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original article

Stroke and Bleeding in Atrial Fibrillation

with Chronic Kidney Disease
Jonas Bjerring Olesen, M.D., Gregory Y.H. Lip, M.D.,
Anne-Lise Kamper, M.D., D.M.Sc., Kristine Hommel, M.D.,
Lars Kber, M.D., D.M.Sc., Deirdre A. Lane, Ph.D.,
Jesper Lindhardsen, M.D., Gunnar Hilmar Gislason, M.D., Ph.D.,
and Christian Torp-Pedersen, M.D., D.M.Sc.

A BS T R AC T
BACKGROUND

Both atrial fibrillation and chronic kidney disease increase the risk of stroke and
systemic thromboembolism. However, these risks, and the effects of antithrombotic
treatment, have not been thoroughly investigated in patients with both conditions.
METHODS

Using Danish national registries, we identified all patients discharged from the
hospital with a diagnosis of nonvalvular atrial fibrillation between 1997 and 2008.
The risk of stroke or systemic thromboembolism and bleeding associated with
nonend-stage chronic kidney disease and with end-stage chronic kidney disease
(i.e., disease requiring renal-replacement therapy) was estimated with the use of
time-dependent Cox regression analyses. In addition, the effects of treatment with
warfarin, aspirin, or both in patients with chronic kidney disease were compared
with the effects in patients with no renal disease.
RESULTS

Of 132,372 patients included in the analysis, 3587 (2.7%) had nonend-stage chronic
kidney disease and 901 (0.7%) required renal-replacement therapy at the time of inclusion. As compared with patients who did not have renal disease, patients with
nonend-stage chronic kidney disease had an increased risk of stroke or systemic
thromboembolism (hazard ratio, 1.49; 95% confidence interval [CI], 1.38 to 1.59;
P<0.001), as did those requiring renal-replacement therapy (hazard ratio, 1.83; 95%
CI, 1.57 to 2.14; P<0.001); this risk was significantly decreased for both groups of
patients with warfarin but not with aspirin. The risk of bleeding was also increased
among patients who had nonend-stage chronic kidney disease or required renalreplacement therapy and was further increased with warfarin, aspirin, or both.

From the Department of Cardiology, Copenhagen University Hospital Gentofte,

Hellerup (J.B.O., J.L., G.H.G., C.T.-P.),
and the Department of Nephrology
(A.-L.K., K.H.) and the Heart Center, Copenhagen University Hospital Rigshospitalet, Copenhagen (L.K.) both in Denmark; and the University of Birmingham
Centre for Cardiovascular Sciences, City
Hospital, Birmingham, United Kingdom
(J.B.O., G.Y.H.L., D.A.L.). Address reprint
requests to Dr. Olesen at the Copenhagen
University Hospital Gentofte, Department
of Cardiology, Post 635, Niels Andersens
Vej 65, 2900 Hellerup, Denmark, or at
jo@heart.dk.
This article was updated on November 15,
2012, at NEJM.org.
N Engl J Med 2012;367:625-35.
DOI: 10.1056/NEJMoa1105594
Copyright 2012 Massachusetts Medical Society.

CONCLUSIONS

Chronic kidney disease was associated with an increased risk of stroke or systemic
thromboembolism and bleeding among patients with atrial fibrillation. Warfarin
treatment was associated with a decreased risk of stroke or systemic thromboembolism among patients with chronic kidney disease, whereas warfarin and aspirin
were associated with an increased risk of bleeding. (Funded by the Lundbeck Foundation.)

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625

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he prevalence of both atrial fib

