited utility.12,13

What is the evidence for anticoagulation in patients with ESRD and AF?
Prospective trials of anticoagulation in AF have generally excluded patients with a glomerular filtration rate < 30 mL/min.14 Chan and colleagues conducted a retrospective study in 1671 hemodialysis patients with atrial fibrillation and found that warfarin use was associated with increased risk of stroke (hazard ratio [HR] 1.93; 95% confidence interval [95% CI], 1.29 to 2.9) compared to nonuse.10 Similar results have been reported by other investigators.7,15 However, Olesen and colleagues have reported a significant reduction in stroke or systemic embolism with warfarin {HR 0.44, 95% CI 0.26-0.74).9 Other investigators have reported positive outcomes as well.16,17 These conflicting findings from observational trials are partly due to differences in study designs, potential misclassification of kidney disease, and non-validated definitions for bleeding criteria. Taken together, these data from observational trials are difficult to interpret and not suitable for clinical decision-making. At present, the available data for DOACs are based on small, observational studies. Many clinicians are waiting for the results of ongoing randomized trials looking at apixaban versus warfarin for AF in hemodialysis patients before using this anticoagulant for routine practice.

What is the current standard of care for stroke prevention in patients with AF and ESRD?
With such conflicting evidence, national guidelines have taken different positions on anticoagulation for patients with ESRD and AF. The Kidney Disease: Improving Globald Outcomes (KDIGO) modified their 2011 consensus statement on cardiovascular disease to recommend against anticoagulation in dialysis patients with AF until further evidence is available.18 The 2016 Focused Update of the Canadian Cardiovascular Society Guidelines for Management of AF suggests against the routine use of anticoagulation or aspirin in patients with ESRD.19 In contrast, the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline for management of patients with AF provide a grade IIa recommendation for use of warfarin in ESRD.20

So what should we do for ESRD patients who develop AF?
Until more robust data are published, a careful patient-specific and interdisciplinary decision should be made weighing risk factors for thrombosis as well as bleeding. Table 1 provides suggested considerations to taken into account. Importantly, patients should be included in this decision-making as much as possible. If the decision is made to anticoagulate, consider strategies to decrease risk of bleeding including appropriate discontinuation of antiplatelet therapy (aspirin and/or P2Y12 inhibitor) and concurrent use of gastroprotection (e.g., proton pump inhibitor or histamine receptor antagonist) in those at high risk of gastrointenstinal bleeding.

 

What is the bottom line?
Many clinicians fail to distinguish the differences in the risk-to-benefit profile of anticoagulation in the general population and those with ESRD. Traditional scoring calculators such as CHADS2-VASc and HAS-BLED do not adequately predict the risk of stroke and bleeding in patients with ESRD; however, clinicians often use these scoring systems and err on the side of anticoagulation based on standard practice in the general population. We must remember though that our first priority is to first do no harm. If there is no clear benefit with a definitive risk of bleeding, we should reconsider the role of anticoagulation in patients with ESRD and AF. Table 1 provides a list of risk factors that may help in identifying patients with who may benefit from anticoagulation versus those who may not. The assessment of both stroke and bleeding should be individualized for the patient, and the patient should be a part of this decision-making process.

 

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

Zachary R. Noel, PharmD, BCCP

Dr. Noel 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 cardiology at the University of Maryland Medical Center in Baltimore, MD. Follow him on Twitter @ZacNoelCardsRx.

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AC in ESRD (Part 1): First, Do No Harm – No Anticoagulation in Patients with End Stage Renal Disease and Atrial Fibrillation

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