Oral Anticoagulants to Prevent Stroke in Nonvalvular Atrial Fibrillation in Patients With CKD Stage 5D: An NKF-KDOQI Controversies Report

Perspective Oral Anticoagulants to Prevent Stroke in Nonvalvular Atrial Fibrillation in Patients With CKD Stage 5D: An NKF-KDOQI Controversies Report Vinod K. Bansal, MD,1 Charles A. Herzog, MD,2 Mark J. Sarnak, MD, MS,3 Michael J. Choi, MD,4 Ravindra Mehta, MD,5 Bernard G. Jaar, MD, MPH,4,6,7 Michael V. Rocco, MD,8 and Holly Kramer, MD, MPH 1,9 Stroke risk may be more than 3-fold higher among patients with chronic kidney disease stage 5D (CKD-5D) compared to the general population, with the highest stroke rates noted among those 85 years and older. Atrial fibrillation (AF), a strong risk factor for stroke, is the most common arrhythmia and affects .7% of the population with CKD-5D. Warfarin use is widely acknowledged as an important intervention for stroke prevention with nonvalvular AF in the general population. However, use of oral anticoagulants for stroke prevention in patients with CKD-5D and nonvalvular AF continues to be debated by the nephrology community. In this National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) controversies report, we discuss the existing observational studies that examine warfarin use and associated stroke and bleeding risks in adults with CKD-5D and AF. Non–vitamin K–dependent oral anticoagulants and their potential use for stroke prevention in patients with CKD-5D and nonvalvular AF are also discussed. Data from randomized clinical trials are urgently needed to determine the benefits and risks of oral anticoagulant use for stroke prevention in the setting of AF among patients with CKD-5D. Am J Kidney Dis. -(-):---. ª 2017 by the National Kidney Foundation, Inc. INDEX WORDS: Atrial fibrillation (AF); nonvalvular AF; bleeding; chronic kidney disease (CKD); CKD stage 5D; dialysis; hemodialysis; dialysis-dependent CKD; Kidney Disease Outcomes Quality Initiative (KDOQI); oral anticoagulants; peritoneal dialysis; stroke; warfarin; hemorrhage; end-stage renal disease (ESRD); transient ischemic attack (TIA); kidney failure.

Introduction The National Kidney Foundation–Kidney Dialysis Outcome Quality Initiative (NKF-KDOQI) was launched to develop guidelines for treating patients with end-stage renal disease treated by dialysis (ie, those with chronic kidney disease stage 5D [CKD5D]). The first guideline, published by NKFKDOQI in 1997, addressed dialysis adequacy and did not discuss cardiovascular disease (CVD) management.1 It was not until 2005 that clinical guidelines for the diagnosis, prevention, and treatment of CVD, including stroke, were published.2 These recommendations were based on observational studies or the clinical experience of the writing group From the 1Division of Nephrology and Hypertension, Department of Medicine, Loyola University Chicago, Maywood, IL; 2 Division of Cardiology, Department of Medicine, Hennepin County Medical Center, University of Minnesota, Minneapolis, MN; 3Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, MA; 4Division of Nephrology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD; 5Division of Nephrology, Department of Medicine, University of California at San Diego, San Diego, CA; 6The Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions; 7The Nephrology Center of Maryland, Baltimore, MD; 8Division of Nephrology, Department of Medicine, Wake Forest University Medical Center, WinstonSalem, NC; and 9Department of Public Health Sciences, Loyola University Chicago, Maywood, IL. Am J Kidney Dis. 2017;-(-):---