rillation and chronic kidney disease increases with age.1,2 The prevalence of atrial
fibrillation is 2.3% among persons 40 years of age
or older and 5.9% among those 65 years of age or
older,2 and the prevalence of end-stage renal disease increases from approximately 0.28% among
persons 45 to 64 years of age to 0.41% among
those 75 years of age or older.1 Many patients
have both disorders,3-6 and the number of such
patients is increasing, owing in part to the aging
population and the improved survival in both
diseases.
Atrial fibrillation increases the risk of stroke
by a factor of 5,7 and chronic kidney disease increases the risk of stroke among patients without atrial fibrillation.1,8 The U.S.-based Renal Data
System has reported that chronic kidney disease
increases the risk of stroke by a factor of 3.7, and
end-stage renal disease (i.e., disease requiring
renal-replacement therapy) increases the risk by
a factor of 5.8.1 Chronic kidney disease has also
been associated with an increase in the risk of
myocardial infarction,9 as has atrial fibrillation,
at least among women.10
To reduce the risk of stroke or systemic thromboembolism, patients with atrial fibrillation
should be treated with antithrombotic therapy.11
However, some studies have suggested that the
use of warfarin may actually increase the risk of
ischemic stroke among patients undergoing dialysis.3,12,13 Furthermore, the risk of bleeding
associated with warfarin treatment is increased
among patients with atrial fibrillation who also
have chronic kidney disease.6 Despite the size of
this patient group, large randomized trials of antithrombotic therapy in patients with atrial fibrillation have typically excluded those who also have
moderate-to-severe chronic kidney disease,14-16
and the treatment of these patients has been
based on data obtained from smaller observational studies.13
The objective of this study was to determine
the risk of stroke or systemic thromboembolism
and bleeding associated with chronic kidney
disease among patients with atrial fibrillation
and to determine whether the effect of warfarin
and aspirin differed between patients with and
those without chronic kidney disease.

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ME THODS
REGISTRY DATA SOURCES

In this Danish cohort study, we linked individuallevel data from national registries, using the personal registration number provided to all Danish
residents. The data were obtained from the Central
Population Registry, the National Patient Registry,
the Registry of Medicinal Product Statistics, the
National Registry on Regular Dialysis and Transplantation, and the National Registry of Causes of
Death.17-22 The details of the information contained
in each of these registries, as well as the diagnoses,
surgical procedures, and pharmacotherapy used for
defining the study population, coexisting conditions, and outcomes, are provided in the Supplementary Appendix, available with the full text of
this article at NEJM.org.
The Lundbeck Foundation provided grant support but had no role in the conduct of the study.
The study was approved by the Danish Data Protection Agency. Approval by an ethics committee
and written informed consent are not required for
retrospective registry studies in Denmark. The
first author vouches for the integrity of the data
and the accuracy of the data analysis.
STUDY POPULATION

We identified all patients discharged from the hospital with a diagnosis of nonvalvular atrial fibrillation during the study period, from 1997 through
2008.17,19 Pharmacotherapy was determined by
means of filled prescriptions and, because treatment may have been changed or intensified during or immediately after hospitalization, the baseline assessment and follow-up period began 7 days
after discharge. Patients were excluded if they
died, had a thromboembolic event, or had major
bleeding during the 7 days before the baseline
assessment (Fig. 1).17-19
CHRONIC KIDNEY DISEASE AND RENALREPLACEMENT THERAPY

Patients with chronic kidney disease who did not

require renal-replacement therapy (i.e., who had
nonend-stage chronic kidney disease) were identified from the National Patient Registry. Patients
requiring renal-replacement therapy (those who
were undergoing maintenance dialysis or who

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Atrial Fibrillation with Chronic Kidney Disease

Figure 1. Study Population, According to Status with Respect to Renal Disease.

Of the 132,372 patients who were discharged from the hospital with a diagnosis of nonvalvular atrial fibrillation during
the study period and who were included in the study, 4488 had renal disease at baseline. The majority of the study
population had no renal disease at baseline, although nonend-stage chronic kidney disease or a disorder necessitating renal-replacement therapy developed in 4572 patients during follow-up.

had received a kidney transplant) were identified

from the National Registry on Regular Dialysis and
Transplantation. Renal status was determined at
baseline and could be modified during follow-up
(Fig. 1). The renal status of patients who were
initially classified as having no chronic kidney
disease could change to nonend-stage chronic
kidney disease and could subsequently change to
disease requiring renal-replacement therapy. The
status of patients with nonend-stage chronic kidney disease initially could change to disease requiring renal-replacement therapy. The status of
patients who initially had disease requiring renalreplacement therapy could not change during
follow-up. Data were not censored in relation to
change in renal status; patients remained in the
analysis until an event occurred or until the end
of follow-up. Thus, patients were analyzed according to their current renal status.

