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Circulation Journal
Official Journal of the Japanese Circulation Society
http://www. j-circ.or.jp
Comparison of Febuxostat and Allopurinol for
Hyperuricemia in Cardiac Surgery
Patients (NU-FLASH Trial)
Akira Sezai, MD, PhD; Masayoshi Soma, MD, PhD; Kin-ichi Nakata, MD, PhD;
Mitsumasa Hata, MD, PhD; Isamu Yoshitake, MD, PhD; Shinji Wakui, MD, PhD;
Hiroaki Hata, MD, PhD; Motomi Shiono, MD, PhD
Background: Febuxostat has been reported to have a stronger effect on hyperuricemia than allopurinol.
Methods and Results: Cardiac surgery patients with hyperuricemia (n=141) were randomized to a febuxostat group
or an allopurinol group. The study was single-blind, so the treatment was not known by the investigators. The primary endpoint was serum uric acid (UA) level. Secondary endpoints included serum creatinine, urinary albumin,
cystatin-C, oxidized low-density lipoprotein (LDL), eicosapentaenoic acid/arachidonic acid ratio, total cholesterol,
triglycerides, LDL, high-density lipoprotein, high-sensitivity C-reactive protein, blood pressure, heart rate, pulse wave
velocity (PWV), ejection fraction, left ventricular mass index (LVMI), and adverse reactions. UA level was significantly lower in the febuxostat group than the allopurinol group from 1 month of treatment onward. Serum creatinine,
urinary albumin, cystatin-C and oxidized LDL were also significantly lower in the febuxostat group. There were no
significant changes in systolic blood pressure, PWV, and LVMI in the allopurinol group, but these parameters all had
a significant decrease in the febuxostat group.
Conclusions: Febuxostat was effective for high-risk cardiac surgery patients with hyperuricemia because it reduced
UA more markedly than allopurinol. Febuxostat also had a renoprotective effect, inhibited oxidative stress, showed
anti-atherogenic activity, reduced blood pressure, and decreased PWV and LVMI.
Key Words: Allopurinol; Febuxostat; Hyperuricemia
I
n recent years, there have been an increasing number of
reports about the association between hyperuricemia and
other lifestyle-related diseases such as hypertension, hyperlipidemia, arteriosclerosis, ischemic heart disease and chronic kidney disease (CKD).1–3 Allopurinol has long been regarded
as a first-line drug for the treatment of hyperuricemia, but adverse reactions such as renal dysfunction, hepatic dysfunction,
Stevens-Johnson syndrome, and hypersensitivity vasculitis, have
been reported with allopurinol, and its efficacy is insufficient
in some cases.4–6 Febuxostat was developed in Japan as another
treatment for hyperuricemia. It became clinically available in the
USA from 2009, Europe from 2010, and Japan from May 2011.
Similar to allopurinol, febuxostat suppresses uric acid (UA)
production by inhibiting xanthine oxidase. Unlike allopurinol,
febuxostat does not inhibit nucleic acid metabolizing enzymes
other than xanthine oxidase, so it is also called a “selective
xanthine oxidase inhibitor”.7–10 Febuxostat has attracted atten-
tion as a new agent for hyperuricemia because it can decrease
serum UA to the therapeutic target level and maintain the reduction in the long term.
Given that allopurinol has low lipid solubility and is excreted
via the kidneys, impaired renal excretion can lead to adverse
reactions. In contrast, febuxostat has a high lipid solubility and
a different carboxyl group from allopurinol, so it is also excreted in the bile. Therefore, it is considered that febuxostat
can be given to patients with renal disease. Clinical studies
comparing allopurinol and febuxostat have shown that the new
drug has a more potent UA-lowering effect.10–12 Previous studies, however, have not made a detailed comparison of the systemic effects of these 2 drugs.
Therefore, we conducted a comparative study of febuxostat
and allopurinol (the Nihon University working group study of
Febuxostat and usuaL Allopurinol therapy for patientS with
Hyperuricemia: NU-FLASH study) with the objectives of elu-
Received January 18, 2013; revised manuscript received February 25, 2013; accepted March 26, 2013; released online May 15, 2013 Time
for primary review: 30 days
Department of Cardiovascular Surgery (A.S., K.N., M.H., I.Y., S.W., H.H., M. Shiono), Department of General Medicine (M. Soma), Nihon
University School of Medicine, Tokyo, Japan
Clinical Trial Registration Information: UMIN (http://www.umin.ac.jp/), Study ID: UMIN00000 5964.
