What is the clinical evidence from this study?

Study design: RCT. Population: Severe heart failure (n=1658). Intervention: Spironolactone vs. Placebo. Primary outcome: Death associated with worsening renal function (HR 1.1, 95% CI 0.79-1.5, p=0.009).

What question did this study set out to answer?

The study aims to evaluate how baseline and worsening renal function affect the efficacy of spironolactone in patients with severe heart failure.

May 18, 2026

Influence of Baseline and Worsening Renal Function on Efficacy of Spironolactone in Patients With Severe Heart Failure

Key Result

Spironolactone maintained its mortality benefit in severe heart failure despite worsening renal function, which increased death risk in placebo (HR 1.9) but not spironolactone (HR 1.1; p-int=0.009).

Key Points

The study aims to evaluate how baseline and worsening renal function affect the efficacy of spironolactone in patients with severe heart failure.
Data was drawn from the RALES trial involving 1,658 patients with heart failure defined by NYHA class III or IV and ejection fraction <35%.
Patients were randomized to either spironolactone at varying doses or placebo and monitored for changes in renal function quantified by eGFR.
Worsening renal function was identified by a 30% drop in eGFR over 12 weeks post-randomization.
Patients with reduced baseline eGFR showed a 10.3% absolute risk reduction in all-cause death compared to 6.4% in those with baseline eGFR >60 ml/min/1.73 m².
Worsening renal function occurred in 17% of the spironolactone group versus 7% in the placebo group (p < 0.001).
The adjusted hazard ratio for death due to WRF in the placebo group was 1.9 (95% CI: 1.3 to 2.6), while it was 1.1 for the spironolactone group (95% CI: 0.79 to 1.5).

Study Design

Type

RCT (n=1,658)

Structured PICO

Does spironolactone reduce mortality and heart failure hospitalizations in patients with severe heart failure across different baseline renal functions and in the presence of worsening renal function?

Population

1,658 patients with severe heart failure (New York Heart Association functional class III or IV) and an ejection fraction <35%

Intervention

Spironolactone 25 mg daily, which could be titrated to 50 mg daily

Comparator

Placebo daily

Outcome

All-cause death and the combined endpoint of death or hospital stays for HFcomposite

Spironolactone provides substantial mortality and hospitalization benefits in severe heart failure patients regardless of baseline renal function or the development of worsening renal function, despite an increased risk of hyperkalemia.

Main Result

Effect estimate: HR 1.1 (95% CI 0.79-1.5)

p-value: p=0.009

Abstract

OBJECTIVES: This study investigated the influence of baseline and worsening renal function (WRF) on the efficacy of spironolactone in patients with severe heart failure (HF). BACKGROUND: Renal dysfunction or decline in renal function is a known predictor of adverse outcome in patients with HF, and treatment decisions are often on the basis of measures of renal function. METHODS: We used data from the RALES (Randomized Aldactone Evaluation Study) in 1,658 patients with New York Heart Association functional class III or IV HF and an ejection fraction 60 ml/min/1.73 m(2) and greater absolute risk reduction compared with those with a higher baseline eGFR (10.3% vs. 6.4%). Moreover, WRF (17% vs. 7% for spironolactone and placebo groups, p < 0.001) was associated with an increased adjusted risk of death in the placebo group (hazard ratio: 1.9, 95% confidence interval: 1.3 to 2.6) but not in those randomized to spironolactone (hazard ratio: 1.1, 95% confidence interval: 0.79 to 1.5, p interaction = 0.009). The risk of hyperkalemia and renal failure was higher in those with worse baseline renal function and those with WRF, particularly in the spironolactone arm, but the substantial net benefit of spironolactone therapy remained. CONCLUSIONS: The absolute benefit of spironolactone was greatest in patients with reduced eGFR. Worsening renal function was associated with a negative prognosis, yet the mortality benefit of spironolactone was maintained.

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