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European Journal of Internal Medicine 31 (2016) 6872

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European Journal of Internal Medicine


journal homepage: www.elsevier.com/locate/ejim

Original Article

Association of statin use and the risk of end-stage renal disease: A


nationwide Asian population-based casecontrol study
Shih-Yi Lin a,b, Cheng-Li Lin c,d, Wu-Huei Hsu a,e, Cheng-Chieh Lin a,f, Chiz-Tzung Chang a,b, Chia-Hung Kao a,g,
a

Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taiwan
Division of Nephrology and Kidney Institute, China Medical University Hospital, Taichung, Taiwan
Management Ofce for Health Data, China Medical University Hospital, Taichung, Taiwan
d
College of Medicine, China Medical University, Taichung, Taiwan
e
Division of Pulmonary and Critical Care Medicine, China Medical University Hospital and China Medical University, Taichung, , Taiwan
f
Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
g
Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
b
c

a r t i c l e

i n f o

a b s t r a c t

Article history:
Received 19 November 2015
Received in revised form 23 January 2016
Accepted 4 February 2016
Available online 24 February 2016
Keywords:
End-stage renal disease
Statins
Casecontrol study

Background: Although experimental models have shown that statins could alleviate glomerular damage and decrease urinary protein excretion, the renal effects of statins remain unclear. A casecontrol study was conducted
using data from Taiwan's National Health Insurance system.
Methods: An end-stage renal disease (ESRD) group comprising 11,486 patients was established. Each patient was
frequency-matched by age, sex, and comorbidities with one person without ESRD from the general population.
Logistic regression analysis was performed to estimate the inuence of statin use on ESRD risk.
Results: The overall adjusted odds ratios (ORs) of ESRD among patients who received statins was 1.59 (95% condence interval = 1.501.68). The raised ESRD risk of statin remained consolidated regardless of statin type
(P b .001), except lovastatin. Further, while stratied by cumulative dene daily dose, the risk of ESRD increased
with accumulative dosage of statins (P for trend b .001).
Conclusion: This population-based casecontrol study showed that statin use might be associated with increased
ESRD risks. Large-scale randomized clinical trial encompassing statins of different kinds and populations of different comorbidities would be helpful to clarify the potential ESRD risks of statin users
2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction
Statins (3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors) have revolutionized the treatment of dyslipidemic and cardiovascular diseases. Given the success of statins in reducing the incidence of
CHD-related morbidity, mortality, and stroke, their use is growing, particularly in patients with diabetes and its major comorbidities [1]. In
contrast to the major benets of statins in improving cardiovascular
outcomes, claims of renal benets of statins are controversial.
Studies of animal models have shown that treatment with statins
could ameliorate the pathological changes of glomeruli, including
decrease hypercellularity and brosis, as well as proteinuria [2,3].
However, while translating into clinical studies, these signicant
renoprotective effects of statin could not be demonstrated clearly.
Some studies have shown that statins treatment could reduce urinary
Corresponding author at: Graduate Institute of Clinical Medicine Science, College of
Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 40447, Taiwan.
Tel.: +886 4 22052121x7412; fax: +886 4 22336174.
E-mail address: d10040@mail.cmuh.org.tw (C.-H. Kao).

excretion of albumin in diabetic or nephrotic patients [4,5], although


other studies did not note similar effects [6,7]. With regard to estimated
glomerular ltration rate (eGFR), the benets of statins also remained
inconclusive. Notably, results of these clinical trials are inconsistent
because of intratrial variability in evaluating outcomes, statistical
methods, heterogeneity of studying population, types of statin prescription, and duration of follow-up [1,8,9].
End-stage renal disease (ESRD) refers to terminal overall renal function failure, generating an economic burden for the whole healthcare
system [10]. The risk factors of ESRD is multifaceted, including cardiovascular disease (CVD), diabetes, hyperlipidemia, hypertension, and
aging. In preventing the progression of chronic kidney disease (CKD)
and further entering the status of ESRD, the core aim is reducing urinary
protein excretion and retarding GFR decline. Meta-analyses and clinical
trials have investigated the effect of statin use on urine protein excretion
and eGFR [1114]. However, no denitive population-based casecontrol study has investigated whether statin use could cause ESRD.
Accordingly, we conducted a nationwide, population-based case
control study to evaluate the renal safety of statin use by investigating
the association between statin use and ESRD risk.

