Key result
Spironolactone preserves survival in severe HF despite a ~90% increased death risk from worsening renal function.
Why the study?
Renal dysfunction or decline in renal function predicts adverse outcomes in HF and guides treatment decisions, but its influence on spironolactone efficacy was not established.
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?
RCT (n=1,658)
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?
Effect estimate: HR 1.1 (95% CI 0.79-1.5)
p-value: p=0.009
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.
Worsening renal function should not prompt spironolactone discontinuation in severe HF; confirms mortality benefit persists independent of renal decline.
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 <35%. Participants were randomized to spironolactone 25 mg, which could be titrated to 50 mg, or placebo daily. Renal function (estimated glomerular filtration rate [eGFR]) was estimated by the Modification of Diet in Renal Disease equation. Worsening renal function was defined as a 30% reduction in eGFR from baseline to 12 weeks post-randomization. RESULTS: Individuals with reduced baseline eGFR exhibited similar relative risk reductions in all-cause death and the combined endpoint of death or hospital stays for HF as those with a baseline eGFR >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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Vardeny et al. (2012) conducted an RCT in Severe heart failure (n=1,658). Spironolactone vs. Placebo was evaluated on Death associated with worsening renal function (HR 1.1, 95% CI 0.79-1.5, p=0.009). 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).
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