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 pop-
ulation 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 because most major CVD trials excluded patients

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 [CKD-
5D]). The first guideline, published by NKF-
KDOQI 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
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 ran-
domized 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

From the 1Division of Nephrology and Hypertension, Depart-
ment 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, Depart-
ment of Medicine, Johns Hopkins Medical Institutions, Baltimore,
MD; 5Division of Nephrology, Department of Medicine, Univer-
sity 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, Winston-
Salem, NC; and 9Department of Public Health Sciences, Loyola
University Chicago, Maywood, IL.
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: vbansal@luc.edu
 2017 by the National Kidney Foundation, Inc.
0272-6386
http://dx.doi.org/10.1053/j.ajkd.2017.08.003

Am J Kidney Dis. 2017;-(-):--- 1


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 NKF-
KDOQI 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 CKD-
5D. 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 evi-
dence 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 ascertain-
ment, 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 popu-
lation generally reflect risk factors noted in the gen-
eral 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 How-
ever, 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
2 Am J Kidney Dis. 2017;-(-):---
Bansal et al
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 popu-
lation, 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 popula-
tion, 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 hemor-
rhagic.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. Approxi-
mately 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), hy-
pertension (1 point), anemia (1 point), diabetes melli-
tus (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 delin-
eate 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 pres-
ence 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 specif-
ically developed for patients with CKD-5D with AF.
The existing stroke risk prediction scores show good
Oral Anticoagulants and Dialysis
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 deter-
mining stroke risk in these prediction formulas, such
as anemia, hypertension, and heart failure, are poorly
defined in patients with CKD-5D and are not uni-
formly associated with stroke risk in this popula-
tion.10 Elucidating heart failure from volume overload
in patients with CKD-5D can be difficult, and blood
pressure levels that define hypertension in this pop-
ulation 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 uncer-
tain. 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 CKD-
5D. 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 pub-
lished between 2014 and 201662-65 have summarized
data from 8 to 20 observational studies with a com-
mon 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], 0.66-
1.35)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 hemor-
rhagic strokes (95% CI, 1.62-3.27), whereas no as-
sociation 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 observa-
tional 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 well-
designed randomized clinical trial.
Am J Kidney Dis. 2017;-(-):---
Bleeding Risk in Patients With CKD-5D
One of the main controversies regarding antico-
agulant 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 gastroin-
testinal bleeding with warfarin use. In the 4 meta-
analyses 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 charac-
terized 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
3

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 ef-
fects 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 supplemen-
tation alters MGP concentrations (ClinicalTrials.gov
identifier NCT02278692) and inhibits the progres-
sion of vascular calcification in patients with CKD-
5D.82
Inhibition of MGP by warfarin may also lead to
increased development of arteriovenous malforma-
tions 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 anti-
coagulated state, but more research is needed.
Warfarin use also may complicate hemodialysis ac-
cess 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 in-
teractions with several drugs, including other anti-
platelet 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 Hemodialy-
sis 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 recommen-
dation 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 Am J Kidney Dis. 2017;-(-):---
Bansal et al
The safety and efficacy of direct-acting oral antico-
agulant drugs compared to warfarin in patients with
CKD-5D remain unknown. The 4 NOACs currently
available include dabigatran (a direct thrombin in-
hibitor) 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 irre-
spective 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 CKD-
5D 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 dif-
ference in the maximum concentration of the drug
was noted.90
No studies have examined drug exposure or
adverse effects with repeated apixaban dosing in pa-
tients 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 concentra-
tions 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
Oral Anticoagulants and Dialysis

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

Warfarin Dabigatran Apixaban Edoxaban Rivaroxaban

Routine dose Adjusted to INR 150 mg, 23/d 5 mg, 13/d 60 mg, 13/d 20 mg, 13/d
CKD dose Adjusted to INR None 2.5 mg, 23/d, if 30 mg, 13/d, if CLcr 15 mg, 13/d, if CLcr
adjustment Scr . 1.5 mg/ 15-50 mL/min 15-50 mL/min
dL 1 age $ 80 y
or weight , 60 kg
Mechanisms of Inhibits synthesis of Direct thrombin Direct factor Xa Direct factor Xa Direct factor Xa
action vitamin K– inhibitor inhibitor inhibitor inhibitor
dependent clotting
factors (II, VII, IV,
X)
4-h dialysis removal ,1% 50%-60% 7% 9% ,1%
Volume of 8 50-70 21 107 50
distribution, L
Excretion Nonrenal 50%-60% renal CYP3A4/5 (P- CVP3A4 (liver CYP3A4/5 and
glycoprotein liver enzyme); 50% CYP2J2 (liver
enzyme); 27% renal; 40% bile enzymes); 36%
renal renal
Reversal agents Vitamin K, fresh Idarucizumab 4-factor prothrombin 4-factor prothrombin 4-factor prothrombin
frozen plasma, 4- complexes complexes complexes
factor prothrombin
complexes
FDA approved for Yes No Yes No No
CKD-5D
Concerns for use in Requires frequent Reversal agent may Reversal agent may Reversal agent may Reversal agent may
CKD-5Da monitoring, high not be readily not be readily not be readily not be readily
interindividual available, lack of available, dosing in available, lack of available, dosing
variability in drug data for safe dosing CKD-5D based on data for safe recommendations in
response, may in CKD-5D pharmacokinetic dosing in CKD-5D CKD-5D based on
increase risk for data only pharmacokinetic
calciphylaxis and data only
vascular
calcification
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 activ-
ity 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 in-
crease bleeding risk in the CKD-5D population re-
mains 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
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 dial-
ysis dependence and vice versa (eg, due to trans-
plantation 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 initi-
ation, dialysis may be complicated by prolonged ac-
cess 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 moni-
toring may divert clinician effort and time, with less
attention given to other patient needs such as pain

Am J Kidney Dis. 2017;-(-):--- 5

 Bansal et al

control, optimization of nutritional status, or social
support. Transitions between dialysis modalities are
also complicated by oral anticoagulant use and clini-
cians may hesitate to continue warfarin use when
patients switch from peritoneal dialysis to hemodial-
ysis therapy. Existing studies have not quantified the
potential effects of oral anticoagulant use on out-
comes, 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 recommen-
dations for stroke prevention in the setting of non-
valvular AF among patients with CKD-5D. The
AHA/ACC/HRS guideline for management of pa-
tients 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 pre-
vention 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 pa-
tients 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 moni-
toring 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 anti-
coagulation 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 pa-
tients with AF published in 2014 again recommended
warfarin for stroke prevention in the general popula-
tion with a grade A recommendation.5 The 2014
AHA/ACC/HRS guideline also recommended
warfarin for stroke prevention in adults with CKD-
5D, 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 filtra-
tion rates , 15 mL/min/1.73 m2 not receive oral an-
ticoagulants 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 CKD-
5D.
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 anti-
coagulation 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 2005 Recommended clinicians adhere to 2001 AHA guideline for stroke
CVD in dialysis patients2 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
KDIGO CVD in CKD clinical update105 2011 Rescinded prior recommendation of routine anticoagulation in CKD-5D with
warfarin for primary prevention of stroke citing knowledge gaps
AHA/ACC/HRS guideline5 2014 Recommended warfarin for stroke prevention with AF for CKD-5D with B
level due to lack of clinical trial evidence
Canadian Cardiovascular Society guideline106 2016 Did not recommend use of warfarin or aspirin for stroke prevention in CKD-
5D 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 Am J Kidney Dis. 2017;-(-):---

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 mo-
dality 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 anti-
coagulation 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 pre-
vent stroke in the CKD-5D population with non-
valvular 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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