To investigate the risk associated with the severity of nonend-stage chronic kidney disease,
patients were stratified in a time-dependent manner according to the treatment dose of loop diuretics, because high doses are frequently used in patients with severe renal failure or the nephrotic
syndrome. We studied the influence of the underlying renal disease in nonend-stage chronic
kidney disease by comparing the following diagnostic groups: autosomal dominant polycystic kidney disease, chronic glomerulonephritis, diabetic
nephropathy, chronic tubulointerstitial nephropathy, hypertensive nephropathy, and other causes.
PHARMACOLOGIC TREATMENT

Baseline pharmacologic treatment with all drugs

other than warfarin and aspirin was determined
on the basis of prescriptions filled from 180 days
before discharge to 7 days after discharge, and

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patients receiving antiplatelet drugs other than

aspirin (i.e., clopidogrel or dipyridamole) were
excluded from the study population (Fig. 1).19
Periods during which each patient was treated
with warfarin, aspirin, or both were determined
throughout follow-up.19-21,23
STROKE AND BLEEDING RISK ASSESSMENT

The predicted risk of stroke or systemic thromboembolism for all patients was assessed with the use
of the CHA2DS2-VASc score,17,24 which reflects
the risk of stroke among patients with atrial fibrillation who are not receiving anticoagulant
therapy, with values ranging from 0 to 9 and with
higher scores indicating greater risk (see Table 1
in the Supplementary Appendix). The predicted
risk of bleeding was assessed with the use of the
HAS-BLED score,18,25 which reflects the risk of
major bleeding among patients with atrial fibrillation who are receiving anticoagulant therapy,
with values ranging from 0 to 9 and with higher
scores indicating greater risk (see Table 2 in the
Supplementary Appendix). Two risk factors typically included in the HAS-BLED score were not
included in this analysis: abnormal renal function (since chronic kidney disease was the subject
of the study) and labile international normalized
ratios (because these data were not available).
STUDY OUTCOMES

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The risk of stroke or systemic thromboembolism associated with nonend-stage chronic kidney disease or disease requiring renal-replacement
therapy was estimated by means of time-dependent Cox proportional-hazards models, with adjustment for changes in renal status or antithrombotic treatment during follow-up. Cox analyses
were adjusted for risk factors in the CHA2DS2-VASc
score (congestive heart failure, hypertension, age
>75 years, diabetes mellitus, history of stroke or
thromboembolism, vascular disease, age 65 to
74 years, female sex), antithrombotic treatment,
and year of inclusion. The total study population
was included in the initial analysis, and subsequent
analyses were restricted to patients with nonendstage chronic kidney disease and to those requiring renal-replacement therapy.
Similar analyses were conducted to assess the
risk of bleeding, with the use of the HAS-BLED
risk factors (hypertension, abnormal liver function,
history of stroke or thromboembolism, history of
bleeding, age 65 years, use of nonsteroidal antiinflammatory drugs, and unhealthy alcohol use).
Finally, the risks of stroke or systemic thromboembolism, bleeding, myocardial infarction, and
death from any cause were estimated by means of
time-dependent Cox proportional-hazards models,
with adjustment for all baseline characteristics.
A two-sided P value of less than 0.05 was
considered to indicate statistical significance. All
analyses were performed with the use of SAS
software, version 9.2 (SAS Institute), and Stata
software, version 11.0 (StataCorp).

Outcomes under investigation were hospitalization

or death from stroke or systemic thromboembolism (peripheral-artery embolism, ischemic stroke,
and transient ischemic attack),17,26 bleeding (gastrointestinal, intracranial, urinary tract, and airR E SULT S
way bleeding),20,21 myocardial infarction,27 and
death from any cause. A secondary analysis of the STUDY POPULATION
risk of stroke or systemic thromboembolism ex- During the 12-year study period, 132,372 patients
with nonvalvular atrial fibrillation were included
cluded transient ischemic attack.
in the cohort (Fig. 1). Of these, 127,884 patients
STATISTICAL ANALYSIS
(96.6%) had no renal disease at baseline, 3587
Comparisons of characteristics among patients (2.7%) had nonend-stage chronic kidney disease,
who had no renal disease, those who had non and 901 (0.7%) required renal-replacement theraend-stage chronic kidney disease, and those re- py. Baseline characteristics of each group are shown
quiring renal-replacement therapy at baseline were in Table 1; medications at baseline other than anperformed with the use of the chi-square test for tithrombotic agents are shown in Table 3 in the
categorical covariates and the KruskalWallis test Supplementary Appendix.
or Students t-test for continuous covariates. Event
Among the patients who had no renal disease
rates for the four study outcomes were calculated initially, nonend-stage chronic kidney disease
according to renal status; the renal status of each developed in 4538 patients (3.5%) after a median
patient was updated during follow-up if renal of 893 days (interquartile range, 313 to 1715), and
function worsened.
renal-replacement therapy was required in 477 pa628

