Post-Acute Myocardial Infarction Heart Failure Research Articles

Hospital protocols and evidence‐based therapies: The importance of integrating aldosterone blockade into the management of patients with post—acute myocardial infarction heart failure

Left ventricular systolic dysfunction (LVSD) and clinical heart failure are common complications of acute myocardial infarction (AMI) and result in substantially increased mortality and morbidity. Evidence-based cardiovascular protective therapies, including angiotensin-converting enzyme inhibitors, beta blockers, antiplatelet agents, and lipid-lowering medications, improve outcomes for these patients. However, this population is significantly undertreated with these guideline-recommended agents. Critical pathways have been demonstrated to improve the quality and consistency of treatment; as such, the new American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of patients with ST-elevation myocardial infarction (STEMI) recommend that critical pathways be implemented for the management of these patients. The recent Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrates that eplerenone, a selective aldosterone blocker, has incremental benefit in decreasing mortality and morbidity when used with standard care therapies in patients post AMI with heart failure and LVSD. The clinical trial evidence coupled with the national guidelines provides a strong rationale for routine incorporation of aldosterone blockade into new or already established critical pathways for AMI complicated by LVSD and heart failure.

Eplerenone Antagonizes Atherosclerosis, But What Is the Agonist?

A recent analysis of the Framingham Heart Study implicated elevated serum aldosterone as an independent risk factor for the development of cardiovascular disease.1 Although adrenal-derived aldosterone may prove to be important in this regard, less evident is the source of aldosterone and the mechanism for mineralocorticoid receptor (MR) activation in studies such as the Randomized ALdactone Evaluation Study (RALES)2 and the Eplerenone Post-acute myocardial infarction Heart failure Efficacy and Survival Study (EPHESUS),3 where MR blockade exerts obvious cardiovascular benefit but adrenal aldosterone levels are normal. In this issue of Hypertension , the article by Takai et al4 documents such a study and thereby adds to the discussion not only of the applicability of MR blockade in cardiovascular disease but also of the mechanisms for MR activation. The authors report that monkeys with diet-induced hypercholesterolemia treated with the selective MR antagonist eplerenone had reduced extent of atherosclerotic lesions in aorta and carotid arteries compared with placebo-treated monkeys. The results extend the beneficial influence of MR blockade to a model with similarities highly relevant to the atherogenic process in humans. Rajagopalan et al5 were the first to demonstrate that local vascular expression of MR might play a role in atherosclerosis. In this study, dietary hypercholesterolemia in rabbits was associated with increased aorta superoxide generation. Eplerenone administration to hypercholesterolemic rabbits normalized superoxide generation, decreased NADH and NADPH oxidase activity to basal levels, and nearly normalized endothelium-dependent vasorelaxation. A study by Keidar et al6 showed similar inhibition of atherosclerosis when eplerenone was administered to apolipoprotein E (apoE)-deficient mice. …

Letter Regarding Article by Weintraub et al, “Cost-Effectiveness of Eplerenone Compared With Placebo in Patients With Myocardial Infarction Complicated by Left Ventricular Dysfunction and Heart Failure”

