eplerenone and Cardiovascular-Diseases

People with chronic kidney disease (CKD) requiring dialysis are at a particularly high risk of cardiovascular death and morbidity. Several clinical studies suggested that aldosterone antagonists would be a promising treatment option for people undergoing dialysis. However, the clinical efficacy and potential harm of aldosterone antagonists for people with CKD on dialysis has yet to be determined.. This review aimed to evaluate the benefits and harms of aldosterone antagonists, both non-selective (spironolactone) and selective (eplerenone), in comparison to control (placebo or standard care) in people with CKD requiring haemodialysis (HD) or peritoneal dialysis (PD).. We searched the Cochrane Kidney and Transplant Register of Studies up to 5 August 2020 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. We included parallel randomised controlled trials (RCTs), cross-over RCTs, and quasi-RCTs (where group allocation is by a method that is not truly random, such as alternation, assignment based on alternate medical records, date of birth, case record number, or other predictable methods) that compared aldosterone antagonists with placebo or standard care in people with CKD requiring dialysis.. Two review authors independently extracted data and assessed risk of bias for included studies. We used a random-effects model meta-analysis to perform a quantitative synthesis of the data. We used the I² statistic to measure heterogeneity among the studies in each analysis. We indicated summary estimates as a risk ratio (RR) for dichotomous outcomes, mean difference (MD) for continuous outcomes, or standardised mean differences (SMD) if different scales were used, with their 95% confidence interval (CI). We assessed the certainty of the evidence for each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach.. We included 16 studies (14 parallel RCTs and two cross-over RCTs) involving a total of 1446 participants. Thirteen studies compared spironolactone to placebo or standard care and one study compared eplerenone to a placebo. Most included studies had an unclear or high risk of bias. Compared to control, aldosterone antagonists probably reduced the risk of death (any cause) for people with CKD requiring dialysis (9 studies, 1119 participants: RR 0.45, 95% CI 0.30 to 0.67; I² = 0%; moderate certainty of evidence). Aldosterone antagonist probably decreased the risk of death due to cardiovascular disease (6 studies, 908 participants: RR 0.37, 95% CI 0.22 to 0.64; I² = 0%; moderate certainty of evidence) and cardiovascular and cerebrovascular morbidity (3 studies, 328 participants: RR 0.38, 95% CI 0.18 to 0.76; I² = 0%; moderate certainty of evidence). While aldosterone antagonists probably increased risk of gynaecomastia compared with control (4 studies, 768 participants: RR 5.95, 95% CI 1.93 to 18.3; I² = 0%; moderate certainty of evidence), aldosterone antagonists may make little or no difference to the risk of hyperkalaemia (9 studies, 981 participants: RR 1.41, 95% CI 0.72 to 2.78; I² = 47%; low certainty of evidence). Aldosterone antagonists had a marginal effect on left ventricular mass among participants undergoing dialysis (8 studies, 633 participants: SMD -0.42, 95% CI -0.78 to 0.05; I² = 77%). In people with CKD requiring dialysis received aldosterone antagonists compared to control, there were 72 fewer deaths from all causes per 1000 participants (95% CI 47 to 98) with a number needed to treat for an additional beneficial outcome (NNTB) of 14 (95% CI 10 to 21) and for gynaecomastia were 26 events per 1000 participants (95% CI 15 to 39) with a number need to treat for an additional harmful outcome (NNTH) of 38 (95% CI 26 to 68).. Based on moderate certainty of the evidence, aldosterone antagonists probably reduces the risk of all-cause and cardiovascular death and probably reduces morbidity due to cardiovascular and cerebrovascular disease in people with CKD requiring dialysis. For the adverse effect of gynaecomastia, the risk was increased compared to control. For this outcome, the absolute risk was lower than the absolute risk of death. It is hoped the three large ongoing studies will provide better certainty of evidence.

