Research

Original Investigation

Warfarin, Kidney Dysfunction, and Outcomes Following

Acute Myocardial Infarction in Patients With Atrial Fibrillation
Juan Jess Carrero, PhD(Pharm and Med); Marie Evans, MD, PhD; Karolina Szummer, MD, PhD; Jonas Spaak, MD, PhD; Lars Lindhagen, PhD;
Robert Edfors, MD; Peter Stenvinkel, MD, PhD; Stefan H Jacobson, MD, PhD; Tomas Jernberg, MD, PhD
Editorial page 913
IMPORTANCE Conflicting evidence exists regarding the association between warfarin

treatment, death, and ischemic stroke incidence in patients with advanced chronic kidney
disease (CKD) and atrial fibrillation.
OBJECTIVE To study outcomes associated with warfarin treatment in relation to kidney
function among patients with established cardiovascular disease and atrial fibrillation.

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DESIGN, SETTING, AND PARTICIPANTS Observational, prospective, multicenter cohort study

from the Swedish Web-System for Enhancement and Development of Evidence-Based Care
in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry
(2003-2010), which includes all Swedish hospitals that provide care for acute cardiac
diseases. Participants included consecutive survivors of an acute myocardial infarction (MI)
with atrial fibrillation and known serum creatinine (N = 24 317), including 21.8% who were
prescribed warfarin at discharge. Chronic kidney disease stages were classified according to
estimated glomerular filtration rate (eGFR).
MAIN OUTCOMES AND MEASURES (1) Composite end point analysis of death, readmission due
to MI, or ischemic stroke; (2) bleeding (composite of readmission due to hemorrhagic stroke,
gastrointestinal bleeding, bleeding causing anemia, and others); or (3) the aggregate of these
2 outcomes within 1 year from discharge date.
RESULTS A total of 5292 patients (21.8%) were treated with warfarin at discharge, and 51.7% had
manifest CKD (eGFR <60 mL/min/1.73 m2 [eGFR<60]). Compared with no warfarin use, warfarin
was associated with a lower risk of the first composite outcome (n = 9002 events) in each CKD
stratum for event rates per 100 person-years: eGFR>60 event rate, 28.0 for warfarin vs 36.1 for
no warfarin; adjusted hazard ratio (HR), 0.73 (95% CI, 0.65 to 0.81); eGFR>30-60: event rate, 48.5
for warfarin vs 63.8 for no warfarin; HR, 0.73 (95% CI, 0.66 to 0.80); eGFR>15-30: event rate,
84.3 for warfarin vs 110.1 for no warfarin; HR, 0.84 (95% CI, 0.70-1.02); eGFR15: event rate, 83.2
for warfarin vs 128.3 for no warfarin; HR, 0.57 (95% CI, 0.37-0.86). The risk of bleeding (n = 1202
events) was not significantly higher in patients treated with warfarin in any CKD stratum for
event rates per 100 person-years: eGFR>60 event rate, 5.0 for warfarin vs 4.8 for no warfarin; HR,
1.10 (95% CI, 0.86-1.41); eGFR>30-60 event rate, 6.8 for warfarin vs 6.3 for no warfarin; HR, 1.04
(95% CI, 0.81-1.33); eGFR>15-30 event rate, 9.3 for warfarin vs 10.4 for no warfarin; HR, 0.82 (95%
CI, 0.48-1.39); eGFR15 event rate, 9.1 for warfarin vs 13.5 for no warfarin; HR, 0.52 (95% CI,
0.16-1.65). Warfarin use in each CKD stratum was associated with lower hazards of the aggregate
outcome (n = 9592 events) for event rates per 100 person-years: eGFR>60 event rate, 32.1 for
warfarin vs 40.0 for no warfarin; HR, 0.76 (95% CI, 0.69-0.84); eGFR>30-60 event rate, 53.6
for warfarin vs 69.0 for no warfarin; HR, 0.75 (95% CI, 0.68-0.82); eGFR>15-30 event rate,
90.2 for warfarin vs 117.7 for no warfarin; HR, 0.82 (95% CI, 0.68-0.99); eGFR15 event rate, 86.2
for warfarin vs 138.2 for no warfarin; HR, 0.55 (95% CI, 0.37-0.83).
CONCLUSIONS AND RELEVANCE Warfarin treatment was associated with a lower 1-year risk for
the composite outcome of death, MI, and ischemic stroke without a higher risk of bleeding in
consecutive acute MI patients with atrial fibrillation. This association was not related to the
severity of concurrent CKD.

JAMA. 2014;311(9):919-928. doi:10.1001/jama.2014.1334

Author Affiliations: Center for

Molecular Medicine, Karolinska
Institutet, Stockholm, Sweden
(Carrero); Division of Renal Medicine,
Karolinska Institutet, Stockholm,
Sweden (Carrero, Evans, Stenvinkel);
Division of Cardiology, Karolinska
Institutet, Stockholm, Sweden
(Szummer, Edfors, Jernberg);
Department of Clinical Sciences,
Danderyd University Hospital,
Karolinska Institutet, Stockholm,
Sweden (Spaak, Jacobson); Uppsala
Clinical Research Center, Sweden
(Lindhagen).
Corresponding Author: Juan Jess
Carrero, Karolinska Institutet,
Divisions of Renal Medicine and
Baxter Novum, Karolinska University
Hospital Huddinge, K56, S-141 86
Stockholm, Sweden
(juan.jesus.carrero@ki.se).

919

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Research Original Investigation

Warfarin, Kidney Dysfunction, and Outcomes After Acute MI

atients with chronic kidney disease (CKD) experience

a marked increased risk of atherothrombotic and
thromboembolic complications, such as myocardial
infarction and stroke, and simultaneously have an increased
risk of bleeding.1,2 Both of these risks increase exponentially
as renal function deteriorates. Embolism from the heart is a
major cause of ischemic stroke, particularly in atrial fibrillation. Patients with concomitant atrial fibrillation and
reduced kidney function are increasingly common, not only
because both conditions share common risk factors, but
also because they promote one another.3,4 Not unexpectedly, patients with CKD and atrial fibrillation have higher
risk of ischemic stroke and thrombembolism than patients
without CKD.5,6
Anticoagulation therapies, such as warfarin, are indicated in most patients with atrial fibrillation and supported
by prospective, randomized trials demonstrating a marked
efficacy. Although such trials have excluded individuals
with renal dysfunction, the use of anticoagulation has also
been extended to patients with CKD. However, in recent
years, observational studies suggest that the use of warfarin
may actually increase the risk of death and stroke among
such patients. 7-9 On the other hand, other reports show
no increased risk in patients with hemodialysis who are
treated with warfarin and patients with CKD and atrial
fibrillation.10-12 This conflicting evidence allows no clear recommendation regarding the use of warfarin in patients with
CKD, despite their high risk of stroke. Further, it is unknown
whether there is a level of renal dysfunction at which the
risk may outweigh the benefit. The objective of this study
was to investigate outcomes associated with warfarin treatment in relation to kidney function among patients with
established cardiovascular disease and atrial fibrillation (ie, a
group of patients having a strong rationale for anticoagulation therapy according to the CHA2DS2-VASc score for atrial
fibrillation stroke risk criteria).13,14