because most major CVD trials excluded patients with advanced kidney disease. Today, CVD remains a major cause of mortality for patients with CKD-5D,3 yet level I evidence from well-designed clinical trials is lacking for most clinical decisions regarding CVD, including stroke prevention in the setting of nonvalvular atrial fibrillation (AF). To date, no randomized trials have examined the efficacy and safety of warfarin or any of the non–vitamin K oral anticoagulants (NOACs) in adults with CKD-5D and nonvalvular AF. The lack of clinical trial data is especially alarming because rates of hospitalized ischemic strokes may be at least 2-fold higher among adults with CKD-5D compared to the general Received January 3, 2017. Accepted in revised form August 8, 2017. In line with AJKD’s procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies, an Acting Editor-in-Chief (Associate Editor Roy D. Bloom, MD) handled the peer-review and decision-making processes. Address correspondence to Vinod K. Bansal, MD, Loyola University Chicago, Division of Nephrology and Hypertension, 2160 S First Ave, Maywood, IL 60153. E-mail: [email protected]  2017 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2017.08.003

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population,4 whereas nonvalvular AF, a strong risk factor for stroke and mortality,5 affects at least 1 of every 10 adults with CKD-5D.6,7 NKF-KDOQI publishes a series of reports addressing controversial questions in nephrology care for which evidence is lacking or contradicting, thus preventing clinical practice guidance. These topics are selected based on responses to surveys posted on the KDOQI website (www.kidney.org/professionals/ guidelines). In a 2016 survey administered by the NKF on the KDOQI website asking “Should warfarin be used in dialysis patients with non-valvular atrial fibrillation?,” 45.1% of 5,063 respondents answered “No,” while 54.9% responded “Yes.” In this NKFKDOQI controversy report, we discuss controversies regarding the benefits and risk of anticoagulant use for stroke prevention in adults with AF and CKD-5D. We also outline areas of research for which evidence is urgently needed to guide clinical decision making regarding stroke prevention for patients with CKD5D. Because nephrology continues to lag behind all other medical subspecialties in total funding for and number of clinical trials, the overall goal of the KDOQI controversy reports is to bring attention to key clinical questions in nephrology for which evidence is lacking and urgently needed. Epidemiology of AF in CKD-5D In CKD-5D, the prevalence of AF ranges from 7% to 27%,3,7-13 depending on methods of ascertainment, with the highest AF prevalence noted with Holter monitoring. Based on diagnosis codes, AF affects at least 1 of every 10 adults with CKD-5D.6,7 However, the optimal method for identifying AF in the CKD-5D population remains poorly evaluated. Risk factors for incident AF in the CKD-5D population generally reflect risk factors noted in the general population, such as hypertension, diabetes, heart failure, and ischemic heart disease.7,10,14 Volume overload frequently accompanies CKD-5D and may lead to left atrial dilatation and subsequent atrial remodeling, heightening the risk for AF.11,13,15-19 The dialysis procedure itself my trigger AF because AF is most likely to occur on dialysis days and during a dialysis session.16,19,20 Dialysis-specific risk factors for AF include high dialysate calcium and low dialysate potassium concentrations.10,12 However, to date, few studies have examined risk factors for AF unique to the CKD-5D population and whether modifying these risk factors reduces AF incidence. Link Between AF and Stroke in CKD-5D In the setting of CKD-5D, AF is associated with an approximately 4-fold increased risk for stroke and

