Serum Potassium and Clinical Outcomes in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)
Background— 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).
Methods and Results— Hospitalized patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction (left ventricular ejection fraction ≤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+ ≥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 ≥6.0 mEq/L) were identified: potassium (K+ greater than the median; 4.3 mEq/L), estimated glomerular filtration rate (≤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.
Conclusions— 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 (≥6.0 mEq/L) when periodic monitoring of serum K+ is instituted.
Received March 11, 2008; accepted July 9, 2008.
In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), the selective aldosterone blocker eplerenone significantly reduced all-cause mortality (15%; P=0.008) and cardiovascular mortality or hospitalization (13%; P=0.002) when used in addition to standard therapy in patients with left ventricular systolic dysfunction, left ventricular ejection fraction ≤40%, and heart failure (HF) after acute myocardial infarction (AMI).1 Additionally, it reduced hospitalization for HF (15%; P=0.03) and sudden cardiac death (21%; P=0.03). This therapeutic strategy has since been adopted into both US2 and European3 guidelines as a class I recommendation for the treatment of post-AMI HF. Many clinicians, however, are hesitant to use this strategy because they fear inducing hyperkalemia and associated complications. This reluctance is attributable at least in part to recent reports of excessive hyperkalemia observed in clinical practice with the use of spironolactone in HF patients.4–6 We therefore examined the relationship between serum K+ and clinical outcomes in EPHESUS to gain further insight into the predictors and risks of hyperkalemia associated with the use of eplerenone in patients with left ventricular systolic dysfunction and HF after AMI.
Editorial p 1609
Clinical Perspective p 1650
EPHESUS Study Design and Patients
The design and main findings of the EPHESUS study have been described in detail elsewhere.1,7 Briefly, EPHESUS was a multicenter, international, randomized, double-blind, placebo-controlled trial. Patients who met the eligibility criteria were randomized 3 to 14 days after AMI to receive eplerenone (n=3319) or placebo (n=3313) in addition to standard medical therapy, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers and β-blockers. The initial dose of eplerenone was 25 mg/d, which was titrated to a maximum of 50 mg/d after 4 weeks if serum K+ was <5.0 mEq/L. Dosage reductions or discontinuations were specified for serum K+ levels above 5.5 mEq/L during the trial, with reinstitution of therapy when K+ levels fell below 5.5 mEq/L (Table 1).1 All end points were adjudicated by a blinded, independent panel.
Eligibility criteria included AMI as documented by standard criteria; left ventricular systolic dysfunction as documented by left ventricular ejection fraction ≤40% on left ventricular angiography, echocardiography, or radionuclide angiography; and HF as documented by presence of pulmonary rales, chest radiography showing pulmonary venous congestion, or presence of a third heart sound. The evidence of left ventricular systolic dysfunction or HF could have been transient, occurring at any time after the index AMI before randomization. Post-AMI patients with diabetes mellitus were required to have left ventricular ejection fraction ≤40% for study inclusion; clinical signs of HF were not necessary in these patients. Patients were excluded from the study if baseline serum K+ was >5.0 mEq/L or serum creatinine was >2.5 mg/dL. The purpose of the present analysis of EPHESUS was to examine (1) the impact of eplerenone on serum K+; (2) the association of baseline characteristics with the development of hyperkalemia at 2 assigned values, >5.5 mEq/L and ≥6.0 mEq/L; and (3) the impact of hyperkalemia (≥6.0 mEq/L) on clinical outcomes.
In EPHESUS, the incidences of serum K+ <3.5 mEq/L, serum K+ >5.5 mEq/L, and serum K+ ≥6.0 mEq/L were assessed by ANCOVA, with the baseline value as the covariate. The mean time (in days) to (1) maximum serum K+ concentration in all EPHESUS patients and (2) serum K+ ≥6.0 mEq/L in patients experiencing hyperkalemia was calculated in the eplerenone and placebo groups, with between-group differences assessed with the t test.
To identify predictors of hyperkalemia in EPHESUS, a stepwise logistic regression was performed on a number of baseline binary variables (Table 2). A significance level of 0.01 was used to enter and stay in the regression model. The present analysis also included the following covariates: age; body mass index; days from index AMI to randomization; left ventricular ejection fraction after the index AMI; and baseline values for systolic and diastolic blood pressure, heart rate, serum K+, serum sodium, serum creatinine, and estimated glomerular filtration rate (eGFR). The National Kidney Foundation recognizes glomerular filtration rate as the best measure of overall kidney function and has set a cutoff point of <60 · min−1 · 1.73 m−2, below which the prevalence of complications of chronic kidney disease increase.8 Glomerular filtration rate estimates in the present study were performed in accordance with the 4-variable equation from the Modification of Diet in Renal Disease study.9
The relationship between changes in serum K+ concentrations and overall mortality in the first 30 days after randomization was assessed by 2 methods. First, mortality in patients with larger changes in serum K+ concentration (a change greater than the median value) was compared with those with smaller changes in serum K+ (a change smaller than the median value). The analysis was based on the time to the first occurrence of the event and was performed with a proportional hazards model stratified by region with treatment, subgroup, and treatment-by-subgroup interactions as factors. Second, mortality was analyzed by quartile of K+ changes. Mortality rates were compared with a χ2 test.
