eplerenone and Heart-Failure

In the EARLIER (Efficacy and Safety of Early Initiation of Eplerenone Treatment in Patients with Acute Heart Failure) trial, eplerenone did not reduce heart failure (HF) hospitalizations or all-cause mortality in 300 patients admitted for acute HF (AHF). However, the trial might have been underpowered for these endpoints, and a comprehensive overview of the effect of eplerenone on diuretic doses and patients' clinical stability is warranted.. The EARLIER trial included Japanese patients hospitalized for AHF randomly assigned to eplerenone or placebo over 6 months. Cox proportional hazards and mixed-effects models were used for analyses.. Three hundred patients were included (mean age, 67 ± 13 years; 73% males). The median furosemide equivalent dose was 40 (20-62) mg at randomization. Patients with higher furosemide-equivalent doses had more severe signs and symptoms of congestion and a higher risk of all-cause mortality or HF hospitalization during 6-month follow-up (adjusted-hazard ratio per 10 mg/day increase = 1.25, 95% confidence interval: 1.05-1.49). Eplerenone significantly decreased furosemide-equivalent diuretic doses and b-type natriuretic levels throughout the follow-up (overall-joint-p < 0.05 for both) and reduced E/e' and inferior vena cava diameter at 4 weeks (both p < 0.05). Additionally, eplerenone significantly reduced left ventricular (LV) end-diastolic diameter at 24 weeks (p < 0.05).. Eplerenone treatment improved the clinical stability particularly during short period following hospitalization for AHF, translated by lower diuretic doses, natriuretic peptide levels, indirect markers of filling pressure and venous congestion, and a smaller LV volume.

Topics: Aged; Aged, 80 and over; Diuretics; East Asian People; Eplerenone; Female; Furosemide; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Treatment Outcome

Diabetic kidney disease (DKD) represents a leading cause of morbidity and mortality in subjects with diabetes and develops in more than one third of diabetic patients. Steroidal mineralocorticoid receptor antagonists (MRAs - eplerenone and spironolactone) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF). However, in clinical practice the use of steroidal MRAs is limited by the significant risk of hyperkalemia, especially in patients with impaired renal function. Finerenone, a novel nonsteroidal MRA, shows a higher selectivity and binding affinity for mineralocorticoid receptor (MR) compared to steroidal MRAs and has been shown to reduce chronic kidney disease (CKD) progression and cardiovascular mortality in patients with CKD and T2DM.. This review summarizes the current evidence on efficacy and safety of finerenone in the treatment of patients with CKD and T2DM, and discusses its mechanisms of action investigated in preclinical studies.. Pharmacological properties of finerenone and its unique tissue distribution are responsible for a lower risk of hyperkalemia. Therefore, finerenone represents a valuable therapeutic tool in patients with CKD/diabetic kidney disease (DKD). Recent studies have shown that finerenone delays the progression of CKD and reduce cardiovascular events in patients with DKD, highlighting its safety and efficacy in this high-risk population.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Naphthyridines; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Spironolactone; Stroke Volume

Finerenone is a novel non-steroidal mineralocorticoid antagonist (MRA) recently approved for the treatment of chronic kidney disease (CKD) in people with type 2 diabetes (T2D). We aim to conduct a systematic review of finerenone to know the efficacy and safety of finerenone in CKD with or without T2D.. A systematic search in the electronic database of PubMed and Google Scholar was made from inception until September 09, 2022, using several MeSH keywords related to finerenone. Ongoing trials were additionally searched from ClinicalTrials.Gov.. Five phase 2 and three phase 3, randomized, double-blind, placebo- or active-controlled studies of finerenone have been published to date and several other randomized and real-world studies of finerenone are currently undergoing.. In short-term studies in patients with CKD and reduced ejection heart failure, with or without T2D, finerenone 20 mg appears to have a better renal outcome compared with spironolactone and a better mortality outcome compared with eplerenone, with significantly lesser hyperkalemia compared to both spironolactone and finerenone. In long-term studies in patients with CKD and T2D, finerenone 10/20 mg significantly reduces the progression of renal disease and reduced CV endpoints (especially heart failure hospitalization) compared to placebo. Finerenone has no effect on HbA1c, body weight, and sexual side effects including gynecomastia, and has only a modest effect on blood pressure. However, hyperkalemia leading to drug withdrawal was significantly higher with finerenone compared to placebo. Safety data in real-world settings is a pressing priority.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eplerenone; Glycated Hemoglobin; Heart Failure; Humans; Hyperkalemia; Male; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Spironolactone

Women with heart failure (HF) are under-represented in individual randomized clinical trials (RCTs). Little is known about sex-specific treatment effects in HF medications. We evaluated sex differences in the response to mineralocorticoid receptor antagonists (MRAs) in major HF MRA trials, including a broad spectrum of left ventricular ejection fraction (LVEF).. Individual patient data fixed-effect meta-analysis was performed using 6167 patients (31.4% were women) recruited in three placebo-controlled RCTs: Randomized Aldactone Evaluation Study (RALES), Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) and Spironolactone for Heart Failure with Preserved Ejection Fraction (TOPCAT)-Americas. Compared to men, women were older, had higher body mass index and lower glomerular filtration rate. They also had higher LVEF and poorer New York Heart Association functional class and were less likely to be taking angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers. Placebo-arm event rates were lower for women compared with men (15.4 vs. 22.1 per 100 person-year; P = 0.002). MRAs reduced consistently, in men and women, the relative risk for cardiovascular death or HF hospitalization (P for interaction = 0.83), cardiovascular death (P for interaction = 0.44) and all-cause death (P for interaction = 0.19). These findings remained consistent after adjustment for potential confounders, regardless of LVEF. There was no sex-specific impact of MRA on the rate of hyperkalaemia and worsening renal function during the median 22 months of follow-up.. In three large MRA RCTs, women were substantially different from men with regard to their clinical features and event rates. Nonetheless, this meta-analysis supports a consistent and beneficial MRA effect regardless of sex.

Topics: Eplerenone; Female; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Sex Characteristics; Spironolactone; Stroke Volume

Recently, nonsteroidal mineralocorticoid receptor (MR) antagonists (MRAs), which have been proposed to be called MR blockers (MRBs), have become available for clinical use, but their clinical role is unknown. We reviewed the clinical roles of MRAs and MRBs based on previous knowledge and as demonstrated in representative clinical trials.. Steroidal MRAs, such as spironolactone and eplerenone, inhibit the action of aldosterone and cortisol in MRs expressed in several organs and cell types, and accumulating clinical studies have revealed that they exert hypotensive and cardiorenal protective effects. Recently, MRBs, including finerenone and esaxerenone, have been developed and are expected to lower the risk of hyperkalemia, which is common when steroidal MRAs are used. Although the differences between MRAs and MRBs in clinical practice have not yet been established, further studies in this field are expected to broaden our understanding. MRBs exert antihypertensive and cardiorenal protective effects, and their potency is thought to be far superior to that of MRAs, because MRBs have both strong MR inhibitory action and high selectivity. Thus, MRBs could be a promising agent for the treatment of hypertension and cardiorenal, cerebral, and metabolic disorders.

Topics: Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Spironolactone

This study aims to assess the comparative benefit and risk profile of treatment with mineralocorticoid receptor antagonists (MRAs) with regard to all-cause mortality (primary endpoint), cardiovascular mortality, or heart failure (HF)-related hospitalization (secondary endpoints) and the safety endpoints hyperkalemia, acute renal failure, and gynecomastia in patients with chronic HF. We conducted a systematic review and network meta-analysis following PRISMA-P and PRISMA-NMA guidelines. From 16 different sources, 14 randomized controlled trials totaling 12,213 patients testing an active treatment of either spironolactone, eplerenone, or canrenone/potassium-canreonate in adults with symptomatic HF due to systolic dysfunction reporting any of the above endpoints were retained. Efficacy in comparison to placebo/standard medical care with respect to all-cause mortality was confirmed for spironolactone and eplerenone while no conclusion could be drawn for canrenone (HR 0.69 (0.62; 0.77), 0.82 (0.75; 0.91), and 0.50 (0.17; 1.45), respectively). Indirect comparisons hint a potential (non-significant) preference of spironolactone over eplerenone (HR 0.84 (0.68; 1.03)). The overall risk of bias was low to intermediate. Results for secondary endpoints as well as sensitivity analyses essentially mirrored these findings. The beta-blocker adjusted meta-analysis for the primary endpoint showed the same tendency as the unadjusted one (HR 0.39 (0.07; 2.03)). Results need to be interpreted with caution, though, as the resultant mix of patient- and study-level covariates produced unstable statistical modeling. We found no significant and systematic superiority of either MRA regarding efficacy toward all endpoints considered in both direct and indirect comparisons.

Topics: Canrenone; Diuretics; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Network Meta-Analysis; Randomized Controlled Trials as Topic; Spironolactone; Treatment Outcome

The efficacy and safety of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure (HF) are controversial. To explore the role of MRAs in HF patients with an ejection fraction of no more than 45%, we conducted a network meta-analysis of randomized controlled trials (RCTs). We systematically searched PubMed, Embase, the Cochrane Library, and Clinicaltrials. RCTs involving the efficacy and/or safety of the use of MRAs in patients with HF were included. Outputs are presented as the surface under the cumulative ranking area (SUCRA) probabilities. Thirteen RCTs involving a total of 13,597 participants were included. Finerenone 10 mg was associated with the lowest probability of achieving at cardiovascular mortality (SUCRA, 5.0%), followed by finerenone 7.5 mg (SUCRA, 31.6%). In reducing N-terminal pro-B-type natriuretic peptide, finerenone 15 mg and finerenone 7.5 mg ranked the best and second best (SUCRA 68.1% and 63.8%, respectively), followed by finerenone 10 mg (SUCRA 59.2%). Spironolactone and canrenone have a higher risk of hyperkalemia and renal deterioration. Regarding the prevention of worsening renal function, finerenone 7.5 mg (SUCRA 14.3%) was the best treatment, followed by finerenone 2.5 mg (SUCRA 16.3%) and finerenone 10 mg (SUCRA 25.6%). Compared with spironolactone and eplerenone, finerenone 10 mg was associated with low risk in the occurrence of cardiovascular mortality, hospitalization, and adverse events (P < 0.01). This network meta-analysis is the first to find that finerenone 7.5-10 mg has the highest probability of being the optimal alternative among MRAs in the treatment of HF patients with an ejection fraction of no more than 45%.

Topics: Eplerenone; Heart Failure; Hospitalization; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Naphthyridines; Natriuretic Peptide, Brain; Network Meta-Analysis; Peptide Fragments; Randomized Controlled Trials as Topic; Renal Insufficiency; Spironolactone; Treatment Outcome

Characterization of mice with cell-specific deletion or overexpression of the mineralocorticoid receptor (MR) shed a new light on its role in health and disease. Pathophysiological MR activation contributes to a plethora of deleterious molecular mechanisms in the development of cardiorenal diseases like chronic kidney disease (CKD) and heart failure (HF). Accordingly, the available steroidal MR antagonists (MRAs) spironolactone (first generation MRA) and eplerenone (second generation MRA) have been shown to be effective in reducing cardiovascular (CV) mortality and morbidity in patients with chronic HF and a reduced left ventricular ejection fraction (HFrEF). However, they remain underutilized, in large part owing to the risk inducing severe adverse events including hyperkalemia and worsening of kidney function, particularly when given on top of inhibitors of the renin angiotensin system (RAS) to patients with concomitant kidney dysfunction. Novel, potent, and selective non-steroidal MRAs (third generation) were identified in drug discovery campaigns and a few entered clinical development recently. One of these is finerenone with different physicochemical, pharmacokinetics, and pharmacological properties in comparison with the steroidal MRAs. Available data from five clinical phase II trials with finerenone in more than 2,000 patients with HF and additional CKD and/or diabetes as well as in patients with diabetic kidney disease demonstrated that neither hyperkalemia nor reductions in kidney function were limiting factors to its use. Moreover, finerenone demonstrated a nominally improved outcome compared to eplerenone in a phase IIb trial with 1,066 patients with HFrEF and concomitant type 2 diabetes mellitus (T2DM) and/or CKD.

Topics: Animals; Cardio-Renal Syndrome; Diabetic Nephropathies; Endothelial Cells; Eplerenone; Fibroblasts; Heart Failure; Humans; Macrophages; Mineralocorticoid Receptor Antagonists; Muscle, Smooth, Vascular; Myocytes, Cardiac; Myocytes, Smooth Muscle; Naphthyridines; Receptors, Mineralocorticoid; Spironolactone; Stroke Volume

Aldosterone has been implicated in atrial remodelling representing a potential target for upstream therapies. Accumulating evidence suggests that mineralocorticoid receptor blockade may have favourable effects on atrial fibrillation (AF) development, although some controversial results have been published. We, therefore, conducted a meta-analysis of randomized clinical trials (RCTs) and observational studies in order to examine the protective role of mineralocorticoid receptor antagonists (MRAs) on AF.. Of the 1337 initially identified records, 3 RCTs and 2 observational studies with 3640 patients were finally analysed. The pooled analysis of the included studies demonstrated that patients treated with MRAs have 31% lower risk of AF compared with controls [relative ratio (RR): 0.69; 95% confidence interval (CI): 0.58-0.83] without any heterogeneity across the studies (I(2) = 0%). This effect was consistent across RCTs (RR: 0.72; 95% CI: 0.55-0.94) and observational studies (RR: 0.67; 95% CI: 0.53-0.84) without heterogeneity. Also, MRAs reduce the risk of AF in both heart failure (HF) (RR: 0.63; 95% CI: 0.50-0.80) and after cardiac surgery (RR: 0.77; 95% CI: 0.61-0.98). Analysing the relative impact of eplerenone and spironolactone, we showed that only eplerenone significantly reduces AF burden (RR: 0.64; 95% CI: 0.44-0.90).. Our meta-analysis suggests that MRAs may be effective in AF prevention especially in the HF setting. However, there are insufficient data for the widespread use of aldosterone antagonists solely for AF prevention. Larger RCTs with long-term follow-up in different clinical settings are needed to clarify the impact of MRAs on AF.

Topics: Aldosterone; Atrial Fibrillation; Cardiac Surgical Procedures; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Spironolactone

Mineralocorticoid receptor antagonists (MRAs) that block aldosterone's effects on both epithelial and non-epithelial receptors have become a mainstay of therapy for chronic heart failure. Given that cardiovascular events remain the leading cause of death for patients with end-stage renal disease (ESRD), the question of whether these MRAs can be employed in dialysis patients arises. This review summarizes the rationale for blocking aldosterone in patients with chronic and end-stage kidney disease and surveys the data on both the efficacy and safety of using MRAs in the ESRD population. A small but growing body of literature suggests that use of MRAs by ESRD patients is associated with lower blood pressure, reduced left ventricular (LV) mass, and improved LV ejection fraction. Recently, a large randomized trial found an overall 3-year mortality rate of 6.4% in ESRD patients on spironolactone 25 mg daily vs. 19.7% in ESRD patients on no MRA therapy (p = 0.002), without a significantly increased risk of hyperkalemia.

Topics: Aldosterone; Blood Pressure; Disease Progression; Eplerenone; Heart Failure; Humans; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Patient Safety; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Spironolactone; Stroke Volume; Survival Analysis; Treatment Outcome; Ventricular Remodeling

Mineralocorticoid receptor antagonists (MRAs) are best known as potassium-sparing diuretics due to their blockade of aldosterone action in renal epithelial tissues. They are also beneficial for the treatment of heart failure, primarily due to effects in non-epithelial tissues. Currently there are only two steroidal MRAs that have been approved for use; spironolactone (and its active metabolite canrenone) and eplerenone. However, the search is on for novel generations of MRAs with increased potency and tissue selectivity. A number of novel non-steroidal compounds are in preclinical and early development, with one agent moving to phase III trials. The development of these agents and the mechanisms for their pharmacologic superiority compared to earlier generations of MRAs will be discussed in this review.

Topics: Aldosterone; Animals; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

Heart failure (HF), with or without reduced ejection fraction, and multidrug-resistant hypertension (RHT) are major worldwide health problems of ever-increasing proportions. The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone have proved valuable additions to the overall management of these disorders in patients without significant renal dysfunction.. Neurohormonal activation, including aldosteronism, in HF and RHT, has provided the pathophysiologic basis for the inclusion of MRA in the overall management of these disorders and the respective survival benefit and control of blood pressure. Furthermore, MRAs attenuate the appearance of secondary hyperparathyroidism that accompanies excretory Ca2+ losses induced by aldosteronism in which elevated parathyroid hormone levels raise the risk of adverse cardiovascular events and atraumatic bone fracture. Serial surveillance of serum electrolytes and creatinine levels is mandated to avoid serious hyperkalemia (potassium concentration >5.5 mEq/L) and its attendant risks in patients receiving MRAs.. Mineralocorticoid receptor antagonists are a valuable addition to the practice of medicine. Their judicious use in patients with HF or RHT can improve treatment of these patients.

Topics: Eplerenone; Heart Failure; Humans; Hyperkalemia; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone; Ventricular Dysfunction, Left

The brand new 2016 ESC guidelines for the treatment of acute and chronic heart failure continue to give a prominent place to mineralocorticoid receptor antagonists in the treatment of chronic heart failure with reduced ejection fraction (HFrEF). In the prevention of HF hospitalization and death, a class I, level of recommendation A, is given to MRAs for patients with HFrEF, who remain symptomatic despite treatment with an ACE-inhibitor and a beta-blocker and have an LVEF below 35 %. This recommendation is primarily based on two landmark trials, the RALES trial (for spironolactone) and the EMPHASIS-HF trial (for eplerenone). A crucial question is, however, why MRAs are advised only in "third place," i.e., after optimal up-titration of ACE-inhibitors and beta-blockers. We wonder whether MRAs could not or should not be given earlier in the treatment of HFrEF, namely before or together with the up-titration of ACE-inhibitors and beta-blockers. Several arguments to support this plea are described in this short paper.

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Practice Guidelines as Topic; Spironolactone; Stroke Volume

Eplerenone is a selective mineralocorticoid receptor antagonist that has been recently included in the treatment of patients with chronic heart failure (CHF) and reduced systolic function. This brief review aims to summarize current evidence on the role of eplerenone in the therapy of patients with CHF. In the EPHESUS trial, 6632 post-myocardial infarction patients with ejection fraction (EF) <40% and clinical HF signs were randomized to eplerenone or placebo added to standard therapy 3 to 14 days after the event. After a 16 month follow-up period, eplerenone given early (<7 days) reduced the primary endpoints of all-cause mortality by 15% and cardiovascular death or cardiovascular hospitalization by 13%. In the subsequent EMPHASIS-HF trial, the efficacy and tolerability of eplerenone were tested in patients with mild CHF (NYHA functional class II) and EF ≤ 30% or between 30 and 35% with QRS duration >130 ms. After a median follow-up of 21 months eplerenone significantly reduced (by 37%) the primary composite outcome of risk of death from CV causes and first hospitalization for HF. Based on the above findings, the addition of eplerenone to standard therapy, at doses to be titrated from 25 to 50mg per day, is currently recommended in CHF patients with functional classes II to IV closely resembling those enrolled in these large clinical trials, with adequate monitoring for side effects (mainly hyperkalemia and renal failure). Whether the same beneficial effects of eplerenone extend to CHF patients with mild symptoms and no additional risk factors are unknown.

Topics: Chronic Disease; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Risk Factors; Spironolactone

Primary aldosteronism, caused by autonomous secretion of aldosterone by the adrenals, is estimated to account for at least 5% of hypertension cases. Hypertension explains the considerable cardiovascular morbidity caused by aldosteronism only partly, calling for specific anti-aldosterone drugs. The pharmacology of aldosterone is complex due to high homology with other steroids, the resemblance of steroid receptors, and the common pathways of steroid synthesis. Classically, pharmacological treatment of aldosteronism relied on the mineralocorticoid receptor (MR) antagonist spironolactone, which is highly effective, but causes considerable, mainly sexual side-effects due to limited selectivity for the MR. New agents have been developed or are being developed that aim at higher selectivity for MR antagonists (eplerenone, dihydropyridine-derived calcium channel blockers (CCB)), or inhibition of aldosterone synthesis. Eplerenone is less potent than spironolactone, but causes fewer adverse effects due to its selectivity for the MR. Non-steroidal MR antagonists have been developed from dihydropyridine CCBs, having lost their CCB activity and being highly selective for the MR. The first clinical studies with these drugs are underway. Aldosterone synthase inhibitors are an attractive alternative, but are prone to interference with cortisol synthesis due to the inhibition of 11-β-hydroxylation, an essential step in both cortisol and aldosterone synthesis, and accumulation of mineralocorticoid precursors. In coming years clinical research will provide the answers as to which drugs and strategies to treat high-aldosterone states are the most effective.

Topics: Aldosterone; Cytochrome P-450 CYP11B2; Dihydropyridines; Drug Interactions; Epithelial Sodium Channel Blockers; Eplerenone; Glucocorticoids; Heart Failure; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone

The role of spironolactone and eplerenone in patients with Heart Failure with preserved Ejection Fraction (HFpEF) is not well defined. Since a growing medical literature has suggested that mineralocorticoid receptor antagonists may be beneficial for patients with HFpEF, this review gives an in-depth update on the role of spironolactone and eplerenone and their implications for therapy in the setting of HFpEF. Eleven clinical studies, including seven randomized trials, were reviewed. Two randomized controlled trials evaluated the effect of eplerenone on different end-points, including 6 minute walk distance (6 MWD), cardiovascular mortality, non-fatal reinfarction, hospitalization for unstable angina and congestive heart failure. Eplerenone did not affect either 6 MWD or event-free survival rates in the overall study population in these two reports. The effects of spironolactone on similar composite endpoints were evaluated in 7 studies in patients with HFpEF. Compared to placebo, hospitalization for heart failure was significantly lower in the spironolactone group and spironolactone was also shown to improve diastolic function and induced beneficial remodeling through a reduction in myocardial fibrosis. The safety profile of spironolactone and eplerenone has been assessed in two recent studies. Data showed that eplerenone and spironolactone are both associated with the occurrence of gynecomastia, mastodynia, and abnormal vaginal bleeding and in addition, they can increase natriuresis and cause renal retention of potassium; furthermore, eplerenone may cause hyperkalemia and promote the onset of metabolic acidosis or hyponatremia. In conclusion although the mineralocorticoid receptor antagonists eplerenone and spironolactone improve clinical outcomes in patients with HFrEF, additional data will be necessary to better define their risk-benefit profile, especially for eplerenone, in the treatment of HFpEF.

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Spironolactone; Stroke Volume

Clinical trials have demonstrated morbidity and mortality benefits of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure. These studies have used either spironolactone or eplerenone as the MRA. It is generally believed that these two agents have the same effects, and the data from studies using one drug could be extrapolated for the other. National and international guidelines do not generally discriminate between spironolactone and eplerenone, but strongly recommend using an MRA for patients with heart failure due to LV systolic dysfunction and post-infarct LV systolic dysfunction. There are no major clinical trials directly comparing the efficacy of these two drugs. This article aims to compare the pharmacokinetics and pharmacodynamics of spironolactone and eplerenone, and to analyse the available data for their cardiovascular indications and adverse effects. We have also addressed the role of special circumstances including co-morbidities, concomitant drug therapy, cost, and licensing restrictions in choosing an appropriate MRA for a particular patient, thus combining an evidence-based approach with personalized medicine.

Topics: Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone; Ventricular Dysfunction, Left

Mineralocorticoid receptor antagonists (MRA's) have been shown to be effective in patients with HFREF while their role in patients with HFPEF remains controversial. Despite a class one indication in both the ESC and AHA/ACC heart failure guidelines in patients with HFREF MRA's remain underused, in large part due to the fear of hyperkalaemia and renal dysfunction. While hyperkalaemia is a potential risk of MRA's, their use when potassium and renal function monitoring is properly carried out is minimal compared with their benefits in appropriate patients. New nonsteroidal MRA's and new potassium binding polymers currently under development hold the promise of further reducing the risks of hyperkalaemia while allowing higher doses of MRA's. They have been shown to overcome diuretic resistance and to potentially extend their benefits to patients with acute decompensated heart failure and those with chronic renal disease. While we await the results of studies with these new agents; application of current guidelines recommended therapies, including MRA's hold the best promise to further reduce cardiovascular mortality, hospitalisations for heart failure, and therefore, health care costs in patients with heart failure.

Topics: Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left

Aldosterone-receptor antagonists dose-dependently reduce both the epithelial and nonepithelial actions of aldosterone. These compounds are used commonly in the treatment of hypertension, with or without aldosteronism, and in the volume-overload periods of various forms of heart failure, cirrhosis, and renal failure. In this regard, the relevant site of action for these compounds is compartmentalized to the distal nephron. The cardiac benefits of aldosterone-receptor blockade now are sufficiently well established to warrant routine use of these compounds for their survival benefits in moderate to advanced stages of heart failure. Aldosterone-receptor antagonists spironolactone and eplerenone commonly are used in the treatment of resistant forms of hypertension. Spironolactone, but not eplerenone, is a commonly used add-on diuretic that provides incremental benefit for salt-and-water excretion in excess of what may be seen with a loop diuretic given together with a thiazide-type diuretic. The dose-response relationship for natriuresis with spironolactone has not been explored completely as to its combination therapy responses. The quite high doses of spironolactone used in patients with cirrhosis and ascites would infer that the overall treatment effect with this compound exceeds simple receptor blockade and may include a nervous system effect that operationally reduces renal sympathetic nerve traffic. The adverse electrolyte and renal function side effects with aldosterone-receptor antagonists are not uncommon in at-risk patients, such as those with chronic kidney disease, and require that dosing be mindful of the tendency of these drugs to importantly increase serum potassium levels.

Topics: Aldosterone; Area Under Curve; Diuretics; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Spironolactone

Aldosterone antagonists (AldoAs) have been used to treat severe chronic heart failure (CHF). There is uncertainty regarding the efficacy of using AldoAs in mild to moderate CHF with New York Heart Association (NYHA) classifications of I to II. This study summarizes the evidence for the efficacy of spironolactone (SP), eplerenone (EP) and canrenone in mild to moderate CHF patients.. PubMed, MEDLINE, EMBASE and OVID databases were searched before June 2012 for randomized and quasi-randomized controlled trials assessing AldoA treatment in CHF patients with NYHA classes I to II. Data concerning the study's design, patients' characteristics and outcomes were extracted. Risk ratio (RR) and weighted mean differences (WMD) or standardized mean difference were calculated using either fixed or random effects models.. Eight trials involving 3929 CHF patients were included. AldoAs were superior to the control in all cause mortality (RR 0.79, 95% CI 0.66, 0.95) and in re-hospitalization for cardiac causes (RR 0.62, 95% CI 0.52, 0.74), the left ventricular ejection fraction was improved by AldoA treatment (WMD 2.94%, P = 0.52). Moreover, AldoA therapy decreased the left ventricular end-diastolic volume (WMD -14.04 ml, P < 0.00001), the left ventricular end-systolic volume (WMD -14.09 ml, P < 0.00001). A stratified analysis showed a statistical superiority in the benefits of SP over EP in reducing LVEDV and LVESV. AldoAs reduced B-type natriuretic peptide concentrations (WMD -37.76 pg ml(-1), P < 0.00001), increased serum creatinine (WMD 8.69 μmol l(-1), P = 0.0003) and occurrence of hyperkalaemia (RR 1.78, 95% CI 1.43, 2.23).. Additional use of AldoAs in CHF patients may decrease mortality and re-hospitalization for cardiac reasons, improve cardiac function and simultaneously ameliorate LV reverse remodelling.

Topics: Canrenone; Chronic Disease; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Severity of Illness Index; Spironolactone; Ventricular Remodeling

Eplerenone is publicized to be extremely effective in reducing mortality from heart failure, with a reasonable side-effect profile. However, it is much more expensive compared with older aldosterone antagonists. We reviewed available evidence to assess whether increased expense was justified with outcomes data.. The authors searched the PubMed, CENTRAL, CINAHL, and EMBASE databases for randomized controlled trials from 1966 through July 2011. Interventions included aldosterone antagonists (Aldactone [Pfizer, NY, NY], canrenone, eplerenone) in systolic heart failure. The comparator included standard medical therapy or placebo, or both. Outcomes assessed were mortality in the intervention versus the comparator groups, and rates of adverse events at the end of at least 8 weeks of follow-up. Event rates were compared using a forest plot of relative risk (RR) (95% confidence interval [CI]) using a random-effects model (Mantel-Haenszel) between the aldosterone antagonists and controls. We included 13 studies for aldosterone antagonists other than eplerenone, and 3 studies for eplerenone. There was significant reduction of mortality with all aldosterone antagonists, but eplerenone (15% mortality relative reduction; RR 0.85; 95% CI, 0.77-0.93; P=.0007) was outperformed by other aldosterone antagonists, namely, spironolactone and canrenone (26% mortality relative reduction; RR 0.74; 95% CI, 0.66-0.83; P <.0001). Reduction in cardiovascular mortality with eplerenone was 17% (RR 0.83; 95% CI, 0.75-0.92; P=.0005), while that with other aldosterone antagonists was 25% (RR 0.75; 95% CI, 0.67-0.84, P <.0001), without contributing significantly to an improved side-effect profile.. Eplerenone does not appear to be more effective in reducing clinical events compared with older, less expensive aldosterone antagonists.

Topics: Canrenone; Cause of Death; Cost-Benefit Analysis; Drug Costs; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone; Survival Rate; Treatment Outcome

Despite numerous pharmacologic and nonpharmacologic treatment strategies, heart failure remains a complex, progressive disorder with significant morbidity and mortality. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and β-blockers have been used as routine treatment options for heart failure for the majority of patients with left ventricular systolic dysfunction who tolerate these agents. Mineralocorticoid receptor antagonists (MRAs) have also demonstrated significant benefits in the treatment of heart failure, which include a reduction in sudden cardiac death and ventricular remodeling; however, these agents have not been recommended for most patients with heart failure. In the most recent American College of Cardiology Foundation and American Heart Association guidelines, MRAs are recommended for patients with New York Heart Association class III or IV symptoms or previous acute myocardial infarction, provided an absence of contraindications or risk factors for developing hyperkalemia. Based on more recent evidence, it is likely that future recommendations and guidelines will further expand the use of MRAs to patients with mild heart failure as well. These agents have the potential to be recommended nearly as universally as ACE inhibitors and β-blockers because of the potential to reduce mortality and hospital admissions for heart failure. The risk of hyperkalemia should be carefully assessed when using these drugs; nonetheless, new strategies being developed may reduce the occurrence of hyperkalemia as well.

Topics: Death, Sudden, Cardiac; Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Practice Guidelines as Topic; Risk Factors; Spironolactone; Ventricular Remodeling

The aldosterone receptor antagonists (ARAs) spironolactone (Aldactone) and eplerenone (Inspra) have become part of standard medical therapy for heart failure, having shown clinical efficacy in randomized trials in patients with advanced symptomatic systolic heart failure, postinfarction heart failure with cardiac dysfunction, and systolic heart failure with mild symptoms. The benefits include a lower rate of death. Yet to be answered is whether the two drugs are clinically equivalent; another question is whether they may benefit everyone with symptomatic heart failure, including diastolic heart failure.

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

Aldosterone antagonists represented by nonselective spironolactone and mineralocorticoid-selective eplerenone are approved for treatment of symptomatic heart failure with reduced systolic function. Their cardioprotective, antifibrotic, and antiarrhythmic effects have been proven in animal experiments, and their effects on morbidity and mortality have been demonstrated in randomized clinical trials. Yet, they remain the most underutilized of all classes of medications for heart failure, primarily because of fear of hyperkalemia. Thorough patient screening and selection is the key for minimizing risks and optimizing benefits from these drugs. Ongoing trials will demonstrate whether the indication for aldosterone antagonists can be expanded to less severe heart failure or patients with preserved systolic function.

