CHEST Commentary

The Intersection of Risk and Benefit

Is Warfarin Anticoagulation Suitable for Atrial
Fibrillation in Patients on Hemodialysis?
Manish M. Sood, MD; Paul Komenda, MD, MHA, CHE; Amy R. Sood, PharmD;
Claudio Rigatto, MD, MSc; and Joe Bueti, MD

The risks and benefits of anticoagulation for stroke prevention with atrial fibrillation is clearly
delineated in the general population. Little evidence exists for patients with end-stage renal
disease (ESRD) about whether the extrapolation of these guidelines is appropriate. In patients
with ESRD who are undergoing hemodialysis, the rates for both stroke and bleeding are 3 to 10
times higher than that for the general population. Furthermore, the proportion of hemorrhagic
to ischemic strokes has increased, making the decision of whether to initiate anticoagulation
problematic. In this commentary, we discuss the existing literature for stroke in atrial fibrillation,
stroke type, risk reduction with anticoagulation, and bleeding risks in the hemodialysis popula-
tion. We comment on validated risk stratification models of stroke prevention and bleeding and
their applicability to patients undergoing hemodialysis. Finally, we recommend treatment
strategies that are based on the existing state of knowledge. (CHEST 2009; 136:1128 –1133)
Abbreviations: CHADS2 ⫽ cardiac failure, hypertension, age, diabetes mellitus, and stroke scoring system; ESRD ⫽ end-
stage renal disease; OAC ⫽ oral anticoagulation; ORBI ⫽ outpatient risk of bleeding index

W fibrillation,
hat is an acceptable risk? The quagmire of atrial
stroke prevention, anticoagulation,
and bleeding in patients with end-stage renal disease
(ESRD) relies heavily on balancing risk and benefit
in the face of unclear direct evidence. Atrial fibrilla-
tion in patients with ESRD who are receiving hemo-
dialysis is common, and the optimal strategy for its
management remains unknown.1,2 Based on extrap-
olation of guidelines established from general popu-
lations studies,3 the current practice is to favor
warfarin anticoagulation therapy to prevent throm-
boembolic events, particularly stroke. Whether these
Manuscript received March 23, 2009; revision accepted May 3,
2009.
Affiliations: From the Department of Medicine (Drs. M. Sood,
Komenda, Rigatto, and Bueti), Department of Pharmacy (Dr. A.
Sood), Health Sciences Centre (Dr. Bueti), and St. Boniface
General Hospital (Drs. M. Sood, A. Sood, Rigatto, and Komenda),
Winnipeg, MB, Canada.
Correspondence to: Manish M. Sood, MD, BG 007, 409 Tache
Ave, St. Boniface General Hospital, Winnipeg, MB, R3X 2A6,
Canada; e-mail: msood@sbgh.mb.ca
© 2009 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians (www.chestjournal.org/site/
misc/reprints.xhtml).
DOI: 10.1378/chest.09-0730
guidelines for anticoagulation apply to patients with
ESRD who are receiving hemodialysis has not been
established. Patients with ESRD who are receiving
hemodialysis are at increased risk of both cerebro-
vascular and bleeding events.4,5 The decision to
initiate warfarin therapy, therefore, requires a care-
ful assessment of the risk/benefit ratio. Based on a
review of the existing published literature, we ex-
plore in this commentary whether warfarin therapy is
suitable for stroke prevention in patients with atrial
fibrillation who are undergoing hemodialysis.
We conducted a literature search of Medline
through Ovid (1966 to January 2009) and of EMBASE
through Ovid (1980 to January 2009). The Medical
Subject Heading terms “atrial fibrillation,” “warfarin,”
and “bleeding” were combined with “end-stage renal
disease,” “dialysis,” and “kidney failure.” Studies that
assessed warfarin use in patients undergoing hemodi-
alysis with a target international normalized ratio of 2 to
3 were included for review.
Prevention of thromboembolic events, particularly
stroke in patients with atrial fibrillation from the
general population, is associated with substantial
reduction in morbidity and mortality.3 A number