fibrillation, ischemic stroke, hemorrhagic stroke, other bleeding, chronic obstructive pulmonary disease, dementia, or cancer were obtained from the SWEDEHEART registry form and
enriched with data linkages to the National Inpatient Registry, which includes diagnoses for all patients hospitalized in
Sweden since 1987 to December 31, 2011 (eTable 1 in the Supplement). Information on patient presentation at admission, hospital course variables, and medication at admission and discharge were also collected. Atrial fibrillation was defined as a
history of atrial fibrillation, electrocardiography showing signs
of atrial fibrillation, or both, either on admission or during the
in-hospital course.

Renal Function Assessment

Estimated glomerular filtration rate (eGFR) was estimated from
serum creatinine values with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation: mL/min/1.73 m2.16
The majority of creatinine assessments were performed by either
enzymatic or corrected Jaffe method (alkaline picrate reaction), both of which are traceable to isotope dilution mass spectroscopy standards. For creatinine measurements performed
with nonisotope dilution mass spectroscopy-traceable methods, values were reduced by 5% prior to being entered into the
CKD-EPI formula.17,18 On the basis of current International
Society of Nephrologys Kidney Disease Improving Global Outcomes (KDIGO) recommendations,19 the following categorization for renal dysfunction was used: normal renal function and
CKD stages 1 and 2, defined as eGFR higher than 60 mL/min/
1.73 m2 (eGFR>60); moderate dysfunction (CKD stage 3), defined as eGFR higher than 30 to 60 mL/min/1.73 m2 (eGFR>30-60);
severe dysfunction (CKD stage 4), defined as eGFR higher than
15 to 30 mL/min/1.73 m2 (eGFR>15-30); and end-stage renal disease (CKD stage 5), defined as eGFR less than or equal to 15 mL
/min/1.73 m2 (eGFR15). In the absence of data on albuminuria,
the category eGFR>60 includes individuals with both normal renal function and CKD stages 1 and 2.

Definition of Exposure and Outcomes

Methods
Patient Population
All patients were informed about their participation in the
registry and the follow-up and had the right to refuse. The
registry and the merging of registries were approved by The
National Board of Health and Welfare and the ethics committee at Karolinska Institutet, Stockholm. We used data
from 2003 to 2010 from the nationwide Swedish WebSystem for Enhancement and Development of EvidenceBased Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry. This registry
includes all Swedish hospitals (N = 72) that provide care for
acute cardiac diseases, and enrolls all consecutive patients
admitted to a coronary care unit with symptoms suggestive
of an acute coronary syndrome.15

Clinical Characteristics
Previous history of diabetes mellitus, hypertension, myocardial infarction, heart failure, peripheral vascular disease, atrial
920

The exposure was prescription of warfarin at discharge as registered in SWEDEHEART. No information on warfarin dosages was available. Mortality data were obtained by data linkages to the Swedish population registry, which included
information about the vital status of all Swedish citizens
through December 31, 2011. Hospitalizations during follow-up due to myocardial infarction, ischemic stroke, or bleeding were obtained from the National Inpatient Registry. Bleeding was defined as readmission due to hemorrhagic stroke,
gastrointestinal bleeding, bleeding causing anemia, and others. Outcome definitions are further expanded in eTable 2 in
the Supplement.
The following outcomes were defined a priori: (1) the composite outcome of death, readmission due to myocardial infarction and ischemic stroke within 1 year from discharge date,
(2) readmission because of bleeding within 1 year from discharge date, and (3) the aggregate of these 2 outcomes. For these
composite end points, the earliest (if any) event was selected.
When analyzing separate end points, patients were censored
for death. No other censoring was applied.

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Warfarin, Kidney Dysfunction, and Outcomes After Acute MI

Original Investigation Research

Statistical Analyses
Data analysis was performed with R (http://www.r-project
.org), version 2.15.0. Statistical significance was a P value less
than .05 with 2-sided testing. Missing data were handled using
multiple imputation by the method of chained equations.20 The
R packages Multivariate Imputation by Chained Equations
(MICE) was used to form 20 imputed data sets.
Warfarin use vs no warfarin use was considered as a
time-fixed binary variable throughout the follow-up period.
Event rates for the study outcomes were calculated for each
renal dysfunction category, reporting crude risk ratios. The
association between warfarin and outcomes was studied by
Cox proportional hazard models. Two sets of multivariable
models were investigated to study the effect of potential confounders: (1) adjustment for age (5-knot restricted cubic
spline), sex, eGFR, preexisting comorbidities (diabetes mellitus, hypertension, myocardial infarction, chronic heart failure, peripheral vascular disease, ischemic stroke, bleeding,
chronic obstructive pulmonary disease, and cancer within
3 years), patient presentation characteristics at admission
(ST segment elevation myocardial infarction [STEMI] and
decompensated heart failure [Killip class 2]), hospital course
(percutaneous coronary intervention and coronary artery
bypass graft), discharge medication (antiplatelet therapy
[none, mono, or dual]), -blockers, angiotensin-converting
enzyme inhibitors/angiotensin receptor blockers, and statins), and center effect (as a random effect via a frailty distribution); and, in a separate model, (2) we further adjusted for
left ventricular ejection fraction due to the large amount of
imputed data for this variable. Inverse-varianceweighted
linear regression was used to assess linear trends across eGFR
categories (using equidistant CKD stages) on studied outcomes. Time to event (cumulative incidence) Kaplan-Meier
curves were plotted across CKD stages with and without warfarin treatment.
Two sensitivity analyses were performed: to assess the
effect of imputation, we (1) ran a complete-case analysis for
the adjusted model (there were 23 056 such patients, corresponding to 94.8% of the total study population); and to
assess the effect of confounding by indication, (2) propensity scores were calculated using random-effects logistic
regression models with warfarin at discharge as the outcome and all variables of the primary analysis model as
explanatory variables.21 Patients were then matched on estimated propensity scores using full matching 22 via the R
packages Optmatch. A caliper of 0.01 was used, except for
the patient category of eGFR 15 , where this led to many
unmatched patients. For this stratum, a caliper of 0.02 was
used instead. The analysis was then done as a Cox regression with warfarin at discharge as a predictor, and the
matching indicator as a random effect using a frailty
model.
In a final step, subgroup analyses were performed to assess the robustness of our results. Not all of these models could
be run successfully due to (1) no warfarin contrast (no contrast in the exposure), (2) too few events (strata with <10
events), and (3) the model failed to converge. When this occurred it is indicated in the corresponding tables.
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Results
Between 2003 and 2010, a total of 158 059 individuals were admitted with an acute myocardial infarction. Atrial fibrillation
was found in 34 087 individuals. Patients were excluded if they
lacked information on serum creatinine (n = 2351), warfarin
treatment (n = 357), or age (n = 2). They were also excluded if
they died before hospital discharge (n = 2580), had been registered in SWEDEHEART previously (n = 4367) or because of
registration errors (n = 113). A patient flowchart is illustrated
in eFigure 1 in the Supplement.

