eplerenone and Myocardial-Infarction

Topics: Animals; Clinical Trials as Topic; Eplerenone; Evidence-Based Medicine; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Percutaneous Coronary Intervention; Recovery of Function; Risk Factors; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

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

Patients should be placed on the following medications: antiplatelet agents, (meta-analysis for aspirin, multiple randomized controlled trials [RCTs] for aspirin plus clopidogrel); a statin; atorvastatin has the best evidence (a single RCT); a beta-blocker (meta-analysis); renin-angiotensin-aldosterone system blockers, whether or not the ejection fraction is diminished after myocardial infarction (MI) (SOR: A, meta-analysis for angiotensin-converting enzyme [ACE] inhibitor; B, single RCT for ACE inhibitor plus aldosterone blocker).

Topics: Angiotensin-Converting Enzyme Inhibitors; Aspirin; Atorvastatin; Clopidogrel; Eplerenone; Heptanoic Acids; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Pyrroles; Spironolactone; Ticlopidine

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

Each year in the UK, an estimated 50,000 patients develop major left ventricular systolic dysfunction (LVSD) and heart failure following a myocardial infarct.1 Such patients have a particularly poor prognosis. Eplerenone (Inspra - Pfizer) is an aldosterone-receptor antagonist for patients who have LVSD and heart failure following a recent myocardial infarct. Here, we discuss whether such patients should receive this drug.

Topics: Contraindications; Drug Costs; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone

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

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

Development of heart failure (HF) or left ventricular systolic dysfunction (LVSD) significantly increases mortality post acute myocardial infarction (AMI). Aldosterone contributes to the development and progression of HF post AMI, and major guidelines now recommend aldosterone blockade in this setting. However, lack of practical experience with aldosterone blockade may make clinicians hesitant to use these therapies. This review is based on a consensus cardiology conference that occurred in May 2005 (New York City) concerning these topics. Potential barriers to the use of aldosterone blockade are discussed and an algorithm for appropriate in-hospital pharmacologic management of AMI with LVSD and/or HF is presented.

Topics: Algorithms; Cardiac Output, Low; Eplerenone; Humans; Hyperkalemia; Hypotension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Risk Factors; Spironolactone; Systole; Ventricular Dysfunction, Left

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

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 blockade has been shown to be effective in reducing total mortality as well as hospitalization for heart failure in patients with systolic left ventricular dysfunction (SLVD) due to chronic heart failure and in patients with SLVD post acute myocardial infarction. The evidence for the effectiveness of aldosterone blockade in chronic heart failure comes from the randomized aldactone evaluation study (RALES) while that for patients post infarction from the eplerenone post acute myocardial infarction efficacy and survival study (EPHESUS). These studies suggest that mineralocorticoid receptor activation remains important despite the use of an angiotensin converting enzyme-inhibitor/angiotensin receptor blocking (ARB) agent and a beta blocker. Increasing evidence suggest that aldosterone blockade has important effects not only on the kidney but on ventricular remodeling, myocardial fibrosis, autonomic balance, fibrinolysis, oxidative stress, and activation of the NF-kappaB and AP-1 signaling pathways. The results of these studies in patients with SLVD has important implications not only for patients with chronic heart failure and post infarction but also for the therapy of patients with essential hypertension and other cardiovascular diseases.

Topics: Aldosterone; Angiotensin Receptor Antagonists; Digoxin; Enzyme Inhibitors; Eplerenone; Female; Humans; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Spironolactone; Systole; Ventricular Dysfunction, Left

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

Aldosterone can cause cardiovascular injury in animals and men. The aldosterone blocker, spironolactone, has been shown to reduce mortality in patients with congestive heart failure. The use of this drug in arterial hypertension has been limited by the high frequency of adverse effects. Recently published data with a new aldosterone blocker, eplerenone, have confirmed the benefits of aldosterone blockade in patients post-myocardial infarction, as well as in the regression of left ventricular hypertrophy in hypertensive patients and of microalbuminuria in Type 2 diabetic patients. The fact that eplerenone is much better tolerated open the possibility of this therapy in cardiovascular, as well as in renal disease.

Topics: Animals; Eplerenone; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

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

This paper reviews traditional approaches for the management of heart failure, as well as the emerging approach of using an aldosterone inhibitor.. In addition to prevention, the goals of heart failure therapy are to relieve symptoms, improve quality of life, slow progression of heart failure through both pharmacologic and nonpharmacologic therapies, minimize or prevent acute exacerbations, reduce hospitalizations, improve survival, favorably influence neurohormones, and reduce costs. Symptoms are alleviated with diuretics and digoxin; if digoxin is used, the target therapeutic range appears to be 0.4-0.8 ng/mL. Large, well-controlled clinical trials have documented the effectiveness of angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking agents in reducing the mortality and morbidity in patients with heart failure ranging from post myocardial infarction left ventricular dysfunction to severe heart failure. Recent large studies have documented the effectiveness of aldosterone receptor antagonists in improving mortality and morbidity in patients with heart failure. There was a 30% reduction in mortality in patients with NYHA class III-IV heart failure when spironolactone compared with placebo was added to a regimen consisting of digoxin, furosemide, and an ACE inhibitor. A later study in which a gamma-blocker was also included in the regimen showed that patients with left ventricular systolic dysfunction with symptoms of mild heart failure following myocardial infarction taking eplerenone had a 15% relative reduction in all-cause mortality and a 21% reduction in sudden cardiac death compared with placebo. The incidence of gynecomastia was 9% and 0.5% for spironolactone and eplerenone, respectively.. The data support adding aldosterone receptor antagonists alongside ACE inhibitors and beta-adrenergic blocking agents as ways to reduce mortality and morbidity in the treatment algorithm for heart failure. More research is needed to determine the usefulness of aldosterone receptor antagonists across the entire spectrum of heart failure.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Biological Availability; Eplerenone; Half-Life; Humans; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Spironolactone

Aldosterone is known to have multiple adverse cardiovascular effects that are reminiscent of but independent from angiotensin II. These effects include endothelial dysfunction, heightened thrombogenicity, inflammation, and reparative fibrosis, and have been described in experimental and human models of aldosterone excess. Recently a number of clinical investigations have demonstrated that mineralocorticoid receptor (MR) antagonism, even in conditions not traditionally associated with systemic activation of the renin-angiotensin II-aldosterone pathway, may provide additional benefits above and beyond angiotensin-converting enzyme (ACE) inhibition and angiotensin receptor blockade. The Eplerenone Neurohormonal Efficacy and Survival Study (EPHESUS) with eplerenone in patients who were post-myocardial infarction underscores the additive benefit of such a strategy in post-infarction patients that typify an at-risk population for recurrent cardiovascular events. The mechanisms operative in acute coronary syndromes (ACS), including inflammation, altered hemostasis, and endothelial dysfunction, overlap significantly with those seen in the EPHESUS patient population. One may therefore hypothesize that MR antagonism with eplerenone may be beneficial in patients with ACS. Another advantage of using eplerenone is that it offers the advantages of MR antagonism without the side effects due to blockade of other nuclear receptors such as the androgen and progesterone receptors. If MR blockade is found to be beneficial in patients with ACS, the potential reduction in morbidity, mortality, and health care costs are profound.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Collagen; Coronary Restenosis; Eplerenone; Humans; Inflammation; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Syndrome; Thrombosis

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

We investigated the effects of the aldosterone blocker eplerenone alone and in combination with angiotensin II type 1 receptor antagonist on ventricular remodeling in rats with left ventricular (LV) dysfunction after extensive myocardial infarction (MI). Adding an aldosterone antagonist to an ACE inhibitor reduces mortality and morbidity in heart failure. Starting 1 day after MI, rats were treated with placebo, eplerenone (100 mg/kg/day), the angiotensin type 1 receptor antagonist candesartan (1 mg/kg/day), or a combination of both for nine weeks. Both monotherapies attenuated the rise in LV end-diastolic dimension (LVDd) and LV end-diastolic volume (LVEDV) compared with placebo, whereas combined treatment further attenuated LVDd and LVEDV and significantly improved LV function. Increased collagen type I and III gene expressions in the noninfarcted LV myocardium from MI placebo rats was attenuated by candesartan, but almost completely prevented by eplerenone and eplerenone/candesartan. The addition of eplerenone to candesartan prevented the increases in LV gene expression of ANP and BNP more effectively than either monotherapy. The aldosterone blocker eplerenone improved LV remodeling in rats with LV dysfunction after extensive MI. Combination therapy with an candesartan substantially potentiates this effect by a complementary prevention of LV fibrosis, cardiac hypertrophy, and molecular alterations.