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Atrial Fibrillation with Chronic Kidney Disease

Table 1. Baseline Characteristics of the Patients.*

No Renal Disease
(N=127,884)

NonEnd-Stage
Chronic Kidney
Disease
(N=3587)

Disease Requiring
Renal-Replacement
Therapy
(N=901)

P Value

73.212.9

76.511.0

66.811.7

<0.001

Congestive heart failure

22,073 (17.3)

1284 (35.8)

171 (19.0)

<0.001

Hypertension

53,917 (42.2)

1952 (54.4)

486 (53.9)

<0.001

75 yr

66,675 (52.1)

2277 (63.5)

267 (29.6)

<0.001

6574 yr

31,245 (24.4)

809 (22.6)

293 (32.5)

<0.001

Diabetes mellitus

10,920 (8.5)

885 (24.7)

129 (14.3)

<0.001

History of stroke or systemic thromboembolism

17,928 (14.0)

644 (18.0)

133 (14.8)

<0.001

Vascular disease

18,174 (14.2)

1034 (28.8)

248 (27.5)

<0.001

Female sex

59,930 (46.9)

1472 (41.0)

303 (33.6)

<0.001

53,917 (42.2)

1952 (54.4)

486 (53.9)

<0.001

Characteristic
Age yr
Risk factors for stroke or thromboembolism no. (%)

Age

Risk factors for bleeding no. (%)

Hypertension
Abnormal liver function
History of stroke or systemic thromboembolism
History of bleeding

2,070 (1.6)

106 (3.0)

36 (4.0)

<0.001

17,928 (14.0)

644 (18.0)

133 (14.8)

<0.001

8,969 (7.0)

584 (16.3)

137 (15.2)

<0.001

Age 65 yr

95,418 (74.6)

3035 (84.6)

533 (59.2)

<0.001

Use of NSAIDs

26,592 (20.8)

843 (23.5)

99 (11.0)

<0.001

Alcohol abuse

4,552 (3.6)

145 (4.0)

43 (4.8)

0.05

Warfarin only

36,638 (28.6)

609 (17.0)

178 (19.8)

<0.001

Aspirin only

23,952 (18.7)

879 (24.5)

153 (17.0)

<0.001

Warfarin and aspirin

10,745 (8.4)

290 (8.1)

45 (5.0)

<0.001

11,720 (9.2)

70 (2.0)

42 (4.7)

16,926 (13.2)

251 (7.0)

165 (18.3)

99,238 (77.6)

3266 (91.1)

694 (77.0)

Antithrombotic medication no. (%)

CHA2DS2-VASc score

<0.001

HAS-BLED score

<0.001

0 or 1

51,262 (40.1)

883 (24.6)

390 (43.3)

46,159 (36.1)

1336 (37.2)

312 (34.6)

30,463 (23.8)

1368 (38.1)

199 (22.1)

* Plusminus values are means SD. NSAIDs denotes nonsteroidal antiinflammatory drugs.
Scores on the CHA2DS2-VASc,17,24 which reflect the risk of stroke in patients with atrial fibrillation who are not receiving anticoagulant therapy, range from 0 to 9; a score of 0 indicates low risk, a score of 1 intermediate risk, and a score
of 2 or more high risk (Table 1 in the Supplementary Appendix).
Scores on the HAS-BLED,18,25 which reflect the risk of major bleeding in patients with atrial fibrillation who are receiving anticoagulant therapy, range from 0 to 9; a score of 0 or 1 indicates low risk, a score of 2 intermediate risk, and a
score of 3 or more high risk (Table 2 in the Supplementary Appendix).

