Background and Disease Burden
Chronic kidney failure requiring haemodialysis represents a significant global health burden, with a markedly increased risk of cardiovascular morbidity and mortality. Cardiovascular disease (CVD) remains the leading cause of death among patients on chronic haemodialysis, accounting for approximately 40-50% of fatalities. Despite this high risk, effective pharmacological strategies to improve cardiovascular prognosis in this population remain elusive. Mineralocorticoid receptor antagonists (MRAs), such as spironolactone, have shown cardiovascular benefit in heart failure populations without kidney failure, exerting anti-fibrotic, anti-inflammatory, and hemodynamic effects. However, their efficacy and safety in the dialysis setting have not been definitively established due to concerns about hyperkalaemia and limited robust clinical trial data. The ALCHEMIST trial was specifically designed to explore whether spironolactone could reduce adverse cardiovascular events in haemodialysis patients at high cardiovascular risk, addressing this critical unmet therapeutic need.
Study Design
ALCHEMIST was an investigator-initiated, multicentre, double-blind, randomised, placebo-controlled, event-driven trial conducted across 64 centres in France, Belgium, and Monaco. The trial enrolled adult patients aged 18 years and older undergoing chronic haemodialysis who had at least one cardiovascular comorbidity or risk factor. The study began with a 4-week run-in period during which participants received open-label spironolactone 25 mg every other day to assess tolerability. Subsequently, patients were randomised 1:1 to receive oral spironolactone titrated up to 25 mg daily or placebo. Randomisation was computer-generated and stratified by centre with block sizes of 4 or 6, ensuring allocation concealment and double-blinding.
The primary endpoint was the time to first major adverse cardiovascular event (MACE), defined as cardiovascular death, non-fatal myocardial infarction, acute coronary syndrome, stroke, or hospitalisation for heart failure. Analysis followed the intention-to-treat principle. Additionally, the investigators conducted an updated meta-analysis of double-blind randomised controlled trials (RCTs) evaluating MRAs in haemodialysis patients, incorporating the ALCHEMIST data.
Key Findings
Between June 2013 and November 2020, 1442 patients were screened; 823 were included and 794 entered the run-in phase. Ultimately, 644 patients were randomised: 320 to spironolactone and 324 to placebo. The cohort was predominantly male (69%) with 31% female participants. Median follow-up was 32.6 months (IQR 17.3-48.4), although the trial was stopped prematurely due to sponsor funding cessation.
Primary Endpoint Outcomes:
– The primary MACE occurred in 78 patients (24%) receiving spironolactone versus 79 patients (24%) receiving placebo.
– Event rates per 100 patient-years were nearly identical: 10.66 (95% CI 8.54-13.31) for spironolactone and 10.70 (8.59-13.35) for placebo.
– Hazard ratio (HR) was 1.00 (95% CI 0.73-1.36; p=0.98), indicating no difference in risk.
Safety Findings:
– Hyperkalaemia (serum potassium >6 mmol/L) was reported in 42% of the spironolactone group and 41% of the placebo group (HR 1.12; 95% CI 0.88-1.43), suggesting no significant increase attributable to spironolactone.
Meta-Analysis Results:
– Pooled analyses did not demonstrate a reduction in all-cause or cardiovascular mortality or non-fatal cardiovascular events with MRAs in haemodialysis populations.
– Incidence of hyperkalaemia events was not significantly higher in MRA-treated patients compared with controls.
Expert Commentary
The ALCHEMIST trial provides robust, though somewhat limited by premature termination, evidence that spironolactone does not confer cardiovascular protection in haemodialysis patients at high cardiovascular risk. The parity in event rates between treatment and placebo groups suggests the complex pathophysiology of cardiovascular disease in kidney failure may not be sufficiently modulated by MRAs alone or at this dose. Moreover, the elevated baseline hyperkalaemia incidence complicates interpretation of safety signals.
This trial contrasts with smaller and less definitive studies that hinted at potential benefits and concerns for increased hyperkalaemia. The updated meta-analysis incorporated these data and strengthens the conclusion that MRAs do not improve survival or reduce cardiovascular events in haemodialysis, challenging prior assumptions and the rationale for off-label use in this context.
Limitations include premature study cessation that may have underpowered detection of smaller effects, and relatively moderate dosing of spironolactone, which some argue might insufficiently block mineralocorticoid receptors in this population. Nevertheless, the consistency of null findings argues against substantial clinical benefit.
These findings underscore the need for novel therapeutic strategies targeting cardiovascular risk in kidney failure beyond conventional neurohormonal modulation.
Conclusion
The ALCHEMIST trial and subsequent meta-analysis conclude that spironolactone, a steroidal mineralocorticoid receptor antagonist, does not reduce major adverse cardiovascular events or mortality in patients with end-stage kidney disease on chronic haemodialysis who are at high cardiovascular risk. Importantly, there was no significant increase in hyperkalaemia attributable to spironolactone. The evidence now advises against the off-label use of spironolactone for cardiovascular protection in this vulnerable population. Clinicians should prioritize established therapies and await future research to define effective cardiovascular risk reduction measures in patients on haemodialysis.
References
Rossignol P, Zannad F, Massy Z, Azizi M, Chorfa F, Coadic J, Ferreira JP, Saraiva F, Mottier D, Guillemin F, Ngueyon Sime W, et al. 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. Lancet. 2025 Aug 16;406(10504):705-718. doi: 10.1016/S0140-6736(25)01194-8. PMID: 40818851.
ClinicalTrials.gov Identifier: NCT01848639