Topics: Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Eplerenone; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Rats; Spironolactone; Tetrazoles; Ventricular Dysfunction, Left; Ventricular Remodeling

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

Topics: Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

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

There is no evidence that loop diuretics improve ventricular remodeling in patients with heart failure. Aldosterone receptor antagonists, which have an effect on natriuresis and diuresis, especially in conjunction with an angiotensin converting enzyme-inhibitor, have been shown to improve ventricular remodeling in patients with left ventricular systolic dysfunction. The mechanisms for this beneficial effect and a reduction in death due to progressive heart failure seen in the randomized aldosterone evaluation study (RALES) is likely related to the effect of aldosterone receptor antagonism on myocardial collagen formation and ventricular hypertrophy. Further proof of this hypothesis should be forthcoming from the results of the Eplerenone Heart Failure Efficacy and Survival Study (EPHESUS) early in 2003 in which the aldosterone receptor antagonist eplerenone is being evaluated in patients with systolic left ventricular dysfunction post myocardial infarction.

Topics: Diuretics; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left; Ventricular Remodeling

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

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

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

Trials using mineralocorticoid receptor antagonists (MRAs) in myocardial infraction (MI) without heart failure (HF) or systolic impairment have been underpowered to assess morbidity-mortality benefit. In EPHESUS 6632 patients were included, of whom 11% had an ejection fraction (EF) of 40% and HF or diabetes. We aim to assess the potential benefit of MRAs in MI with EF of 40%.. Cox models with interaction term for EF. The primary outcome was a composite of cardiovascular death or hospitalization for cardiovascular reasons.. Patients with an EF of 40% benefit similarly from MRA therapy to those with an EF <40%.. In EPHESUS, 753 patients had an EF = 40% and 5864 an EF < 40%. Patients with an EF = 40% were younger (63 vs 64 years), had lower heart rate (73 vs 75 bpm), less atrial fibrillation (10% vs 14%), previous MI (21% vs 28%), HF hospitalization (5% vs 8%), and had more often reperfusion therapy and/or revascularization (55% vs 44%). The mean EF was 40.0 ± 0.3% in those with EF = 40% vs 32.2 ± 5.9% in those with EF < 40%. The primary outcome occurred in 13.3% (10 events per 100 py) of the patients with EF = 40% vs 22.9% (19 events per 100 py) in those with EF < 40%; adjusted HR for EF = 40% vs <40% = 0.65 (0.53-0.81). Eplerenone reduced the event-rate homogenously regardless of EF (interaction. Eplerenone reduces hospitalizations and mortality in patients with MI and EF = 40% similarly to patients with EF < 40%. These findings suggest that MI patients with EF in the "mid-range zone" may also benefit from MRA therapy which might help clinicians in their treatment decisions.

Topics: Cause of Death; Dose-Response Relationship, Drug; Eplerenone; Female; France; Hospitalization; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Morbidity; Myocardial Infarction; Stroke Volume; Survival Rate; Treatment Outcome; Ventricular Function, Left

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

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

EPHESUS was a multicentre, double-blind clinical trial in which 6632 patients with acute myocardial infarction (AMI) complicated by LV systolic dysfunction (LVSD) were randomized to receive eplerenone (n = 3319) or placebo (n = 3313). A total of 1580 EPHESUS patients were treated with PCI, which is now the standard treatment for AMI. This EPHESUS substudy examined the effects of eplerenone upon cardiovascular outcomes in PCI-treated patients.. EPHESUS patients were divided into PCI-treated and non-PCI-treated cohorts, and the effect of eplerenone upon mortality and other major adverse cardiovascular outcomes was assessed in each cohort. The PCI-treated patients (n = 1580) were younger, and had better renal function and fewer co-morbidities than non-PCI-treated patients (n = 5052). Cardiovascular mortality was significantly lower in PCI-treated patients as compared with non-PCI-treated patients (7% vs. 16%, P < 0.0001). However, the incidence of non-fatal events was similar in PCI-treated and non-PCI-treated cohorts. There was no statistical difference between the PCI-treated and non-PCI-treated cohorts in the primary or secondary outcomes of the trial. Eplerenone administration, compared with placebo, in the PCI-treated cohort did not affect PCI-related clinical outcomes, including recurrence of angina, the occurrence of acute coronary syndromes, or the need for further revascularization.. The beneficial effects of eplerenone in the EPHESUS trial exist for both PCI- and non-PCI-treated AMI patients with LVSD. Eplerenone has minimal, if any, effect upon reducing PCI-related adverse events in the PCI-treated cohort.

Topics: Aged; Aged, 80 and over; Comorbidity; Double-Blind Method; Eplerenone; Female; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Percutaneous Coronary Intervention; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

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

Galectin-3 is a biomarker associated with inflammation and fibrosis that predicts adverse outcome and relates to biomarkers of extracellular matrix turnover in patients with heart failure, particularly when left ventricular (LV) systolic function is preserved. Whether galectin-3 is related to LV remodeling after acute myocardial infarction is unknown.. Circulating galectin-3 and various extracellular matrix biomarkers were measured in 100 patients (age, 58.9±12.0 years; 77% men) admitted with acute myocardial infarction and LV dysfunction, at baseline (mean 46 hours) and at 24 weeks, with cardiac MRI at each time-point. LV remodeling was defined as change in LV end-systolic volume index. Relationships among galectin-3, biomarkers, and LV remodeling were analyzed across the entire cohort, then according to median baseline LV ejection fraction. Galectin-3 levels were elevated in 22 patients (22%) at baseline and increased significantly over time from 14.7±5.5 to 16.3±6.6 ng/mL (P=0.007). Baseline galectin-3 did not correlate with any LV parameters at baseline or change in any parameter over time. Galectin-3 was positively associated with remodeling in patients with supramedian baseline LV ejection fraction (ie, >49.2%; r=0.40; P=0.01) but not when LV ejection fraction was ≤49.2%. Galectin-3 correlated significantly with matrix metalloproteinase-3 and monocyte chemoattractant protein-1 at baseline, biomarkers that have been shown to relate to LV remodeling in this cohort.. Galectin-3 correlated significantly with certain biomarkers involved in extracellular matrix turnover, although no definite relationship was identified with LV remodeling. Whether galectin-3 plays a pathological role in remodeling remains unclear but merits further study.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00132093.

Topics: Aged; Eplerenone; Extracellular Matrix; Female; Galectin 3; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Remodeling

Several clinical trials have shown that in patients with acute myocardial infarction (MI), statin therapy improves cardiovascular (CV) outcomes, but in these trials patients with acute heart failure (HF) were excluded or only a few were included. In patients with chronic HF, statin therapy does not reduce all-cause or CV mortality. We aimed to assess the association between statin therapy and clinical outcomes in the setting of acute HF with systolic dysfunction complicating acute MI.. We performed a post-hoc analysis in 6632 patients included in the EPHESUS trial. The mean age of patients was 64 years and 71% were male. Overall, 47% of patients had a statin prescribed at baseline. Cox regression models and a secondary analysis using propensity score matching were fit to assess the association between statin prescription and clinical outcomes. During a mean follow-up of 16 ± 7 months, all-cause death occurred in 385 (12%) patients with and in 647 (18%) patients without a statin (P < 0.001). After extensive adjustment, the risk of all-cause death was 20% lower in patients on statin [hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.69-0.92, P = 0.001]. This positive association was mostly due to a lower risk of CV death (HR 0.76, 95% CI 0.65-0.88, P = 0.0002). In contrast, statin use was associated with a higher risk of non-CV hospitalizations (HR 1.16, 95% CI 1.02-1.33, P = 0.02).. Our results suggest that patients with acute HF complicating acute MI may benefit from being on statin therapy. Prospective clinical trials are required to validate these findings.