Topics: Bias; Cardiovascular Diseases; Cause of Death; Cerebrovascular Disorders; Eplerenone; Gynecomastia; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Placebos; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Spironolactone

Cardiovascular and renal diseases are one of the main health problems in all industrialized countries. Their incidence is constantly increasing due to the aging of the population and the greater prevalence of obesity and type 2 diabetes. Clinical evidence suggests that aldosterone and the activation of mineralocorticoid receptors (MR) have a role in the pathophysiology of cardiovascular and renal diseases. Moreover, clinical studies demonstrate the benefits of mineralocorticoid receptor antagonists (MRAs) on mortality and progression of heart and kidney disease. In addition to renal effects on body fluid homeostasis, aldosterone has multiple extrarenal effects including the induction of inflammation, vascular rigidity, collagen formation and stimulation of fibrosis. Given the fundamental role of MR activation in renal and cardiac fibrosis, effective and selective blocking of the signal with MRAs can be used in the clinical practice to prevent or slow down the progression of heart and kidney diseases. The aim of the present work is to review the role of MRAs in light of the new evidence as well as its potential use as an antifibrotic in chronic kidney disease (CKD). The initial clinical results suggest that MRAs are potentially useful in treating patients with chronic kidney disease, particularly in cases of diabetic nephropathy. We don't yet have efficacy and safety data on the progression of kidney disease up to the end stage (ESRD) and filling this gap represents an important target for future trials.

Topics: Aldosterone; Body Fluids; Cardiovascular Diseases; Clinical Trials as Topic; Cytokines; Diabetic Nephropathies; Eplerenone; Fibrosis; Heart; Heart Diseases; Homeostasis; Humans; Kidney; Mineralocorticoid Receptor Antagonists; Naphthyridines; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Spironolactone

Patients who require dialysis are at high risk for cardiovascular mortality, which may be improved by mineralocorticoid receptor antagonists (MRAs).. Systematic review and meta-analysis of randomized controlled trials.. Adults undergoing long-term hemodialysis or peritoneal dialysis with or without heart failure.. Randomized controlled trials evaluating an MRA in dialysis and reported at least one outcome of interest.. Spironolactone (8 trials) or eplerenone (1 trial) compared to placebo (7 trials) or standard of care (2 trials).. Cardiovascular and all-cause mortality, hyperkalemia, serum potassium level, hypotension, change in blood pressure, and gynecomastia.. We identified 9 trials including 829 patients. The overall quality of evidence was low due to methodologic limitations in most of the included trials. The relative risk (RR) for cardiovascular mortality was 0.34 (95% CI, 0.15-0.75) for MRA-treated compared with control patients. The RR for all-cause mortality was 0.40 (95% CI, 0.23-0.69). The RR for hyperkalemia for MRA treatment was 3.05 (95% CI, 1.21-7.70). Sensitivity analyses demonstrated wide variability in RRs for cardiovascular mortality, all-cause mortality, and hyperkalemia, suggesting further uncertainty in the confidence of the primary results.. Trial quality and size insufficient to robustly and precisely identify a treatment effect.. Given the uncertainty of both the benefits and harms of MRAs in dialysis, large high-quality trials are required.

Topics: Cardiovascular Diseases; Cause of Death; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Renal Dialysis; Spironolactone

The accompanying special issue reviews the role of eplerenone and spironolactone in the management of various cardiovascular and renal conditions.

Topics: Cardiovascular Diseases; Eplerenone; Humans; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Spironolactone; Treatment Outcome

The clinical utility and ultimately guideline recommendations for aldosterone receptor-blocking agents in cardiovascular disorders is clearly mentioned by a number of major clinical outcome trials. This article reviews the pharmacology, clinical efficacy and safety of the two currently available receptor blocking agents: spironolactone and eplerenone. The potential utility of eplerenone and other mineralocorticoid receptor agents beyond current clinical indications will also be examined.