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tients (0.4%) after a median of 217 days (interquartile range, 33 to 681). Of the 1378 patients requiring renal-replacement therapy during the study
period, 1074 (77.9%) were receiving hemodialysis,
212 (15.4%) were receiving peritoneal dialysis,
and 92 (6.7%) underwent kidney transplantation.
The outcomes did not differ significantly according to the type of renal-replacement therapy.
Rates of stroke or systemic thromboembolism,
bleeding, myocardial infarction, and death from
any cause are shown according to renal status in
Table 2. All event rates were markedly increased
in both groups of patients with renal disease. The
distribution between the three types of stroke or
thromboembolic outcomes and the four types of
bleeding outcomes is shown in Table 4 in the
Supplementary Appendix.

risk factors, antithrombotic therapy, and year of

inclusion. As compared with patients who did not
have renal disease, the risk of stroke or systemic
thromboembolism was increased among patients
with nonend-stage chronic kidney disease (hazard ratio, 1.49; 95% confidence interval [CI], 1.38 to
1.59; P<0.001) and among those requiring renalreplacement therapy (hazard ratio, 1.83; 95% CI,
1.57 to 2.14; P<0.001). The results were similar in
a sensitivity analysis for the outcome of stroke or
systemic thromboembolism that excluded transient
ischemic attack (Table 5 in the Supplementary
Appendix). Among patients with nonend-stage
chronic kidney disease, no significant association
between the risk of stroke or systemic thromboembolism and dose of loop diuretics was found
(Table 6 in the Supplementary Appendix). Among
the diagnostic groups analyzed, the risk of stroke
or systemic thromboembolism was increased to the
greatest degree among patients with hypertensive
nephropathy and to the lowest degree among those
with chronic tubulointerstitial nephropathy (for
whom the increase in risk was not significant; see
Table 6 in the Supplementary Appendix).
Warfarin treatment was associated with a
significantly decreased risk of stroke or systemic
thromboembolism overall and among patients
requiring renal-replacement therapy, and with a
nonsignificantly decreased risk among patients
with nonend-stage chronic kidney disease (Table 3). In an analysis that compared all patients
who had any renal disease with those who had no
renal disease, warfarin decreased the risk of stroke
or systemic thromboembolism (hazard ratio, 0.76;
95% CI, 0.64 to 0.91; P=0.003), as did warfarin
plus aspirin (hazard ratio, 0.74; 95% CI, 0.56 to
0.98; P=0.04). Aspirin was associated with an
increased risk of stroke or systemic thromboembolism overall (Table 3) and among patients who
had any renal disease, as compared with those
who had no renal disease (hazard ratio, 1.17; 95%
CI, 1.01 to 1.35; P=0.04). The risk of stroke or
systemic thromboembolism in association with
chronic kidney disease was of the same magnitude in multivariate Cox regression models that
were adjusted for all baseline characteristics
(Fig. 1 in the Supplementary Appendix).

RISK OF STROKE OR THROMBOEMBOLISM

RISK OF BLEEDING

Table 2. Event Rates, According to Status with Respect to Renal Disease.*

Event

Event Rate per 100

Person-yr
(95% CI)

No. of
Person-yr

No. of
Events

461,734

16,648

3.61 (3.553.66)

13,078

842

6.44 (6.026.89)

2,922

164

5.61 (4.826.54)

457,605

16,195

3.54 (3.483.59)

12,515

1,097

8.77 (8.269.30)

2,734

243

480,745

9,037

1.88 (1.841.92)

13,500

784

5.81 (5.416.23)

2,925

175

5.98 (5.166.94)

493,305

55,297

11.21 (11.1211.30)

14,052

5,431

38.65 (37.6339.69)

3,114

914

29.35 (27.5131.32)

Stroke or thromboembolism
No renal disease
Nonend-stage CKD
Disease requiring renalreplacement therapy
Bleeding
No renal disease
Nonend-stage CKD
Disease requiring renalreplacement therapy

8.89 (7.8410.08)

Myocardial infarction
No renal disease
Nonend-stage CKD
Disease requiring renalreplacement therapy
Death
No renal disease
Nonend-stage CKD
Disease requiring renalreplacement therapy

* A patients renal status could change during follow-up. CI denotes confidence

interval, and CKD chronic kidney disease.

Table 3 shows the results from Cox regression The risk of bleeding was higher among patients
models of the risk of stroke or systemic throm- with nonend-stage chronic kidney disease and
boembolism, with adjustment for CHA2DS2-VASc among those requiring renal-replacement thera630

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0.70 (0.650.75)

1.06 (1.031.09)

Hypertension

<0.001
<0.001

1.12 (1.081.15)

1.12 (1.071.16)

3.24 (3.143.35)

1.32 (1.251.39)

2.03 (1.922.16)

3.56 (3.383.76)

1.05 (1.021.09)

1.03 (0.991.08)

0.69 (0.640.74)

1.10 (1.061.14)

0.59 (0.560.61)

1.00

1.00

Hazard Ratio
(95% CI)