Patient Characteristics
The remaining 24 317 patients were included in the analysis
and 21.8% of these were prescribed warfarin at discharge.
Table 1 and Table 2 summarize baseline characteristics of included patients stratified by warfarin treatment. Patients
treated with warfarin did not differ from patients receiving no
warfarin with regard to basic demographics. However, several comorbidities, such as heart failure, diabetes, and ischemic stroke, were more common in individuals treated with warfarin. In both groups, the CHADS2 score was 2 or higher in the
majority of patients. Clinical history of hemorrhagic stroke and
bleeding seemed more frequent among patients who did not
receive warfarin at discharge. There was a similar rate of patient inclusion during the different admission years.
As many as 51.7% of patients were considered to have
CKD stage 3 or higher, with an eGFR higher than 60 mL/min/
1.73 m2. Of these, 41.7% of patients had CKD stage 3, 8.1% had
CKD stage 4, and 2.0% had CKD stage 5. eTable 3 in the
Supplement shows patient characteristics according to CKD
stages and warfarin treatment. As CKD categories increased
in severity, patients tended to be older and less often smokers. The prevalence of comorbid diabetes, hypertension, cardiovascular disease (myocardial infarction, chronic heart failure, peripheral vascular disease, and ischemic stroke), as well
as the number of patients with a CHADS2 score of 2 or higher
increased with the worsening of CKD stages. Patients with
CKD also presented more severe symptoms, such as heart
failure (Killip class 2), at admission, but the number of
patients presenting with STEMI and the proportion of percutaneous coronary interventions performed decreased. Dual
antiplatelet therapy and statin treatment at discharge seemed
less common across worsening CKD stages, but the proportion of patients receiving calcium antagonists or diuretics
tended to increase. Patients with CKD stage 5 were less often
prescribed warfarin (13.8%) compared with other categories
(eGFR>60, 22.0%; eGFR>30-60, 22.4%; eGFR>15-30, 18.9%). In all
CKD strata, patients receiving warfarin more often had a history of heart failure, ischemic stroke, and diabetes, as well as
a higher CHADS2 score. History of hemorrhagic stroke or
prior bleeding tended to be less common among patients
treated with warfarin across the different CKD strata.

Outcome Analyses
The number of patients who developed the composite outcome, bleeding events, and the aggregate of these 2 outJAMA March 5, 2014 Volume 311, Number 9

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Research Original Investigation

Warfarin, Kidney Dysfunction, and Outcomes After Acute MI

Table 1. Demographics, Clinical and In-Hospital Course Characteristics of 24 317 Myocardial Infarction Patients
With Atrial Fibrillation and Stratified According to Warfarin Treatment at Discharge
All Patients
(n = 24 317)

No. (%)

No Warfarin
(n = 19 025)

Warfarin
(n = 5292)

Demographics
Age, median (range), y

79 (29-103)

Men

80 (32-103)

78 (29-98)

14 451 (59.4)

11 069 (58.2)

3382 (63.9)

Smoking, n = 21 278

2801 (13.2)

2329 (14.1)

472 (10.0)

BMI, median (10th-90th), n = 9990

25.7 (21.1-32.0)

25.5 (20.9-31.7)

26.2 (21.6-33.0)

2003-2004

5888 (24.2)

4731 (24.9)

1157 (21.9)

2005-2006

6257 (25.7)

5037 (26.5)

1220 (23.1)

2007-2008

6416 (26.4)

4929 (25.9)

1487 (28.1)

2009-2010

5756 (23.7)

4328 (22.7)

1428 (27.0)

Creatinine, median (10th-90th), mg/dL

1.07 (0.70-1.83)

1.07 (0.73-1.84)

1.09 (0.75-1.80)

eGFR, median (10th-90th)

58.9 (29.9-87.5)

58.8 (29.4-87.7)

59.2 (31.5-87.1)

>60

11 734 (48.3)

9150 (48.1)

2584 (48.8)

>30-60

10 139 (41.7)

7869 (41.4)

2270 (42.9)

1966 (8.1)

1594 (8.4)

372 (7.0)

478 (2.0)

412 (2.2)

66 (1.2)

6842 (28.1)

5231 (27.5)

1611 (30.4)

Admission, No. (% of patients included), y

eGFR strata, mL/min/1.73 m2a

>15-30
15
Comorbidities and presentation at admission
Diabetes mellitus
Hypertension

13 025 (53.6)

Myocardial infarction
Heart failure

10 165 (53.4)

2860 (54.0)

9577 (39.4)

7504 (39.4)

2073 (39.2)
2677 (50.6)

10485 (43.1)

7808 (41.0)

Peripheral vascular disease

2188 (9.0)

1683 (8.8)

505 (9.5)

Ischemic stroke

4626 (19.0)

3392 (17.8)

1234 (23.3)

Hemorrhagic stroke
Any stroke

455 (1.9)

401 (2.1)

54 (1.0)

5485 (22.6)

4807 (21.5)

1398 (26.4)

Any bleeding

2513 (10.3)

2133 (11.2)

380 (7.2)

Chronic obstructive pulmonary disease

3049 (12.5)

2374 (12.5)

675 (12.8)

160 (0.8)

146 (0.8)

14 (0.3)

1020 (4.2)

851 (4.5)

169 (3.2)

Dementia
Cancer diagnosis within 3 y
CHADS2 score 2

19161 (78.8)