Topics: Aldosterone; Animals; Cardiovascular Agents; Cardiovascular Diseases; Eplerenone; Humans; Hydrocortisone; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Spironolactone

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

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

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

With an increasingly aging population, the need for effective treatment of cardiovascular diseases (eg, heart failure, hypertension, and ischemic heart disease) cannot be overemphasized. The vital importance of mineralocorticoid receptor antagonists for treating cardiovascular conditions has only been appreciated in the last decade. The re-emergence of mineralocorticoid receptor antagonists has provided clinicians with an important tool towards complete blockade of the renin-angiotensin-aldosterone axis.

Topics: Animals; Canrenoic Acid; Cardiovascular Diseases; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Spironolactone

Recent clinical studies have indicated the utility of mineralocorticoid receptor (MR) antagonists in cardiovascular and renal injuries. Chronic treatment with aldosterone/salt resulted in severe cardiac and renal injuries in rats. Further studies showed that the aldosterone-induced organ injuries were associated with increases in expression of NADPH oxidase components and reactive oxygen species (ROS) levels. Treatment with a selective MR antagonist, eplerenone, prevented the elevation of ROS levels and ameliorated organ injuries. In vitro studies also showed that MR is highly expressed in cultured vascular smooth muscle cells, glomerular mesangial cells and renal fibroblasts. In these cells, aldosterone-induced cell injuries were associated with increases in NADPH oxidase activity and superoxide generation. Further, the aldosterone-dependent cell injuries were markedly attenuated by treatment with eplerenone. These accumulating data support the notion that the aldosterone/MR is involved in the pathogenesis of cardiovascular and renal injuries through NADPH oxidase-dependent ROS production.

Topics: Aldosterone; Animals; Cardiovascular Diseases; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; NADPH Oxidases; Oxidative Stress; Rats; Reactive Oxygen Species; Receptors, Mineralocorticoid; Renal Insufficiency; Spironolactone

Although the pro-inflammatory and pro-fibrotic actions of aldosterone on the vasculature have been reported, the effects and molecular mechanisms of aldosterone on endothelial function are yet to be determined. We investigated how aldosterone regulates endothelial nitric oxide synthase (eNOS) function in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated for 16 hrs with 10(-7) mol/l of aldosterone. The concentration of reactive oxygen species (ROS) was estimated by measuring DCF chemiluminescence. Signal transduction was estimated by Western immunoblots. Realtime RT-PCR was performed to measure expression of transcripts of endogenous GTP cyclohydrolase-1 (GCH1) and components of NAD(P)H oxidase. In order to eliminate the possible effect of the glucocorticoid receptor (GR), and to emphasize the role of mineralocorticoid receptor (MR), we used GR siRNA and knocked down GR expression in several experiments. NO output was estimated by intracellular cGMP concentration. ROS production increased significantly in aldosterone-treated HUVEC, but was abolished by pre-treatment with eplerenone. Transcripts of p47(phox) were increased by aldosterone treatment. Vascular endothelial growth factor (VEGF)-induced eNOS Ser 1177 but not Akt Ser 473 phosphorylation levels were reduced significantly by pretreatment with aldosterone. Pretreatment with either eplerenone or okadaic acid restored phosphorylation levels of eNOS Ser 1177 in aldosterone-treated cells, suggesting that protein phosphatase (PP) 2A was upregulated by aldosterone via MR. The decrease in NO output caused by aldosterone pretreatment was reversed significantly by either 5,6,7,8-tetrahydrobiopterin (BH(4)), GCH1 overexpression, or p47(phox) knockdown. These results suggest that aldosterone inhibits eNOS function through bimodal mechanisms of BH(4) deficiency and PP2A activation.

