ORIGINAL ARTICLE
Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms
November 14, 2010 (10.1056/NEJMoa1009492)
- Abstract
- Article
- References
- The activation of mineralocorticoid receptors by aldosterone and cortisol has deleterious effects in patients with cardiovascular disease.1 In the placebo-controlled Randomized Aldactone Evaluation Study (RALES),2 adding the mineralocorticoid-receptor antagonist spironolactone to recommended therapy in patients with systolic heart failure and moderate-to-severe symptoms (i.e., New York Heart Association [NYHA] functional class III or IV symptoms) decreased the rate of death from any cause and the risk of hospitalization for cardiovascular reasons. In the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),3 the selective mineralocorticoid-receptor antagonist eplerenone, added to recommended medical therapy, reduced the rates of death from any cause and hospitalization for cardiovascular reasons among patients with acute myocardial infarction complicated by left ventricular systolic dysfunction and heart failure. Consequently, current guidelines recommend the use of a mineralocorticoid-receptor antagonist in these patients.4,5The aim of our Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) was to investigate the effects of eplerenone, added to evidence-based therapy, on clinical outcomes in patients with systolic heart failure and mild symptoms (i.e., NYHA functional class II symptoms).6
METHODS
Study Oversight
The executive steering committee (see the Supplementary Appendix, available with the full text of this article at NEJM.org) designed and oversaw the conduct of the trial and data analysis in collaboration with representatives of the study sponsor (Pfizer). The trial was monitored by an independent data and safety monitoring committee. Data were collected, managed, and analyzed by the sponsor according to a predefined statistical analysis plan, and the analyses were replicated by an independent academic statistician. The manuscript was prepared by an academic writing group, whose members had unrestricted access to the data, and was subsequently revised by all the authors. All the authors made the decision to submit the manuscript for publication and assume responsibility for the accuracy and completeness of the data and analyses.Study Patients
The design of the EMPHASIS-HF trial has been published in detail,6 and the trial protocol and statistical analysis plan are available at NEJM.org. The trial was approved by each center's ethics committee. All patients provided written informed consent.Eligibility criteria were as follows: an age of at least 55 years, NYHA functional class II symptoms, an ejection fraction of no more than 30% (or, if >30 to 35%, a QRS duration of >130 msec on electrocardiography), and treatment with an angiotensin-converting–enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), or both and a beta-blocker (unless contraindicated) at the recommended dose or maximal tolerated dose.Randomization was to occur within 6 months after hospitalization for a cardiovascular reason. Patients who had not been hospitalized for a cardiovascular reason within 6 months before the screening visit could be enrolled if the plasma level of B-type natriuretic peptide (BNP) was at least 250 pg per milliliter or if the plasma level of N-terminal pro-BNP was at least 500 pg per milliliter in men and 750 pg per milliliter in women.Key exclusion criteria were acute myocardial infarction, NYHA class III or IV heart failure, a serum potassium level exceeding 5.0 mmol per liter, an estimated glomerular filtration rate (GFR) of less than 30 ml per minute per 1.73 m2 of body-surface area, a need for a potassium-sparing diuretic, and any other clinically significant, coexisting condition.Study Procedures
We used a computerized randomization system involving concealed study-group assignments to randomly assign patients to receive eplerenone (Inspra, Pfizer) or matching placebo. Eplerenone was started at a dose of 25 mg once daily and was increased after 4 weeks to 50 mg once daily (or started at 25 mg on alternate days, and increased to 25 mg daily, if the estimated GFR was 30 to 49 ml per minute per 1.73 m2), provided the serum potassium level was no more than 5.0 mmol per liter.Thereafter, investigators evaluated patients every 4 months and were instructed to decrease the dose of the study drug if the serum potassium level was 5.5 to 5.9 mmol per liter and to withhold the study drug if the serum potassium level was 6.0 mmol per liter or more. Potassium was to be remeasured within 72 hours after the dose reduction or study-drug withdrawal, and the study drug was to be restarted only if the level was below 5.0 mmol per liter.Study Outcomes
The primary outcome was a composite of death from cardiovascular causes or a first hospitalization for heart failure. The prespecified adjudicated secondary outcomes were hospitalization for heart failure or death from any cause, death from any cause, death from cardiovascular causes, hospitalization for any reason, and hospitalization for heart failure, among others (listed in Table 2TABLE 2Primary Outcome, Component Events, and Key Secondary Outcomes.). Adjudication of the outcomes was carried out by an independent committee (see the Supplementary Appendix) according to prespecified criteria.