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2-fold increased risk for death.6,7,10,11,14,21 Although the proportion of strokes associated with AF in the CKD-5D population remains poorly quantified, w20% of all ischemic strokes are attributed to AF in the general population.22 Regardless of the population, strokes in the setting of AF are associated with higher morbidity and mortality.21-25 Stroke-associated mortality may be increased by 50% when strokes occur in the setting of AF.25 Age-adjusted stroke rates as determined by stroke-related hospitalizations are overall approximately 3- to 9-fold higher in the CKD-5D population compared to the general population, with the highest hazard rates for stroke associated with CKD-5D noted among white women.26 The overall risk for strokes among adults with CKD-5D increases upon dialysis therapy initiation27 and may be .5% during the first 2 years after dialysis therapy initiation. Risk factors for stroke include advanced age, diabetes, and white race.28 In the CKD-5D population, at least 75% of strokes are ischemic in nature, while up to 25% are hemorrhagic.27-30 Silent strokes are common and existing data suggest that the prevalence of silent strokes may be up to 5-fold higher in the CKD-5D population versus the general population.27,29,30 Most strokes in patients with CKD-5D are lacunar infarcts, and brain white matter lesions are common in this population.30-32 Overall prognosis is poor for an adult with CKD-5D who experiences a stroke. Approximately one-third of all strokes among adults with CKD-5D are fatal events and most who survive a stroke will die within 1 year.28 Information on how to best predict stroke risk in the CKD-5D population remains scant and precludes the ability to identify the patients at high risk for stroke. In the general population, several prediction scores may be used to estimate stroke risk based on established risk factors. The most commonly used prediction scores are CHADS2,33 CHA2DS2-VASc,34 ATRIA,35 and the R2CHADS2.36 The CHADS2 score includes age (65-74 years, 1 point; $75 years, 2 points), female sex (1 point), congestive heart failure (1 point), hypertension (1 point), anemia (1 point), diabetes mellitus (1 point), and previous stroke, transient ischemic attack, or thromboembolism (2 points).37 The CHAD2DS2-VASc adds vascular disease (1 point) to the CHADS2 score and may be used to further delineate bleeding risk.34 Scores of 2 points or higher indicate a $4% risk for stroke during the next year. The ATRIA and R2CHADS2 scores include the presence of CKD as a risk factor for stroke, whereas all other prediction scores do not.35,38,39 No stroke risk prediction scores have been specifically developed for patients with CKD-5D with AF. The existing stroke risk prediction scores show good

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calibration of stroke risk in the general population, but poor discrimination and calibration in the CKD-5D population.40,41 Heightened stroke risk exists in the CKD-5D population with nonvalvular AF regardless of CHADS2DS2-VASc score, with .80% of patients having scores of 2 or higher.40 The factors determining stroke risk in these prediction formulas, such as anemia, hypertension, and heart failure, are poorly defined in patients with CKD-5D and are not uniformly associated with stroke risk in this population.10 Elucidating heart failure from volume overload in patients with CKD-5D can be difficult, and blood pressure levels that define hypertension in this population remain controversial.42,43 Oral Anticoagulation for Stroke Prevention in CKD-5D Warfarin remains the most widely prescribed anticoagulant to prevent stroke in the setting of AF, although NOAC use is increasing.44 However, whether warfarin use reduces stroke risk in patients with nonvalvular AF and CKD-5D remains uncertain. Warfarin use prevents nearly two-thirds of all strokes in the general population with nonvalvular AF, and the overall benefits outweigh associated risks, including bleeding.45 Stroke risk reduction with warfarin use has not been supported by observational studies of patients with CKD5D. The majority of studies report either a small risk reduction with warfarin use or no effect.10,14,22,40,46-61 Data for stroke risk with warfarin use in the setting of AF among patients receiving peritoneal dialysis remain limited56 because the overwhelming majority of studies examining the benefits of warfarin use in the CKD-5D population have focused on patients receiving hemodialysis. Several meta-analyses published between 2014 and 201662-65 have summarized data from 8 to 20 observational studies with a common core of 6 studies. The pooled hazard rate for stroke associated with warfarin use relative to no use ranged from 0.95 (95% confidence interval [CI], 0.661.35)65 to 1.50 (95% CI, 1.13-1.99).64 Warfarin use in the setting of AF versus no use was reported to be associated with a 2.3-fold increased risk for hemorrhagic strokes (95% CI, 1.62-3.27), whereas no association was noted with warfarin use and ischemic strokes (hazard ratio, 1.01; 95% CI, 0.65-1.57).64 These meta-analyses are all limited by the observational study design of the pooled studies because warfarin use is not random but is determined by multiple patient-specific (age, comorbid conditions, social support, and education level) and nonspecific factors (eg, physician practice patterns). The only study design that can overcome this bias is a welldesigned randomized clinical trial.