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 Table 1—CHADS2 Score for Determination of the Risk
of Stroke Based on Baseline Comorbidities
Score Predicted Annualized Stroke Rate, % (95% CI)
0 1.9 (1.2–3.0)
1 2.8 (2.0–3.8)
2 4.0 (3.1–5.1)
3 5.9 (4.6–7.3)
4 8.5 (6.3–11.1)
5 12.5 (8.2–17.5)
6 18.2 (10.5–27.4)
Scoring system is as follows: 2 points for stroke or transischemic
attack and 1 point for each of congestive heart failure, hypertension,
age ⬎ 75 years, and diabetes mellitus.11
of randomized trials have demonstrated the effi-
cacy of warfarin anticoagulation therapy in the
reduction of stroke events at virtually all levels of
risk, except for the lowest risk patient group wherein
bleeding-related risk exceeds or begins to exceed
thromboembolic risk. In the general population, the
absolute risk of a thromboembolic event in patients
with untreated atrial fibrillation is 3 to 5% per year,
with a 21 to 67% relative risk reduction of stroke
with the use of antithrombotic therapy.6 – 8 The ab-
solute bleeding risk is approximately 1% per year,
which increases to 1.3 to 1.5% per year if the patient
is receiving oral anticoagulation (OAC) therapy.9
These well-defined stroke and bleed rates10,11 have
resulted in prospectively validated risk scores that for
the non-ESRD population predict the annual stroke
rate, its relative risk reduction with OAC, and the
bleeding risk both for hospital inpatients and for
outpatients (Tables 1, 2).
In patients with ESRD who are undergoing he-
modialysis, however, insufficient data exist to guide
therapeutic decision making because this cohort of
patients often is excluded from clinical studies.12,13
The systematic exclusion of patients with ESRD
continues in the evaluation of newer OAC agents and
in ongoing randomized controlled trials.13–15 Five
Table 2—Modified ORBI
Annual Risk of Bleeding Annual Risk of
Risk in Patients Without Bleeding in Patients
Score Group ESRD With ESRD
0 Low 3 10
1–2 Moderate 8 Approximately 32*
3 High 30 54
Scoring system is as follows: 2 points for both current and previous
stroke and 1 point for each of age ⬎ 65 years, current or previous
stroke, history of GI bleed, creatinine concentration ⬎ 133 ␮mol,
recent myocardial infarct, severe anemia, diabetes mellitus, and atrial
fibrillation.
*Moderate bleeding risk was determined as the midpoint of risk
between the high-risk and low-risk groups: (high ⫺ low)/2 ⫹ low.
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observational studies1,16 –19 evaluate atrial fibrillation
and outcomes in patients with ESRD (Table 3),
three of which were retrospective. The prevalence of
atrial fibrillation (4.6 to 25.8% per year) and OAC
use for this condition (4.2 to 22% per year) was
highly variable. Stroke rates in patients with atrial
fibrillation ranged from 1 to 4.97% per year, except
for the cohort reported by Vázquez et al,19 in which
the stroke rate was 23.1% per year in a small number
of patients (6 of 23 patients). One study1 reporting
the impact of OAC in preventing stroke in the atrial
fibrillation population found a higher stroke rate in
patients receiving OAC than in those not receiving
such therapy (4.46% vs 1.0% per year, respectively),
suggesting confounding by indication. Any infer-
ences that can be drawn from these studies are
limited by the observational cohort study design; the
small number of subjects; the lack of assessment of
bleeding rates; and an inability to assess and control
for the interfering effects of antiplatelet therapy,
OAC, heparin use with the hemodialysis procedure,
and uremic platelet dysfunction. Therefore, the de-
cision to use anticoagulation therapy rests on the
perceived risk of thromboembolic stroke vs that for
bleeding.
The stroke rate in patients with ESRD who are
undergoing hemodialysis is 4 to 10 times higher than
that in the general population, with a mortality rate
due to stroke between 4.8% and 12.7%.20 Recent
results from the Anticoagulation and Risk Factors in
Atrial Fibrillation study21 have suggested a progres-
sive increase in thromboembolism risk with the
presence of proteinuria and as the estimated glomer-
ular filtration rate declines. The case-mix adjusted
hazard ratio for thromboembolism was 1.39 (95%
CI, 1.13 to 1.71) for an estimated glomerular filtra-
tion rate of ⬍ 45 mL/min, with no significant differ-
ence if patients with ESRD were excluded. Both
ischemic and hemorrhagic stroke rates have been
found to be elevated relative to those in the general
population. The hemorrhagic stroke rate is four to six
times higher in patients with ESRD than in the
general population.4,5,22 The ischemic stroke rate is
elevated as well (relative risk, 4.3 to 10.1). No study
has subclassified ischemic stroke into thromboem-
bolic, thrombotic, and lacunar infarcts.4 With the
high rates of hypertension and diabetes mellitus in
the ESRD population, it is possible that the majority
of the strokes are small-vessel lacunar infarcts rather
than thromboembolic in origin. This raises a disturb-
ing question. Are we anticoagulating a population
wherein the risk of hemorrhagic stroke could possi-
bly approach or exceed that of a thromboembolic
event secondary to atrial fibrillation? Clearly, the
subclassification of stroke type is central to assessing
CHEST / 136 / 4 / OCTOBER, 2009 1129
 Table 3—Major Studies in the ESRD Population Comparing the Rates of Atrial Fibrillation, Stroke, and
Hemorrhage