Topics: Aldosterone; Animals; Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Patient Selection; Severity of Illness Index; Spironolactone

Topics: Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Benzazepines; Cardiac Resynchronization Therapy; Combined Modality Therapy; Cyclic Nucleotide-Gated Cation Channels; Eplerenone; Heart Failure; Heart Rate; Hemodynamics; Humans; Ivabradine; Mineralocorticoid Receptor Antagonists; Spironolactone; Stroke Volume; Survival Rate

Although mineralocorticoid receptor (MR) antagonists are indicated in systolic heart failure, they are underprescribed in patients with appropriate indications for their prescription and often used in those in whom the evidence for probable benefit is scant. The rate of adverse events in practice has exceeded that foreshadowed by randomized controlled trials (RCTs). With the recent publication of the landmark therapeutic trial (EMPHASIS), it is timely to review the appropriate use of these agents in heart failure.. This review addresses the pathophysiological importance of MR activation in heart failure and summarizes pivotal RCTs of MR antagonists in heart failure.. MR antagonism reduces mortality and morbidity in heart failure with reduced systolic function in severe chronic disease, in heart failure complicating myocardial infarction and also in those with impaired systolic function (but only mild symptoms). Evidence for benefits in a significant proportion of 'real-life' patients with heart failure, including those with preserved left ventricular ejection fraction, is lacking. MR antagonism is an important part of the pharmaceutical armamentarium in managing heart failure but must be prescribed with careful case selection, taking note of the evidence of where risks are acceptable and benefits are likely.

Topics: Aldosterone; Animals; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Spironolactone; Treatment Outcome

Topics: Albuminuria; Diabetes Mellitus, Type 2; Eplerenone; Female; Heart Failure; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Practice Guidelines as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Spironolactone; Treatment Outcome

Historically, aldosterone receptor antagonists (ARA) have been classified as 'potassium sparing diuretics'. However, the positive effect of spironolactone, the most extensively studied ARA, on morbidity and mortality observed in humans suffering cardiac insufficiency could not be explained by the renal effect of the drug alone, and a pivotal clinical study has led to extensive research. Many experimental studies have demonstrated that ARA have previously unexpected beneficial effects on the cardiovascular system including reduction in remodelling of the vascular smooth muscle cells and myocytes and improvement of endothelial cell dysfunction in heart failure. These effects improve vascular compliance and slow down the progression of left ventricular dysfunction and end-organ damage. Furthermore, aldosterone receptor blockade also restores the baroreceptor reflex, improving heart rate variability in heart failure in humans. Some of these effects have been demonstrated in dog models of cardiac disease and so justified further investigation of the potential benefit of ARA in dogs with congestive heart failure (CHF). Positive effects of spironolactone on morbidity and mortality appear to have been seen in studies conducted in dogs suffering from naturally occurring CHF. In addition, eplerenone has been shown to have benefits in canine models of heart failure. The precise mechanisms by which ARA produce these beneficial effects in dogs remain to be determined but this group of drugs clearly provide therapeutic actions out-with their diuretic effects.

Topics: Animals; Autonomic Nervous System; Cardiovascular System; Dog Diseases; Dogs; Eplerenone; Heart Failure; Mineralocorticoid Receptor Antagonists; Spironolactone

Two aldosterone inhibitors are currently licensed for heart failure (HF) in the UK: spironolactone and eplerenone. Recent clinical guidelines recommend eplerenone after an acute myocardial infarction (MI) for patients with symptoms and/or signs of HF and left ventricular dysfunction.. The primary objective was to evaluate relative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone in patients with postMI HF and explore the possibility of conducting an indirect comparison of spironolactone and eplerenone. A second objective was to undertake value-of-information (VOI) analyses to determine the need for further research to identify research questions critical to decision-making and to help inform the design of future studies.. Relevant databases including MEDLINE, EMBASE and CENTRAL were searched between September and December 2008. Randomised controlled trials (RCTs) of spironolactone, eplerenone, canrenone or potassium canrenoate were included if conducted in a postMI HF population. Trials of general HF patients with a subgroup of postMI HF patients were considered if they had at least 100 ischaemic participants per arm and the authors provided subgroup data when contacted. Adverse events summary data were sought from recognised reference sources and RCTs or observational studies in any population that recruited more than 100 participants.. The comparative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone was derived using Bayesian meta-regression drawing on a wider 'network' of aldosterone trials to those considered in the main clinical effectiveness review. An alternative scenario was also considered assuming a 'class effect' for the aldosterone antagonists in terms of major clinical events, but allowing for potential differences in side effect profiles. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs) where appropriate. Uncertainty in cost-effectiveness results was also presented and used to inform future research priorities using VOI analyses based on expected value of perfect information (EVPI). A probabilistic decision analytic model was developed to estimate cost-effectiveness of spironolactone, eplerenone and standard care for management of postMI HF, provide estimates relevant to the NHS and explore alternative approaches to an indirect comparison between spironolactone and eplerenone. The model incorporated a lifetime horizon to estimate outcomes in terms of quality-adjusted life-years (QALYs) and costs from the NHS persepctive. In the base-case analysis, 2-year treatment duration was assumed, consistent with the follow-up in the main RCTs. Other scenarios were explored to examine the robustness of alternative assumptions including impact of different treatment durations.. Searches yielded five RCTs: two spironolactone trials of poor methodological quality and three trials of which only one (of eplerenone) specifically examined postMI HF (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study, EPHESUS). One trial of spironolactone (Randomised Aldactone Evaluation Study, RALES) and one of canrenone (Antiremodelling Effect of Aldosterone receptors blockade with canrenone In mild Chronic Heart Failure, AREA IN-CHF) comprised general HF, but data were available for an ischaemic subgroup. Structural similarity of spironolactone and eplerenone suggests that they may be interchangeable, but formal indirect comparison between the three trials was severely limited by trial differences. Relative safety data were limited from RCTs and observational sources. Hyperkalaemia rates varied, but were generally higher than for placebo; data were insufficient to assess discontinuation because of hyperkalaemia.Gynaecomastia rates were higher with spironolactone. Adverse event data were sparse. Systematic review of economic evidence identified three main published studies but none used a UK perspective or attempted to compare cost-effectiveness in postMI HF. The new decision model indicated that eplerenone was the most cost-effective strategy for postMI HF (ICER of eplerenone compared with standard care was 4457 pounds per QALY, increasing to 7893 pounds per QALY if treatment continued over the patient's lifetime); in neither scenario did spironolactone appear cost-effective. The ICER of eplerenone was consistently under the 20,000-30,000 pounds per QALY threshold used to establish value for money in the NHS. Uncertainty resulted in EVPI estimates between 820M pounds (base-case) and 1265M pounds (lifetime treatment duration scenario). When class effect for mortality and hospitalisations was assumed spironolactone emerged as the most cost-effective treatment and EVPI estimates were negligible. If class effect is considered more plausible than the results of the evidence synthesis model then there would be limited value in additional research.. Exchangeability between trials was poor and there was a lack of robust data in RCTs.. Only two good-quality trials of aldosterone inhibitors in the postMI HF population were found, but lack of exchangeability with respect to study populations, meant that a comparison between these drugs could not be done. It consistently emerged that, compared with usual care, use of an aldosterone antagonist appears to be a highly cost-effective strategy for the management of postMI HF patients in the NHS. An adequately powered, well-conducted RCT that directly compares spironolactone and eplerenone is required to provide more robust evidence on the optimal management of postMI HF patients.

Topics: Bayes Theorem; Clinical Trials as Topic; Cost-Benefit Analysis; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Quality-Adjusted Life Years; Spironolactone; State Medicine; United Kingdom

In this article, we review the evidence supporting the use of eplerenone for improving cardiovascular prognosis. Activation of the renin-angiotensin-aldosterone system plays a major role in the pathogenesis of heart disease, and blockage of this system has been shown to improve prognosis in several cardiovascular conditions. The 2 marketed aldosterone antagonists, spironolactone and eplerenone, improve prognosis in patients with left ventricular (LV) dysfunction and are effective antihypertensive medications. In addition, a potential role for aldosterone antagonists in the treatment of patients with heart failure and preserved LV function has been suggested and is currently being evaluated in clinical trials. In patients with myocardial infarction having LV dysfunction and evidence of heart failure, eplerenone improves cardiovascular outcomes and attenuates myocardial remodeling. In addition, eplerenone is effective for the treatment of hypertension, where it regresses both LV hypertrophy and proteinuria (2 powerful markers of increased cardiovascular risk). In contrast to spironolactone, eplerenone essentially lacks the sexual side effects that sometimes limit the use of spironolactone. Hyperkalemia is the main potential side effect of eplerenone, especially when used in combination with other medications that can cause hyperkalemia. Adequate patient selection and monitoring are therefore of utmost importance when using this medication. In conclusion, eplerenone is a medication that offers the cardiovascular therapeutic and prognostic benefits of aldosterone antagonism but with fewer side effects compared to spironolactone.

Topics: Cardiovascular Diseases; Eplerenone; Heart Failure; Humans; Hyperkalemia; Hypertension; Hypertrophy, Left Ventricular; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Renin-Angiotensin System; Risk; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Eplerenone is an aldosterone receptor antagonist indicated for the treatment of hypertension and congestive heart failure. Eplerenone contains an epoxy group, which offers greater mineralocorticoid receptor specificity. It is an effective antihypertensive that has been shown to reduce morbidity and mortality in individuals with left ventricular dysfunction post myocardial infarction. Studies are continuing to determine whether the benefit of mineralocorticoid receptor blockade in advanced congestive heart failure is also observed when eplerenone treatment is initiated in earlier stages of the disease. The most common side effect is hyperkalemia necessitating close monitoring in individuals with diabetes and proteinuria, heart failure or in those who are taking moderate CYP450 3A4 inhibitors. It is category B in pregnancy.

Topics: Animals; Controlled Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Spironolactone

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cardiomegaly; Cardiovascular Diseases; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Peptidyl-Dipeptidase A; Spironolactone

Fifty years after its discovery, aldosterone continues to stimulate interest as a therapeutic target. Early studies focused on aldosterone's actions on hypertension, the kidney, and electrolyte handling. More recently, its actions on the heart and cardiovascular system have become more apparent. Aldosterone causes cardiac fibrosis and remodeling, and stimulates neurohormonal systems that adversely affect the cardiovascular system. Aldosterone antagonism attenuates these negative effects. Clinical studies have applied this science and demonstrated improved morbidity and mortality with aldosterone blockade, specifically in patients with chronic heart failure and patients who are postmyocardial infarction and with depressed left ventricular function. This article will address the pathophysiology of aldosterone in cardiac fibrosis and remodeling, review the current clinical trial data, and explore the application of aldosterone blockade in an expanded heart failure population. The Randomized Aldactone Evaluation Study showed that the aldosterone antagonist spironolactone reduced mortality when compared to placebo in patients with chronic advanced heart failure. Similarly, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study demonstrated a significant reduction in mortality and hospitalizations for patients randomized to the aldosterone antagonist eplerenone. A more provocative question is whether aldosterone antagonism will afford the same protection in patient populations with heart failure and preserved left ventricular function. Clinical trials are underway, and results are eagerly awaited.

Topics: Aldosterone; Cardiovascular Agents; Drug Therapy, Combination; Eplerenone; Fibrosis; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardium; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Increasing recognition of the role of aldosterone in cardiovascular disease has been supported by a significant body of evidence from animal models. This evidence has been translated into clinical practice, and large-scale, randomized, placebo-controlled trials have confirmed the beneficial effects of mineralocorticoid blockade in patients with heart failure. As a consequence, there has been a resurgence in the use of mineralocorticoid-receptor antagonists in clinical practice that has prompted the search for a potent and specific antagonist without the sexual side effects of spironolactone. Eplerenone, a mineralocorticoid-receptor antagonist with minimal binding to the progesterone and androgen receptors, is now licensed for treatment of heart failure in Europe and heart failure and hypertension in the US; it has also been proposed as a treatment for a variety of cardiovascular conditions. This article reviews the current concepts of the actions of aldosterone at a cellular level. Recent findings regarding its role as a cardiovascular hormone, both in animal models and human studies, are discussed. We also describe the development of mineralocorticoid-receptor blockers following the isolation of aldosterone and discuss the subsequent search for a specific mineralocorticoid antagonist. In addition we detail the effects of eplerenone in a number of clinical situations and outline its potential future applications.

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone

Antialdosteronic treatment is used again in heart failure. It pursues the neurohormonal blockage of the final effector of the renin-angiotensin axis. Employed agents include espironolactone and, more recently, eplerenone (which lacks the adverse effects of the former such as gynecomastia). They have beneficial effects both in advanced heart failure (NYHA class III or IV) and heart insufficiency appearing after myocardial infarction. It remains to be demonstrated if they are also effective in less advanced chronic heart insufficiency (NYHA class II) and diastolic cardiac failure, though several ongoing studies are testing this benefit. Trials with antialdosteronics have shown improvements in overall mortality, even when patients were already receiving full therapy including ACEIs and, lastly, beta-blockers. The limitation of antialdosteronics is hyperkaliemia, which occurs more frequently in the general population than in patients enrolled in clinical trials, since the former is an elderly population with greater comorbility and submitted to less controls. Therefore, antialdosteronic treatment cannot be administered in some cases (especially if there is a renal function impairment) and a careful monitoring of the serum ionnograme is mandatory.

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

Improved understanding of the adverse pharmacological properties of aldosterone has prompted investigation of the clinical benefits of blocking aldosterone at the receptor level. This article reviews the pharmacology, clinical efficacy, and tolerability of the two available blocking agents, spironolactone and eplerenone. A Medline search identified clinical studies assessing spironolactone and eplerenone. Priority was given to large, well-controlled, clinical trials and comparative studies. Pharmacological differences between spironolactone and eplerenone include lower affinity of eplerenone for progesterone, androgen, and glucocorticoid receptors; more consistently demonstrated nongenomic properties for eplerenone; and the presence of long-acting metabolites for spironolactone. Both agents effectively treat hypertension and heart failure but comparisons are complicated by the deficiency of head-to-head trials and differences between patient populations. There are differences in the tolerability profiles; spironolactone is associated with dose-dependent sexual side effects. Both agents produce dose-dependent increases in potassium concentrations, although the effect with spironolactone appears to be greater when both agents are administered at recommended doses. Choice of a specific agent should be based on individual patient issues, such as the nature of heart failure and patient concerns about adverse events.

Topics: Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone

Topics: Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Hydrocortisone; Hypertension; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Spironolactone

Topics: Aldosterone; Chronic Disease; Contraindications; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Prognosis; Randomized Controlled Trials as Topic; Spironolactone; Survival Rate

Aldosterone is an important mediator in the pathogenesis of heart failure, and increased plasma aldosterone levels are associated with a poor prognosis. Aldosterone-receptor blocking drugs can slow the progression of left ventricular remodeling and reduce the occurrence of sudden cardiac death. Two widely publicized clinical trials provide data demonstrating survival benefits with spironolactone and eplerenone in chronic and postinfarction heart failure. The publication of these trials has generated widespread enthusiasm for spironolactone and eplerenone, leading to the more frequent and sometimes unbridled use of these drugs in the medical community. We herein describe the likely mechanisms of action of aldosterone-receptor antagonists, discuss the existing clinical evidence supporting their use, and provide practical advice on their use in the management of patients with heart failure.

Topics: Aldosterone; Contraindications; Drug Therapy, Combination; Eplerenone; Heart Failure; Humans; Hypertension; Kaplan-Meier Estimate; Mineralocorticoid Receptor Antagonists; Practice Guidelines as Topic; Spironolactone

Aldosterone blockade is now seen as a crucial therapeutic strategy in the management of cardiovascular disease progression. There is increasing evidence that blocking the rennin-angiotensin-aldosterone system results in a reduction in overall cardiovascular risk. For 40 years, the only agent in this class was spironolactone. Despite its efficacy, the sexual side effects of spironolactone have resulted in poor compliance at best and discontinuation of therapy at worst. A newer agent, eplerenone, has been recently licensed for the treatment of heart failure and in the US also for hypertension. This article reviews the pathophysiology of aldosterone and critically reviews the present evidence for the efficacy and potential role for the new selective aldosterone-receptor antagonist, eplerenone.

Topics: Animals; Antihypertensive Agents; Cardiovascular Agents; Drug and Narcotic Control; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Spironolactone; Treatment Outcome

The presence of heart failure or left ventricular systolic dysfunction in the setting of acute myocardial infarction is associated with poor prognosis. Aldosterone is an important downstream mediator of the renin-angiotensin-aldosterone system that promotes myocardial collagen deposition, myocardial fibrosis, apoptosis, ventricular remodeling, and endothelial dysfunction. It may play an important role in the increased morbidity and mortality and the development and progression of heart failure after acute myocardial infarction. Extending the findings from the Randomized Aldactone Evaluation Study (RALES) in patients with chronic heart failure, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that the selective aldosterone blocker eplerenone offered a significant survival benefit, attenuation of progression of heart failure, and prevention of sudden cardiac death when used in addition to optimal medical therapy. The current evidence-based guidelines now suggest that aldosterone blockade should be an integral component of heart failure therapy to improve outcomes in this high-risk population.

Topics: Eplerenone; Evidence-Based Medicine; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Receptors, Mineralocorticoid; Risk Factors; Spironolactone; Ventricular Dysfunction, Left

Many patients with heart failure should receive an aldosterone receptor antagonist, ie, either spironolactone (Aldactone) or the newer agent eplerenone (Inspra)--in addition to an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) or both, and a beta-blocker. We review the evidence and indications.

Topics: Angiotensin-Converting Enzyme Inhibitors; Eplerenone; Forecasting; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Risk Factors; Spironolactone

Based on the RALES study, in patients with moderate to severe chronic heart failure and reduced left ventricular function, the nonselective aldosterone antagonist spironolactone has a well-established role in combination with ACE inhibition, beta-blockade and diuretics. This indication was recently reinforced by the guideline for chronic heart failure therapy of the German Cardiac Society, although there is no formal approval for spironolactone for this indication in Germany.. Heart failure after acute myocardial infarction represents a new indication for aldosterone receptor blockade. In the EPHESUS trial of patients with acute myocardial infarction, reduced ejection fraction, and clinical signs of heart failure, the selective aldosterone antagonist eplerenone in combination with ACE inhibition and beta-blockade significantly reduced mortality. The best benefit was achieved by early treatment, i. e., starting 3-7 days post myocardial infarction. In addition, as early as after 30 days, eplerenone-treated patients had significantly reduced mortality and hospitalization. Eplerenone was approved for the indication heart failure after acute myocardial infarction in late 2004 in Germany.. The present review summarizes the pathophysiological basis, the experimental and clinical trials that constitute the rationale for therapy with aldosterone antagonists in patients with acute myocardial infarction and heart failure. Tips for use in clinical practice are given which allow to profit from the effective potential for mortality and morbidity reduction of aldosterone receptor blockade and to minimize the risk of serious hyperkalemia.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Diuretics; Drug Approval; Drug Therapy, Combination; Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Practice Guidelines as Topic; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Topics: Aldosterone; Animals; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Reactive Oxygen Species; Receptors, Mineralocorticoid; Spironolactone; Ventricular Remodeling

Topics: Clinical Trials as Topic; Drug Costs; Eplerenone; Europe; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone; United Kingdom

Aldosterone plays a pivotal role in sodium and water homeostasis, in particular in patients with heart failure or high blood pressure. These medications, when used on top of a standard therapy, improve the outcome of patients with heart failure and are also effective in lowering blood pressure of hypertensive patients. The major risk associated with the use of these antagonists is hyperkalemia, which can be prevented in avoiding their prescription in patients with impaired renal function. Eplerenone has the advantage, compared with spironolactone, to be better tolerated in terms of "hormonal" adverse effects.

Topics: Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Eplerenone; Heart Failure; Humans; Hypertension; Hypokalemia; Mineralocorticoid Receptor Antagonists; Spironolactone; Treatment Outcome

In recent years, there has been a striking paradigm shift with respect to our understanding of the widespread effects of aldosterone. Whereas the role of angiotensin II in mediating progressive renal disease and heart failure has been documented extensively, more recent evidence has implicated aldosterone as an important pathogenetic factor in addition to angiotensin II in the development of these diseases. The focus of this review is aldosterone and progressive renal dysfunction. The extensive preclinical and clinical evidence supporting the efficacy of aldosterone blockade in abrogating proteinuria is summarized. The frequency and clinical importance of aldosterone "escape" is reviewed. Therapeutic considerations to reduce the incidence of hyperkalemia with aldosterone blockade are discussed. The studies reviewed have several important clinical implications for considering new treatment algorithms for patients with incipient nephropathy. Because full doses of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers attenuate but do not abrogate progression of renal dysfunction, add-on aldosterone blockade therapy may constitute a rational therapeutic strategy for retarding progression of renal disease.

Topics: Aldosterone; Algorithms; Disease Progression; Disease Susceptibility; Drug Labeling; Eplerenone; Fibrosis; Heart Failure; Humans; Hyperkalemia; Kidney; Mineralocorticoid Receptor Antagonists; Renal Agents; Renal Insufficiency; Spironolactone

To evaluate the pharmacology, pharmacokinetics, safety, and clinical use of eplerenone in heart failure (HF).. English-language MEDLINE searches were performed from 1966 to May 2004. Key words included eplerenone, aldosterone receptor antagonist, heart failure, myocardial infarction, left-ventricular dysfunction, and cost-effectiveness. Additional references were identified from bibliographies of selected articles.. Human trials evaluating the efficacy, safety, and cost-effectiveness of aldosterone receptor antagonists in HF were evaluated.. Eplerenone is the first selective aldosterone receptor antagonist. The drug is indicated to improve the survival of stable patients with left-ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of HF following acute myocardial infarction. Efficacy and safety in this population have been demonstrated in a large, randomized clinical trial. Eplerenone is associated with severe and sometimes life-threatening hyperkalemia. Patients with reduced renal function and diabetes, as well as those on other drugs that increase potassium levels, are at highest risk. Eplerenone is metabolized by the cytochrome P450 system and may interact with drugs that interfere with this system. A major advantage of eplerenone over the nonselective aldosterone receptor antagonist spironolactone is lack of binding to progesterone and androgen receptors, which is associated with drug-induced gynecomastia, breast pain, and impotence.. The addition of eplerenone to traditional HF therapy has been shown to reduce morbidity and mortality in patients who develop left-ventricular dysfunction after acute myocardial infarction. Eplerenone's selectivity reduces sex hormone-related adverse effects. Despite these benefits, the overall cost-effectiveness has yet to be determined.

Topics: Animals; Cardiovascular Agents; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Molecular Structure; Randomized Controlled Trials as Topic; Spironolactone

Topics: Arrhythmias, Cardiac; Drug Interactions; Eplerenone; Evidence-Based Medicine; Heart Failure; Humans; Hypertension; Myocardial Infarction; Patient Selection; Quality of Life; Risk Factors; Spironolactone; United States

Topics: Aldosterone; Chronic Disease; Death, Sudden, Cardiac; Diuretics; Eplerenone; Fibrosis; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardium; Randomized Controlled Trials as Topic; Spironolactone; Sulfonamides; Torsemide; Ventricular Remodeling

The role of aldosterone-antagonists in the treatment of congestive heart failure. Despite the advances of the treatment of congestive heart failure, nearly half of the patients diagnosed with this disease five years ago are alive today. Experimental and human studies have demonstrated, that under special pathologic condition, the heart extracts aldosterone, and aldosterone extraction in the heart stimulates increased collagen turnover culminating in ventricular remodeling. Aldosterone blockade has been shown to be effective in reducing total mortality and hospitalization for heart failure in patients with systolic left ventricular dysfunction due to chronic heart failure (RALES study with spironolactone) and in patients with systolic left ventricular dysfunction post acute myocardial infarction (EPHESUS study with eplerenone). These clinical studies have shown that mineralocorticoid receptor activation remains important despite the use of angiotensin converting enzyme inhibitor or angiotensin receptor blocking agent and a beta blocker. In the ACC/AHA (and in the European and Hungarian) guidelines for the evolution and management of chronic heart failure, the indication of spironolactone was defined of Class Ila, Level of Evidence: B in CHF of stage C. The eplerenone (in US: INSPRA) was approved for the management of CHF patients after myocardial infarction with ejection fraction < 40%. Eplerenone, compared with spironolactone, is associated with a lower incidence of gynecomastia and other sex hormone-related adverse effect (breast pain, menstrual abnormalities). The spironolactone should not be used in patients with a creatinine above 220 mikromol/l. Despite the guidelines recommendation, spironolactone has been widely used in patients without consideration of their functional class or ejection fraction, without optimization of background treatment with ACE inhibitors and beta-blockers.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Severity of Illness Index; Spironolactone; Stroke Volume

The mechanisms associated with aldosterone production both systemically and locally as well as the effects of aldosterone blockade on the pathophysiology of heart failure (HF) have been extensively reviewed in this series and elsewhere. This article will review the clinical evidence supporting the use of aldosterone blocking agents (AB)in patients with HF and speculate on some potential future uses.

Topics: Angiotensin-Converting Enzyme Inhibitors; Diuretics; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Spironolactone

Spironolactone and eplerenone are mineralocorticoid- blocking agents used for their ability to block a host of epithelial and nonepithelial actions of aldosterone. These compounds are of proven benefit in reducing blood pressure and urine protein excretion, and in conferring cardiovascular gain in diverse circumstances of heart failure. However, as enthusiasm grows for use of mineralocorticoid-blocking agents, the risks inherent to use of such drugs become more pertinent. Whereas the endocrine side effects of spironolactone are in reality little more than a cosmetic disfigurement, the potassium-sparing properties of spironolactone and eplerenone can prove life-threatening if hyperkalemia develops. However, for most patients the risk of developing hyperkalemia should not dissuade the prudent clinician from use of these compounds. Hyperkalemia should be considered as a possibility in any patient receiving these medications and as such is best addressed preemptively.

Topics: Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Spironolactone

Mineralocorticoid receptor (MR) antagonism has proven to effectively attenuate the pathophysiological effects of aldosterone in clinical and experimental settings of hypertension and heart failure. MR activates transcription of target genes upon aldosterone binding, and eplerenone selectively binds to MR and blocks aldosterone- mediated activation. In this review, we summarize the preclinical and clinical evidence supporting the beneficial effects of eplerenone (INSPRA), a selective aldosterone blocker, in the treatment of hypertension and heart failure. We also review the current status in understanding the molecular mechanisms of action of the MR and its ligand. In addition, we compare the effects of eplerenone and spironolactone, a nonselective aldosterone blocker, on the transcriptional activity of MR and provide a molecular explanation for the improved side-effect profile of eplerenone compared with spironolactone.

Topics: Aldosterone; Animals; Eplerenone; Heart Failure; Hypertension; Ligands; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Spironolactone; Transcription, Genetic

This report summarizes the new therapeutic approaches in post-ischaemic heart failure given the important sanitary and socioeconomic impact resulting from the clinical management of this syndrome. Ventricular remodeling, causing changes to left ventricular anatomy and function, is the major cause of heart dysfunction. The physio-pathological role of the renin-angiotensin-aldosterone system has emerged from experimental studies and has been confirmed by the efficacy of ACE-inhibition. Although treatment with spironolactone (a non selective aldosterone antagonist) significantly reduces both the hospitalization and the mortality of NYHA III patients, this compound has important side effects. In this review we examine the efficacy of eplerenone, a new aldosterone receptor antagonist, with a more selective activity with respect to spironolactone. Several studies versus placebo have demonstrated that this molecule, alone or in combination with anti-hypertensive drugs, is very effective in left ventricular hypertrophy and in post-ischaemic heart failure treatment. In particular, we will consider the EPHESUS as the most important study both for the size of patient group and for the experimental plan. Finally, as regards the culture and experience of single physicians, a simple flow chart of the therapy of post-ischaemic heart failure is proposed.

Topics: Decision Trees; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

Eplerenone (Inspra) is a selective aldosterone blocker. When added to standard medical therapy, eplerenone significantly improved morbidity and mortality in patients with left ventricular (LV) systolic dysfunction and clinical evidence of heart failure following acute myocardial infarction (MI), in a well designed, placebo-controlled trial known as EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study). Although eplerenone was generally well tolerated, it was associated with a higher incidence of hyperkalaemia than placebo.Cost-effectiveness analyses based on this trial have been performed in the US, The Netherlands, Germany, France and Spain. Direct medical costs were analysed based on prospectively collected resource-use data with local costs applied; modelling was conducted to calculate incremental costs per life-year or QALY gained, with survival curves assumed to remain parallel after treatment ended. Eplerenone was associated with a gain of 0.0304 life-years (approximately 11 days) compared with placebo during the study period. Based on these analyses, eplerenone was cost effective compared with placebo in patients with LV systolic dysfunction and heart failure after an MI when added to standard therapy for 16 months. The incremental cost per life-year gained for eplerenone versus placebo (for a range of three different life-expectancy projections) was 10,402-21,876 US dollars in the US (year 2001 costs, except for eplerenone [2004]) [equivalent to 12,274-25,814 euro; mid-2001 exchange rate], 5,365-12,795 euro for The Netherlands (year 2003 costs), 6,956-14,628 euro for Germany, 5,432-11,423 euro for France and 8,626-18,141 euro for Spain (year of costing not reported). The US, Dutch, French and Spanish analyses estimated that >90% of observations for incremental cost per life-year gained were below a threshold of 50,000 US dollars or 50,000 euro. Incremental costs per QALY gained for eplerenone versus placebo in the US, Dutch, French and Spanish analyses were 15,330-32,405 US dollars (18,089-38,238 euro), 12,148, 8,005-16,922 euro and 12,713-26, 873 euro, respectively. Clinical and pharmacoeconomic data comparing eplerenone with another active drug, such as spironolactone, in this patient population are not available. In conclusion, when added to standard therapy in patients with LV systolic dysfunction and heart failure after an acute MI, eplerenone was associated with significant reductions in mortality an

Topics: Aged; Cost-Benefit Analysis; Economics, Pharmaceutical; Eplerenone; Female; Heart Failure; Heart Rupture, Post-Infarction; Humans; Male; Middle Aged; Multicenter Studies as Topic; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Spironolactone

Since the introduction of ACE-inhibitors into clinical practice, the diuretic treatment with the classical aldosterone antagonist spironolactone has disappeared. It was generally believed that chronic treatment with ACE-inhibitors significantly reduces aldosterone secretion via reduction of angiotensin II-dependent aldosterone formation. However, aldosterone "escape" occurs: Even during chronic treatment with ACE-inhibitors, plasma levels of aldosterone rise again, which is associated with increased cardiovascular risk. Furthermore, extrarenal actions of aldosterone have been demonstrated, which detrimentally affect coagulation, autonomic activity, inflammatory signalling, hemodynamics, and fibrosis, subsequently leading to cardiovascular damage. Recently published studies (RALES, EPHESUS) convincingly support the concept of detrimental cardiovascular aldosterone actions even during chronic ACE-inhibition. In addition to those cardiovascular effects, aldosterone antagonism has beneficial impacts on ascites, chronic renal disease, renal volume regulation, and hypokalemia induced by diuretics. Of note, aldosterone dependent mechanisms are believed to be even involved in essential hypertension, and the value of aldosterone antagonism is currently tested in those patients. In conclusion, an old-fashioned, previously abandoned treatment strategy is currently celebrating its revival.

Topics: Aldosterone; Cardiovascular Diseases; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Eplerenone; Heart Failure; Hemodynamics; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Receptors, Mineralocorticoid; Spironolactone; Water-Electrolyte Balance

Aldosterone has a variety of detrimental effects on the heart and vasculature and is increasingly recognized as an important target in chronic heart failure, as illustrated by the Randomized Aldactone Evaluation Study. In this article, the evidence supporting the cardiovascular effects of aldosterone in humans and the proven benefits of aldosterone-receptor antagonists in heart failure shall be discussed.

Topics: Aldosterone; Autonomic Nervous System Diseases; Endomyocardial Fibrosis; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone; Vascular Diseases; Water-Electrolyte Imbalance

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Diuretics; Drug Therapy, Combination; Eplerenone; Heart Failure; Humans; Hydrazones; Natriuretic Agents; Natriuretic Peptide, Brain; Neurotransmitter Agents; Pyridazines; Simendan; Spironolactone; Treatment Outcome; United States

The classical mineralocorticoid effect of aldosterone on unidirectional transepithelial sodium transport in the kidney was long thought to be the predominant effect of this hormone. However, there is convincing evidence for additional extrarenal actions of aldosterone that are mediated via activation of mineralocorticoid receptors (MRs) in the heart, vasculature and brain. It is now postulated that many of the detrimental effects of aldosterone are mediated through MR activation in these nonclassical target organs. The selective aldosterone blocker, eplerenone (Inspra), is under development for human therapeutic use for treatment of hypertension and heart failure post-myocardial infarction (MI). Clinical and preclinical studies have linked elevated aldosterone to hypertension, left ventricular and vascular remodeling, cardiac, renal, and cerebral vascular inflammation and injury, and increased risk of mortality in heart failure patients. Multiple studies in experimental models of hypertension and heart failure demonstrate that selective blockade of aldosterone by eplerenone effectively preserves cardiac function, attenuates maladaptive left ventricular remodeling and tissue and vascular injury in part by reducing vascular inflammation in aldosterone target organs.

