Harry Shi

Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms

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

Eplerenone and Atrial Fibrillation in Mild Systolic Heart Failure Results From the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) Study

OBJECTIVES The purpose of this study was to analyze the incidence of new atrial fibrillation or flutter (AFF) in the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) database. BACKGROUND Aldosterone antagonism in heart failure might influence atrial fibrosis and remodeling and, therefore, risk of developing AFF. The development of new AFF was a pre-specified secondary endpoint in the EMPHASIS-HF study. METHODS Patients in New York Heart Association functional class II and with ejection fraction ≤35% were eligible for EMPHASIS-HF. History of AFF at baseline was reported by investigators using the study case report form. New onset AFF (in those with no history of AFF at baseline) was reported using a specific endpoint form; in a sensitivity analysis we also examined the effect of eplerenone on AFF reported as an adverse event. RESULTS New onset AFF was significantly reduced by eplerenone: 25 of 911 (2.7%) versus 40 of 883 (4.5%) in the placebo group (hazard ratio [HR]: 0.58, 95% confidence interval [CI]: 0.35 to 0.96; p = 0.034). The reduction in the primary endpoint with eplerenone was similar among patients with and without AFF at baseline (HR: 0.60, 95% CI: 0.46 to 0.79 vs. HR: 0.70, 95% CI: 0.57 to 0.85, respectively; p for interaction = 0.41). The risk of cardiovascular (CV) death or hospital admission for worsening heart failure, the primary endpoint, was not significantly different in subjects with and without AFF at baseline (both study groups combined: HR: 1.23, 95% CI: 0.81 to 1.86; p = 0.33). CONCLUSIONS In patients with systolic heart failure and mild symptoms, eplerenone reduced the incidence of new onset AFF. The effects of eplerenone on the reduction of major CV events were similar in patients with and without AFF at baseline.

Safety and Efficacy of Eplerenone in Patients at High Risk for Hyperkalemia and/or Worsening Renal Function : Analyses of the EMPHASIS-HF Study Subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure)

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

Rationale and design of the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF)

In chronic heart failure (HF), aldosterone antagonists have been shown to improve survival in patients with low ejection fraction and moderate‐to‐severe symptoms [New York Heart Association (NYHA) classes III and IV]. Efficacy of these agents was also shown when they were administered to patients with left ventricular dysfunction and signs and symptoms of CHF early after acute myocardial infarction. It is not known whether the selective aldosterone antagonist eplerenone can improve outcomes in mildly symptomatic patients. The Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS‐HF) was designed to evaluate the effect of eplerenone on mortality and morbidity in patients with chronic systolic HF in NYHA class II.

Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: The Randomized Double-Blind Reminder Study

AIMS 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. METHODS AND RESULTS 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. CONCLUSION 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. CLINICAL TRIAL REGISTRATION NCT01176968.

Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms Analysis of Repeat Hospitalizations

Background— Eplerenone is known to reduce time to first hospitalization for heart failure or cardiovascular death in patients with heart failure and mild symptoms. In chronic diseases such as heart failure, characterized by repeat hospitalizations, analyzing all heart failure hospitalizations, not just the first, should give a more complete picture of treatment benefits. Methods and Results— The Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure (EMPHASIS-HF) trial compared eplerenone with placebo in 2737 patients with mild heart failure, followed for a median 2.08 years (interquartile range, 1.08–3.10 years). Data were collected on all hospitalizations, with a focus on those due to heart failure. Heart failure hospitalization rates in the eplerenone and placebo groups were 10.70 and 16.99 per 100 patient-years, respectively. Allowing for skewness in the frequency of hospitalizations by using the negative binomial generalized linear model, the rate ratio (eplerenone versus placebo) was 0.53 (95% confidence interval, 0.42–0.66; P<0.0001). A plot of cumulative hospitalization rates over time revealed that most of the reduced risk on eplerenone occurred in the first year of follow-up. Several baseline variables strongly predicted the risk of hospitalization. More complex statistical methods, adjusting for mortality (as informative censoring), made a negligible difference in these findings. Conclusions— Eplerenone markedly reduces the risk of heart failure hospitalizations in patients with heart failure and mild symptoms to a greater extent than is captured by only studying the time to first hospitalization. Future clinical trials in heart failure would gain from incorporating repeat hospitalizations into their primary evaluation of treatment effects. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00232180.

The impact of eplerenone at different levels of risk in patients with systolic heart failure and mild symptoms : insight from a novel risk score for prognosis derived from the EMPHASIS-HF trial

AIMS 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. METHODS AND RESULTS 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. CONCLUSION 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.

History of Hypertension and Eplerenone in Patients With Acute Myocardial Infarction Complicated by Heart Failure

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.

Eplerenone and new-onset diabetes in patients with mild heart failure: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)

No studies have examined the effect of mineralocorticoid receptor antagonist therapy on new‐onset diabetes. In addition, though the combination of diabetes and chronic heart failure (CHF) carries a poor prognosis, few studies have examined predictors of new‐onset diabetes in those with CHF.

Clinical Benefit of Eplerenone in Patients with Mild Symptoms of Systolic Heart Failure Already Receiving Optimal Best Practice Background Drug Therapy: Analysis of the EMPHASIS-HF Study

Background—In EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), eplerenone significantly reduced major cardiovascular events versus placebo in 2737 patients with mild symptoms of heart failure and an ejection fraction of <35%, in addition to recommended therapy. However, it is not known whether such benefits were preserved in patients receiving optimal background drug therapy, that is, high doses of angiotensin-converting enzyme inhibitor (ACEi, or angiotensin receptor blocker), &bgr;-blocker, or both drug classes. Methods and Results—We further analyzed EMPHASIS-HF according to the use and dose of these background drug classes. Patients receiving ≥50% of target dose were considered to be receiving high doses; patients on <50% or no drug comprised the low-dose group. The primary end point of the study (cardiovascular death/heart failure hospitalization), as well as all-cause mortality, was evaluated in this way. The beneficial clinical effects of eplerenone (as observed in the main study) were preserved for the EMPHASIS-HF primary end point in patients receiving higher doses of ACEi or angiotensin receptor blocker, &bgr;-blocker, or both (hazard ratio for eplerenone versus placebo, ACEi/angiotensin receptor blocker: high dose, 0.67; low dose, 0.65; &bgr;-blockers: high dose, 0.55; low dose, 0.72; both ACEi/angiotensin receptor blocker and &bgr;-blocker: high dose, 0.59; low dose, 0.68; P value for interaction 0.80, 0.15, and 0.53, respectively), as well as for all-cause mortality. There were no major safety issues, except a borderline increased risk of hypotension with eplerenone in those on high-dose ACEi or ACEi/&bgr;-blocker. Conclusions—Eplerenone provides substantial benefit on major events (with an acceptable safety profile) in patients with mild symptoms of systolic heart failure, even in those already receiving high doses of standard background therapies. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00232180.