Topics: Acute Disease; Aged; Double-Blind Method; Drug Therapy, Combination; Eplerenone; Female; Heart Failure, Systolic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Propensity Score; Spironolactone; Stroke Volume; Survival Analysis; Treatment Outcome; United States

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

Hyperglycemia predicts death in cardiovascular disease, but intensive glucose-lowering strategies increase mortality rates in diabetes. The present analysis investigated the prognostic value of postadmission blood glucose (BG) concentration on clinical outcomes in high-risk patients with heart failure after acute myocardial infarction.. A total of 6,496 patients from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) were categorized into 4 groups by plasma glucose concentration: ≤4.5 mmol/L (hypoglycemia), 4.5-5.5 mmol/L (normoglycemia), 5.5-8.3 mmol/L (elevated glucose level), and >8.3 mmol/L (severe hyperglycemia). We evaluated the time to all-cause death (primary end point) and time to cardiovascular death or hospitalization (secondary end point). Hypo- and severe hyperglycemia were prevalent in 509 (8%) and 1,588 (24%) patients, respectively. There was a U-shaped relationship between BG level and incidence of all-cause death (11.8% in patients with normoglycemia vs 15.1% and 19.9% in those with hypo- and severe hyperglycemia; P < .001). The incidence of the secondary end point was increased only in hyperglycemic patients (36% vs 23% in normoglycemic patients; P < .001). In multivariate Cox regression analysis, hypoglycemia (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.06-1.81; P = .002) and severe hyperglycemia (HR 1.52, CI 1.27-1.83; P < .0001) proved to be strong predictors of all-cause death. There was no significant interaction between eplerenone treatment and blood glucose levels regarding clinical outcomes.. In heart failure after acute myocardial infarction, both hypo- and hyperglycemia at the postacute phase identify patients with increased risk of death during long-term follow-up.

Topics: Aged; Blood Glucose; Diabetes Complications; Double-Blind Method; Eplerenone; Female; Humans; Hyperglycemia; Hypoglycemia; Incidence; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Proportional Hazards Models; Risk Factors; Spironolactone; Treatment Outcome; Ventricular Dysfunction, Left

Following acute myocardial infarction (AMI), the acute inflammatory response contributes to wound healing but also to progressive myocardial injury. Interleukin-21 (IL-21) plays a key role in immunoregulation; whether IL-21 is associated with left ventricular (LV) remodelling after AMI is unknown.. Plasma IL-21 concentrations were measured in 100 patients (age 58.9 ± 12.0 years, 77% male) admitted with AMI and LV dysfunction, at baseline (mean 46 h) and again at 24 weeks; cardiac magnetic resonance and measurement of B-type natriuretic peptide, monocyte chemoattractant protein-1, matrix metalloproteinase (MMP)-2, -3, -9, and tissue inhibitor of metalloproteinase (TIMP)-1, -2, -4 occurred at both time-points. Remodelling was defined as change in LV end-systolic volume index (ΔLVESVI).. Plasma IL-21 concentration was unchanged over time (48.1 [SD 35.4]pg/mL at baseline vs. 48.8 [61.3]pg/mL at 24 weeks, p=0.92). Baseline IL-21 correlated significantly with ΔLVESVI (r=0.30, p=0.005) and change in LV end-diastolic volume index (r=0.33, p=0.003). On multivariate analysis, plasma IL-21 was an independent predictor of remodelling. IL-21 was also significantly associated with higher TIMP-4 concentrations and lower MMP-9 concentrations at baseline.. IL-21 predicts adverse remodelling following AMI in patients with LV dysfunction. Whether it plays a direct pathophysiological role in remodelling merits further study.

Topics: Aged; Biomarkers; Double-Blind Method; Eplerenone; Female; Humans; Interleukins; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Middle Aged; Mineralocorticoid Receptor Antagonists; Multivariate Analysis; Myocardial Infarction; Predictive Value of Tests; Spironolactone; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinase-4; Tissue Inhibitor of Metalloproteinases; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Mineralocorticoid receptor (MR) antagonists improve cardiovascular outcomes in patients with heart failure complicating acute myocardial infarction (AMI) and in chronic heart failure. It is unclear whether these beneficial effects are due solely to aldosterone blockade, as MR has a similar affinity for cortisol. We examined the relationships between plasma and urinary steroid hormones and left ventricular (LV) remodelling in patients with LV dysfunction following AMI.. Plasma concentrations of renin, aldosterone, and N-terminal pro-brain natriuretic peptide (NT-proBNP), and 24 h urinary excretion rates of tetrahydroaldosterone (THAldo) and total cortisol metabolites were measured in 93 patients at a mean of 46 h following AMI prior to contrast-enhanced cardiac magnetic resonance (ceCMR). Patients were then randomized to 24 weeks of placebo or eplerenone therapy in addition to standard treatment, after which ceCMR was repeated. In placebo-treated patients, aldosterone, NT-proBNP, and excretion rates of THAldo and total cortisol metabolites were univariate predictors of remodelling (i.e. change in LV end-systolic volume index); aldosterone (P = 0.040) and total cortisol metabolite excretion (P = 0.038) remained independent predictors on multivariate analysis. None of the measured biomarkers predicted remodelling in the presence of eplerenone. Plasma and urinary aldosterone measures, and urinary cortisol metabolites, were not only related to larger infarct volumes and greater infarct remodelling over time, but were also higher in patients with microvascular obstruction on baseline ceCMR.. Aldosterone and cortisol are associated with medium-term LV remodelling when measured early after AMI. The beneficial effects of MR antagonism may relate to blockade of both aldosterone- and cortisol-induced MR activation.

Topics: Aldosterone; Biomarkers; Double-Blind Method; Echocardiography; Electrocardiography; Eplerenone; Female; Follow-Up Studies; Heart Ventricles; Humans; Hydrocortisone; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prospective Studies; Spironolactone; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Von Willebrand factor (VWF) and tissue plasminogen activator (t-PA) predict adverse cardiovascular outcome following acute myocardial infarction (AMI) and are weakly associated with pre-discharge left ventricular ejection fraction (LVEF). We examined the relationships between VWF, t-PA antigen, matrix metalloproteinase (MMP)-2,-3, and -9, and B-type natriuretic peptide (BNP), and their predictive effect on serial change in LV volumes in a cohort of patients admitted with AMI. Plasma VWF, t-PA antigen, MMP-2,-3,-9, and BNP were measured at a mean 46 h after AMI in 100 patients (mean age 58.9 +/- 12 years, 77% male) with depressed LVEF. Cardiac magnetic resonance (CMR) imaging was then performed. Biomarker measurement and CMR were repeated at 12 and 24 weeks. Plasma concentrations of VWF, BNP and MMP-9 were elevated while t-PA antigen concentration was at the upper limits of normal; over 24 weeks VWF, t-PA antigen, MMP-9 and BNP decreased significantly. Baseline VWF correlated with BNP (r = 0.35, P < 0.001) and MMP-3 (r = 0.24, P = 0.019) as did t-PA antigen (r = 0.27, P = 0.007 for BNP; r = 0.40, P < 0.001 for MMP-3). t-PA antigen, VWF, MMP-3 and BNP were univariate predictors of LV end-systolic volume at 24 weeks; tPA antigen and BNP remained significant independent predictors on multivariate analysis. t-PA antigen and VWF are related to medium-term LV volumes after AMI, and to MMP-3. This novel link between the coagulation-fibrinolysis system and matrix turnover merits further study in understanding the pathophysiology of adverse ventricular remodeling after AMI.

Topics: Aged; Biomarkers; Double-Blind Method; Eplerenone; Female; Humans; Male; Matrix Metalloproteinases; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Natriuretic Peptide, Brain; Predictive Value of Tests; Spironolactone; Stroke Volume; Tissue Plasminogen Activator; Ventricular Remodeling; von Willebrand Factor

This study sought to assess, for the first time, the relationship between serum concentrations of the soluble interleukin-1 receptor family member ST2 (sST2) and serial change in left ventricular (LV) function after acute myocardial infarction (AMI).. Serum sST2 levels are elevated early after AMI and are associated with lower pre-discharge LV ejection fraction and adverse cardiovascular outcomes.. The sST2 levels were measured in 100 patients (mean age 58.9 +/- 12.0 years; 77% male), admitted with AMI with resultant LV systolic dysfunction, at baseline and at 12 and 24 weeks. Patients underwent cardiac magnetic resonance imaging and measurement of N-terminal pro-brain natriuretic peptide, norepinephrine, and aldosterone at each time point.. Median sST2 decreased from 263.3 pg/ml at baseline to 140.0 pg/ml at 24 weeks (p < 0.001). Serum sST2 correlated significantly with LV ejection fraction at baseline (r = -0.30, p = 0.002) and 24 weeks (r = -0.23, p = 0.026); change in sST2 correlated with change in LV end-diastolic volume index (r = -0.24, p = 0.023). Level of sST2 was positively associated with infarct volume index at baseline (r = 0.26, p = 0.005) and 24 weeks (r = 0.22, p = 0.037), and with change in infarct volume index (r = -0.28, p = 0.001). Level of sST2 was significantly higher in patients with greater infarct transmurality and endocardial extent, and in the presence of microvascular obstruction. Level of sST2 correlated significantly with norepinephrine and aldosterone, but not with N-terminal pro-brain natriuretic peptide.. Measurement of sST2 early after AMI assists in the prediction of medium-term LV functional recovery. Novel relationships were observed between sST2, infarct magnitude/evolution, and aldosterone. Serum sST2 may be of pathophysiological importance in ventricular and infarct remodeling after AMI. (Effects of Eplerenone on Left Ventricular Remodelling Following Heart Attack; NCT00132093).