Topics: Aldosterone; Blood Vessels; Brain; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Myocardium; Receptors, Mineralocorticoid; Spironolactone; Vasculitis, Central Nervous System; Ventricular Remodeling

There has been a recent revival of interest in aldosterone receptor antagonists for the treatment of chronic heart failure. This was largely triggered by fresh insights into the role of aldosterone in a number of key pathophysiological processes, including fibrosis and remodeling, inflammation, and the potentiation of catecholamine effects. The therapeutic efficacy of spironolactone (Aldactone), Pfizer) in severe chronic heart failure was established by the Randomized Aldactone Evaluation Study, but hormonal side effects (gynecomastia) associated with the drug posed a problem. More recently, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study has provided firm support for the use of eplerenone (Inspra, Pfizer) in heart failure following acute myocardial infarction in addition to neurohormonal blockade with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and beta-blockers. This strategy can be expected to benefit both mortality and morbidity. Due to the fact that eplerenone is a selective aldosterone receptor antagonist, it does not cause troublesome hormonal side effects. This is an important feature of the drug that is likely to help maintain compliance.

Topics: Aldosterone; Chronic Disease; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Treatment Outcome

The pathophysiology of heart failure is reviewed, with particular focus on the role of abnormal neurohormonal activation of the sympathetic nervous system and the renin-angiotensin-aldosterone axis in the pathophysiology of this syndrome.. Events preceding myocardial infarction and heart failure are driven in part by norepinephrine, angiotensin II, and aldosterone. The sympathetic nervous system likely evolved to mediate acute regulation of the cardiovascular system, not the sustained activation that is seen in heart failure. Overexpression of beta1-receptors in animal models results in decreased left ventricular ejection fraction and ventricular remodeling. In patients with systolic dysfunction, beta-blockade has improved left ventricular function and decreased the risk of sudden death. Chronic exposure to excess angiotensin II produces eccentric ventricular hypertrophy, vasoconstriction, and sodium retention. Angiotensin-converting enzyme (ACE) inhibition causes only a transient depression of aldosterone concentrations; the chronic benefit from ACE inhibition in patients with heart failure likely results from augmentation of bradykinin and not from the inhibition of angiotensin II production. Administration of eplerenone, a selective mineralocorticoid receptor antagonist, following induction of ischemic injury in animals, blocked the progressive ventricular dilatation and reduction in systolic function observed in control animals; clinical studies indicate that those findings can be translated to human cardiovascular disease. Overactivity of the mineralocorticoid receptor in cardiomyocytes could be important even in the absence of excessive levels of aldosterone. Clinical studies demonstrated that strategies of neurohormonal blockade using an ACE inhibitor, angiotensin II receptor antagonist, and beta-blocker are ineffective in reducing circulating aldosterone in patients with heart failure caused by left ventricular systolic dysfunction.. Aldosterone is a key deleterious hormone influencing all forms of cardiovascular disease, including hypertension, myocardial infarction, and heart failure. Treatment of many cardiovascular diseases should include specific antagonism of the adverse pathophysiologic consequences of aldosterone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Renin-Angiotensin System; Spironolactone; Sympathetic Nervous System

Prolonged overactivation of neurohormonal mechanisms in heart failure produces deleterious effects on the cardiovascular system and leads to poor prognosis. Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers have been shown to interrupt this excessive overactivity and improve survival. Activation of the renin-angiotensin system leads to increased synthesis of aldosterone in heart failure. Some aldosterone production is independent of ACEs; therefore, ACE inhibition does not entirely suppress the excessive formation of aldosterone. An excess of aldosterone in heart failure leads to sodium retention and myocardial fibrosis. The use of aldosterone antagonists, combined with standard therapy for heart failure, improves morbidity and mortality.

Topics: Aldosterone; Eplerenone; Fibrosis; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardium; Spironolactone

More than 5 million people in the United States alone have congestive heart failure, and an estimated 40 million have established risks and warrant therapy. Mineralocorticoid antagonists have emerged as a new paradigm for the treatment of congestive heart failure. They have established benefits among patients with chronic symptomatic systolic dysfunction, and recent studies have demonstrated substantial effect on the morbidity and mortality among patients with heart failure after myocardial infarction. The exact biologic mechanism is thus far unknown.. Within the last 5 years, efforts have intensified to help define better the biologic mechanisms by which mineralocorticoid receptor antagonisms exert the observed clinical benefit. Elegant human studies have demonstrated some important observations. First, under conditions of increased plasma aldosterone concentrations, the heart will extract aldosterone. Second, aldosterone extraction in the heart stimulates increased collagen turnover culminating in ventricular remodeling. Third, among people with chronic systolic or diastolic heart failure, aldosterone is actually produced and secreted by the heart. Finally, antagonism of the mineralocorticoid receptor will attenuate or abrogate many of these deleterious effects.. Combined clinical and detailed mechanistic investigations have established mineralocorticoid receptor antagonism as the new treatment paradigm for congestive heart failure. Recent clinical data have demonstrated that treatment of patients with a combination of mineralocorticoid receptor antagonism (eplerenone) and angiotensin converting enzyme-inhibitor (ACE-I) results in substantial reduction in left ventricular mass. Furthermore, a federally funded initiative to treat more than 6000 patients with diastolic heart failure with spironolactone is in its final phases of planning. It is foreseeable that, along with ACE-I and beta-blockers, mineralocorticoid receptor antagonism will become part of the treatment paradigm for people across the entire spectrum of cardiovascular disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Drug Therapy, Combination; Enalapril; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Spironolactone; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Spironolactone; Survival Analysis; Treatment Outcome

Angiotensin converting enzyme (ACE) inhibitor therapy does not reliably suppress aldosterone production, and 'aldosterone escape' occurs in up to 40% of patients with congestive heart failure (CHF). Aldosterone levels correlate with the risk of cardiovascular events. Aldosterone adversely affects the risk of cardiovascular events via mineralocorticoid receptors in the heart, blood vessels and other sites. Notably, aldosterone contributes to endothelial dysfunction and attenuates endothelium-dependent vasodilatation, at least partly by reducing nitric oxide bioavailability. Aldosterone also promotes myocardial fibrosis and cardiac remodelling by enhancing collagen synthesis, resulting in increased myocardial stiffness and increased left ventricular mass. These mechanisms mediated by aldosterone contribute to increased risk of ventricular arrhythmias and sudden cardiac death. Two major prospective trials, including one in which patients routinely received ACE inhibitor and beta blocker therapy, have shown that the use of an aldosterone blocker significantly reduces all-cause mortality, sudden cardiovascular death and hospitalisation in patients with acute or chronic left ventricular dysfunction or CHF. Inhibition of aldosterone's effect on mineralocorticoid receptors should now be considered standard therapy in these patient populations.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Death, Sudden, Cardiac; Endothelium, Vascular; Eplerenone; Fibrosis; Heart Failure; Humans; Myocardium; Spironolactone; Ventricular Remodeling

Mineralocorticoid hormones, specifically aldosterone, have been shown to be increasingly important in the development and maintenance of cardiovascular disorders, particularly hypertension and congestive heart failure. The use of the mineralocorticoid receptor blocker, spironolactone, has been fraught with side effects, largely related to the poor specificity of this agent. Eplerenone, a new and more specific mineralocorticoid receptor blocker with little effect on sex-hormone receptors, has offered an alternative approach. Many studies in hypertension as well as a major and compelling study in congestive heart failure have documented the efficacy and specificity of eplerenone with a minimum of side effects. The major findings with this new agent are presented herein.

Topics: Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Eplerenone; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Prognosis; Randomized Controlled Trials as Topic; Severity of Illness Index; Spironolactone; Survival Analysis; Treatment Outcome

Eplerenone (Inspra) is a selective aldosterone blocker. Oral eplerenone is approved for use in patients with left ventricular (LV) systolic dysfunction and clinical evidence of heart failure following acute myocardial infarction (MI) in the US and in European countries (e.g. the UK and The Netherlands). The addition of eplerenone to standard medical therapy significantly improved mortality and morbidity in patients with LV systolic dysfunction and clinical evidence of heart failure following acute MI in the large, well designed EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study) trial. The beneficial effects of eplerenone on all-cause mortality and cardiovascular mortality were seen within 30 days of randomisation. Eplerenone was generally well tolerated. Although a higher incidence of hyperkalaemia occurred with eplerenone than with placebo, the incidence of hypokalaemia was significantly lower with eplerenone treatment. Thus, the addition of eplerenone to standard medical therapy is an important new strategy for further improving mortality and morbidity in post-MI patients with LV systolic dysfunction and heart failure.

Topics: Animals; Area Under Curve; Economics, Pharmaceutical; Eplerenone; Half-Life; Heart Failure; Humans; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Rats; Spironolactone; Ventricular Dysfunction, Left

THE ROLE OF ALDOSTERONE: Aldosterone is the key hormone in salt-water homeostasis. In heart failure, it participates in the appearance and maintenance of signs of congestion. Predominantly synthesised in the glomerular area of the cortico-adrenal glands, extra adrenal production areas have recently been identified notably in the brain, the heart and the large artery trunks. Aldosterone is activated in the cells by the intracellular mineral corticoid receptor. IN CARDIOVASCULAR-PATHOLOGIES: In chronic heart failure, patients treated with conversion enzyme inhibitor may escape from the renin-angiotensin blockade and this may lead to increased aldosterone plasma levels. This increase can induce not only vascular lesions and myocardial fibrosis but also renal and cerebral lesions.. In patients with NYHA stage III or IV heart failure, addition of spironolactone to the treatment with conversion enzyme inhibitor, diuretic and/or digitalis leads to a reduction in morbidity and mortality, as demonstrated in the RALES study. The mechanisms by which spironolactone has a beneficial effect remain discussed.. The prescription of spironolactone is limited by hormonal side effects it provokes.. Eplerenone, a new competitive aldosterone receptor antagonist that appears to be devoid of such side effects and which, at least experimentally may well have the same beneficial effects, is presently under clinical assessment.

Topics: Adrenergic beta-Antagonists; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Diuretics; Eplerenone; Heart Failure; Homeostasis; Humans; Mineralocorticoid Receptor Antagonists; Multicenter Studies as Topic; Placebos; Randomized Controlled Trials as Topic; Receptors, Mineralocorticoid; Spironolactone; Time Factors

Based upon the results of the RALES trial and accumulating evidence about the role of aldosterone and aldosterone receptor antagonism in various disease states, the authors anticipate that aldosterone receptor antagonists will become standard therapy, along with ACE inhibitors and beta-adrenergic receptor blocking agents, in patients with heart failure that is caused by systolic left ventricular dysfunction. Furthermore, the prospect of the use of these agents in other disease states that have implicated an activated rennin-angiotensin-aldosterone cascade, such as diastolic dysfunction, aging, and atherosclerosis, remains to be tested. Until further data from well-designed, prospective, randomized trials are available, the use of aldosterone receptor antagonists should be restricted to patients with severe or progressive heart failure caused by systolic left ventricular dysfunction in whom serum creatinine level is < or = 2.0 mg/dL and serum potassium levels are < 5.0 meq/L at baseline.

Topics: Aldosterone; Cardiovascular Agents; Endothelium, Vascular; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Muscle, Smooth, Vascular; Myocardium; Plasminogen Activator Inhibitor 1; Progesterone; Randomized Controlled Trials as Topic; Spironolactone; Treatment Outcome

The American College of Cardiology provided much useful new information to inform those who care for patients with heart failure about what they should and should not adopt into current clinical practice. The EPHESUS trial suggests a much wider role for aldosterone antagonists for the management of heart failure and left ventricular systolic dysfunction. SPORTIF-III indicates we may have a safer, simpler warfarin substitute soon. ASCOT reinforces the potential futility of statin therapy unless it is well targeted. The results of the COMPANION study investigating cardiac resynchronisation devices and implantable defibrillators were encouraging but inconclusive and/or hard to interpret. UK-PACE again questions the use of dual chamber pacing. T-wave alternans is an interesting experimental technique that may be useful in selecting which patients need an implantable defibrillator, although the technology needs testing in an appropriate patient population.

Topics: Anticoagulants; Cardiac Pacing, Artificial; Defibrillators, Implantable; Electrocardiography; Eplerenone; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mineralocorticoid Receptor Antagonists; Pacemaker, Artificial; Spironolactone; Ventricular Dysfunction, Left; Warfarin

In the Eplerenone Postacute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) the effects of selective aldosterone blockade with eplerenone on cardiovascular mortality and morbidity were studied in patients with reduced left ventricular function postacute myocardial infarction. Data from this landmark study suggest that eplerenone can be an effective addition to the therapy of patients with congestive heart failure and is associated with fewer side effects than spironolactone. Further research is warranted concerning the possible benefits of this new agent in disease states other than congestive heart failure in which an activated renin-angiotensin-aldosterone system system has been implicated.

Topics: Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Spironolactone; Ventricular Function, Left

Recent studies suggest that aldosterone may play a larger role than once appreciated in normal physiologic function and cardiovascular disease. Some of the adverse cardiovascular effects that have been described include cardiac and vascular fibrosis, vascular necrosis and inflammation, impaired endothelial function, reduced fibrinolysis, hypertension, left ventricular hypertrophy (LVH), congestive heart failure, and cardiac arrhythmias. In light of these findings, the ability to block the actions of aldosterone has gained increased therapeutic importance. Eplerenone is a selective aldosterone receptor blocker that displays little interaction with androgen and progesterone receptors. Eplerenone has already been approved for the treatment of systemic hypertension and has been evaluated in numerous hypertension subgroups, including patients with low plasma renin activity; diabetes; LVH; uncontrolled blood pressure while receiving monotherapy with angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, calcium channel blockers, or beta-blockers; and in black patients. Results of these trials indicate that eplerenone lowers blood pressure and reduces end-organ damage. Further proof of the therapeutic importance of mineralocorticoid receptor blockade comes from the eplerenone post acute myocardial infarction survival and efficacy study (EPHESUS). In this large-scale clinical outcome trial, eplerenone was shown to reduce total mortality by 15% as well as the combined endpoint of cardiovascular mortality/cardiovascular hospitalization by 13% when administered at a mean of 7.3 days post myocardial infarction to patients with evidence of systolic left ventricular dysfunction and symptoms of heart failure. Eplerenone is well tolerated, with an adverse effect profile comparable to placebo. The advent of selective aldosterone blockers, such as eplerenone, should prove to be of great therapeutic value in hypertension control and prevention of cardiovascular disease and associated end-organ damage.

Topics: Animals; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Hypertension; Hypertrophy, Left Ventricular; Mineralocorticoid Receptor Antagonists; Spironolactone

Aldosterone is an important and independent target for therapeutic intervention in hypertension and hypertension-related diseases. Its actions, once thought to be limited to the distal convoluted tubule of the kidney, are now recognised to be wide-ranging, including interactions with mineralocorticoid receptors in diverse cardiovascular sites to mediate vascular and myocardial remodelling and dysfunction. The latter are referred as non-epithelial actions. Spironolactone, an aldosterone receptor antagonist, is indicated for the treatment of mineralocorticoid hypertension, but its use is limited by an adverse effect profile that includes not only by hyperkalaemia, but also antiandrogenic and progestational effects resulting from its poor specificity for the aldosterone receptor. Eplerenone is the first selective aldosterone receptor antagonist to be developed and recently gained approval from the US FDA for treatment of systemic hypertension. This was based on studies which demonstrated that eplerenone had a blood pressure-lowering profile that was equivalent to existing antihypertensive agents, was useful for treatment of low-renin and systolic hypertension, maintained utility even as add-on therapy to other antihypertensive agents, and exerted beneficial effects on hypertension-related left ventricular hypertrophy and renal impairment. Perhaps most notably, eplerenone was generally well tolerated, and did not cause the antiandrogenic and progestational adverse effects commonly observed with spironolactone.

Topics: Aldosterone; Clinical Trials as Topic; Diuretics; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Renin-Angiotensin System; Spironolactone

Topics: Aldosterone; Eplerenone; Forecasting; Heart Failure; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Patient Selection; Randomized Controlled Trials as Topic; Spironolactone; Systole; Ventricular Dysfunction, Left

Mineralocorticoid receptor (MR) blockade is effective in reducing total mortality and the incidence of heart failure in patients with systolic left ventricular dysfunction (SLVD) associated with chronic heart failure or post myocardial infarction. Pre-clinical and clinical studies in SLVD have shown that MR blockade reduces sudden cardiac death, left ventricular remodelling, left ventricular hypertrophy, endothelial dysfunction, autonomic imbalance, renal dysfunction and improves fibrinolysis. While MR blockade promotes sodium excretion and the combination of an angiotensin-converting enzyme inhibitor and a MR blocker have been shown to be more effective than either alone in causing natriuresis, it is unlikely that their beneficial effects can be explained solely on this basis. Aldosterone has been shown to have a number of adverse effects, including activation of other neurohumeral mediators, stimulation of active reactive oxygen species (ROS), activation of the NF-Greek small letter kappa kappabeta and AP-1 signalling pathways, vascular inflammation and fibrosis, myocardial hypertrophy, autonomic imbalance, and a decrease in fibrinolysis. MR blockade is, however, effective both in situations with and without an increase in serum aldosterone level, since the MR can be occupied and activated by cortisol as well as by aldosterone. In view of these mechanisms, MR blockade may play an important role not only on SLVD, but also in essential hypertension with normal systolic function, diastolic heart failure, valvular heart disease, vascular stiffening with ageing, progression of renal disease, and diabetes mellitus. This hypothesis will, however, require further prospective evaluation.

Topics: Animals; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Spironolactone; Ventricular Dysfunction, Left

In most countries the last two decades have seen a very substantial rise in the prevalence of heart failure, and in a majority of patients hypertension is both an antecedent condition and a contributing cause. Heart failure is also a major cause of hospital admissions; its amelioration and, as far as possible, prevention is therefore important in terms not only of morbidity and premature mortality for the individual patient, but also containment of healthcare costs. Over the past 5 years, mineralocorticoid receptor (MR) antagonists have been used in two major outcome trials (the Randomized Aldactone Evaluation Study [RALES] with spironolactone, and the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study [EPHESUS]), in severe (New York Heart Association class III) and post-myocardial infarct heart failure, respectively. Experimental studies have largely focused, however, on various animal models of hypertension; on the basis of a portfolio of clinical studies on the efficacy of eplerenone, administered either alone and in combination as an antihypertensive agent, the novel MR antagonist was approved by the FDA for the treatment of hypertension, though it has yet to be launched. In this review, the two major outcome studies (RALES, EPHESUS) are discussed in the context of the new biology of aldosterone action. The relevance to heart failure of current experimental studies, largely on vascular protection, will also be discussed.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Animals; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Hydrocortisone; Hypertension; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Spironolactone

To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of eplerenone, a new selective aldosterone blocker.. Primary literature and review articles were obtained via MEDLINE search (1966-April 2002). Additional studies and abstracts were identified from the bibliographies of reviewed literature.. Studies and review articles related to eplerenone, aldosterone, aldosterone antagonist, and spironolactone were reviewed. Data pertinent to this article were included.. Eplerenone is a selective aldosterone blocker. Recent data have demonstrated the deleterious effects of aldosterone in several chronic disease states including hypertension and heart failure. Animal studies using eplerenone have shown a positive role for aldosterone antagonism in the treatment of hypertension, heart failure, myocardial infarction, renal disease, and atherosclerosis. In humans, eplerenone appears to be effective for the treatment of hypertension. An ongoing study will examine the effect of eplerenone for heart failure. To date, the incidence of adverse effects with eplerenone has been slightly lower than with spironolactone.. Eplerenone appears to be a promising drug in a new class of agents called selective aldosterone blockers. The drug may be approved for treatment of hypertension in 2002. Additional studies are ongoing that may provide information on other clinical uses for this medication.

Topics: Animals; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone

Topics: Aldosterone; Animals; Cardiomegaly; Clinical Trials as Topic; Desoxycorticosterone; Eplerenone; Fibrosis; Heart; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Myocardium; Rats; Rats, Inbred SHR; Receptors, Mineralocorticoid; Spironolactone

The recent revival of interest in aldosterone receptor antagonists for the treatment of cardiovascular disease has been underpinned by fresh insights into the pathophysiological role of aldosterone in cardiovascular disease, especially with regard to its widespread 'non-epithelial' actions, as well as by key findings from dinical studies. The therapeutic efficacy of spironolactone (Pharmacia Corp) in severe chronic heart failure is established. Emerging evidence from an extensive development program for eplerenone (Pharmacia Corp), a novel selective aldosterone receptor antagonist, may further expand the evidence base for aldosterone receptor antagonism, including its potential in treating hypertension. Importantly, eplerenone does not appear to cause the hormonal side effects observed with spironolactone.

Topics: Aldosterone; Animals; Cardiovascular Diseases; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone

Eplerenone, an aldosterone receptor antagonist from Searle is being developed as a potential treatment for renal disease, congestive heart failure and hypertension. It is in phase III clinical trials 1312280], [353548]. Monsanto (now Pharmacia) expects to launch the compound in 2002 [370466]. Pharmacia anticipates filing for congestive heart failure in 2002 [374505]. A global phase III survival trial was initiated in the US and approximately 30 other countries in January 2000. The trial will evaluate whether eplerenone can reduce the rate of mortality in patients who have recently had a heart attack that resulted in a diagnosis of heart failure 13535481.

Topics: Animals; Antihypertensive Agents; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Hypertension; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Spironolactone

Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT(1)) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels--a phenomenon termed "aldosterone synthesis escape." Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone--the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs)--is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease.

Topics: Animals; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone

Activation of the renin-angiotensin-aldosterone system is associated with unsatisfactory outcomes in patients with hypertension and congestive heart failure, in that activation of this system is correlated strongly with both the incidence and extent of end-organ damage. Despite the availability of the angiotensin-converting enzyme inhibitors and the AT1 receptor antagonists, unblocked aldosterone levels remain an important risk factor for cardiovascular disease progression. New preclinical data generated over the past few years strongly support the hypothesis that aldosterone has important deleterious effects on the cardiovascular system independent of the classical action of this hormone on renal epithelial cells. The new selective aldosterone receptor antagonist eplerenone has been shown to produce significant cardioprotective effects in experimental models of cardiovascular disease. Early clinical testing suggests that eplerenone may have important therapeutic benefit in the treatment of hypertension and heart failure.

Topics: Aldosterone; Animals; Cardiovascular System; Clinical Trials as Topic; Endothelium, Vascular; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Protective Agents; Receptors, Mineralocorticoid; Renin-Angiotensin System; Spironolactone; Tissue Survival

Inappropriate elevations in plasma aldosterone levels have multiple actions that play an important role in the pathophysiology of hypertension and heart failure. Patients with hypertensive cardiovascular disease are at increased risk for coronary artery disease, myocardial infarction, congestive heart failure, and sudden cardiac death. Despite long-term treatment with an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker, aldosterone levels usually remain high in these patients. The effectiveness of low-dose spironolactone raises the possibility that a nonselective aldosterone antagonist can block the deleterious effects of aldosterone on the cardiovascular system. However, side effects limit the use of this drug in many patients. The advent of selective aldosterone antagonists, which have a lower affinity for androgen and progesterone receptors, should minimize these side effects, leading to better compliance.

Topics: Aldosterone; Animals; Antihypertensive Agents; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Spironolactone

Early heart failure prevention is central in patients with type 2 diabetes, and mineralocorticoid receptor antagonists (MRAs) have shown to improve prognosis. We investigated the effect of high-dose MRA, eplerenone, on cardiac function and structure in patients with type 2 diabetes and established or increased risk of cardiovascular disease but without heart failure.. In the current randomized, placebo-controlled clinical trial, 140 patients with high-risk type 2 diabetes were randomized to high-dose eplerenone (100-200 mg daily) or placebo as add-on to standard care for 26 weeks. Left ventricular systolic and diastolic function, indexed left ventricular mass (LVMi), and global longitudinal strain (GLS) were assessed using echocardiography at baseline and after 26 weeks of treatment.. In the present echo sub-study, no change in left ventricular function was observed following high-dose MRA therapy in patients with type 2 diabetes when evaluated by conventional echocardiography.. Date of registration 25/08/2015 (EudraCT number: 2015-002,519-14).

Topics: Diabetes Mellitus, Type 2; Echocardiography; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

Heart failure remains one of the most prevalent clinical syndromes associated with significant morbidity and mortality. According to current guidelines, the prescription of a MRA is recommended to reduce the risk of HF hospitalization and death in all patients with symptomatic heart failure and no contraindications for this therapy.. The aim of our study was to determine the efficacy of eplerenone vs. spironolactone on left ventricular systolic function by measuring left ventricle ejection fraction (LVEF) in patients with chronic heart failure, especially their effect on preventing hospitalization, reducing mortality, and improving clinical status among patients with chronic HF.. From June 2021 to June 2022, the study was a randomized, prospective clinical trial single blind study. A total of 142 patients of chronic heart failure with reduced ejection fraction were selected by random sampling. Each patient was randomly allocated into either of the two groups and was continued receiving treatment with either spironolactone (Spiron-HF group) or eplerenone (Epler-HF group). Patients in Epler-HF group were compared with an arm of the same size and matched by age and gender patients in Spiron-HF group for management of chronic HFrEF. Each patient was evaluated clinically, biochemically, and echocardiographically at the beginning of treatment (baseline) after 6 months and at the end of 12th month. Echocardiography was performed to find out change in left ventricular systolic function.. After 12 months of treatment, significant improvement of left ventricular ejection fraction was observed in eplerenone treated arm (37.9 ± 3.8 ± 4.6 in Spiron-HF group versus 40.1 ± 5.7 in Epler-HF group; P < 0.05). A significant reduction in left ventricular end-systolic volume (6.3 ± 2.5ml in Spiron-HF versus 17.8± 4.4ml in Epler-HF group; P < 0.05) and left ventricular systolic diameter volume (2.7 ± 0.5ml in Spiron-HF versus 6.7 ± 0.2ml in Epler-HF group; P < 0.05), occurred after 12 months of treatment. Left ventricular global longitudinal strain (LV GLS) was significantly improved in Epler-HF group compared with Spiron-HF group (0.6 ± 0.4 versus 3.4 ± 0.9; P < 0.05). There were no significant differences observed in reduction of left ventricular end-diastolic volume (2.2 ± 0.5 ml versus 4.7 ± 1.1ml; P =0.103) and left ventricular diastolic diameter (1.2 ± 0.6 versus 1.7 ± 0.3; P=0.082) in both arms. The effects of both MRA agents spironolactone and eplerenone on the primary composite outcome, each of the individual mortality and hospital admission outcomes are shown in Figure 1 and 2. Patients of the Epler-HF group showed statistically significant lower cardiovascular mortality (HR 0.53; 95% CI 0.34-0.82; p= 0.007) and all-cause mortality (HR 0.64; 95% CI 0.44-0.93; p= 0.022) than patients of the Spiron-HF group. The statistical analysis did not show a statistically significant difference between Epler -HF and Spiron-HF study groups regarding the risk of the primary composite outcome; cardiovascular death or hospitalization due to HF (Hazard Ratio (HR) eplerenone vs. spironolactone = 0.95; 95% Confidence Interval (CI) 0.73- 1.27; p= 0.675).. Our study has demonstrated favorable effects of eplerenone on cardiac remodeling parameters and reduction of cardiovascular mortality and all-cause mortality compared with spironolactone in the treatment of HFrEF. The ability of eplerenone to effectively block the mineralocorticoid receptor while minimizing side effects and a significant reduction in the risk of hospitalization and cardiovascular death confirms its key role in the treatment of patients with chronic HFrEF.

Topics: Chronic Disease; Eplerenone; Heart Failure; Hospitalization; Humans; Mineralocorticoid Receptor Antagonists; Prospective Studies; Single-Blind Method; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Function, Left

Eplerenone reduces the risk of cardiovascular death or first hospitalization for heart failure (HF) in patients with HF and a reduced ejection fraction (HFrEF), but it is still frequently underused in routine practice. We evaluated the time course of benefits of eplerenone after its initiation in HFrEF patients from the EMPHASIS-HF trial.. The EMPHASIS-HF trial was a double-blind randomized clinical trial assessing the effect of eplerenone in patients (n = 2737, mean age 68.6 ± 7.6 years, 22.3% women) with HFrEF and mild symptoms. The time trajectories for the effect of eplerenone versus placebo on the primary composite endpoint (cardiovascular death or first hospitalization for HF) were investigated using Cox proportional hazards models with truncated data at each day post-randomization. A significant reduction in the primary composite endpoint was observed 26 days after randomization (hazard ratio 0.58; 95% confidence interval, 0.34-1.00, p = 0.049). Eplerenone was first associated with a significant reduction in the primary endpoint in 35 days or less in most subgroups, including patients with HF history ≥18 months (day 24), estimated glomerular filtration rate <60 ml/min (day 12), ischaemic HF aetiology (day 28), age ≥65 years (day 28), narrow QRS (day 30), higher MAGGIC score (day 35), lower potassium (day 30), left ventricular ejection fraction ≥30% (day 28) or already treated with beta-blockers (day 25).. Eplerenone provides statistically significant and clinically meaningful benefits shortly after treatment initiation in most patients, irrespective of clinical profile. This result reinforces the need for an early initiation of eplerenone in HFrEF, as part of rapidly instituting guideline-directed medical therapy.

Topics: Aged; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Spironolactone; Stroke Volume; Ventricular Function, Left

A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated.. In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642-1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213-1.434). The safety profile for eplerenone was as expected.. The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power.

Topics: Aged; Eplerenone; Female; Heart Failure; Humans; Male; Spironolactone; Stroke Volume; Ventricular Function, Left

Sodium changes are common in myocardial infarction (MI) complicated with left ventricular systolic dysfunction (LVSD) and/or heart failure (HF). Sodium handling is fine-tuned in the distal nephron, were eplerenone exhibits some of its pleotropic effects. Little is known about the effect of eplerenone on serum sodium and the prognostic relevance of sodium alterations in patients with MI complicated with LVSD and/or HF.. The EPHESUS trial randomized 6632 patients to either eplerenone or placebo. Hyponatremia and hypernatremia were defined as sodium < 135 mmol/L or > 145 mmol/L, respectively. Linear mixed models and time updated Cox regression analysis were used to determine the effect of eplerenone on sodium changes and the prognostic importance of sodium changes, respectively. The primary outcomes were all-cause mortality and a composite of cardiovascular (CV) mortality and CV-hospitalization.. A total of 6221 patients had a post-baseline sodium measurement, 797 patients developed hyponatremia (mean of 0.2 events/per patient) and 1476 developed hypernatremia (mean of 0.4 events/per patient). Patients assigned to eplerenone had a lower mean serum sodium over the follow-up (140 vs 141 mmol/L; p < 0.0001) and more often developed hyponatremia episodes (15 vs 11% p = 0.0001) and less often hypernatremia episodes (22 vs. 26% p = 0.0003). Hyponatremia, but not hypernatremia was associated with adverse outcome for all outcome endpoints in the placebo group but not in the eplerenone group (interaction p value < 0.05 for all). Baseline sodium values did not influence the treatment effect of eplerenone in reducing the various endpoints (interaction p value > 0.05 for all). Development of new-onset hyponatremia following eplerenone initiation did not diminish the beneficial eplerenone treatment effect.. Eplerenone induces minor reductions in serum sodium. The beneficial effect of eplerenone was maintained regardless of the baseline serum sodium or the development of hyponatremia. Sodium alterations should not refrain clinicians from prescribing eplerenone to patients who had an MI complicated with LVSD and/or HF.. ClinicalTrials.gov identifier: NCT00232180. Serum sodium and eplerenone use in patients with a myocardial infarction and left ventricular dysfunction or heart failure: insights from the EPHESUS trial.

Topics: Eplerenone; Heart Failure; Humans; Myocardial Infarction; Sodium; Treatment Outcome; Ventricular Dysfunction, Left

Heart failure (HF), as a serious health condition, is characterised by the decreasing ability of the heart to pump enough blood around the body. This study compared the effects of spironolactone and eplerenone on the echocardiographic variables of the left ventricular (LV) function in symptomatic patients diagnosed with new-onset systolic HF.. This study was a randomised controlled trial, including 85 symptomatic patients with new-onset systolic HF (namely, dilated cardiomyopathy). The patients were then randomly assigned to two groups in a 1:1 ratio and received either spironolactone or eplerenone in addition to optimal HF therapy for 6 months. Echocardiography was performed to visualise alterations in two-dimensional, pulse Doppler, tissue Doppler, and deformation indices of LV function.. The results revealed that the group receiving eplerenone had a significantly greater increase in LV ejection fraction (LVEF) and a decrease in end-systolic LV internal diameter compared with the group receiving spironolactone (intergroup p=0.002 and p=0.006, respectively). There was a significant reduction in the end-diastolic LV internal diameter and the left atrial diameter, and a significant rise in tissue Doppler peak systolic mitral annular velocity in the group taking eplerenone; there were no significant changes in these variables in the group receiving spironolactone (intergroup p=0.006 and p=0.049, respectively). Accordingly, eplerenone had greater favourable effects on LVEF and the global longitudinal strain than spironolactone (B=5.207 [p<0.001] and B= -2.072 [p=0.044]), respectively.. This study established that adding eplerenone to optimal HF therapy might be associated with more improvements in echocardiographic variables of LV function than spironolactone in symptomatic patients with new-onset systolic HF.