14 829 (77.9)

4332 (81.9)

Previous PCI

2907 (12.0)

2185 (11.5)

722 (13.6)

Previous CBAG

3145 (12.9)

2244 (11.8)

901 (17.0)

Decompensated heart failure (Killip 2),

n = 23 392

6188 (26.5)

4858 (26.6)

1330 (25.9)

STEMI

5163 (21.5)

4194 (22.3)

969 (18.5)

PCI

7217 (29.7)

5774 (30.3)

1443 (27.3)

Hospital course

CABG

509 (2.1)

375 (2.0)

134 (2.5)

Left ventricular ejection fraction <50%,

n = 13 979

8549 (61.2)

6364 (59.6)

2185 (66.1)

New atrial fibrillation

5903 (24.8)

4940 (26.6)

963 (18.5)

Intravenous inotrope

933 (3.9)

763 (4.0)

170 (3.2)

comes increased with the worsening of CKD categories

(Table 3), as did the rate at which these events occurred
(Table 3, Figure 1 [panels A and C], and Figure 2 [panel A]).
Within each CKD category and compared with patients
receiving no warfarin, those receiving warfarin had a lower
number of events of the composite of death, myocardial
infarction, or stroke (eGFR>60, 23.5% with warfarin vs 28.8%
without warfarin; eGFR >30-60 , 36.3% with warfarin vs
44.0% without warfarin; eGFR>15-30, 53.2% with warfarin vs
922

SI conversion factors: To convert

creatinine to mol/L, multiply by
88.4.
a

The eGFRs were estimated from

serum creatinine values with the
Chronic Kidney Disease
Epidemiology Collaboration
equation.

61.0% without warfarin; eGFR15, 53.0% with warfarin vs

66.0% without warfarin), as well as the number of aggregated events (death, myocardial infarction, stroke, and
bleeding; eGFR>60, 26.4% with warfarin vs 31.1% without
warfarin; eGFR >3 0 - 6 0 , 39.1% with warfarin vs 46.4%
without warfarin; eGFR>15-30, 55.1% with warfarin vs 63.0%
w ithout warfarin; eGFR 1 5 , 5 4.5% w ith warfarin vs
68.7% without warfarin), as well as a lower incidence rate
(Table 3, Figure 1 [panel B], and Figure 2 [panel B]). The

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Abbreviations: BMI, body mass index

(calculated as weight in kilograms
divided by height in meters squared);
CABG, coronary artery bypass graft;
eGFR, estimated glomerular filtration
rate; PCI, percutaneous coronary
intervention; STEMI, ST-segment
elevation myocardial infarction.

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Warfarin, Kidney Dysfunction, and Outcomes After Acute MI

Original Investigation Research

Table 2. Medication at Admission and at Discharge in Patients With Myocardial Infarction and Atrial Fibrillation, Stratified by Warfarin Treatment at
Discharge
All Patients
(n = 24 317)

No Warfarin
(n = 19 025)

Warfarin
(n = 5292)

Medication, No. (%)

Admission

Discharge

Admission

Discharge

Admission

Discharge

Warfarin

4311 (17.9)

5292 (21.7)

1098 (5.8)

0 (0)

3213 (60.9)

5292 (100)

9942 (40.9)

10 619 (56.3)

7910 (41.6)

1388 (26.4)

2032 (38.5)

Mono antiplatelet therapy

12 007 (49.8)

Dual antiplatelet therapy

1259 (5.2)

10 895 (44.8)

1130 (6.0)

10 009 (52.6)

129 (2.4)

886 (16.8)

12 676 (52.5)

19 536 (80.4)

11 265 (59.6)

17 263 (90.8)

1411 (26.8)

2273 (43.0)

Aspirin
Other antiplatelet therapy
-blockers

1875 (7.8)

12 211 (50.3)

1638 (8.7)

10 677 (56.2)

237 (4.5)

1534 (29.0)

13 905 (57.7)

21 049 (86.6)

10 585 (56.1)

16 393 (86.2)

3320 (63.1)

4656 (88.1)

Calcium antagonists

5073 (21.1)

4284 (17.7)

3924 (20.8)

3278 (17.3)

1149 (21.9)

1006 (19.1)

Digoxin

3428 (14.2)

4205 (17.3)

2344 (12.4)

2861 (15.1)

1084 (20.6)

1344 (25.4)

Angiotensin-converting enzyme inhibitors and angiotensin receptor II blockers

10 080 (41.7)

3961 (66.6)

7445 (39.4)

12 212 (64.2)

2635 (50.0)

3961 (74.9)

Diuretics

11 514 (47.7)

3483 (60.9)

8788 (46.6)

11 310 (59.5)

2726 (51.7)

3483 (65.9)

7414 (30.7)

3792 (64.7)

5481 (29.1)

11 915 (62.7)

1933 (36.7)

3792 (71.8)

Statins

Table 3. Number and Proportion of Events and Crude Relative Risks for Composite and Single Outcomes Stratified by Warfarin Treatment in
Individuals With Differing Severity of Chronic Kidney Disease
eGFR Strata, mL/min/1.73 m2
Outcomes, No. (%)a

>60b

All Patients

No. of patients

24 317

Composite of death, myocardial infarction,

and ischemic strokec

9002 (37.0)

11 734

>15-30b

10 139

3239 (27.6)

15b

1966

478

4286 (42.3)

1170 (59.5)

307 (64.2)
272 (53.0)

Warfarin

1664 (31.4)

607 (23.5)

824 (36.3)

1004 (53.2)

No warfarin

7338 (38.6)

2632 (28.8)

3462 (44.0)

205 (61.0)

Relative risk (95% CI)

0.82 (0.78-0.85)

0.82 (0.76-0.88)

0.83 (0.78-0.88)

0.87 (0.79-0.97)

1202 (4.9)

506 (4.3)

526 (5.2)

132 (6.7)

Bleeding

35 (66.0)
0.80 (0.63-1.02)
38 (7.9)

Warfarin

277 (5.2)

118 (4.6)

130 (5.7)

25 (6.7)

4 (6.1)

No warfarin

925 (4.9)

388 (4.2)

396 (5.0)

107 (6.7)

34 (8.3)

Relative risk (95% CI)

Composite of death, myocardial infarction,
ischemic stroke, and bleedingd

1.08 (0.94-1.23)

1.08 (0.88-1.32)

1.14 (0.94-1.38)

1.00 (0.66-1.52)

0.73 (0.27-2.00)

9592 (39.4)

