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


1. Feig DI, Mazzali M, Kang DH, Nakagawa T, Price K, Kannelis J, et al. Serum uric acid: a risk factor and a target for treatment? J Am Soc Nephrol. 2006; 17(4 Suppl 2):S69–73. doi: 10.1681/ASN.2005121331 16565251

2. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med.2008; 359: 1811–1821. doi: 10.1056/NEJMra0800885 18946066

3. Kuwabara M, Niwa K, Hisatome I, Nakagawa T, Roncal-Jimenez CA, Andres-Hernando A, et al. Asymptomatic hyperuricemia without comorbidities predicts cardiometabolic diseases: five-year Japanese cohort study. Hypertension. 2017; 69: 1036–1044. doi: 10.1161/HYPERTENSIONAHA.116.08998 28396536

4. Richette P, Perez-Ruiz F, Doherty M, Jansen TL, Nuki G, Pascual E, et al. Improving cardiovascular and renal outcomes in gout: what should we target? Nat Rev Rheumatol. 2014; 10: 654–661. doi: 10.1038/nrrheum.2014.124 25136785

5. Puddu P, Puddu GM, Cravero E, Vizioli L, Muscari A. Relationships among hyperuricemia, endothelial dysfunction and cardiovascular disease: molecular mechanisms and clinical implications. J Cardiol. 2012; 59: 235–242. doi: 10.1016/j.jjcc.2012.01.013 22398104

6. Battelli MG, Polito L, Bolognesi A. Xanthine oxidoreductase in atherosclerosis pathogenesis: not only oxidative stress. Atherosclerosis. 2014; 237: 562–567. doi: 10.1016/j.atherosclerosis.2014.10.006 25463089

7. Nomura J, Busso N, Ives A, Matsui C, Tsujimoto S, Shirakura T, et al. Xanthine oxidase inhibition by febuxostat attenuates experimental atherosclerosis in mice. Sci Rep. 2014; 4: 4554. doi: 10.1038/srep04554 24686534

8. Schroder K, Vecchione C, Jung O, Schreiber JG, Shiri-Sverdlov R, van Gorp PJ, et al. Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type diet. Free Radic Biol Med. 2006; 41: 1353–1360. doi: 10.1016/j.freeradbiomed.2006.03.026 17023262

9. Becker MA, Schumacher HR Jr., 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. doi: 10.1056/NEJMoa050373 16339094

10. Malik UZ, Hundley NJ, Romero G, Radi R, Freeman BA, Tarpey MM, et al. Febuxostat inhibition of endothelial-bound XO: implications for targeting vascular ROS production. Free Radic Biol Med. 2011; 51: 179–184. doi: 10.1016/j.freeradbiomed.2011.04.004 21554948

11. Sezai A, Soma M, Nakata K, Hata M, Yoshitake I, Wakui S, et al. Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients (NU-FLASH Trial). Circ J. 2013; 77: 2043–2049. doi: 10.1253/circj.cj-13-0082 23676888

12. White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018; 378: 1200–1210. doi: 10.1056/NEJMoa1710895 29527974

13. Bredemeier M, Lopes LM, Eisenreich MA, Hickmann S, Bongiorno GK, d'Avila R, et al. Xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord. 2018; 18: 24. doi: 10.1186/s12872-018-0757-9 29415653

14. Oyama J, Tanaka A, Sato Y, Tomiyama H, Sata M, Ishizu T, et al. Rationale and design of a multicenter randomized study for evaluating vascular function under uric acid control using the xanthine oxidase inhibitor, febuxostat: the PRIZE study. Cardiovasc Diabetol. 2016; 15: 87. doi: 10.1186/s12933-016-0409-2 27317093

15. Kinoshita M, Yokote K, Arai H, Iida M, Ishigaki Y, Ishibashi S, et al. Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017. J Atheroscler Thromb. 2018; 25: 846–984. doi: 10.5551/jat.GL2017 30135334

16. Oyama J, Murohara T, Kitakaze M, Ishizu T, Sato Y, Kitagawa K, et al. The effect of sitagliptin on carotid artery atherosclerosis in type 2 diabetes: the PROLOGUE randomized controlled trial. PLoS Med. 2016; 13: e1002051. doi: 10.1371/journal.pmed.1002051 27351380

17. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr. 2008; 21: 93–111; quiz 189–90. doi: 10.1016/j.echo.2007.11.011 18261694

18. Lundby-Christensen L, Almdal TP, Carstensen B, Tarnow L, Wiinberg N. Carotid intima-media thickness in individuals with and without type 2 diabetes: a reproducibility study. Cardiovasc Diabetol. 2010; 9: 40. doi: 10.1186/1475-2840-9-40 20727128