Topics: Echocardiography; Eplerenone; Heart Failure; Heart Failure, Systolic; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone; Ventricular Function, Left

The purpose of this study was to investigate the effects of mineralocorticoid receptor antagonists (MRAs) on systolic blood pressure (SBP) and outcomes according to baseline SBP in patients with heart failure with reduced ejection fraction (HFrEF).. MRAs are greatly underused in patients with HFrEF, often because of fear of adverse events. Concern about hypotension has been raised by the demonstration that MRAs are particularly effective treatment for resistant hypertension.. The effect of MRA therapy was studied in 4,396 patients with HFrEF randomized in the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials.. Mean SBP change from baseline to 6 months was +1.4 ± 18.1 mm Hg in the placebo group and -1.2 ± 17.9 mm Hg in the MRA group. The between-treatment difference was 2.6 mm Hg (95% confidence interval [CI]: 1.5 to 3.6; p < 0.001). All outcomes were reduced by MRA therapy overall, with consistent effects across SBP categories (e.g., all-cause mortality, overall hazard ratio [HR] of 0.72; 95% CI: 0.64 to 0.82; p < 0.001; SBP ≤105 mm Hg; HR: 0.72; 95% CI: 0.56 to 0.94; SBP >105 to ≤115 mm Hg; HR: 0.78; 95% CI: 0.60 to 1.02; SBP >115 to ≤125 mm Hg; HR: 0.71; 95% CI: 0.53 to 0.94; SBP >125 to ≤135 mm Hg; HR: 0.79; 95% CI: 0.57 to 1.10; and SBP > 135 mm Hg; HR: 0.67; 95% CI: 0.50 to 0.90; p for interaction = 0.95). Hypotension was infrequent and not more common with MRA therapy than with placebo, overall (4.6% vs. 3.9%; p = 0.25) or in any SBP category.. MRA treatment had little effect on SBP in patients with HFrEF, and the clinical benefits were not modified by baseline SBP. MRA treatment infrequently caused hypotension, even when the baseline SBP was low. The treatment discontinuation rates between MRA and placebo therapy were similar. Low SBP is not a reason to withhold MRA therapy in patients with HFrEF.

Topics: Aged; Blood Pressure; Eplerenone; Female; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Spironolactone; Stroke Volume; Treatment Outcome

Loop diuretics are used for congestion relief, and dose adaptations are usually a consequence of the clinicians' clinical judgement about the congestive status of the patient. In EPHESUS (Eplerenone in Patients With Systolic Dysfunction After Myocardial Infarction), many patients required diuretics for congestion relief. We thus hypothesized that blinded allocation to eplerenone would lead clinicians to reduce loop diuretics, as a consequence of the improvement in patients' status.. Cox and mixed-effects models were used over a median follow-up of 1.3 years in 6632 patients.. A total of 6632 patients were included; at baseline, 3352 (50.5%) did not have diuretics, 2195 (33.1%) had diuretic doses between 1 and 40 mg/day, and 1085 (16.4%) had diuretic doses >40 mg/day. Patients with higher furosemide equivalent doses had a worse clinical status. Both baseline and follow-up incremental loop diuretic doses were associated with worse prognosis. Eplerenone treatment was associated with lower prescribed loop diuretic doses throughout the follow-up; lower doses were observed at 90 days and decreased further at 180 days and beyond. Eplerenone treatment led to a mean furosemide equivalent dose reduction of -2.2 mg/day (-2.9 to -1.6) throughout the follow-up. Eplerenone was effective in reducing morbidity and mortality regardless of the baseline loop diuretic dose used: hazard ratio for the outcome of cardiovascular death or heart failure hospitalization was 0.83 ([95% CI, 0.75-0.92];. Eplerenone treatment led to a loop diuretic dose reduction during follow-up without evidence of treatment effect modification by loop diuretics. These findings suggest that eplerenone reduces congestive signs and symptoms, which enables clinicians to reduce loop diuretic doses.

Topics: Aged; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Recovery of Function; Sodium Potassium Chloride Symporter Inhibitors; Systole; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

This study sought to assess the effect of MRA treatment (vs. placebo) in older patients (≥75 years of age) compared with younger patients (<75 years of age) with heart failure (HF).. Mineralocorticoid receptor antagonists (MRAs) have been shown to reduce morbidity and mortality in patients with HF with reduced ejection fraction (HFrEF) and in a subset of patients with HF with preserved EF (HFpEF). Notwithstanding, MRAs are underused, especially in the elderly. Pooling the individual patient data (IPD) provided more statistical power with which to assess the efficacy and safety of MRA treatment in this subpopulation.. An IPD meta-analysis was performed using Cox proportional hazards models stratified by trial. A total of 1,756 patients (853 randomized to placebo and 903 to MRA) ≥75 years of age, along with 4,411 patients (2,242 randomized to placebo and 2,169 to MRA) <75 years of age were included. The primary outcome was a composite of death from cardiovascular causes or hospitalization for HF.. The treatment groups were well balanced. Patients ≥75 years of age or older and those 80 years of age, 61% were male, 30% had diabetes, and the mean estimated glomerular filtration rate 59 ml/min. The primary outcome occurred in 331 patients (38.8%) in the placebo group versus 281 (31.1%) in the MRA group (hazard ratio: 0.74; 95% confidence interval: 0.63 to 0.86; p < 0.001; and the heterogeneity p value [heterogeneity p = Cochran's Q p value of treatment effect by study interaction] was 0.52). Cardiovascular death and all-cause death were also reduced by MRAs without significant between-trial or age (younger vs. older) heterogeneity. Worsening renal function and hyperkalemia occurred more frequently in patients taking MRAs (vs. placebo). Compared to younger patients, worsening renal function (but not hyperkalemia) was found more frequently in the elderly.. MRAs reduced morbidity and mortality in elderly patients with HF, a beneficial effect that is more marked in patients with HFrEF but homogenous across HFrEF and HFpEF. Implementation of measures that increase MRA treatment in this population are warranted.

Topics: Age Factors; Aged; Aged, 80 and over; Eplerenone; Female; Heart Failure; Humans; Male; Meta-Analysis as Topic; Middle Aged; Mineralocorticoid Receptor Antagonists; Spironolactone; Stroke Volume

Circulating endothelial progenitor cells have an important role in the process of vascular repair. Impaired recruitment and function of endothelial progenitor cells is related to the pathophysiology of congestive heart failure. Endothelial progenitor cells have been shown to express the mineralocorticoid receptor.. To investigate the effect of mineralocorticoid receptor antagonists on endothelial progenitor cells in patients with heart failure.. Twenty-four patients with compensated heart failure, who were not under mineralocorticoid receptor antagonist therapy, were recruited. Either eplerenone (n=8) or spironolactone (n=16) therapy was initiated. Circulating endothelial progenitor cell level, identified as the proportion of mononuclear cells expressing vascular endothelial growth factor receptor 2 (VEGFR-2), CD133, and CD34, was evaluated by flow cytometry at baseline and after 8 weeks. Following 7 days of culture, colonies were counted by microscopy and MTT assay was performed on randomly selected patients (n=12) to estimate viability.. Both median CD34+/VEGFR2+ and median CD133+/VEGFR2+ increased significantly (P = 0.04 and 0.02, respectively). However, the number of colonies and viability of the cells after therapy (as assessed by the MTT assay) was not significantly different compared with the baseline.. These preliminary results suggest that mineralocorticoid receptor blockade may enhance endothelial progenitor cells recruitment in patients with compensated heart failure.

Topics: AC133 Antigen; Aged; Antigens, CD34; Cell Survival; Cohort Studies; Endothelial Progenitor Cells; Eplerenone; Female; Flow Cytometry; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Prospective Studies; Spironolactone; Vascular Endothelial Growth Factor Receptor-2

Mineralocorticoid receptor antagonists (MRAs) decrease morbidity and mortality in patients with heart failure (HF). However, spironolactone, a non-selective MRA, has been shown to exert a harmful effect on glucose homeostasis. The objective of this multicenter, randomized, controlled, double-blind trial was to compare the effects of spironolactone to those of the selective MRA eplerenone on glucose homeostasis among 62 HF patients with glucose intolerance or type II diabetes. Trial registration number:NCT01586442.

Topics: Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Eplerenone; Female; Glucose Intolerance; Glycated Hemoglobin; Heart Failure; Homeostasis; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Prospective Studies; Spironolactone; Stroke Volume

The mineralocorticoid receptor antagonist eplerenone improved clinical outcomes among patients with heart failure with reduced ejection faction (HFrEF) in the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study. However, similar efficacy and safety have not been established in Japanese patients. We evaluated the efficacy and safety of eplerenone in patients with HFrEF in a multicenter, randomized, double-blind placebo-controlled outcome study (ClinicalTrials.gov Identifier: NCT01115855). The aim of the study was to evaluate efficacy predefined as consistency of the primary endpoint with that of EMPHASIS-HF at a point estimate of <1 for the hazard ratio.Methods and Results:HFrEF patients with NYHA functional class II-IV and an EF ≤35% received eplerenone (n=111) or placebo (n=110) on top of standard therapy for at least 12 months. The primary endpoint was a composite of death from cardiovascular causes or hospitalization for HF. The primary endpoint occurred in 29.7% of patients in the eplerenone group vs. 32.7% in the placebo group [hazard ratio=0.85 (95% CI: 0.53-1.36)]. Hospitalization for any cause and changes in plasma BNP and LVEF were favorable with eplerenone. A total of 17 patients (15.3%) in the eplerenone group and 10 patients (9.1%) in the placebo group died. Adverse events, including hyperkalemia, were similar between the groups.. Eplerenone was well-tolerated in Japanese patients with HFrEF and showed results consistent with those reported in the EMPHASIS-HF study.

Topics: Aged; Antihypertensive Agents; Chronic Disease; Double-Blind Method; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Treatment Outcome

To characterize eplerenone pharmacokinetics (PK) in Japanese chronic heart failure (CHF) patients and to estimate the impact of factors that may affect eplerenone PK, population pharmacokinetic (PPK) analysis was conducted. In addition, PK of Japanese CHF and Western CHF patients from a previous clinical pharmacology study were compared in the analysis. Eplerenone PK was characterized by a 1-compartment PPK model with first-order absorption and lag time in Japanese CHF patients. The population mean of apparent oral clearance (CL/F) in Japanese CHF patients was estimated as 5.31 L/h, which was similar to the mean CL/F for Western CHF patients. In the full model approach, creatinine clearance (CLcr) on CL/F and body weight on apparent central volume of distribution (Vc/F) were selected as factors that may affect PK. The effect of CLcr on CL/F predicted that CL/F would be decreased by 25% when CLcr was decreased from 80 mL/min to 50 mL/min. The effect of body weight on Vc/F predicted that Vc/F would be decreased by 18% when body weight was decreased from 80 kg to 60 kg. Distribution of individual CL/F estimates for Japanese CHF patients overlapped CL/F observed values for Western CHF patients, and CL/F values for Western CHF patients were contained within the distribution of CL/F estimates for Japanese CHF patients. No obvious difference between Japanese and Western subjects was detected even in the updated model by adding the data obtained from Western CHF patients and Western healthy adults to the model constructed with data from Japanese CHF patients.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Chronic Disease; Double-Blind Method; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Models, Biological; Spironolactone

Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI.. In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients.. When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint).. Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies.. In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies.

Topics: Aged; Biomarkers; Endothelin-1; Eplerenone; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Natriuretic Peptide, Brain; Predictive Value of Tests; Spironolactone; Survival Rate; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left

Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, was evaluated in Japanese patients with heart failure (HF) with reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.. ARTS-HF Japan was a randomized, double-blind, phase 2b study. Patients (n=72) received oral, once-daily (o.d.) finerenone (2.5, 5, 7.5, 10 or 15 mg, up-titrated to 5, 10, 15, 20, or 20 mg, respectively, on day 30) or eplerenone (25 mg every other day, increased to 25 mg o.d. on day 30, and 50 mg on day 60) for 90 days. The primary endpoint was the proportion of individuals with a decrease of >30% in plasma NT-proBNP at day 90. Safety endpoints included the incidence of hyperkalemia. Decreases in NT-proBNP occurred in 23.1% of patients in the eplerenone group and 15.4%, 23.1%, 45.5%, 27.3% and 45.5% in the 2.5→5 mg, 5→10 mg, 7.5→15 mg, 10→20 mg and 15→20 mg finerenone groups, respectively (all P=NS). Mean changes in serum potassium levels were similar between groups.. Because of the small sample size, limited conclusions can be drawn. Considering the results of ARTS-HF and that finerenone was well tolerated in Japanese patients in ARTS-HF Japan, the safety and efficacy of finerenone should be further explored in a large outcomes trial including Japanese patients. (Circ J 2016; 80: 1113-1122).

Topics: Adult; Chronic Disease; Diabetes Mellitus; Double-Blind Method; Eplerenone; Heart Failure; Humans; Hyperkalemia; Japan; Naphthyridines; Natriuretic Peptide, Brain; Patient Safety; Peptide Fragments; Renal Insufficiency, Chronic; Spironolactone

To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.. Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: NCT01807221). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7-10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg finerenone groups, respectively (P = 0.42-0.88). Except for the 2.5→5 mg finerenone group, the composite clinical endpoint occurred numerically less frequently in finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups.. Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the finerenone 10→20 mg group should be further explored in a large outcomes trial.

Topics: Aged; Chronic Disease; Diabetes Mellitus; Double-Blind Method; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Natriuretic Peptide, Brain; Peptide Fragments; Renal Insufficiency, Chronic; Spironolactone

Aldosterone is one of the major factors to cause organ damage during an acute phase of heart failure (HF), and many reports have demonstrated that patients with acute decompensated HF (ADHF) have high blood aldosterone concentrations, and the high aldosterone concentrations predict poor prognosis in patients with HF. These findings suggest that eplerenone, an antagonist of aldosterone receptors may provide a new concept and strategy for the treatment of ADHF, protecting the heart and other organs during chronic phases, depending on the restoration of hemodynamic abnormalities.. EARLIER is an event-driven clinical trial with an estimated enrolment of 300 patients hospitalized with ADHF with reduced left ventricular ejection fraction. ADHF includes ischemic or non-ischemic HF, and patients can be enrolled within 72 h after the visit to the hospital. We randomize the patients taking standard therapies for ADHF to the eplerenone and placebo groups. Eplerenone, either 25 or 50 mg, is administered for 6 months in the eplerenone group, and the corresponding placebo is administered in the placebo group on top of the standard care. We set the primary endpoint as the incidence of the composite endpoint (cardiac death or first re-hospitalization due to cardiac disease) 6 months after the enrollment, and also check the quality of life, i.e., exercise capacity and safety features of eplerenone.. EARLIER is a clinical trial of eplerenone targeting ADHF and also the first multicenter investigator-initiated phase III trial in the cardiovascular field in Japan, funded by the Japanese government.

Topics: Acute Disease; Adult; Clinical Protocols; Double-Blind Method; Early Medical Intervention; Eplerenone; Female; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Spironolactone; Young Adult

To investigate the safety and potential efficacy of the novel non-steroidal mineralocorticoid receptor antagonist finerenone in patients with worsening chronic heart failure and reduced left ventricular ejection fraction (HFrEF) and at high risk of hyperkalaemia and worsening renal dysfunction.. The MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF; NCT01807221) is a multicentre, randomized, double-blind, active-comparator-controlled, six-parallel-group, phase 2b dose-finding study. In total, 1060 patients with HFrEF and concomitant type 2 diabetes mellitus and/or chronic kidney disease (CKD) will be randomized within 7 days of emergency presentation to hospital for worsening chronic HF to receive finerenone (one of five doses in the range 2.5-20.0 mg once daily) or eplerenone (25 mg every second day to 50 mg once daily for 90 days). The primary objective is to investigate the safety and potential efficacy (measured as the percentage of individuals with a decrease in plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP] of more than 30% relative to baseline at day 90 ± 2) of different oral doses of finerenone compared with eplerenone. Other objectives are to assess the effects of finerenone on a composite clinical endpoint (death from any cause, cardiovascular hospitalizations, or emergency presentations for worsening chronic HF), and on changes in health-related quality of life from baseline.. ARTS-HF is the first phase 2b clinical trial to investigate the effects of finerenone on plasma NT-proBNP in a high-risk population of patients who have worsening chronic HF with type 2 diabetes mellitus and/or CKD presenting at the emergency department.

Topics: Comorbidity; Diabetes Mellitus, Type 2; Double-Blind Method; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Natriuretic Agents; Natriuretic Peptide, Brain; Peptide Fragments; Renal Insufficiency, Chronic; Spironolactone

We examined the relationship between different degrees of QRS prolongation and different QRS morphologies and clinical outcomes in patients with heart failure, reduced ejection fraction (HF-REF), and mild symptoms in the Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure trial (EMPHASIS-HF). We also evaluated the effect of eplerenone in these patients according to QRS duration/morphology.. Patients were categorized as: QRS duration (ms) (i) <120 (n = 1375); (ii) 120-149 (n = 517); and (iii) ≥150 (n = 383), and QRS morphology (i) normal (n = 1252); (ii) left bundle branch block (BBB) (n = 608); and (iii) right BBB/intraventricular conduction defect (IVCD) (n = 415). The outcomes examined were the composite of cardiovascular death or heart failure hospitalization and all-cause mortality. Both abnormal QRS duration and QRS morphology were associated with higher risk, e.g. the rates of the composite outcome were: 10.2, 17.6, and 15.5 per 100 patient-years in the <120, 120-149, and ≥150 ms groups, respectively. Eplerenone reduced the risk of the primary outcome and mortality, compared with placebo, consistently across the QRS duration/morphology subgroups.. We found that even moderate prolongation of QRS duration and right BBB/IVCD were associated with a high risk of adverse outcomes in HF-REF. Eplerenone was similarly effective, irrespective of QRS duration/morphology.

Topics: Aged; Double-Blind Method; Electrocardiography; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Random Allocation; Spironolactone; Stroke Volume; Survival Rate; Treatment Outcome

Although hypertension contributes significantly to worsen cardiovascular risk, blood pressure increment in subjects with heart failure is paradoxically associated with lower risk. The objective was to determine whether pulse pressure and pulse wave velocity (PWV) remain prognostic markers, independent of treatment in heart failure with reduced left ventricular function. The investigation involved 6632 patients of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study. All subjects had acute myocardial infarction with left ventricular ejection fraction <40% and signs/symptoms of heart failure. Carotid-femoral PWV was measured in a subpopulation of 306 subjects. In the overall population, baseline mean arterial pressure <90 mm Hg was associated with higher all-cause death (hazard ratio, 1.14 [95% confidence interval, 1.00-1.30]; P<0.05), whereas higher left ventricular ejection fraction or pulse pressure was associated with lower rates of all-cause death, cardiovascular death/hospitalization, and cardiovascular death. In the subpopulation, increased baseline PWV was associated with worse outcomes (all-cause death: 1.16 [1.03-1.30]; P<0.05 and cardiovascular deaths: 1.16 [1.03-1.31]; P<0.05), independent of age and left ventricular ejection fraction. Using multiple regression analysis, systolic blood pressure and age were the main independent factors positively associated with pulse pressure or PWV, both in the entire population or in the PWV substudy. In heart failure and low ejection fraction, our results suggest that pulse pressure, being negatively associated with outcome, is more dependent on left ventricular function and thereby no longer a marker of aortic elasticity. In contrast, increased aortic stiffness, assessed by PWV, contributes significantly to cardiovascular death.

Topics: Aged; Arterial Pressure; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Predictive Value of Tests; Prognosis; Pulse Wave Analysis; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left

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).. 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.. 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.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00232180.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Eplerenone; Female; Follow-Up Studies; Glomerular Filtration Rate; Heart Failure; Hospitalization; Humans; Hyperkalemia; Incidence; Longitudinal Studies; Male; Mineralocorticoid Receptor Antagonists; Multivariate Analysis; Potassium; Prognosis; Risk Factors; Spironolactone; Survival Rate

We aimed to assess the impact of eplerenone on cardiovascular (CV) outcomes in STEMI without known heart failure, when initiated within 24 h of symptom onset.. In this randomized, placebo-controlled, double-blind trial, we assigned 1012 patients with acute STEMI and without a history of heart failure to receive either eplerenone (25-50 mg once daily) or placebo in addition to standard therapy. The primary endpoint was the composite of CV mortality, re-hospitalization, or, extended initial hospital stay, due to diagnosis of HF, sustained ventricular tachycardia or fibrillation, ejection fraction ≤40%, or elevated BNP/NT-proBNP at 1 month or more after randomization. BNP elevation was defined as BNP levels or values above 200 pg/mL or NT-proBNP values above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or above 1800 pg/mL (patients older than 75). After a mean follow-up of 10.5 months, the primary endpoint occurred in 92 patients (18.2%) in the eplerenone group and in 149 patients (29.4%) in the placebo group [adjusted hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45-0.76; P < 0.0001]. The primary endpoint was driven by a high BNP/NT-proBNP level (adjusted HR, 0.60; 95% CI, 0.45-0.79; P < 0.0003). Adverse event rates were similar in both groups. Serum potassium levels exceeded 5.5 mmol/L in 5.6 vs. 3.2% (P = 0.09) and were below 3.5 mmol/L in 1.4 vs. 5.6% of patients (P = 0.0002), in the eplerenone and placebo groups, respectively.. The addition of eplerenone during the acute phase of STEMI was safe and well tolerated. It reduced the primary endpoint over a mean 13 months follow-up mostly because of significantly lower BNP/NT-proBNP levels. Additional studies are needed to clarify the role of early use of MRAs in STEMI patients without heart failure.. NCT01176968.

Topics: Double-Blind Method; Eplerenone; Female; Heart Failure; Humans; Length of Stay; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Patient Readmission; Spironolactone; Treatment Outcome

In EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), eplerenone significantly reduced major cardiovascular events versus placebo in 2737 patients with mild symptoms of heart failure and an ejection fraction of <35%, in addition to recommended therapy. However, it is not known whether such benefits were preserved in patients receiving optimal background drug therapy, that is, high doses of angiotensin-converting enzyme inhibitor (ACEi, or angiotensin receptor blocker), β-blocker, or both drug classes.. We further analyzed EMPHASIS-HF according to the use and dose of these background drug classes. Patients receiving ≥ 50% of target dose were considered to be receiving high doses; patients on <50% or no drug comprised the low-dose group. The primary end point of the study (cardiovascular death/heart failure hospitalization), as well as all-cause mortality, was evaluated in this way. The beneficial clinical effects of eplerenone (as observed in the main study) were preserved for the EMPHASIS-HF primary end point in patients receiving higher doses of ACEi or angiotensin receptor blocker, β-blocker, or both (hazard ratio for eplerenone versus placebo, ACEi/angiotensin receptor blocker: high dose, 0.67; low dose, 0.65; β-blockers: high dose, 0.55; low dose, 0.72; both ACEi/angiotensin receptor blocker and β-blocker: high dose, 0.59; low dose, 0.68; P value for interaction 0.80, 0.15, and 0.53, respectively), as well as for all-cause mortality. There were no major safety issues, except a borderline increased risk of hypotension with eplerenone in those on high-dose ACEi or ACEi/β-blocker.. Eplerenone provides substantial benefit on major events (with an acceptable safety profile) in patients with mild symptoms of systolic heart failure, even in those already receiving high doses of standard background therapies.

Topics: Adrenergic Antagonists; Adrenergic beta-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Benchmarking; Drug Therapy, Combination; Eplerenone; Female; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Spironolactone

The study sought to investigate the safety and efficacy of eplerenone in patients at high risk for hyperkalemia or worsening renal function (WRF) in EMPHASIS-HF, a trial that enrolled patients at least 55 years old with heart failure and reduced ejection fraction (HF-REF), in New York Heart Association (NYHA) functional class II and with an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m(2) and serum potassium <5.0 mmol/l. Patients were receiving optimal therapy and most had been hospitalized for a cardiovascular reason within 180 days of inclusion.. Underuse of eplerenone in patients with HF-REF may be due to fear of inducing hyperkalemia or WRF in high-risk patients.. This was a pre-specified analysis of subgroups of patients at high risk of hyperkalemia or WRF (patients ≥ 75 years of age, with diabetes, with eGFR <60 ml/min/1.73 m(2), and with systolic blood pressure < median of 123 mm Hg), examining the major safety measures (potassium >5.5, >6.0, and <3.5 mmol/l; hyperkalemia leading to study-drug discontinuation or hospitalization; and hospitalization for WRF) as well as the primary outcome (hospitalization for HF or cardiovascular mortality).. In all high-risk subgroups, patients treated with eplerenone had an increased risk of potassium >5.5 mmol/l but not of potassium >6.0 mmol/l, and of hospitalization for hyperkalemia or discontinuation of study medication due to adverse events. Eplerenone was effective in reducing the primary composite endpoint in all subgroups.. In patients with chronic HF-REF, in NYHA functional class II, and meeting specific inclusion and exclusion criteria, including an eGFR >30 ml/min/1.73 m(2) and potassium <5.0 mmol/l, eplerenone was both efficacious and safe when carefully monitored, even in subgroups at high risk of developing hyperkalemia or WRF. (A Comparison Of Outcomes In Patients In New York Heart Association [NYHA] Class II Heart Failure When Treated With Eplerenone Or Placebo In Addition To Standard Heart Failure Medicines [EMPHASIS-HF Study]; NCT00232180).

Topics: Aged; Aged, 80 and over; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Hyperkalemia; Kidney Function Tests; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Risk Factors; Spironolactone; Survival Rate; Treatment Outcome

There is no proven pharmacological strategy for the treatment of the failing systemic right ventricle (SRV) but myocardial fibrosis may play a role in its pathophysiology.. We designed a double-blind, placebo-controlled clinical trial to assess the effects of eplerenone 50mg during 12 months on cardiac magnetic resonance parameters (SRV mass and ejection fraction) and neurohormonal and collagen turnover biomarker (CTB) levels.. Twenty six patients with atrial switch repair for transposition of the great arteries were randomized to eplerenone (n=14) or placebo (n=12) and 14 healthy volunteers served as controls for comparison of baseline neurohormones and CTB levels. The study population showed a good baseline profile in terms of SRV mass (57.4 ± 17 g/m(2)) and ejection fraction (54.9 ± 7.5%). However, levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), C terminal propeptide of type I procollagen (CICP) and C-terminal Telopeptide of type I Collagen (ICTP) were significantly elevated when compared to healthy controls. After one year of treatment, a trend toward reduction of CICP, N-terminal pro-Matrix Metalloproteinase 1 (NT-proMMP1), Tissue Inhibitor of Metalloproteinases 1 (TIMP1) and galectin 3 levels and a lower increase in ICTP in patients under eplerenone was observed. The reduction of SRV mass and the improvement of SRV function with eplerenone were not conclusive.. Patients with SRV treated with eplerenone showed an improvement of an altered baseline CTB profile suggesting that reduction of myocardial fibrosis might be a therapeutic target in these patients.

Topics: Adult; Aldosterone; Cardiac Imaging Techniques; Collagen; Double-Blind Method; Eplerenone; Female; Fibrosis; Follow-Up Studies; Heart Failure; Humans; Magnetic Resonance Imaging; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Spironolactone; Transposition of Great Vessels; Treatment Outcome; Ventricular Dysfunction, Right; Young Adult

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).. 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 -1.4±0.3 mL · min(-1) · 1.73 m(-2) compared with placebo (P<0.0001), an effect that appeared within the first month (-1.3±0.4 mL · min(-1) · 1.73 m(-2)) and persisted throughout the study. Overall, 914 patients experienced a decline in eGFR >20% 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; P=0.017). In multivariate analyses, determinants of this early decline in eGFR were female sex, age ≥65 years, smoking, left ventricular ejection fraction <35%, and use of eplerenone and loop diuretic. An early decline in eGFR by >20% 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.. 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.

Topics: Aged; Eplerenone; Glomerular Filtration Rate; Heart Failure; Heart Failure, Systolic; Humans; Kidney; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

BAY 94-8862 is a novel, non-steroidal, mineralocorticoid receptor antagonist with greater selectivity than spironolactone and stronger mineralocorticoid receptor binding affinity than eplerenone. The aims of the MinerAlocorticoid Receptor Antagonist Tolerability Study (ARTS; NCT01345656) are to evaluate the safety and tolerability of BAY 94-8862 in patients with heart failure associated with a reduced left ventricular ejection fraction (HFREF) and chronic kidney disease (CKD), and to examine the effects on biomarkers of cardiac and renal function. Methods ARTS is a multicentre, randomized, double-blind, placebo-controlled, parallel-group study divided into two parts. In part A, oral BAY 94-8862 [2.5, 5, or 10 mg once daily (o.d.)] is compared with placebo in ∼60 patients with HFREF and mild CKD. Outcome measures include serum potassium concentration, biomarkers of renal injury, estimated glomerular filtration rate (eGFR), and albuminuria. Part B compares BAY 94-8862 (2.5, 5, or 10 mg o.d., or 5 mg twice daily), placebo, and open-label spironolactone (25-50 mg o.d.) in ∼360 patients with HFREF and moderate CKD. Outcome measures include the change in serum potassium concentration with BAY 94-8862 vs. placebo (primary endpoint) and vs. spironolactone, safety and tolerability, biomarkers of cardiac and renal function or injury, eGFR, and albuminuria. BAY 94-8862 pharmacokinetics are also assessed. Perspectives ARTS is the first phase II clinical trial of BAY 94-8862 and is expected to provide a wealth of information on BAY 94-8862 in patients with HFREF and CKD, including the optimal dose range for further studies.

Topics: Aldosterone; Confidence Intervals; Double-Blind Method; Eplerenone; Female; Health Status Indicators; Heart Failure; Humans; Kidney Failure, Chronic; Male; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Research Design; Severity of Illness Index; Spironolactone

No studies have examined the effect of mineralocorticoid receptor antagonist therapy on new-onset diabetes. In addition, though the combination of diabetes and chronic heart failure (CHF) carries a poor prognosis, few studies have examined predictors of new-onset diabetes in those with CHF.. In patients with symptomatically mild CHF who participated in the placebo-controlled Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, we examined the effect of the aldosterone antagonist, eplerenone, on physician-diagnosed diabetes using univariate Cox proportional hazard analysis. To identify predictors of new-onset diabetes (measures of glycaemia were not available), data from trial arms were combined and multivariate Cox proportional hazard analyses and receiver operating characteristic curve analyses were conducted. At baseline, the mean age of 1846 initially non-diabetic patients was 69 years and mean left ventricular ejection fraction was 26%. Over 21 months, 69 (3.7%) developed diabetes (33 on eplerenone, 36 on placebo). Eplerenone had no effect on new-onset diabetes [hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.59-1.52] and no effect on the composite of new-onset diabetes or mortality (HR 0.80, 95% CI 0.64-1.01). Independent predictors of new-onset diabetes included digoxin therapy, higher serum alanine aminotransferase, longer duration of heart failure, current or previous smoker, higher waist circumference, lower age, and higher systolic blood pressure with a combined c-statistic of 0.74.. Eplerenone had no effect on new-onset diabetes in patients with CHF, but further large-scale studies are required to address this question comprehensively. Commonly recorded parameters provided useful information for predicting new-onset diabetes.

Topics: Aged; Diabetes Mellitus; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Male; Mineralocorticoid Receptor Antagonists; Prognosis; Proportional Hazards Models; Risk Factors; Severity of Illness Index; Spironolactone

Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms.. In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.. The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).. Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.).