Mailing address: Akira Sezai, MD, PhD, Department of Cardiovascular Surgery, Nihon University School of Medicine, 30-1 Oyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan. E-mail: [email protected]
ISSN-1346-9843 doi: 10.1253/circj.CJ-13-0082
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]
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SEZAI A et al.
Figure 1. Study flow.
cidating the efficacy and systemic effects of febuxostat.
Methods
Study Protocol
The subjects were 141 outpatients with serum UA ≥8 mg/dl
who were not on anti-hyperuricemic therapy, and who underwent cardiac surgery at Nihon University Hospital at least 1
year previously. The age range of the eligible patients was ≥20
years to <90 years.
Exclusion criteria were (1) renal dysfunction with an estimated glomerular filtration rate (eGFR) ≤20 ml · min–1 · 1.73 m–2;
(2) hepatic dysfunction (aspartate aminotransferase [AST]
>39 U/L or alanine aminotransferase [ALT] >44 U/L); (3) treatment with mercaptopurine hydrate or azathiopurine; (4) pregnancy; and (5) other reasons that made patients unsuitable for
this study as judged by the attending physician. In this study,
patients were randomly assigned to oral treatment with febuxostat (Teijin Pharma, Tokyo, Japan) or allopurinol (Glaxo
SmithKline, Tokyo, Japan) using the lottery method. This study
used a single-blind method where the treatment assigned was
known by the patients but not by the investigators and measurers. The details of the study were explained to each patient and
informed consent was obtained. Approval of the institutional
review board was also obtained and the study was registered
with the University Hospital Medical Information Network
(study ID: UMIN000005964).
Endpoints
The primary endpoint was serum UA level after treatment.
The secondary endpoints were as follows: serum creatinine
(s-Cr), eGFR, urinary albumin, cystatin-C, oxidized low-density lipoprotein (O-LDL), eicosapentaenoic acid/arachidonic
acid (EPA/AA) ratio, total cholesterol (T-cho), triglycerides
(TG), LDL, high-density lipoprotein (HDL), high-sensitivity
C-reactive protein (hs-CRP), blood pressure in both arms (systolic, mean, and diastolic pressure; SBP, mBP, and DBP), heart
rate (HR), pulse wave velocity (PWV), ejection fraction (EF),
left ventricular mass index (LVMI) measured on echocardiography, and adverse reactions.
UA, s-Cr, T-cho, TG, LDL, and HDL were measured before the start of treatment as well as after 1, 3, and 6 months
of treatment, while urinary albumin, cystatin-C, O-LDL, and
the EPA/AA ratio were measured before treatment and after 3
and 6 months of treatment. EF and LVMI were evaluated by
a specialist echocardiographer (using VIVID 7; GE Healthcare
Japan, Tokyo, Japan) according to the formula of Devereux et
al before and after 6 months of treatment. PWV was measured
with Form ABI/PWV (BP-203RPE II; Omron-Colin, Tokyo,
Japan) before and after 6 months of treatment, and BP and HR
were measured simultaneously. Adverse reactions were classified as acute attacks of gout, skin reactions, renal dysfunction (increase of s-Cr by ≥50%), hepatic dysfunction (increase
of AST/ALT by ≥50%), gastrointestinal symptoms, and allergic reactions. Management of the reactions (discontinuation
of the test drug etc) was decided by the attending physician.
