Background— Mineralocorticoid receptor antagonists improve outcomes in patients with systolic heart failure but may induce worsening of renal function (WRF) and hyperkalemia (HK). We assessed the risk factors for mineralocorticoid receptor antagonist–related WRF and for HK, as well as the association between HK and WRF with clinical outcomes in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Methods and Results— Serial changes in estimated glomerular filtration rate and in serum potassium were available in 2737 patients during a median 21-month follow-up. HK variably defined as serum K >4.5, 5, or 5.5 mmol/L occurred in 74.7%, 32.5%, and 8.9% patients enrolled in EMPHASIS-HF, respectively. WRF defined as a decrease in estimated glomerular filtration rate >20% or >30% from baseline occurred in 27% and 14% of patients, respectively. Patients assigned eplerenone displayed modest and early but significant and persistent (1) rise in serum potassium and (2) reduction in estimated glomerular filtration rate when compared with those assigned placebo. In multivariate analyses, eplerenone was associated with a higher incidence of WRF and HK, which were interrelated and also associated with baseline patient characteristics (eg, age ≥75 years, hypertension, diabetes mellitus, nonwhite race, ejection fraction <30%, and treatment with an antiarrythmics drug or loop diuretic). Eplerenone retained its survival benefits without any significant interaction with the association between HK >5.5 mmol/L only and WRF and worse outcomes. Conclusions— In patients with heart failure receiving optimal therapy, WRF and HK were more frequent when eplerenone was added, but their occurrence did not eliminate the survival benefit of eplerenone. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00232180.

Background-We evaluated the effect of the selective mineralocorticoid receptor antagonist eplerenone on renal function and the interaction between changes in renal function and subsequent cardiovascular outcomes in patients with heart failure and left ventricular systolic dysfunction after an acute myocardial infarction in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Methods and Results-Serial changes in estimated glomerular filtration rate (eGFR) were available in 5792 patients during a 24-month follow-up. Patients assigned to eplerenone had a decline in eGFR with an adjusted mean difference of Ϫ1.4Ϯ0.3 mL ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 compared with placebo (PϽ0.0001), an effect that appeared within the first month (Ϫ1.3Ϯ0.4 mL ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 ) and persisted throughout the study. Overall, 914 patients experienced a decline in eGFR Ͼ20% in the first month, 16.9% and 14.7% in the eplerenone and placebo groups, respectively (odds ratio, 1.15; 95% confidence interval, 1.02-1.30; Pϭ0.017). In multivariate analyses, determinants of this early decline in eGFR were female sex, age Ն65 years, smoking, left ventricular ejection fraction Ͻ35%, and use of eplerenone and loop diuretic. An early decline in eGFR by Ͼ20% was associated with worse cardiovascular outcomes independently of baseline eGFR and of the use of eplerenone, which retained its prognostic benefits even under these circumstances. Conclusions-In patients with heart failure after acute myocardial infarction and receiving standard medical care, an early decline in eGFR is not uncommon and is associated with poor long-term outcome. Eplerenone induced a moderately more frequent early decline in eGFR, which did not affect its clinical benefit on cardiovascular outcomes. (Circulation. 2012;125:271-279.)Key Words: cardiorenal syndrome Ⅲ eplerenone Ⅲ kidney Ⅲ heart failure I mpaired renal function is a major adverse prognostic factor in acute and chronic heart failure (HF), 1-5 although most pharmacological treatments that improve the prognosis of patients with HF cause a decline in renal function. Clinical Perspective on p 279Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have prevented the progression of albuminuria and/or kidney dysfunction in various patient populations but may induce an acute deterioration in estimated glomerular filtration rate (eGFR) in HF patients. 6 -9 Mineralocorticoid receptor antagonists have also been shown to reduce proteinuria in patients with chronic kidney disease 10 -12 ; however, their long-term effect on renal function remains uncertain 10,11 and has not been reported in HF. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that the addition of the low-dose mineralocorticoid receptor antagonist eplerenone to standard medical therapy in patients with acute myocardial infarction and HF with left Continuing medical education (CME) credit is available for this article. Go to ...

Aims/hypothesisTo assess the effect of an angiotensin receptor blocker (ARB) on serum potassium and the effect of a serum potassium change on renal outcomes in patients with type 2 diabetes and nephropathy.MethodsWe performed a post hoc analysis in patients with type 2 diabetes participating in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Renal outcomes were defined as a composite of doubling of serum creatinine or end-stage renal disease.ResultsAt month 6, 259 (38.4%) and 73 (10.8%) patients in the losartan group and 151 (22.8%) and 34 (5.1%) patients in the placebo group had serum potassium ≥5.0 mmol/l and ≥5.5 mmol/l, (p < 0.001), respectively. Losartan was an independent predictor for serum potassium ≥5.0 mmol/l at month 6 (OR 2.8; 95% CI 2.0–3.9). Serum potassium at month 6 ≥ 5.0 mmol/l was in turn associated with increased risk for renal events (HR 1.22; 95% CI 1.00–1.50), independent of other risk factors. Adjustment of the overall treatment effects for serum potassium augmented losartan’s renoprotective effect from 21% (6–34%) to 35% (20–48%), suggesting that the renoprotective effects of losartan are offset by its effect on serum potassium.Conclusions/interpretationIn this study, we found that treatment with the ARB losartan is associated with a high risk of increased serum potassium levels, which is in turn associated with an increased risk of renal outcomes in patients with diabetes and nephropathy. Whether additional management of high serum potassium would further increase the renal protective properties of losartan is an important clinical question.