Patients, Warfarin in Stroke Rate, Major Hemorrhage

Study/Year Design No. AF AF Stroke Non-AF Rate

Wiesholzer et al16/ Retrospective; 1,111 pt-yr 430 14.2 22 Total, 3.78 2.8 Not reported
2001 AF, 2.0
Stroke rate in AF with
OAC, 4.46
Stroke rate in AF
without OAC, 1.0
Vázquez et al19/2000 Prospective, single-center, 190 13.6 Not reported 23.1† (6/26) 4.3* (7/164) Not reported
1-yr follow-up
Genovesi et al1/2008 Prospective multicenter, 476 4.6 4.2 2.7 2.2 Not reported
69-mo follow-up
To et al18/2007 Retrospective, single-center, 155 25.8 12.5 Total, 3.04 Total, 10.6
3-yr duration AF group, 4.97 AF group, 16.2
Abbott et al17/2003 USRDS administrative 3,374 1.25† 8.1 AF group, 3.0 Not reported
database, 4 yr
All data are presented as percentage per year. To calculate the event percentage per year, events were assumed to occur at the same rate each
year. AF ⫽ atrial fibrillation; USRDS ⫽ US Renal Data System; pt-yr ⫽ patient-years.
*Death or thromboembolic phenomena.
†Percentage of patients requiring hospital admission for a primary diagnosis of atrial fibrillation.