http://dx.doi.org/10.1016/j.ejim.2016.02.012
0953-6205/ 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

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69

2. Methods

2.4. Variables of interest

2.1. Data source

We considered major comorbidities such as diabetes (ICD-9-CM


code 250), hypertension (ICD-9-CM codes 401405), coronary artery
disease (CAD; ICD-9-CM codes 410414), congestive heart failure
(CHF; ICD-9-CM code 428), cancer (ICD-9-CM codes 140208), and
proteinuria (ICD-9-CM codes 791.0) as baseline covariates. Six statin
drugs available commercially in Taiwan were analyzed: simvastatin,
uvastatin, lovastatin, atorvastatin, pravastatin, and rosuvastatin.
Medication use records were retrieved from ambulatory and inpatient
claims data. We calculated patients' cumulative dened daily dose
(cDDD) of each type of statin, namely, simvastatin (ATC C10AA01),
lovastatin (ATC C10AA02), pravastatin (ATC C10AA03), uvastatin
(ATC C10AA04), atorvastatin (ATC C10AA05), and rosuvastatin (ATC
C10AA07). For each type of statin, the cDDD was partitioned into 2
levels according to their median dose.

This study used data retrieved from the National Health Insurance
Research Database (NHIRD) of Taiwan's National Health Insurance
(NHI) program. Participation in the system is obligatory; the NHI program provides coverage to more than 99% of the 23.74 million residents
in the country and is contracted with 97% of all hospitals and clinics in
Taiwan [15]. The NHIRD includes complete information on inpatient
care, ambulatory care, dental care, and prescribed drugs and provides
researchers with scrambled identication numbers associated with
the relevant claim information, including each patient's sex, date of
birth, registry of medical services, and prescriptions. This data set contains deidentied secondary data; therefore, no information could be
used to identify any patient. This study was approved by the Ethics
Review Board of China Medical University (CMUH104-REC2-115). The
diagnoses and procedures were based on International Classication
of Diseases, Ninth Revision, Clinical Modication (ICD-9-CM) codes.

2.2. Strength of data source


The strengths of our study are its population-based design, generalizability of ndings, and use of population-based data and NHIRD records using a large sample size and having low loss to follow-up in the
longitudinal design, including study and control cohorts. In addition,
NHIRD covers a highly representative sample of Taiwan's general population because the reimbursement policy is universal and operated by a
single buyer, the government in Taiwan. All insurance claims should be
scrutinized by medical reimbursement specialists and peer review according to the standard diagnosed criteria in the study. If these doctors
or hospitals make wrong diagnoses or coding, they will be punished
with a lot of penalties. Therefore, the diagnoses of ESRD [1618] and hyperlipidemia [1921] based on ICD-9 codes in this study should be highly reliable.

2.5. Statistical analysis


The baseline characteristics between the ESRD and the non-ESRD
groups were compared using the chi-square test. We used the t-test to
analyze continuous variables. Odds ratios (ORs) and 95% condence intervals (CIs) for factors associated with ESRD risk were estimated using
conditional logistic regression models. All analyses were performed
using SAS statistical software for Windows (Version 9.3; SAS Institute,
Inc., Cary, NC, USA), and the signicance level was set at .05.
3. Results
Table 1 summarizes the baseline characteristics proles of the patients. A total of 22,972 patients with hyperlipidemia were enrolled in
this study. The duration from diagnosis of CKD to diagnosis of ESRD is

Table 1
Baseline characteristics between end-stage renal disease group and non-end-stage renal
disease group.
ESRD

2.3. Patients selected


Patients were identied from 2 subsets of the NHIRD. Subjects with
hyperlipidemia (ICD-9-CM code 272) constituted the base population.
We rst identied patients aged at least 20 years and with renal diseases (ICD-9-CM code 580589) and incident ESRD (ICD-9-CM code
585) by using the 20062009 records of the NHIRD Registry of Catastrophic Illnesses Patient Database. The rst-time ESRD diagnosis date
served as the index date. Finally, we extracted 11486ESRD patients
with complete age or sex information and without a history of statin
use before hyperlipidemia diagnosis to comprise the ESRD group. Control patients were also identied from the Longitudinal Health Insurance Database 2000 (LHID 2000), which contains the claims data of
one million people sampled randomly from the NHIRD 2000 enrollment
le. No signicant difference exists in sex, age, or health care costs between cohorts in the LHID2000 and all insurance enrollees. For each patient with ESRD, we randomly selected one patient with renal diseases
but without ESRD from the same period. We selected 1 control subject
for each case from the LHID2000 matched on age within 10 years, gender, medications including angiotensin-converting enzyme inhibitor
(ACEI), angiotensin II receptor blockers (ARB), NSAID (nonsteroid
anti-inammatory drugs), ezetimibe, fenobirate/gembibrozil, and
resins, and comorbidity of diabetes (ICD-9-CM code 250), hypertension
(ICD-9-CM codes 401405), coronary artery disease (CAD; ICD-9-CM
codes 410414), congestive heart failure (CHF; ICD-9-CM code 428),
and cancer (ICD-9-CM codes 140208), proteinuria (ICD-9-CM code
581, 791.0), year of diagnosis of renal diseases, and year of diagnosis
of ESRD.