Topics: Aged; Biomarkers; Cohort Studies; Double-Blind Method; Eplerenone; Female; Humans; Interleukin-1 Receptor-Like 1 Protein; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Predictive Value of Tests; Receptors, Cell Surface; Spironolactone; Stroke Volume; Treatment Outcome; Ventricular Remodeling

Microvascular obstruction (MO) is associated with large acute myocardial infarction and lower left ventricular (LV) ejection fraction and predicts greater remodeling, but whether this effect is abolished by contemporary antiremodeling therapies is subject to debate. We examined the influence of several infarct characteristics, including MO, on LV remodeling in an optimally treated post-acute myocardial infarction cohort, using contrast-enhanced cardiac magnetic resonance.. One hundred patients (mean age, 58.9+/-12 years, 77%men) underwent contrast-enhanced cardiac magnetic resonance at baseline (approximately 4 days) and at 12 and 24 weeks. The effects on LV remodeling (ie, change in LV end-systolic volume index [DeltaLVESVi]) of infarct site, transmurality, endocardial extent, and the presence of early and late MO were analyzed. Mean baseline infarct volume index decreased from 34.0 (21.2) mL/m(2) to 20.9 (12.9) mL/m(2) at 24 weeks (P<0.001). Infarct site had no influence on remodeling, but greater baseline infarct transmurality (r=0.47, P<0.001) and endocardial extent (r=0.26, P<0.01) were associated with higher DeltaLVESVi. Early MO was seen in 69 patients (69%) and persisted as late MO in 56 patients (56%). Patients with late MO underwent significantly greater remodeling than those without MO (DeltaLVESVi, +4.1 [13.4] versus -7.0 [12.7] mL/m(2), respectively, P=0.001); those with early MO only displayed an intermediate DeltaLVESVi (-4.9 [13.0] mL/m(2)). Importantly, late MO was seen frequently despite optimal coronary blood flow having been restored at angiography.. Late MO on predischarge contrast-enhanced cardiac magnetic resonance remains an ominous predictor of adverse LV remodeling despite powerful antiremodeling therapy and may be useful in the risk stratification of survivors of acute myocardial infarction.

Topics: Chi-Square Distribution; Contrast Media; Double-Blind Method; Eplerenone; Female; Gadolinium DTPA; Humans; Image Processing, Computer-Assisted; Linear Models; Magnetic Resonance Angiography; Male; Microcirculation; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Placebos; Predictive Value of Tests; Spironolactone; Statistics, Nonparametric; Systole; Ventricular Dysfunction, Left; Ventricular Remodeling

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

Apelin, a novel peptide with a putative role in cardiovascular homeostasis, has gained interest as an endogenous inotrope, but has yet to be described following acute myocardial infarction (AMI) in man. We aimed to characterize plasma apelin concentrations following AMI and to examine its relationship with clinical and prognostic biomarkers.. Plasma concentrations of apelin, N-terminal probrain natriuretic peptide (NT-proBNP), norepinephrine, and arginine vasopressin were measured in 100 patients [mean age 58.9 +/- 12 (SD) years, 77% male] admitted with AMI, with echocardiographic left ventricular (LV) ejection fraction <40%, at mean 46 h after admission and at 24 weeks. Cardiac magnetic resonance imaging was performed pre-discharge and at 24 weeks. Thirty-eight subjects with no cardiac history acted as controls. Apelin concentration was reduced early after AMI (0.54 +/- 0.25 vs. 3.22 +/- 3.01 ng/mL, P <0.001) and remained low at 24 weeks, although it did increase significantly from baseline to 0.62 +/- 0.36 ng/mL, P = 0.030. Apelin had no relationship with any parameter of LV function over time. A relationship was found between baseline apelin and norepinephrine (r = 0.26, P = 0.008). Both NT-proBNP and norepinephrine correlated with adverse ventricular function after AMI.. Plasma apelin concentration is reduced early after AMI, increases significantly over time, but remains depressed at 24 weeks.

Topics: Apelin; Biomarkers; Chromatography, High Pressure Liquid; Double-Blind Method; Echocardiography; Eplerenone; Female; Follow-Up Studies; Heart Ventricles; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Magnetic Resonance Imaging; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Spironolactone; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Remodeling

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

Aldosterone antagonism reduces cardiovascular morbidity and mortality in patients with left ventricular (LV) systolic dysfunction and heart failure or diabetes after acute myocardial infarction (AMI). The mechanism of this effect is unclear. We performed a contrast-enhanced cardiac magnetic resonance study to assess the effects of eplerenone on LV remodeling after AMI.. One hundred patients (mean age, 58.9 +/- 12 years; 77% male) with LV systolic dysfunction but without heart failure or diabetes were randomized to 24 weeks' double-blind treatment with eplerenone or placebo started 1 to 14 days after AMI. Contrast-enhanced cardiac magnetic resonance was performed, and plasma concentrations of matrix metalloproteinase-2 (MMP-2) and MMP-9 were measured before randomization and at 12 and 24 weeks.. Baseline LV ejection fraction was, by chance, significantly higher in eplerenone than in placebo-treated patients. Eplerenone had no effect on the primary end point (change in LV end-systolic volume index); after covariate adjustment, the primary end point fell by 6.1 +/- 2.7 mL/m2 with eplerenone compared to placebo (P = .027), and LV end-diastolic volume index fell by 7.5 +/- 3.4 mL/m2 (P = .031); eplerenone did not significantly influence LV ejection fraction. Eplerenone, after covariate adjustment, significantly decreased MMP-2 and increased MMP-9 over 24 weeks relative to placebo.. In a population of patients with AMI with high uptake of contemporary antiremodeling therapy, eplerenone provides modest incremental protection against LV remodeling, only after covariate adjustment.

Topics: Aged; Biomarkers; Double-Blind Method; Eplerenone; Female; Humans; Magnetic Resonance Imaging; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Treatment Outcome; Ventricular Remodeling

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

The EPHESUS study demonstrated that aldosterone blockade with eplerenone decreased mortality in patients with left ventricular systolic dysfunction (LVSD) and heart failure after acute myocardial infarction (AMI). The EPHESUS pharmacoeconomic analysis was performed to evaluate the cost-effectiveness of eplerenone in the Swiss setting.. A total of 6,632 patients with LVSD and heart failure after AMI were randomized to eplerenone or placebo and followed for a mean of 16 months. The co-primary endpoints were all-cause death and the composite of cardiovascular death/cardiovascular hospitalization. The evaluation of resource use included hospitalizations, outpatient services, and medications. Survival beyond the trial period was estimated using 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 was estimated. The perspective of the Swiss third party payers was used. Daily treatment costs of eplerenone were set at CHF 3.88. All other resources were valued on the basis of official tariffs. Discounting of the results was performed at a rate of 3%.. The number of life-years gained with eplerenone was 0.1083 based on Framingham, 0.0661 with Saskatchewan and 0.1518 with Worcester survival estimates. Total costs were CHF 1,028 higher over the trial period in the eplerenone arm, due to drug cost. The incremental cost-effectiveness ratio was CHF 10,145 per life-year gained with Framingham, CHF 16,178 with Saskatchewan, and CHF 7,693 with Worcester survival estimates. The corresponding costs per QALY were CHF 15,219, CHF 23,965 and CHF 11,337, respectively.. Eplerenone is effective in reducing mortality and, in Switzerland, is also cost-effective in increasing years of life for patients with LVSD after AMI.