The target serum UA level was ≤6.0 mg/dl, and the dose of
each test drug was increased up to a maximum of 60 mg/day
for febuxostat or 300 mg/day for allopurinol. In patients with
eGFR ≤30 ml · min–1 · 1.73 m–2, the maximum daily dose was
40 mg for febuxostat and 200 mg for allopurinol. eGFR was
calculated according to the methods proposed for Japanese
persons by the Japanese Society of Nephrology (men, 194 × sCr–1.094 × age–0.287; women, 194 × sCr–1.094 × age–0.287 × 0.739).13
Statistical Analysis
For parametric data, results are expressed as mean ± SEM. For
time-course analysis, repeated-measures ANOVA with Fisher’s
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Febuxostat vs. Allopurinol for Hyperuricemia
Table 1. Baseline Subject Characteristics
Total
Febuxostat
140
71
69
67.4±10.3
67.4±9.7
66.4±10.8
115/25
58/13
57/12
IHD
57
30
27
Valvular disease
58
29
29
Aortic disease
24
12
12
1
0
1
n
Age (years)
Gender (M/F)
Allopurinol
Basic disease
Congenital disease
Risk factors
Diabetes mellitus
51
28
23
Hypertension
113
58
55
Dyslipidemia
95
50
45
109
56
53
Cerebrovascular disease
20
12
8
Obesity
36
19
17
Smoking
61
29
32
ARB
78
41
37
ACEI
9
4
5
65
31
34
CKD
Medication
Calcium antagonist
β-blocker
Statin
Furosemide
70
34
36
113
58
55
48
26
22
Data given as mean ± SEM or n. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker;
CKD, chronic kidney disease; IHD, ischemic heart disease.
protected least squares difference test was used. Comparisons
between the febuxostat group and the allopurinol group were
done with the t-test. In all analyses, P<0.05 was considered
statistically significant.
Results
Among the 150 registered patients, 6 patients with eGFR
≤20 ml · min–1 · 1.73 m–2 and 3 patients with hepatic dysfunction were excluded, and a total of 141 patients were included,
that is, 71 were assigned to the febuxostat group and 70 to the
allopurinol group. Allopurinol was discontinued in 1 patient
who developed acute liver abscess after 4 months of treatment.
This patient died at 6 months after the start of treatment. Finally, 71 patients were available for analysis in the febuxostat
group and 69 patients were analyzed in the allopurinol group
after follow-up (Figure 1). The baseline characteristics of the
2 groups are listed in Table 1. Among the 113 patients with
hypertension, some were being treated with angiotensin II receptor blocker (ARB), angiotensin-converting enzyme inhibitor (ACEI), β-blocker, or furosemide after cardiac surgery not
for anti-hypertensive purposes but for cardioprotective or diuretic purposes. Among the present subjects, only 7 in each in
the 2 groups were not being treated with either ARB, ACEI,
β-blocker, or furosemide.
Primary Endpoint
UA There was no significant difference in UA between the
2 groups before the start of treatment (8.61±0.96 mg/dl in the
febuxostat group vs. 8.56±0.98 mg/dl in the allopurinol group,
P=0.7329; Figure 2), but the UA level was significantly lower
in the febuxostat group than the allopurinol group from 1 month
after the start of treatment (1 month, P<0.0001; 3 months,
Figure 2. Change in uric acid level.
P=0.001; 6 months, P=0.0009). The target UA level (≤6.0 mg/dl)
was achieved in 71.8% of the febuxostat group and in 30.4%
of the allopurinol group after 1 month of treatment, while it
was respectively reached in 91.5% and in 65.2% after 3 months,
and in 95.8% and in 69.6% after 6 months. These rates were
all significantly higher in the febuxostat group than the allo-
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SEZAI A et al.
Table 2. Changes in Renal Function and Lipid Parameters
Before treatment
1 month
3 months
6 months
Febuxostat
1.25±0.31
1.16±0.29*,#
1.14±0.29#
1.14±0.30*,#
Allopurinol
1.24±0.35
1.27±0.42
1.24±0.40
1.26±0.39
Febuxostat
47.5±17.3
51.3±18.0#
52.0±18.1#
52.0±18.0#
Allopurinol
48.5±16.6
48.3±17.8
49.6±17.9
48.3±17.1
Febuxostat
166.1±27.2　160.6±27.7　166.1±28.1　166.5±30.2　Allopurinol
159.8±31.4　160.6±29.9　162.4±28.9　165.0±28.5　Febuxostat
171.8±105.1
154.5±95.3　152.5±96.4　167.0±168.3
Allopurinol
167.6±106.8
174.4±126.6
180.9±131.7
172.0±124.4
Febuxostat
91.0±23.6
87.4±25.9
88.5±21.1
91.5±22.2
Allopurinol
86.8±27.7
87.7±26.3
86.9±23.2
88.6±24.2
Febuxostat
55.6±18.0
52.7±14.0
53.6±13.9
54.8±14.4
Allopurinol
55.4±16.5
51.4±12.9
52.1±12.1
53.1±17.3
Febuxostat
0.19±0.39
0.16±0.23
0.15±0.17
0.17±0.21
Allopurinol
0.19±0.21
0.37±1.05
0.24±0.40
0.30±0.52*
Serum creatinine
eGFR
T-cho
Triglycerides
LDL
HDL
hs-CRP
Data given as mean ± SEM. *P<0.05 Febuxostat vs. Allopurinol; #P<0.05 before vs. each level. eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; T-cho, total cholesterol.