potential benefit vs harm independent of the gener-
alized bleeding risk with OAC.
The adverse effects of warfarin therapy encompass
both bleeding and nonbleeding events. The risk of
bleeding in patients with ESRD who are undergoing
hemodialysis is elevated and exacerbated by expo-
sure to OAC. In the general population, the annual
bleeding risk in patients with atrial fibrillation de-
pends on the degree of comorbidity, with patients at
low, medium, and high risk facing rates of 3%, 8%,
and 30% per year, respectively.9 In patients with
ESRD who are undergoing hemodialysis, two more
recent studies23,24 examined the bleeding risk
(Table 4). Holden et al23 completed a retrospective
review of 255 patients who were undergoing hemo-
dialysis for 1,028 person-years and found major
bleed rates of 0.8% and 3.1% per patient-year,
respectively, for patients receiving warfarin therapy
Table 4 —Comparison of Major Bleeding Rates
Between Patients With ESRD on OAC and the General
Population
Major Hemorrhage Major Hemorrhage
Study Rate Without OAC Rate With OAC
General population
Estes et al6 0.7
ORBI low risk
ORBI medium risk
ORBI high risk
ESRD population
Holden et al23 0.8
Elliott et al24 2.5–11
All data are presented as % per year.
and those not receiving warfarin therapy. In a sys-
tematic review by Elliott et al,24 which included data
from two cohort studies (264 patients total), the rate
of major bleeding was much higher at 26 to 54% per
year. Combined, these two studies show an increase
in bleeding risk of 3 to 10 times with the addition of
OAC for patients with ESRD.
Additional adverse effects of warfarin therapy may
be unique to the ESRD population that is undergo-
ing hemodialysis. Acting as a vitamin K antagonist,
warfarin reduces the function of endogenous vitamin
K-dependent inhibitors of calcification, such as the
matrix Gla protein, thereby possibly facilitating vas-
cular calcification.25 This association between warfa-
rin therapy and calcification of the aortic valve and
coronary arteries has been reported26 and is an area
of concern. The most severe, destructive form of
vascular calcification is calcific uremic arteriopathy
(formerly known as calciphylaxis).27 Calcific uremic
arteriopathy occurs in 1 to 4% of patients in the
dialysis population and carries a poor prognosis, with
a 12-month mortality rate of 45%.28 Often affecting
the skin and leading to nonhealing ulceration and
subcutaneous calcification, calcific uremic arteriopa-
thy responds poorly to treatment.27 Multiple case
reports29 –31 have established the association between
1.3 warfarin use and the development of calciphylaxis.
3
Considering the uncertainties regarding stroke
8
30 phenotype, bleeding risk, and the vascular calcifica-
tion risks, determining the risk-benefit profile of
3.1 anticoagulation therapy in patients in the ESRD
26–54 population who are undergoing hemodialysis be-
comes exceedingly difficult. As mentioned, validated