Topics: Adult; Aged; Cost-Benefit Analysis; Eplerenone; Female; Health Care Costs; Humans; Male; Middle Aged; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

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

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

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

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

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

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

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

We present a case of a 48-year-old white HIV-1 positive man who presented an acute myocardial infarction. The patient was on ART for the last ten years with emtricitabine/tenofovir and ritonavir-boosted fosamprenavir. Eplerenone 25 mg/day was also initiated due to a left ventricular dysfunction. A week after discharge a routine laboratory examination revealed severe hyperkalaemia. Due to suspicion of a potential drug-drug interaction, both eplerenone and ARVs were interrupted. Despite daily treatment for hyperkalaemia, serum potassium levels normalized after two weeks. Eplerenone is metabolized by the hepatic P450 cytochrome isoenzyme CYP3A4; therefore, concomitant administration with CYP3A4 inhibitors, like ritonavir, may increase plasma levels of eplerenone and, therefore, the risk of side effects, mainly hyperkalaemia. Based on this case, it is important to alert the medical community of this possible life-threatening drug-drug interaction between eplerenone and ritonavir-boosted protease inhibitor.

Topics: Drug Interactions; Eplerenone; HIV Infections; HIV Protease Inhibitors; Humans; Hyperkalemia; Male; Middle Aged; Myocardial Infarction; Pharmaceutical Preparations; Ritonavir

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

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

Myocardial infarction (MI) is a major cause of death worldwide. Here, we identify the macrophage MR (mineralocorticoid receptor) as a crucial pathogenic player in cardiac wound repair after MI. Seven days after left coronary artery ligation, mice with myeloid cell-restricted MR deficiency compared with WT (wild type) controls displayed improved cardiac function and remodeling associated with enhanced infarct neovascularization and scar maturation. Gene expression profiling of heart-resident and infarct macrophages revealed that MR deletion drives macrophage differentiation in the ischemic microenvironment toward a phenotype outside the M1/M2 paradigm, with regulation of multiple interrelated factors controlling wound healing and tissue repair. Mechanistic and functional data suggest that inactivation of the macrophage MR promotes myocardial infarct healing through enhanced efferocytosis of neutrophils, the suppression of free radical formation, and the modulation of fibroblast activation state. Crucially, targeted delivery of MR antagonists to macrophages, with a single administration of RU28318 or eplerenone-containing liposomes at the onset of MI, improved the healing response and protected against cardiac remodeling and functional deterioration, offering an effective and unique therapeutic strategy for cardiac repair.

Topics: Animals; Cell Differentiation; Cellular Microenvironment; Disease Models, Animal; Eplerenone; Gene Expression Profiling; Heart; Liposomes; Macrophages; Mice; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Myocardium; Receptors, Mineralocorticoid; Ventricular Remodeling; Wound Healing

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

This study aimed to evaluate the role of eplerenone on the modulation of interleukin (IL)-1β and IL-33/sST2 signaling pathway in an experimental model of left ventricular (LV) systolic dysfunction after acute myocardial infarction (MI). MI rats were randomly assigned to no treatment (MI group, n = 10), to receive eplerenone (Epl group, n = 10), or anakinra (Ana group, n = 10). LV function was assessed by echocardiography. IL-1β, IL-33/sST2, and cardiac fibrosis biomarkers were analyzed by quantitative real-time reverse transcription polymerase chain reaction (PCR). Rats with MI showed significant reduction of LV systolic function, but treatment with eplerenone or anakinra improved left ventricular end-diastolic volume (LVEDV) and LVEDV/mass values. In the infarcted myocardium, compared with sham animals, the MI group had higher level of IL-33, sST2, and IL-1β, as well as higher concentrations of markers of fibrosis and inflammation. Treatment with anakinra downregulated sST2 but with no effects on IL-33. Eplerenone reduced levels of sST2 and IL-1β significantly. Both anakinra and eplerenone treatments were associated with lower levels of fibrosis and inflammatory markers. IL-1β could induce expression of sST2, accelerating the progression of heart failure after acute MI. Eplerenone could improve LV function by reducing expression of IL-1β and sST2.

Topics: Acute Disease; Animals; Antihypertensive Agents; Eplerenone; Interleukin-1beta; Interleukin-33; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-1; Signal Transduction; Ventricular Dysfunction, Left

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

The transcription factor TBX1 plays an important role in the embryonic development of the heart. Nothing is known about its involvement in myocardial remodeling after acute myocardial infarction (AMI) and whether its expression can be modulated by a treatment with proven benefit such as mineralocorticoid receptor blockade.. Acute myocardial infarction was induced in 60 rats via left coronary artery ligation: 50 animals were randomized to be euthanized after 1, 2, 4, 12, or 24 weeks; 10 animals were treated with eplerenone (100 mg/kg/days) 7 days before the AMI until their euthanasia (4 weeks later); 8 additional animals underwent surgery without ligation (control). We analyzed the cardiac expression of TBX1, fetal genes, and fibrosis markers.. The gene and protein expression of TBX1 was increased in the infarcted myocardium, peaking 1 week after AMI (P < .01), without changes in the noninfarcted myocardium. Levels of the fetal genes and fibrosis markers also increased, peaking 4 weeks (P < .001) and 1 week (P < .01) after AMI, respectively. The TBX1 expression was correlated with that of the fibrosis markers (P < .01) but not the fetal genes. Eplerenone reduced the TBX1 increase and fibrosis induced by AMI, with an association improvement in ventricular function and remodeling in echocardiography.. These results show the reactivated expression of TBX1 and indicate its involvement in cardiac fibrosis and remodeling after AMI and its participation in the benefit from mineralocorticoid receptor blockade.

Topics: Actinin; Animals; Atrial Natriuretic Factor; Blotting, Western; Eplerenone; Fibrosis; Gene Expression Regulation, Developmental; Heart; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Myocardium; Myosin Heavy Chains; Natriuretic Peptide, Brain; Rats; Real-Time Polymerase Chain Reaction; RNA, Messenger; Spironolactone; T-Box Domain Proteins; Ventricular Remodeling

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; Humans; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone

After myocardial infarction (post-MI), inflammation and apoptosis contribute to progressive cardiac remodeling and dysfunction. Cardiac mineralocorticoid receptor (MR) and β-adrenergic signaling promote apoptosis and inflammation. Post-MI, MR activation in the brain contributes to sympathetic hyperactivity and an increase in cardiac aldosterone. In the present study, we assessed the time course of macrophage infiltration and apoptosis in the heart as detected by both terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and active caspase-3 immunostaining in both myocytes and nonmyocytes, as well as the effects of central MR blockade by intracerebroventricular infusion of eplerenone at 5 μg/day on peak changes in macrophage infiltration and apoptosis post-MI. Macrophage numbers were markedly increased in the infarct and peri-infarct zones and to a minor extent in the noninfarct part of the left ventricle at 10 days post-MI and decreased over the 3-mo study period. Apoptosis of both myocytes and nonmyocytes was clearly apparent in the infarct and peri-infarct areas at 10 days post-MI. For TUNEL, the increases persisted at 4 and 12 wk, but the number of active caspase-3-positive cells markedly decreased. Central MR blockade significantly decreased CD80-positive proinflammatory M1 macrophages and increased CD163-positive anti-inflammatory M2 macrophages in the infarct. Central MR blockade also reduced apoptosis of myocytes by 40-50% in the peri-infarct and to a lesser extent of nonmyocytes in the peri-infarct and infarct zones. These findings indicate that MR activation in the brain enhances apoptosis both in myocytes and nonmyocytes in the peri-infarct and infarct area post-MI and contributes to the inflammatory response.

Topics: Aldosterone; Animals; Apoptosis; Caspase 3; Disease Models, Animal; Eplerenone; Macrophages; Male; Myocardial Infarction; Rats, Wistar; Receptors, Mineralocorticoid; Spironolactone; Ventricular Remodeling

Evidence-based medicine aims to apply best evidences to medical decision making. Although evidence are established using the scientific method, decision making has received less priority. Decision making is a mental process requiring a systematic analysis of evidences for a specific use, leading to a final choice of action. In many scientific disciplines involving decision and control, this process has been significantly improved by making it as a system (a set of interacting entities forming an integrated whole). Hypothesizing that most medical decisions can be described as a system, we present a schematic systematic loop, based on four traditional medical steps (nosology, semeiology, pathophysiology, and therapy), and on the four transitions between these steps. Steps are evaluated by reproducibility, transitions are evaluated by predictability. This leads to formulate eight basic questions for testing the reliability of any loop. We applied this approach to a specific study (EPHESUS) to show its interest in the control of the medical knowledge provided by a study and in indicating where evidence is missing. A systematic approach helps evidence-based medicine in structuring evidences for better medical decisions and in determining which research needs priority.