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Combined Modality Therapy; Defibrillators, Implantable; Double-Blind Method; Eplerenone; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Proportional Hazards Models; Spironolactone

Cardiac fibrosis is a major determinant of myocardial stiffness, diastolic dysfunction, and heart failure (HF). By reducing cardiac fibrosis, aldosterone antagonists have the potential to be beneficial in heart failure with preserved ejection fraction (HFpEF).. In a randomized, double-blind, placebo-controlled trial of 44 patients with HFpEF, we examined the effects of eplerenone, an aldosterone antagonist, on changes in 6-minute walk distance (primary end point), diastolic function, and biomarkers of collagen turnover (secondary end points). All patients had a history of hypertension, 61% were diabetic, and 52% had prior HF hospitalization. After 6 months of treatment, similar improvements in 6 minute walk distance were noted in the eplerenone and placebo groups (P = .91). However, compared with placebo, eplerenone was associated with a significant reduction in serum markers of collagen turnover (procollagen type I aminoterminal peptide, P = .009 and carboxy-terminal telopeptide of collagen type I, P = .026) and improvement in echocardiographic measures of diastolic function (E/E', P = .01).. Although eplerenone was not associated with an improvement in exercise capacity compared to placebo, it was associated with significant reduction in markers of collagen turnover and improvement in diastolic function. Whether these favorable effects will translate into morbidity and mortality benefit in HFpEF remains to be determined.

Topics: Aged; Aged, 80 and over; Biomarkers; Collagen; Double-Blind Method; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Spironolactone; Stroke Volume

Aldosterone antagonism has been studied in patients with advanced heart failure (HF) and also in patients with post-myocardial infarction and left ventricular (LV) dysfunction with HF symptoms. Few data are available on effects of aldosterone antagonism in patients with mild-to-moderate HF.. In a multicenter, randomized, double-blind, placebo-controlled study in patients with mild-to-moderate HF and LV systolic dysfunction, patients with New York Heart Association class II/III HF and LV ejection fraction (EF) < or =35% were randomly assigned to receive eplerenone 50 mg/d versus placebo in addition to contemporary background therapy. Quantitative radionuclide ventriculograms to assess LV volumes and ejection fraction were performed at baseline and again after 9 months of double-blind treatment and were analyzed in a central core laboratory, blinded to treatment. The primary efficacy analysis was the between-group comparison of the change in LV end-diastolic volume index. Secondary analyses examined changes in LV end-systolic volume index and ejection fraction as well as markers of collagen turnover. Of the total 226 patients enrolled, 117 were randomly assigned to receive eplerenone and 109 to receive placebo. There was high use of contemporary background therapy at baseline, with > 90% use of angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers and > 90% use of beta-blockers. Over 36 weeks of treatment, there was no apparent between-group difference in the changes in end-diastolic volume index or end-systolic volume index. There was a reduction in the collagen turnover marker procollagen type I N-terminal propeptide and plasma B-type natriuretic peptide in the eplerenone group compared with placebo (P=0.01 and P=0.04, respectively). There was no change in symptom status or quality-of-life measures.. In a clinically stable, well-treated population of patients with mild-to-moderate HF symptoms and LV dysfunction, 36 weeks of treatment of aldosterone antagonism with eplerenone at a dose of 50 mg daily had no detectable effect on parameters of LV remodeling.

Topics: Aged; Cohort Studies; Double-Blind Method; Eplerenone; Female; Gated Blood-Pool Imaging; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Natriuretic Peptide, Brain; Procollagen; Quality of Life; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

It has been reported that mineralocorticoid receptor antagonist improves the prognosis of chronic heart failure (CHF). Recently, hemoglobin A₁(c) (HbA₁(c)) levels have been reported to be an independent risk factor for mortality in CHF, suggesting the important role of insulin resistance in CHF. We compared the metabolic effect of a selective mineralocorticoid receptor blocker eplerenone with spironolactone in CHF patients.. One hundred seven stable outpatients with mild CHF, who were already receiving standard therapy for CHF, were randomized (1:2) to spironolactone (25 mg/d) or eplerenone (50 mg/d). Plasma levels of B-type natriuretic peptide, adiponectin, HbA₁(c) and cortisol were measured before and after 4 months treatment with spironolactone or eplerenone.. There were no differences in baseline characteristics including hemodynamic parameters and plasma levels of biomarkers between 2 groups. In both groups, plasma B-type natriuretic peptide levels were significantly decreased and plasma aldosterone levels were significantly increased after 4 months. In patients receiving spironolactone (n = 34), plasma adiponectin levels were significantly decreased (12.6 ± 1.4-11.2 ± 1.3 μg/mL, P < .0001) and HbA₁(c) and cortisol levels were significantly increased (5.61 ± 0.1-5.8 ± 0.1%, P < .0001, 11.3 ± 0.8-14.7 ± 1.3 μg/dL, P = .003, respectively). In patients receiving spironolactone, there was a significant positive correlation between the change in cortisol and the change in HbA₁(c) (r = 0.489, P = .003). In contrast, in patients receiving eplerenone (n = 73), plasma levels of adiponectin, HbA₁(c) and cortisol did not change.. These findings indicated that the metabolic effect of eplerenone differed from that of spironolactone and that eplerenone had a superior metabolic effect especially on HbA₁(c) in CHF patients.

Topics: Aged; Biomarkers; Dose-Response Relationship, Drug; Eplerenone; Female; Glycated Hemoglobin; Heart Failure; Humans; Hydrocortisone; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Spironolactone; Treatment Outcome

Although a variety of prognostic tools have been shown to predict rehospitalization and mortality in heart failure patients, their utility in assessing future costs is less clear. We assessed whether health status assessment with the Kansas City Cardiomyopathy Questionnaire (KCCQ) predicts future costs in stable heart failure outpatients with left ventricular dysfunction after myocardial infarction.. We evaluated 12-month cost utilization data from 1516 heart failure outpatients enrolled in the Quality-of-Life Substudy of the Eplerenone Post-Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Multivariable hierarchical models assessed whether the KCCQ (categorized as 0 to <25, 25 to <50, 50 to <75, and 75 to 100) was an independent predictor of future resource use. At baseline, 685 patients (45.2%) had good health status (KCCQ scores > or =75), whereas 510 (33.6%), 262 (17.3%), and 59 (3.9%) had fair (KCCQ, 50 to 74), poor (KCCQ, 25 to 49), and the worst (KCCQ <25) health status, respectively. After multivariable adjustment, compared with patients with good health status, patients with fair health status incurred incremental 1-year costs of $1520 (cost ratio, 1.23; 95% confidence interval, 1.05 to 1.43), whereas patients with poor and the worst health status incurred incremental 1-year costs of $4265 (cost ratio, 1.63; 95% confidence interval, 1.34 to 1.99) and $8999 (cost ratio, 2.34; 95% confidence interval, 1.62 to 3.38), respectively (P<0.0001 for association with KCCQ). Further adjustment for New York Heart Association class led to only partial attenuation of this relationship (P=0.0002).. Health status assessment predicts resource use and costs over the next year in stable heart failure outpatients with left ventricular dysfunction after myocardial infarction.

Topics: Acute Disease; Aged; Cohort Studies; Eplerenone; Female; Follow-Up Studies; Health Care Costs; Health Status; Heart Failure; Humans; Internationality; Male; Middle Aged; Myocardial Infarction; Spironolactone; Survival Rate; Ventricular Dysfunction, Left

Aldosterone stimulates cardiac collagen synthesis. Circulating biomarkers of collagen turnover provide a useful tool for the assessment of cardiac remodeling in patients with congestive heart failure and left ventricular systolic dysfunction after acute myocardial infarction.. In a substudy of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), which evaluated the effects of the selective aldosterone receptor antagonist eplerenone versus placebo, serum levels of collagen biomarkers were measured in 476 patients with congestive heart failure after acute myocardial infarction complicated with left ventricular systolic dysfunction. The combination of the type I collagen telopeptide and brain natriuretic peptide levels above median at baseline was associated with all-cause mortality and the composite end point of cardiovascular death or heart failure hospitalization, with hazard ratios of 2.49 (P=0.039) and 3.03 (P=0.002), respectively. During follow-up, levels of aminoterminal propeptide of type I and type III procollagen were found to be consistently lower in the eplerenone group and significantly lower beginning at 6 months.. Changes in biomarkers of collagen synthesis and degradation suggest that extracellular matrix remodeling is an active process in patients with congestive heart failure and left ventricular systolic dysfunction after acute myocardial infarction. High type I collagen telopeptide and high brain natriuretic peptide serum levels are associated with the highest event rate. Eplerenone suppresses post-acute myocardial infarction collagen turnover changes.

Topics: Aged; Biomarkers; Collagen Type I; Collagen Type III; Death, Sudden, Cardiac; Eplerenone; Extracellular Matrix; Female; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Placebos; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Spironolactone; Ventricular Dysfunction, Left

The associations of a history of hypertension with subsequent outcomes after acute myocardial infarction have not been examined in propensity-matched studies. Of the 6,632 patients with acute myocardial infarctions and left ventricular systolic dysfunction in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), 4,407 had histories of hypertension. Propensity scores for a history of hypertension, estimated for each patient using 64 baseline characteristics, were used to match 1,990 pairs of patients with and without hypertension. Matched Cox regression models were used to estimate associations between hypertension and outcomes during a mean of 16 months of follow-up. Heart failure (HF) hospitalization occurred in 11.9% and 8.8% of patients, respectively, with and without hypertension (hazard ratio [HR] for hypertension vs no hypertension 1.36, 95% confidence interval [CI] 1.10 to 1.68, p = 0.004). The association between a history of hypertension and HF hospitalization was significant only in patients without previous HF (n = 3,495, HR 1.48, 95% CI 1.18 to 1.84, p = 0.001), but not in those with previous HF (n = 485, HR 1.09, 95% CI 0.73 to 1.62, p = 0.688, p for interaction = 0.179). A history of hypertension was not associated with all-cause mortality (HR 1.02, 95% CI 0.86 to 1.22, p = 0.790) or cardiovascular hospitalization (HR 1.08, 95% CI 0.92 to 1.27, p = 0.339). In conclusion, a history of hypertension was associated with subsequent HF hospitalization after acute myocardial infarction, especially in patients without histories of HF, suggesting that hypertension increased the risk for hospitalization with incident HF but did not affect hospitalization for worsening HF symptoms in those with prevalent HF.

Topics: Aged; Double-Blind Method; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Hypertension; Incidence; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Probability; Prognosis; Proportional Hazards Models; Risk Assessment; Risk Factors; Spironolactone; Survival Analysis

Heart rate turbulence (HRT) is a promising marker for risk of mortality after acute myocardial infarction (AMI). We investigated HRT for risk stratification in high-risk patients after MI. HRT from 24-hour Holter monitoring in 481 hospitalized patients after AMI with heart failure and/or diabetes with left ventricular dysfunction before randomization in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Over a 1-year follow-up, 55 died, 49 of cardiovascular causes. HRT onset (TO) and slope (TS) were calculated using previous and cohort-optimized cutpoints and their independent contribution to risk of cardiovascular death determined. Models were tested with <5 ventricular premature complexes (PVCs) categorized as normal (n = 452) and with <5 VPCs excluded (n = 342). In EPHESUS, optimal cutpoints were TS < or = 3.0 and TO > or = 0.0. The strongest model for predicting cardiovascular mortality used EPHESUS cutpoints excluding subjects with <5 VPCs. On 3-category HRT model multivariate analysis (TS and TO normal, TS or TO abnormal, TS and TO abnormal), both TS and TO abnormal (relative risk 3.64, 95% confidence interval 1.55 to 8.55, p = 0.003) and left ventricular ejection fraction < or =30% (relative risk 1.97, 95% confidence interval 1.04 to 3.73, p = 0.037) independently predicted cardiovascular death. In conclusion, HRT is an independent predictor of cardiovascular death in a high-risk population after AMI, with a possibly higher optimal cutpoint for HRT slope than previously reported.

Topics: Aged; Electrocardiography, Ambulatory; Eplerenone; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Risk Assessment; Spironolactone; Ventricular Dysfunction, Left

Heart failure (HF) with reduced left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) is associated with increased readmission rates. This study evaluated the effects of eplerenone, a selective aldosterone blocking agent, on the duration of subsequent hospitalizations for HF in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).. The EPHESUS study included 6,632 patients post-AMI with LVEF < or =40% and clinical HF or diabetes, receiving standard therapy, randomized to either eplerenone 25 mg, titrated to 50 mg daily, or placebo, with a mean follow-up of 16 months. Analyses of the length of stay and total number of days of HF hospitalizations per patient were conducted on a subgroup of 828 patients with subsequent HF hospitalizations, overall and across 5 distinct geographic regions.. Eplerenone was associated with a 1.6-day reduction in the mean length of HF hospitalization (9.2 vs 10.8 days with placebo; P = .019) and 3.6-day reduction in the total days spent in the hospital for HF (13.3 vs 16.9 days with placebo; P = .0006). These benefits were observed in all geographic regions.. In patients post-AMI with reduced LVEF and HF or diabetes, eplerenone added to standard therapy reduced the mean length and total days of HF hospitalizations compared to placebo in all regions. Given the high cost of hospital care for HF, these findings may translate into an economic benefit to health care worldwide.

Topics: Aged; Double-Blind Method; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Length of Stay; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

To test the hypothesis that an earlier post-acute myocardial infarction (AMI) eplerenone initiation in patients with left ventricular systolic dysfunction (LVSD) and heart failure (HF) is associated with better long-term outcomes.. The 6632 patients of the EPHESUS study were randomized from day 3 to 14 after the index AMI (median = 7 days), of these 3319 were assigned to eplerenone. We analysed the differential effects of time-to-eplerenone initiation vs. placebo, based on the median time to initiation of treatment (<7 days-'earlier', > or =7days-'later'). Effects on outcomes were evaluated over a mean 16-month follow-up, using Cox proportional hazards regression analysis. The earlier eplerenone initiation (<7 days) reduced the risk of all-cause mortality by 31% (P = 0.001) when compared with the 'earlier' placebo' and also reduced the risks of cardiovascular (CV) hospitalization/CV mortality by 24% (P < 0.0001) and sudden cardiac death (SCD) by 34% (P < 0.0001). In contrast, later eplerenone initiation (> or =7 days) had no significant effect on outcomes. Interactions between time-to-randomization and treatment were significant. These associations remained substantially unchanged after risk adjustment in multivariable models.. An earlier eplerenone administration (3-7days) post-AMI improved outcomes in patients with LVSD and HF. This benefit was not observed when eplerenone was initiated later (> or =7days).

Topics: Death, Sudden, Cardiac; Double-Blind Method; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Proportional Hazards Models; Risk Factors; Spironolactone; Survival Rate; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left

In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (n=6632), eplerenone-associated reduction in all-cause mortality was significantly greater in those with a history of hypertension (Hx-HTN). There were 4007 patients with Hx-HTN (eplerenone: n=1983) and 2625 patients without Hx-HTN (eplerenone: n=1336). Propensity scores for eplerenone use, separately calculated for patients with and without Hx-HTN, were used to assemble matched cohorts of 1838 and 1176 pairs of patients. In patients with Hx-HTN, all-cause mortality occurred in 18% of patients treated with placebo (rate, 1430/10 000 person-years) and 14% of patients treated with eplerenone (rate, 1058/10 000 person-years) during 2350 and 2457 years of follow-up, respectively (hazard ratio [HR]: 0.71; 95% CI: 0.59 to 0.85; P<0.0001). Composite end point of cardiovascular hospitalization or cardiovascular mortality occurred in 33% of placebo-treated patients (3029/10 000 person-years) and 28% of eplerenone-treated patients (2438/10 000 person-years) with Hx-HTN (HR: 0.82; 95% CI: 0.72 to 0.94; P=0.003). In patients without Hx-HTN, eplerenone reduced heart failure hospitalization (HR: 73; 95% CI: 0.55 to 0.97; P=0.028) but had no effect on mortality (HR: 0.91; 95% CI: 0.72 to 1.15; P=0.435) or on the composite end point (HR: 0.91; 95% CI: 0.76 to 1.10; P=0.331). Eplerenone should, therefore, be prescribed to all of the post-acute myocardial infarction patients with reduced left ventricular ejection fraction and heart failure regardless of Hx-HTN.

Topics: Aged; Cause of Death; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Eplerenone; Female; Heart Failure; Humans; Hypertension; Logistic Models; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Multivariate Analysis; Myocardial Infarction; Probability; Prognosis; Risk Assessment; Spironolactone; Survival Analysis; Treatment Outcome

Aldosterone blockade is recommended for patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction; however, the perceived risk of hyperkalemia may limit implementation of this therapeutic approach. This subanalysis examined the relationship between eplerenone, serum potassium (K(+)), and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).. Hospitalized patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction (left ventricular ejection fraction < or =40%) treated with standard therapy were randomized 3 to 14 days after the acute myocardial infarction to additional treatment with eplerenone (25 to 50 mg/d; n=3319) or placebo (n=3313). Patients were excluded if baseline K(+) was >5.0 mEq/L or serum creatinine was >2.5 mg/dL. In patients receiving standard therapy, the addition of eplerenone resulted in a 4.4% absolute increase in the incidence of K(+) >5.5 mEq/L, a 1.6% increase of K(+) > or =6.0 mEq/L, and a 4.7% absolute decrease in hypokalemia (K(+) <3.5 mEq/L). Four independent baseline predictors of hyperkalemia (defined as > or =6.0 mEq/L) were identified: potassium (K(+) greater than the median; 4.3 mEq/L), estimated glomerular filtration rate (< or =60 mL . min(-1) . 1.73 m(-2)), history of diabetes mellitus, and prior use of antiarrhythmic agents. None of these independent baseline risk factors significantly impacted the cardiovascular benefit of eplerenone for reducing all-cause mortality.. Use of selective aldosterone blockade with eplerenone within the dose range of 25 to 50 mg/d in post-acute myocardial infarction patients with heart failure and left ventricular systolic dysfunction who are treated with standard therapy improves outcomes without an excess of risk of hyperkalemia (> or =6.0 mEq/L) when periodic monitoring of serum K(+) is instituted.

Topics: Aged; Eplerenone; Female; Heart Failure; Humans; Hyperkalemia; Incidence; Logistic Models; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Potassium; Predictive Value of Tests; Risk Factors; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) randomized clinical trial demonstrated the efficacy of eplerenone, a new aldosterone antagonist diuretic, with standard treatment versus standard treatment alone in the reduction of cardiovascular mortality and cardiovascular-related hospital readmissions for patients with heart failure after an acute myocardial infarction.. We assessed the incremental cost per life-year saved of eplerenone in the French context versus standard treatment.. A within-trial study was designed. A piecewise regression model yielded death rates and survival gains adjusted for patients' characteristics, based on the extraction of comparable patients from the Saskatchewan Health database. Resource use was collected alongside the clinical trial data. Only direct medical costs were considered. All costs were in 2003 euros. Costs and outcomes were discounted at 5%.. The overall mortality rate was 14.4% in the treatment group versus 16.7% in the placebo group (p=0.008). Combined cardiovascular deaths and hospitalization rates were 26.7% in the treatment group versus 30.3% in the placebo group (p=0.002). The discounted survival gain was 3.2 weeks. The incremental cost per life-year saved was euro15,382 (95% confidence interval 8274-42,723). Seventy-four per cent of the values of the incremental cost-effectiveness ratio fell under a euro15,000 per life-year saved threshold.. The cost of eplerenone leads to an acceptable level of incremental cost per life-year saved when compared with existing treatments in the cardiovascular domain for the prevention of cardiovascular death and morbidity in patients with heart failure after an acute myocardial infarction.

Topics: Cost-Benefit Analysis; Drug Costs; Drug Therapy, Combination; Eplerenone; Health Care Costs; Heart Failure; Hospitalization; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Proportional Hazards Models; Risk Assessment; Secondary Prevention; Spironolactone; Stochastic Processes; Time Factors; Treatment Outcome

Aldosterone antagonists have been proven to be beneficial in severe heart failure (HF) as a result of systolic dysfunction. We sought to determine if there is a disparity in their utilization compared with ACE inhibitors and beta-adrenoceptor antagonists (beta-blockers).. In the first part of the study, we asked physicians to answer a questionnaire presenting a hypothetical HF patient. In the second part, we reviewed hospital charts of patients with HF exacerbation.. Spironolactone was used less frequently than other drugs. At home, 75.0% of patients were receiving ACE inhibitors, 66.7% received beta-blockers, and 38.2% received spironolactone (p < 0.001). During the admission, 93.1% of patients received ACE inhibitors and 58.3% received spironolactone (p < 0.001).. Despite good evidence, underutilization of aldosterone antagonists in patients matching the population of the RALES (Randomized Aldactone Evaluation Study) trial persists in both outpatient and inpatient settings. The difference between the usage of ACE inhibitors and spironolactone is significant in patients with systolic dysfunction equally qualifying for both medications.

Topics: Adrenergic beta-Antagonists; Adult; Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Drug Therapy, Combination; Drug Utilization; Eplerenone; Female; Heart Failure; Humans; Inpatients; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Patient Discharge; Spironolactone; Surveys and Questionnaires

In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), aldosterone blockade with eplerenone decreased mortality in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. The present study was performed to evaluate the cost-effectiveness of eplerenone compared with placebo in these patients.. A total of 6632 patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction were randomized to eplerenone or placebo and followed up for a mean of 16 months. The coprimary end points were all-cause mortality and the composite of cardiovascular mortality/cardiovascular hospitalization. The evaluation of resource use included hospitalizations, outpatient services, and medications. Eplerenone was priced at the average wholesale price, 3.60 dollars per day. Survival beyond the trial period was estimated from data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. The incremental cost-effectiveness of eplerenone in cost per life-year and quality-adjusted life-year gained compared with placebo was estimated. The number of life-years gained with eplerenone was 0.1014 based on Framingham (95% CI, 0.0306 to 0.1740), 0.0636 with Saskatchewan (95% CI, 0.0229 to 0.1038), and 0.1337 with Worcester (95% CI, 0.0438 to 0.2252) data. Cost was 1391 dollars higher over the trial period in the eplerenone arm (95% CI, 656 to 2165) because of drug cost. The incremental cost-effectiveness ratio was 13,718 dollars per life-year gained with Framingham (96.7% under 50,000 dollars per life-year gained), 21,876 dollars with Saskatchewan, and 10,402 dollars with Worcester.. Eplerenone compared with placebo in the treatment of heart failure after acute myocardial infarction is effective in reducing mortality and is cost-effective in increasing years of life by commonly used criteria.

Topics: Aged; Cause of Death; Comorbidity; Cost-Benefit Analysis; Double-Blind Method; Drug Costs; Eplerenone; Female; Health Care Costs; Heart Failure; Humans; Life Expectancy; Male; Middle Aged; Mortality; Myocardial Infarction; Quality-Adjusted Life Years; Spironolactone; Ventricular Dysfunction, Left

Topics: Double-Blind Method; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Spironolactone

This study sought to assess the impact of the selective aldosterone blocker eplerenone on mortality 30 days after randomization in patients after acute myocardial infarction (AMI) with a left ventricular ejection fraction (LVEF) < or =40% and clinical signs of heart failure.. In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), eplerenone reduced all-cause mortality by 15% (p = 0.008) over a mean follow-up of 16 months when used with standard therapy in patients after AMI with an LVEF < or =40% and clinical signs of heart failure.. We analyzed the effect of eplerenone 25 mg/day initiated 3 to 14 days after AMI (mean, 7.3 days) on the co-primary end points of time to death from any cause and the composite end point of time to death from cardiovascular (CV) causes or hospitalization for CV events, and the secondary end points of CV mortality, sudden cardiac death, and fatal/nonfatal hospitalization for heart failure, after 30 days of therapy in the EPHESUS trial.. At 30 days after randomization, eplerenone reduced the risk of all-cause mortality by 31% (3.2% vs. 4.6% in eplerenone and placebo-treated patients, respectively; p = 0.004) and reduced the risk of CV mortality/CV hospitalization by 13% (8.6% vs. 9.9% in eplerenone and placebo-treated patients, respectively; p = 0.074). Eplerenone also reduced the risk of CV mortality by 32% (p = 0.003) and the risk of sudden cardiac death by 37% (p = 0.051).. Eplerenone 25 mg/day significantly reduced all-cause mortality 30 days after randomization (when initiated at a mean of 7.3 days after AMI) in addition to conventional therapy in patients with an LVEF < or =40% and signs of heart failure. Based on its early survival benefit, eplerenone should be administered in the hospital after AMI.

Topics: Aged; Coronary Angiography; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Eplerenone; Female; Follow-Up Studies; Heart Failure; Heart Function Tests; Humans; Male; Middle Aged; Myocardial Infarction; Probability; Proportional Hazards Models; Reference Values; Severity of Illness Index; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Disease-specific health status instruments such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) can quantify symptoms, functional limitations, and quality of life in patients with heart failure. Understanding the relationship between KCCQ scores and prognosis may assist clinicians in both interpreting KCCQ scores and stratifying risk in patients.. We examined the prognostic value of the KCCQ in a prospective, international cohort of 1516 patients with heart failure after a recent acute myocardial infarction. We focused on the relationship between the KCCQ overall score (KCCQ-os), measured at the first outpatient visit (4 weeks after enrollment), and subsequent 1-year cardiovascular mortality or hospitalization (n=258, 20.3%). KCCQ-os was strongly associated with subsequent cardiovascular events in that those with a score > or =75 had an 84% 1-year event-free survival compared with 59% for those with a score <25 (P<0.001). After demographic and other clinical characteristics were controlled for in multivariable models, KCCQ-os remained strongly associated with outcome (hazard ratio, 2.02; 95% CI, 1.24 to 3.27 for KCCQ-os <25; P<0.001).. In outpatients with heart failure complicating an acute myocardial infarction, KCCQ-os is strongly associated with subsequent 1-year cardiovascular mortality and hospitalization. Use of the KCCQ in outpatient clinical practice can both quantify patients' health status and provide insight into their prognosis.

Topics: Adult; Aged; Aged, 80 and over; Americas; Cardiovascular Diseases; Cohort Studies; Comorbidity; Disease-Free Survival; Eplerenone; Europe; Female; Health Status Indicators; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Prospective Studies; Risk Factors; Severity of Illness Index; Spironolactone

Aldosterone blockade reduces mortality and morbidity among patients with severe heart failure. We conducted a double-blind, placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.. Patients were randomly assigned to eplerenone (25 mg per day initially, titrated to a maximum of 50 mg per day; 3319 patients) or placebo (3313 patients) [correction] in addition to optimal medical therapy. The study continued until 1012 deaths occurred. The primary end points were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia.. During a mean follow-up of 16 months, there were 478 deaths in the eplerenone group and 554 deaths in the placebo group (relative risk, 0.85; 95 percent confidence interval, 0.75 to 0.96; P=0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes (relative risk, 0.83; 95 percent confidence interval, 0.72 to 0.94; P=0.005). The rate of the other primary end point, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (relative risk, 0.87; 95 percent confidence interval, 0.79 to 0.95; P=0.002), as was the secondary end point of death from any cause or any hospitalization (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.98; P=0.02). There was also a reduction in the rate of sudden death from cardiac causes (relative risk, 0.79; 95 percent confidence interval, 0.64 to 0.97; P=0.03). The rate of serious hyperkalemia was 5.5 percent in the eplerenone group and 3.9 percent in the placebo group (P=0.002), whereas the rate of hypokalemia was 8.4 percent in the eplerenone group and 13.1 percent in the placebo group (P<0.001).. The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.

Topics: Aged; Blood Pressure; Death, Sudden, Cardiac; Double-Blind Method; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Potassium; Spironolactone; Survival Analysis; Ventricular Dysfunction, Left

The American College of Cardiology provided much useful new information to inform those who care for patients with heart failure about what they should and should not adopt into current clinical practice. The EPHESUS trial suggests a much wider role for aldosterone antagonists for the management of heart failure and left ventricular systolic dysfunction. SPORTIF-III indicates we may have a safer, simpler warfarin substitute soon. ASCOT reinforces the potential futility of statin therapy unless it is well targeted. The results of the COMPANION study investigating cardiac resynchronisation devices and implantable defibrillators were encouraging but inconclusive and/or hard to interpret. UK-PACE again questions the use of dual chamber pacing. T-wave alternans is an interesting experimental technique that may be useful in selecting which patients need an implantable defibrillator, although the technology needs testing in an appropriate patient population.

Topics: Anticoagulants; Cardiac Pacing, Artificial; Defibrillators, Implantable; Electrocardiography; Eplerenone; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mineralocorticoid Receptor Antagonists; Pacemaker, Artificial; Spironolactone; Ventricular Dysfunction, Left; Warfarin

Topics: Aged; Defibrillators, Implantable; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Pacemaker, Artificial; Spironolactone; Ventricular Dysfunction, Left

Topics: Acute Disease; Diabetes Complications; Drug Administration Schedule; Drug Therapy, Combination; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Treatment Outcome

Topics: Adenosine; Angioplasty, Balloon, Coronary; Anti-Arrhythmia Agents; Antihypertensive Agents; Atherectomy, Coronary; Atrial Fibrillation; Azithromycin; Chlamydophila Infections; Coronary Disease; Defibrillators, Implantable; Double-Blind Method; Eplerenone; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy, Left Ventricular; Myocardial Reperfusion; Pyridines; Radiology, Interventional; Spironolactone; Stents; Thiazepines; Thrombolytic Therapy

Although quantification of the impact of treatment on survival remains the cornerstone of clinical research, the assessment of a broader range of disease outcomes is growing increasingly important. This manuscript provides an overview of the considerations made regarding quantification of a range of clinical and economic outcomes in the EPHESUS (EPlerenone's neuroHormonal Efficacy and SUrvival Study) study, a 6200-patient, randomized, controlled trial of aldosterone blockade in patients with heart failure as a complication of acute myocardial infarction.. Relevant clinical outcomes include disease progression (mortality, hospitalization), health status (symptoms, functioning, and quality of life), and costs. The primary hypothesis for the quality of life component of EPHESUS is that eplerenone will improve health status as defined by the Kansas City Cardiomyopathy Questionnaire summary score. In addition to the Kansas City Cardiomyopathy Questionnaire, the Short Form-12, the EuroQOL, the Medical Outcomes Study-Depression Scale and an Anxiety measure will be collected throughout the trial. Health care resource utilization including hospitalizations, emergency room visits, outpatient procedures and tests, and medications will also be collected. Analyses will estimate and describe the effect of aldosterone blockade on costs over time. If both the clinical effect and costs are greater for patients receiving aldosterone blockade, then eplerenone's cost-effectiveness will be estimated.. The EPHESUS trial has been designed to quantify a wide range of clinical outcomes. This broad range of data will allow a comprehensive assessment of the potential benefits of aldosterone blockade on patient health status and costs.

Topics: Antihypertensive Agents; Cost-Benefit Analysis; Disease Progression; Eplerenone; Health Status Indicators; Heart Failure; Hospital Costs; Hospitalization; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Quality of Life; Research Design; Severity of Illness Index; Spironolactone; Treatment Outcome

Eplerenone is a selective mineralocorticoid receptor antagonist. Its approved for the therapy of patients with chronic heart failure with left ventricular systolic dysfunction and for the patients after myocardial infarction complicated by heart failure and left ventricular dysfunction. It´s also recommended for the therapy of primary hyperaldosteronism and the treatment of drug resistant hypertension.

Topics: Cardiovascular Diseases; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone; Ventricular Dysfunction, Left

The mineralocorticoid receptor antagonists (MRAs) eplerenone and spironolactone are beneficial in heart failure with reduced ejection fraction (HFrEF), but have not been prospectively compared. We compared clinical outcomes, daily dosages, and discontinuation rates for the two drugs in a nationwide cohort.. We identified all patients with HFrEF in the period 2016-2020, who were alive and had initiated MRA treatment at study start, 180 days after HF diagnosis. We estimated the 2-year risk of a composite of death and HF hospitalization, as well as each component separately, using Kaplan-Meier, cumulative incidence functions, and Cox proportional hazards models adjusted for age, sex, and comorbidities. Secondly, we assessed treatment withdrawal, cross-over, and daily drug dosage.. We included 7479 patients; 653 (9%) on eplerenone and 6840 (91%) on spironolactone. Patients in the eplerenone group were younger (median age 65 vs. 69 years), and more often men (91% vs. 68%), both P < 0.001. In adjusted analyses, with spironolactone as reference, there were no differences in the risk of the composite of all-cause death and HF hospitalization (HR 1.02, 95% CI 0.82-1.27), all-cause death (HR 0.93, 95% CI 0.67-1.30), or HF hospitalization (HR 1.10, 95% CI 0.84-1.42). Treatment withdrawal occurred in 34% in the eplerenone group and 53% in the spironolactone group (P < 0.001), treatment cross-over in 3%, and 10%, respectively. Daily dose >25 mg at 12 months, was observed in 230 patients (37%) in the eplerenone group and 771 patients (12%) in the spironolactone (P < 0.001).. In a contemporary nationwide cohort of patients with new-onset HFrEF who initiated MRA, we found no differences in clinical outcomes associated with initiation of eplerenone vs. spironolactone. Treatment was more frequently withdrawn, and daily drug dosage was lower among patients treated with spironolactone.