Topics: Aldosterone; Animals; Biopterins; Cardiovascular Diseases; Cells, Cultured; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphoprotein Phosphatases; Reactive Oxygen Species; Receptors, Mineralocorticoid; Spironolactone

Over the last decade a wealth of studies have shed new light on the role of aldosterone in the pathogenesis of cardiovascular diseases. It is now evident that in addition to its classical role in increasing sodium re-absorbtion in the kidney , aldosterone also exhibits several nonepithelial effects such as the induction of inflammation, fibrosis and necrosis in various organs. Herein we review the experimental evidences for the protective effects of mineralocorticoid receptor blockade in the prevention and treatment of target organ damage, both in animals and in humans. We also discuss the pharmacological and clinical differences between the two available mineralocorticoid receptor blockers, spironolactone and eplerenone.

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

Topics: Aldosterone; Animals; Cardiovascular Diseases; Endothelium, Vascular; Epithelial Sodium Channels; Eplerenone; Fibrosis; Humans; Mineralocorticoid Receptor Antagonists; Muscle, Smooth, Vascular; Myocardium; Oxidative Stress; Receptors, Mineralocorticoid; Sodium Channels; Sodium-Potassium-Exchanging ATPase; Sodium, Dietary; Spironolactone

Recently, it has become clear that the action of aldosterone is far more complicated than it was previously thought. Beyond regulating sodium and volume homeostasis by its epithelial action, the hormone exhibits its effects in other organs, such as the heart, blood vessels and central nervous system. Some of these actions, so called non-genomic effects, are not related to the aldosterone-induced stimulation of classical mineralocorticoid receptors. In this paper we discuss the progress made in understanding the physiological function of aldosterone and the role of its excess in the etiology of cardiovascular disorders. In the second part of this article, we provide an overview of the clinically-proven benefits of a new selective aldosterone-receptor antagonist, eplerenone.

Topics: Aldosterone; Cardiovascular Diseases; Eplerenone; Humans; Spironolactone

Aldosterone is well recognized as a cause of sodium reabsorption, water retention, and potassium and magnesium loss; however, it also produces a variety of other actions that lead to progressive target organ damage in the heart, vasculature, and kidneys. Aldosterone interacts with mineralocorticoid receptors to promote endothelial dysfunction, facilitate thrombosis, reduce vascular compliance, impair baroreceptor function, and cause myocardial and vascular fibrosis. Although angiotensin II has been considered the major mediator of cardiovascular damage, increasing evidence suggests that aldosterone may mediate and exacerbate the damaging effects of angiotensin II. While angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers reduce plasma aldosterone levels initially, aldosterone rebound, or 'escape' may occur during long-term therapy. Therefore, aldosterone blockade is required to reduce the risk of progressive target organ damage in patients with hypertension and heart failure. This may be achieved nonselectively with spironolactone or with use of the selective aldosterone blocker eplerenone. While both agents have been demonstrated to be effective antihypertensive agents, eplerenone may produce improved target organ protection as witnessed in a variety of clinical settings, without the antiandrogenic and progestational effects commonly observed with spironolactone.

Topics: Aldosterone; Angiotensin II; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular Diseases; Endothelium, Vascular; Eplerenone; Humans; Kidney; Mineralocorticoid Receptor Antagonists; Myocardium; 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

The renin-angiotensin-aldosterone system (RAAS) plays an integral role in blood pressure regulation and has long been a target of pharmacologic approaches to controlling blood pressure. Traditionally, clinical interventions involving the RAAS have focused mainly on inhibiting the action of angiotensin II with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and limited attention has been devoted to direct inhibition of the action of aldosterone. Recent advances in understanding the role of aldosterone in cardiovascular injury have elevated the importance of direct inhibition of the action of this hormone in the long-term control of blood pressure and have led to the development of the selective aldosterone blocker eplerenone. This article reviews the role of the RAAS in the development of hypertension and discusses the rationale for the use of eplerenone with other medications affecting the RAAS to control blood pressure.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Drug Therapy, Combination; Eplerenone; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Spironolactone

Data from animal studies and clinical trials indicate that aldosterone causes cardiovascular and renal injury through mineralocorticoid receptor-dependent mechanisms. However, although aldosterone receptor antagonism reduces mortality in patients with congestive heart failure, the progestational and antiandrogenic side effects of the nonspecific aldosterone receptor antagonist, spironolactone, have limited its usefulness in the treatment of hypertension. This review provides an overview of the pharmacology, efficacy, and safety of a new, more selective aldosterone receptor antagonist, eplerenone, in the context of emerging concepts of the role of aldosterone in cardiovascular toxicity.