Statistical Analysis
The initial assumptions were that, with 2584 patients and an annual event rate of 18% in the placebo group (based on data from a subgroup analysis of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity–Added trial [CHARM-Added; ClinicalTrials.gov number, NCT00634309]),7 our trial would require 813 patients with a primary outcome occurring within 48 months to achieve 80% power to detect an 18% relative reduction in the risk of the primary outcome in the eplerenone group as compared with the placebo group (with a two-sided alpha of 0.05). Because the overall blinded event rate was lower than expected, the sample size was increased to 3100 patients, according to a protocol amendment adopted in June 2009.The data and safety monitoring committee's charter specified interim analyses of the primary outcome after approximately 271 and 542 events had occurred, with a statistical stopping guideline for an overwhelming benefit (two-sided P<0.001 in favor of eplerenone). On May 6, 2010, after the second interim analysis, the data and safety monitoring committee reported to the executive committee chairs that the prespecified stopping boundary for an overwhelming benefit had been crossed. The full executive committee was informed, decided to stop the trial, and notified the sponsor of this decision on May 9, 2010. Operationally, May 25, 2010, was chosen as the trial cutoff date for all efficacy and safety analyses reported here.Comparability of baseline characteristics between the two study groups was assessed by means of a two-sample t-test, for continuous variables, or Fisher's exact test, for categorical variables. The analyses of the adjudicated primary and secondary outcomes were conducted on data from all patients who had undergone randomization, according to the intention-to-treat principle, with the use of Kaplan–Meier estimates and Cox proportional-hazards models. Hazard ratios, 95% confidence intervals, and P values were calculated with the use of models adjusted for the following prespecified baseline prognostic factors: age, estimated GFR, ejection fraction, body-mass index, hemoglobin value, heart rate, systolic blood pressure, diabetes mellitus, history of hypertension, previous myocardial infarction, atrial fibrillation, and left bundle-branch block or QRS duration greater than 130 msec. Sensitivity analyses were also performed, by means of unadjusted Cox models.The consistency of the treatment effect was assessed among 20 prespecified subgroups. The effect in each subgroup was analyzed with the use of a Cox proportional-hazards model, without adjustment for covariates. The treatment-by-subgroup interaction was evaluated by means of a Cox proportional-hazards model with terms for treatment, subgroup, and their interaction.The number of patients who would need to be treated to prevent one primary-outcome event from occurring was determined according to the method of Altman and Andersen.8 Post hoc comparisons between the two groups of the total number of hospitalizations for any reason and for heart failure were performed with the use of a t-test, assuming a Poisson distribution. Serious adverse events, anticipated adverse events, and adverse events leading to permanent study-drug withdrawal were tabulated according to randomized group assignment and analyzed by means of Fisher's exact test.RESULTS
Study Patients
From March 30, 2006, through May 25, 2010, we recruited 2737 patients at 278 centers in 29 countries. Of these patients, 1364 were randomly assigned to eplerenone and 1373 to placebo. The two groups were balanced with respect to baseline characteristics, and all the patients were receiving recommended pharmacologic therapy for systolic heart failure (Table 1TABLE 1Baseline Characteristics of the Patients, According to Study Group.).
