Sunao Kojima1, Kazuaki Uchiyama2, Naoto Yokota3, Eiichi Tokutake4, Yutaka Wakasa5, Shinya Hiramitsu6, Masako Waki7, Hideaki Jinnouchi8, Hirokazu Kakuda9, Takahiro Hayashi10, Naoki Kawai11, Masahiro Sugawara12, Hisao Mori13, Kenichi Tsujita14, Kunihiko Matsui15, Ichiro Hisatome16, Yusuke Ohya17, Kazuo Kimura18, Yoshihiko Saito19, Hisao Ogawa20. 1. Department of Internal Medicine, Sakurajyuji Yatsushiro Rehabilitation Hospital, Yatsushiro. 2. Uchiyama Clinic, Yoshikawa-ku, Joetsu. 3. Yokota Naika, Hanagashima-cho, Miyazaki. 4. Tokutake Iin, Kawaguchi. 5. Wakasa Medical Clinic, Kanazawa. 6. Hiramitsu Heart Clinic, Nagoya. 7. Shizuoka City Shizuoka Hospital, Shizuoka. 8. Jinnouchi Hospital Diabetes Care Center, Kumamoto. 9. Kakuda Iin, Takamatsu, Kahoku. 10. Hayashi Medical Clinic, Sakai. 11. Kawai Naika Clinic, Gifu. 12. Sugawara Clinic, Nerima-ku. 13. Fuji Health Promotion Center, Fuji. 14. Department of Cardiovascular Medicine, Kumamoto University, Kumamoto. 15. Department of Family, Community and General Medicine, Kumamoto University Hospital, Kumamoto. 16. Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, Yonago. 17. Department of Cardiovascular Medicine, Nephrology and Neurology, University of the Ryukyus School of Medicine, Okinawa. 18. Division of Cardiology, Yokohama City University Medical Center, Yokohama. 19. Department of Cardiovascular Medicine, Nara Medical University, Kashihara. 20. Kumamoto University, Kumamoto, Japan.
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]), >4 to ≤5 mg/dl (2.12 [1.07, 4.20], >6 to ≤7 mg/dl (2.42 [1.05, 5.60]), and >7 mg/dl (4.73 [2.13, 10.5]) had significantly higher risks for a primary composite event than those achieving SUA levels >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.
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]), >4 to ≤5 mg/dl (2.12 [1.07, 4.20], >6 to ≤7 mg/dl (2.42 [1.05, 5.60]), and >7 mg/dl (4.73 [2.13, 10.5]) had significantly higher risks for a primary composite event than those achieving SUA levels >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.