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

0.002

0.11

<0.001

<0.001

<0.001

P Value

No Renal Disease
(N=127,884)

1.06 (0.921.22)

0.89 (0.761.05)

2.71 (2.343.15)

1.16 (0.991.36)

1.52 (1.181.94)

1.87 (1.482.36)

1.13 (0.981.30)

0.98 (0.841.14)

0.76 (0.561.03)

1.25 (1.071.47)

0.84 (0.691.01)

1.00

1.49 (1.381.59)

Hazard Ratio
(95% CI)

0.44

0.17

<0.001

0.07

0.001

<0.001

0.10

0.78

0.08

0.01

0.07

<0.001

P Value

NonEnd-Stage Chronic Kidney

Disease
(N=3587)

* Results from the time-dependent Cox regression analyses were adjusted for year of inclusion.
Numbers of patients are from baseline data. Because the analyses were time-dependent, these numbers changed during follow-up.
The reference group for the hazard ratio for each thromboembolism risk factor is the group of all patients in the study without that risk factor.

1.10 (1.061.15)
1.12 (1.081.15)

Vascular disease

Female sex

<0.001

<0.001

1.32 (1.261.38)
3.20 (3.103.31)

Diabetes

2.02 (1.912.14)

History of stroke or systemic

thromboembolism

<0.001

3.48 (3.313.66)

75 yr

<0.001

<0.001

6574 yr

Age

1.03 (0.991.07)

Congestive heart failure

Risk factors for thromboembolism

0.18

<0.001

1.11 (1.071.15)

Warfarin and aspirin

<0.001

0.59 (0.570.62)

<0.001

P Value

Aspirin

1.00

Hazard Ratio
(95% CI)

Warfarin

None

Antithrombotic therapy

All participants

Characteristic

Total Population
(N=132,372)

Table 3. Hazard Ratios for Stroke or Systemic Thromboembolism.*

1.34 (0.971.85)

1.11 (0.781.58)

1.99 (1.362.91)

1.41 (0.952.10)

2.18 (1.463.24)

2.46 (1.603.79)

1.05 (0.761.45)

0.96 (0.641.43)

0.82 (0.371.80)

0.88 (0.591.32)

0.44 (0.260.74)

1.00

1.83 (1.572.14)

Hazard Ratio
(95% CI)

0.08

0.57

<0.001

0.09

<0.001

<0.001

0.78

0.84

0.62

0.54

0.002

<0.001

P Value

Disease Requiring RenalReplacement Therapy

(N=901)

Atrial Fibrillation with Chronic Kidney Disease

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py than among patients without renal disease,

and treatment with warfarin, aspirin, or both incrementally increased this risk (Table 4). Among
all patients who had any renal disease, as compared with those who had no renal disease, there
was an increased risk of bleeding with warfarin
(hazard ratio, 1.33; 95% CI, 1.16 to 1.53; P<0.001),
aspirin (hazard ratio, 1.17; 95% CI, 1.02 to 1.34;
P=0.03), and warfarin plus aspirin (hazard ratio,
1.61; 95% CI, 1.32 to 1.96; P<0.001). Among patients with nonend-stage chronic kidney disease,
the risk of bleeding increased with a higher dose
of loop diuretics (Table 6 in the Supplementary
Appendix). The risk of bleeding was highest among
patients with chronic glomerulonephritis and
lowest among those with chronic tubulointerstitial nephropathy (Table 6 in the Supplementary
Appendix). The risk of bleeding among patients
with chronic kidney disease was of similar magnitude in the multivariate Cox regression model (Fig.
1 in the Supplementary Appendix).
RISKS OF MYOCARDIAL INFARCTION AND DEATH
FROM ANY CAUSE

On the basis of multivariate Cox regression models,

nonend-stage chronic kidney disease and disease
requiring renal-replacement therapy were both
associated with an increased risk of myocardial
infarction, as compared with no renal disease
(hazard ratio with nonend-stage chronic kidney
disease, 2.00; 95% CI, 1.86 to 2.16; P<0.001; hazard
ratio with disease requiring renal-replacement
therapy, 3.00; 95% CI, 2.58 to 3.50; P<0.001).
Both categories of renal disease were also associated with an increased risk of death from any
cause (hazard ratio with nonend-stage chronic
kidney disease, 2.37; 95% CI, 2.30 to 2.44; P<0.001;
hazard ratio with disease requiring renal-replacement therapy, 3.35; 95% CI, 3.13 to 3.58; P<0.001)
(Fig. 1 in the Supplementary Appendix).