Table 3. Changes in Other Parameters
Before treatment
3 months
6 months
Febuxostat
144.5±371.9
77.0±216.2*
62.5±131.2*
Allopurinol
143.8±272.2
176.7±294.4
163.2±233.8
Febuxostat
1.46±0.48
1.39±0.40*
1.44±0.47
Allopurinol
1.46±0.52
1.58±0.55
1.55±0.49
Urinary albumin
Cystatin-C
Oxidized LDL
Febuxostat
95.8±27.6
92.6±33.0
84.2±27.3*
Allopurinol
93.1±31.9
97.3±28.4
99.8±26.0
Febuxostat
0.43±0.32
0.50±0.37*
0.46±0.35*
Allopurinol
0.44±0.24
0.37±0.21
0.36±0.18
Febuxostat
60.9±9.2　–
61.0±8.4　Allopurinol
61.6±9.7　–
61.9±8.9　EPA/AA ratio
EF (%)
Data given as mean ± SEM. *P<0.05. Febuxostat vs. Allopurinol. AA, arachidonic acid; EF, ejection fraction; EPA,
eicosapentaenoic acid; LDL, low-density lipoprotein.
purinol group (1 month, P<0.0001; 3 months, P=0.00016; 6
months, P<0.0001).
Secondary endpoints
s-Cr and eGFR There were no differences in pretreatment
s-Cr or eGFR between the 2 groups (s-Cr, P=0.9406; eGFR,
P=0.7114; Table 2). s-Cr was significantly lower after 1 and
6 months of treatment in the febuxostat group than the allopurinol group (1 month, P=0.0498; 6 months, P=0.0412), and it
had a significant decrease relative to baseline at all timepoints
in this group (all P<0.0001). There were no significant differences in eGFR between the febuxostat group and the allopurinol group after the start of treatment (1 month, P=0.1375; 3
months, P=0.3267; 6 months, P=0.1132), but there was a significant increase relative to baseline at all timepoints in the
febuxostat group (all P<0.0001).
Urinary Albumin There was no difference in the pretreatment level between the 2 groups (P=0.9545), but the albumin
levels measured after 3 and 6 months were significantly lower
in the febuxostat group than the allopurinol group (3 months,
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Febuxostat vs. Allopurinol for Hyperuricemia
Figure 3. Change in blood pressure.
P=0.0449; 6 months, P=0.0215; Table 3).
Cystatin-C There was no difference in the pretreatment
cystatin-C level between the 2 groups (P=0.9821), but the
3-month level was significantly lower in the febuxostat group
than the allopurinol group (3 months, P=0.0181; 6 months,
P=0.1859; Table 3).
O-LDL There was no difference in the pretreatment level
between the 2 groups (P=0.5964), but the 6-month level was
significantly lower in the febuxostat group (3 months, P=0.375;
6 months, P=0.0007; Table 3).
EPA/AA Ratio There was no difference in the pretreatment
ratio between the 2 groups (P=0.8116), but the 3-month and
6-month levels were significantly higher in the febuxostat group
than the allopurinol group (3 months, P=0.0131; 6 months,
P=0.0416; Table 3).
T-cho, TG, LDL, and HDL There were no differences in
these parameters between the 2 groups either before or after
treatment (Table 2).
hs-CRP There was no difference in pretreatment hs-CRP
between the 2 groups (P=0.9973) but the 6-month level was
significantly lower in the febuxostat group than the allopurinol
group (1 month, P=0.0957; 3 months, P=0.0884; 6 months,
P=0.0452; Table 2).
