Influence of Baseline and Worsening Renal Function on Efficacy of Spironolactone in Patients With Severe Heart Failure: Insights From the Randomized Aldactone Evaluation Study

Study Questions:

Does renal function impact the efficacy of spironolactone?


This was a secondary analysis of the RALES study, enrolling 1,658 patients with New York Heart Association class III or IV heart failure (HF) and an ejection fraction <35%. Patients with a creatinine >2.5 mg/dl or potassium >5 mmol/L were excluded. Patients were randomized to spironolactone (25-50 mg daily) versus placebo. Glomerular filtration rate (eGFR) was estimated by the Modification of Diet in Renal Disease equation. Reduced renal function was defined as an eGFR <60 ml/min/1.73 m2 and worsening renal function (WRF) was a 30% reduction in eGFR from baseline. Outcomes were assessed based on eGFR and drug use.


Of 1,658 patients evaluated, 792 (48%) had reduced renal function at baseline. Patients with renal dysfunction were older, and more likely to be diabetic, female, and to have ischemic cardiomyopathy. Risks of hyperkalemia and renal failure were higher in those with worse baseline renal function and those with WRF. There were 670 deaths during follow-up and 909 events (death or HF hospitalization). Spironolactone led to a 30% relative risk reduction for mortality or hospitalization. Patients with baseline renal dysfunction had a greater absolute risk reduction for mortality than those with higher renal function (10.3% vs. 6.4%). WRF occurred in 199 (12%). In the placebo group, WRF was associated with higher mortality (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.3-2.6). In the spironolactone arm, WRF did not confer increased mortality risk (HR, 1.1; 95% CI, 0.79-1.5) and an interaction was present between treatment and WRF for outcome (p = 0.009). The frequency of hyperkalemia (K >5.5 mmol/L) was higher in patients with a reduced eGFR at baseline (odds ratio, 1.5; 95% CI, 1.2-2.0), and the risk was great in patients taking spironolactone who had WRF (odds ratio, 3.6; 95% CI, 1.5-8.6) during the study.


The authors concluded that HF patients with reduced eGFR had worse outcomes, but simultaneously sustained the greatest benefit from spironolactone therapy.


Many practitioners caring for patients with HF and renal dysfunction shy away from prescribing mineralocorticoid receptor antagonists due to risks for hyperkalemia. In this analysis, hyperkalemia was nearly 4 times more common in those patients with a baseline eGFR <60 taking spironolactone compared with placebo. This risk, while real, must be weighed against the mortality benefits from spironolactone. Clearly, very careful laboratory monitoring is needed, and patients need to be educated on dietary sources of potassium while taking the agent.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Acute Heart Failure, Diet

Keywords: Odds Ratio, Risk, Follow-Up Studies, Risk Reduction Behavior, Mineralocorticoid Receptor Antagonists, Apolipoprotein A-I, Hyperkalemia, Creatinine, Spironolactone, New York, Renal Insufficiency, Potassium, Cardiomyopathies, Heart Failure, Glomerular Filtration Rate, Diet, Confidence Intervals, Respiratory Sounds, Diabetes Mellitus

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