comparison of febuxostat and allopurinol for hyperuricemia

Circulation Journal Vol.77, August 2013

Circulation JournalOfficial Journal of the Japanese Circulation Societyhttp://www.j-circ.or.jp

tion as a new agent for hyperuricemia because it can decrease serum UA to the therapeutic target level and maintain the re-duction 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 ex-creted 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 stud-ies, however, have not made a detailed comparison of the sys-temic 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-

n recent years, there have been an increasing number of reports about the association between hyperuricemia and other lifestyle-related diseases such as hypertension, hy-

perlipidemia, arteriosclerosis, ischemic heart disease and chron-ic kidney disease (CKD).1–3 Allopurinol has long been regarded as a first-line drug for the treatment of hyperuricemia, but ad-verse 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-

I

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 Oyaguchi-

kamimachi, Itabashi-ku, Tokyo 173-8610, Japan. E-mail: [email protected] doi: 10.1253/circj.CJ-13-0082All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

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 pri-mary 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 signifi-cantly 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. (Circ J 2013; 77: 2043 – 2049)

Key Words: Allopurinol; Febuxostat; Hyperuricemia

ORIGINAL ARTICLECardiovascular Surgery


2044 SEZAI A et al.

(TG), LDL, high-density lipoprotein (HDL), high-sensitivity C-reactive protein (hs-CRP), blood pressure in both arms (sys-tolic, 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 echocardiog-raphy, and adverse reactions.

UA, s-Cr, T-cho, TG, LDL, and HDL were measured be-fore 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 clas-sified as acute attacks of gout, skin reactions, renal dysfunc-tion (increase of s-Cr by ≥50%), hepatic dysfunction (increase of AST/ALT by ≥50%), gastrointestinal symptoms, and al-lergic 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 AnalysisFor parametric data, results are expressed as mean ± SEM. For time-course analysis, repeated-measures ANOVA with Fisher’s

cidating the efficacy and systemic effects of febuxostat.

MethodsStudy ProtocolThe subjects were 141 outpatients with serum UA ≥8 mg/dl who were not on anti-hyperuricemic therapy, and who under-went 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 esti-mated 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) treat-ment with mercaptopurine hydrate or azathiopurine; (4) preg-nancy; 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 fe-buxostat (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 measur-ers. 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).

EndpointsThe 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-den-sity lipoprotein (O-LDL), eicosapentaenoic acid/arachidonic acid (EPA/AA) ratio, total cholesterol (T-cho), triglycerides

Figure 1. Study flow.


2045Febuxostat vs. Allopurinol for Hyperuricemia

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-

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.

ResultsAmong the 150 registered patients, 6 patients with eGFR ≤20 ml · min–1 · 1.73 m–2 and 3 patients with hepatic dysfunc-tion 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. Fi-nally, 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 re-ceptor blocker (ARB), angiotensin-converting enzyme inhibi-tor (ACEI), β-blocker, or furosemide after cardiac surgery not for anti-hypertensive purposes but for cardioprotective or di-uretic 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 EndpointUA 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,

Table 1. Baseline Subject Characteristics

Total Febuxostat Allopurinol

n 140 71 69

Age (years) 67.4±10.3 67.4±9.7 66.4±10.8

Gender (M/F) 115/25 58/13 57/12

Basic disease

IHD 57 30 27

Valvular disease 58 29 29

Aortic disease 24 12 12

Congenital disease 1 0 1

Risk factors

Diabetes mellitus 51 28 23

Hypertension 113 58 55

Dyslipidemia 95 50 45

CKD 109 56 53

Cerebrovascular disease 20 12 8

Obesity 36 19 17

Smoking 61 29 32

Medication

ARB 78 41 37

ACEI 9 4 5

Calcium antagonist 65 31 34

β-blocker 70 34 36

Statin 113 58 55

Furosemide 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.

Figure 2. Change in uric acid level.


2046 SEZAI A et al.

in this group (all P<0.0001). There were no significant differ-ences in eGFR between the febuxostat group and the allopuri-nol 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 sig-nificant increase relative to baseline at all timepoints in the febuxostat group (all P<0.0001).

Urinary Albumin There was no difference in the pretreat-ment 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,

purinol group (1 month, P<0.0001; 3 months, P=0.00016; 6 months, P<0.0001).

Secondary endpointss-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 allopu-rinol group (1 month, P=0.0498; 6 months, P=0.0412), and it had a significant decrease relative to baseline at all timepoints

Table 2. Changes in Renal Function and Lipid Parameters

Before treatment 1 month 3 months 6 months

Serum creatinine

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

eGFR

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

T-cho

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　　Triglycerides

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

LDL

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

HDL

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

hs-CRP

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*

Data given as mean ± SEM. *P<0.05 Febuxostat vs. Allopurinol; #P<0.05 before vs. each level. eGFR, estimated glomer-ular filtration rate; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipopro-tein; T-cho, total cholesterol.

