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Randomized Controlled Trial
. 2025 Aug 16;406(10504):705-718.
doi: 10.1016/S0140-6736(25)01194-8.

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

Patrick Rossignol  1 , Faiez Zannad  2 , Ziad Massy  3 , Michel Azizi  4 , Fatima Chorfa  5 , Julien Coadic  6 , João Pedro Ferreira  7 , Francisca Saraiva  8 , Dominique Mottier  6 , Francis Guillemin  9 , Willy Ngueyon Sime  10 , Sanae Bouali  2 , Bénédicte Rossignol  2 , Joëlle Nortier  11 , Isabelle Simon  12 , Christophe Robino  13 , Manuela Davin  13 , Pierre M Bataille  14 , François Chantrel  15 , Nelly Castin  16 , Vincent Esnault  17 , Isabelle Kazes  18 , Thierry Hannedouche  19 , Nassim Kamar  20 , Jean-Michel Achard  21 , Caroline Fenerol  22 , Carine Achard-Hottelart  23 , Yves Dimitrov  24 , Nicolas Girerd  2 , Delphine Maucourt-Boulch  5 , Luc Frimat  25 ; ALCHEMIST study group
Collaborators, Affiliations
Randomized Controlled Trial

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

Patrick Rossignol et al. Lancet. .

Erratum in

  • Department of Error.
    [No authors listed] [No authors listed] Lancet. 2025 Oct 11;406(10512):1564. doi: 10.1016/S0140-6736(25)02058-6. Lancet. 2025. PMID: 41076294 No abstract available.

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.

Funding: French Ministry of Health.

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Conflict of interest statement

Declaration of interests PR and FZ report support for the present manuscript from the French Government since the initial planning of the work, paid to institution. ZM reports support from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp and Dohme-Chibret, Genzyme/Sanofi, Lilly, Otsuka, and Boehringer, paid to institution; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, GSK, and Boehringer, paid to charities. NK reports support from Merck Sharp and Dohme, paid to institution; personal consulting fees from Biotest, Bristol Myers Squibb, Chiesi, ExeVIR, Grifols, Hansa, MSD, Synklino, and Takeda; personal honoraria from Astellas, Biotest, Bristol Myers Squibb, CSL Behring, Chiesi, Gilead, Grifolis, Hansa, MSD, GlaxoSmithKline, Pierre Fabre, Medison, Neovii, New Bridge, Roche, Sanofi, Sandoz, and Takeda; personal support for meetings or travel from Astellas, Biotest, Bristol Myers Squibb, CSL Behring, Chiesi, Gilead, Grifols, Hansa, MSD, GlaxoSmithKline, Pierre Fabre, Medison, Neovii, New Bridge, Roche, Sanofi, Sandoz, and Takeda; personal payments for participation on a data safety monitoring board or advisory board from Alexion, Astellas, AstraZeneca, Biotest, Bristol Myers Squibb, Chiesi, ExeViR, Grifols, Hansa, MSD, Synklino, and Takeda; and royalties from UpToDate. MA reports funding from Novartis, Recor, and AstraZeneca, paid to institution; personal payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novo Nordisk and Servier; personal support for meetings or travel from Novartis; and personal consulting fees from AstraZeneca, Novartis, Alnylam, Medtronic, and Recor. JN reports funding from the Novartis Hospital Pharmacy in 2024 and from the Baxter Kidney Care Advisory Board 2024, paid to institution. JPF reports funding for research projects from Boehringer-Ingelheim, AstraZeneca, Novartis, Bial, Bayer, and Salamandra, paid to institution. FS reports grants from the Portuguese Foundation for Science and Technology, paid to institution. TH reports funding from the Agence de Biomédecine (French Biomedical Agency), paid to institution; personal consulting fees from AstraZeneca, Bayer, and Fresenius Medical Care; and honoraria for lectures and presentations from AstraZeneca, Bayer, Boehringer, Fresenius, Pfizer, Sanofi, and Vifor. NG reports personal consulting fees from AstraZeneca, Bayer, Boehringer, Lilly, Cardiostory, Novartis, Novo Nordisk, Roche Diagnostics, Echosens, and NP Medical; and personal support for meetings or travel from AstraZeneca, Bayer, Boehringer, Lilly, Novartis, Novo Nordisk, and NP Medical. PR reports personal consulting fees from AstraZeneca, Bayer, Boehringer-Ingelheim, Fresenius, Novartis, Novo Nordisk, Vera Therapeutics, and Vifor; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astra Zeneca, Bayer, Boehringer-Ingelheim, and Vifor; personal support for meetings or travel from AstraZeneca, Bayer, Boehringer-Ingelheim, Vera Therapeutics, and Vifor; personal payments for participation on a data safety monitoring board or advisory board from Bayer, Idorsia, and Sequana Medical; and stock options with G3P. FZ reports personal consulting fees from 89bio, Applied Therapeutics, Bayer, Betagenon, Biopeutics, Boehringer, Cardior, Cellprothera, Cereno, Corteria, CVRx, Merck, Northsea, Otsuka, Owkin, Ribocure, and Salubris; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Boehringer, CVRx, Lupin, Merck, and Viatris; personal payments for participation on a data safety monitoring board or advisory board from Merck; stock options with Cereno Pharmaceutical; and is the founder and owner of the CardioVascular Clinical Trialists Forum. LF reports honoraria for lectures and presentations from Vifor; was President of the Société Francophone de Néphrologie Dialyse et Transplantation from October, 2021, to September, 2023; and reports funding from Astellas for the acquisition of computers for his nephrology department, paid to institution. All other authors declare no competing interests.

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