Influence of baseline and worsening renal function on efficacy of spironolactone in patients with severe heart failure: Insights from rales (randomized aldactone evaluation study)

Orly Vardeny, Dong Hong Wu, Akshay Desai, Patrick Rossignol, Faiez Zannad, Bertram Pitt, Scott D. Solomon

Research output: Contribution to journalArticlepeer-review

222 Scopus citations


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 m2 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.

Original languageEnglish (US)
Pages (from-to)2082-2089
Number of pages8
JournalJournal of the American College of Cardiology
Issue number20
StatePublished - Nov 13 2012

Bibliographical note

Funding Information:
The RALES trial was funded by Searle (Skokie, Illinois). Dr. Desai is a consultant for Novartis, Boston Scientific, Reata, and Intel; and received a research grant from AtCor Medical, Inc. Dr. Rossignol has received a travel grant from Pfizer . Dr. Zannad received consultancy fees from Bayer, Biomérieux, Biotronik, BostonScientific, CVCT, Novartis, and Pfizer, Resmed, Servier, and Takeda; and received grants to institution BG-Medicine, Roche Diagnostics. Dr. Pitt is a consultant for Pfizer, Merck, Bayer, Novartis, Takeda, Lilly, Bristol-Myers Squibb, Relypsa, BG-Medicine, and AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.


  • heart failure
  • renal dysfunction
  • spironolactone


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