SBP, mBP, DBP, HR, and PWV There was no difference
in pretreatment SBP between the 2 groups (right, P=0.7321;
left, P=0.4123) and also no difference in the 6-month level
(right, P=0.0092; left, P=0.135), but there was a significant
decrease at 6 months vs. baseline in the febuxostat group (right,
P=0.001; left, P=0.0004; Figures 3,4). In addition, there was
no difference in pretreatment mBP between the 2 groups (right,
P=0.6203; left, P=0.9941) and also no difference in the 6-month
level (right, P=0.3856; left, P=0.1641), but the 6-month mBP
was significantly lower than baseline in the febuxostat group
(right, P=0.0024; left, P=0.0004). Furthermore, there was no
difference in pretreatment DBP between the 2 groups (right,
P=0.4809; left, P=0.3759) and also no difference in the 6 month
level (right, P=0.0796; left, P=0.2266), but the 6 month level
was significantly lower than the pretreatment level in the febuxostat group (right, P=0.0001; left, P=0.0003). There was
no significant difference in pretreatment HR between the 2
groups (67.8±11.0 beats/min in the febuxostat group and 68.9±
9.9 beats/min in the allopurinol group, P=0.7861), and also no
difference in HR at 6 months (66.2±11.1 beats/min vs. 68.9±
9.6 beats/min, P=0.1342). There was also no difference in pretreatment PWV between the 2 groups (right, P=0.5373; left,
P=0.7556) and no difference in PWV after 6 months (right,
P=0.665; left, P=0.1835) but the 6 month level was significantly lower than the pretreatment value in the febuxostat group
(right, P=0.0276; left, P=0.0127).
EF and LVMI There were no differences in pretreatment
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SEZAI A et al.
Figure 5. Change in left ventricular mass index.
Figure 4. Change in pulse wave velocity.
EF and LVMI between the 2 groups (EF, P=0.6544; LVMI,
P=0.5989; Table 3; Figure 5). There was also no difference
in EF at 6 months between the 2 groups, but LVMI was significantly lower in the febuxostat group than the allopurinol
group after 6 months (P<0.0001).
Adverse Reactions Treatment was not discontinued due
to adverse reactions in any patient from either group, but mild
attacks of gout occurred in 1 patient from each group after 1
month of treatment. These episodes soon resolved. In the
febuxostat group, hepatic function parameters (AST, ALT)
showed a 30% increase in 2 patients after 1 month of treatment, but this improved by the next examination.
Discussion
In this study, febuxostat reduced serum UA more markedly
than allopurinol. In addition, febuxostat had a renoprotective
effect based on the levels of urinary albumin and cystatin-C,
as well as inhibiting oxidative stress, based on the O-LDL.
Furthermore, the EPA/AA ratio (an index of arteriosclerosis)
was significantly increased in the febuxostat group, while PWV
and LVMI were significantly lower in the febuxostat group
than the allopurinol group.
It has already been reported that febuxostat achieves a significant early decrease of UA compared with allopurinol.11,12
Allopurinol is excreted via the kidneys and its active metabolite (oxipurinol) has low lipid solubility, so a decrease of the
dosage is needed in patients with renal dysfunction. In contrast, efficacy and tolerability of febuxostat have been demonstrated without dosage adjustment because it has no active
metabolites and biliary excretion occurs in addition to renal
excretion.7,8 Siu et al reported that allopurinol inhibits the
progression of renal dysfunction by lowering the UA level and
decreasing s-Cr in CKD patients with hyperuricemia.12
Goicoechea et al compared allopurinol with placebo in 113
CKD patients and reported a significant decrease of UA and
significant improvement of eGFR, as well as a 71% decrease
of cardiovascular events in the allopurinol group.14 The US
febuxostat study assessed the influence of febuxostat on renal
function in 116 patients and found that a greater decrease of
serum UA led to stronger inhibition of the decline in renal
function.15 Detailed investigation, however, has not been conducted in Japan, so we measured urinary albumin and cystatinC in addition to s-Cr and eGFR as indexes of renal function in
the present study. The usefulness of urinary albumin and cystatin-C as indexes of renal function has been reported previously.16 In the present study, febuxostat significantly improved
urinary albumin and cystatin-C after 3 months in addition to
s-Cr and eGFR compared with allopurinol, indicating that it
had a more potent renoprotective effect, presumably by lowering the serum UA more markedly.