DISCUSSION
In a large cohort study, we found that among
patients with atrial fibrillation, nonend-stage
chronic kidney disease and disease requiring renalreplacement therapy were both associated with
increased risks of stroke or systemic thromboembolism and bleeding. Among patients with
nonend-stage chronic kidney disease, the risk
of stroke or systemic thromboembolism was not
influenced by the severity of the renal disease (as
632

of

m e dic i n e

determined by the intensity of treatment with loop

diuretics), whereas the risk of bleeding was associated with the dose of loop diuretics and with
the cause of the chronic kidney disease. The risks
of myocardial infarction and death from any cause
were also increased among patients with atrial
fibrillation who had chronic kidney disease, as
compared with those who had no renal disease.
In addition, we found that warfarin reduced the
risk of stroke or systemic thromboembolism in
the whole study population and among patients
with chronic kidney disease, whereas aspirin did
not reduce this risk. Both warfarin and aspirin
increased the risk of bleeding.
The most effective treatment for stroke thromboprophylaxis in patients with atrial fibrillation
is oral anticoagulant therapy.28 However, clinical
trials of thromboprophylaxis in atrial fibrillation
have largely excluded patients with kidney disease.
Indeed, given the predominantly renal excretion of
some of the new oral anticoagulant agents, only
patients with a creatinine clearance of 30 ml per
minute or more have been studied, with some
trials adjusting the dose of the study drug for
those patients with moderate chronic kidney disease.14,15 We found that warfarin therapy was associated with a significant reduction in the risk of
stroke or thromboembolism among patients with
chronic kidney disease but that the risk of bleeding among such patients was significantly increased. Thus, the net clinical effect of warfarin
treatment requires careful assessment in patients
with chronic kidney disease,16 and the data do
not provide clear guidance regarding indications
for anticoagulant therapy in patients with both
atrial fibrillation and chronic kidney disease.
Certainly, close monitoring of the international
normalized ratio is required when warfarin is
administered. Ideally, the role of warfarin (or of
other, newer anticoagulant agents) in patients
with atrial fibrillation who have chronic kidney
disease should be evaluated in a clinical trial.
Our study is limited by its observational cohort
design, and there may be residual confounding,
although we attempted to adjust the analysis for
baseline clinical characteristics. The frequencies
of risk factors in the study population may also
be underestimated, since we identified patients
with heart failure, hypertension, and diabetes on
the basis of filled prescriptions and thus were
not able to identify patients who were treated
with diet and lifestyle interventions alone. Al-

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2.15 (2.042.26)

<0.001
<0.001

1.23 (1.181.28)
2.44 (2.332.55)
2.09 (2.002.17)
1.12 (1.081.16)
1.40 (1.301.52)

History of stroke or systemic

thromboembolism

History of bleeding

Age 65 yr

Use of NSAIDs

Alcohol abuse

1.43 (1.321.56)

1.12 (1.081.17)

2.12 (2.032.20)

2.54 (2.422.67)

1.24 (1.191.30)

1.40 (1.251.57)

1.01 (0.981.04)

2.18 (2.072.30)

1.21 (1.161.26)

1.28 (1.231.33)

1.00

1.00

Hazard Ratio
(95% CI)

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

0.58

<0.001

<0.001

<0.001

P Value

No Renal Disease
(N=127,884)

1.01 (0.731.39)

1.10 (0.961.26)

1.61 (1.351.92)

1.70 (1.451.99)

1.04 (0.891.22)

1.31 (0.901.91)

0.99 (0.871.11)

1.63 (1.322.02)

1.12 (0.961.30)

1.36 (1.171.59)

1.00

2.24 (2.102.38)

Hazard Ratio
(95% CI)

0.97

0.19

<0.001

<0.001

0.62

0.16

0.81

<0.001

0.14

<0.001

<0.001

P Value

NonEnd-Stage Chronic
Kidney Disease (N=3587)

* Results from the time-dependent Cox regression analyses were adjusted for year of inclusion. NSAIDs denotes nonsteroidal antiinflammatory drugs.
Numbers of patients are from baseline data. Because the analyses were time-dependent, these numbers changed during follow-up.
The reference group for the hazard ratio for each bleeding risk factor is the group of all patients in the study without that risk factor.