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Bleeding Risk in Patients With CKD-5D One of the main controversies regarding anticoagulant use in patients with CKD-5D concerns the well-recognized high risk for gastrointestinal bleeding in this population. Major bleeding requiring hospitalization affects approximately 14% to 20% of patients during the first 4 years after initiating dialysis therapy.66,67 Some,21,46,48,55,57,59,68 but not all,40,62,69 studies show increased risk for gastrointestinal bleeding with warfarin use. In the 4 metaanalyses of observational studies mentioned in the previous section, the overall pooled bleeding risk associated with warfarin use versus no use in patients with CKD-5D was very similar, with hazard ratios ranging from 1.19 to 1.30.62-65 This risk for gastrointestinal bleeding with warfarin use may be underestimated considering the 20-fold higher risk for gastrointestinal bleeding in patients with CKD-5D in the absence of warfarin use compared to the general population.70 The concerns of increasing bleeding risk with anticoagulant use in CKD-5D are compounded by the poor ability to identify patients with high bleeding risk. Scores for predicting major bleeding risk in the setting of AF, such as HAS-BLED,71 HEMORR2HAGES,72 and the Outpatient Bleeding Risk Index (OBRI),73 show poor predictive accuracy in the CKD-5D population.74 The HAS-BLED score is based on the presence of hypertension, abnormal kidney and liver function, previous stroke or bleeding, presence of labile international normalized ratio (INR), being elderly, or drug or alcohol use,71 whereas the HEMORR2HAGES score includes most of the factors in the HAS-BLED score plus the presence of malignancy, reduced platelet count or activity, anemia, and polymorphisms in the CYP2C9 gene.72 None of these prediction scores for major bleeding in the setting of AF have been validated in patients with CKD-5D. Warfarin and Its Use in CKD-5D Warfarin may have unique risks in patients with CKD-5D. Warfarin antagonizes the effects of vitamin K via inhibiting the synthesis of clotting factors (II, VII, IV, and X) and anticoagulant proteins (C and S). Warfarin necrosis, a rare complication, occurs within a few days of drug therapy initiation and is characterized by purpura and hemorrhagic necrosis.75 In patients with CKD-5D, warfarin use also increases the risk for calciphylaxis, a disorder characterized by calcification and thrombosis of dermal arteries and painful skin lesions.76 Although not necessary or sufficient, warfarin remains the strongest risk factor overall for developing calciphylaxis among patients with CKD-5D.76,77

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Warfarin

inhibits

the

vitamin

K–dependent

g-carboxylation activation of matrix Gla proteins

(MGPs), inhibitors of vascular mineralization.78 MGP has high affinity for calcium and acts in part via binding bone morphogenetic protein, an osteogenic differentiation factor.79 Inhibition of MGP activation leads to increased vascular calcification,80,81 and effects may be exaggerated by ongoing vitamin K deficiency due to poor diet and/or frequent antibiotic use in patients with CKD-5D.43 Clinical trials are ongoing to examine whether vitamin K supplementation alters MGP concentrations (ClinicalTrials.gov identifier NCT02278692) and inhibits the progression of vascular calcification in patients with CKD5D.82 Inhibition of MGP by warfarin may also lead to increased development of arteriovenous malformations in the brain.83,84 Observational studies suggest that intracerebral hemorrhage risk may increase by more than 2-fold with warfarin use in patients with AF and CKD-5D,59,69 and it is possible that this increased risk may not be solely due to an anticoagulated state, but more research is needed. Warfarin use also may complicate hemodialysis access maintenance. If the fistula or graft clots in a patient receiving warfarin, patients usually require heparin bridging and hospitalization, which greatly increase the cost of vascular access care and patient burden. Vascular access interventions such as balloon-assisted maturations may even be avoided in some cases due to the complications of warfarin use. Vitamin K antagonists such as warfarin may also enhance venous neointimal hyperplasia and may delay access maturing and reduce the longevity of a graft or fistula.85 To avoid under- or overcoagulation, warfarin use requires constant monitoring, an activity measured by the INR as a standardized prothrombin time. Warfarin response is sensitive to changes in diet and its interactions with several drugs, including other antiplatelet agents such as aspirin.86 Substantial interindividual variability in response to warfarin also exists and variability appears highest in patients with advanced CKD, including stage 5D.68,87 Hemodialysis treatments require heparin to avoid clotting of the dialyzer, but its use in combination with warfarin has not been examined. Warfarin Alternatives and Their Use in Patients With CKD-5D Novel NOACs are given a B level of recommendation for use in stroke prevention in the setting of nonvalvular AF by the AHA/ACC/HRS (American Heart Association/American College of Cardiology/ Heart Rhythm Society) guideline, but they are not recommended for use in patients receiving dialysis.5 4