Topics: Decision Making; Eplerenone; Evidence-Based Medicine; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Reproducibility of Results; Spironolactone; Survival Rate; Ventricular Dysfunction, Left

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

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

Low-dose mineralocorticoid receptor antagonists reduce morbidity and mortality in patients with heart failure and myocardial infarction, despite normal plasma aldosterone levels. Since apoptosis plays an important role in heart failure and postinfarction left ventricular remodeling, we examined whether low-dose mineralocorticoid receptor antagonists modulate cardiomyocyte death by regulating the apoptosis repressor protein apoptosis repressor with caspase recruitment domain to lessen the extent of apoptosis. Hearts from adult male Sprague-Dawley rats were subjected to regional ischemia followed by reperfusion ex vivo, with mineralocorticoid receptor antagonists added to perfusates before ischemia. Low-dose spironolactone (10 nmol/L) or eplerenone (100 nmol/L) significantly reduced infarct size. Spironolactone also prevented cleavage of the apoptotic chromatin condensation inducer in the nucleus and of the inhibitor of caspase-activated DNAse induced by ischemia-reperfusion, thereby abolishing chromatin condensation and internucleosomal cleavage. Ischemia-reperfusion-induced activation of caspases 2, 3, and 9, but not caspase 8, was prevented by spironolactone, suggesting targeted regulation of the intrinsic pathway. Low-dose spironolactone and eplerenone prevented loss of the apoptosis repressor with the caspase recruitment domain and reduced myocyte death. In H9c2 cells, mineralocorticoid receptor activation by aldosterone resulted in apoptosis repressor with caspase recruitment domain degradation and enhanced apoptosis; these actions were prevented by coadministration of spironolactone. Using a triple lysine mutant we identified that aldosterone enhances posttranscriptional degradation of the apoptosis repressor with a caspase recruitment domain via the ubiquitin-proteasomal pathway. Our data demonstrate that low-dose mineralocorticoid receptor antagonists reduce infarct size and apoptosis in the reperfused myocardium by preventing the apoptosis repressor with caspase recruitment domain degradation.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Caspase 2; Caspase 3; Caspase 9; Cell Line; Dose-Response Relationship, Drug; Enzyme Activation; Eplerenone; Immunoblotting; In Vitro Techniques; Male; Mineralocorticoid Receptor Antagonists; Muscle Proteins; Myocardial Infarction; Proteolysis; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Spironolactone

We sought to assess possible interactions between eplerenone use and a plasma marker of collagen turnover on prognosis in patients after acute myocardial infarction (AMI) and preserved left ventricular (LV) ejection fraction (≥40%). Three hundred three patients with AMI (58 ± 11 years old, 249 men) and preserved systolic LV function were studied prospectively for 24 months. Plasma levels of matrix metalloproteinase-9 (MMP-9) were assessed on day 7 after AMI. Patients were categorized according to whether (n = 201) or not (n = 102) they received eplerenone (25 mg/day) and their baseline MMP-9 levels using the cut-off level suggested by receiver operating characteristics analysis (12.7 ng/ml). Death from cardiovascular causes, nonfatal reinfarction, hospitalization for unstable angina, and development of heart failure symptoms were considered study end points. Eplerenone use was not associated with better prognosis in the entire study group (p = 0.132). However, a significant beneficial eplerenone effect on outcome was observed in patients with low baseline levels of MMP-9 (event-free survival for eplerenone vs noneplerenone arm 65% vs 35%, p = 0.005). Eplerenone had no effect (p = 0.741) in the subgroup of patients with high baseline MMP-9 levels. In conclusion, in patients after AMI with preserved LV systolic function, low baseline levels of MMP-9 identify a subgroup of patients in whom eplerenone use is associated with a survival benefit.

Topics: Aged; Biomarkers; Enzyme-Linked Immunosorbent Assay; Eplerenone; Female; Humans; Male; Matrix Metalloproteinase 9; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Proportional Hazards Models; Prospective Studies; ROC Curve; Spironolactone; Statistics, Nonparametric; Systole; Ventricular Function, Left

Topics: Death, Sudden, Cardiac; Defibrillators, Implantable; Eplerenone; Health Knowledge, Attitudes, Practice; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Practice Guidelines as Topic; Risk Factors; Spironolactone; Time Factors; Treatment Outcome

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

Pre-treatment with mineralocorticoid receptor (MR) antagonists is reported to reduce myocardial infarct size from ischaemia/reperfusion. Here, we tested whether the MR antagonists potassium canrenoate and eplerenone could protect in the more clinically relevant schedule of administration at the end of ischaemia.. In all models, hearts were subjected to 30 min regional ischaemia followed by 120 min (rabbits 4 h) reperfusion. A bolus of canrenoate 5 min prior to reperfusion in open-chest mice decreased infarct size in a dose-dependent manner. Maximum protection was seen at 1 mg/kg where infarction was 18% of that in the control (P < 0.001). Ecto-5'-nucleotidase (CD73) as well as adenosine A(2b) receptor knock-out mice could no longer be protected, suggesting a role for adenosine and the A(2b) receptor in the mechanism. A 1 mg/kg bolus of canrenoate prior reperfusion also reduced infarct size in open-chest rabbits. To explore the underlying mechanisms, we studied isolated rat hearts. Eplerenone (10 microM) at the end of ischaemia was similarly protective in the rat heart and the protection was abolished by co-treatment with inhibitors of the adenosine receptor, protein kinase C, PI3-kinase, and ERK. In addition, eplerenone or canrenoate treatment increased phosphorylation of the pro-survival kinases Akt and ERK1/2 at reperfusion in the rat hearts.. Taken together, MR antagonists when given at the end of ischaemia are highly effective and potent cardioprotective drugs with a signalling similar to that of ischaemic pre-conditioning and, hence, could be a very promising candidate for the treatment of acute myocardial infarction in man.

Topics: Animals; Canrenoic Acid; Eplerenone; Ischemic Preconditioning, Myocardial; Mice; Mice, Knockout; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Myocardial Reperfusion Injury; Phosphorylation; Phosphotransferases; Rabbits; Rats; Rats, Wistar; 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: Eplerenone; Female; Follow-Up Studies; Humans; Hypertension; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Renal Insufficiency, Chronic; Spironolactone; Treatment Outcome

Monocyte chemoattractant protein-1 (MCP-1) is elevated after acute myocardial infarction (AMI), and potentiates left ventricular (LV) remodeling in murine models of AMI. We examined the relationships between serum MCP-1, change in LV function and biomarkers related to remodeling in a cohort of AMI patients.. Serum MCP-1 concentrations were measured in 100 patients (age 58.9+/-12.0 years, 77% male) admitted with AMI and LV dysfunction, at baseline (mean 46 h), 12 and 24 weeks; cardiac magnetic resonance imaging and measurement of matrix metalloproteinase-2 (MMP-2), MMP-3 and MMP-9 occurred at each time-point.. MCP-1 increased significantly from 697 [483, 997]pg/mL at baseline to 878 [678, 1130]pg/mL at 24 weeks (p<0.001). MMP-3 concentration increased while MMP-9 decreased significantly over time; MMP-2 concentration did not change significantly. BASELINE MCP-1 correlated with change in (Delta) LV end-systolic volume index (DeltaLVESVI; r= -0.48, p=0.01) and with DeltaLV ejection fraction (DeltaLVEF; r=0.50, p=0.02). However, DeltaMCP-1 correlated positively with DeltaLVESVI (r=0.40, p=0.006) and negatively with DeltaLVEF (r= -0.36, p=0.004). MCP-1 had no relationship with any MMP.. MCP-1 may have a dichotomous role following AMI, aiding early infarct healing but potentiating later remodeling, which merits further study before any therapeutic trials of MCP-1 modulation in humans.

Topics: Biomarkers; Chemokine CCL2; Cohort Studies; Contrast Media; Eplerenone; Female; Humans; Magnetic Resonance Imaging; Male; Matrix Metalloproteinases; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Aldosterone receptor antagonism reduces mortality and improves post-myocardial infarction (MI) remodeling. Because aldosterone and estrogen signaling pathways interact, we hypothesized that aldosterone blockade is sex-specific. Therefore, we investigated the impact of eplerenone on left ventricular (LV) remodeling and gene expression of male infarcted rats versus female infarcted rats. MI and Sham animals were randomized to receive eplerenone (100 mg/kg/day) or placebo 3 days post-surgery for 4 weeks and assessed by echocardiography. In the MI placebo group, left ventricular end-diastolic dimension (LVEDD) increased from 7.3 +/- 0.4 mm to 10.2 +/- 1.0 mm (p < 0.05) and ejection fraction (EF) decreased from 82.3 +/- 4% to 45.5 +/- 11% (p < 0.05) in both sexes (p = NS between groups). Eplerenone attenuated LVEDD enlargement more effectively in females (8.8 +/- 0.2 mm, p < 0.05 vs. placebo) than in males (9.7 +/- 0.2 mm, p = NS vs. placebo) and improved EF in females (56.7 +/- 3%, p < 0.05 vs. placebo) but not in males (50.6 +/- 3%, p = NS vs. placebo). Transcriptomic analysis using Rat_230-2.0 microarrays (Affymetrix) revealed that in females 19% of downregulated genes and 44% of upregulated genes post-MI were restored to normal by eplerenone. In contrast, eplerenone only restored 4% of overexpressed genes in males. Together, these data suggest that aldosterone blockade reduces MI-induced cardiac remodeling and phenotypic alterations of gene expression preferentially in females than in males. The use of transcriptomic signatures to detect greater benefit of eplerenone in females has potential implications for personalized medicine.

Topics: Animals; Cluster Analysis; Eplerenone; Female; Fibrosis; Gene Expression Profiling; Gene Expression Regulation; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Placebos; Rats; Rats, Wistar; Sex Characteristics; Spironolactone; Ventricular Remodeling

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

In order to allocate health care resources more efficiently, it is necessary to relate health improvements provided by new medicines to their cost. It is necessary to ascertain when the additional cost of introducing a new health technology is justified by the additional health gain produced. Eplerenone is a new medicine that reduces the risk of death after myocardial infarction (MI) but produces additional cost to the health system. The contingent valuation approach can be used to measure the monetary value of this risk reduction and to estimate society's willingness to pay (WTP) for a new medicine that reduces the risk of death after MI by 2% points. We used a contingent valuation approach to evaluate WTP amongst members of the general population. We used the ex-ante and the ex-post approach. In the ex-ante approach, subjects are asked if they would accept an increase in their taxes in order to have access to eplerenone should they need it in the future. In the ex-post approach, subjects are asked if they would pay a certain amount of money as co-payment per month during 5 years if they suffered an MI. We used the dichotomous choice method, using five bids in each approach. The WTP was estimated using both single-bound and double-bound dichotomous choice (SBDC, DBDC). Extensive piloting (n = 187) preceded the final survey (n = 350). The WTP in the ex-ante case was euro 58 per year under both SBDC and DBDC. In the ex-post case, monthly WTP was euro 141 for the SBDC and euro 85 for the DBDC. Subjects with higher income and subjects with a higher perception of risk showed a higher WTP (P 0.05). Society is willing to pay an additional amount of money in order to give eplerenone to present and future patients. We estimate that euro 85 per month is a conservative estimate of the monetary value of a 2% risk reduction in mortality after MI and to spend this additional amount of money in Eplerenone can be considered an efficient policy.

Topics: Attitude to Health; Cost-Benefit Analysis; Eplerenone; Female; Financing, Personal; Focus Groups; Health Care Surveys; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Risk Reduction Behavior; Spain; 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

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiac Output, Low; Chronic Disease; Death, Sudden, Cardiac; Drug Therapy, Combination; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Renin-Angiotensin System; Spironolactone; Treatment Outcome

Topics: Angioplasty, Balloon, Coronary; Clopidogrel; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Platelet Aggregation Inhibitors; Spironolactone; Ticlopidine

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

Mineralocorticoid receptor blockade improves mortality early after myocardial infarction (MI). This study investigated the vascular effects of mineralocorticoid receptor blockade in the early phase postinfarction in rats. Starting immediately after coronary ligation, male Wistar rats were treated with placebo or eplerenone (100 mg/kg/d). After 7 days, hemodynamic assessment was performed and endothelial function was determined. Maximum acetylcholine-induced relaxation was significantly attenuated in aortic rings from rats with heart failure after MI, and ameliorated by eplerenone treatment. Endothelium-independent relaxation by DEA-NONOate was similar among the groups. Endothelial NO synthase phosphorylation was reduced in the aorta of MI rats and restored by eplerenone therapy. Angiotensin I-induced vasoconstriction as well as angiotensin-converting enzyme protein levels were enhanced in aortas from MI placebo rats, and reduced by mineralocorticoid receptor inhibition. Aortic reactive oxygen species formation as well as the expression of the NAD(P)H oxidase subunit p22(phox) were increased after MI and normalized in eplerenone treated rats. In conclusion, mineralocorticoid receptor antagonism improved endothelial dysfunction in the early phase post-MI. Underlying mechanisms involve inhibition of vascular angiotensin-converting enzyme upregulation and improvement of endothelial NO synthase-derived NO bioavailability.

Topics: Animals; Aorta, Thoracic; Disease Models, Animal; Dose-Response Relationship, Drug; Eplerenone; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; NADPH Oxidases; Organ Culture Techniques; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Spironolactone; Time Factors; Vasodilation; Vasodilator Agents; Vasomotor System

Topics: Aldosterone; Angiotensin II; Animals; Endothelium, Vascular; Eplerenone; Humans; Mice; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Oxidative Stress; Rats; Signal Transduction; Spironolactone

Mineralocorticoid receptor antagonism with eplerenone reduces mortality in heart failure, possibly because of blockade of the deleterious effects of aldosterone. To investigate these effects, rat Langendorff hearts were exposed to aldosterone and/or eplerenone. Under normal conditions, aldosterone increased left ventricular pressure and decreased coronary flow. Eplerenone did not block these effects. Eplerenone reduced infarct size (from 68+/-2% to 53+/-4%; P<0.05) and increased left ventricular pressure recovery (from 44+/-2% to 60+/-5%; P<0.05) after 45 minutes of coronary artery occlusion and 3 hours of reperfusion, whereas aldosterone did not affect these parameters. To verify the origin of cardiac aldosterone, hearts were perfused with 3 to 30 nmol/L aldosterone and either frozen immediately or exposed to washout. Without washout, cardiac aldosterone was 1.5 times aldosterone in coronary effluent (CE), that is, too high to be explained on the basis of its presence in extracellular fluid. The cardiac levels of aldosterone correlated with its CE levels (r=0.81; P<0.01), and both were unaffected by eplerenone. During washout, tissue aldosterone disappeared monophasically (half life, 9+/-1 minutes), and CE aldosterone disappeared biphasically (half life 1+/-0 and 8+/-1 minutes, respectively). During buffer perfusion, cardiac aldosterone was at or below the detection limit. In conclusion, eplerenone improves the condition of the heart after ischemia and reperfusion. This does not relate to interference with the inotropic and vasoconstrictor effects of aldosterone. The majority of cardiac aldosterone, if not all, is derived from the circulation. The rapid, mineralocorticoid receptor-independent kinetics of aldosterone suggest that its accumulation in the heart involves cell surface binding rather than internalization.

Topics: Aldosterone; Animals; Cardiotonic Agents; Drug Interactions; Eplerenone; Heart; Hemodynamics; In Vitro Techniques; Kinetics; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Myocardial Ischemia; Myocardium; Rats; Rats, Wistar; Spironolactone

Topics: Adrenergic beta-Antagonists; Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Drug Therapy, Combination; Eplerenone; Humans; Hypolipidemic Agents; Myocardial Infarction; Placebos; Randomized Controlled Trials as Topic; Risk Factors; Spironolactone; Time Factors

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

Eplerenone, a selective aldosterone blocker, has been shown to attenuate cardiac fibrosis and decrease cardiovascular events in both experimental and clinical studies. We examined the cardioprotective effect of eplerenone in myocardial infarction (MI) rats receiving different levels of salt in their diet. The MI rats were randomly divided into five groups: Group CL, animals received a low-salt diet (0.015%); Group EpL, a low-salt diet with eplerenone (100 mg/kg/day in food); Group CH, a high-salt diet (0.9%); Group EpH, a high-salt diet with eplerenone; and Group C, a normal salt diet (0.3%). These diets were continued for 4 weeks. Echocardiographic and histomorphological examinations revealed that the administration of eplerenone significantly improved the cardiac function, significantly suppressed compensatory cardiac hypertrophy and significantly reduced cardiac fibrosis in both the interstitial and the perivascular areas in the high-salt diet group (Group EpH). However, eplerenone had no observable effects in the low-salt diet group (Group EpL). Also, these examinations demonstrated that the left ventricular remodeling after MI was suppressed and the cardiac function was improved in the group receiving a low-salt diet without eplerenone (Group CL), even though there was a significant increase of aldosterone level in blood, in comparison to the group receiving a high-salt diet without eplerenone (Group CH). These results indicate that the cardioprotective effect of eplerenone varies depending on the salt intake.

Topics: Aldosterone; Animals; Cardiomegaly; Diet, Sodium-Restricted; Echocardiography; Eplerenone; Fibrosis; Food-Drug Interactions; Heart; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Rats; Rats, Wistar; Sodium Chloride; Spironolactone; Ventricular Remodeling

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

Topics: Arrhythmias, Cardiac; Defibrillators, Implantable; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Stroke Volume

Topics: Aldosterone; Cardiac Output, Low; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone

To examine the effects of eplerenone, a selective aldosterone blocker, on cardiac function after myocardial infarction (MI) and myocardial remodelling related transcriptional factors and mRNA expression in non-infarcted myocardium.. MI was induced by ligation of the coronary artery in Wistar rats. Rats were randomly assigned to a vehicle treated group or an eplerenone treated group (100 mg/kg/day).. At four weeks after MI, left ventricular (LV) end diastolic pressure, LV weight, and LV end diastolic dimension were increased in MI rats. Eplerenone significantly reduced the increase in LV end diastolic pressure, LV weight, and LV end diastolic dimension. In the MI rats the decreased ejection fraction indicated systolic dysfunction and the increased E wave to A wave ratio and E deceleration rate indicated diastolic dysfunction. Eplerenone significantly attenuated this systolic and diastolic dysfunction. Myocardial interstitial fibrosis, transcriptional activities of activator protein 1 and nuclear factor kappaB, and mRNA expression of monocyte chemoattractant protein 1, plasminogen activator inhibitor 1, atrial natriuretic peptide, brain natriuretic peptide, and collagen types I and III were significantly increased at four weeks after MI. Eplerenone significantly attenuated interstitial fibrosis and suppressed transcriptional activity and mRNA expression of these genes.. When administered after MI, eplerenone prevents cardiac remodelling accompanied by systolic and diastolic dysfunction and inhibits abnormal myocardial transcriptional activities and gene expression.

Topics: Animals; Blood Pressure; Blotting, Northern; Body Weight; Coronary Vessels; Echocardiography, Doppler; Eplerenone; Heart; Heart Ventricles; Ligation; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Organ Size; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Spironolactone; Transcription Factors; Ventricular Remodeling

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: Cost-Benefit Analysis; Drug Costs; Eplerenone; Health Care Costs; Humans; Myocardial Infarction; Placebos; Spironolactone; 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

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

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Drug Therapy, Combination; Eplerenone; Germany; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Prognosis; Spironolactone; Survival Rate

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 incidence of cardiovascular diseases increases rapidly with age, and the elderly suffer higher morbidity and mortality. Aldosterone blockers have shown benefits in patients with left ventricular (LV) dysfunction and heart failure after myocardial infarction (MI). However, aldosterone blockade efficacy has not been explored in aged animals with MI. Methods and results Small-to-moderate MI was induced by coronary artery ligation in 16-month old rats, divided into 3 groups: sham-operated (control, n = 9), MI (n = 9), and MI fed a diet containing eplerenone (120 mg/kg/day, MI+Eplerenone, n = 9) given 18 days postsurgery and up to sacrifice 3 months later. At sacrifice, untreated MI rats did not show overt systolic dysfunction but they had (1) echocardiographic evidences of impaired relaxation (increase of E wave deceleration time and of isovolumic relaxation time, decrease of peak E wave velocity), (2) hemodynamically impaired LV relaxation (LV -dP/dt from 7413 +/- 720 to 4956 +/- 475 mm Hg/s, P < .05), and (3) significant increase of collagen content in LV interstitium (from 4.27 +/- 0.23 to 5.34 +/- 0.24%, P < .01) and in aorta (from 19 +/- 1 to 24 +/- 2%, P < .05). Eplerenone normalized echocardiographic and hemodynamic evidences of diastolic dysfunction, as well as myocardial interstitial collagen and aortic fibrosis (all parameters statistically different from untreated MI).. In aged rats with small to moderate MI, eplerenone normalized diastolic relaxation, possibly through a reduction of interstitial fibrosis.

Topics: Analysis of Variance; Animals; Aorta; Diastole; Echocardiography; Eplerenone; Hemodynamics; Kidney; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Spironolactone; Treatment Outcome; Ventricular Function, Left

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

Topics: Acute Disease; Catecholamines; Collagen; Eplerenone; Heart Rate; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Randomized Controlled Trials as Topic; Spironolactone; Treatment Outcome; Ventricular Dysfunction; Ventricular Remodeling

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: Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Research Design; Spironolactone; Ventricular Dysfunction, Left

Topics: Death, Sudden, Cardiac; Eplerenone; Humans; Hypokalemia; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

Topics: Contraindications; Creatinine; Eplerenone; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Ventricular Dysfunction, Left

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

We investigated the effects of the aldosterone blocker eplerenone alone and in combination with angiotensin-converting enzyme (ACE) inhibition on ventricular remodeling in rats with left ventricular (LV) dysfunction after extensive myocardial infarction (MI).. Adding an aldosterone antagonist to ACE inhibition reduces mortality and morbidity in heart failure.. Starting 10 days after MI, rats were treated with placebo, eplerenone (100 mg/kg/day), the ACE inhibitor trandolapril (0.3 mg/kg/day), or a combination of both for nine weeks.. Both monotherapies attenuated the rise in LV end-diastolic pressure (LVEDP) and LV end-diastolic volume (LVEDV) compared with placebo, whereas combined treatment further attenuated LVEDP and LVEDV, significantly improved LV function and reduced plasma norepinephrine levels. The time constant of LV pressure isovolumic decay (tau) was prolonged in placebo MI rats, significantly shortened by eplerenone, and normalized by eplerenone/trandolapril. Increased collagen type I gene expression and collagen content in the noninfarcted LV myocardium from MI placebo rats was attenuated by trandolapril, but almost completely prevented by eplerenone and eplerenone/trandolapril. The addition of eplerenone to ACE inhibition prevented sarcoplasmic-reticulum calcium ATPase downregulation and the increases in LV gene expression of beta-MHC and atrial natriuretic factor more effectively than either monotherapy. Furthermore, combination treatment attenuated the increase in myocardial angiotensin II type 1 receptor expression and increased phosphorylated endothelial nitric oxide synthase protein levels.. The aldosterone blocker eplerenone improved LV remodeling in rats with LV dysfunction after extensive MI. Combination therapy with an ACE inhibitor substantially potentiates this effect by a complementary prevention of LV fibrosis, cardiac hypertrophy, and molecular alterations.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Drug Synergism; Drug Therapy, Combination; Endothelium, Vascular; Eplerenone; Hemodynamics; Indoles; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Nitric Oxide Synthase; Rats; Spironolactone; Ventricular Dysfunction, Left; Ventricular Remodeling

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

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

Myocardial infarction (MI) initiates adaptive tissue remodeling, which is essential for heart function (such as infarct healing) but is also important for maladaptive remodeling (for example, reactive fibrosis and left ventricular dilation). The effect of aldosterone receptor antagonism on these processes was evaluated in Sprague-Dawley rats using eplerenone, a selective aldosterone receptor antagonist. Infarct healing and left ventricular remodeling were evaluated at 3, 7, and 28 days after MI by determination of the diastolic pressure-volume relationship of the left ventricle, the infarct-thinning ratio, and the collagen-volume fraction. Eplerenone did not affect reparative collagen deposition as was evidenced by a similar collagen volume fraction in the infarcted myocardium between eplerenone and vehicle-treated groups at 7 and 28 days post-MI. In addition, the thinning ratio, which is an index of infarct expansion, was comparable between the eplerenone and vehicle-treated animals at 7 and 28 days post-MI. A protective effect of eplerenone was demonstrated at 28 days post-MI, where reactive fibrosis in the viable myocardium was reduced in eplerenone-treated animals compared with vehicle-treated animals. Thus aldosterone receptor antagonism does not retard infarct healing but rather protects against maladaptive responses after MI.

Topics: Animals; Eplerenone; Fibrosis; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Spironolactone; Ventricular Remodeling

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