Verinurad Plus Allopurinol for Heart Failure With Preserved Ejection Fraction: The AMETHYST Randomized Clinical Trial.

IF 14.8 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

JAMA cardiology Pub Date : 2024-10-01 DOI:10.1001/jamacardio.2024.2435

Dalane W Kitzman, Adriaan A Voors, Robert J Mentz, Gregory D Lewis, Shira Perl, Robin Myte, Grace Kaguthi, C David Sjöström, Christian Källgren, Sanjiv J Shah

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引用次数: 0

Abstract

Importance: 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.

Objective: 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.

Interventions: 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.

Main outcomes and measures: 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).

Results: 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.

Conclusions and relevance: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT04327024.

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Verinurad 加别嘌呤醇治疗射血分数保留型心力衰竭：AMETHYST 随机临床试验。

重要性：血清尿酸（SUA）水平升高可能导致内皮功能障碍；因此，SUA 是射血分数保留型心力衰竭（HFpEF）的一个有吸引力的治疗目标。然而，据作者所知，此前还没有随机临床试验评估过在 HFpEF 中降低 SUA：研究新型尿酸盐转运体-1抑制剂verinurad对SUA水平升高的HFpEF患者的疗效和安全性：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 个中心进行，纳入了 40 岁及以上、患有高频心衰且 SUA 水平大于 6 mg/dL 的患者。数据分析时间为 2022 年 8 月至 2024 年 5 月：符合条件的患者按1:1:1的比例随机接受每日一次口服韦利诺12毫克加别嘌呤醇300毫克、别嘌呤醇300毫克单药或安慰剂治疗，经过8周的滴定期后再接受24周的治疗。别嘌呤醇与威利脲联合治疗可预防威利脲诱发的尿酸盐肾病，纳入别嘌呤醇单药治疗组是为了考虑联合治疗组中别嘌呤醇的影响。所有患者在随机分组后的头 12 周内每天口服 0.5 至 0.6 毫克秋水仙碱：主要终点包括峰值摄氧量（VO2）、堪萨斯城心肌病问卷症状总分（KCCQ-TSS）和SUA水平从基线到第32周的变化；以及安全性/耐受性（包括判定的心血管事件）：159 名随机患者（每个治疗组 53 人；中位数 [IQR] 年龄 71 [40-86] 岁；103 名男性 [65%]）的 N 端脑钠肽中位数（IQR）为 527 (239-1044) pg/mL，SUA 水平为 7.5 (6.6-8.4) mg/dL。4）毫克/分升，与别嘌醇（平均变化率为-37.6%；95% CI为-45.3%至-28.9%）或安慰剂（平均变化率为0.8%；95% CI为-11.8%至15.2%；P）相比，维利那联合别嘌醇（平均变化率为-59.6%；95% CI为-64.4%至-54.2%）可在更大程度上降低SUA水平：这项随机临床试验的结果表明，尽管SUA大幅降低，但与别嘌醇单药或安慰剂相比，verinurad联合别嘌醇并不能显著改善HFpEF患者的VO2峰值或症状：试验注册：ClinicalTrials.gov Identifier：试验注册：ClinicalTrials.gov Identifier：NCT04327024。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

JAMA cardiology Medicine-Cardiology and Cardiovascular Medicine

CiteScore

45.80

自引率

1.70%

发文量

264

期刊介绍： JAMA Cardiology, an international peer-reviewed journal, serves as the premier publication for clinical investigators, clinicians, and trainees in cardiovascular medicine worldwide. As a member of the JAMA Network, it aligns with a consortium of peer-reviewed general medical and specialty publications. Published online weekly, every Wednesday, and in 12 print/online issues annually, JAMA Cardiology attracts over 4.3 million annual article views and downloads. Research articles become freely accessible online 12 months post-publication without any author fees. Moreover, the online version is readily accessible to institutions in developing countries through the World Health Organization's HINARI program. Positioned at the intersection of clinical investigation, actionable clinical science, and clinical practice, JAMA Cardiology prioritizes traditional and evolving cardiovascular medicine, alongside evidence-based health policy. It places particular emphasis on health equity, especially when grounded in original science, as a top editorial priority.