3528 (30.1)

4536 (44.7)

1209 (61.5)

319 (66.7)

Warfarin

1809 (34.2)

681 (26.4)

887 (39.1)

205 (55.1)

36 (54.5)

No warfarin

7783 (40.9)

2847 (31.1)

3649 (46.4)

1004 (63.0)

283 (68.7)

Relative risk (95% CI)

Death
Warfarin
No warfarin
Relative risk (95% CI)
Myocardial infarction
Warfarin
No warfarin
Relative risk (95% CI)

0.84 (0.80-0.87)

0.85 (0.79-0.91)

0.84 (0.80-0.89)

0.87 (0.79-0.97)

0.79 (0.63-1.00)

5358 (22.0)

1564 (13.3)

2633 (26.0)

907 (46.1)

254 (53.1)

924 (17.5)

274 (10.6)

469 (20.7)

149 (40.1)

32 (48.5)

4434 (23.3)

1290 (14.1)

2164 (27.5)

758 (47.6)

222 (53.9)

0.75 (0.70-0.80)

0.75 (0.67-0.85)

0.75 (0.69-0.82)

0.84 (0.74-0.96)

0.90 (0.69-1.17)

4682 (19.3)

1848 (15.7)

2203 (21.7)

506 (25.7)

125 (26.2)

927 (17.5)

356 (13.8)

469 (20.7)

92 (24.7)

10 (15.2)

3755 (19.7)

1492 (16.3)

1734 (22.0)

414 (26.0)

115 (27.9)

0.95 (0.78-1.16)

0.54 (0.30-0.98)

0.89 (0.83-0.95)

0.84 (0.76-0.94)

0.94 (0.86-1.03)

1145 (4.7)

477 (4.1)

560 (5.5)

92 (4.7)

Warfarin

172 (3.3)

85 (3.3)

76 (3.3)

11 (3.0)

0 (0)

No warfarin

973 (5.1)

392 (4.3)

484 (6.2)

81 (5.1)

16 (3.9)

Relative risk (95% CI)

0.64 (0.54-0.75)

0.77 (0.61-0.97)

Ischemic stroke

Abbreviations: eGFR, estimated glomerular filtration rate.

a

>30-60b

The composite and aggregated outcomes take the earliest event in time for
that individual, and thus the number of events considered does not
necessarily equal the sum of the counts of the original composite events. The
explanation is that patients can have more than 1 of the events considered
during disease course.

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0.54 (0.43-0.69)

16 (3.3)

0.58 (0.31-1.08)

The eGFRs were estimated from serum creatinine values with the Chronic
Kidney Disease Epidemiology Collaboration equation.

Event count is as follows: 3551 deaths, 4573 myocardial infarctions, and 878
ischemic strokes.

Event count is as follows: 3347 deaths, 4501 myocardial infarctions, 1028

ischemic strokes, and 716 bleeding events.

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923

Research Original Investigation

Warfarin, Kidney Dysfunction, and Outcomes After Acute MI

Figure 1. Kaplan-Meier Curves for Individuals With Differing Degrees of Renal Function Stratified by Warfarin Use
Composite of death, myocardial infarction, and ischemic stroke
A Stratified by severity of chronic kidney disease

0.7

0.7

15
>15-30

0.6

Cumulative Incidence

0.6

Cumulative Incidence

Stratified by severity of chronic kidney disease and warfarin treatment

eGFR, mL/min/1.73m2

0.5
>30-60

0.4
0.3

>60

0.2
0.1

0.5
0.4
0.3
0.2
0.1

0.0

0.0
0

10

12

Time, mo
No. at risk, eGFR, mL/min/1.73 m2
>60
10 188
11 734
9654
>30-60 10 139
8118
7429
>15-30 1966
1385
1173
478
15
336
270

9277
6905
1040
233

8979
6475
944
203

8733
6127
864
182

No. at risk, eGFR, mL/min/1.73 m2

Warfarin treated
2308
>60
2584
2209
1904
>30-60 2270
1762
282
>15-30 372
248
54
15
66
44
No warfarin
>60
7880
9150
7445
>30-60 7869
6214
5667
>15-30 1594
1103
925
15
282
412
226

8495
5853
796
171

10

12

2135
1656
223
40

2085
1577
205
36

2033
1495
192
32

1977
1446
174
31

7142
5249
817
193

6894
4898
739
167

6700
4632
672
150

6518
4407
622
140

Time, mo

Composite of bleeding
C

Stratified by severity of chronic kidney disease

Stratified by severity of chronic kidney disease and warfarin treatment

0.14

0.14
eGFR, mL/min/1.73m2
15

0.10
>15-30
0.08
0.06

>30-60
>60

0.04
0.02

0.12

Cumulative Incidence

Cumulative Incidence

0.12

0.10
0.08
0.06
0.04
0.02

0.00

0.00
0

10

12

Time, mo
No. at risk, eGFR, mL/min/1.73 m2
11 034
>60
11 734
10 664
>30-60 10 139
9020
8487
>15-30 1966
1556
1364
15
370
322
478

10 374
8077
1245
281

10 156
7709
1137
253

9950
7391
1053
227

9771
7141
992
200

No. at risk, eGFR, mL/min/1.73 m2

Warfarin treated
2467
>60
2584
2404
2089
>30-60 2270
1976
306
>15-30 372
283
55
15
66
48
No warfarin
8567
>60
9150
8260
>30-60 7869
6931
6511
>15-30 1594
1250
1081
15
315
412
274

10

12

2337
1891
257
43

2298
1828
241
38

2250
1763
227
34

2211
1712
213
31

8037
6186
988
238

7858
5881
896
215

7700
5628
826
193

7560
5429
779
169

Time, mo

Panels A and C depict the cumulative incidence curves for patients according to chronic kidney disease stages. Panels B and D stratify chronic kidney disease stages
by warfarin exposure. Y-axis scale segments in blue indicate range from 0.0 to 0.14.