Topics: Aged; Cohort Studies; Eplerenone; Heart Failure; Humans; Male; Spironolactone; Stroke Volume; Treatment Adherence and Compliance; Ventricular Dysfunction, Left

It is unknown how the efficacy and safety of mineralocorticoid receptor antagonists vary according to duration of heart failure with reduced ejection fraction (HFrEF).. In this study, we sought to evaluate the safety and efficacy of eplerenone according to duration of HFrEF.. In 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.. The 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; P. Patients 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).

Topics: Eplerenone; Heart Failure; Hospitalization; Humans; Mineralocorticoid Receptor Antagonists; Stroke Volume

Patients with bilateral primary aldosteronism (PA) generally are treated with antihypertensive drugs, but optimal treatment for patients with complications due to refractory hypertension has not been established. In this report, we present a case with bilateral PA who presented with persistent hypertension, despite treatment with 6 drugs, and left-dominant heart failure, which was improved after unilateral adrenalectomy.. A 61-year-old man was admitted to our hospital because of severe left-dominant heart failure. His heart rhythm was atrial fibrillation and the left ventricle was diffusely hypertrophic and hypokinetic. Coronary arteries were normal on coronary arteriogram. Primary aldosteronism was suspected based on severe hypokalemia (2.5 mEq/L) and plasma aldosterone concentration (PAC; 1,410 pg/mL). Although computed tomography (CT) showed a single left cortical nodule, adrenal vein sampling (AVS) indicated bilateral PA. Early in the case, heart failure and hyperkalemia in this patient were improved by treatment with a combination of 6 antihypertensive drugs (spironolactone 25 mg/day, eplerenone 100 mg/day, azosemide 60 mg/day, tolvaptan 7.5 mg/day, enalapril 5 mg/day, and bisoprolol fumarate 10 mg/day); however, heart failure relapsed after four months of treatment. We hypothesized that hypertension caused by excess aldosterone was inducing the patient's heart failure. In order to reduce aldosterone secretory tissue, a laparoscopic adrenalectomy was performed for the left adrenal gland, given the higher level of aldosterone from the left gland compared to the right. Following surgery, the patient's heart failure was successfully controlled despite the persistence of high PAC. Treatment with anti-hypertensive medications was reduced to two drugs (eplerenone 100 mg/day and bisoprolol fumarate 10 mg/day). In order to elucidate the mechanism of drug resistance, immunohistochemistry (IHC) and real time-polymerase chain reaction (RT-PCR) assays were performed to assess the expression of steroidogenic factor 1 (SF-1), a regulator of steroid synthesis in adrenal tissue. IHC and RT-PCR demonstrated that the expression of SF-1 in this patient (at both the protein and mRNA levels) was higher than that observed in unilateral PA cases that showed good responsivity to drug treatment.. Unilateral adrenalectomy to reduce aldosterone secretory tissue may be useful for patients with drug-refractory, bilateral PA. Elevated expression of SF-1 may be involved in drug resistance in PA.

Topics: Adrenal Glands; Adrenalectomy; Aldosterone; Antihypertensive Agents; Bisoprolol; Eplerenone; Heart Failure; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged

Topics: Eplerenone; Heart Failure; Hospitals; Humans; Mineralocorticoid Receptor Antagonists; Patient Discharge; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left

Overactivation of the mineralocorticoid receptor (MR) is involved in many diseases, such as hypertension, kidney disease, and heart failure. Thus, MR antagonists (MRAs) are expected to be beneficial to patients with these diseases. In order to identify novel nonsteroidal MRAs that overcome the issues of already marketed steroidal MRAs, we searched for new compounds guided by our hypothesis that T-shaped compounds with a hydrophobic core structure, two polar functional groups at both extremities able to interact with MR, and a bulky substituent that can interfere with the folding of the C-terminal helix 12 may exhibit antagonist activity toward MR. We discovered that the novel 1,4-benzoxazin-3-one derivative

Topics: Animals; Antihypertensive Agents; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Oxazines; Rats; Receptors, Mineralocorticoid; Sulfonamides

Topics: Biomarkers; Eplerenone; Follow-Up Studies; Heart Failure; Humans; Magnetic Resonance Spectroscopy; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Spironolactone

In the absence of previous direct comparative studies, we aimed to evaluate the effectiveness of spironolactone and eplerenone in patients with heart failure and reduced ejection fraction (HFrEF) in a real-world clinical setting.. Using Fine-Gray´s competing risk regression, we compared the clinical outcomes of 293 patients with chronic HF and left ventricular ejection fraction <40% treated with eplerenone and 293 propensity-score matched individuals treated with spironolactone. Study subjects were selected from a prospective cohort of 1404 ambulatory patients with HFrEF seen since 2010 to 2019 in a single specialized HF clinic, among which 992 received a mineralocorticoid receptor antagonist at baseline. Median follow-up was 3.95 years.. No statistically significant differences between patients treated with eplerenone versus spironolactone were observed with regard to the risk of the primary composite end-point cardiovascular death or HF hospitalization (HR 0.95; 95% CI 0.73-1.23; p= 0.677). However, eplerenone use was associated to lower cardiovascular mortality (HR 0.55; 95% CI 0.35-0.85; p= 0.008) and lower all-cause mortality (HR 0.67; 95% CI 0.47-0.95; p= 0.027). The incidence of drug suspension due to side effects (HR 0.58, 95% CI 0.40-0.85; p= 0.005) and drug suspension due to any reason (HR 0.70, 95% CI 0.51-0.97; p= 0.033) were lower among patients treated with eplerenone.. In this observational, real-world, propensity-score matched study of patients with HFrEF, eplerenone was associated to lower cardiovascular mortality and lower all-cause mortality than spironolactone.

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Prospective Studies; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone

Mineralocorticoid receptor antagonists (MRAs) inhibit the overactivation of mineralocorticoid receptors (MRs), resulting in potassium retention and diuresis, and are widely used in clinical practice. They were classified into steroidal MRAs (such as spironolactone and eplerenone) and new nonsteroidal MRAs (such as finerenone) according to the molecular structure. Three most commonly used MRs are clinically available at present, spironolactone, eplerenone and finerenone. The efficacy and safety of the three drugs differ from each in the treatment of chronic kidney disease, heart failure, hypertension and other diseases. It is, thus, of great necessary to reach a multidisciplinary expert consensus on the clinical practice of MRAs to improve the understanding of medical workers in China on steroidal and nonsteroidal MRAs, and help them with rational administration of the drugs.. 盐皮质激素受体拮抗剂（MRA）能够抑制盐皮质激素受体的过度激活，在临床上可用于多种慢性疾病的治疗。根据分子结构，MRA可分为传统的甾体类（如螺内酯和依普利酮）和新一代的非甾体类（如非奈利酮等）。目前临床使用较多的3种MRA为螺内酯、依普利酮和非奈利酮，在治疗慢性肾脏病、心力衰竭和高血压等疾病的疗效和安全性方面均有所区别。本共识旨在进一步提高临床医师对甾体类及非甾体类MRA的认识，有助于合理选择及应用MRA。.

Topics: Consensus; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

Topics: Diabetes Mellitus, Type 2; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic

The aim: To increase the treatment effectiveness of CHF patients after MI with stenting by using magnesium and potassium salts of gluconic acid, eplerenone, and rivaroxaban in complex therapy.. Materials and methods: The research was performed at the premises of Ivano-Frankivsk Regional Clinical Cardiology Centre, Ukraine. 84 patients with CHF after past MI were examined.. Results and conclusions: A more pronounced anti-ischemic effect has been linked to the use of combination therapy with rivaroxaban on the background of basic therapy (BT) in patients with CHF after MI, compared with the use of magnesium and potassium salts of gluconic acid or eplerenone. The use of eplerenone in the complex treatment of these patients on the background of BT has been proven to provide a pronounced reverse remodeling of the left myocardium in the postinfarction period.

Topics: Eplerenone; Gluconates; Heart Failure; Humans; Magnesium; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Myocardium; Potassium; Rivaroxaban; Salts; Spironolactone

After myocardial infarction (MI) complicated by heart failure (HF), eplerenone reduced serum concentrations of amino-terminal propeptide of type III collagen (PIIINP) and carboxy-terminal propeptide of type I collagen (PICP). Determining a subgroup who are more prone to decrease their collagen content and to respond better to the antifibrotic effects of mineralocorticoid receptor antagonists (MRA) may be relevant for a personalized treatment approach. Whether circulating microRNAs may identify a subgroup that have experienced a more pronounced antifibrotic effect of eplerenone as measured by a PICP and PIIINP decrease is unclear.. A set of circulating microRNAs linked to cardiac fibrosis (mir-1, mir-21, mir-29a, mir-29b, mir-101, mir-122, mir-133a) were measured at baseline in 198 patients in the biomarker substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Associations between baseline microRNA levels and changes in both PIIINP and PICP from baseline to month 9 were studied using multivariable analysis of covariance, adjusting for age, sex, history of hypertension and diabetes mellitus, prescription of ACE-inhibitors or angiotensin receptor blockers, baseline PIIINP or PICP, and eplerenone treatment. Furthermore, a treatment-by-microRNA interaction was studied.. From the selected microRNAs, only mir-133a was associated with a PICP decrease (ß-6.43, 95%CI-12.71 to -0.15,p = 0.045). None of the microRNAs was associated with a PIIINP change. The microRNAs did not predict an effect of eplerenone on PICP and PIIINP changes.. Although serum mir-133a was associated with PICP change, none of the microRNAs previously linked to cardiac fibrosis predicted an antifibrotic response to eplerenone. Further study is needed to identify other suitable targets for a personalized treatment approach.

Topics: Eplerenone; Heart Failure; Humans; MicroRNAs; Mineralocorticoid Receptor Antagonists; Myocardial Infarction

Patients with heart failure with reduced ejection fraction (HFrEF) and insulin-treated diabetes have a high risk of cardiovascular complications. Mineralocorticoid receptor antagonists may mitigate this risk. We aim to explore the effect of eplerenone on cardiovascular outcomes and all-cause mortality in HFrEF patients with diabetes, including those treated with insulin in the EMPHASIS-HF trial (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms).. The primary outcome was the composite of heart failure hospitalization or cardiovascular death. Cox models with treatment-by-diabetes subgroup interaction terms were used.. The median follow-up was 21 (10-33) months. Of the 2737 patients included, 623 (23%) had non-insulin-treated diabetes, 236 (9%) had insulin-treated diabetes and 1878 did not have diabetes. Patients with insulin-treated diabetes were younger, more often women, with higher body mass index, waist circumference, more frequent ischemic heart failure cause, impaired kidney function, and longer diabetes duration. Compared with patients without diabetes, those with insulin-treated diabetes had a 2-fold higher risk of having a primary outcome event. The hazard ratio (95% CI) for the effect of eplerenone, compared with placebo, on the primary outcome was 0.31 (0.19-0.50) in insulin-treated diabetes, 0.69 (0.50-0.93) in non-insulin-treated diabetes, and 0.72 (0.58-0.88) in patients without diabetes; interaction. Patients with insulin-treated diabetes experienced a greater benefit from eplerenone than those with diabetes not treated with insulin and people without diabetes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00232180.

Topics: Aged; Diabetes Mellitus; Eplerenone; Female; Heart Failure; Heart Failure, Systolic; Humans; Insulins; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Risk Factors; Spironolactone; Treatment Outcome

Background Guidelines recommend mineralocorticoid receptor antagonist (MRA) use in patients with left ventricular ejection fraction ≤40% following a myocardial infarction plus heart failure or diabetes mellitus, based on mortality benefit in the EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trial. The objective of this study was to evaluate the real-world utilization of MRAs for patients with ST-segment-elevation myocardial infarction (STEMI) with left ventricular dysfunction. Methods and Results The prospective, population-based, Vancouver Coastal Health Authority STEMI database was linked with local outpatient cardiology records from 2007 to 2018. EPHESUS criteria were used to define post-STEMI MRA eligibility (left ventricular ejection fraction ≤40% plus clinical heart failure or diabetes mellitus, and no dialysis-dependent renal dysfunction). The primary outcome was MRA prescription among eligible patients at discharge and the secondary outcome was MRA prescription within 3 months postdischarge. Of 2691 patients with STEMI, 317 (12%) were MRA eligible, and 70 (22%) eligible patients were prescribed an MRA at discharge. Among eligible patients with no MRA at discharge, 12/126 (9.5%) with documented postdischarge follow-up were prescribed an MRA within 3 months. In multivariable analysis, left ventricular ejection fraction (odds ratio [OR], 1.55 per 5% left ventricular ejection fraction decrease; 95% CI, 1.26-1.90) and calendar year (OR, 1.23 per year, 95% CI, 1.11-1.37) were associated with MRA prescription at discharge. Other prespecified variables were not associated with MRA prescription. Conclusions In this contemporary STEMI cohort, only 1 in 4 MRA-eligible patients were prescribed an MRA within 3 months following hospitalization despite high-quality evidence for use. Novel decision-support tools are required to optimize pharmacotherapy decisions during hospitalization and follow-up to target this gap in post-STEMI care.

Topics: Aged; Aged, 80 and over; Canada; Databases, Factual; Drug Prescriptions; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Logistic Models; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Multivariate Analysis; Prospective Studies; ST Elevation Myocardial Infarction; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left

Topics: Collagen Type I; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Peptide Fragments; Procollagen; Spironolactone; Ventricular Dysfunction, Left

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca

Topics: Animals; Calcium-Binding Proteins; Cardiomyopathies; Eplerenone; Heart Failure; Metoprolol; Mice; Mutation; Phenotype; Risk; Treatment Failure

This study compared ways of describing treatment effects. The objective was to better explain to clinicians and patients what they might expect from a given treatment, not only in terms of relative and absolute risk reduction, but also in projections of long-term survival.. The restricted mean survival time (RMST) can be used to estimate of long-term survival, providing a complementary approach to more conventional metrics (e.g., absolute and relative risk), which may suggest greater benefits of therapy in high-risk patients compared with low-risk patients.. Relative and absolute risk, as well as the RMST, were calculated in heart failure with reduced ejection fraction (HFrEF) trials.. As examples, in the RALES trial (more severe HFrEF), the treatment effect metrics for spironolactone versus placebo on heart failure hospitalization and/or cardiovascular death were a hazard ratio (HR) of 0.67 (95% confidence interval [CI]: 0.5 to 0.77), number needed to treat = 9 (7 to 14), and age extension of event-free survival +1.1 years (-0.1 to + 2.3 years). The corresponding metrics for EMPHASIS-HF (eplerenone vs. placebo in less severe HFrEF) were 0.64 (0.54 to 0.75), 14 (1 to 22), and +2.9 (1.2 to 4.5). In patients in PARADIGM-HF aged younger than 65 years, the metrics for sacubitril/valsartan versus enalapril were 0.77 (95% CI: 0.68 to 0.88), 23 (15 to 44), and +1.7 (0.6 to 2.8) years; for those aged 65 years or older, the metrics were 0.83 (95% CI: 0.73 to 0.94), 29 (17 to 83), and +0.9 (0.2 to 1.6) years, which provided evidence of a greater potential life extension in younger patients. Similar observations were found for lower risk patients.. RMST event-free (and overall) survival estimates provided a complementary means of evaluating the effect of therapy in relation to age and risk. They also provided a clinically useful metric that should be routinely reported and used to explain the potential long-term benefits of a given treatment, especially to younger and less symptomatic patients.

Topics: Eplerenone; Heart Failure; Humans; Infant; Mineralocorticoid Receptor Antagonists; Spironolactone; Stroke Volume

After myocardial infarction complicated by heart failure or diabetes, eplerenone (compared to placebo) significantly decreases amino-terminal propeptide of type III procollagen (PIIINP). Determining the subset of patients who are more prone to have a decrease in PIIINP and those who may respond better to the anti-fibrotic effects of mineralocorticoid receptor antagonists (MRA) therapy may be relevant for a personalized treatment approach. The aim of this study is to identify predictors of a PIIINP decrease and assess potential subgroups of "responders" to eplerenone.. Clinical factors and biomarkers were evaluated as predictors of a PIIINP decrease from randomization to month 9 in 323 patients from the biomarker substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Additionally, the association between PIIINP decrease and the composite of cardiovascular (CV) death or CV hospitalization were also explored. External validation was performed in the REMINDER trial.. In patients who had a myocardial infarction, clinical factors used in combination and treatment with eplerenone were associated with a PIIINP decrease. Interestingly, higher randomization PIIINP levels might help in identifying patients more prone to have an "anti-fibrotic response" when treated with MRAs. Predictors of an antifibrotic response after MI complicated by HF. Several clinical factors and biomarkers predicted a PIIINP decrease after an MI complicated by HF. There was a significant interaction between baseline PIIINP levels and eplerenone treatment: patients with baseline PIIINP ≥ 3.6 mmol/L treated with eplerenone had the best response (PIIINP decrease).

Topics: Aged; Biomarkers; Clinical Decision-Making; Eplerenone; Female; Fibrosis; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardium; Patient Selection; Peptide Fragments; Predictive Value of Tests; Procollagen; Randomized Controlled Trials as Topic; Reproducibility of Results; Risk Factors; ST Elevation Myocardial Infarction; Time Factors; Treatment Outcome; Ventricular Remodeling

Differences in the clinical impacts of the aldosterone receptor antagonists spironolactone and eplerenone in patients with heart failure (HF) are unclear. Among 838 prospectively enrolled patients hospitalized for HF, 90 treated with eplerenone were compared with 90 treated with spironolactone. The primary endpoint was a composite of cardiovascular death and hospitalization. A serial evaluation of the clinical parameters was performed 1 year after discharge. The mean dose of spironolactone was 27 ± 8 mg and of eplerenone was 34 ± 15 mg. During follow-up (mean 594 ± 317 days), primary endpoints occurred in 27 patients in the eplerenone group (30.0%) and 25 patients in the spironolactone group (27.8%). There were no significant intergroup differences in the primary endpoint (log-rank, p = 0.956). Serial changes in left ventricular ejection fraction, serum brain natriuretic peptide, systolic blood pressure, and estimated glomerular filtration rate did not differ significantly between groups. Although gynecomastia in men was common in the spironolactone group (p = 0.018), the discontinuation rates due to adverse events were similar in the two groups (p = 0.135). Subgroup analyses suggested that eplerenone was associated with a lower hazard rate of the primary endpoint in female patients (interaction, p = 0.076). Among patients with HF, eplerenone and spironolactone have similar impacts on cardiovascular outcomes and safety.

Topics: Acute Disease; Aged; Eplerenone; Female; Follow-Up Studies; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Prospective Studies; Spironolactone; Time Factors; Treatment Outcome; Ventricular Function, Left

Topics: Eplerenone; Female; Health Services Misuse; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Stroke Volume; Time; Ventricular Dysfunction, Left

Topics: Animals; Biological Availability; Disease Models, Animal; Eplerenone; Gene Expression Regulation; Heart Failure; Mice; Mineralocorticoid Receptor Antagonists; Myocytes, Cardiac; Naphthyridines; Tenascin

There are no studies of mineralocorticoid receptor antagonist (MRA) treatment examining outcome in unselected real-life patients with myocardial infarction (MI) and heart failure (HF). There is uncertainty regarding effects of MRA in relation to left ventricular ejection fraction (LVEF) and chronic kidney disease (CKD). The aim was to assess MRA use and compare outcomes in MI patients with HF in relation to LVEF and CKD.. Patients with MI and HF registered in the Swedish myocardial infarction registry, SWEDEHEART, 2005-2014, were included. Associations between MRA use and all-cause mortality up to 3 years were assessed with multivariable Cox regression, stratified by EF groups and presence of CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m. In patients with MI and HF, MRA use was associated with better long-term survival in patients with LVEF <40% but not in those with LVEF ≥50%, while the mortality risk was similar in MRA-treated patients with or without CKD.

Topics: Aged; Aged, 80 and over; Eplerenone; Female; Follow-Up Studies; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Percutaneous Coronary Intervention; Registries; Retrospective Studies; Spironolactone; Stroke Volume; Survival Rate; Sweden; Time Factors; Treatment Outcome; Ventricular Function, Left

Topics: Eplerenone; Heart Failure; Mineralocorticoid Receptor Antagonists; Obesity, Abdominal; Spironolactone

There is increasing evidence for a crucial role of aberrant mineralocorticoid receptor (MR) activation in heart failure, with clinical studies showing beneficial effects of MR blockade. However, the mechanisms of MR activation in heart failure remain unclear. In this study, we observed that the small GTPase Rac1 contributes to myocardial MR activation, whereas Rac1-MR pathway activation leads to cardiac dysfunction. Mouse hearts subjected to chronic pressure overload induced by transverse aortic constriction showed Rac1 activation and increased nuclear accumulation of MR and expression of MR target genes, suggesting MR activation. Pharmacological inhibition of Rac1 and heterozygous deletion of Rac1 in cardiomyocytes suppressed Rac1-induced MR signaling and reduced NADPH oxidase 4 gene induction and reactive oxygen species overproduction, which attenuated transverse aortic constriction-induced cardiac hypertrophy and dysfunction. Consistently, treatment with the selective MR antagonist eplerenone blocked transverse aortic constriction-induced MR signaling and NADPH oxidase 4 gene upregulation, which improved cardiac hypertrophy and dysfunction. These findings suggest that Rac1-MR pathway activation in the myocardium is involved in development of heart failure induced by pressure load via recruitment of the responsible isoform of NADPH oxidase. Thus, the cardiac Rac1-MR-NADPH oxidase 4 pathway may be a therapeutic target for treatment of the pressure-overloaded heart.

Topics: Animals; Disease Models, Animal; Eplerenone; Heart Failure; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Myocytes, Cardiac; Neuropeptides; Oxidative Stress; rac1 GTP-Binding Protein; Receptors, Mineralocorticoid; Signal Transduction; Spironolactone; Ventricular Pressure; Ventricular Remodeling

The objective of this study was to determine the cost-effectiveness of eplerenone compared with usual care in patients with chronic heart failure and New York Heart Association (NYHA) Class II symptoms.A Markov model was constructed with 5 health states to reflect NYHA symptom status (Classes I-IV) and death. All subjects began in the "Class II" health state and then moved to other symptom health states or died. Subjects could also be hospitalized for HF in any cycle. Transition probabilities were derived from the Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure (EMPHASIS-HF) study. Decision analysis was applied to compare an Eplerenone Group with a Usual Care Group (UCG). In the UCG, 47.3% of subjects in Class II and 93.7% of subjects in Classes III and IV were assumed to be taking spironolactone (as per published data). In the Eplerenone Group, all subjects in Classes II, III, and IV were assumed to be taking eplerenone. The efficacy of spironolactone was assumed to be the same as eplerenone. Cost and utility data were derived from published sources. A discount rate of 5.0% was applied to future costs and benefits. The outcome of interest was incremental cost-effectiveness ratio (ICER) (cost per year of live saved (YoLS) and quality-adjusted life years (QALY) gained).Over 10 years the model predicted that for each patient compared with usual care, eplerenone would lead to 0.26 YoLS (discounted) and 0.19 QALYs gained (discounted), at a net cost of AUD $6961 (discounted). These equate to ICERs of AUD 28,001 per YoLS and AUD 37,452 per QALY gained. Sensitivity analyses indicated a 99.0% likelihood of eplerenone being cost-effective compared with usual care at a willingness to pay threshold of AUD 50,000 per QALY gained.From an Australian healthcare perspective, the addition of eplerenone in management of patients with chronic heart failure and NYHA Class II symptoms represents a cost-effective strategy compared with usual care.

Topics: Australia; Chronic Disease; Cost-Benefit Analysis; Eplerenone; Heart Failure; Hospitalization; Humans; Medication Therapy Management; Mineralocorticoid Receptor Antagonists; Severity of Illness Index; Spironolactone; Survival Analysis

Cardiovascular diseases, such as arterial hypertension, heart failure, coronary artery disease, peripheral circulatory problems and atrial fibrillation are increasingly present in aged patients. Comorbidities, mainly diabetes, renal dysfunction, chronic bronchitis and degenerative joint diseases, are also frequent and need additional drug treatment. The usual polypharmacy often causes side effects due to overdosage and/or drug interactions. The main difficulty in choosing the proper therapeutic regimen consists in the lack of suitable dosing guidelines with adapted therapeutic targets for the older multimorbid population, usually not represented in the large controlled trials forming the basis of general recommendations. European guidelines for hypertension and heart failure are discussed as examples.

Topics: Aged; Aged, 80 and over; Cardiovascular Agents; Cardiovascular Diseases; Combined Modality Therapy; Comorbidity; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Eplerenone; Female; Guideline Adherence; Heart Failure; Humans; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Pacemaker, Artificial; Risk Factors; Spironolactone

A 28-year-old man was referred to our hospital for the treatment of congestive heart failure and severe hypertension. The patient was diagnosed with malignant phase hypertension based on the presence of marked hypertension with left ventricular hypertrophy, exudate retinopathy, and renal failure. Intensive therapy for hypertension and heart failure with a combination of antihypertensive drugs including nitroglycerin, nifedipine, eplerenone and candesartan successfully lowered his blood pressure and further improved the renal function. Eplerenone could be one of the choices of antihypertensive drugs in combination therapy in patients with malignant phase hypertension with progressive heart and renal failure.

Topics: Adrenergic beta-Antagonists; Adult; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Calcium Channel Blockers; Creatinine; Drug Therapy, Combination; Eplerenone; Heart Failure; Humans; Hypertension, Malignant; Male; Nifedipine; Nitroglycerin; Obesity; Renal Insufficiency; Spironolactone; Tetrazoles; Treatment Outcome; Vasodilator Agents

Alternative activation of macrophages plays protective role in cardiac remodelling in heart failure and the activity of mineralocorticoid receptor may determine the phenotype of these cells. We examined the influence of eplerenone, aldosterone, and IL-4 on descriptors of alternative activation in blood monocytes collected from 19 patients with heart-failure and 20 healthy volunteers. “Heart failure” macrophages in comparison with “healthy” macrophages had increased mineralocorticoid activity, NO and reactive oxygen species production, expression of iNOS mRNA and protein, but decreased expression of arginase I and mannose receptor proteins, and activity of MnSOD and CuZnSOD. Aldosterone increased mineralocorticoid activity, NO and reactive oxygen species production, iNOS mRNA and protein expression, MnSOD and CuZnSOD activity. Eplerenone attenuated the effects of aldosterone on all but MnSOD and CuZnSOD variables. Eplerenone alone increased the production of NO, MnSOD and CuZnSOD activity, arginase I gene and protein expression, and mannose receptor gene and protein expression, but decreased mineralocorticoid activity only in “heart failure” macrophages. The latter suggests altered function of mineralocorticoid receptor in heart failure. Increased mineralocorticoid activity accounts for increased NO production, iNOS gene and protein expression but does not explain the increased basal reactive oxygen species production and decreased markers of alternative activation in “heart failure” macrophages. In the lack of change in basal mineralocorticoid activity, eplerenone increases markers of alternative activation in a mineralocorticoid receptor-independent manner. Because of changes in iNOS and NO variable, eplerenone induced qualitatively different activation of macrophages from that obtained with IL-4.

Topics: Aged; Aldosterone; Arginase; Cell Survival; Drug Interactions; Eplerenone; Female; Gene Expression Regulation; Healthy Volunteers; Heart Failure; Humans; Interleukin-4; Lectins, C-Type; Macrophage Activation; Macrophages; Male; Mannose Receptor; Mannose-Binding Lectins; Middle Aged; Mineralocorticoid Receptor Antagonists; Nitric Oxide; Nitric Oxide Synthase Type II; Phenotype; Reactive Oxygen Species; Receptors, Cell Surface; Receptors, Mineralocorticoid; Spironolactone; Superoxide Dismutase

Mineralocorticoid receptor(MR) antagonism reduces sudden cardiac death in heart failure, but the underlying mechanism remains poorly understood. Concurrent treatment with an MR antagonist during rapid ventricular pacing (RVP) prevents development of adverse ventricular electrophysiological remodeling, interstitial fibrosis, inflammatory cytokine gene activation, and ventricular tachyarrhythmia inducibility without diminishing the extent of systolic dysfunction. We hypothesized that attenuating preexistent inflammatory pathways and myocardial fibrosis with eplerenone after systolic heart failure is established by rapid pacing can reduce electrical activation delays and arrhythmia vulnerability.. Dogs subjected to RVP for 8 weeks in the absence or presence of eplerenone treatment during the final 4 weeks of pacing were assessed by echocardiography, electrophysiology study,ventricular fibrosis measurements, and inflammatory cytokine mRNA expression analysis. Eplerenone reversed preexistent ventricular activation delays, interstitial fibrosis, inflammatory cytokine (interleukin-6, tumor necrosis factor-α) gene overexpression, and arrhythmia vulnerability in ventricular paced dogs with heart failure. Eplerenone failed to improve left ventricular systolic dysfunction or chamber enlargement. A correlation between severity of fibrosis and ventricular arrhythmia inducibility was found.. MR antagonism regresses rapid pacing-induced electrical delays, inflammatory cytokine gene activation, and fibrosis in heart failure. Ventricular arrhythmia vulnerability in heart failure is correlated with extent of fibrosis and electrical activation delays during premature excitation.

Topics: Action Potentials; Animals; Anti-Inflammatory Agents; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Cardiovascular Agents; Disease Models, Animal; Dogs; Eplerenone; Fibrosis; Heart Failure; Hypertrophy, Left Ventricular; Inflammation Mediators; Interleukin-6; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Spironolactone; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Pharmacological blockade of the mineralocorticoid receptor (MR) ameliorates end-organ damage in chronic heart failure. However, the clinical use of available steroidal MR antagonists is restricted because of concomitant hyperkalemia especially in patients with diminished kidney function. We have recently identified a novel nonsteroidal MR antagonist, finerenone, which uniquely combines potency and selectivity toward MR. Here, we investigated the tissue distribution and chronic cardiorenal end-organ protection of finerenone in comparison to the steroidal MR antagonist, eplerenone, in 2 different preclinical rat disease models. Quantitative whole-body autoradiography revealed that [C]-labeled finerenone equally distributes into rat cardiac and renal tissues. Finerenone treatment prevented deoxycorticosterone acetate-/salt-challenged rats from functional as well as structural heart and kidney damage at dosages not reducing systemic blood pressure. Finerenone reduced cardiac hypertrophy, plasma prohormone of brain natriuretic peptide, and proteinuria more efficiently than eplerenone when comparing equinatriuretic doses. In rats that developed chronic heart failure after coronary artery ligation, finerenone (1 mg·kg·d), but not eplerenone (100 mg·kg·d) improved systolic and diastolic left ventricular function and reduced plasma prohormone of brain natriuretic peptide levels. We conclude that finerenone may offer end-organ protection with a reduced risk of electrolyte disturbances.

Topics: Animals; Autoradiography; Cardiomegaly; Disease Models, Animal; Eplerenone; Heart Failure; Kidney Diseases; Male; Mineralocorticoid Receptor Antagonists; Naphthyridines; Natriuretic Peptide, Brain; Peptide Fragments; Rats; Rats, Sprague-Dawley; Rats, Wistar; Spironolactone; Tissue Distribution

Differential outcomes in patients with acute systolic heart failure (HF) complicating acute myocardial infarction (AMI) and the efficacy of mineralocorticoid receptor antagonists according to non-ST-segment and ST-segment elevation myocardial infarction (NSTEMI, STEMI) status has not been specifically investigated.. In the EPHESUS study, 6632 patients with acute HF and left ventricular ejection fraction<40% were randomized 3-14 days post-AMI (median 7.3 ± 3.0 days) to receive eplerenone (n=3319) or placebo (n=3313). Among them, 6392 patients with available data on baseline ST-segment status (4634 STEMI; 1758 NSTEMI) were compared using a Cox model analysis stratified according to quintiles of propensity score (PS), taking into account major baseline risk factors, including revascularization.. STEMI and NSTEMI patients differed significantly across a large variety of baseline characteristics. During 30 months of follow-up, all-cause death occurred in 19% and 13% (P<0.0001), cardiovascular death in 16% and 12% (P<0.0001), cardiovascular death and hospitalization in 33% and 26% (P<0.0001) and death from progression of HF in 5% and 3% (P<0.0001) of unadjusted NSTEMI and STEMI patients, respectively. After Cox model PS adjustment without revascularization, NSTEMI status still proved to be a risk factor for all-cause death, cardiovascular death and death from progression of HF. After Cox model PS adjustment including revascularization, none of the outcomes differed between STEMI and NSTEMI patients. Eplerenone morbidity and mortality benefits were consistent in the STEMI and NSTEMI subgroups.. In patients with acute systolic HF complicating AMI, eplerenone improves outcomes equally in STEMI and NSTEMI patients. Worse outcomes associated with NSTEMI could be explained by more co-morbidities, less aggressive therapies and, mainly, less frequent revascularization.