<0.001

<0.001

<0.001

<0.001

1.01 (0.981.04)
1.37 (1.231.52)

Hypertension

Abnormal liver function

Risk factors for bleeding

0.52

<0.001

1.21 (1.161.26)

Warfarin and aspirin

<0.001

1.28 (1.231.33)

<0.001

P Value

Warfarin

1.00

Hazard Ratio
(95% CI)

Total Population
(N=132,372)

Aspirin

None

Antithrombotic therapy

All participants

Characteristic

Table 4. Hazard Ratios for Bleeding.*

1.33 (0.702.54)

0.91 (0.621.33)

1.36 (1.031.80)

2.09 (1.502.91)

0.93 (0.631.36)

0.74 (0.341.64)

0.92 (0.711.20)

1.71 (0.982.99)

1.63 (1.182.26)

1.27 (0.911.77)

1.00

2.70 (2.383.07)

Hazard Ratio
(95% CI)

0.39

0.63

0.03

<0.001

0.70

0.46

0.55

0.06

0.003

0.15

<0.001

P Value

Disease Requiring RenalReplacement Therapy

(N=901)

Atrial Fibrillation with Chronic Kidney Disease

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633

The

n e w e ng l a n d j o u r na l

though the positive predictive value of the diagnosis of atrial fibrillation is very high (99%),29 the
inclusion of only hospitalized patients with atrial
fibrillation is likely to have resulted in an overestimate of the proportion of patients who were
at increased risk for thromboembolism and bleeding. The bleeding outcome was restricted to hospitalization or death related to gastrointestinal
bleeding, intracranial bleeding, bleeding from the
urinary tract, and airway bleeding, and the results cannot be applied to the risk of other types
of bleeding.20,21 The outcomes of stroke or systemic thromboembolism and myocardial infarction are well validated, and the information on
all-cause mortality is accurate,26,27 as is the information on renal-replacement therapy.22 Since we
did not have brain-imaging data for the patients
in the study, some strokes that were reported as
ischemic may actually have been hemorrhagic,
but Krarup and colleagues did not find this potential bias to be of importance.26 Despite the
accuracy of filled prescriptions as a measure of
medication use,30 aspirin can also be bought over
the counter in Denmark, and the use of aspirin
may therefore be underestimated. It is also possible that the increased risk of stroke or systemic
thromboembolism that was associated with aspirin in our analysis was due to confounding by
indication. Finally, some of the dialysis centers in
Denmark have reported that they provide warfarin without the use of prescriptions for patients
who require renal-replacement therapy (primarily
those receiving hemodialysis).

of

m e dic i n e

In conclusion, in a large cohort study, we

found that nonend-stage chronic kidney disease
and disease requiring renal-replacement therapy
were independently associated with increased risks
of stroke or systemic thromboembolism, bleeding, myocardial infarction, and death among
patients with atrial fibrillation. The effect of
warfarin was similar among patients with atrial
fibrillation and those without chronic kidney
disease, reducing the risk of stroke or systemic
thromboembolism and increasing the risk of
bleeding. In contrast, aspirin was not associated
with a reduced risk of stroke or systemic thromboembolism but was associated with an increased
risk of bleeding.
Supported by the Lundbeck Foundation.
Dr. Olesen reports receiving travel support from AstraZeneca
and Boehringer Ingelheim on behalf of his institution; Dr. Lip,
receiving consulting fees from Astellas, AstraZeneca, Bayer,
Biotronik, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim,
Merck, Portola, and Sanofi Aventis, and being on speakers bureaus for Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and Sanofi Aventis; Dr. Kber, being on a speakers bureau for Servier; Dr. Lane, receiving grant support from Bayer
HealthCare on behalf of her institution, lecture fees from Bayer
HealthCare, Bristol-Myers Squibb/Pfizer, and Boehringer Ingelheim, and payment for the development of educational presentations from Bayer HealthCare, Bristol-Myers Squibb/Pfizer,
and Boehringer Ingelheim; and Dr. Torp-Pedersen, receiving
consulting fees from Cardiome and Merck on behalf of himself
and from Sanofi Aventis on behalf of himself and his institution, grant support from Bristol-Myers Squibb on behalf of his
institution, lecture fees from Cardiome, Merck, and Sanofi
Aventis, and travel support from Bristol-Myers Squibb/Pfizer.
No other potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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