Kitzman Dalane W, Voors Adriaan A, Mentz Robert J, Lewis Gregory D, Perl Shira, Myte Robin, Kaguthi Grace, Sjöström C David, Källgren Christian, Shah Sanjiv J
Department of Internal Medicine, Sections on Cardiovascular Medicine and Geriatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
University of Groningen, Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands.
JAMA Cardiol. 2024 Oct 1;9(10):892-900. doi: 10.1001/jamacardio.2024.2435.
Elevated serum uric acid (SUA) level may contribute to endothelial dysfunction; therefore, SUA is an attractive target for heart failure with preserved ejection fraction (HFpEF). However, to the authors' knowledge, no prior randomized clinical trials have evaluated SUA lowering in HFpEF.
To investigate the efficacy and safety of the novel urate transporter-1 inhibitor, verinurad, in patients with HFpEF and elevated SUA level.
DESIGN, SETTING, AND PARTICIPANTS: This was a phase 2, double-blind, randomized clinical trial (32-week duration) conducted from May 2020 to April 2022. The study took place at 59 centers in 12 countries and included patients 40 years and older with HFpEF and SUA level greater than 6 mg/dL. Data were analyzed from August 2022 to May 2024.
Eligible patients were randomized 1:1:1 to once-daily, oral verinurad, 12 mg, plus allopurinol, 300 mg; allopurinol, 300 mg, monotherapy; or placebo for 24 weeks after an 8-week titration period. Allopurinol was combined with verinurad to prevent verinurad-induced urate nephropathy, and the allopurinol monotherapy group was included to account for allopurinol effects in the combination therapy group. All patients received oral colchicine, 0.5 to 0.6 mg, daily for the first 12 weeks after randomization.
Key end points included changes from baseline to week 32 in peak oxygen uptake (VO2), Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), and SUA level; and safety/tolerability (including adjudicated cardiovascular events).
Among 159 randomized patients (53 per treatment group; median [IQR] age, 71 [40-86] years; 103 male [65%]) with median (IQR) N-terminal pro-brain natriuretic peptide level of 527 (239-1044) pg/mL and SUA level of 7.5 (6.6-8.4) mg/dL, verinurad plus allopurinol (mean change, -59.6%; 95% CI, -64.4% to -54.2%) lowered SUA level to a greater extent than allopurinol (mean change, -37.6%; 95% CI, -45.3% to -28.9%) or placebo (mean change, 0.8%; 95% CI, -11.8% to 15.2%; P < .001). Changes in peak VO2 (verinurad plus allopurinol, 0.27 mL/kg/min; 95% CI, -0.56 to 1.10 mL/kg/min; allopurinol, -0.17 mL/kg/min; 95% CI, -1.03 to 0.69 mL/kg/min; placebo, 0.37 mL/kg/min; 95% CI, -0.45 to 1.19 mL/kg/min) and KCCQ-TSS (verinurad plus allopurinol, 4.3; 95% CI, 0.3-8.3; allopurinol, 4.5; 95% CI, 0.3-8.6; placebo, 1.2; 95% CI, -3.0 to 5.3) were similar across groups. There were no adverse safety signals. Deaths or cardiovascular events occurred in 3 patients (5.7%) in the verinurad plus allopurinol group, 8 patients (15.1%) in the allopurinol monotherapy group, and 6 patients (11.3%) in the placebo group.
Results of this randomized clinical trial show that despite substantial SUA lowering, verinurad plus allopurinol did not result in a significant improvement in peak VO2 or symptoms compared with allopurinol monotherapy or placebo in HFpEF.
ClinicalTrials.gov Identifier: NCT04327024.
血清尿酸（SUA）水平升高可能导致内皮功能障碍；因此，SUA是射血分数保留的心力衰竭（HFpEF）的一个有吸引力的治疗靶点。然而，据作者所知，此前尚无随机临床试验评估降低SUA水平对HFpEF的影响。
研究新型尿酸转运蛋白-1抑制剂维立尿酸在SUA水平升高的HFpEF患者中的疗效和安全性。
设计、地点和参与者：这是一项2期双盲随机临床试验（为期32周），于2020年5月至2022年4月进行。该研究在12个国家的59个中心开展，纳入年龄40岁及以上、患有HFpEF且SUA水平高于6mg/dL的患者。数据于2022年8月至2024年5月进行分析。
符合条件的患者按1:1:1随机分组，分别接受每日一次口服维立尿酸12mg加别嘌醇300mg、别嘌醇300mg单药治疗或安慰剂治疗，为期24周，此前有8周的滴定期。别嘌醇与维立尿酸联合使用以预防维立尿酸引起的尿酸肾病，纳入别嘌醇单药治疗组以考量联合治疗组中别嘌醇的作用。所有患者在随机分组后的前12周每天口服秋水仙碱0.5至0.6mg。
主要终点包括从基线到第32周的峰值摄氧量（VO₂）、堪萨斯城心肌病问卷总症状评分（KCCQ-TSS）和SUA水平的变化；以及安全性/耐受性（包括判定的心血管事件）。
159例随机分组的患者（每组53例；年龄中位数[四分位间距]为71[40 - 86]岁；男性103例[65%]），N末端脑钠肽前体水平中位数（四分位间距）为527（239 - 1044）pg/mL，SUA水平为7.5（6.6 - 8.4）mg/dL，维立尿酸加别嘌醇组（平均变化，-59.6%；95%置信区间，-64.4%至-54.2%）降低SUA水平的幅度大于别嘌醇组（平均变化，-37.6%；95%置信区间，-45.3%至-28.9%）或安慰剂组（平均变化，0.8%；95%置信区间，-11.8%至15.2%；P < 0.001）。各组间峰值VO₂（维立尿酸加别嘌醇组，0.27mL/kg/min；95%置信区间，-0.56至1.10mL/kg/min；别嘌醇组，-0.17mL/kg/min；95%置信区间，-1.03至0.69mL/kg/min；安慰剂组，0.37mL/kg/min；95%置信区间，-0.45至1.19mL/kg/min）和KCCQ-TSS（维立尿酸加别嘌醇组，4.3；95%置信区间，0.3 - 8.3；别嘌醇组，4.5；95%置信区间，0.3 - 8. June 6；安慰剂组，1.2；95%置信区间，-3.0至5.3）的变化相似。未发现不良安全信号。维立尿酸加别嘌醇组有3例患者（5.7%）发生死亡或心血管事件，别嘌醇单药治疗组有8例患者（15.1%），安慰剂组有6例患者（11.3%）。
这项随机临床试验的结果表明，在HFpEF患者中，尽管维立尿酸加别嘌醇能大幅降低SUA水平，但与别嘌醇单药治疗或安慰剂相比，并未使峰值VO₂或症状得到显著改善。
ClinicalTrials.gov标识符：NCT04327024。