HomeCirculationVol. 112, No. 5Letter Regarding Article by Weintraub et al, “Cost-Effectiveness of Eplerenone Compared With Placebo in Patients With Myocardial Infarction Complicated by Left Ventricular Dysfunction and Heart Failure” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter Regarding Article by Weintraub et al, “Cost-Effectiveness of Eplerenone Compared With Placebo in Patients With Myocardial Infarction Complicated by Left Ventricular Dysfunction and Heart Failure” Eric C. Stecker and John H. McAnulty Eric C. SteckerEric C. Stecker Division of Cardiology, Oregon Health and Science University, Portland, Ore Search for more papers by this author and John H. McAnultyJohn H. McAnulty Division of Cardiology, Oregon Health and Science University, Portland, Ore Search for more papers by this author Originally published2 Aug 2005https://doi.org/10.1161/CIRCULATIONAHA.105.557173Circulation. 2005;112:e74To the Editor:An economic analysis of a treatment contributes greatly to decisions about its use in individuals and large populations. However, the analysis performed on the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival (EPHESUS) trial1 would be more relevant if eplerenone had been compared with spironolactone rather than to placebo. We agree with the the statement of Weintraub et al that “there is no direct comparison of eplerenone to spironolactone, making a comparison of the two aldosterone blockers speculative.” Still, even at the time of the beginning of this trial, spironolactone had been demonstrated to be an inexpensive, clinically effective aldosterone antagonist in the setting of heart failure. The EPHESUS investigators previously argued that because spironolactone has an unknown effect in the setting of acute myocardial infarction, there was no ethical imperative to have used an active control–equivalence design.2 Although that is true, there was and is a distinct public health imperative for such a design. It is critically important to know rather than speculate about whether 2 medications with similar effects but quite disparate costs and side-effect profiles have equivalent mortality and morbidity outcomes. Unfortunately, there is no requirement or incentive for manufacturers to make such comparisons, and public research funds are not sufficient to systematically clarify such uncertainties. In this case, the lack of a spironolactone arm in EPHESUS has left clinicians with the ethical ambiguity—if not dilemma—about whether they are needlessly wasting healthcare resources by using eplerenone rather than spironolactone in EPHESUS-type patients.1 Weintraub WS, Zhang Z, Mahoney EM, Kolm P, Spertus JA, Caro J, Ishak J, Goldberg R, Tooley J, Willke R, Pitt B. Cost-effectiveness of eplerenone compared with placebo in patients with myocardial infarction complicated by left ventricular dysfunction and heart failure. Circulation. 2005; 111: 1106–1113.LinkGoogle Scholar2 Aggarwal A, Coca SG, Buller GK, Blaustein DA, Schwenk MH, Pitt B; the EPHESUS Investigators. Eplerenone in patients with left ventricular dysfunction. N Engl J Med. 2003; 349: 88–89.CrossrefGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Martin N, Manoharan K, Davies C and Lumbers R (2021) Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction, Cochrane Database of Systematic Reviews, 10.1002/14651858.CD012721.pub3, 2021:5 Martin N, Manoharan K, Thomas J, Davies C and Lumbers R (2018) Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction, Cochrane Database of Systematic Reviews, 10.1002/14651858.CD012721.pub2 August 2, 2005Vol 112, Issue 5 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.105.557173PMID: 16061750 Originally publishedAugust 2, 2005 PDF download Advertisement SubjectsCongenital Heart Disease

Cost-Effectiveness of Eplerenone Compared With Placebo in Patients With Myocardial Infarction Complicated by Left Ventricular Dysfunction and Heart Failure

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.

ACE inhibitors and mineralocorticoid receptor blockade in patients with congestive heart failure

The two major outcome trials on the combination of angiotensin-converting enzyme (ACE) inhibitors and mineralocorticoid receptor (MR) antagonists in heart failure are RALES (Randomized Aldactone Evaluation Study) and EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study). There have also been studies in essential hypertension, and in diabetic hypertensive patients, on the cardiac and renal effects of ACE inhibitors and MR antagonists, individually and in combination. In the clinical studies on heart failure, in outcome trials and the smaller studies using surrogate end points, a combination of ACE inhibition and MR blockade is superior to ACE inhibition alone, and in the hypertension studies to either agent alone. Some insight into their distinct sites of protective action may be gained from studies on experimental animal preparations. The principal caveat in the use of combination therapy is the possibility of hyperkalemia, which should be minimal in patients with creatine clearance greater than 30 mL/min and with the low doses of MR antagonist shown to be effective in outcome trials.

Eplerenone

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

Aldosterone in heart failure: Pathophysiology and treatment

Aldosterone produces adverse effects on the vasculature (endothelial dysfunction) and on the myocardium (myocardial fibrosis). These effects have adverse clinical consequences that result in increases in deaths caused by sudden death and by progressive heart failure. The Randomized Aldactone Evaluation Study and the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study show this clearly. Aldosterone blockade should become a regular third neuroendocrine-blocking drug in patients with chronic heart failure.

The effect of eplerenone on all-cause mortality and heart failure hospitalization in the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS)

Purpose: In EPHESUS, eplerenone (EPL) significantly decreased the risk of hospitalization for heart failure (HF) versus placebo (PBO) when added to standard HF treatment in patients with left ventricular dysfunction (LVD) and signs of HF after acute myocardial infarction (AMI). Because HF hospitalization is a major morbid event for HF patients, we retrospectively evaluated the effect of EPL added to standard HF treatment on the composite endpoint of time to all-cause mortality or HF hospitalization in high-risk subgroups and determined the risk of death in patients hospitalized for HF.

Efficacy of aldosterone receptor antagonism in heart failure: Potential mechanisms

Results of the Randomized Aldactone Evaluation Study and the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study indicate aldosterone receptor antagonism, together with angiotensin-converting enzyme inhibition and loop diuretics, is a most effective strategy in reducing risk for all-cause and cardiovascular-related mortality and morbidity in patients with symptomatic heart failure. Responsible mechanisms are likely multifactoral. As a circulating hormone, aldosterone has well-known endocrine properties that contribute to the pathophysiology of congestive heart failure. This includes Na+ resorption at the expense of K+ excretion in such tissues as kidneys, colon, sweat, and salivary glands. Mg2+ excretion at these sites is likewise enhanced by aldosterone, whereas adrenal aldosterone secretion is regulated by extracellular Mg2+. Other endocrine actions of aldosterone receptor-ligand binding include: a reduction in biologically active cytosolic-free Mg2+, with intracellular Ca2+ loading in nonepithelial cells such as peripheral blood mononuclear cells; its influence on endothelial cell function; and its central actions, including the choroid plexus, activity of the hypothalamic paraventricular nucleus, and autonomic nervous system. De novo generation of aldosterone within the cardiovasculature is recognized and findings suggest its auto/paracrine properties contribute to tissue repair. Each of these actions is interrupted by aldosterone receptor antagonism and therefore may contribute to its salutary response in heart failure.