The safety and efficacy of direct-acting oral anticoagulant drugs compared to warfarin in patients with CKD-5D remain unknown. The 4 NOACs currently available include dabigatran (a direct thrombin inhibitor) and apixaban, edoxaban, and rivaroxaban (factor Xa inhibitors). These drugs are vitamin K– independent and have significant renal excretion and a prolonged half-life in kidney failure (Table 1).88 In all phase 3 trials of NOACs, adults with an estimated creatinine clearance # 25 mL/min were excluded. Dabigatran, a direct thrombin inhibitor, is 80% excreted by the kidneys and has been approved by the US Food and Drug Administration (FDA) at the lower dose of 75 mg daily in patients with advanced CKD, but it is not recommended for use in patients with CKD-5D (Table 1). Dabigatran has been associated with lower risk for strokes and death but higher risk for gastrointestinal bleeding compared to warfarin in the general population 65 years and older.89 Only 35% of dabigatran is protein bound and it is the only NOAC that can be removed with hemodialysis.90 The main route of excretion of apixaban is via the liver enzyme CYP3A4, and 27% of the drug is excreted in urine unchanged.91 In clinical trials, the apixaban dosage was reduced from 5 mg twice daily to 2.5 mg twice daily when patients met 2 of the 3 criteria: age older than 80 years, weight , 60 kg, and serum creatinine concentration . 1.5 mg/dL.92 Based on this study, the authors concluded apixaban to be superior to warfarin for reducing stroke or systemic embolism with lower risks for major bleeding irrespective of kidney function. However, phase 3 trials of apixaban excluded patients with serum creatinine concentrations . 2.5 mg/dL. In 2014, apixaban was approved by the FDA for use in patients with CKD5D based on a single-dose pharmacokinetic study in 8 patients receiving dialysis.93 With the 5-mg dose, overall drug exposure (area under the curve) was 36% higher compared with healthy controls, and no difference in the maximum concentration of the drug was noted.90 No studies have examined drug exposure or adverse effects with repeated apixaban dosing in patients with CKD-5D. In a recent study, Mavrakanas et al94 studied 8 patients receiving hemodialysis and concluded that apixaban, 2.5 mg, twice a day gave adequate plasma concentrations and that increasing it to 5 mg twice daily had supratherapeutic concentrations and was not recommended. Therefore, the safety of apixaban use in patients with CKD-5D remains unknown.90 Currently, the recommended apixaban dosage for patients with CKD-5D is 5 mg twice daily and is reduced to 2.5 mg twice daily if the patient is 80 years or older or has a body weight # 60 kg.95 Rivaroxaban, a direct factor Xa inhibitor, shows similar pharmacokinetic properties as apixaban, with Am J Kidney Dis. 2017;-(-):---

Oral Anticoagulants and Dialysis Table 1. Selected Characteristics of Oral Anticoagulants and Concerns for Use in CKD-5D Warfarin

Routine dose CKD dose adjustment

Adjusted to INR Adjusted to INR

Dabigatran

150 mg, 23/d None

Mechanisms of action

Inhibits synthesis of Direct thrombin vitamin K– inhibitor dependent clotting factors (II, VII, IV, X) 4-h dialysis removal ,1% 50%-60% Volume of 8 50-70 distribution, L Excretion Nonrenal 50%-60% renal

