To date, no pharmacologic therapies have been proven to improve the cardiovascular prognosis of individuals with kidney failure requiring chronic hemodialysis. To address this gap, Patrick Rossignol, MD, PhD, and colleagues examined the effects of spironolactone, a steroidal mineralocorticoid receptor antagonist, on cardiovascular outcomes among patients receiving chronic hemodialysis at high risk for cardiovascular events.
The study (ALCHEMIST) was an investigator-initiated, multicenter, double-blind, randomized, placebo-controlled, event-driven trial. ALCHEMIST was conducted at 64 academic hospitals, general hospitals, and nonprofit or private practice dialysis centers in France, Belgium, and Monaco. Patients were eligible to enroll if they were 18 years of age or older and had kidney failure requiring chronic hemodialysis and at least one cardiovascular comorbidity or risk factor.
The study began with a 4-week run-in period, with participants receiving open-label oral spironolactone 25 mg every other day. Participants were then randomly assigned 1:1 to receive oral spironolactone, titrated to 25 mg per day, or placebo. The primary end point of interest was time to first major adverse cardiovascular event, defined as cardiovascular death, nonfatal myocardial infarction, acute coronary syndrome, stroke, or hospitalization for heart failure.
The researchers analyzed the end point among the intention-to-treat population. In addition, they incorporated data from ALCHEMIST into a meta-analysis of double-blind, randomized controlled trials of mineralocorticoid receptor antagonists among patients receiving chronic hemodialysis.
A total of 794 patients entered the run-in period. Of those, 320 patients were randomly assigned to spironolactone, and 324, to placebo. Due to a lack of funding from the sponsor, the trial was stopped prematurely. Median follow-up was 32.6 months.
In the spironolactone group, the primary end point occurred in 24% (n=78) of the patients, compared with 24% (n=79) of patients in the placebo group (hazard ratio [HR]1.00; 95% CI, 0.73-1.36; P=0.98). In the spironolactone group, hyperkalemia (potassium concentration >6 mmol/L) was reported in 42% (n=135) of patients, compared with 41% (n=134) in the placebo group (HR, 1.12; 95% CI, 0.88-1.43).
Results of the meta-analysis suggest that there was no reduction in all-cause or cardiovascular mortality of nonfatal cardiovascular events associated with mineralocorticoid receptor antagonists and no increase in the odds of hyperkalemia events (serum potassium concentration >6 mmol/L) associated with mineralocorticoid receptor antagonists.
In summary, the authors said, “In patients with kidney failure on hemodialysis 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 the setting is not supported by available evidence.”
