Influence of baseline and worsening renal function on efficacy of spironolactone in patients With severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study).
OBJECTIVE
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.
University of Wisconsin School of Pharmacy, Madison, WI, USA. ovardeny@pharmacy.wisc.edu
Orly
O
Vardeny
Dong Hong
DH
Wu
Akshay
A
Desai
Patrick
P
Rossignol
Faiez
F
Zannad
Bertram
B
Pitt
Scott D
SD
Solomon
D004232:Diuretics / Q000494:pharmacology / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D006760:Hospitalization; D006801:Humans; D007902:Length of Stay; D008297:Male; D011379:Prognosis; D012307:Risk Factors; D013148:Spironolactone / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D004232:Diuretics; D013148:Spironolactone