A total of 45 patients (3.3%) in the eplerenone group and 51 patients (3.7%) in the placebo group were enrolled on the basis of a QRS duration that was greater than 130 msec (with an ejection fraction >30 to 35%); 195 patients (14.3%) in the eplerenone group and 190 patients (13.8%) in the placebo group were enrolled on the basis of the BNP or N-terminal pro-BNP criterion (with no hospitalization for cardiovascular reasons within the 180 days before screening). Half the patients reported having had a myocardial infarction, but all cases of infarction had occurred more than 30 days before the screening visit.Study-Drug Administration and Follow-up
Eight patients (four in each study group) did not start the study medication and were not included in the safety analysis. After completion of the dose-adjustment phase, at 5 months, 60.2% of patients who had been assigned to receive eplerenone were taking the higher dose (50 mg daily); the corresponding proportion in the placebo group was 65.3%. Among the patients taking the study drug at 5 months, the mean (±SD) doses in the eplerenone and placebo groups, respectively, were 39.1±13.8 mg and 40.8±12.9 mg.At the trial cutoff date, the study drug had been discontinued in 222 patients (16.3%) receiving eplerenone and 228 patients (16.6%) receiving placebo. Among these patients, the median time from randomization to the last dose was 533 days for eplerenone and 494 days for placebo.At the trial cutoff date, 17 patients (1.2%) in the eplerenone group and 15 patients (1.1%) in the placebo group were lost to follow-up. If contact could not be made at the trial cutoff date, the data were censored in the analysis at the time of the last contact. The median duration of follow-up among all patients was 21 months, with 4783 patient-years of follow-up.Study Outcomes
Death from cardiovascular causes or hospitalization for heart failure (the primary outcome) occurred in 249 patients (18.3%) in the eplerenone group and 356 patients (25.9%) in the placebo group (Figure 1AFIGURE 1Cumulative Kaplan–Meier Estimates of Rates of the Primary Outcome and Other Outcomes, According to Study Group. and Table 2). The hazard ratio for the primary outcome in the eplerenone group, as compared with the placebo group, was 0.63 (95% confidence interval [CI], 0.54 to 0.74; P<0.001). The effect of eplerenone on this outcome was consistent in an unadjusted analysis (hazard ratio, 0.66; 95% CI, 0.56 to 0.78; P<0.001) (Table 2). It was also consistent across all prespecified subgroups (Figure 2FIGURE 2
Hazard Ratios for Hospitalization for Heart Failure or Death from Cardiovascular Causes (the Primary Outcome) with Eplerenone versus Placebo, According to Prespecified Subgroups.).
Death from any cause or hospitalization for heart failure occurred in 270 patients (19.8%) in the eplerenone group as compared with 376 patients (27.4%) in the placebo group (hazard ratio, 0.65; 95% CI, 0.55 to 0.76; P<0.001) (Table 2). A total of 171 patients (12.5%) in the eplerenone group and 213 patients (15.5%) in the placebo group died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008) (Figure 1B and Table 2). A total of 147 deaths (10.8%) in the eplerenone group and 185 (13.5%) in the placebo group were attributed to cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01) (Table 2).In the eplerenone group, 408 patients (29.9%) were hospitalized for any reason, as compared with 491 (35.8%) patients in the placebo group (hazard ratio, 0.77; 95% CI, 0.67 to 0.88; P<0.001) (Figure 1C and Table 2). Of the patients receiving eplerenone, 164 (12.0%) were hospitalized for heart failure, as compared with 253 patients (18.4%) receiving placebo (hazard ratio, 0.58; 95% CI, 0.47 to 0.70; P<0.001) (Figure 1D and Table 2). The total number of hospitalizations (including second and subsequent hospitalizations) was also lower in the eplerenone group (750, vs. 961 in the placebo group, for a 24% reduction; P<0.001), as were the total numbers of hospitalizations for cardiovascular reasons (509 vs. 699, for a 29% reduction; P<0.001) and hospitalizations for heart failure (273 vs. 429, for a 38% reduction; P<0.001). Findings for all other prespecified adjudicated secondary outcomes and other outcomes are summarized in Table 2, in which all the results are adjusted for prespecified baseline variables.The estimated number of patients who would need to be treated to prevent one primary outcome from occurring, per year of follow up, was 19 (95% CI, 15 to 27), and the estimated number needed to treat to postpone one death, per year of follow up, was 51 (95% CI, 32 to 180).Safety
During the course of the study, 188 patients (13.8%) receiving eplerenone and 222 patients (16.2%) receiving placebo discontinued the study drug because of an adverse event (P=0.09). Relevant adverse events are summarized in Table 3TABLE 3Selected Investigator-Reported Adverse Events and Those Leading to Permanent Withdrawal of the Study Drug, According to Study Group..