No, N = 11,486

Yes, N = 11,486

P value

Gender
Women
Men
Age group (year)
64
6574
75
Mean (SD) (year)

5828
5658

50.7
49.3

5833
5653

50.8
49.2

4961
3474
3051
65.9

43.2
30.3
26.6
11.8

4775
3524
3187
66.0

41.6
30.7
27.8
12.2

0.75

Medications
Statin
ACEI/ARB
NSAID
Ezetimibe
Fenobirate and gembibrozil
Resin

6683
10,282
10,654
367
4908
152

58.2
89.5
92.8
3.20
42.7
1.32

7845
10,262
10,648
374
4991
161

68.3
89.3
92.7
3.26
43.5
1.40

b0.001
0.67
0.88
0.79
0.27
0.61

6795
10,917
4697

59.2
95.1
40.9

6832
10,882
4687

59.5
94.7
40.8

0.62
0.29
0.89

6151
1872
787
1720

53.6
16.3
6.85
15.0

6187
1874
801
1864

53.9
16.3
6.97
16.2

0.63
0.97
0.72
0.01

Baseline comorbidities
Diabetes
Hypertension
Chronic obstructive
pulmonary disease
CAD
CHF
Cancer
Proteinuria

0.95

0.03

Chi-square test and *t-test comparing subjects with and without end-stage renal disease.
Data are presented as the number of subjects in each group, with percentages given in
parentheses.
ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blockers;
NSAID, nonsteroid anti-inammatory drugs.

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S.-Y. Lin et al. / European Journal of Internal Medicine 31 (2016) 6872

5.91 3.99 years in statin group and 5.88 3.88 years in non-statin
group (P = 0.51). Of the patients with ESRD, 50.8% were women and
41.6% were aged less than 64 years. The mean ages of the ESRD cases
and non-ESRD controls were 66.0 years (12.2 years) and 65.9 years
(11.8 years), respectively. Previous statin use was signicantly more
common in the ESRD group (68.3%) than in the non-ESRD controls
(58.2%) (P b 0.001).
3.1. Risk of ESRD and association with individual statin
Table 2 shows the crude and adjusted ORs of ESRD risk based on statin use. The OR of ESRD risk was 1.59-fold (95% CI = 1.501.68) higher
for patients who received statins than it was for patients who did not.
Similar results were observed when we transferred to investigate the
ESRD risk of individual statin (OR = 1.16, 95% CI = 1.091.23 for simvastatin; OR = 1.21, 95% CI = 1.121.31 for pravastatin; OR = 1.54, 95%
CI = 1.431.66 for uvastatin; OR = 1.68, 95% CI = 1.591.78 for atorvastatin; OR = 1.50, 95% CI = 1.401.62 for rosuvastatin, respectively).
While analyzing statin type, statin users of simvastatin, uvastatin, atorvastatin, pravastatin, and rosuvastatin had increasing risk of ESRD than
non-statin users.
3.2. Association between ESRD risk with cumulative DDD dose of statins
Furthermore, after estimating ESRD risk by using cDDD for statins,
statin use was again associated with a higher risk of ESRD (Table 3).
Compared with patients who did not receive statins, ESRD risk was
highest in patients who used at least 600 cDDD of statins (OR = 1.99,
95% CI = 1.832.16), followed by at least 251600 cDDD of statins
(OR = 1.65, 95% CI = 1.521.79), at least 75-250cDDD of statins
(OR = 1.50, 95% CI = 1.391.63), and less than 75 cDDD of statins
(OR = 1.34, 95% CI = 1.241.45). With increasing cDDD of statin, statin
users had increasing risk of ESRD while compared with non-statin users
(P for trend b0.001).
3.3. Risk of ESRD and association with cumulative DDD of individual statin
We further examined whether association of statin compound type
and its cDDD and ESRD risk is also existed. Compared with patients
who did not receive statins, ESRD risk was highest in patients who
used 320cDDD of uvastatin (OR = 2.13, 95% CI = 1.832.49), followed by 90cDDD of atorvastatin (OR = 2.10, 95% CI = 1.922.31), and
50 cDDD of rosuvastatin (OR = 1.91, 95% CI = 1.642.23) (Table 4).
Regardless which individual statin was used, ESRD risk of statin user is
increasing with increasing cDDD of individual statin.
4. Discussion
This nationwide, population-based casecontrol study discovered
that after adjusting for age, sex, and matched for ESRD-associated
Table 2
Odds ratio and 95% condence intervals of end-stage renal disease associated with individual statins.
Variable
Medications
Statin
Individual statins
Simvastatin
Lovastatin
Pravastatin
Fluvastatin
Atorvastatin
Rosuvastatin
P b 0.001.