Topics: Aldosterone; Animals; Cardiovascular Diseases; Cardiovascular System; Disease Models, Animal; Eplerenone; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Spironolactone; Treatment Outcome

Topics: Aldosterone; Animals; Cardiac Output, Low; Cardiovascular Diseases; Eplerenone; Humans; Inflammation; Metaphor; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Spironolactone

Interruption of the renin-angiotensin-aldosterone system (RAAS) at different levels is target-organ protective in several disease states; however, complete blockade is unlikely to be achieved due to escape mechanisms whenever blockade is attempted, incomplete knowledge of the role of all elements of the RAAS, and lack of pharmacotherapy against some elements that have been shown to contribute to disease states. Aldosterone has been overlooked as a mediator of RAAS escape and a key factor in target-organ injury despite the use of available RAAS blockers. Aldosterone is thought to play a role in the development of hypertension, alteration in vascular structure, vascular smooth muscle hypertrophy, endothelial dysfunction, structural renal injury, proteinuria, left ventricular remodeling, collagen synthesis, and myocardial fibrosis. Aldosterone receptor antagonists have been shown to antagonize all these effects in experimental models. Clinical trials with aldosterone antagonists showed an improvement in survival and left ventricular mass index in patients with congestive heart failure, and a reduction in urinary protein excretion and left ventricular mass index in patients with type 2 diabetes and early nephropathy who developed aldosterone synthesis escape. Consequently, aldosterone receptor antagonists may have specific benefits for reducing target-organ injury, particularly if there is evidence of RAAS escape.

Topics: Aldosterone; Cardiovascular Diseases; Eplerenone; Humans; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Spironolactone

Topics: Aldosterone; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Eplerenone; Female; Humans; Male; Mineralocorticoid Receptor Antagonists; Prognosis; Receptors, Mineralocorticoid; Renal Insufficiency; Risk Assessment; Spironolactone; Survival Analysis; Treatment Outcome

Until relatively recently, the mineralocorticoid hormone aldosterone was thought to be produced uniquely in the adrenal cortex and to act exclusively on epithelia to promote sodium retention and potassium excretion. However, it is now known that aldosterone also acts on nonepithelial tissues, such as brain, heart, and blood vessels, and that enzymes required for aldosterone biosynthesis are expressed in these same tissues, which may be consistent with local aldosterone production acting in a paracrine fashion. A number of studies indicate that aldosterone exerts clearly deleterious effects when levels are inappropriate for salt status. For example, aldosterone in a high-salt environment initiates a vascular inflammation response that leads to cardiac and vascular pathologies. In experimental models of hypertension and heart failure, the nonepithelial effects of aldosterone are mediated via classical mineralocorticoid receptors, and are largely or completely abolished by administration of the selective aldosterone blocker eplerenone or by reduction of circulating aldosterone by adrenalectomy. In the present manuscript, we review some of the most recent discoveries in the field of aldosterone biology, with special emphasis on the mechanisms involved in the deleterious actions of this mineralocorticoid in cardiovascular tissues.