In humans, UA is produced as the terminal metabolite of
purine metabolism via xanthine oxidase. Xanthine oxidase is
involved in the production of reactive oxygen species, and it
has been reported that production of reactive oxygen by endothelial-bound xanthine oxidase is more potently inhibited by
febuxostat than by allopurinol.17 In this study, O-LDL was
used as an index of oxidative stress. The effect of febuxostat
on O-LDL has not been reported before, but Rajendra et al
reported that O-LDL was decreased by allopurinol.18 That
study, however, used a considerably higher allopurinol dose
(600 mg/day); and no change of O-LDL was observed after
allopurinol treatment in the present study because the dose
range was lower (100–300 mg). In contrast, O-LDL was significantly decreased by febuxostat and was significantly lower
in the febuxostat group than the allopurinol group, thereby
demonstrating inhibition of oxidative stress. There have been
no reports with regard to the effect on the EPA/AA ratio (an
index of arteriosclerosis) of allopurinol or febuxostat. In this
study, an anti-atherogenic effect was not observed with allopurinol, but treatment with febuxostat decreased this ratio. It
has been reported that fatty acids influence PWV, blood pressure, arterial stiffness, and mortality.19 We found that PWV
and LVMI were both significantly lower in the febuxostat group
than the allopurinol group. Khan et al studied the association
of UA with arterial stiffness and endothelial function in stroke
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Febuxostat vs. Allopurinol for Hyperuricemia
patients, and reported that lowering UA is important for improving arterial stiffness, while high UA increases the PWV
by inhibiting the cholinergic response.20 In the present study,
PWV and LVMI were decreased in the febuxostat group, presumably because blood pressure was reduced by febuxostat,
which was more potent at reducing UA, oxidative stress, and
atherogenesis than allopurinol, resulting in a decrease of PWV
and LVMI.
Rajendra et al reported that high-dose allopurinol is effective for vascular oxidative stress, and has the potential to reduce the incidence of cardiovascular event.18 Noman et al carried out exercise testing in 65 patients with stable angina and
reported that time to ST depression and time to occurrence of
chest pain were significantly increased in patients treated with
high-dose allopurinol, and that brain natriuretic peptide was
also decreased in the allopurinol group.21 Kao et al reported in
53 CKD patients that endothelial function according to flowmediated dilation and LVMI, indices of vascular endothelial
damage, is significantly decreased in the allopurinol group,22
and Hirsch et al studied patients with heart failure and reported that allopurinol acutely improves the relative and absolute concentrations of myocardial high-energy phosphates and
ATP flux through creatine kinase.23 Allopurinol is beginning
to be reported to decrease the risk of cardiovascular events due
to its preventive effects against vascular endothelial damage,
and its anti-ischemic effect.24,25 It is expected that febuxostat
would have results equal to or better than those reports, but
studies on this subject have not been done at present.
The present study has shown that febuxostat had a stronger
UA-lowering effect and renoprotective effect, and was also
superior to allopurinol at inhibiting oxidative stress atherogenesis, hypertension, and vascular endothelial damage. Thus, febuxostat was considered to be more likely to prevent cardiovascular events than allopurinol. The effect of febuxostat on
cardiovascular events, however, is an interesting point that
requires investigation in a larger number of subjects over a
longer period in the future.
Conclusion
In addition to reducing UA to a significantly lower level than
allopurinol, febuxostat had a renoprotective effect, inhibited
oxidative stress, displayed anti-atherogenic activity, had an
anti-hypertensive effect, and prevented vascular endothelial
damage in cardiac surgery patients with hyperuricemia. As a
result, febuxostat was considered to have the potential to prevent cardiovascular event.
Acknowledgments
We would like to express our sincere appreciation to Hisakuni Sekino,
MD, PhD and Kazuaki Obata, medical technologist at Sekino Hospital for
their constructive advice and cooperation.
Disclosures
Conflict of Interest Statement: None of the authors have any conflicts of
interest associated with this study. Financial Support: There are no relationships with industry.
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