Optimal uric acid levels by febuxostat treatment and cerebral, cardiorenovascular risks: post hoc analysis of a randomized controlled trial
Authors: Kojima Sunao , Uchiyama Kazuaki , Yokota Naoto , Tokutake Eiichi , Wakasa Yutaka , Hiramitsu Shinya , Waki Masako , Jinnouchi Hideaki , Kakuda Hirokazu , Hayashi Takahiro , Kawai Naoki , Sugawara Masahiro , Mori Hisao , Tsujita Kenichi , Matsui Kunihiko , Hisatome Ichiro , Ohya Yusuke , Kimura Kazuo , Saito Yoshihiko , Ogawa Hisao ,   the Febuxostat for Cerebral and Cardiorenovascular Events Prevention Study (FREED) investigators, Maeda Itaru , Matsui Hiroki , Okamoto Toshiya , Omiya Hideaki , Takeda Fumihiko , Takeda Hiroki , Suzuki Yasushi , Shimasaki Tomoji , Kaneko Chikako , Yamaki Mario , Naganuma Fumio , Nakano Masayuki , Maki Takeshi , Enomoto Nobuyuki , Hogi Toshibumi , Kanouzawa Kouichi , Okuaki Yasushi , Shibuya Tomoyuki , Tokutake Eiichi , Yanagisawa Masatoshi , Asano Tetsuichi , Akahata Masaki , Baba Takao , Harada Yoshiaki , Ichihara Atsuhiro , Kobayashi Yukinobu , Kurumatani Hitoshi , Miyahara Masaki , Moritani Shigeki , Ohno Kunihiko , Okuda Takeshi , Osamura Yoshiaki , Otaki Masayuki , Sugawara Masahiro , Sudo Hideaki , Taguchi Kazumi , Tominaga Shukuko , Watanabe Himasatotoshi , Yuuya Kirino , Chin Keiichi , Etsuda Hirokuni , Hatori Nobuo , Iroden Kumio , Kamegaya Yoshitaka , Kikuchi Hideki , Kimura Kazuo , Mori Hisao , Nagasu Takao , Nakayama Riichirou , Nishimura Masato , Ori Masahisa , Tani Kenji , Yamamoto Hareaki , Yamagami Jun , Yuasa Shohei , Uchiyama Kazuaki , Maeda Kazuo , Hayakawa Hiroyuki , Kakuda Hirokazu , Nakano Shigeru , Tatsumura Toshiki , Wakasa Yutaka , Yanagi Masayuki , Kuroda Masahiko , Kawade Yasuhiko , Kawai Naoki , Kumazaki Toshihide , Miwa Yoshiyuki , Noda Yoshiki , Sagoh Masachika , Sasaki Minoru , Takai Kuniyuki , Takeda Tomoo , Totani Rieko , Yoshida Reiki , Harada Masaki , Waki Masako , Waki Riichiro , Arakawa Tomoharu , Hiramitsu Shinya , Ogawa Takuo , Okamoto Shinya , Isoda Tsugio , Masuda Izuru , Takenaka Ken , Akioka Kaname , Hayashi Takahiro , Ikeda Kazuo , Kanazawa Hidetaka , Kinugawa Toru , Kitano Shoichi , Kubota Yoshiko , Kurihara Yojiro , Matsuo Miyuki , Matsushita Masayuki , Nishimura Hiroshi , Seo Toshihiko , Watanabe Masahiro , Arao Jun , Katsuya Tomohiro , Kusunose Naotaka , Nakatani Yuji , Nozaki Akira , Ote Nobushige , Samejima Kenichi , Shigenobu Kazuya , Ayame Hideo , Matsuda Shoshi , Fujimoto Takashi , Honda Soichi , Oka Nobuaki , Ota Akira , Tanaka Osame , Matsuoka Nobuo , Matsumoto Kengo , Matsuno Toshifumi , Yoshida Katsumi , Maruyoshi Hidetomo , Goto Seiichi , Hanaoka Youichi , Otonari Takatoshi , Takaki Koji , Tohaya Masahiro , Yoshida Tetsuro , Honjo Koji , Jinnouchi Hideaki , Kan Hirofumi , Kojima Shinobu , Maki Akira , Matsunaga Toshiro , Matsuo Shuichi , Miyagi Hiroo , Omori Kunihiro , Otsuka Eiji , Toihata Masamitsu , Tsujita Kenichi , Eto Takuma , Kawano Shuichi , Miyata Jyunichi , Yokota Naoto , Oya Yusuke , Kojima Sunao , Uchiyama Kazuaki , Yokota Naoto , Tokutake Eiichi , Wakasa Yutaka , Hiramitsu Shinya , Waki Masako , Jinnouchi Hideaki , Kakuda Hirokazu , Hayashi Takahiro , Kawai Naoki , Sugawara Masahiro , Mori Hisao , Hisatome Ichiro , Ohya Yusuke , Kimura Kazuo , Saito Yoshihiko , Ogawa Hisao , Ogata Yasuhiro , Yasuda Satoru , Yonehara Toshiro , Yoshimura Michihiro , Matsui Kunihiko , Hashimoto Yoichiro , Fujimoto Kazuteru , Sakamoto Tomohiro , Uekihara Soichi 
Published: October 2021

Abstract

Objectives
Hyperuricaemia is recognized as an independent risk marker for cardiovascular and renal diseases. However, uric acid is a powerful free-radical scavenger, and the optimal level of serum uric acid (SUA) determining outcomes is unknown. This study explored whether interventional treatments for excessive SUA reduction were harmful and what constituted the optimal lowering of SUA levels for the prevention of events in patients with asymptomatic hyperuricaemia.

Methods
This was a post hoc analysis of a randomized trial (Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy [FREED]) in which 1070 older patients with asymptomatic hyperuricaemia were enrolled and allocated to febuxostat (n = 537) or non-febuxostat treatment group (n = 533). We assessed the relationship between the endpoint (withdrawal or study completion) SUA levels and clinical outcomes. Primary endpoint was defined as a composite of all-cause mortality, cerebral and cardiorenovascular events.

Results
In the febuxostat group, patients achieving SUA levels ≤4 mg/dl (hazard ratio: 2.01 [95% CI: 1.05, 3.87]), &gt;4 to ≤5 mg/dl (2.12 [1.07, 4.20], &gt;6 to ≤7 mg/dl (2.42 [1.05, 5.60]), and &gt;7 mg/dl (4.73 [2.13, 10.5]) had significantly higher risks for a primary composite event than those achieving SUA levels &gt;5 to ≤6 mg/dl (P = 0.003 [log-rank test]). This J-shaped relationship applied to patients with renal impairment (P = 0.007 [Gray’s test]) and was not significant in the non-febuxostat treatment group (P = 0.212 [log-rank test]).

Conclusion
Optimal SUA level by febuxostat treatment is 5–6 mg/dl for reducing all-cause mortality, cerebral, cardiovascular and renal events. Excessive SUA reduction may be harmful in older hyperuricaemic populations.

Trial Registration
ClinicalTrial.gov, https://clinicaltrials.gov, NCT01984749