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Cause of Death; Comorbidity; Coronary Thrombosis; Disease Progression; Electrocardiography; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Multicenter Studies as Topic; Myocardial Infarction; Myocardial Revascularization; Prognosis; Proportional Hazards Models; Randomized Controlled Trials as Topic; Retrospective Studies; Spironolactone; Treatment Outcome

Topics: Eplerenone; Female; Heart Failure; Hospitalization; Humans; Hyperkalemia; Male; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Spironolactone

Still no randomised controlled trials versus spironolactone, but a prematurely terminated placebo-controlled trial with 2737 patients.

Topics: Chronic Disease; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Spironolactone

Topics: Chronic Disease; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

Right ventricular (RV) failure due to increased pressure load causes significant morbidity and mortality in patients with congenital heart diseases and pulmonary arterial hypertension. It is unknown whether renin-angiotensin-aldosterone-system (RAAS) inhibition (the cornerstone of left ventricular failure treatment) is effective in RV failure. We investigated the effects of combination treatment of aldosterone-blocker eplerenone+angiotensin II receptor blocker losartan (Ep/Lo) on RV remodeling and function in a model of RV failure due to increased pressure load.. Rats (n=48) were randomized for pulmonary artery banding (PAB) or sham surgery and for losartan (20 mg/kg/d)+eplerenone (100 mg/kg/d) treatment (Ep/Lo) or vehicle (VEH). RV function was assessed by echocardiography and pressure-volume analysis at 5 and 11 weeks, or at the occurrence of clinical RV failure symptoms necessitating termination. PAB resulted in RV failure in all rats, as defined by reduced cardiac output, RV stroke volume, increased RV end diastolic pressure and liver congestion as well as RV fibrosis, hypertrophy and reduced capillary density. Clinical RV failure necessitated termination in 5/12 PAB-VEH rats. Angiotensin II type 1-receptor expression in the RV was reduced in PAB rats indicating local RAAS activation. Treatment of PAB rats with Ep/Lo significantly lowered arterial pressures, but had no significant effect on RV function, remodeling or survival compared to PAB-VEH rats.. RAAS inhibition does not beneficially affect experimental RV failure due to chronic pressure load. This is of high clinical relevance, because it indicates that the RV response to RAAS inhibition might fundamentally differ from that of the LV.

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Eplerenone; Heart Failure; Losartan; Male; Random Allocation; Rats; Rats, Wistar; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Right

The addition of an aldosterone receptor antagonist on top of current optimal therapy (based on angiotensin II inhibition) has demonstrated an important clinical benefit in heart failure patients with systolic dysfunction. Whether this finding also applies to heart failure patients with preserved systolic function is unknown. Therefore, we have studied the effect of adding eplerenone to standard pharmacological heart failure therapy (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and diuretic and β-blocker) in the progression of heart failure in spontaneously hypertensive heart failure (SHHF) rats.. Two-month-old SHHF rats were randomized to receive no treatment (SHHF group), a standard heart failure therapy (quinapril-torasemide-carvedilol; ST-SHHF group), or the combination of eplerenone and standard heart failure therapy (Eple+ST-SHHF group) for 20 months. Untreated SHHF was characterized by progressive left ventricular hypertrophy, fibrosis, and myocardial contractile and relaxation abnormalities, leading to pulmonary congestion. Despite similar blood pressure control, the addition of eplerenone to standard heart failure therapy further prevented left ventricular hypertrophy, contractile and relaxation alterations, and pulmonary congestion than standard heart failure therapy alone. ST-SHHF and Eple + ST-SHHF rats showed similar inhibition of structural extracellular matrix proteins collagen I, collagen III and fibronectin and metalloproteinase (MMP)-2, MMP-7, MMP-12, and MMP-13. However, only the coadministration of eplerenone with standard heart failure therapy normalized the expression of matricellular proteins thrombospondin 1, tenascin C, periostin, and secreted protein acidic rich in cysteine/osteonectin to values comparable to normotensive rats.. In a hypertensive heart failure rat model, the addition of eplerenone to conventional heart failure therapy further improves cardiac structural and functional parameters, delaying the progression of heart failure. These beneficial effects of eplerenone were associated with normalization of matricellular protein expression.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Drug Therapy, Combination; Eplerenone; Heart; Heart Failure; Hypertension; Hypertrophy, Left Ventricular; Male; Matrix Metalloproteinases; Mineralocorticoid Receptor Antagonists; Myocardium; Random Allocation; Rats; Rats, Inbred SHR; Spironolactone

Topics: Double-Blind Method; Early Medical Intervention; Eplerenone; Germany; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Multicenter Studies as Topic; Myocardial Infarction; Prognosis; Randomized Controlled Trials as Topic; Spironolactone; Survival Rate

The use of a placebo arm in clinical trials is unethical if there is an active comparator that is acceptably safe and effective. We argue that reasonable evidence of effectiveness and safety of an inexpensive alternative to an expensive therapy is sufficient to require that the inexpensive therapy be included as a comparator when the expensive therapy is tested, and that use of an inactive placebo comparator only is not ethical. For example, studies of the expensive drug eplerenone for congestive heart failure have not included a spironolactone arm, although there is reasonable evidence that spironolactone would be safe and effective, and spironolactone is inexpensive. The requirement to study inexpensive therapies is based on avoidance of unnecessary cost in medical care as an example of non-maleficence. Several ethical actors in the design, conduct, and publication of clinical trials and their results bear responsibility for the appropriate conduct of clinical trials. That responsibility includes protecting study subjects from being asked to participate in clinical trials that serve primarily to promote the use of new and expensive therapies.

Topics: Clinical Trials as Topic; Cost-Benefit Analysis; Drug Costs; Eplerenone; Ethics Committees, Research; Ethics, Research; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Periodicals as Topic; Placebos; Research Personnel; Severity of Illness Index; Spironolactone; Therapeutic Equipoise; Treatment Outcome; United States; United States Food and Drug Administration

The conventional reporting of composite endpoints in clinical trials has an inherent limitation in that it emphasizes each patient's first event, which is often the outcome of lesser clinical importance. To overcome this problem, we introduce the concept of the win ratio for reporting composite endpoints. Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. Consider a primary composite endpoint, e.g. cardiovascular (CV) death and heart failure hospitalization (HF hosp) in heart failure trials. For each matched pair, the new treatment patient is labelled a 'winner' or a 'loser' depending on who had a CV death first. If that is not known, only then they are labelled a 'winner' or 'loser' depending on who had a HF hosp first. Otherwise they are considered tied. The win ratio is the total number of winners divided by the total numbers of losers. A 95% confidence interval and P-value for the win ratio are readily obtained. If formation of matched pairs is impractical then an alternative win ratio can be obtained by comparing all possible unmatched pairs. This method is illustrated by re-analyses of the EMPHASIS-HF, PARTNER B, and CHARM trials. The win ratio is a new method for reporting composite endpoints, which is easy to use and gives appropriate priority to the more clinically important event, e.g. mortality. We encourage its use in future trial reports.

Topics: Angiotensin II Type 1 Receptor Blockers; Aortic Valve Stenosis; Benzimidazoles; Biphenyl Compounds; Cardiac Catheterization; Cardiovascular Diseases; Clinical Trials as Topic; Endpoint Determination; Eplerenone; Heart Failure; Hospitalization; Humans; Matched-Pair Analysis; Mineralocorticoid Receptor Antagonists; Proportional Hazards Models; Risk Factors; Spironolactone; Tetrazoles

Aldosterone antagonists (or mineralocorticoid receptor antagonists [MRAs]) are guideline-recommended therapy for patients with moderate to severe heart failure (HF) symptoms and reduced left ventricular ejection fraction (LVEF), and in postmyocardial infarction patients with HF. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial evaluated the MRA eplerenone in patients with mild HF symptoms. Eplerenone reduced the risk of the primary endpoint of cardiovascular death or HF hospitalization (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.54-0.74, P < .001) and all-cause mortality (adjusted HR 0.76, 95% CI 0.62-0.93, P < .008) after a median of 21 months. Based on EMPHASIS-HF, an MRA is recommended for patients with New York Heart Association (NYHA) Class II-IV symptoms and reduced LVEF (<35%) on standard therapy (Strength of Evidence A). Patients with NYHA Class II symptoms should have another high-risk feature to be consistent with the EMPHASIS-HF population (age >55 years, QRS duration >130 msec [if LVEF between 31% and 35%], HF hospitalization within 6 months or elevated B-type natriuretic peptide level). Renal function and serum potassium should be closely monitored. Dose selection should consider renal function, baseline potassium, and concomitant drug interactions. The efficacy of eplerenone in patients with mild HF symptoms translates into a unique opportunity to reduce morbidity and mortality earlier in the course of the disease.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Eplerenone; Heart; Heart Failure; Hospitalization; Humans; Kidney; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left

Endothelial progenitor cells (EPCs) are known to play a significant role in reendothelialization and vascular repair. Recently, a mineralocorticoid receptor was demonstrated to be expressed by EPCs. The study aimed to evaluate a potential influence of eplerenone treatment on the total number of EPCs in patients with chronic heart failure.. Eighty-seven male patients with chronic heart failure were included (age: 23-83 years; body mass index 29.1 ± 5.1 kg/m²; New York Heart failure classification (NYHA) I: 29 patients, NYHA II: 32 patients, NYHA III: 26 patients). Numbers of circulating EPCs were quantified immediately using flow cytometry. Twenty-eight patients received therapy with eplerenone. Patients were further characterized by echocardiography, spirometry and laboratory markers.. Patients with ongoing eplerenone administration showed higher levels of circulating cells expressing CD34+ (p<0.05) and CD34+KDR+ (p<0.05) and CD34+CD133+KDR+ cells (p<0.05). The effects of eplerenone treatment could be shown to be independent of NYHA status, genesis of the underlying cardiovascular morbidity, left ventricular function and co-medication.. Patients with chronic heart failure treated with eplerenone show higher numbers of EPCs. The clinical benefit for treatment with eplerenone has been demonstrated even for patients with mild heart failure and might be partially mediated by EPCs.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Endothelial Cells; Eplerenone; Exercise; Heart Failure; Humans; Male; Middle Aged; Spironolactone; Stem Cells; Ultrasonography; Young Adult

Topics: Benzazepines; Cardiac Resynchronization Therapy; Cardiotonic Agents; Eplerenone; Europe; Heart Failure; Humans; Infusions, Intravenous; Iron; Ivabradine; Life Style; Mineralocorticoid Receptor Antagonists; Practice Guidelines as Topic; Societies, Medical; Spironolactone

The typical presentation of heart failure in primary care is insidious, with progressive breathlessness on exertion, ankle swelling, orthopnoea or paroxysmal nocturnal dyspnoea. Not all patients will have all these symptoms, and in many patients there may be other causes. If a GP suspects heart failure, then the key blood test is B-type natriuretic peptide (BNP). If the BNP is normal then heart failure is unlikely and other diagnoses should be considered. If it is raised, or if there is a past history of myocardial infarction, the patient requires further assessment, which must include echocardiography and a specialist assessment. The underlying cardiac abnormality should be identified. An ECG is often very useful and if it is completely normal it makes heart failure less likely. Both the NICE and the ESC guidance emphasise the importance of lifestyle management (regular appropriate exercise, avoiding excessive salt and alcohol consumption). ACE inhibitors (or angiotensin receptor blockers) and beta-blockers licensed for heart failure (carvedilol, bisoprolol, nebivolol) remain the mainstay of treatment in addition to as small a dose of diuretic as possible to control any fluid retention. Aldosterone antagonism is recommended by the 2012 ESC guidance for all patients who remain symptomatic despite an ACE inhibitor and beta-blocker. If the rhythm is sinus but the heart rate is 75 beats per minute, therapy needs to be optimised, perhaps by increasing the beta-blocker dose, if possible, or by the addition of ivabradine.

Topics: Algorithms; Benzazepines; Cyclic Nucleotide-Gated Cation Channels; Eplerenone; Heart Failure; Humans; Ivabradine; Mineralocorticoid Receptor Antagonists; Natriuretic Peptide, Brain; Patient Care Team; Peptide Fragments; Spironolactone; Ventricular Dysfunction, Left

Topics: Aged; Controlled Clinical Trials as Topic; Creatinine; Dose-Response Relationship, Drug; Eplerenone; Female; Glomerular Filtration Rate; Heart Failure; Humans; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Spironolactone; Ventricular Dysfunction, Left

Topics: Cardiovascular Diseases; Combined Modality Therapy; Defibrillators, Implantable; Eplerenone; Heart Failure; Hospitalization; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

To determine independent associations of diabetes mellitus with outcomes in a propensity-matched cohort of patients with acute myocardial infarction (AMI) and systolic heart failure (HF).. In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial, hospitalized AMI patients complicated by left ventricular ejection fraction ≤40% and symptoms of HF receiving standard therapy were randomized 3-14 days post-AMI to receive eplerenone 25-50 mg/day (n = 3319) or placebo (n = 3313). Of the 6632 patients, 2142 (32%) had a history of diabetes, who were older and sicker. Using propensity scores for diabetes, we assembled a cohort of 1119 pairs of patients with and without diabetes who were balanced on 64 baseline characteristics. Incident fatal or nonfatal recurrent AMI occurred in 136 (12%) and 87 (8%) of matched patients with and without diabetes, respectively, during 2.5 years of follow-up [hazard ratio (HR) when diabetes was compared with no-diabetes, 1.61; 95% confidence interval (CI), 1.23-2.10; P = 0.001]. Diabetes was associated with nonfatal AMI (HR, 1.68; 95% CI, 1.23-2.31; P = 0.001) but not with fatal AMI (HR, 1.42; 95% CI, 0.88-2.28; P = 0.146). Hazard ratios (95% CIs) for the association of diabetes with all-cause mortality, cardiovascular mortality, all-cause hospitalization, and cardiovascular hospitalization were 1.12 (0.93-1.37; P = 0.224), 1.11 (0.90-1.37; P = 0.318), 1.13 (1.00-1.27; P = 0.054), and 1.20 (1.01-1.44; P = 0.042), respectively.. In post-AMI patients with systolic HF, diabetes mellitus is a significant independent risk factor for recurrent short-term nonfatal AMI, but had no association with fatal AMI.

Topics: Aged; Diabetic Angiopathies; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Propensity Score; Randomized Controlled Trials as Topic; Recurrence; Spironolactone; Treatment Outcome

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone; Stroke Volume

Topics: Aldosterone; Cardiovascular Diseases; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Sodium, Dietary; Spironolactone; Stroke Volume

Topics: Blood Pressure; Cardiovascular Diseases; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Regression Analysis; Spironolactone

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

Topics: Aldosterone; Biomarkers; Canrenone; Cause of Death; Double-Blind Method; Early Termination of Clinical Trials; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Hyperkalemia; Male; Mineralocorticoid Receptor Antagonists; Models, Cardiovascular; Molecular Structure; Multicenter Studies as Topic; Myocardial Infarction; Patient Selection; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Research Design; Risk; Spironolactone

Topics: Eplerenone; Heart Failure; Hospitalization; Humans; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Severity of Illness Index; Spironolactone; Stroke Volume

The purpose of this study was to determine whether a diuretic effect may be detectable in patients treated with eplerenone, a mineralocorticoid receptor antagonist, as compared with placebo during the first month of EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival study) (n = 6,080) and whether this was associated with eplerenone's beneficial effects on cardiovascular outcomes.. The mechanism of the survival benefit of eplerenone in patients with heart failure post-myocardial infarction remains uncertain.. A diuretic effect was indirectly estimated by changes at 1 month that was superior to the median changes in the placebo group in body weight (-0.05 kg) and in the estimated plasma volume reduction (+1.4%). A potassium-sparing effect was defined as a serum potassium increase greater than the median change in the placebo group: +0.11 mmol/l.. In the eplerenone group, body weight (p < 0.0001) and plasma volume (p = 0.047) decreased, whereas blood protein and serum potassium increased (both, p < 0.0001), as compared with the placebo group, suggesting a diuretic effect induced by eplerenone, associated with a potassium-sparing effect. A diuretic effect, as defined by an estimated plasma volume reduction, was independently associated with 11% to 19% better outcomes (lower all-cause death, cardiovascular death or cardiovascular hospitalization, all-cause death or hospitalization, hospitalization for heart failure). Potassium sparing was also independently associated with 12% to 34% better outcomes. There was no statistically significant interaction between the observed beneficial effects of eplerenone (9% to 17%) on cardiovascular outcomes and potassium-sparing or diuretic effects.. Eplerenone's beneficial effects on long-term survival and cardiovascular outcomes are independent from early potassium-sparing or diuretic effects, suggesting that mineralocorticoid receptor antagonism provides cardiovascular protection beyond its diuretic and potassium-sparing properties.

Topics: Aged; Clinical Trials as Topic; Diuresis; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Potassium; Spironolactone

Topics: Diuresis; Eplerenone; Female; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Potassium; Spironolactone

Topics: Aldosterone; Animals; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

The EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure and Survival Study) showed that the use of aldosterone blockade with eplerenone decreased mortality in patients with heart failure after acute myocardial infarction, and a subsequent analysis showed eplerenone to be highly cost effective in this population.. To assess the cost effectiveness of eplerenone in an EPHESUS subgroup population who were taking both ACE inhibitors and beta-blockers (beta-adrenoceptor antagonists) at baseline. In the EPHESUS, a total of 6632 patients were randomized to receive eplerenone 25-50 mg/day (n = 3319) or placebo (n = 3313) concurrently with standard therapy and were followed for up to 2.5 years. Of these, 4265 (64.3%) patients (eplerenone: n = 2113; placebo: n = 2152) were taking both ACE inhibitors and beta-blockers at baseline.. Resource use after the initial hospitalization included additional hospitalizations, outpatient services, emergency room visits, and medications. Eplerenone was priced at an average wholesale price of $US3.60 per day (year 2004 value). Bootstrap methods were used to estimate the fraction of the joint distribution of the cost and effectiveness. A net-benefit regression model was used to derive the propensity score-adjusted cost-effectiveness curve. The incremental cost effectiveness of eplerenone in cost per life-year gained (LYG) and cost per quality-adjusted life-year (QALY) gained beyond the trial period was estimated using data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. Both costs and effectiveness were discounted at 3%. Although not all resource use could be accounted for, the overall perspective was societal.. As in the overall EPHESUS population, the total direct treatment costs were higher in the eplerenone arm than the placebo arm for patients who were taking both ACE inhibitors and beta-blockers ($US14,563 vs $US12,850, difference = $US1713; 95% CI 721, 2684). The number of LYGs with eplerenone compared with placebo was 0.1665 based on the Framingham data, 0.0979 using the Saskatchewan data, and 0.2172 using the Worcester data. The incremental cost-effectiveness ratio (ICER) was $US10,288/LYG with the Framingham data, $US17,506/LYG with the Saskatchewan data, and $US7888/LYG with the Worcester data (99% <$US50,000/LYG for all three sources). The ICERs were systematically higher when calculated as the cost per QALY gained ($US14,926, $US25,447, and $US11,393, respectively) as the utilities were below 1 with no difference between the treatment arms.. As for the overall EPHESUS population, aldosterone blockade with eplerenone is effective in reducing mortality and is cost effective in increasing years of life for the EPHESUS subgroup of patients who were taking both ACE inhibitors and beta-blockers.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eplerenone; Female; Follow-Up Studies; Health Care Costs; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Regression Analysis; Spironolactone

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Early Termination of Clinical Trials; Eplerenone; Germany; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Spironolactone; Survival Rate; United States

Topics: Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Spironolactone

Aldosterone blockade reduces sudden cardiac death in heart failure, but the underlying mechanism is unclear.. This study's aim was to determine whether chronic eplerenone treatment protects against detrimental ventricular electrical remodeling and development of an arrhythmogenic substrate in a rapid ventricular pacing (RVP)-induced heart failure model.. Dogs were assigned randomly to oral placebo or eplerenone treatment and divided into 4 groups: 2 sham-operated (no RVP) and 2 RVP groups. After 5 weeks of no RVP or RVP along with concurrent placebo or eplerenone treatment, dogs underwent echocardiographic assessments of systolic function and chamber size and electrophysiologic measurements of ventricular repolarization, refractoriness, conduction, tachyarrhythmia inducibility, and myocardial activation delays after premature stimulation.. Eplerenone failed to prevent left ventricular systolic dysfunction or chamber enlargement in RVP dogs. Eplerenone attenuated prolongation of ventricular repolarization and refractoriness, increases in dispersion of repolarization and refractoriness, fractionation of ventricular electrograms, and delays in myocardial activation after premature stimulation at short coupling intervals and improved arrhythmia vulnerability score in RVP dogs with heart failure. Ventricular tachyarrhythmia inducibility in heart failure dogs was predicted by activation delays after premature stimulation at short coupling intervals, which were prevented by eplerenone. Eplerenone did not alter electrophysiological parameters in no-RVP dogs without heart failure.. Eplerenone attenuates heart failure-related ventricular electrical remodeling and tachyarrhythmia vulnerability. Inhibition of myocardial activation delays during premature excitation may contribute to preventing development of an arrhythmogenic ventricular substrate in heart failure.

Topics: Animals; Disease Models, Animal; Dogs; Electrocardiography; Eplerenone; Heart Failure; Mineralocorticoid Receptor Antagonists; Spironolactone; Tachycardia, Ventricular; Ventricular Remodeling

Topics: Angiotensin-Converting Enzyme Inhibitors; Death, Sudden, Cardiac; Drug Therapy, Combination; Eplerenone; Evidence-Based Medicine; Heart Failure; Humans; Kidney Function Tests; Mineralocorticoid Receptor Antagonists; Potassium; Spironolactone; Survival Analysis

The influence of chronic administration of eplerenone on the intracrine as well as on the extracellular action of angiotensin II (Ang II) on L-type inward calcium current was investigated in the failing heart of cardiomyopathic hamsters (TO-2).For this, eplerenone (200 mg/kg/day) was administered orally to 2 month-old cardiomyopathic hamsters for a period of 3 months. Measurements of the peak inward calcium current (I(Ca)) was performed in single cells under voltage clamp using the whole cell configuration. The results indicated that eplerenone suppressed the intracrine action of Ang II (10(-)(8) M) on peak I(Ca) density. Moreover, the intracellular dialysis of the peptide did not change the time course of I(Ca) inactivation in animals treated chronically with eplerenone. The extracellular administration of Ang II (10(-)(8) M) incremented the peak I(Ca) density by only 20+/-8% (n=30) compared with 38+/-4% (n=35) (P<0.05) obtained in age-matched cardiomyopathic hamsters not exposed to eplerenone. Interestingly, the inhibitory of eplerenone (10(-7) M) on the intracrine action of Ang II was also found, in vitro, but required an incubation period of, at least, 24 h. The inhibitory action of eplerenone on the intracellular action of Ang II was partially reversed by exposing the eplerenone-treated cells to aldosterone (10 nM) for a period of 24 h what supports the view that: a) the mineralocorticoid receptor(MR) was involved in the modulation of the intracrine action of the peptide; b) the effect of eplerenone on the intracrine as well as on the extracellular action of Ang II was related ,in part, to a decreased expression of membrane-bound and intracellular AT1 receptors.. a) eplerenone inhibits the intracrine action of Ang II on inward calcium current and reduces drastically the effect of extracellular Ang II on I(Ca); b) aldosterone is able to revert the effect of eplerenone; c) the mineralocorticoid receptor is an essential component of the intracrine renin angiotensin aldosterone system.

Topics: Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Calcium Signaling; Cardiomyopathies; Cricetinae; Eplerenone; Heart Failure; Mineralocorticoid Receptor Antagonists; Models, Cardiovascular; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; Renin-Angiotensin System; Spironolactone

Topics: Drug Administration Schedule; Emergencies; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Spironolactone; Ventricular Remodeling

Topics: Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone

The Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial demonstrated that selective aldosterone blockade with eplerenone significantly reduced total mortality by 15%, combined cardiovascular (CV) mortality/CV hospitalization by 13%, CV mortality by 17% and sudden cardiac death by 21%, vs. placebo when added to standard care in patients with left ventricular systolic dysfunction (LVSD) and signs of congestive heart failure (CHF) following acute myocardial infarction (AMI). We retrospectively evaluated the effect of eplerenone vs. placebo in a subset of 1483 diabetic patients with LVSD and signs of CHF following AMI.. Diabetic status was determined from medical histories at screening. Analyses were based on time to first occurrence of an event. Results were based on a Cox's proportional hazards regression model stratified by region with treatment, subgroup and treatment-by-subgroup interaction as factors. The 95% confidence intervals for the risk ratios were based on the Wald's test.. Treatment with eplerenone in diabetic patients with CHF following AMI reduced the risk of the primary endpoint, a composite of CV mortality or CV hospitalization, by 17% (p = 0.031). The absolute risk reduction of the primary endpoint was greater in the diabetic cohort (5.1%) than in the non-diabetic cohort (3%). Hyperkalaemia occurred more often with eplerenone than with placebo (5.6 vs. 3%, p = 0.015). Among the diabetic cohorts, the prespecified endpoint of 'any CV disorder' occurred in 28% of the eplerenone group and 35% of the placebo group (p = 0.007).. Eplerenone treatment may reduce adverse CV events in diabetic patients with LVSD and signs of CHF following AMI.

Topics: Aged; Clinical Trials as Topic; Diabetes Complications; Eplerenone; Female; Heart Failure; Humans; Hyperkalemia; Hyperuricemia; Hypokalemia; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Retrospective Studies; Risk Factors; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Mineralocorticoid receptor (MR) blockade reduces morbidity and mortality after acute myocardial infarction; however, the underlying mechanisms are still under investigation. This study examined whether MR antagonism promotes healing of the infarcted myocardium. Starting immediately after coronary ligation, male Wistar rats were treated with the selective MR antagonist eplerenone (100 mg/kg per day by gavage) or placebo for 2 to 7 days. At 7 days, eplerenone therapy versus placebo significantly reduced thinning and dilatation of the infarcted wall, improved left ventricular function, and enhanced neovessel formation in the injured myocardium. At 2 days, eplerenone-treated rats displayed lower plasma corticosterone levels, higher circulating blood monocytes, and more macrophages infiltrating the infarcted myocardium. MR blockade led to a transient upregulation (at days 2 and 3 but not at day 7) of monocyte chemoattractant protein-1, tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interleukin-10, and interleukin-4 and an increase in factor XIIIa protein expression in the healing myocardium. Prevention of macrophage accumulation into the infarct zone by treatment with liposome-encapsulated clodronate almost abrogated the protein expression of factor XIIIa and the beneficial effects of eplerenone on infarct expansion. In conclusion, selective MR blockade immediately after myocardial infarction accelerated macrophage infiltration and transiently increased the expression of healing promoting cytokines and factor XIIIa in the injured myocardium resulting in enhanced infarct neovascularization and reduced early LV dilation and dysfunction.

Topics: Aldosterone; Animals; Clodronic Acid; Collagen; Cytokines; Eplerenone; Factor XIIIa; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Monocytes; Myocardial Infarction; Myocarditis; Myocardium; Neovascularization, Physiologic; Rats; Rats, Wistar; RNA, Messenger; Spironolactone; Ventricular Function, Left; Wound Healing

1. It is currently assumed that translational research goes from benchtop to bedside; that aldosterone elevates blood pressure via its effects on salt and water homeostasis; that mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) share a common immediate ancestor; and that aldosterone plays a deleterious role in essential hypertension and heart failure. 2. Meta-analysis of clinical trials in essential hypertension, in which eplerenone was dose-titrated to attain diastolic blood pressure < 90 mmHg, showed no relationship between blood pressure response and electrolyte effects, as judged by change in plasma (K). 3. Reexamination of sequence data, and insights from the S810L MR mutant gene causing juvenile hypertension exacerbated by pregnancy, suggest that MR were the first to branch off the primordial ancestor for MR, GR, androgen receptors (AR) and progesterone receptors (PR). 4. In clinical trials of MR blockade in heart failure and essential hypertension baseline aldosterone levels are in the low to normal range and sodium status unremarkable. Under such circumstances cortisol appears to be responsible for MR activation, thus exculpating aldosterone in these conditions. 5. On the basis of these clinical studies, there is need to revisit the basic biology of aldosterone and MR as translational research very clearly goes both ways.

Topics: Aldosterone; Amino Acid Sequence; Antihypertensive Agents; Biomedical Research; Clinical Trials as Topic; Corticosterone; Dose-Response Relationship, Drug; Eplerenone; Genetic Predisposition to Disease; Heart Failure; Humans; Hypertension; Receptors, Mineralocorticoid; Spironolactone

Cardiac aldosterone levels have not been evaluated in diastolic heart failure (DHF), and its roles in this type of heart failure remain unclear. This study aimed to detect cardiac aldosterone by use of a liquid chromatographic-mass spectrometric method and to assess the effects of mineralocorticoid receptor blockade on hypertensive DHF. Dahl salt-sensitive rats fed 8% NaCl diet from 7 wk (hypertensive DHF model) were divided at 13 wk into three groups: those treated with subdepressor doses of eplerenone (12.5 or 40 mg x kg(-1) x day(-1)) and an untreated group. Dahl salt-sensitive rats fed 0.3% NaCl diet served as controls. Cardiac aldosterone was detected in the DHF rats but not in the control rats, with increased ventricular levels of mineralocorticoid receptor. Cardiac levels of 11-deoxycorticosterone, corticosterone, and 11-dehydrocorticosterone were not different between the control and DHF rats, but the tissue level of corticosterone that has an affinity to mineralocorticoid receptor was 1,000 times as high as that of aldosterone. Aldosterone synthase activity and CYP11B2 mRNA were undetectable in the ventricular tissue of the DHF rats. Administration of eplerenone attenuated ventricular hypertrophy, ventricular fibrosis, myocardial stiffening, and relaxation abnormality, leading to the prevention of overt DHF. In summary, the myocardial aldosterone level increased in the DHF rats. However, its value was extremely low compared with corticosterone, and no evidence for enhancement of intrinsic myocardial aldosterone production was found. The upregulation of mineralocorticoid receptor may play a central role in the pathogenesis of DHF, and blockade of mineralocorticoid receptor is likely an effective therapeutic regimen of DHF.