459 Risk/benefit analysis of hyperkalemia in the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS)

459 Risk/benefit analysis of hyperkalemia in the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS)

455 Length of stay for heart failure hospitalization in the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS)

455 Length of stay for heart failure hospitalization in the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS)

Eplerenone in the treatment of chronic heart failure

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 β-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.

Aldosterone and cardiovascular remodelling: focus on myocardial failure.

Heart failure is a clinical syndrome that may result from different disease states or conditions that injure the myocardium. The activation of circulating neurohormones, particularly aldosterone, may play a pivotal role in left ventricular (LV) remodelling. The Randomized Aldactone Evaluation Study and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival trial have emphasised the clinical importance of aldosterone. This review addresses some of the proposed mechanisms of LV remodelling in heart failure.

Aldosterone blockade in heart failure

Aldosterone plays a key role in the pathophysiology of heart failure. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers may not suppress aldosterone production in the long term. This allows aldosterone to exert its effects on myocardial fibrosis and cardiac remodelling, endothelial function, electrolytes and baroreceptor response. The Randomized Aldactone Evaluation Study (RALES) tested spironolactone against placebo in patients with severe heart failure. The study found a 30% reduction in the risk of death among patients treated with spironolactone and a 31% reduction in the risk of death from cardiac causes. Patients in the spironolactone group had significantly lower risks of death from progression of heart failure and sudden cardiac death. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) investigated the effects of eplerenone against placebo in patients with myocardial infarction complicated by left ventricular dysfunction. Compared to placebo, the relative risk of death from any cause was 0.85 in eplerenone-treated patients, and the relative risk of death or hospitalisation for cardiovascular events was 0.87. The reduction in the risk of sudden death from cardiac causes was statistically significant. In conclusion, aldosterone blockade should form part of optimal therapy for patients with heart failure.

2003: The year in heart failure*1

2003: The year in heart failure*1

Eplerenone

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.

The cardiovascular effects of eplerenone, a selective aldosterone-receptor antagonist

Background: The role of the renin-angiotensin-aldosterone system in the pathophysiology and treatment of hypertension and heart failure has been extensively studied. Angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers have been shown to effectively reduce blood pressure, protect the kidney, and reduce morbidity and mortality in patients with heart failure. Therefore, there is increased interest in the effects of aldosterone and the use of aldosterone-receptor antagonists in the treatment of cardiovascular disease. Eplerenone is the first selective aldosterone-receptor antagonist approved for the treatment of hypertension and left ventricular (LV) dysfunction after acute myocardial infarction (AMI). Objective: The goal of this article was to review the pharmacologic properties, clinical efficacy, and tolerability of eplerenone in the treatment of hypertension, LV dysfunction, and proteinuria. Methods: Relevant English-language articles were identified through searches of MEDLINE (1966–May 2003), Current Contents, and International Pharmaceutical Abstracts (1970–May 2003) using the terms hypertension, heart failure, eplerenone, aldosterone, and aldosterone antagonist. Other pertinent publications were identified from the reference lists of the identified articles. Information was also obtained from abstracts presented at national meetings and data on file with the manufacturer. Results: In clinical trials, eplerenone alone and in combination with renin-angiotensin blockade significantly reduced both systolic and diastolic blood pressure compared with placebo ( P < 0.05 to P < 0.001). In EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study), the addition eplerenone to optimal medical therapy reduced morbidity and mortality in patients with AMI and LV dysfunction, although the incidence of serious hyperkalemia was also significantly greater. In comparisons with spironolactone, eplerenone was associated with a lower incidence of gynecomastia and other sex hormone-related adverse effects. Conclusions: Either alone or in combination with other antihypertensive agents, eplerenone appears to be effective for the treatment of hypertension. Morbidity and mortality were reduced when eplerenone was added to standard therapy for LV dysfunction complicating AMI. The use of eplerenone for hypertension or heart failure may be limited in patients at risk for hyperkalemia.

New therapy update. Inspra (eplerenone tablets).

New therapy update. Inspra (eplerenone tablets).

Selective aldosterone blockade with eplerenone in patients with congestive heart failure

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

Selective aldosterone blockade with eplerenone in patients with congestive heart failure

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