Benefit Of Eplerenone Research Articles

Effect of eplerenone according to duration of heart failure in EMPHASIS-HF: It is never too late to start an MRA in HFrEF

Abstract Background In the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure trial (EMPHASIS-HF), the mineralocorticoid receptor antagonist (MRA) eplerenone reduced both the risk of death and heart failure (HF) hospitalization in patients with HF and reduced ejection fraction (HFrEF) and mild symptoms. However, many patients are still not prescribed an MRA and physicians may be reluctant to add another treatment in patients with longstanding HF who appear to be "stable" on their current therapy. Purpose As little is known about how the effect of MRA therapy varies by the duration of HF, we examined the efficacy of eplerenone according to time from HF diagnosis among patients in EMPHASIS-HF. The primary trial outcome was the composite of a first hospitalization for HF or cardiovascular death. Methods Three patient groups of similar size were created according to the duration of HF: <1 year, ≥1 to <5 years, and ≥5 years. Outcomes were analysed using Cox regression and the Kaplan-Meier estimate. Treatment effects were examined according to HF duration category and also using the duration of HF as a continuous variable. Results The number of patients in each group was: 975 (<1 year), 769 (1 - <5 years), and 988 (≥5 years), respectively. Patients with longer duration of HF were older and more frequently had an ischaemic aetiology of HF. Additionally, a longer duration of HF was associated with lower eGFR levels, wider QRS duration, and a higher proportion of atrial fibrillation at baseline. The rate of the primary outcome (per 100 person-year) increased with HF duration: 9.8 (95% CI: 8.4-11.4) for <1 year, 13.5 (11.6-15.7) for 1 - <5 years, and 17.6 (15.6-19.8) for ≥5 years. Similar trends were seen in all other outcomes (Figure 1). The hazard ratios for the effect of eplerenone compared to placebo on the primary outcome were 0.57 (95% CI: 0.42-0.79) for <1 year, 0.81 (0.60-1.10) for 1- <5 years, and 0.61 (0.48-0.78) for ≥5 years; P for interaction = 0.24. The benefits of eplerenone were also consistent across the duration of HF examined as a continuous variable (Figure 2). For the primary outcome, The number needed to treat (NNT) over the duration of the trial, for the primary outcome, was 14 for <1 year, 13 for 1 - <5 years and only 10 for ≥5 years duration. Conclusions Patients with a longer duration of HF had worse clinical status and a higher rate of events, but the benefit of eplerenone was consistent in people with longer-standing HF and HF of shorter duration. These data suggest that it is never too late to start an MRA in patients with HFrEF. Figure 1. Outcomes according to heart failure duration category Abbreviations: CV cardiovascular; HF heart failure Figure 2. Treatment effects according to the duration of heart failure Abbreviations: CV cardiovascular; HF heart failureFigure 1Figure 2

Underutilization of Mineralocorticoid Antagonists in Patients With Heart Failure With Reduced Ejection Fraction

BackgroundIt is unknown how the efficacy and safety of mineralocorticoid receptor antagonists vary according to duration of heart failure with reduced ejection fraction (HFrEF). ObjectivesIn this study, we sought to evaluate the safety and efficacy of eplerenone according to duration of HFrEF. MethodsIn the EMPHASIS-HF trial, 3 patient groups were created according to HFrEF duration: <1 year, 1 to <5 years, and ≥5 years. The primary outcome was the composite of heart failure (HF) hospitalization or cardiovascular death. Outcomes were adjusted for prespecified prognostic variables and examined with the use of Cox regression models. ResultsThe numbers of patients in each group were: 975, <1 year; 769, 1 to <5 years; and 988, ≥5 years. Patients with longer-standing HF were older and more frequently had cardiovascular and noncardiovascular comorbidities. The rate of the primary outcome (per 100 person-years) increased with HFrEF duration: 9.8 (95% CI: 8.4-11.4) for <1 year, 13.5 (95% CI: 11.6-15.7) for 1 to <5 years, and 17.6 (95% CI: 15.6-19.8) for ≥5 years. The benefits of eplerenone were consistent across HF duration: HRs for the primary outcome were 0.57 (95% CI: 0.42-0.79) for <1 year, 0.81 (95% CI: 0.60-1.10) for 1 to <5 years, and 0.61 (95% CI: 0.48-0.78) for ≥5 years; Pinteraction = 0.24. The absolute benefit was greatest in the longest-duration group: the number needed to treat for the primary outcome was 14 for <1 year, 13 for 1 to <5 years, and 10 for ≥5 years duration. ConclusionsPatients with longer-standing HFrEF had worse clinical status and a higher rate of events, but the benefit of eplerenone was consistent regardless of HFrEF duration. (A Comparison of Outcomes in Patients in NYHA Class II Heart Failure When Treated With Eplerenone or Placebo in Addition to Standard Heart Failure Medicines [EMPHASIS-HF]; NCT00232180)

