The largest international trial to evaluate spironolactone in dialysis patients has definitively shown that the mineralocorticoid receptor antagonist does not reduce cardiovascular risk in this high-risk population, despite earlier promising signals from smaller studies. The ACHIEVE trial results, published in The Lancet and presented at the 62nd European Renal Association Congress, challenge previous hypotheses about the cardioprotective potential of aldosterone blockade in patients with kidney failure.
Trial Design and Patient Population
The ACHIEVE study enrolled 2,538 participants from 143 dialysis centers across 12 countries, making it the largest trial to date examining spironolactone in dialysis patients. All participants had been receiving dialysis for at least three months and were either over 45 years old or over 18 with diabetes. The trial began recruiting in 2018 and concluded in December 2024.
Of the 3,565 patients initially recruited, 2,532 patients were randomized after completing a seven-week open-label run-in phase that confirmed tolerability of spironolactone 25 mg daily. Participants were then assigned to receive either spironolactone or placebo with median follow-up designed to assess major cardiovascular outcomes.
Primary Outcome Results
The primary composite outcome of cardiovascular death or hospitalization for heart failure occurred in 20.5% of patients in the spironolactone group versus 21.6% in the placebo group, yielding a hazard ratio of 0.92 (95% CI, 0.78 to 1.09; P = .35). This difference was not statistically significant, indicating no cardiovascular benefit from spironolactone treatment.
Specifically, cardiovascular death or hospitalization for heart failure occurred in 258 patients in the spironolactone group compared to 276 in the placebo group. The trial was stopped early for futility after an independent monitoring committee determined there was little chance of seeing a meaningful benefit.
Safety Concerns and Secondary Outcomes
While spironolactone failed to demonstrate cardiovascular benefit, it significantly increased safety risks. Severe hyperkalemia occurred more frequently in the spironolactone group at 6.6% compared with 4.5% in the placebo group, representing a 44% increased risk (HR, 1.44; 95% CI, 1.03 to 2.01).
"This can be a serious safety concern in an already vulnerable group," noted principal investigator Michael Walsh, MD, of McMaster University and senior scientist at the Population Health Research Institute.
Rates of secondary outcomes—including cardiac death, vascular death, all-cause mortality, and all-cause hospitalizations—were also similar between groups. Sensitivity analyses, including per-protocol and expanded heart failure hospitalization definitions, produced similar findings.
Gender Differences Observed
The study noted a potential difference in cardiovascular events between men and women, although more research is needed to understand the underlying reasons. Among men, 163 events occurred in the spironolactone group versus 201 in the placebo group. However, among women, 95 events occurred in the spironolactone group compared to 75 in the placebo group.
Clinical Context and Rationale
The trial was designed based on strong biological rationale and encouraging preliminary data. "Aldosterone has been pretty heavily implicated, with a high risk ratio for those who have elevated aldosterone and, in fact, aldosterone is elevated in most dialysis patients," Walsh explained. "So it seemed like it would be a widespread target to be able to try and treat and in previous small studies, there was a very large signal for risk reduction of cardiovascular mortality, like up to 60% reduction in cardiovascular mortality probably too good to be believed, which is why we felt like we needed to do a large, high quality study."
In people with normal kidney function, spironolactone reduces cardiovascular events by blocking aldosterone, a hormone that causes heart remodeling, fibrosis, and raises cardiovascular risk. However, the ACHIEVE results demonstrate that people receiving dialysis do not respond the same way to treatments proven effective in the general population.
Implications for Clinical Practice
Heart disease remains the leading cause of death in the dialysis population, responsible for approximately 40% of all deaths among the estimated 2.5 million people worldwide who receive dialysis for kidney failure. The negative results from ACHIEVE represent a significant setback in the search for effective cardiovascular interventions in this vulnerable population.
"So far, very few interventions appear to actually be effective, so there's a lot of hope around any intervention that will actually reduce cardiovascular mortality," Walsh noted. "We really hoped that spironolactone could make a difference for people on dialysis. While the results are not what we wanted, they provide much-needed clarity. This study moves us one step closer to finding effective and safe treatments for a group that urgently needs them."
The ACHIEVE trial was funded by the Canadian Institutes of Health Research, Medical Research Future Fund, Health Research Council, British Heart Foundation, Population Health Research Institute, St. Joseph's Healthcare Hamilton, Accelerating Clinical Trials Canada, CanSOLVE CKD, and Dalhousie Department of Medicine.