Topics: Aldosterone; Animals; Brain; Cardiovascular Diseases; Eplerenone; Heart; Humans; Kidney; Mineralocorticoid Receptor Antagonists; Myocardium; Randomized Controlled Trials as Topic; Salts; Spironolactone

Aldosterone contributes to hypertension, cardiac and vascular remodeling, and heart failure. The significant risk reduction provided by the addition of spironolactone to standard therapy in patients with severe heart failure has renewed interest in aldosterone blockade.. This review describes recent clinical studies of eplerenone, a selective aldosterone blocker, in patients with hypertension.. In a 16-week study, eplerenone was more effective than placebo or losartan in lowering systolic blood pressure (BP) and diastolic BP in black patients with mild to moderate hypertension. The BP-lowering efficacy of eplerenone was similar in blacks and whites. In a separate study in patients whose BP was controlled inadequately by angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, addition of eplerenone significantly reduced systolic BP, and to a lesser extent, diastolic BP. There were no significant changes in potassium levels in this study. Eplerenone increased active renin and aldosterone levels, indicating that it blocks the renin-angiotensin-aldosterone system. Gynecomastia, or breast tenderness, was uncommon and occurred at a rate comparable to placebo.. Eplerenone is a selective aldosterone blocker that effectively lowers BP in both white and black patients with hypertension and provides meaningful further antihypertensive efficacy when added to patients whose hypertension is inadequately controlled by angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers.

Topics: Aldosterone; Antihypertensive Agents; Black People; Blood Pressure; Cardiovascular Diseases; Clinical Trials as Topic; Eplerenone; Humans; Hypertension; Kidney Diseases; Losartan; Mineralocorticoid Receptor Antagonists; Potassium; Renin-Angiotensin System; 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

Topics: Aged; Cardiovascular Diseases; Elective Surgical Procedures; Eplerenone; Female; Heart; Heart Atria; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Models, Biological; Random Allocation; Reperfusion Injury; 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

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

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

Mineralocorticoid receptor antagonist (MRA) when combined with either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may provide additional benefits of cardiovascular and kidney disease risk reduction in patients with diabetic kidney disease (DKD) and hypertension. We evaluated the effectiveness of combination therapy (MRAs, either spironolactone or eplerenone, plus ACEI/ARB) compared with monotherapy (ACEI/ARB only) in patients with DKD and hypertension.. Retrospective cohort study was performed in patients (age ≥ 18 years) with hypertension, diabetes, and albuminuria between 2008 and 2018 within an integrated health system. MRA with ACEI/ARB compared to ACEI/ARB alone was evaluated on composite of cardiovascular events, progression to end-stage kidney disease, or all-cause mortality. Hyperkalemia was compared as a safety outcome.. We identified 1282 patients who received MRAs with ACEI/ARBs and 5484 patients who received ACEI/ARBs alone. Median exposure time for combination therapy was 126 days. The rates per 100 person-years of cardiovascular, kidney, or all-cause mortality outcomes were 12.2 and 9.2 for combination therapy and monotherapy, respectively (hazard ratios = 1.24, 95% Confidence Interval (CI):0.94, 1.63). Patients receiving combination therapy had greater reduction in urine albumin-to-creatinine ratio compared with monotherapy (Mean reduction: 823 and 585 mg/g; p < 0.001, respectively). Hyperkalemia was more frequent in combination therapy versus monotherapy (22.3 vs. 10.9 per 100 person-years for combination and monotherapy, respectively; hazard ratios = 1.78, 95%CI: 1.42, 2.24).. Among patients with DKD and hypertension, the short-term use of MRAs, either spironolactone or eplerenone, in combination with ACEI/ARBs, was not associated with lower risk of cardiovascular or kidney outcomes compared with ACEI/ARB monotherapy. The risk of hyperkalemia and the short duration of combination therapy may suggest a real-world clinical challenge for MRA with ACEI/ARB combination therapy.

