Safety of Eplerenone in Heart Failure Patients
Abstract & Commentary
By Michael H. Crawford, MD, Editor
SourceS: Eschalier R, et al. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: Analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure). J Am Coll Cardiol 2013;62:1585-1593. Bart BA, Nelson S. Eplerenone: Another drug to add to the mix? J Am Coll Cardiol 2013;62:1594-1595.
Mineralocorticoid receptor antagonists (MRA) reduce hospitalizations and mortality in symptomatic heart failure patients due to systolic dysfunction treated with ACEI/ARB and beta-blockers. However, their use is suboptimal in practice surveys because of concerns about safety and the belief that randomized trials excluded high-risk patients. Also, observational studies have shown no benefit of spironolactone. Thus, the investigators in the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF) evaluated the safety and efficacy of eplerenone (25-50 mg/day) in the prespecified subgroup of high-risk patients characterized by age = 75 years, diabetes, chronic kidney disease, and systolic blood pressure < 123 mmHg. Patients in EMPHASIS-HF were > age 55 years, New York Heart Association Functional class II, EF < 30%, on ACEI/ARB plus beta-blockers, a cardiac hospitalization < 6 months, and a BNP > 250 pg/mL. Patients with glomerular fibrillation rate (GFR) < 30 mL/min/1.73m2 or need for a potassium-sparing diuretic were excluded. The endpoints for this analysis were abnormal potassium levels, hyperkalemia leading to study discontinuation, hospitalization for hyperkalemia or worsening renal function, a change in GFR, and the primary endpoint of hospitalization for heart failure or cardiovascular death. In the 2737 patients randomized to eplerenone or placebo, eplerenone reduced the risk of cardiac death and heart failure hospitalization (hazard ratio 0.63; 95% confidence interval, 0.54-0.74; P < 0.001) and was 0.54-0.66 in the high-risk subgroups. Overall and in the high-risk subgroups, eplerenone increased the incidence of potassium > 5.5 mmol/L, but not > 6.0. Also, eplerenone increased the risk of hospitalization for hyperkalemia as well as study drug discontinuation for adverse events overall and in the high-risk groups. The authors concluded that eplerenone, when carefully up titrated and monitored in symptomatic, systolic heart failure patients, results in a favorable risk-benefit ratio even in patients at high risk for renal dysfunction, hyperkalemia, or hypotension.
MRAs for heart failure have been a tough sell to clinicians in the trenches for several reasons. Physicians see the major hassle of the close monitoring of potassium, renal function, and blood pressure required, which is poorly reimbursed. Also, they fear the liability of a drug that could theoretically raise potassium to levels where sudden death is a reality. Patients see this as one more drug added to the many others they are taking. Heart-failure polypharmacy increases costs, and the likelihood of drug interactions and adverse effects. In addition, observational studies have shown hyperkalemia rates in the 25-40% range, not the 12% overall seen in this study. The highest rate observed in this study was 17% in those in the GFR between 30-60 group. Since the primary endpoint was reduced by 37%, the authors conclude that the benefits of MRAs outweigh the risks.
It should be pointed out that their patients were highly selected. They excluded those with uncontrolled hypertension, potassium values > 5.0, GRF < 30, mental illness, alcohol or drug dependence, liver disease, and cytochrome P450 CYP 3A4 inducer or inhibitor use. Also, dosing was titrated carefully starting with 25 mg every other day for those with a GFR between 30-49, and the maximum dose was 50. Mean dose was 40 mg/day. If the potassium was between 5.5-5.9, the dose was readjusted and if > 6.0 eplerenone was stopped. Potassium was monitored carefully at 1 week post any initiation or dose change, then at 1 month and every 4-6 months thereafter. Finally, they emphasize that their conclusions are limited to the type of patients they selected and that they have to be carefully monitored. Whether this tight patient selection and monitoring is feasible in real-world practice is questionable.
With regard to risk, they point out that although mild increases in potassium were observed in the whole trial population and the high-risk subgroups, potassium values > 6.0 were not more frequent compared to placebo. However, they had few patients with very high values, so the study was not powered to assess potassium > 6.0. Also, they did not observe worsening renal function or hypotension as compared to placebo therapy in any high-risk subgroup. Thus, they believe that with careful patient selection and monitoring, the benefits of MRA therapy in symptomatic systolic heart failure patients outweigh the risks. With regard to the observational studies that showed higher adverse event rates, they point out that some of those studies included heart failure patients with preserved EF, those with GRF < 30, and some on potassium-sparing diuretics. Such patients were excluded from this study and are not candidates for MRA therapy. In addition, some had a preponderance of older patients compared to this study. Finally, most of the observational studies used spironolactone, which may not have the same risk-benefit ratio as eplerenone.