19. Ishizu T, Seo Y, Machino T, Kawamura R, Kimura T, Murakoshi N, et al. Prognostic impact of plaque echolucency in combination with inflammatory biomarkers on cardiovascular outcomes of coronary artery disease patients receiving optimal medical therapy. Atherosclerosis. 2011; 216: 120–124. doi: 10.1016/j.atherosclerosis.2011.01.048 21353222

20. Tomiyama H, Ishizu T, Kohro T, Matsumoto C, Higashi Y, Takase B, et al. Longitudinal association among endothelial function, arterial stiffness and subclinical organ damage in hypertension. Int J Cardiol. 2018; 253: 161–166. doi: 10.1016/j.ijcard.2017.11.022 29174285

21. Liu P, Wang H, Zhang F, Chen Y, Wang D, Wang Y. The effects of allopurinol on the carotid intima-media thickness in patients with type 2 diabetes and asymptomatic hyperuricemia: a three-year randomized parallel-controlled study. Intern Med. 2015; 54: 2129–2137. doi: 10.2169/internalmedicine.54.4310 26328636

22. Higgins P, Walters MR, Murray HM, McArthur K, McConnachie A, Lees KR, et al. Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial. Heart. 2014; 100: 1085–1092. doi: 10.1136/heartjnl-2014-305683 24790069

23. MacIsaac RL, Salatzki J, Higgins P, Walters MR, Padmanabhan S, Dominiczak AF, et al. Allopurinol and cardiovascular outcomes in adults with hypertension. Hypertension. 2016; 67: 535–540. doi: 10.1161/HYPERTENSIONAHA.115.06344 26865199

24. Kim SC, Schneeweiss S, Choudhry N, Liu J, Glynn RJ, Solomon DH. Effects of xanthine oxidase inhibitors on cardiovascular disease in patients with gout: a cohort study. Am J Med. 2015; 128: 653.e7–653.e16.

25. Cuenca JA, Balda J, Palacio A, Young L, Pillinger MH, Tamariz L. Febuxostat and cardiovascular events: a systematic review and meta-analysis. Int J Rheumatol. 2019; 2019: 1076189. doi: 10.1155/2019/1076189 30863448

26. Zhang M, Solomon DH, Desai RJ, Kang EH, Liu J, Neogi T, et al. Assessment of cardiovascular risk in older patients with gout initiating febuxostat versus allopurinol. Circulation. 2018; 138: 1116–1126. doi: 10.1161/CIRCULATIONAHA.118.033992 29899013

27. Yamanaka H, Japanese Society of Gout and Nucleic Acid Metabolism. Japanese guideline for the management of hyperuricemia and gout: second edition. Nucleosides Nucleotides Nucleic Acids. 2011; 30: 1018–1029. doi: 10.1080/15257770.2011.596496 22132951

28. Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castaneda-Sanabria J, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017; 76: 29–42. doi: 10.1136/annrheumdis-2016-209707 27457514

29. Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012; 64: 1431–1446.

30. Viggiano D, Gigliotti G, Vallone G, Giammarino A, Nigro M, Capasso G. Urate-lowering agents in asymptomatic hyperuricemia: role of urine sediment analysis and musculoskeletal ultrasound. Kidney Blood Press Res. 2018; 43: 606–615. doi: 10.1159/000489145 29689561

31. Kojima S, Matsui K, Hiramitsu S, Hisatome I, Waki M, Uchiyama K, et al. Febuxostat for cerebral and caRdiorenovascular events prEvEntion stuDy. Eur Heart J. 2019; 40: 1778–1786. doi: 10.1093/eurheartj/ehz119 30844048

32. Kimura K, Hosoya T, Uchida S, Inaba M, Makino H, Maruyama S, et al. Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: a randomized trial. Am J Kidney Dis. 2018; 72: 798–810. doi: 10.1053/j.ajkd.2018.06.028 30177485

33. Kokubo Y, Watanabe M, Higashiyama A, Nakao YM, Nakamura F, Miyamoto Y. Impact of intima-media thickness progression in the common carotid arteries on the risk of incident cardiovascular disease in the suita study. J Am Heart Assoc. 2018; 7.pii: e007720. doi: 10.1161/JAHA.117.007720 29858361

34. Versari D, Gossl M, Mannheim D, Daghini E, Galili O, Napoli C, et al. Hypertension and hypercholesterolemia differentially affect the function and structure of pig carotidartery. Hypertension. 2007; 50: 1063–1068. doi: 10.1161/HYPERTENSIONAHA.107.093260 17968002

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