Table 3. Changes in Other Parameters

Before treatment 3 months 6 months

Urinary albumin

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

Cystatin-C

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

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

EPA/AA ratio

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

EF (%)

Febuxostat 60.9±9.2　　 – 61.0±8.4　　 Allopurinol 61.6±9.7　　 – 61.9±8.9　　

Data given as mean ± SEM. *P<0.05. Febuxostat vs. Allopurinol. AA, arachidonic acid; EF, ejection fraction; EPA, eicosapentaenoic acid; LDL, low-density lipoprotein.



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 fe-buxostat 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 pre-treatment 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 signifi-cantly 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

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;

Figure 3. Change in blood pressure.


2048 SEZAI A et al.

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 con-ducted in Japan, so we measured urinary albumin and cystatin-C in addition to s-Cr and eGFR as indexes of renal function in the present study. The usefulness of urinary albumin and cys-tatin-C as indexes of renal function has been reported previ-ously.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 lower-ing 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 endo-thelial-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 sig-nificantly 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 allo-purinol, but treatment with febuxostat decreased this ratio. It has been reported that fatty acids influence PWV, blood pres-sure, 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

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 sig-nificantly 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 treat-ment, but this improved by the next examination.

DiscussionIn 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 sig-nificant early decrease of UA compared with allopurinol.11,12 Allopurinol is excreted via the kidneys and its active metabo-lite (oxipurinol) has low lipid solubility, so a decrease of the dosage is needed in patients with renal dysfunction. In con-trast, efficacy and tolerability of febuxostat have been demon-strated 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

Figure 4. Change in pulse wave velocity.

Figure 5. Change in left ventricular mass index.



intervention. Circ J 2011; 75: 692 – 697. 3. Kansui Y, Ohtsubo T, Goto K, Sakata S, Ichishima K, Fukuhara M,

et al. Association of serum uric acid with blood pressure in Japanese men: Cross-sectional study in work-site group. Circ J 2011; 75: 2827 – 2832.

4. Fagugli RM, Gentile G, Ferrara G, Brugnano R. Acute renal and hepatic failure associated with allopurinol treatment. Clin Nephrol 2008; 70: 523 – 526.

5. Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Bouwes Bavinck JN, Sidoroff A, et al. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol 2008; 58: 25 – 32.

6. Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005; 353: 2450 – 2461.

7. Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T. An extremely potent inhibitor of xanthine oxidoreductase: Crystal struc-ture of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem 2003; 278: 1848 – 1855.

8. Matsumoto K, Okamoto K, Ashizawa N, Nishino T. FYX-051: A novel and potent hybrid-type inhibitor of xanthine oxidoreductase. J Pharmacol Exp Ther 2011; 336: 95 – 103.

9. Burns CM, Wortmann RL. Gout therapeutics: New drugs for an old disease. Lancet 2011; 377: 165 – 177.

10. Tatuo H, Iwao O. A repeated oral administration study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase in patients with impaired renal function in Japan. J Clin Rheumatol 2011; 17: S27 – S34.

11. Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K, Nakamura T, et al. Multicenter, open-label study of long-term administration of febuxostat (TMX-67) in Japanese patients with hyperuricemia in-cluding gout. J Clin Rheumatol 2011; 17: S50 – S56.

12. Siu Y, Leung, K, Tong MK, Kwan T. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006; 47: 51 – 59.

13 Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53: 982 – 992.

14. Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincon A, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 2010; 5: 1388 – 1393.

15. Whelton A, Macdonald PA, Zhao L, Hunt B, Gunawardhana L. Renal function in gout: Long-term treatment effects of febuxostat. J Clin Rheumatol 2011; 17: 7 – 13.

16. Peralta CA, Shlipak MG, Judd S, Cushman M, McClellan W, Zakai NA, et al. Detection of chronic kidney disease with creatinine, cys-tatin C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality. JAMA 2011; 305: 1545 – 1552.

17. Malik UZ, Hundley NJ, Romero G, Radi R, Freeman BA, Tarpey MM, et al. Febuxostat inhibition of endothelial-bound XO: Implica-tions for targeting vascular ROS production. Free Radic Biol Med 2011; 51: 179 – 184.

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patients, and reported that lowering UA is important for im-proving 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, pre-sumably 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 effec-tive for vascular oxidative stress, and has the potential to re-duce the incidence of cardiovascular event.18 Noman et al car-ried 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 flow-mediated 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 re-ported that allopurinol acutely improves the relative and abso-lute 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 atherogen-esis, hypertension, and vascular endothelial damage. Thus, fe-buxostat was considered to be more likely to prevent cardio-vascular 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.

ConclusionIn 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 pre-vent cardiovascular event.

AcknowledgmentsWe 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.

DisclosuresConflict of Interest Statement: None of the authors have any conflicts of interest associated with this study. Financial Support: There are no rela-tionships with industry.

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Izzo JL, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 2003; 289: 2560 – 2572.

2. Park SH, Shin WY, Lee EY, Gil HW, Lee SW, Lee SJ, et al. The impact of hyperuricemia on in-hospital mortality and incidence of acute kidney injury in patients undergoing percutaneous coronary

comparison of febuxostat and allopurinol for hyperuricemia

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