近日，加拿大安大略省圣约瑟夫医院Michael Walsh团队比较了接受维持性透析的患者中使用螺内酯与安慰剂的疗效。2025年8月16日出版的《柳叶刀》杂志发表了这项成果。

目前还没有确切的药物治疗可以改善慢性血液透析肾衰竭患者的心血管预后。该研究旨在分析甾体矿物皮质激素受体拮抗剂螺内酯对心血管事件高危血液透析患者心血管结局的影响。

ALCHEMIST是一项研究者发起的、多中心、双盲、随机、安慰剂对照、事件驱动的试验，在法国、比利时和摩纳哥的64所大学医院、综合医院和非营利或私人诊所透析中心进行。年龄在18岁及以上的慢性血液透析肾衰竭患者至少有一种心血管合并症或危险因素，他们被纳入一个为期4周的训练期，每隔一天口服25mg的开放标签口服螺内酯。参与者被随机分配（1:1）到口服螺内酯滴定至每天25毫克或安慰剂。随机化序列由计算机生成，并由中心按4或6个分组分层，并在每个分组内排列处理。随机分配是双盲的。主要终点是发生首次重大心血管不良事件（心血管死亡、非致死性心肌梗死、急性冠状动脉综合征、中风或因心力衰竭住院）的时间，并在意向治疗人群中进行分析。研究组还对血液透析患者中矿皮质激素受体拮抗剂的双盲随机对照试验进行了更新的荟萃分析，并纳入了ALCHEMIST的数据。

2013年6月13日至2020年11月24日期间，1442名患者在当地进行了合格筛选。823名患者纳入试验，794名患者进入磨合期。644名患者被随机分配到螺内酯组（n=320）或安慰剂组（n=324）。男性444例（69%），女性200例（31%）。由于缺乏发起人的资助，该试验过早停止。中位随访32.6个月（IQR 17.3 ~ 48.4）。主要终点发生在螺内酯组320例患者中的78例（24%）（每100患者年10.66例）和安慰剂组324例患者中的79例（24%）（每100患者年10.70例）[8.59 - 13.35]；风险比[HR] 1·00；p = 0·98)。螺内酯组135例（42%）和安慰剂组134例（41%）患者报告高钾血症高于6 mmol/L （HR 1.12）。在荟萃分析中，矿皮质激素受体拮抗剂没有降低全因或心血管死亡率或非致死性心血管事件，也没有增加高钾血症事件（血清钾浓度>；6 mmol/L）的几率。

研究结果表明，在血液透析肾衰竭和心血管不良结局高风险的患者中，螺内酯不能降低重大心血管事件的发生率。最新的荟萃分析显示，矿皮质激素受体拮抗剂并不能降低全因死亡率或心血管死亡率。因此，现有证据不支持在这种情况下超说明书使用螺内酯。

附：英文原文

Title: Spironolactone in patients on chronic haemodialysis at high risk of adverse cardiovascular outcomes (ALCHEMIST): a multicentre, double-blind, randomised, placebo-controlled trial and updated meta-analysis

Author: Patrick Rossignol, Faiez Zannad, Ziad Massy, Michel Azizi, Fatima Chorfa, Julien Coadic, Joo Pedro Ferreira, Francisca Saraiva, Dominique Mottier, Francis Guillemin, Willy Ngueyon Sime, Sanae Bouali, Bénédicte Rossignol, Jolle Nortier, Isabelle Simon, Christophe Robino, Manuela Davin, Pierre M Bataille, Franois Chantrel, Nelly Castin, Vincent Esnault, Isabelle Kazes, Thierry Hannedouche, Nassim Kamar, Jean-Michel Achard, Caroline Fenerol, Carine Achard-Hottelart, Yves Dimitrov, Nicolas Girerd, Delphine Maucourt-Boulch, Luc Frimat, Jean-Michel Achard, Carine Achard Hottelart, Didier Aguilera, Asma Alla, Vincent Allot, Mahmoud Allouache, Walid Arkouche, Michel Azizi, Daniela Babici, Nolwenn Bacle-Rabot, Jean-Louis Bacri, Aurore Barthelemy, Grégoire Basse, Pierre Bataille, Stanislas Bataille, Dorothée Bazin-Kara, Clémence Bechade, Stefanie Beier, Larbi Bencheikh, Jean-Christophe Bendini, Valérie Betz, Pascal Bindi, Béatrice Birmele, Vincent Bisaccia, Laurène Blacher, Frédérique Bocquentin, Claire Borni Duval, Alexandra Botte, Sanae Bouali, Julien Bouet, Rehouni Boulahrouz, Franck Bourdon, Antoine Braconnier, Philippe Brunet, Flora Brunner, Thanh Cao-Huu, Claire Cartery, Nelly Castin, Etienne Cellot, Jean-Marc Chalopin, Jacques Chanliau, Franois Chantrel, Marion Chapal, Christophe Charasse, Emmanuelle Charlin, Vianney Charpy, Fatima Chorfa, Gabriel Choukroun, Pierre Clavel, Julien Coadic, Jean-Marie Coulibaly, Grégoire Couvrat-Desvergnes, Jolle Cridlig, Romain Crochette

