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Special Issue: Current evidence and perspectives for hypertension management in Asia

Differential effect of a xanthine oxidase inhibitor on arterial stiffness and carotid atherosclerosis: a subanalysis of the PRIZE study

Hypertension Research volume 45, pages 602–611 (2022)Cite this article

Abstract

Atherosclerosis and arterial stiffness are phenotypes of atherosclerotic vascular damage. Atherosclerosis originates from endothelial vascular damage and forms focal morphological lesions; arterial stiffness originates from diffuse medial-layer damage in the arterial tree. Thus, the two phenomena reflect different facets of atherosclerotic vascular damage, and they both gradually progress. We conducted a subanalysis to compare the long-term effects of febuxostat on atherosclerosis and arterial stiffness in the PRIZE study (a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial to examine the effect of febuxostat on carotid atherosclerosis). Among 514 study participants, arterial stiffness parameters (brachial-ankle pulse wave velocity or cardio-ankle vascular index) were obtained at baseline, 12 months, and 24 months in 100 subjects. Among them, 48 subjects were allocated to the control group (i.e., nonpharmacological lifestyle modification for hyperuricemia), and 52 subjects were allocated to the febuxostat treatment group. While the decrease in serum uric acid was greater in the febuxostat group than in the control group, the adjusted percentage decrease in arterial stiffness parameters at month 24 was greater in the febuxostat group than in the control group, with a mean between-group difference (febuxostat − control) of −5.099% (95% confidence interval (CI) −10.009% to −0.188%, p = 0.042). Thus, long-term treatment with febuxostat may exert beneficial effects on arterial stiffness without improving carotid atherosclerosis. A long-term study to examine the effect of febuxostat on cardiovascular outcomes related to increased arterial stiffness is warranted.

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Acknowledgements

The authors thank the members of the Data and Safety Monitoring Board (Hiroyuki Daida, MD, PhD (Juntendo University Graduate School of Medicine, Tokyo, Japan); Junya Ako, MD, PhD, (Kitasato University School of Medicine, Sagamihara, Japan); Kazuo Kitagawa, MD, PhD (Tokyo Women’s Medical University, Tokyo, Japan)) and the Clinical Events Committee (Wataru Shimizu, MD, PhD (Nippon Medical School, Tokyo, Japan); Yoshio Kobayashi, MD, PhD (Chiba University Graduate School of Medicine, Chiba, Japan) and Masaharu Ishihara (Hyogo College of Medicine, Nishinomiya, Japan)). We also thank Yasunori Sato, PhD (Keio University School of Medicine, Tokyo, Japan), and Shusuke Tani, PhD (Nouvelle Place Inc., Tokyo, Japan), for their statistical support, and we thank Mikiko Kagiyama (Saga University, Saga, Japan) and Itsuka Suzuki (Nouvelle Place Inc., Tokyo, Japan) for secretarial assistance.

Author contributions

All authors helped conceptualize this trial. KS and HT wrote the draft of the article. HY performed statistical analysis. All authors confirmed the data collection and study selection criteria. All authors enrolled patients and performed study quality assessment. All authors approved the final version of the manuscript.

Funding

This work was funded by Teijin Pharma Limited, Japan (to KN). The funder of the trial had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

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Authors and Affiliations

  1. Department of Cardiology, Tokyo Medical University, Tokyo, Japan

    Kazuki Shiina & Hirofumi Tomiyama

  2. Department of Cardiovascular Medicine, Saga University, Saga, Japan

    Atsushi Tanaka & Koichi Node

  3. Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan

    Hisako Yoshida

  4. Department of General Internal Medicine, Saitama Red Cross Hospital, Saitama, Japan

    Kazuo Eguchi

  5. Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan

    Kazuomi Kario

  6. Department of Clinical Research, National Hospital Organization, Tochigi Medical Center, Utsunomiya, Japan

    Toru Kato

  7. Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima, Japan

    Hiroki Teragawa

  8. Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan

    Shigeru Toyoda

  9. Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan

    Mitsuru Ohishi

  10. Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan

    Yoshihiro Fukumoto

  11. Department of Intensive Care Medicine, National Defense Medical College, Tokorozawa, Japan

    Bonpei Takase

  12. Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Tomoko Ishizu

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  1. Kazuki Shiina
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the PRIZE Study Investigators

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Correspondence to Kazuki Shiina.

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Conflict of interest

KS and HT were supported by Omron, Asahi Calpis Wellness and Teijin Pharma. AT has received honoraria from Boehringer Ingelheim and research funding from GlaxoSmithKline. KK received significant research grants from Teijin Pharma and Fukuda Denshi. HT has received honoraria from Abbott Medical Japan, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Kowa, Ono, Mitsubishi Tanabe, and Takeda. YF has received research grants from Sanofi KK and Shionogi & Co. Ltd; honoraria from the Public Health Research Foundation, AstraZeneca KK, Eisai Co. Ltd, and Kowa Pharmaceutical Co Ltd; and research grants and honoraria from MSD KK, Otsuka Pharmaceutical Co Ltd, Daiichi Sankyo Co Ltd, Sumitomo Dainippon Pharma Co Ltd, Teijin Pharma Ltd, Bayer Yakuhin, Ltd, Mochida Pharmaceutical Co Ltd, Astellas Pharma Inc., Sanwa Kagaku Kenkyusho Co Ltd, Takeda Pharmaceutical Co Ltd, Mitsubishi Tanabe Pharma Corp, Pfizer Japan Inc., Ono Pharmaceutical Co Ltd, and AstraZeneca KK. TI has received research grants from Ono, Daiichi Sankyo, and Teijin; has carried out joint research with Canon Medical systems and PIA; and is an employee of Tsukuba Echo Core Laboratory. KN has received honoraria from MSD, Astella, AstraZeneca, Novartis Pharma, Ono Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Eli Lilly Japan, Boehringer Ingelheim Japan, and Takeda Pharmaceutical; research grants from Asahi Kasei, Astellas, Mitsubishi Tanabe Pharma, Teijin Pharma, Terumo, Boehringer Ingelheim Japan, Eli Lilly and Company, Mochida Pharmaceutical, and Fuji Yakuhin; and scholarships from Daiichi Sankyo Healthcare, Teijin Pharma, Medtronic, and Bayer Yakuhin.

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Shiina, K., Tomiyama, H., Tanaka, A. et al. Differential effect of a xanthine oxidase inhibitor on arterial stiffness and carotid atherosclerosis: a subanalysis of the PRIZE study. Hypertens Res 45, 602–611 (2022). https://doi.org/10.1038/s41440-022-00857-9

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