crude relative risk of bleeding was not significantly higher

in patients treated with warfarin in any CKD stratum
(eGFR >60 : relative risk [RR], 1.08 [95% CI, 0.88 to 1.32];
eGFR>30-60: RR, 1.14 [95% CI, 0.94 to 1.38]; eGFR>15-30: RR,
1.00 [95% CI, 0.66 to 1.52]; eGFR15: RR, 0.73 [95% CI, 0.27 to
2.00], Figure 1, panel D). Regardless of CKD stage, the number of deaths was lower in patients treated with warfarin
compared with patients receiving no warfarin. The rate of
readmissions due to myocardial infarction and ischemic
924

strokes were lower in the patients treated with warfarin

across all renal function strata.
Table 4 shows the results from the Cox regression analyses. For each stratum of CKD, warfarin treatment was associated with a lower risk of the composite outcome of death,
myocardial infarction, and stroke (eGFR>60: adjusted hazard
ratio [HR], 0.73 [95% CI, 0.65 to 0.81]; eGFR>30-60: HR, 0.73
[95% CI, 0.66 to 0.80]; eGFR>15-30: HR, 0.84 [95% CI, 0.70 to
1.02]; eGFR15: HR, 0.57 [95% CI, 0.37 to 0.86]), as well as a

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Warfarin, Kidney Dysfunction, and Outcomes After Acute MI

Original Investigation Research

Figure 2. Kaplan-Meier Curves for Individuals With Differing Degrees of Renal Function Stratified by Warfarin Use
Aggregate of death, myocardial infarction, ischemic stroke, bleeding
A Stratified by severity of chronic kidney disease

0.7

0.7

15
>15-30

0.5
>30-60
0.4
>60

0.3
0.2
0.1

0.6

Cumulative Incidence

0.6

Cumulative Incidence

Stratified by severity of chronic kidney disease and warfarin treatment

eGFR, mL/min/1.73m2

0.5
0.4
0.3
0.2
0.1

0.0

0.0
0

10

12

Time, mo
No. at risk, eGFR
>60
11 734
>30-60 10 139
>15-30 1966
478
15

10 070
8018
1354
331

9475
7270
1135
263

9040
6715
997
226

10

12

Time, mo
8715
6255
899
195

8454
5878
822
172

8206
5603
757
159

No. at risk, eGFR

Warfarin treated
>60
2584
>30-60 2270
>15-30 372
15
66
No warfarin
>60
9150
>30-60 7869
>15-30 1594
15
412

2382
1881
273
54

2176
1716
239
44

2081
1608
215
40

2022
1522
197
36

1964
1433
184
31

1903
1383
167
30

7788
6137
1081
277

7299
5554
896
219

6959
5107
782
186

6693
4733
702
159

6490
4445
638
141

6303
4220
590
129

Panel A depicts the cumulative incidence curves for patients according to chronic kidney disease stages. Panel B stratifies chronic kidney disease stages by warfarin
exposure.

lower risk of the aggregated composite outcome further

considering bleeding (eGFR>60: HR, 0.76 [95% CI, 0.69 to
0.84]; eGFR >3 0 - 6 0 : HR, 0.75 [95% CI, 0.68 to 0.82];
eGFR>15-30: HR, 0.82 [95% CI, 0.68 to 0.99]; eGFR15: HR,
0.55 [95% CI, 0.37 to 0.83]). For the patients treated with
warfarin, the bleeding risk was not higher and there was no
significant trend across differing CKD categories (eGFR>60:
HR, 1.10 [95% CI, 0.86 to 1.41]; eGFR>30-60: HR, 1.04 [95% CI,
0.81 to 1.33]; eGFR >15-30 : HR, 0.82 [95% CI, 0.48 to 1.39];
eGFR15: HR, 0.52 [95% CI, 0.16 to 1.65]). The magnitude of
the association between warfarin treatment and outcomes
was little modified by multivariable adjustment, and no linear trends were observed across strata. Similar results for
the primary analysis were observed in complete-case analyses or propensity scorematching. Information on the performance of the propensity scorematching and the balance
between variables in warfarin-exposed and nonexposed
individuals is shown in eTable 4 through eTable 9 in the
Supplement.

Subgroup Analyses
Several subgroup analyses were undertaken to study the robustness of our findings (eTable 10 and eTable 11 in the Supplement). Similar results for the primary analysis were found for
the composite outcome of death, myocardial infarction, and
ischemic stroke, and the same was true when further considering bleeding risk as an aggregate. The low number of bleeding events in the subgroup populations limits drawing solid
conclusions and these analyses were not performed.
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Discussion
Recent observational studies have prompted concern about the
value of warfarin anticoagulation in CKD stage 5 or dialysis patients with atrial fibrillation. In these studies, warfarin treatment was associated with an increased risk of stroke, death,
or both,7-9 resulting in modification of current guidelines,
which call for caution regarding warfarin use in this patient
group.23 Our study addressed this issue in a large cohort of consecutive patients with myocardial infarction, atrial fibrillation, and varying severity of CKD. We report that warfarin treatment was associated with a lower 1-year risk of the composite
end point of death, myocardial infarction, and ischemic stroke
without a higher risk of bleeding. This association was observed in patient strata with moderate, severe, or end-stage
CKD. Our finding partially accords with the recent study by Olesen and coauthors12 from Denmark, where warfarin treatment was associated with a lower risk of stroke or thromboembolism in patients with atrial fibrillation irrespective of their
renal function. Compared with that study, our analysis may
offer some advantages, as we estimated renal function by eGFR
rather than International Classification of Diseases codes for renal replacement therapy initiation. The use of International
Classification of Diseases codes probably underestimates CKD
prevalence24 and also offers no possibility to assess risks associated with impaired renal function prior to renal replacement therapy. In addition, we expand to a nationally representative sample of high-risk individuals that virtually all have
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925

Research Original Investigation

Warfarin, Kidney Dysfunction, and Outcomes After Acute MI

Table 4. Risk for Developing Composite and Single Outcomes Associated to Warfarin Treatment in All Patients and in Individuals With Differing
Severity of Chronic Kidney Disease
eGFR Strata, HR (95% CI)a
All

>60

>30-60

>15-30

15

P Value
for Trend

Composite outcome of death, myocardial infarction, and ischemic stroke

No. of person-years (person per
100 years)
Warfarin
No warfarin

41.5

21.7

17.0

2.3

0.4

138.0

72.8

54.2

8.8

2.1

40.1

28.0

48.5

84.3

83.2

Event rate per 100 person-years

Warfarin
No warfarin

53.2

36.1

63.8

110.1

128.3

Crude HR

0.77 (0.73-0.81)

0.79 (0.72-0.86)

0.77 (0.72-0.84)

0.79 (0.68-0.93)

0.68 (0.48-0.96)

.58

Adjusted HR modelsb

0.73 (0.68-0.78)

0.73 (0.65-0.81)

0.73 (0.66-0.80)

0.84 (0.70-1.02)

0.57 (0.37-0.86)

.81

Complete cases

0.73 (0.68-0.78)

0.72 (0.65-0.81)

0.72 (0.66-0.80)