Topics: Adolescent; Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetic Nephropathies; Drug Therapy, Combination; Eplerenone; Humans; Hypertension; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Retrospective Studies; Spironolactone; Treatment Outcome

Visit-to-visit office blood pressure (BP) variability (BPV) has been associated with morbidity and mortality outcomes in several cardiovascular conditions. The aim of this study was to evaluate the association between BPV and outcomes in patients with heart failure and reduced ejection fraction and the effect of eplerenone on BPV.. We evaluated the associations between BPV, calculated as SBP coefficient of variation (SBP-CoV = SD/mean × 100%), and the primary composite endpoint of cardiovascular mortality or heart failure hospitalization (HFH), and its components, in 2549 patients from the Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms trial. Lower SBP-CoV was independently associated with a higher risk of all the studied outcomes, while higher as well as lower SBP-CoV were associated with a higher risk of cardiovascular death. After a median follow-up period of 21 months the risk of the composite outcome of cardiovascular death or HFH was almost double in the lower SBP-CoV tertile as compared with the intermediate tertile [adjusted hazard ratio: 2.01, 95% confidence interval (1.62-2.51), P < 0.001]. The relationship between SBP-CoV and outcomes was not modified by eplerenone (P value for interaction = 0.48). An interaction was detected between mean SBP and SBP-CoV for the primary outcome (P = 0.048) and for HFH (P = 0.018). The effect modification was slight, but lower SBP-CoV was associated with worse outcomes in patients with both low and high SBP, while this interaction was less clear for patients with SBP in the 'normal' range.. In our patients with heart failure and reduced ejection fraction and mild symptoms, both a lower and higher SBP-CoV were associated with worse outcomes. SBP-CoV did not modify the benefit of eplerenone. Further studies are warranted to clarify the role of BPV in heart failure. CLINICALTRIALS.. NCT00232180.

Topics: Aged; Blood Pressure; Blood Pressure Determination; Cardiovascular Diseases; Eplerenone; Female; Heart Failure, Systolic; Hospitalization; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Office Visits; Prognosis; Proportional Hazards Models; Randomized Controlled Trials as Topic; Stroke Volume; Ventricular Dysfunction, Left

Topics: Aldosterone; Cardiovascular Diseases; Eplerenone; Humans; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Spironolactone

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

Besides the well-known roles of aldosterone as a mineralocorticoid in regulating homeostasis of electrolytes and volume, recent studies revealed that it is also a potent proinflammation factor inducing reactive oxygen species and up-regulating a panel of fibrosis related genes. Under pathological circumstances, excessive aldosterone is involved in a lot of chronic diseases, including hypertension, cardiac fibrosis, congestive heart failure, ventricular remodeling, and diabetic nephropathy. Therefore, the inhibition of aldosterone synthase (CYP11B2), which is the pivotal enzyme in aldosterone biosynthesis, was proposed as a superior approach. Expected pharmacodynamic effects have been demonstrated in both animal models and clinical trials after the application of CYP11B2 inhibitors. The importance of selectivity over other steroidogenic CYP enzymes, in particular 11β-hydroxylase (CYP11B1), was also revealed. Recently, much more selective CYP11B2 inhibitors have been reported, which could be promising drug candidates for the treatment of aldosterone related diseases.

Topics: Aldosterone; Animals; Benzimidazoles; Cardiovascular Diseases; Cytochrome P-450 CYP11B2; Fadrozole; Humans; Indans; Indoles; Kidney Diseases; Mineralocorticoids; Naphthalenes; Quinolines; Receptors, Mineralocorticoid

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

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

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

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: Cardiovascular Diseases; Drug Interactions; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone

Since the isolation and purification of aldosterone from adrenal extracts 50 years ago (Experientia 9 (1953) 33), scientists have learned a great deal about how and where aldosterone acts, the factors that control its release, what is its role in the pathophysiology of cardiovascular disease, how to make and study aldosterone antagonists, and for what medical purposes these agents are useful. In this paper, we will discuss the evolution of aldosterone antagonists from the relatively nonselective spironolactone (Aldactone), to the highly selective eplerenone (Inspra). Eplerenone represents a molecule with improved steroid receptor selectivity and pharmacokinetic properties in man compared to spironolactone. Recent clinical results have demonstrated that these improvements translate into tolerability and efficacy in patients with cardiovascular disease.

Topics: Aldosterone; Animals; Cardiovascular Diseases; Clinical Trials as Topic; Eplerenone; Gynecomastia; History, 20th Century; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone