Incidence, Determinants, and Prognostic Significance of Hyperkalemia and Worsening Renal Function in Patients With Heart Failure Receiving the Mineralocorticoid Receptor Antagonist Eplerenone or Placebo in Addition to Optimal Medical Therapy

Abstract

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.

Association Between Mineralocorticoid Receptor Antagonist Use and Outcome in Myocardial Infarction Patients With Heart Failure

“…Eplerenone, however, was safe in carefully monitored risk patients in a substudy of EMPHASIS‐HF 29. In a subanalysis of RALES, the absolute benefit of spironolactone was greatest in patients with reduced kidney function30 and a subanalysis from EMPHASIS‐HF showed positive effect on survival despite worsening renal function 31. Our findings support that MRA may be used in patients with MI and HF, even in the presence of CKD.…”

Incidence, Predictors, and Outcomes Related to Hypo- and Hyperkalemia in Patients With Severe Heart Failure Treated With a Mineralocorticoid Receptor Antagonist

“…7 Previous analyses in HF noted poorer outcomes in patients with potassium levels below 4.0 mmol/L, 8,9 and incident hypokalemia may be potentially attenuated by the use of MRAs. An analysis of the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) study showed that clinical benefits with eplerenone remained even in those who developed hyperkalemia, 10 but whether elevations in potassium levels reduce the clinical benefit observed with MRAs in patients with severe HF is unknown.…”

Regional Differences in Heart Failure With Preserved Ejection Fraction Trials

“…7 Together, the findings in patients from the Americas enrolled in TOPCAT substantiate the concept that there could be a true pathophysiological continuum from HF-PEF to HF-REF involving cardiorenal interactions and response profiles similar to RAAS inhibition therapy, with increased rates of worsening renal function and hyperkalemia in patients from the Americas treated with MRA, albeit with better clinical outcomes. Similarly, although a serum potassium level >5 mmol/L has been shown to be associated with an increase in cardiovascular deaths in patients with HF-REF without or with chronic kidney disease, trials have shown that patients with HF-REF receiving an angiotensin-converting enzyme inhibitor, an angiotensin receptor antagonist, or an MRA (spironolactone or eplerenone) have better clinical outcomes despite experiencing more frequent episodes of hyperkalemia [8][9][10] and or worsening renal function 8,9 shortly after RAAS inhibitor initiation or thereafter. In HEAAL (Heart Failure End Point Evaluation of Angiotensin II Antagonist Losartan) 8 and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), 10 high-dose losartan or eplerenone was associated with more frequent worsening renal function and hyperkalemia than low-dose losartan or placebo, respectively.…”