Topics: Aldosterone; Angiotensin II; Animals; Blotting, Western; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP11B2; Diastole; Eplerenone; Heart Failure; Heart Ventricles; Male; Mass Spectrometry; Mineralocorticoid Receptor Antagonists; Myocardial Contraction; Myocardium; Rats; Rats, Inbred Dahl; Receptors, Mineralocorticoid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spironolactone; Steroids; Stroke Volume; Ventricular Function, Left

We investigated the role of nuclear factor kappaB (NF-kappaB) in the cytokine-mediated induction of cyclooxygenase-2 activity in the paraventricular nucleus of hypothalamus (PVN), a critical cardiovascular and autonomic center, in rats with heart failure (HF). Sprague-Dawley rats underwent coronary artery ligation to induce HF or sham surgery. HF rats were treated orally for 6 weeks with vehicle (tap water), the NF-kappaB inhibitor pyrrolidine dithiocarbamate (150 mg/kg per day), or the mineralocorticoid receptor antagonist eplerenone (30 mg/kg per day), which has been shown to reduce circulating proinflammatory cytokines in this model. Compared with sham surgery, HF rats had higher (P<0.05) levels of aldosterone, interleukin-1beta and norepinephrine in plasma and prostaglandin E2 in cerebrospinal fluid. In the PVN, NF-kappaB p50 precursor p105 mRNA increased, and mRNA for its inhibitor, IkappaB, decreased (P<0.05). Cyclooxygenase-2 mRNA and protein expression was increased in perivascular cells of the PVN. Both pyrrolidine dithiocarbamate and eplerenone reduced (P<0.05) p105 mRNA and increased IkappaB mRNA in PVN. Both also reduced (P<0.05) cyclooxygenase-2 mRNA and protein expression in PVN, cerebrospinal fluid prostaglandin E2, and plasma norepinephrine. Eplerenone, but not pyrrolidine dithiocarbamate, reduced plasma interleukin-1beta. Pyrrolidine dithiocarbamate and eplerenone had no effect on plasma aldosterone. The results suggest that activation of NF-kappaB is an intermediary step in cytokine-mediated induction of cyclooxygenase-2 in the PVN of HF rats. By enhancing access of prostaglandin E2 to hypothalamic neurons, this mechanism may contribute to augmented sympathetic nerve activity in HF.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Eplerenone; Heart Failure; Male; NF-kappa B; Paraventricular Hypothalamic Nucleus; Pyrrolidines; Rats; Rats, Sprague-Dawley; Spironolactone; Thiocarbamates

Topics: Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone

Long-term monotherapy with the aldosterone receptor blocker eplerenone in dogs with HF was previously shown to improve LV systolic and diastolic function. This study examined the effects of long-term monotherapy with the aldosterone receptor blocker eplerenone on mRNA and protein expression of the cytoskeletal proteins titin, tubulin, fibronectin and vimentin, the matrix metalloproteinases (MMPs)-1, -2 and -9, and the tissue inhibitors of MMPs (TIMPs)-1 and -2 in left ventricular (LV) myocardium of dogs with heart failure (HF).. HF was produced in 12 dogs by intracoronary microembolizations. Dogs were randomized to 3 months oral therapy with eplerenone (10 mg/kg twice daily, n = 6) or to no therapy at all (HF-control, n = 6). LV tissue from six normal dogs was used for comparison. mRNA expression was measured using reverse-transcriptase polymerase chain reaction (RT-PCR) and protein expression using Western blots.. Compared to NL dogs, control dogs showed upregulation of mRNA and protein expression for tubulin, fibronectin, MMP-1, -2 and -9, and down-regulation of mRNA and protein expression for total titin. Normalization of mRNA and protein expression for all these genes was seen after treatment with eplerenone. N2BA/N2B-titin mRNA expression ratio increased significantly in dogs with HF treated with eplerenone. No differences in expression for vimentin, TIMP-1 and -2 were observed among groups.. In dogs with HF, long-term eplerenone therapy normalizes mRNA and protein expression of key cytoskeletal proteins and MMPs. Reversal of these molecular maladaptations may partly explain the improvement in LV diastolic function seen after long-term therapy with eplerenone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cytoskeletal Proteins; Dogs; Eplerenone; Heart Failure; Matrix Metalloproteinases; Mineralocorticoid Receptor Antagonists; RNA, Messenger; Spironolactone; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2

Renin-angiotensin-aldosterone system activation may be involved in the pathogenesis of atrial arrhythmias in congestive heart failure (CHF). The effects of aldosterone blockade on atrial tachyarrhythmias have not been evaluated. This study's aim was to determine whether selective aldosterone blockade suppresses atrial tachyarrhythmia inducibility and modifies atrial electrical and/or structural remodeling in a canine model of rapid ventricular pacing (RVP)-induced CHF.. Dogs were assigned randomly to treatment with oral placebo or eplerenone (50 mg/day) and divided into four groups: two sham-operated (no RVP) and two RVP groups. After 5 weeks of no RVP or RVP at 230 beats/min along with concurrent placebo or eplerenone treatment, dogs underwent electrophysiologic and echocardiographic studies. Sustained atrial tachyarrhythmia inducibility (>10-minute duration), atrial effective refractory periods (ERPs), systolic and diastolic function, and left atrial and left ventricular (LV) chamber sizes were assessed. Placebo-treated RVP dogs developed CHF with LV systolic and diastolic dysfunction, left atrial and LV enlargement, increased atrial ERPs, and inducible sustained atrial tachyarrhythmias. Eplerenone treatment in RVP dogs significantly suppressed sustained atrial tachyarrhythmia inducibility, nonuniformly prolonged atrial ERPs and attenuated LV diastolic dysfunction without modifying left atrial or LV dilation or ejection fractions in CHF. Isoproterenol (2-4 microg/min) reversed eplerenone's atrial antiarrhythmic and ERP prolonging effects in CHF. Eplerenone did not alter atrial ERPs in sham (no RVP) dogs without CHF.. Eplerenone suppresses inducibility of sustained atrial tachyarrhythmias, selectively prolongs atrial ERPs, and attenuates LV diastolic remodeling in RVP-induced CHF. Aldosterone blockade may be a promising new approach for atrial tachyarrhythmia prevention in CHF.

Topics: Administration, Oral; Animals; Dogs; Eplerenone; Heart Atria; Heart Conduction System; Heart Failure; Mineralocorticoid Receptor Antagonists; Random Allocation; Spironolactone; Tachycardia; Treatment Outcome; Ventricular Dysfunction, Left

Topics: Administration, Oral; Animals; Dogs; Eplerenone; Heart Atria; Heart Conduction System; Heart Failure; Mineralocorticoid Receptor Antagonists; Random Allocation; Spironolactone; Tachycardia; Treatment Outcome; Ventricular Dysfunction, Left

Aldosterone promotes cardiovascular inflammation and remodeling, both of which are characteristic changes in hypertensive and failing hearts. Since chronic inhibition of nitric oxide (NO) synthase with N(omega)-nitro-L-arginine methyl ester (L-NAME) induces systemic hypertension associated with cardiovascular inflammation and remodeling, we examined the potential role of aldosterone in this process using eplerenone, a selective aldosterone receptor antagonist. Ten-week-old male Wistar-Kyoto rats were randomly divided into 3 groups: the control group (no treatment), the L-NAME group (received L-NAME 1 g/L in drinking water), and the L-NAME+Eplerenone group (L-NAME plus eplerenone at 100 mg/kg/day). After 8 weeks of the treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (198 +/- 7 vs. 141 +/- 3 mmHg, P < 0.05). Eplerenone did not affect the increase in blood pressure caused by L-NAME (189 +/- 12 mmHg). Chronic inhibition of NO synthesis increased the plasma aldosterone concentration and CYP11B2 mRNA in adrenal glands. Cardiac inflammation and fibrosis were detected in the L-NAME group, while both changes were completely prevented by eplerenone. Cardiac hypertrophy was induced in L-NAME group, but was partially prevented by eplerenone. In the L-NAME group, left ventricular fractional shortening (LVFS: 27 +/- 2 vs. 38 +/- 1%) and E/A ratio (1.7 +/- 0.1 vs. 2.1 +/- 0.1) were significantly lower and LV end-diastolic pressure (LVEDP) was higher (4.9 +/- 0.6 vs. 13.9 +/- 0.5 mmHg) without LV enlargement, compared with those in the control group (P < 0.05). Eplerenone completely normalized LVFS (36 +/- 2%), E/A ratio (2.2 +/- 0.1), and LVEDP (6.2 +/- 0.7 mmHg). These results suggest that chronic inhibition of NO synthesis induces cardiac inflammation and dysfunction via an aldosterone receptor-dependent mechanism.

Topics: Actins; Aldosterone; Animals; Blotting, Western; Cytochrome P-450 CYP11B2; Drug Therapy, Combination; Eplerenone; Fibrosis; Heart Failure; Heart Ventricles; Hypertension; Immunohistochemistry; Male; Mineralocorticoid Receptor Antagonists; NF-kappa B; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peptide Fragments; Proliferating Cell Nuclear Antigen; Protein Precursors; Random Allocation; Rats; Rats, Inbred WKY; Receptors, Mineralocorticoid; RNA, Messenger; Spironolactone; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: ADAM Proteins; ADAM17 Protein; Dose-Response Relationship, Drug; Eplerenone; Heart Failure; Humans; Monocytes; Spironolactone; Tumor Necrosis Factor-alpha

Blocking brain mineralocorticoid receptors (MRs) reduces the high circulating levels of tumor necrosis factor (TNF)-alpha in heart failure (HF) rats. TNF-alpha and other proinflammatory cytokines activate neurons in the paraventricular nucleus (PVN) of hypothalamus, including corticotropin-releasing hormone (CRH) neurons, by inducing cyclooxygenase (COX)-2 activity and synthesis of prostaglandin E2 by perivascular cells of the cerebral vasculature. We tested the hypothesis that systemic treatment with a MR antagonist would reduce hypothalamic COX-2 expression and PVN neuronal activation in HF rats. Rats underwent coronary ligation to induce HF, confirmed by echocardiography, or sham surgery, followed by 6 weeks treatment with eplerenone (30 mg/kg per day, orally) or vehicle (drinking water). Eplerenone-treated HF rats had lower plasma TNF-alpha, interleukin (IL)-1beta and IL-6, less COX-2 staining of small blood vessels penetrating PVN, fewer PVN neurons expressing Fra-like activity (indicating chronic neuronal activation), and fewer PVN neurons staining for TNF-alpha, IL-1beta, and CRH than vehicle-treated HF rats. COX-2 and CRH protein expression in hypothalamus were 1.7- and 1.9-fold higher, respectively, in HF+vehicle versus sham+vehicle rats; these increases were attenuated (26% and 25%, respectively) in HF+eplerenone rats. Eplerenone-treated HF rats had less prostaglandin E2 in cerebrospinal fluid, lower plasma norepinephrine levels, lower left ventricular end-diastolic pressure, and lower right ventricle/body weight and lung/body weight ratios, but no improvement in left ventricular function. Treatment of HF rats with anticytokine agents, etanercept or pentoxifylline, produced very similar results. This study reveals a previously unrecognized effect of MR antagonism to minimize cytokine-induced central neural excitation in rats with HF.

Topics: Animals; Cytokines; Drug Synergism; Echocardiography; Eplerenone; Etanercept; Heart Failure; Hypothalamus; Immunoglobulin G; Inflammation Mediators; Male; Mineralocorticoid Receptor Antagonists; Myocardial Ischemia; Pertussis Toxin; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor; Spironolactone

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Death, Sudden, Cardiac; Defibrillators, Implantable; Drug Therapy, Combination; Eplerenone; Evidence-Based Medicine; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prospective Studies; Randomized Controlled Trials as Topic; Risk Factors; Spironolactone; Stem Cell Transplantation; Time Factors; Treatment Outcome

The effect of chronic administration of eplerenone on cardiac remodelling and electrical properties was investigated in the failing heart of cardiomyopathic hamsters (TO-2) at five months of age.. Two-month-old hamsters were treated with eplerenone (200 mg/kg/day) administered into the chow for a period of three months. Measurements of membrane potential were performed with intracellular microelectrodes connected to a high impedance DC amplifier. The thickness of the ventricular wall as well as the area of fibrosis were measured. To investigate the influence of eplerenone on the electrogenic sodium pump myocytes were isolated from the ventricle and the pump current density was measured in voltage clamped cells using the whole cell clamp configuration.. The results indicated that: 1) the width of the left and right ventricular wall was significantly reduced; 2) the heart weight/body weight ratio was decreased by 38+/-2.4% (n=24) (p<0.05); 3) the fibrotic area in the left ventricle (LV) was reduced by 12.6+/-2% (n=25) (p<0.05); 4) the incidence of cardiac arrhythmias was decreased from 58+/-3.8% (n=20) in the control to 40+/-4.1% (n=20) (p<0.05) in animals treated with eplerenone. Moreover, a significant reduction in the dispersion of the QT interval was found with the drug; 5) eplerenone increased the resting potential of ventricular fibres from 64.3+/-1.5 mV to 73.4+/-1.4 mV (n=30) (p<0.05), an effect related to the activation of an electrogenic sodium pump. The conduction velocity, in longitudinal direction, was enhanced from 50+/-2.2 cm/s (n=10) in the controls to 59+/-2.4 cm/s (n=13) (p<0.05) in animals treated with eplerenone.. Eplerenone reduces cardiac remodelling, the incidence of cardiac arrhythmias and improves impulse propagation, an effect in part related to the antifibrotic effect of the drug but also to the activation of the electrogenic sodium pump.

Topics: Animals; Cell Separation; Cricetinae; Electrocardiography; Electrophysiology; Eplerenone; Heart Conduction System; Heart Failure; Membrane Potentials; Myocardium; Sodium-Potassium-Exchanging ATPase; Spironolactone; Ventricular Remodeling

Although aldosterone, acting via mineralocorticoid receptors, causes left ventricular (LV) hypertrophy in experimental models of high-aldosterone hypertension, little is known about the role of aldosterone or mineralocorticoid receptors in mediating adverse remodeling in response to chronic pressure overload.. We used the mineralocorticoid receptor-selective antagonist eplerenone (EPL) to test the role of mineralocorticoid receptors in mediating the transition from hypertrophy to failure in mice with chronic pressure overload caused by ascending aortic constriction (AAC). One week after AAC, mice were randomized to regular chow or chow containing EPL (200 mg/kg per day) for an additional 7 weeks. EPL had no significant effect on systolic blood pressure after AAC. Eight weeks after AAC, EPL treatment improved survival (94% versus 65%), attenuated the increases in LV end-diastolic (3.4+/-0.1 versus 3.7+/-0.1 mm) and end-systolic (2.0+/-0.1 versus 2.5+/-0.2 mm) dimensions, and ameliorated the decrease in fractional shortening (42+/-2% versus 34+/-4%). EPL also decreased myocardial fibrosis, myocyte apoptosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2. These beneficial effects of EPL were associated with less myocardial oxidative stress, as assessed by 3-nitrotyrosine staining, reduced expression of the adhesion molecule intercellular adhesion molecule-1, and reduced infiltration by macrophages.. Mineralocorticoid receptors play an important role in mediating the transition from LV hypertrophy to failure with chronic pressure overload. The effects of mineralocorticoid receptor stimulation are associated with alterations in the interstitial matrix and myocyte apoptosis and may be mediated, at least in part, by oxidative stress and inflammation.

Topics: Animals; Aorta; Apoptosis; Blood Pressure; Cell Size; Chronic Disease; Constriction, Pathologic; Drug Evaluation, Preclinical; Eplerenone; Fibrosis; Heart Failure; Hypertrophy, Left Ventricular; Intercellular Adhesion Molecule-1; Ligation; Male; Matrix Metalloproteinases; Mice; Mineralocorticoid Receptor Antagonists; Myocarditis; Myocardium; Myocytes, Cardiac; Oxidative Stress; Pressure; Random Allocation; Receptors, Mineralocorticoid; Spironolactone; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tyrosine

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

The mechanisms underlying the clinical benefits of mineralocorticoid receptor antagonism in patients with left ventricular (LV) dysfunction and heart failure (CHF) after myocardial infarction (MI) are poorly understood.. We investigated whether long-term (9 weeks) aldosterone antagonism with eplerenone (100 mg/kg/day) provides additional benefit to angiotensin II type 1 (AT1) receptor inhibition with irbesartan (50 mg/kg/day) on cardiac remodeling after MI in rats.. Eplerenone monotherapy, like AT1 receptor blockade, significantly reduced LV end-diastolic pressure (LVEDP), end-systolic volume (LVESV) and end-diastolic volume (LVEDV) compared to placebo. Improvement of LV dilation by aldosterone antagonism was associated with a significant reduction of increased AT1 receptor, angiotensin-converting enzyme (ACE) and endothelin-1 gene expression in the noninfarcted LV myocardium. Combination therapy with irbesartan led to a substantial further leftward shift of the LV pressure-volume curve and decrease in LVEDP, LVESV and LVEDV. Moreover, combination therapy significantly improved LV systolic and diastolic function and reversed LV alterations of alpha- and beta-myosin heavy-chain isoforms, ANF and SERCA2 ATPase expression more effectively than monotherapies. LV collagen type I and type III expression as well as interstitial fibrosis were substantially increased in placebo CHF rats, similarly decreased by eplerenone and irbesartan, and further reduced by eplerenone/irbesartan. However, no additive effects of eplerenone/irbesartan on myocardial AT1 receptor, ACE and endothelin-1 mRNAs were observed.. Aldosterone receptor antagonism provides additional benefit to AT1 receptor blockade on LV function and remodeling associated with improvement of molecular alterations responsible for progressive contractile dysfunction post-MI.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Blotting, Western; Collagen Type I; Eplerenone; Heart Failure; Hemodynamics; Irbesartan; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Spironolactone; Tetrazoles; Ventricular Remodeling

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Spironolactone; Ventricular Dysfunction, Left

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Eplerenone; Heart Failure; Humans; Myocardial Infarction; Neurotransmitter Agents; Prognosis; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left

Topics: Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Patient Selection; Prognosis; Risk Assessment; Spironolactone

Topics: Death, Sudden, Cardiac; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Risk; Spironolactone; Stroke Volume; Time Factors; Ventricular Dysfunction, Left

Aldosterone plays an important role in the pathophysiology of congestive heart failure (CHF), and spironolactone improves cardiovascular function and survival rates in patients with CHF. We hypothesized that the mineralocorticoid receptor blockade (MRB) exerted its beneficial effects by reducing oxidative stress and changing the balance between the counter-acting enzymes angiotensin-converting enzyme (ACE) and ACE2. Monocyte-derived macrophages were obtained from 10 patients with CHF before and after 1 month of treatment with spironolactone (25 mg/d). Spironolactone therapy significantly (P<0.005) reduced oxidative stress, as expressed by reduced lipid peroxide content, superoxide ion release, and low-density lipoprotein oxidation by 28%, 53%, and 70%, respectively. Although spironolactone significantly (P<0.01) reduced macrophage ACE activity by 47% and mRNA expression by 53%, ACE2 activity and mRNA expression increased by 300% and 654%, respectively. In mice treated for 2 weeks with eplerenone (200 mg.kg(-1).d(-1)), cardiac ACE2 activity significantly (P<0.05) increased by 2-fold and was paralleled by increased ACE2 activity in macrophages. The mechanism of aldosterone antagonist action was studied in mouse peritoneal macrophages (MPMs) in vitro. Although ACE activity and mRNA were significantly increased by 250 nmol/L aldosterone, ACE2 was significantly reduced. Cotreatment with eplerenone (2 micromol/L) attenuated these effects. In MPM obtained from p47 knockout mice, where NADPH oxidase is inactive, as well as in control MPMs treated with NADPH oxidase inhibitor, aldosterone did not increase ACE or decrease ACE2. MRB reduced oxidative stress, decreased ACE activity, and increased ACE2 activity, suggesting a protective role for MRB by possibly increasing generation of angiotensin (1-7) and decreasing formation of angiotensin II. These effects are mediated, at least in part, by NADPH oxidase.

Topics: Adult; Aged; Aldosterone; Angiotensin-Converting Enzyme 2; Animals; Carboxypeptidases; Eplerenone; Heart Failure; Humans; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Middle Aged; Mineralocorticoid Receptor Antagonists; NADPH Oxidases; Oxidative Stress; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Spironolactone

Topics: Clinical Trials as Topic; Drug Therapy, Combination; Eplerenone; Heart Failure; Hospital Mortality; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Survival Rate

Topics: Aldosterone; Clinical Trials as Topic; Eplerenone; Heart Failure; Hormone Antagonists; Humans; Hyperkalemia; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone

Spironolactone, a nonselective aldosterone blocker, has a cardioprotective effect; however, significant endocrine side effects limit its use. Eplerenone is a new selective aldosterone blocker. We investigated whether eplerenone attenuates cardiac remodeling and improves function in a mouse model of heart failure and whether coadministration of eplerenone and an angiotensin-converting enzyme inhibitor (ACEi) provides better cardioprotection than either agent alone.. C57BL/6J mice were subjected to myocardial infarction (MI) by ligating the left anterior descending coronary artery. Two weeks later, the mice were either left untreated or treated with (1) eplerenone, (2) ACEi, or (3) eplerenone plus ACEi for 12 weeks. Systolic blood pressure (SBP) was measured and echocardiography performed before MI and weekly thereafter. At the end of the study, interstitial collagen fraction (ICF) and myocyte cross-sectional area (MCSA) were examined histologically. We found that (1) eplerenone significantly improved ejection fraction and cardiac output and decreased left ventricular (LV) systolic area, LV weight, ICF, and MCSA independently of changes in SBP compared with untreated animals; (2) ACEi had similar beneficial effects, accompanied by a significant reduction in SBP; and (3) combined treatment offered limited additional benefit beyond monotherapy.. In mice with MI, eplerenone attenuates progression of heart failure comparably to ACEi, and its effect is independent of BP lowering.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Output; Collagen; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Eplerenone; Heart Failure; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Muscle Cells; Myocardial Infarction; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Remodeling

The edematous states, specifically those in CHF and cirrhosis of the liver, are associated with excessive aldosterone secretion and represent states of secondary hyperaldosteremia. Aldosterone promotes sodium retention by the renal tubules. Spironolactone, first introduced 50 years ago (1953), blocks the action of aldosterone on renal transport of electrolytes, thus acting as an effective diuretic, and in addition, has potentiating effects on other diuretics, including the thiazides. Spironolactone has undesirable side effects that have limited its clinical use; the most significant are impotence, gynecomastia, and hirsutism. Eplerenone, a recently introduced selective ARA, decreases morbidity and mortality in patients with CHF following MI and has none of the androgenic or estrogenic side effects of spironolactone. Eplerenone is an effective alternative for spironolactone.

Topics: Aged; Eplerenone; Female; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone; Water-Electrolyte Balance

Topics: Aged; Eplerenone; Female; Heart Failure; Humans; Incidence; Male; Mineralocorticoid Receptor Antagonists; Spironolactone; United States

Topics: Contraindications; Diuretics; Drug Interactions; Eplerenone; Heart Failure; Humans; Spironolactone

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diuretics; Drug Therapy, Combination; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Placebos; Prognosis; Randomized Controlled Trials as Topic; Spironolactone; Time Factors

Topics: Controlled Clinical Trials as Topic; Diuretics; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Placebos; Spironolactone; Stroke Volume; Time Factors

Topics: Aldosterone; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

Topics: Diuresis; Dose-Response Relationship, Drug; Drug Interactions; Eplerenone; Fees, Pharmaceutical; Half-Life; Heart Failure; Humans; Hyperkalemia; Hypertension; Randomized Controlled Trials as Topic; Spironolactone

Topics: Angiotensin-Converting Enzyme Inhibitors; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Spironolactone; Ventricular Remodeling

An increased risk of thrombembolic events in congestive heart failure (CHF) has been attributed to a hypercoagulable state including vascular endothelial dysfunction and platelet activation. After experimental myocardial infarction, male Wistar rats were treated with placebo, the ACE inhibitor trandolapril, the selective aldosterone receptor antagonist eplerenone or the combination of both, for 10 weeks. Platelet-bound fibrinogen and surface-expressed P-selectin were not modulated in rats without CHF compared with sham-operated animals, but were significantly increased in CHF rats (LVEDP>15 mmHg). In CHF rats, ACE inhibition significantly reduced platelet P-selectin expression while bound fibrinogen was not modulated. Eplerenone reduced P-selectin expression to a comparable extent, while platelet-bound fibrinogen was normalised. Combination therapy with eplerenone and trandolapril completely abolished both the increased P-selectin expression as well as fibrinogen binding. Phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) at both Ser(157) and Ser(239), which reflects the activity of platelet inhibitors including nitric oxide, was significantly reduced in platelets from placebo-treated CHF rats, and was completely normalised by combination treatment, but only marginally increased by either mono-therapy. The results show that platelet activation was evident only in CHF rats. Monotherapy with ACE inhibition or eplerenone partially reduced this increased platelet activation, which was completely rescued to basal levels by combination therapy. Increased nitric oxide bioavailability can only partially explain the reduced platelet activation by eplerenone and ACE inhibition.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Adhesion Molecules; Drug Therapy, Combination; Eplerenone; Fibrinogen; Heart Failure; Indoles; Male; Microfilament Proteins; Mineralocorticoid Receptor Antagonists; Nitric Oxide; P-Selectin; Phosphoproteins; Platelet Activation; Rats; Rats, Wistar; Renin-Angiotensin System; Spironolactone

Aldosterone classically promotes unidirectional transepithelial sodium transport, thereby regulating blood volume and blood pressure. Recently, both clinical and experimental studies have suggested additional, direct roles for aldosterone in the cardiovascular system. To evaluate aldosterone activation of cardiomyocyte mineralocorticoid receptors, transgenic mice overexpressing 11beta-hydroxysteroid dehydrogenase type 2 in cardiomyocytes were generated using the mouse alpha-myosin heavy chain promoter. This enzyme converts glucocorticoids to receptor-inactive metabolites, allowing aldosterone occupancy of cardiomyocyte mineralocorticoid receptors. Transgenic mice were normotensive but spontaneously developed cardiac hypertrophy, fibrosis, and heart failure and died prematurely on a normal salt diet. Eplerenone, a selective aldosterone blocker, ameliorated this phenotype. These studies confirm the deleterious consequences of inappropriate activation of cardiomyocyte mineralocorticoid receptors by aldosterone and reveal a tonic inhibitory role of glucocorticoids in preventing such outcomes under physiological conditions. In addition, these data support the hypothesis that aldosterone blockade may provide additional therapeutic benefit in the treatment of heart failure.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Aldosterone; Animals; Blood Pressure; Cardiomegaly; Disease Models, Animal; Echocardiography; Eplerenone; Female; Fibrosis; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Heart Failure; Hydroxysteroid Dehydrogenases; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mineralocorticoid Receptor Antagonists; Myocardium; Myocytes, Cardiac; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spironolactone; Up-Regulation; Ventricular Dysfunction, Left

To investigate the effects of adding the selective aldosterone receptor antagonist eplerenone to ACE inhibition on endothelium-dependent vasodilation in rats with chronic heart failure (CHF).. Addition of the non-selective aldosterone antagonist spironolactone to ACE-inhibitors reduces mortality and morbidity in CHF and improves endothelial vasomotor dysfunction, but is associated with considerable side-effects.. Starting 10 days after extensive myocardial infarction (MI) or sham-operation, Wistar rats were treated either with placebo, the ACE inhibitor trandolapril (TR, 0.3 mg/kg body weight per day), the selective aldosterone receptor antagonist eplerenone (EPL, 100 mg/kg per day) or a combination of both for 9 weeks.. Maximum acetylcholine-induced, nitric oxide-dependent relaxation was significantly attenuated in aortic rings from rats with CHF compared with sham-operated animals (R(max) 55% vs. 87%). EPL alone slightly and TR significantly improved NO-mediated relaxation (CHF-EPL 66%; CHF-TR: 78%), while treatment with both EPL and TR completely restored endothelium-dependent vasorelaxation (CHF-EPL-TR: 83%). Aortic superoxide formation was significantly increased in rats with CHF compared with sham-operated animals, but was normalised by treatment with EPL or TR-EPL. Expression of the endothelial nitric oxide synthase was decreased in CHF and normalised in all treatment groups.. In experimental CHF, the selective aldosterone antagonist EPL reduced the increased vascular superoxide formation. Although a combination of TR and EPL normalised endothelium-dependent relaxation, ACE inhibition as a monotherapy was almost equally effective.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blotting, Western; Drug Therapy, Combination; Endothelium, Vascular; Eplerenone; Heart Failure; In Vitro Techniques; Indoles; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Nitroprusside; Rats; Rats, Wistar; Spironolactone; Vasodilator Agents

Topics: Double-Blind Method; Eplerenone; Female; Heart Failure; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Spironolactone; Treatment Outcome

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Animals; Class Ib Phosphatidylinositol 3-Kinase; Cognition Disorders; Contraindications; Drug Therapy, Combination; Enalapril; Eplerenone; Fibrinolytic Agents; Heart Failure; Humans; Hypertension; Hypertrophy, Left Ventricular; Isoenzymes; Mice; Mice, Knockout; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Myocardial Reperfusion; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Receptors, Adrenergic, beta; Spironolactone

Topics: Diuretics; Eplerenone; Gynecomastia; Heart Failure; Humans; Male; Middle Aged; Spironolactone

Topics: Cardiovascular Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

Topics: Controlled Clinical Trials as Topic; Death, Sudden, Cardiac; Diuretics; Double-Blind Method; Eplerenone; Female; Follow-Up Studies; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Multicenter Studies as Topic; Myocardial Infarction; Placebos; Prospective Studies; Retrospective Studies; Risk Factors; Spironolactone; Time Factors; Ventricular Dysfunction, Left

There is growing evidence that aldosterone plays an important role in the development of endorgan-damage e.g. vascular and cardiac fibrosis, remodeling and endothelial dysfunction. Aldosterone-antagonism has become a novel therapeutic principle beyond its sodium retention properties in the treatment of cardiovascular diseases. In patients with severe left ventricular dysfunction spironolactone could reduce death and hospitalisation. A new selective aldosterone antagonist, eplerenone, was effective in patients with left ventricular dysfunction after myocardial infarction added to optimal medical therapy.

Topics: Aldosterone; Clinical Trials as Topic; Eplerenone; Germany; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone; Survival Rate; Treatment Outcome; Ventricular Dysfunction, Left

Topics: Carbazoles; Cardiac Pacing, Artificial; Carvedilol; Eplerenone; Europe; Heart Failure; Humans; Metoprolol; Myocardial Infarction; Prognosis; Propanolamines; Spironolactone; Tumor Necrosis Factor-alpha; Uric Acid

Topics: Aldosterone; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Hypertension; Spironolactone

In heart failure (HF), aldosterone has been implicated in the formation of reactive interstitial fibrosis, a maladaptation that contributes to left ventricular (LV) remodeling. Eplerenone is a novel selective aldosterone blocker. The present study examined the effects of long-term monotherapy with eplerenone on the progression of LV dysfunction and remodeling in dogs with chronic HF.. HF was produced in 14 dogs by intracoronary microembolizations that were discontinued when LV ejection fraction (EF) was between 30% and 40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with eplerenone (10 mg/kg twice daily, n=7) or no therapy at all (control, n=7). Hemodynamic measurements were made just before randomization and were repeated at the end of 3 months of therapy. In control dogs, LV end-diastolic and end-systolic volume increased significantly (62+/-4 versus 68+/-4 mL, P<0.001, and 38+/-3 versus 47+/-3 mL, P<0.001, respectively), and EF decreased significantly (38+/-1% versus 31+/-2%, P<0.001). In contrast, end-diastolic volume, end-systolic volume, and EF remained unchanged during the 3 months of treatment in eplerenone-treated dogs. LV end-diastolic wall stress increased significantly in control dogs but decreased significantly in eplerenone-treated dogs. Compared with control, eplerenone was associated with a 28% reduction in cardiomyocyte cross-sectional area, a 37% reduction of volume fraction of reactive interstitial fibrosis, and a 34% reduction of volume fraction of replacement fibrosis.. Our results indicate that long-term therapy with eplerenone prevents progressive LV dysfunction and attenuates LV remodeling in dogs with chronic HF.

Topics: Administration, Oral; Animals; Chronic Disease; Disease Models, Animal; Disease Progression; Dogs; Echocardiography; Enzyme Activation; Eplerenone; Fibroblast Growth Factor 2; Heart; Heart Failure; Hemodynamics; Mineralocorticoid Receptor Antagonists; Myocardium; RNA, Messenger; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Impressive clinical benefits have been derived by inhibiting the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors. There is growing evidence that aldosterone plays a contributing role in the pathogenesis of heart failure beyond its sodium retention properties. EPHESUS, a trial of a novel aldosterone antagonist, eplerenone, in patients with myocardial infarction, left ventricular dysfunction and pulmonary congestion will determine whether this approach produces additive clinical benefits in modernly managed patients.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Spironolactone

Topics: Aldosterone; Double-Blind Method; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Multicenter Studies as Topic; Myocardial Infarction; Randomized Controlled Trials as Topic; Research Design; Sample Size; Spironolactone; Survival Analysis; Systole

Despite major advances many cardiovascular disorders remain poorly controlled. As a result the search for newer agents goes on. Anti-neurohormonal agents have been the most successful agents: beta-blockers, ACE inhibitors and angiotensin receptor blockers. To these we now add anti-aldosterone strategies with the phenomenal success of spironolactone in reducing mortality in severe heart failure. A more recent and more selective aldosterone receptor antagonist has been developed, eplerenone, and it shows considerable promise in managing and preventing the complications of hypertension. It may have a role both being anti-fibrotic and anti-neurohormonal in mild to moderate heart failure, in post-MI left ventricular dysfunction and in progressive renal disease. The EPHESUS trial which randomised patients with heart failure due to impaired left ventricular systolic function aims to randomise 6,200 patients to eplerenone or placebo on top of standard therapy and follow subjects until 1,012 deaths have occurred (approx. 2.5 years of follow up). This and other trials with the novel strategy of selective aldosterone antagonism are eagerly awaited. The beneficial effects established by the earliest anti-neurohormonal agents give us confidence that further benefits could be obtained by this intellectual strategy.

Topics: Eplerenone; Heart Failure; Humans; Hypertrophy, Left Ventricular; Mineralocorticoid Receptor Antagonists; Spironolactone