eplerenone and Death--Sudden--Cardiac

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

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

Sudden cardiac death (SCD) from cardiac arrest, one of the most common types of cardiac-related death, is most often triggered by ventricular arrhythmia (VA). It has been reported that aldosterone antagonists (AAs) have the benefit of reducing SCD in patients with heart failure (HF). It also has been indicated in animal experiments and clinical trials that AAs may have an antiarrhythmic effect.. AAs have an effect on VA in patients with HF or coronary artery disease.. We searched the Cochrane Central Register of Controlled Trials, PubMed, Current Controlled Trials, and the National Research Register, and identified randomized controlled trials on the effect of AAs on VA.. All together, 7 trials with a total of 8635 patients were identified and extracted. AAs reduced the risk of SCD in patients with HF by 21% (relative risk [RR]: 0.79, 95% confidence interval [CI]: 0.67-0.93). AAs significantly reduced the episodes of ventricular premature complexes (mean difference 705 ± 646 episodes per 24 hours). Risk of ventricular tachycardia was reduced by 72% (RR: 0.28, 95% CI: 0.10-0.77).. The additional administration of AAs in patients with HF or coronary artery disease shows a benefit in reducing the risk of SCD and may also be effective for reducing episodes of ventricular premature complexes and ventricular tachycardia.

Topics: Confidence Intervals; Death, Sudden, Cardiac; Diuretics; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Risk; Spironolactone

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

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

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

Our objective was to create a simple prognostic risk score for patients with systolic heart failure and mild symptoms. We then assessed the efficacy of eplerenone across different categories of risk.. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure trial (EMPHASIS-HF) was an international randomized trial, comparing eplerenone with placebo in 2737 patients with systolic heart failure and mild symptoms. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure, over a median 2.1 years follow-up. Using multivariable Cox modelling age, sex, systolic blood pressure, estimated glomerular filtration rate, diabetes, BMI, haemoglobin, prior heart failure (HF) hospitalization, prior myocardial infarction/coronary artery bypass surgery (CABG), and heart rate were identified as strong independent risk factors. Estimates from the model were converted into a simple integer risk score which was categorized into three groups of low-, medium-, and high risk. In placebo patients, the rates (per 100 patient-years) for the primary outcome were 7.6, 19.0, and 39.4 in the low-, medium-, and high-risk groups, respectively. On eplerenone, these rates were reduced to 5.6, 12.2, and 24.2, respectively. Eplerenone was beneficial across all risk categories and the hazard ratios were similar. The absolute treatment benefit was greatest among those at highest risk. Similar patterns emerged for all-cause mortality and for all HF hospitalizations.. This easy-to-use integer risk score should be of value in quantifying individual patient risk in patients with systolic HF and mild symptoms. The relative benefits of eplerenone appeared consistent across the whole spectrum of risk, including those at lower risk.

Topics: Adult; Aged; Death, Sudden, Cardiac; Eplerenone; Female; Heart Failure, Systolic; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Prognosis; Proportional Hazards Models; Risk Assessment; Spironolactone

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

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

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: 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

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

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: 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

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; Death, Sudden, Cardiac; Eplerenone; Humans; Placebos; Primary Prevention; Spironolactone; Time Factors

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

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