Issue&Volume: 2025/08/16

Abstract:

Background

No pharmacological therapy has been shown with certainty to improve the cardiovascular prognosis in patients with kidney failure on chronic haemodialysis. We aimed to investigate the effects of the steroidal mineralocorticoid receptor antagonist spironolactone on cardiovascular outcomes in patients on haemodialysis who are at high risk of cardiovascular events.

Methods

ALCHEMIST was an investigator-initiated, multicentre, double-blind, randomised, placebo-controlled, event-driven trial conducted at 64 university hospitals, general hospitals, and non-profit or private practice dialysis centres in France, Belgium, and Monaco. Adult patients aged 18 years and older with kidney failure on chronic haemodialysis with at least one cardiovascular comorbidity or risk factor were enrolled into a 4-week run-in period on open-label oral spironolactone 25 mg every other day. Participants were randomly assigned (1:1) to oral spironolactone titrated to 25 mg per day or placebo. The randomisation sequence was computer generated and stratified by centre in blocks of 4 or 6, and permutation of treatments within each block. The random assignment was double-blinded. The primary endpoint was time to first major adverse cardiovascular event (cardiovascular death, non-fatal myocardial infarction, acute coronary syndrome, stroke, or hospitalisation for heart failure) and was analysed in the intention-to-treat population. We also performed an updated meta-analysis of double-blind, randomised controlled trials of mineralocorticoid receptor antagonists in patients on haemodialysis incorporating data from ALCHEMIST. The study was registered with ClinicalTrials.gov, NCT01848639.

Findings

Between June 13, 2013, and Nov 24, 2020, 1442 patients were locally screened for eligibility. 823 patients were included in the trial and 794 entered the run-in period. 644 patients were randomly assigned to spironolactone (n=320) or placebo (n=324). 444 (69%) patients were men and 200 (31%) were women. The trial was stopped prematurely due to lack of funding from the sponsor. Median follow-up was 32·6 months (IQR 17·3–48·4). The primary endpoint occurred in 78 (24%) of 320 patients in the spironolactone group (10·66 per 100 patient-years [95% CI 8·54–13·31]) and 79 (24%) of 324 patients in the placebo group (10·70 per 100 patient-years [8·59–13·35]; hazard ratio [HR] 1·00 [95% CI 0·73–1·36]; p=0·98). Hyperkalaemia above 6 mmol/L was reported in 135 (42%) patients in the spironolactone group and 134 (41%) in the placebo group (HR 1·12 [95% CI 0·88–1·43]). In the meta-analysis, mineralocorticoid receptor antagonists did not reduce all-cause or cardiovascular mortality or non-fatal cardiovascular events and did not increase the odds of hyperkalaemia events (serum potassium concentration >6 mmol/L).

Interpretation

In patients with kidney failure on haemodialysis and with high risk of adverse cardiovascular outcomes, spironolactone did not reduce the incidence of major cardiovascular events. The updated meta-analysis shows that mineralocorticoid receptor antagonists did not reduce all-cause or cardiovascular mortality. Therefore, off-label use of spironolactone in this setting is not supported by available evidence.

DOI: 10.1016/S0140-6736(25)01194-8

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01194-8/abstract