Case no./
Control no.

Odds ratio

(95% CI)

7845/6683

1.59

(1.50, 1.68)

3108/2793
2935/2827
1693/1438
2123/1472
4831/3504
2032/1446

1.16
1.05
1.21
1.54
1.68
1.50

(1.09, 1.23)
(0.99, 1.12)
(1.12, 1.31)
(1.43, 1.66)
(1.59, 1.78)
(1.40, 1.62)

Table 3
Odds ratio and 95% condence intervals of end-stage renal disease associated with cumulative dene daily dose (cDDD) of statins.

Non-use of statins
Statins
b75 cDDD
75250 cDDD
251600 cDDD
N 600 cDDD
P for trend

Case number/
control number

Odds ratio

(95% CI)

3641/4803

1.00

(Reference)

1883/1897
1891/1714
1915/1583
2156/1489

1.34
1.50
1.65
1.99
b0.001

(1.24, 1.45)
(1.39, 1.63)
(1.52, 1.79)
(1.83, 2.16)

The cumulative DDD is partitioned in to 4 segments by quartile.


P b 0.001.

comorbidities, statin users had a 1.59-fold higher risk of developing


ESRD compared with non-statin users. Cumulative exposure to statins
was associated positively with an increased ESRD risk. Further analyzing
ESRD risk of statin user based on statin type and its cDDD demonstrated
that patients receiving 320cDDD of uvastatin had up to2.13-fold
higher risk of ESRD compared with non-statin user.
Statins have been used across most patient subgroups, including
CHD, diabetes, CKD, and aging, in recent decades. SHARP trial has
showed that simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the primary atherosclerotic events in patients with advanced
chronic kidney disease [22]. Unless adverse effects or intolerance to
statins develop, statin use typically continues long-term [23]. A strict
evaluation of the renal safety of such prolonged exposure is crucial, particularly its effects on those who are vulnerable to CKD and ESRD.
This is the rst large-scale population-based study to evaluate the
ESRD risks of statin use across patient subpopulations and statin types.
Epidemiological evidence has clearly demonstrated that dyslipidemia
is a risk factor for CKD [24,25]. In the Helsinki Heart Study, men with a
low-density lipoprotein (LDL) to high-density lipoprotein (HDL) ratio
of more than 4.4 have a more rapid decline in eGFR (approximately
3% in 5 years) than those whose ratio was less than 3.2 [24]. Furthermore, experimental models have shown that statin use could reduce
podocyte damage, glomerulosclerosis, and interstitial brosis [2628].
The renoprotection of statins observed in vitro and in rats is believed
Table 4
Odds ratio and 95% condence intervals of end-stage renal disease associated with cumulative dene daily dose (cDDD) of individual statins.
Case number/
control number

Odds ratio

(95% CI)

Non-use of statins

3641/4803

1.00

(reference)

Simvastatin#
b95 cDDD
95 cDDD

1571/1433
1537/1360

1.46
1.53

(1.31, 1.63)
(1.37, 1.71)

Fluvastatin
b320 cDDD
320 cDDD

1078/766
1045/706

1.86
2.13

(1.61, 2.16)
(1.83, 2.49)

Lovastatin#
b90 cDDD
90 cDDD

1495/1422
1440/1405

1.43
1.33

(1.28, 1.60)
(1.19, 1.49)

Atorvastatin
b90 cDDD
90 cDDD

2325/1906
2506/1598

1.63
2.10

(1.48, 1.78)
(1.92, 2.31)

Pravastatin
b55 cDDD
55 cDDD

819/686
874/752

1.58
1.51

(1.35, 1.85)
(1.29, 1.76)

Rosuvastatin
b50 cDDD
50 cDDD

973/683
1059/763

1.84
1.91

(1.57, 2.16)
(1.64, 2.23)

The cumulative dene daily dose is partitioned in to 2 segments by median.


#
The cumulative dene daily dose is partitioned in to 2 segments by median.
P b 0.001.

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to result from both its lipid-lowering and pleiotropic effects [29]. However, clinical evidence that statins assist in preserving renal function is
not strong or consistent across all studies [12]. In the ALLHAT-LLT trial,
pravastatin had no signicant effects on halting GFR decline in hypertensive dyslipidemia CKD patients compared with typical care [30].
In the CARE study, the renal benets of statins only appeared in patients with proteinuria or eGFR 40 mL/min [31]. Intrinsic kidney
disease would be the key factor determining in whether statin has
renoprotective effects [32]. A meta-analysis by Sandhu et al. revealed
that statin therapy provided signicant renal benets only in populations with CVD [33]. However, the meta-analysis by Yan et al. have
showed that high-intensity statin therapy in CKD patients on renal protection remains unclear [34]. The mechanism of selected renal benets
of statins on certain subpopulations is still poorly understood. This selected renal benet could not be explained sufciently by the lipidlowering effects and modulatory effects of statins.
In our analysis, the ESRD risks of statin use existed constantly and
were related to cDDD of statin use, even after matched controls for
major risk factors of ESRD. We also matched for ACEI/ARB, NSAID, and
other lipid-lowering agents that might have benets and harms on
renal function. There was no difference in duration from diagnosis of
CKD to diagnosis of ESRD in stain group and non-statin group (5.91
3.99 years vs 5.88 3.88 years, P = 0.51). Therefore, the baseline selection bias between study group and control group is minimized in this
study. Of which among our study population, more than 94% had hypertension, more than 59% had diabetes, and more than 53% had CVD.
Regardless of the three most common comorbidities of ESRD,
i.e., hypertension, diabetes, or CAD, the adjusted ESRD risk is still up to
1.59-fold higher in statin users. Our results demonstrated clearly that
statin use is associated with increased risk of ESRD.
Previous studies investigating renal effects of statins usually classied patients rst by eGFR or urinary protein excretion at baseline.
Then the primary outcomes were changes of eGFR and urinary protein
excretion. However, solely urine protein excretion or eGFR alone
might not reect distinct long-term effects of statins on kidneys
[3436]. Lai et al. have also used NHIRD and they found that atorvastatin
and rosuvastatin would cause deterioration in eGFR in diabetes patients
with CKD stage 1 and stage 2 but improvement in CKD stage 3, 4, and 5
[37]. Their results are conict with the ndings of CARE study [31,37]
Besides, the median follow-up duration of their study is only 200 days,
which is hardly to evaluate the long-term effects on statin no renal function [37]. They did not consider proteinuria as a confounding factor,
which would cause selection bias. Bangalore et al. have summarized trials and reported that atorvastatin had no renal-related adverse effects
[38]. However, their renal outcomes is dened too broadly to conclude
a denite effects of atorvastatin on actual renal function loss, the
major concern in clinical practice. Further, the nding of Bangalore
et al. is hardly extrapolated to other statins and follow-up period of
their study is approximately 2 years [38]. The discrepancy results between previous and our study might result from the heterogeneity of
glomerular and tubulointerstitial pathological changes, different selection of study subpopulations, and follow-up period. The potential mechanism of statin-induced renoprotection or renal hazards in certain
patient subpopulation is not well understood.
Current guidelines have recommended that long-term use of statin
is protective against vascular events [23]. However, long-term statin
use may be a concern in terms of cognitive impairment [39,40], hepatic
dysfunction [41], diabetes [42], and sexual dysfunction [43]. Dormuth
et al. have discovered that patients receiving high dose statins had
1.34-fold higher risk of admission for acute kidney injury while compared with low dose statins [44]. Our results clearly allude to an association between dose response effect of statin and adverse ESRD risk. This
data added evidence of causation between statin and ESRD.
Our research has several strengths and advantages over previous
studies. First, we enrolled more than 11,400 patients who used statins,
which is one of the largest populations of any study investigating the