Administration of finerenone in chronic kidney disease

Spironolactone is a first-generation and non-selective mineralocorticoid receptor antagonist (MRA). It is extensively well-studied and recommended due to increased accessibility for patients. Unfortunately, it is often discontinued in several cases due to its association with hyperkalemia. The apparent benefit of eplerenone over spironolactone is its mineralocorticoid receptor (MR) selectivity. However, it is also characterized by low-potency and higher cost compared to spironolactone. The high adverse-effect profile of spironolactone and eplerenone has led to the innovation of novel medications such as non-steroidal MRAs. Among these medications, finerenone is the most advanced agent. Finerenone is associated with decreased proteinuria, reduced risk of hyperkalemia and increased preservation of renal function with comparable benefit in heart failure compared to selective and nonselective MRAs. The nonsteroidal structure of finerenone affects mineralocorticoid receptor binding, lipophilicity and polarity which have potent effects on distribution, the degree of attachment to blood proteins, transportation, and tissue diffusion.

Impact of eplerenone on major cardiovascular outcomes in patients with systolic heart failure according to baseline heart rate.

Increased resting heart rate is a risk factor for cardiovascular mortality and morbidity. Mineralocorticoid receptor antagonists (MRAs) have been shown to improve cardiac sympathetic nerve activity, reduce heart rate and attenuate left ventricular remodelling. Whether or not the beneficial effects of MRA are affected by heart rate in heart failure patients with reduced ejection fraction (HFREF) is unclear. We undertook a secondary analysis of data from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure study to assess if clinical outcomes, as well as the efficacy of eplerenone, varied according to heart rate at baseline. High resting heart rate of 80bpm and above predisposed patients to greater risk of all outcomes in the trial, regardless of treatment allocation. The beneficial effects of eplerenone were observed across all categories of heart rate. Eplerenone reduced the risk of primary endpoint, the composite of cardiovascular death and hospitalisation for heart failure, by 30% (aHR 0.70; 95% CI 0.54-0.91) in subjects with heart rate ≥ 80bpm, and by 48% (aHR 0.52; 95% CI 0.33-0.81) in subjects with heart rate ≤ 60bpm. Eplerenone also reduced the risks of hospitalisation for heart failure, cardiovascular deaths and all-cause deaths independently of baseline heart rate. Baseline heart rate appears to be an important predictor of major clinical outcome events in patients with HFREF, as has been previously reported. The benefits of eplerenone were preserved across all categories of baseline heart rate, without observed heterogeneity in the responses.

Does aspirin detract from the benefits of mineralocorticoid receptor antagonists in patients with heart failure and a reduced left ventricular ejection fraction? Probably!

Does aspirin detract from the benefits of mineralocorticoid receptor antagonists in patients with heart failure and a reduced left ventricular ejection fraction? Probably!

PHARMACOECONOMIC ASPECTS OF EPLERENONE USAGE IN CHRONIC HEART FAILURE

Eplerenone (Inspra, Pfizer) improves the prognosis of patients with chronic heart failure and heart failure after acute myocardial infarction. Since Russia eplerenone pharmacoeconomics issues rarely discussed, the analysis of the literature on this topic was performed. 2 studies examined effects of eplerenone in patients with chronic heart failure, 6 — in patients with heart failure after myocardial infarction. The only Russian study on pharmacoeconomics of eplerenone used data from studies in both groups. Due to distinctive methodology, currencies and date of publication, direct comparison of these studies is difficult. However, all studies have demonstrated the pharmacoeconomic benefits of eplerenone in patients with heart failure. A conclusion provided about the need for additional pharmacoeconomic studies of eplerenone in Russian Federation.

Structural Heart Disease and ST2: Cross-Sectional and Longitudinal Associations With Echocardiography

To further explore the potential role of sST2 in the progression of cardiac disease, this section reviews both the associations with cross-sectional findings and longitudinal changes in cardiac structure and function measured by echocardiography and cardiac magnetic resonance imaging with sST2 levels in a variety of patient populations with or at-risk for cardiovascular disease. In a Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department substudy in patients with acute dyspnea, sST2 levels were found associated with left ventricular ejection fraction (LVEF), and both estimated right ventricular (RV) systolic pressure and RV hypokinesis. In a large cohort of ambulatory patients referred for echocardiograms, sST2 was predominantly associated with RV and not LV structural findings. In contrast, in the Framingham Heart Study, a community cohort of >3,300 participants, sST2 was not associated with either echocardiographic finding, although in the Cardiovascular Health Study, sST2 appeared strongly associated with the presence of diastolic dysfunction. Little evidence exists on the relation of sST2 levels with longitudinal change in cardiac structure and function. A substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) evaluated the association among LV remodeling (defined as an increase in LV end-systolic and -diastolic volumes), sST2, and the benefit of eplerenone and found that sST2 levels were good surrogates of left ventricular remodeling. In the same line, the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) study found that more time spent with an sST2 level less than the cutoff of 35ng/L identified patients with a greater probability of a decrease in LV diastolic index over 1 year.

Diuretics

Diuretics have been recommended as first-line treatment of hypertension and are also valuable in the management of hypervolemia and electrolyte disorders. This review summarizes the key features of the most commonly used diuretics. We then provide an update of clinical trials for diuretics during the past 5 years. Compared to other classes of medications, thiazide diuretics are at least as effective in reducing cardiovascular events (CVEs) in patients with hypertension and are more effective than β-blockers and angiotensin-converting enzyme inhibitors in reducing stroke. Observational cohort data and a network analysis have shown that CVEs are lowered by one-fifth from chlorthalidone when compared to the commonly used thiazide, hydrochlorothiazide. Relative to placebo, chlorthalidone increases life expectancy. In those aged 80 years and older, the diuretic, indapamide, lowers CVEs relative to placebo. The aldosterone antagonist, eplerenone, lowers total mortality in early congestive heart failure. The benefit of eplerenone following acute myocardial infarction (MI) is limited to administration within 3 to 6 days post-MI. Aldosterone antagonists have been shown to lower the incidence of sudden cardiac death and to reduce proteinuria. In the setting of heart failure, long acting loop diuretics azosemide and torasemide are more effective in improving heart failure outcomes than the far more commonly used short acting furosemide. Evening dosing of diuretics appears to lower CVEs relative to morning dosing. In conclusion, diuretics are a diverse class of drugs that remain extremely important in the management of hypertension and hypervolemic states.

Clinical benefits of Eplerenone in patients with systolic NYHA II heart failure when initiated shortly after hospital discharge

Purpose: Cardiovascular hospitalization (CVH) in patients with heart failure (HF) is associated with a high post-discharge rate of re-admission and CV death. Eplerenone might be effective in reducing the incidence of these adverse clinical outcomes. Methods: The EMPHASIS-HF trial compared eplerenone to placebo added to standard therapy in 2737 patients with NYHA class II HF and LV ejection fraction <35%. In a post-hoc analysis in the 2338 patients randomized within 180 days of a CVH, we assessed the interaction between the time from the index CVH to randomization and the primary outcome of CV death or hospitalization for HF (HHF) using multivariable Cox survival models. Results: Most of the index CVH were HHF (N=1496, 64.0%) and acute coronary syndromes (N=390, 16.7%). The median time from index CV event was 42 days. In the <42 days group, median time since index CV event was 12 days and interquartile range was 5 to 26 days. The relative risk reductions in CV death/HHF, HHF and all-cause mortality were similar (p for interaction=0.65, 0.44 and 0.40 respectively) whether treatment was initiated <42 days or 42+ days after index CV event. Because event rates were higher in the <42 days group (14.1% in the <42 days group vs 11.8% in the 42+ days group for CV death/HHF), this subgroup had higher absolute risk reductions (11.4% in Eplerenone arm versus 17.0% in the placebo arm in the <42 days group, 10.0% versus 13.6% in the 42+ days group). ![Figure][1] Survival curves for CV death or HFH Conclusion: Eplerenone improves survival and prevents readmission when initiated relatively soon after a hospitalization for HF or acute coronary syndromes in patients with NYHA class II systolic HF. [1]: pending:yes

Novel approaches to heart rate modulation in chronic heart failure

Copyright © Polskie Towarzystwo Kardiologiczne INTRODUCTION The most recent version of the European Society of Cardiology (ESC) Guidelines for the management of heart failure (HF) has introduced two important innovations for the medical treatment of chronic HF with reduced ejection fraction (EF): mineralo-corticoid receptor antagonists (MCRA) and the If channel blocker ivabradine have now a recognised indication in patients remaining symptomatic despite diuretics, angiotensin converting enzyme inhibitors (or angiotensin receptor blockers in case of intolerance) and beta-blockers [1]. Mineralo-corticoid receptor antagonists are recommended following the EMPHASIS trial which demonstrated the benefit of eplerenone on cardiovascular mortality or HF hospitalisations as well as on all causes mortality in mild to moderate HF patients with reduced EF [2]. According to the ESC Guidelines, ivabradine should be considered when patients remain symptomatic despite the addition of a MCRA and when they have an increased heart rate (HR) ≥ 70 bpm in the context of sinus rhythm. This new recommendation derives from the results of the large outcome trial using this new agent, the SHIFT trial (Systolic Heart Failure Treatment with the If inhibitor Ivabradine trial) [3].

Clinical Summaries

Clinical Summaries

The Role of Aldosterone Blockade in Post-MI Heart Failure

Aldosterone is an important mediator of the renin-angiotensin-aldosterone system (RAAS) and plays a major role in the pathophysiology of cardiovascular disease as well as regulation of fluid and electrolyte balance. In experimental models, aldosterone has been shown to promote endothelial dysfunction, induce vascular inflammation, myocardial ischemia and necrosis, increase collagen synthesis in cardiac fibroblasts, contribute to plasminogen activator inhibitor-1 regulation, decrease baroreceptor sensitivity and reflex function, block myocardial uptake of norepinephrine, increase oxidative stress, and stimulate cardiomyocyte apoptosis. Experimental data as well as clinical research has shown that aldosterone stimulates myocardial fibrosis and promotes LV remodeling post-MI. Moreover, therapy with ACE inhibitors or angiotension receptor blockers cannot adequately suppress these harmful effects of aldosterone. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that selective aldosterone blockade with eplerenone significantly reduced mortality and morbidity when used in addition to standard therapy, including ACE inhibitors or ARBs and β-blockers, in patients with AMI complicated by LVSD and heart failure. The benefits of eplerenone on all-cause mortality and sudden cardiac death in EPHESUS were observed within 30 days of randomization, indicating the benefit of early initiation of treatment with eplerenone post-infarction, in addition to standard therapy. Recent ACC/ AHA and the HFSA guidelines have recommended the use of eplerenone in post-MI HF patients. Incorporation of eplerenone use into hospital critical pathways, and dissemination of information regarding patient selection, drug administration and monitoring of serum potassium are important steps to encourage increased utilization of this therapy in clinical practice.

Trends and Treatment of Heart Failure Developing After Acute Myocardial Infarction

The development of heart failure and/or left ventricular systolic dysfunction following acute myocardial infarction remains prevalent despite improvements in the diagnosis and management over the past decades. Although transient in some cases, the majority of these patients continue to carry a substantially higher mortality risk. New data on the benefits of eplerenone and carvedilol from large clinical trials have added to the complexity of polypharmacy in this patient subgroup, although aggressive medical strategies to prevent or reverse infarct-related left ventricular remodeling remains the most effective method to save lives and prevent disabilities.