0.87 (0.71-1.05)

0.56 (0.37-0.87)

.76

Propensity scorematching

0.79 (0.75-0.84)

0.79 (0.72-0.87)

0.78 (0.73-0.85)

0.82 (0.70-0.96)

0.63 (0.42-0.94)

.73

Adjusted HR + LVEF

0.72 (0.68-0.77)

0.72 (0.65-0.80)

0.73 (0.66-0.80)

0.84 (0.69-1.01)

0.57 (0.38-0.88)

.75

Bleeding
No. of person-years (person per
100 years)
Warfarin

46.0

23.6

19.2

2.7

0.4

157.0

81.3

62.8

10.3

2.5

Warfarin

6.0

5.0

6.8

9.3

9.1

No warfarin

5.9

4.8

6.3

10.4

13.5

No warfarin
Event rate per 100 person-years

Crude HR

1.03 (0.90-1.18)

1.05 (0.86-1.29)

1.08 (0.89-1.32)

0.92 (0.60-1.42)

0.68 (0.24-1.92)

.42

Adjusted HR modelsb

1.02 (0.86-1.20)

1.10 (0.86-1.41)

1.04 (0.81-1.33)

0.82 (0.48-1.39)

0.52 (0.16-1.65)

.14

Complete cases

1.02 (0.86-1.21)

1.17 (0.91-1.51)

1.01 (0.78-1.29)

0.72 (0.41-1.26)

0.54 (0.16-1.77)

.04

Propensity scorematching

1.03 (0.90-1.18)

1.05 (0.86-1.30)

1.08 (0.89-1.32)

0.93 (0.60-1.44)

0.46 (0.11-1.89)

.51

Adjusted HR + LVEF

1.02 (0.86-1.20)

1.11 (0.87-1.43)

1.04 (0.81-1.33)

0.81 (0.48-1.39)

0.51 (0.16-1.64)

.13

Composite outcome of death, myocardial infarction, ischemic stroke, and bleeding

No. of person-years (person per
100 years)
Warfarin

21.2

16.6

2.3

0.4

40.5

No warfarin

71.3

52.9

8.5

2.0

134.7

Warfarin

44.7

32.1

53.6

90.2

86.2

No warfarin

57.8

40.0

69.0

117.7

138.2

Event rate per 100 person-years

Crude HR

0.79 (0.75-0.83)

0.81 (0.75-0.88)

0.79 (0.74-0.85)

0.80 (0.69-0.93)

0.65 (0.46-0.93)

.31

Adjusted HR modelsb

0.75 (0.70-0.80)

0.76 (0.69-0.84)

0.75 (0.68-0.82)

0.82 (0.68-0.99)

0.55 (0.37-0.83)

.83

Complete cases

0.75 (0.70-0.80)

0.76 (0.68-0.84)

0.75 (0.68-0.82)

0.82 (0.68-1.00)

0.56 (0.37-0.86)

.84

Propensity scorematching

0.81 (0.77-0.86)

0.82 (0.75-0.90)

0.80 (0.74-0.86)

0.82 (0.70-0.96)

0.61 (0.42-0.90)

.46

Adjusted HR + LVEF

0.75 (0.70-0.80)

0.75 (0.68-0.84)

0.75 (0.68-0.82)

0.82 (0.68-0.99)

0.56 (0.37-0.84)

.87

0.66 (0.60-0.72)

0.66 (0.56-0.77)

0.63 (0.55-0.71)

0.82 (0.66-1.02)

0.72 (0.46-1.14)

.41
.69

Single outcomes (adjusted HRs)

Death
Myocardial infarction

0.87 (0.80-0.95)

0.83 (0.72-0.95)

0.91 (0.80-1.03)

1.05 (0.79-1.40)

0.47 (0.23-0.97)

Ischemic stroke

0.57 (0.47-0.69)

0.64 (0.48-0.84)

0.49 (0.37-0.66)

0.71 (0.34-1.47)

MF

Abbreviations: eGFR, estimated glomerular filtration rate; HR, hazard ratio;

LVEF, left ventricular ejection fraction; MF, model failed to converge.

926

In each stratum, patients not receiving warfarin were considered as referent.

The eGFRs were estimated according to the Chronic Kidney Disease
epidemiology collaboration equation (CKD-EPI): mL/min/1.73 m2.

Adjusted models considered multivariate adjustment for age, sex, center,

eGFR, preexisting comorbidities (diabetes mellitus, hypertension, myocardial
infarction, congestive heart failure, cerebrovascular disease, ischemic stroke,
bleeding, chronic obstructive pulmonary disease, cancer, and atrial

fibrillation), patient presentation characteristics at admission (ST-segment

elevation myocardial infarction, Killip 2), hospital course (percutaneous
coronary intervention and coronary artery bypass graft surgery), and
discharge medication (antiplatelet therapy, -blockers, angiotensin-converting
enzyme inhibitors/angiotensin receptor blockers, and statins). A final model
tested further adjustment for left ventricular ejection fraction. Sensitivity
analyses are also shown, including the analysis of complete cases and
propensity scorematching (see methods).

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Warfarin, Kidney Dysfunction, and Outcomes After Acute MI

an indication for warfarin therapy and have detailed information on concurrent anticoagulant and antiplatelet therapy. Our
observations also accord with post hoc analyses from the Stroke
Prevention in Atrial Fibrillation Study III (SPAF III) trial,11 in
which 516 participants with atrial fibrillation and CKD stage 3
were studied and the risk for ischemic stroke or systemic embolism was reduced by 76% for adjusted-dose warfarin compared with aspirin plus low, subtherapeutic doses of warfarin.
Finally, the higher stroke risk associated with warfarin use in
dialysis patients reported by Wizemann and coauthors7 was
only observed for individuals aged 75 or older. Because adverse effects of treatment are not open to bias, findings in our
study may suggest not denying warfarin to patients with atrial
fibrillation after a myocardial infarction because of compromised renal function. Similar to preceding evidence, however, our results are also observational in nature and do not
provide conclusive guidance regarding anticoagulant therapy
in patients with atrial fibrillation and CKD. Nevertheless, clear
ethical concerns may not allow such trials.
Our study has several strengths that merit consideration,
including its richness of information on patient clinical characteristics and confirmation of atrial fibrillation by both patient history and electrocardiographic findings during hospital course. Although no independent adjudication or
verification of clinical events has been performed in our study,
the validity of the Swedish Inpatient Register is considered
high, in particular for diagnoses such as myocardial infarction, heart failure, atrial fibrillation, or stroke.25 The use of a
unique personal identification number for all Swedish citizens and continuously updated national registries on death
date, cause of death, and emigration allow a virtually complete follow-up with no losses. Furthermore, Swedish health
care is tax-funded and access is homogenous throughout the
country. Therefore the likelihood of confounding by different access to health care or treatment due to socioeconomic
differences may not be relevant in this analysis.
Previous studies have reported an increased risk of bleeding in patients treated with warfarin with moderate to advanced CKD12 or requiring dialysis.7-10,26,27 In our data, we observed no higher bleeding risk or nonstatistically significant
hazards in relation to warfarin treatment and CKD strata. The
discrepancy between our results and those observed in dialysis populations7-9 may in part be attributed to differences in
indications for warfarin treatment and to general differences
in standard care between countries and centers.28 In this sense,
patients with CKD stage 5 requiring or not requiring dialysis
are reported to have a greater need of warfarin dose adjustment and poor time in therapeutic international normalized