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 risk-benefit models exist for the general population,
the largest of which are the cardiac failure, hyper-
tension, age, diabetes mellitus, and stroke scoring
system (CHADS2) for the prediction of annual
stroke risk with atrial fibrillation and the outpa-
tient risk of bleeding index (ORBI).10,11 Aside
from the CHADS2, numerous other risk stratifica-
tion schemes32–35 have been developed, with the risk
factors of age, prior stroke, hypertension, and diabe-
tes mellitus being the most predictive. No studies
have included declines in renal function as predic-
tors of future stroke. Considerable discrepancy exists
among the schemes, with two recent studies33,36
finding patients categorized as high risk ranging from
16.4 to 89.4% and low risk ranging from 9 to 49%,
depending on the scheme used. Lo et al37 has
proposed extrapolation of these risk scores despite a
lack of validation in the ESRD population. For
example, the ORBI scores 1 point each for anemia
and creatinine levels ⬎ 133 ␮mol, which would
mean that the majority of patients with ESRD have
a minimum score of 2, placing them in the middle
risk category of bleeding (8% annual bleeding risk).
Using the annual bleeding rates from the systematic
review by Elliott et al,24 the ORBI can be crudely
modified to be more applicable to the ESRD popu-
lation (Table 2). If the minimum score obtainable by
a patient with ESRD is 2, then the approximate
annual bleeding risk is 32%, far exceeding the 8%
per year rate in the general population. Although
crude, this modification to the ORBI significantly
increases the risk profile of bleeding and is based on
the most applicable evidence available to date.
The paradigm of risk stratification in this popula-
tion must consider the high mortality rate and
comorbid conditions in the hemodialysis population.
For example, cardiovascular mortality is 30 to 500%
higher in the ESRD population based on age, and
the estimated life expectancy of a patient between 65
and 69 years of age who is receiving hemodialysis is
roughly 4 years, decreasing to 2.5 years for patients
who are ⬎ 80 years of age.38,39 According to the US
Renal Data System 2008 report,40 the average age of
an incident dialysis patient is 64.4 years, with the
fastest growing population being those ⱖ 75 years of
age (65% rate increase since 2000). Factors predic-
tive of increased bleeding, such as diabetes mellitus
(44.8%) and hypertension (27%), are the most com-
mon causes of ESRD. Vitamin K deficiency second-
ary to malnutrition, frequent antibiotic use, and
abnormal cholesterol metabolism may lead to fluc-
tuations in responsiveness to OAC.41 Finally, factors
such as quality of life, a wish for decreased medical
procedures and interventions, and decreased pill
burden may tip the decision in favor of not antico-
agulating.
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As outlined, multiple competing factors are
present when attempting to risk stratify OAC use in
patients with ESRD who are undergoing hemodial-
ysis. If we are to extrapolate from the general
population, the majority of these patients would
receive anticoagulation therapy; but, is extrapolation
appropriate? Therapy with statins, BP reduction, and
renin-angiotensin system inhibitors have all failed to
reduce mortality in the dialysis population despite
evidence42– 44 of considerable benefit in the general
population. Thus, the first step in management
involves determining an individual risk-benefit as-
sessment of whether to start OAC (Table 5). Con-
sideration of age, comorbidities, concomitant anti-
platelet use, bleeding and stroke history, and the
patient’s wishes must be weighed carefully. Numer-
ous factors favor the limited use of OAC in this
population, such as the high rate of hemorrhagic
stokes, the possibility that the majority of ischemic
strokes may be lacunar, the high bleeding risk, the
shortened lifespan of dialysis patients, and the in-
creased risk of vascular calcification. An approach
where OAC for stroke prevention in patients with
ESRD and atrial fibrillation who are undergoing
hemodialysis should be provided only in those per-
sons who are at high risk for stroke seems reasonable
based on the existing literature. Using this approach,
OAC then should be offered only to patients who
appear to have the highest stroke risk, such as those
with a CHADS2 score greater than a modified ORBI
score (difference ⱖ 2), patient preference, known
atrial thrombus, prosthetic heart valves, mitral ste-
Table 5—Suggested Risk Stratification for OAC Use in
Stroke Prevention in Patients With Persistent or
Paroxysmal Atrial Fibrillation on Hemodialysis
Risk Stratification Description
Favors OAC Age ⬎ 75 years and risk factors*;
Previous TIA or stroke;
Known atrial thrombus;
Patient preference;
CHADS2 score greater than or equal to the
ORBI score by 2 points;
Prosthetic heart valve; and
Mitral stenosis
Favors no OAC† Age ⬍ 65 years with no risk factors*;
Uncontrolled hypertension;
Concurrent antiplatelet agent use;
History of or active calciphylaxis;
Previous life-threatening hemorrhage;
Severe malnutrition;
Noncompliance; and
Frequent falls
*Risk factors include diabetes mellitus, hypertension, and congestive
heart failure.
†In patients not suitable for OAC, consider the use of antiplatelet
agents.
CHEST / 136 / 4 / OCTOBER, 2009 1131
 nosis, or history of previous thromboembolic stroke.
Due to the increased risk of bleeding, patients at low
risk such as those who are ⬍ 65 years of age, have
normal echocardiograms, and are without hyperten-
sion, diabetes, or congestive heart failure will likely
derive little benefit from OAC. Patients with uncon-
trolled hypertension, concurrent use of antiphospho-
lipid antibodies, previous severe hemorrhage, a his-
tory of treatment noncompliance, frequent falls,
calciphylaxis, or severe malnutrition should be con-
sidered relatively contraindicated for the use of OAC
due to the high risk of subsequent hemorrhage or
complications. Although we are cognizant that this
approach is controversial, it would appear to be a
legitimate approach to treatment as the evidence at
this point is limited, and the risk profile appears to be
different in the dialysis population.
In medicine, we always strive to optimize the
patients’ risk-benefit profile by making evidence-
based decisions that are socially acceptable and
ethically responsible. The understanding of an ac-
ceptable risk-benefit profile often is difficult. Fur-
thermore, our natural tendency is to intervene and
treat. The dilemma of OAC use for stroke prevention
in patients with atrial fibrillation and ESRD who are
undergoing hemodialysis illustrates these competing
factors and the difficult decisions that clinicians face.
Acknowledgments
Author contributions: All authors contributed to, reviewed, and
approved this manuscript.
Financial/nonfinancial disclosures: The authors have re-
ported to the ACCP that no significant conflicts of interest exist
with any companies/organizations whose products or services
may be discussed in this article.
Other contributions: We thank Dr. Martina Reslerova for her
generous contributions to this manuscript.
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