At 1 month, the mean change in serum creatinine level from baseline was 0.15±0.35 mg per deciliter (13.3±30.9 μmol per liter) in the eplerenone group, as compared with 0.07±0.29 mg per deciliter (6.2±25.6 μmol per liter) in the placebo group. At the trial cutoff date, the serum creatinine level had increased from baseline by 0.09±0.37 mg per deciliter (8.0±32.7μmol per liter) and 0.04±0.40 (3.5±35.4 μmol per liter), respectively.At 1 month, the mean change in potassium level from baseline was 0.16±0.51 mmol per liter in the eplerenone group, as compared with 0.04±1.16 mmol per liter in the placebo group (P=0.001). At the trial cutoff date, potassium levels had increased from baseline by 0.16±0.56 and 0.05±0.53 mmol per liter, respectively (P<0.001 for both comparisons). A serum potassium level above 5.5 mmol per liter was reported in 158 of 1336 patients (11.8%) in the eplerenone group and 96 of 1340 patients (7.2%) in the placebo group (P<0.001). A serum potassium level above 6.0 mmol per liter occurred in 33 of 1336 patients (2.5%) in the eplerenone group and 25 of 1340 patients (1.9%) in the placebo group (P=0.29). A serum potassium level below 4.0 mmol per liter was reported in 519 of 1336 patients (38.8%) in the eplerenone group and 648 of 1340 patients (48.4%) in the placebo group (P<0.001). A serum potassium level below 3.5 mmol per liter was reported in 100 of 1336 patients (7.5%) in the eplerenone group and 148 of 1340 patients (11.0%) in the placebo group (P=0.002).Systolic blood pressure decreased during the study period to a greater degree in the eplerenone group, with a mean overall reduction of 2.5±17.9 mm Hg, than in the placebo group, with a reduction of 0.3±17.2 mm Hg (P=0.001). There were no other clinically significant differences between the two groups with respect to laboratory variables, reported adverse events, or adverse events leading to permanent withdrawal of the study drug.DISCUSSION
We evaluated the effect of adding eplerenone to recommended treatment for systolic heart failure in patients with mild symptoms (NYHA functional class II symptoms). The rate of the primary outcome, a composite of death from cardiovascular causes or hospitalization for heart failure, was 18.3% in the eplerenone group versus 25.9% in the placebo group. This effect of eplerenone was consistent across all prespecified subgroups. With eplerenone, there was also a reduction in both the rate of death from any cause and the rate of hospitalization for any reason.The mechanisms by which mineralocorticoid-receptor antagonists such as eplerenone provide cardiovascular protection in patients with heart failure are not completely understood. Activation of the mineralocorticoid receptor by both aldosterone and cortisol plays an important role in the pathophysiology of heart failure,1,9 and mineralocorticoid receptors are overexpressed in the failing heart.10,11 Despite therapy with ACE inhibitors, ARBs, and beta-blockers, patients with even mild heart failure may have persistently elevated plasma aldosterone and cortisol levels.12-17Mineralocorticoid receptors are not blocked by these treatments.Activation of the mineralocorticoid receptor has been shown to promote cardiac fibrosis in experimental models.18 In patients with heart failure,19 as well as in patients after myocardial infarction, the use of mineralocorticoid-receptor antagonists decreases extracellular-matrix turnover, as assessed by measuring serum levels of collagen biomarkers.20,21 Experimental and clinical studies suggest that mineralocorticoid-receptor antagonists favorably affect several other important mechanisms known to have a role in the progression of heart failure.1,15,22,23In our study, as anticipated, there was an increased incidence of hyperkalemia among patients receiving eplerenone. This finding underscores the need to measure serum potassium levels serially and to adjust the dose of eplerenone accordingly. We attempted to minimize the risk of hyperkalemia by excluding patients with a baseline serum potassium level above 5.0 mmol per liter and a baseline estimated GFR below 30 ml per minute per 1.73 m2.In contrast, the risk of hypokalemia was significantly reduced among patients receiving