ARTICLE INFORMATION
Author Contributions: Dr Jernberg had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Carrero, Evans,
Szummer, Spaak, Edfors, Stenvinkel, Jernberg.
Acquisition of data: Jacobson, Jernberg.
Analysis and interpretation of data: Carrero, Evans,
Szummer, Spaak, Lindhagen, Jernberg.

Original Investigation Research

ratio (INR) range, with a tendency to supratherapeutic INR

values.29,30 In Scandinavian countries, the care and time in
therapeutic range for INR is generally very good and above
75%.28,31 Warfarin-associated bleeding in patients with CKD
may be more common when INR is not tightly controlled. This
was observed by Chan and coauthors,9 where the association
with mortality in patients with hemodialysis was only observed for high warfarin-prescribed dosages. Also, the study
by Knoll and coauthors32 from a single-center study with
weekly and tight INR control showed that no patient with hemodialysis under sufficient warfarin anticoagulation had a
stroke or a fatal bleeding event.
Some limitations need to be taken into consideration when
interpreting our findings. The first limitation pertains to the
inclusion criteria (patients with myocardial infarction and atrial
fibrillation), which may make generalizability of the study results to other patient populations difficult. Although we are
able to account for the most important confounders and confirm our results by propensity scorematching, residual confounding is still likely to exist and should be acknowledged as
a limitation of this and any other observational study. For instance, we could not control for the duration of atrial fibrillation, deep venous thrombosis, pulmonary embolism, or valvular replacement. Besides the lack of information on the
patients INRs, we acknowledge that the number of patients
with CKD stage 5 included is low and merits caution in its interpretation, even more in subgroup analyses. Nevertheless,
no linear trends were observed across the different CKD strata.
Finally, we base our results on a single creatinine measurement, which may result in nondifferential misclassification.
Certainly, there is concern that warfarin use in dialysis patients may accentuate vascular calcification33 or induce calcific uremic arteriopathy, a vasculopathy with a high mortality rate.34 Although our study is not designed to address this
issue, death rates were not increased in patients with CKD stage
5 receiving warfarin in our analysis. It is plausible, nevertheless, that a 1-year follow-up is too short to capture the longerterm effects of warfarin on the vascular calcification process.

Conclusions
Warfarin treatment was associated with a lower 1-year risk of
the composite outcome of death, myocardial infarction, and
ischemic stroke, without a higher risk of bleeding, in consecutive patients with acute myocardial infarction and atrial fibrillation. This association was not related to the severity of concurrent CKD.

Drafting of the manuscript: Carrero.

Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Lindhagen.
Obtained funding: Jacobson, Jernberg.
Administrative, technical, and material support:
Jacobson.
Study supervision: Jernberg.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for

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Disclosure of Potential Conflicts of Interest. Dr

Carrero reports receiving grant funding from the
Centre for Gender Medicine at Karolinska Institutet,
the Swedish Medical Research Council, and the
Westman Foundation. Dr Evans reports consulting
for Amgen. Dr Szummer reports receiving grant
funding from ALF Medicin (the regional agreement
on medical training and clinical research between
Stockholm County Council and Karolinska
Institutet). Dr Spaak reports receiving grant funding

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927

Research Original Investigation

Warfarin, Kidney Dysfunction, and Outcomes After Acute MI

from AbbVie; payment for lectures from Abbot and

Merck (MSD); payment for the development of
educational presentations from MSD; travel
accommodations from Medtronic; and receiving
support from the Karolinska Cardiorenal Theme
Center. Dr Stenvinkel reports serving on the board
for Abbott, Gambro, Keryx Biopharmaceuticals,
Takeda, and Vifor Pharma; giving expert testimony
for the Norwegian Research Council; receiving
grant funding from Bayer, the Swedish Medical
Research Council, and the Westman Foundation;
and receiving payment for lectures from Amgen,
Baxter, Bayer, Diaverum, Keryx, and Shire. Dr
Jacobson reports receiving support from the
Karolinska Cardiorenal Theme Center and payment
for lectures from Amgen and Fresenius Medical
Care. Dr Jernberg reports receiving grant funding
from the Swedish Heart and Lung Foundation and
ALF Medicin. No other disclosures were reported.

9. Chan KE, Lazarus JM, Thadhani R, Hakim RM.

Warfarin use associates with increased risk for
stroke in hemodialysis patients with atrial
fibrillation. J Am Soc Nephrol. 2009;20(10):22232233.
10. Winkelmayer WC, Liu J, Setoguchi S, Choudhry
NK. Effectiveness and safety of warfarin initiation in
older hemodialysis patients with incident atrial
fibrillation. Clin J Am Soc Nephrol.
2011;6(11):2662-2668.
11. Hart RG, Pearce LA, Asinger RW, Herzog CA.
Warfarin in atrial fibrillation patients with moderate
chronic kidney disease. Clin J Am Soc Nephrol.
2011;6(11):2599-2604.

Funding/Support: This work was supported by a

grant from the Swedish Foundation for Strategic
Research.

12. Olesen JB, Lip GY, Kamper AL, et al. Stroke and
bleeding in atrial fibrillation with chronic kidney
disease. N Engl J Med. 2012;367(7):625-635.

Role of the Sponsor: The funder was not involved

in the design and conduct of the study; collection,
management, analysis, or interpretation of the
data; and preparation, review, or approval of the
manuscript, or decision to submit the manuscript
for publication.

13. Camm AJ, Lip GY, De Caterina R, et al. 2012

focused update of the ESC Guidelines for the
management of atrial fibrillation. Eur Heart J.
2012;33(21):2719-2747.

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