Reversal agents

Vitamin K, fresh Idarucizumab frozen plasma, 4factor prothrombin complexes Yes No

FDA approved for CKD-5D Concerns for use in Requires frequent CKD-5Da monitoring, high interindividual variability in drug response, may increase risk for calciphylaxis and vascular calcification

Apixaban

Edoxaban

Rivaroxaban

5 mg, 13/d 60 mg, 13/d 20 mg, 13/d 2.5 mg, 23/d, if 30 mg, 13/d, if CLcr 15 mg, 13/d, if CLcr Scr . 1.5 mg/ 15-50 mL/min 15-50 mL/min dL 1 age $ 80 y or weight , 60 kg Direct factor Xa Direct factor Xa Direct factor Xa inhibitor inhibitor inhibitor

7% 21

9% 107

,1% 50

CYP3A4/5 (PCVP3A4 (liver CYP3A4/5 and glycoprotein liver enzyme); 50% CYP2J2 (liver enzyme); 27% renal; 40% bile enzymes); 36% renal renal 4-factor prothrombin 4-factor prothrombin 4-factor prothrombin complexes complexes complexes

Yes

No

No

Reversal agent may Reversal agent may Reversal agent may Reversal agent may not be readily not be readily not be readily not be readily available, lack of available, dosing in available, lack of available, dosing data for safe recommendations in data for safe dosing CKD-5D based on in CKD-5D pharmacokinetic dosing in CKD-5D CKD-5D based on pharmacokinetic data only data only

Note: Data in table based on references 89-91, 93-95, 97, 98. Abbreviations: CKD-5D, chronic kidney disease stage 5D; CLcr, creatinine clearance; FDA, US Food and Drug Administration; INR, international normalized ratio; Scr, serum creatinine. a All drugs lack clinical trial data supporting efficacy for stroke prevention in patients with CKD-5D.

30% of the drug excreted in urine (Table 1). In ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), individuals with creatinine clearances , 30 mL/min were excluded.96 In May 2016, the FDA added information for the use of rivaroxaban in patients with CKD-5D, stating that administration of rivaroxaban, 15 mg, once daily will result in concentrations and pharmacodynamic activity similar to those observed in the phase 3 clinical trial.97,98 However, whether a 15-mg once-daily dose of rivaroxaban will reduce the risk for stroke or increase bleeding risk in the CKD-5D population remains unknown. The use of NOACs is increasing in patients with CKD-5D. Among 29,977 patients with AF with CKD-5D, 6% of all oral anticoagulant prescriptions were NOACs (mostly apixaban) and 15% of these prescriptions were for full drug doses.44 Risk for Am J Kidney Dis. 2017;-(-):---

hemorrhagic death was highest with dabigatran and rivaroxaban compared to warfarin in this cohort of patients with AF and CKD-5D.44 Transitions and the Patient’s Perspective The transition from dialysis independence to dialysis dependence and vice versa (eg, due to transplantation or in the context of acute kidney injury) is a period associated with high rates of hospitalization and mortality, especially for older patients. Studies examining warfarin use and stroke risk have largely ignored these transitions. For patients who are on anticoagulation therapy before dialysis therapy initiation, dialysis may be complicated by prolonged access bleeding, excessive bruising, and patient discomfort. These complications can dampen patient enthusiasm for hemodialysis and decrease quality of life. Use of warfarin and its required frequent monitoring may divert clinician effort and time, with less attention given to other patient needs such as pain 5

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control, optimization of nutritional status, or social support. Transitions between dialysis modalities are also complicated by oral anticoagulant use and clinicians may hesitate to continue warfarin use when patients switch from peritoneal dialysis to hemodialysis therapy. Existing studies have not quantified the potential effects of oral anticoagulant use on outcomes, mortality, and patient-reported quality of life during these periods of transition. Guideline Recommendations for Stroke Prevention in Patients With CKD-5D Table 2 summarizes clinical guideline recommendations for stroke prevention in the setting of nonvalvular AF among patients with CKD-5D. The AHA/ACC/HRS guideline for management of patients without CKD with AF currently recommends anticoagulation for stroke prevention for patients with a prior stroke or transient ischemic attack or a $4% predicted risk for stroke over the next year.5 In 2001, the AHA published recommendations for stroke prevention in the setting of AF.99 Warfarin and aspirin use were given a grade A recommendation for stroke prevention based on data from 5 placebo-controlled trials100-104 that showed significant stroke risk reduction with warfarin use in patients with AF and other stroke risk factors. The 2005 NKF-KDOQI clinical practice guideline for CVD in dialysis patients recommended that clinicians adhere to the 2001 AHA guideline for stroke prevention.2 However, this statement was graded as a C level recommendation due to lack of level I evidence from randomized clinical trials for stroke prevention in the CKD-5D population. The 2005 NKF-KDOQI guideline also stated that antithrombotic interventions for stroke prevention should be accompanied by careful monitoring because patients with CKD-5D have increased risk for bleeding.2 In 2011, the KDIGO (Kidney Disease: Improving Global Outcomes) group highlighted the knowledge

gaps regarding the risks and benefits of warfarin for stroke prevention in the CKD-5D population. KDIGO rescinded the prior recommendation for routine anticoagulation therapy for patients with CKD-5D with warfarin for primary prevention of stroke in the setting of nonvalvular AF105 and stated that until new data become available, routine anticoagulation in patients with CKD-5D and AF is not indicated. The AHA/ACC/HRS guideline for management of patients with AF published in 2014 again recommended warfarin for stroke prevention in the general population with a grade A recommendation.5 The 2014 AHA/ACC/HRS guideline also recommended warfarin for stroke prevention in adults with CKD5D, but this recommendation received a B grade level due to lack of clinical trial data. The Canadian Cardiovascular Society guideline for the management of AF suggested that patients with glomerular filtration rates , 15 mL/min/1.73 m2 not receive oral anticoagulants or aspirin for stroke prevention.106 However, to date, no large-scale randomized clinical trial has determined the risks and benefits of standard therapies such as warfarin for stroke prevention in the setting of nonvalvular AF among patients with CKD5D. Research Recommendations Box 1 outlines research recommendations for preventing stroke in the setting of nonvalvular AF in the CKD-5D population. Ongoing clinical trials may someday provide the necessary evidence needed to fully evaluate the risks and benefits of anticoagulation for stroke prevention in patients with CKD-5D. RENAL-AF (Renal Hemodialysis Patients Allocated Apixaban Versus Warfarin in Atrial Fibrillation) is a phase 4, randomized, open-label, blinded end-point, evaluation trial that will compare apixaban, 5 mg twice daily and 2.5 mg twice daily, for selected patients with daily warfarin adjusted to a target INR of 2 to 3 (ClinicalTrials.gov identifier

Table 2. Guidelines Regarding Oral Anticoagulant Use in CKD-5D Guideline

Year

Recommendations

NKF-KDOQI clinical practice guideline for CVD in dialysis patients2

2005

KDIGO CVD in CKD clinical update105

2011

AHA/ACC/HRS guideline5

2014

Canadian Cardiovascular Society guideline106

2016

Recommended clinicians adhere to 2001 AHA guideline for stroke prevention; C level recommendation due to lack of randomized trial evidence; antithrombotic interventions for stroke should be accompanied by careful monitoring due to bleeding risk Rescinded prior recommendation of routine anticoagulation in CKD-5D with warfarin for primary prevention of stroke citing knowledge gaps Recommended warfarin for stroke prevention with AF for CKD-5D with B level due to lack of clinical trial evidence Did not recommend use of warfarin or aspirin for stroke prevention in CKD5D with AF (GFR , 15 mL/min)