eplerenone. This is important because a serum potassium level below 4.0 mmol per liter has been associated with an increased risk of death from any cause among patients with systolic heart failure.22Our study has some limitations. Our results may not be applicable to all patients with mild symptoms, because to be eligible for the study, patients had to have additional factors known to increase cardiovascular risk, including an age over 55 years, in most cases an ejection fraction of no more than 30%, and a recent hospitalization for a cardiovascular reason. Use of an implantable cardioverter–defibrillator was relatively infrequent, but this finding is similar to those in recent registries and trials.24,25 The early stopping of the trial may have resulted in overestimation of the magnitude of the treatment effect,26 but the results are consistent with those seen in RALES.2In conclusion, our study showed that, as compared with placebo, eplerenone added to recommended therapy for systolic heart failure in patients with mild symptoms was associated with a reduction in the rate of death from a cardiovascular cause or hospitalization for heart failure. Similar reductions were seen in rates of death from any cause, death from cardiovascular causes, hospitalization for any reason, and hospitalization for heart failure.This article (10.1056/NEJMoa1009492) was published on November 14, 2010, at NEJM.org.Supported by Pfizer.Dr. Zannad reports receiving fees for serving on the board of Boston Scientific, consulting fees from Novartis, Takeda, AstraZeneca, Boehringer Ingelheim, GE Healthcare, Relypsa, Servier, Boston Scientific, Bayer, Johnson & Johnson, and Resmed, and speaker's fees from Pfizer and AstraZeneca and that his institution receives grant support from BG Medicine and Roche Diagnostics on his behalf. Dr. McMurray reports receiving grant support from the Eugene Braunwald Endowment for the Advancement of Cardiovascular Discovery and Care. Dr. Krum reports receiving travel reimbursements from Pfizer. Mr. Shi and Dr. Vincent report being employees of Pfizer and receiving stock options and travel reimbursements from Pfizer. Dr. Pocock reports receiving consulting fees from Servier, Amgen, AstraZeneca, and Novartis and that his institution receives grants from Servier and AstraZeneca on his behalf. Dr. Pitt reports receiving fees for serving on the board of Novartis, consulting fees from Takeda, AstraZeneca, Boehringer Ingelheim, GE Healthcare, Relypsa, BG Medicine, Nile Therapeutics, Merck, Forest Laboratories, and Novartis, grant support from Forest Laboratories and Novartis, and stock options from Relypsa, BG Medicine, Nile Therapeutics, and Aurasenc and that his institution receives grant support from Forest Laboratories on his behalf and he and his institution receive grant support from Bayer. No other potential conflict of interest relevant to this article was reported.Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.SOURCE INFORMATION
From INSERM, Centre d'Investigation Clinique 9501 and Unité 961, Centre Hospitalier Universitaire, and the Department of Cardiology, Nancy University, Nancy, France (F.Z.); the British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.); the Department of Epidemiology and Preventive Medicine, Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); the Department of Cardiology, Thorax Center, University Medical Center, Groningen, the Netherlands (D.J.V.); the Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (K.S.); Pfizer, New York (H.S., J.V.); the Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London (S.J.P.); and University of Michigan School of Medicine, Ann Arbor (B.P.).Address reprint requests to Dr. Zannad at the Clinical Investigation Center, INSERM, Institut Lorrain du Coeur et des Vaisseaux, F-54500, Vandoeuvre-lès-Nancy, Nancy, France, or at f.zannad@chu-nancy.fr.Members of the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) study group are listed in the Supplementary Appendix, available at NEJM.org.This article is dedicated to the memory of Dr. Helmut Drexler (deceased), who was a member of the EMPHASIS-HF Executive Committee.Para acceder al documento en formato pdf, pincha el siguiente link:
