The RALES study (the Randomized Aldactone Evaluation Study) was the first to give evidence of improved outcomes of patients treated with spironolactone in comparison with placebo. The trial included 1663 patients with chronic heart failure with reduced ejection fraction (average ejection fraction (EF) in the trial was 25%), NYHA class III or IV, that were already treated with standard heart failure therapy at the time (ACE inhibitors, digoxin, diuretics). The trial was terminated early due to significantly lower overall mortality in the group receiving spironolactone. (10) Major objections to the study included exclusion of patients with significant chronic renal failure and the small percentage of patients treated with beta-blockers. The RALES results were not applied so well in clinical practice due to higher incidence of hyperkalemia and renal insufficiency in real-life post-marketing studies. (11) In this context, a better safety profile and wider clinical use was expected from eplerenone, a more selective MRA. The EPHESUS randomized controlled trial (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) significantly contributed to wider clinical use of eplerenone. 6642 patients were randomized to eplerenone or placebo 3-14 days after myocardial infarction with systolic dysfunction of the left ventricle (EF <40%) and signs of heart failure (or just systolic dysfunction of the LV in patients with diabetes mellitus). In comparison with the RALES study, most of the patients were now treated with standard therapy for myocardial infarction with heart failure (ACE inhibitors or angiotensin-receptor blockers (ARB), beta-blockers, acetyl-salicylic acid, and diuretics). Significantly lower cardiovascular mortality, rates of sudden cardiac death, and less hospitalizations were demonstrated in patients treated with eplerenone. It is important to emphasize that the overall lower rates of cardiovascular mortality were primarily due to lower rates of sudden cardiac death, and this effect was already observed at 30 days post randomization. (12) One of the EPHESUS trial sub-analyses showed that a positive effect of eplerenone on major outcomes was observed only if eplerenone was started early in the course of treatment, i.e. in the first 7 days following myocardial infarction. (13) Given that fact, eplerenone became one of the standard therapies for patients with myocardial infarction and heart failure.

Treatment with eplerenone is also supported by findings of the EMPHASIS-HF trial (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure). In this trial, 2737 patients with heart failure with reduced EF (<30-35%) and NYHA II class were randomized to eplerenone or placebo. Additional criteria that patients had to meet for eligibility was either a cardiovascular hospitalization 6 months prior to randomization or elevated biomarkers (BNP or NT-proBNP). Patients treated with eplerenone had 37% lower cardiovascular mortality and a lower number of heart failure hospitalizations. (14)

Patients with heart failure with preserved EF often have the same signs and symptoms as those with heart failure with reduced ejection fraction. Their mortality is also similar, with significant burden of sudden cardiac death. (15) Therefore, one of the leading problems of modern-day cardiology is the lack of evidence-based treatments for patients in this heart failure category. Heart failure with preserved EF shares similar pathophysiological pathways, including adverse activation of RAAS and subsequent negative cardiac remodeling in terms of interstitial fibrosis and left ventricular hypertrophy. Furthermore, some authors consider endothelial dysfunction to be one of the key mechanisms underlying this syndrome. All of these mechanisms indicate a potential role of MRA in patients with heart failure with preserved EF. (16, 17) Small studies have shown positive effects of MRA on left ventricular hypertrophy and echocardiographic diastolic function indices, while positive effects on major outcomes have not yet been shown. (18) The clear beneficial signal of spironolactone in this patient population comes from the overall negative RCT TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). Although the trial did not prove lower mortality overall in patients with heart failure with preserved EF treated with spironolactone, it did show lower incidence of heart failure hospitalizations. (19) Several sub-analysis of the trial focusing only on patients from North and South America showed geographical differences in outcomes and positive effect of spironolactone on cardiovascular mortality in those patients. (20) These data indicate the existence of specific patient profiles that clearly benefit from treatment with mineralocorticoid receptor antagonists. (5, 21)

The EPHESUS trial results showed positive effects of eplerenone on sudden cardiac death in patients soon after myocardial infarction with heart failure. (12) Furthermore, the EMPHASIS-HF study showed significant reduction of its secondary endpoint of atrial fibrillation incidence in the group of patients treated with eplerenone (42% reduction in comparison with the control group). (14, 22)

In the EMPHASIS-HF trial, outcome benefits of eplerenone were present even in subgroups with greater risk of worse outcomes, such as patients with chronic renal disease, diabetes mellitus, and in those older than 75 years. (23)

The results of a few small studies indicate greater benefit of eplerenone treatment in comparison with spironolactone for patients with heart failure and diabetes mellitus. Patients treated with spironolactone had higher HbA1c and cortisol and worse endothelial dysfunction in comparison with those treated with eplerenone. The selectivity of eplerenone may partially explain this observation. Nevertheless, the results of this studies require confirmation in large RCTs. (24, 25)

Given the anti-inflammatory and anti-fibrotic properties of eplerenone, its early administration following myocardial infarction in patients without heart failure was also studied. The REMINDER clinical trial randomized 1012 patients with myocardial infarction without heart failure to early administration of eplerenone or placebo. Although it did not have the statistical power to assess major outcomes, it did show excellent eplerenone tolerability if administered within 24 hours of myocardial infarction and patients receiving eplerenone had significantly lower NT-proBNP concentrations at 30 days as well as 18 months after myocardial infarction. (26)

The latest European Society of Cardiology guidelines for treating arterial hypertension define resistant arterial hypertension as not achieving target blood pressure values (systolic <140 mmHg and/or diastolic <90 mmHg) by standard treatment (optimal or maximally tolerated doses of ACE inhibitors/ARBs, calcium blockers, or thiazide diuretics), confirmed by ambulatory blood pressure monitoring in patients who are fully compliant to prescribed therapies. Adding spironolactone 50 mg daily, and, if not tolerated, eplerenone in a dose of 50-100 mg daily has the I B recommendation level for management of resistant arterial hypertension (Table 1). (27)

In all of the large RCTs patients receiving eplerenone had significantly higher creatinine and potassium, but without difference in renal failure incidence. Furthermore, there was no death attributable to hyperkalemia in any of the trials. Viewed from a different perspective, there is significantly less hypokalemia and less deaths induced by ventricular arrhythmias as a consequence of hypokalemia. Generally, there is a low risk of hyperkalemia in patients with no preexistent renal disease. It is recommended to check potassium levels approximately one month after initiation of therapy. In patients with chronic renal disease, acute exacerbation of chronic renal disease, or who concomitantly take nephrotoxic drugs, potassium and renal function should be monitored more closely. (5, 28-30)