Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: A randomized, controlled trial

Autoři: Atsushi Tanaka aff001;  Isao Taguchi aff002;  Hiroki Teragawa aff003;  Nobukazu Ishizaka aff004;  Yumiko Kanzaki aff004;  Hirofumi Tomiyama aff005;  Masataka Sata aff006;  Akira Sezai aff007;  Kazuo Eguchi aff008;  Toru Kato aff009;  Shigeru Toyoda aff010;  Ryoichi Ishibashi aff011;  Kazuomi Kario aff012;  Tomoko Ishizu aff013;  Shinichiro Ueda aff014;  Koji Maemura aff015;  Yukihito Higashi aff016;  Hirotsugu Yamada aff006;  Mitsuru Ohishi aff017;  Kotaro Yokote aff018;  Toyoaki Murohara aff019;  Jun-ichi Oyama aff001;  Koichi Node aff001
Působiště autorů: Department of Cardiovascular Medicine, Saga University, Saga, Japan aff001;  Department of Cardiology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan aff002;  Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima, Japan aff003;  Department of Cardiology, Osaka Medical College, Takatsuki, Japan aff004;  Department of Cardiology, Tokyo Medical University, Tokyo, Japan aff005;  Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan aff006;  The Department of Cardiovascular Surgery, Nihon University School of Medicine, Tokyo, Japan aff007;  Department of Internal Medicine, Hanyu General Hospital, Hanyu, Japan aff008;  Department of Clinical Research, National Hospital Organization, Tochigi Medical Center, Utsunomiya, Japan aff009;  Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan aff010;  Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Kimitsu Chuo Hospital, Kisarazu, Japan aff011;  Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan aff012;  Department of Clinical Laboratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan aff013;  Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus, Nishihara, Japan aff014;  Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan aff015;  Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan aff016;  Department of Cardiovascular Medical and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan aff017;  Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan aff018;  Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan aff019
Vyšlo v časopise: Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: A randomized, controlled trial. PLoS Med 17(4): e32767. doi:10.1371/journal.pmed.1003095
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003095



An elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia.

Methods and findings

The study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10–60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat − control], −0.007 mm [95% confidence interval (CI) −0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, −0.016 mm [95% CI −0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI −0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI −0.5% to 3.3%] in the control group (n = 193); mean between-group difference, −0.2% [95% CI −2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI −0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, −2.62 mg/dL [95% CI −2.86 mg/dL to −2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia.


In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population.

Trial registration

University Hospital Medical Information Network Clinical Trial Registry UMIN000012911.

Klíčová slova:

Adverse events – Arthritis – Cardiovascular diseases – Gout – Uric acid – Common carotid arteries – Cardiovascular therapy


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2020 Číslo 4

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