Abbreviations: ACC, American College of Cardiology; AF, atrial fibrillation; AHA, American Heart Association; CKD-5D, chronic kidney disease stage 5D; CVD, cardiovascular disease; GFR, glomerular filtration rate; HRS, Heart Rhythm Society; KDIGO, Kidney Disease: Improving Global Outcomes; NKF-KDOQI, National Kidney Foundation–Kidney Disease Outcomes Quality Initiative. 6

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Oral Anticoagulants and Dialysis Box 1. Research Recommendations for Oral Anticoagulant Use in Patients With CKD-5D 1. Determine the safety and effectiveness and optimal level of anticoagulation based on INR or other parameters of vitamin K–dependent oral anticoagulants for stroke prevention in patients with AF and CKD-5D 2. Identify optimal methods for quantifying AF incidence and associated risk factors according to dialysis modality and prescription 3. Ascertain how AF and AF type in the CKD-5D population influence stroke risk, heart disease, and mortality 4. Determine the safety and effectiveness of non–vitamin K–dependent oral anticoagulants in patients with CKD-5D 5. Examine patient preferences for stroke prevention vs attendant risks for bleeding and other complications with oral anticoagulants 6. Examine morbidity and mortality with oral anticoagulant use during clinical transition periods 7. Develop and validate prediction scores for bleeding risk in patients with AF and CKD-5D 8. Develop and validate prediction scores for stroke risk in patients with AF and CKD-5D 9. Determine whether heparin dosing during dialysis should be reduced or stopped in patients receiving warfarin or non–vitamin K–dependent oral anticoagulants 10. Develop safe and effective therapies that reduce the overall bleeding risk in patients with CKD-5D 11. Examine the economic burden of AF and associated stroke in the CKD-5D population Abbreviations: AF, atrial fibrillation; CKD-5D, chronic kidney disease stage 5D; INR, international normalization ratio.

NCT02942407). A second trial (ClinicalTrials.gov identifier NCT02933697) is AXADIA (Compare Apixaban and Vitamin-K Antagonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease). This open-labeled, randomized, controlled, phase 3b trial of 222 patients will assess the safety of apixaban, 2.5 mg, twice daily versus the vitamin K antagonist phenprocoumon, a derivative of coumarin, to achieve an INR between 2 and 3 in patients with nonvalvular AF with CKD-5D. Finally, the AVKDIAL (Oral Anticoagulation in Hemodialysis Patients) study (ClinicalTrials.gov identifier NCT02886962) is a phase 4 open-label randomized trial comparing the hemorrhagic and thrombotic risks of oral anticoagulation with vitamin K antagonists versus no anticoagulation in 855 patients with AF with CKD-5D. Conclusions In conclusion, numerous observational studies have examined the use of oral anticoagulants in patients with CKD-5D and associated stroke risk. However, findings from these observational studies are likely biased by the indications for oral anticoagulant use or confounding by indication. Large-scale clinical trials are underway and when completed, may help Am J Kidney Dis. 2017;-(-):---

clinicians provide the best treatment possible to prevent stroke in the CKD-5D population with nonvalvular AF.

ACKNOWLEDGEMENTS The authors thank the NKF members who completed the KDOQI controversies survey on the NKF website. Support: No financial support was provided. Financial Disclosure: Dr Herzog reports an equity interest in Johnson & Johnson and has received an honorarium from Bristol Myers Squibb for participation in an advisory board meeting in 2015. Dr Choi acknowledges consultancy to the Glaxo Smith Kline Data Monitoring Safety Board and the Genentech Advisory Board. Dr Bansal is Medical Director at Loyola University Outpatient Dialysis Center. Drs Jaar, Kramer, Mehta, Rocco, and Sarnak declare that they have no relevant financial interests. Other Disclosures: Dr Choi is NKF President; Dr Jaar is KDOQI Vice Chair (Education); Dr Rocco is KDOQI Chair, and Dr Kramer is KDOQI Vice Chair (Commentaries). Peer Review: Evaluated by 3 external peer reviewers and an Acting Editor-in-Chief.

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