71

renal effects of statins. Second, most previous clinical trials and metaanalysis adopted urinary protein excretion and eGFR as primary outcomes. This study used ESRD as a clear and denite end point. Third,
this study was based on data from the NHIRD, which covers more
than 99% of the population of Taiwan and provides a representative
and homogeneous data set, thereby enabling the investigation of the incidence of ESRD, and includes critical information such as age, sex, drug
dosages, and comorbidities. Fourth, we studied and analyzed all statin
types, including hydrophilic statins (uvastati, pravastatin, and
rosuvastatin) and lipophilic statins (atorvastatin, lovastatin, and simvastatin) together rather than investigating the renal outcomes of only
one statin type. We demonstrated clearly the association between
renal outcomes and accumulative dosage of statins across statin types.
Thus, our results are more useful in determining whether statins benet
or harm kidney function than they are in analyzing the effects of duration of statin use.
Several limitations of this study should be mentioned. First, patient
information such as socioeconomic status, family medical history,
smoking habits, and obesity, all of which may contribute to ESRD, was
not included in the data set. Second, the NHIRD information did not include laboratory data such as levels of blood pressure, plasma glucose,
cholesterol, HbA1C, urinary protein excretion, and eGFR; therefore, we
could not investigate the interactive effects of statins in reducing cholesterol and renal function decline. However, such analysis has been
performed in many previous studies, the results of which have been
inconclusive. Thus, this study alternatively attempted to use comprehensive nationwide registry data to study renal outcomes among patients who received statins. Finally, this is a casecontrol observational
study. The dyslipidemic population was selected based on ICD-9
codes. Since the causes of dyslipidemia are multifaceted, the response
and compliance to statin would differ among individuals. With this intrinsic limit of study design, the casual relationship among the etiologies
of dyslipidemia, statin use, and ESRD risk is hardly claried. Our current
observation prompted for future research of alternative interventional
study design.
In conclusion, these ndings demonstrate the ESRD risk of statin
users in dyslipidemic patients. Patients receiving different statin types
had different corresponding ESRD risks. The risk of ESRD among those
who receive statins increases with accumulative statin dosage. Although the mechanism of statins that causes renal hazards is unknown,
selecting an appropriate dyslipidemic population to receive statins
would maximize the cardiovascular protection and renal safety and of
statins. Large-scale randomized clinical trial encompassing statins of
different kinds and populations of different comorbidities would be
helpful to clarify the potential ESRD risks of statin users.
Author contributions
Conception/design: Shih-Yi Lin, Chia-Hung Kao; provision of study
materials: Chia-Hung Kao; collection and/or assembly of data: Shih-Yi
Lin, Cheng-Li Lin, Chia-Hung Kao; data analysis and interpretation:
Shih-Yi Lin, Cheng-Li Lin, Wu-Huei Hsu, Cheng-Chieh Lin, Chiz-Tzung
Chang, Chia-Hung Kao; Manuscript writing: Shih-Yi Lin, Cheng-Li Lin,
Wu-Huei Hsu, Cheng-Chieh Lin, Chiz-Tzung Chang, Chia-Hung Kao;
nal approval of manuscript: Shih-Yi Lin, Cheng-Li Lin, Wu-Huei Hsu,
Cheng-Chieh Lin, Chiz-Tzung Chang, Chia-Hung Kao.
Conict of interests
This study is supported in part by the Taiwan Ministry of Health and
Welfare Clinical Trial and Research Center of Excellence (MOHW105TDU-B-212-133019); the China Medical University Hospital, Academia
Sinica Taiwan Biobank Stroke Biosignature Project (BM10501010037);
the NRPB Stroke Clinical Trial Consortium (MOST 104-2325-B-039005); the Tseng-Lien Lin Foundation; the Taichung, Taiwan, Taiwan
Brain Disease Foundation; the Taipei, Taiwan, and Katsuzo and Kiyo

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S.-Y. Lin et al. / European Journal of Internal Medicine 31 (2016) 6872

Aoshima Memorial Funds, Japan; and the CMU under the Aim for Top
University Plan of the Ministry of Education, Taiwan. The funders had
no role in study design, data collection and analysis, decision to publish,
or preparation of the manuscript. No additional external funding received for this study.
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