The overall impact of eplerenone on mortality by the end of the study under 2 “worst-case” scenarios for hyperkalemia (≥6.0 mEq/L) was assessed as a means of detecting the potential causality of drug-induced hyperkalemia on death not identified by the adjudication process. In the first scenario, it was assumed that in addition to all deaths attributed to hyperkalemia by the independent committee, the worst case would be if all sudden cardiac deaths were also due to increased serum K+. In the second scenario, it was assumed that in addition to all deaths attributed to hyperkalemia by the independent committee, all sudden cardiac deaths and all deaths due to unknown causes were also due to increased serum K+. A proportional hazards model was used with treatment and region as factors, and a log-rank test was used for equality of time-to-event distribution stratified by region.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Baseline characteristics were similar between treatment groups (Table 3). Significantly more eplerenone-treated patients had serum K+ >5.5 mEq/L (15.6% versus 11.2%, P<0.001) and serum K+ ≥6.0 mEq/L (5.4% versus 3.8%, P=0.002) than the placebo group (Figure 1); however, hypokalemia (<3.5 mEq/L) was significantly less frequent in the eplerenone group (8.4% versus 13.1%, P<0.001; Figure 1). Withdrawal from the study because of hyperkalemia was <1% in both treatment groups (placebo 0.3%, eplerenone 0.7%; P≤0.05).
Time to Hyperkalemia
The mean time to reach maximum serum K+ values after randomization was similar in both the eplerenone- and placebo-treated patients (mean [SE] 168 [3.4] days for eplerenone versus 159 [3.4] days for placebo; P=0.058). The maximum values occurred within 90 days of study in 59% of eplerenone-treated patients and in 62% of placebo-treated patients. Figure 2 illustrates time to maximum K+ values for all EPHESUS patients by treatment group. Figure 3 shows the time to reach the first occurrence of serum K+ ≥6.0 mEq/L in eplerenone- and placebo-treated patients for any patients who experienced this level of serum K+ at any time during the study.
Predictors of Hyperkalemia
Stepwise logistic regression identified 4 independent predictors of serum K+ ≥6.0 mEq/L in both eplerenone- and placebo-treated patients: (1) eGFR <60 · min−1 · 1.73 m−2, (2) history of diabetes mellitus, (3) elevated baseline serum K+ (greater than the median value of 4.3 mEq/L), and (4) prior use of antiarrhythmics. The rates of hyperkalemia (serum K+ ≥6.0 mEq/L) in these subgroups generally reflect those seen in the overall population.
Further analyses demonstrated that the presence of these 4 independent risk factors for hyperkalemia (serum K+ ≥6.0 mEq/L) did not detract from the cardiovascular benefit of eplerenone (treatment interaction for eplerenone versus all-cause mortality: eGFR P=0.128; diabetes mellitus P=0.347; K+ P=0.289; antiarrhythmic drug use P=0.936). Moreover, these 4 risk factors had no significant interaction with the efficacy of eplerenone in reducing all-cause mortality, cardiovascular death, or sudden cardiac death (Table 4). These findings were consistent for serum K+ >5.5 mEq/L.
When the incidence of hyperkalemia was analyzed according to eGFR, lower eGFR values were associated with numerically higher rates of hyperkalemia in both the placebo and eplerenone groups. Larger differences in the incidence of hyperkalemia were observed between the treatment groups only in patients with eGFR <60 · min−1 · 1.73 m−2 (Table 5).
Hyperkalemia and Mortality
Effect of Potassium Changes on All-Cause Mortality at 30 Days
The median change in serum K+ from baseline to day 30 was 0.2 mEq/L for both treatment groups combined. Of the patients who died in the first 30 days, 41% (106/260) had a change in serum K+ that was less than the median, and 43% (111/260) had a change in serum K+ that was greater than the median (the remaining 16% did not have data on the change in K+). Among those with a serum K+ change less than the median, 3.8% of patients in the placebo group and 2.9% in the eplerenone group died (relative risk 0.813, P=0.32). The corresponding values for patients with a serum K+ change above the median were 4.2% and 2.5%, respectively (relative risk 0.84, P=0.39). When all-cause mortality rates were evaluated by quartiles of K+ changes, no indication was found that serum K+ changes in the first 30 days had any significant effect on all-cause mortality (P=0.11; Table 6).
Adjudication and Worst-Case Scenarios
In the entire study population, 1 death was adjudicated to hyperkalemia, and this death occurred in the placebo group. Worst-case scenarios, which were developed to find any association between K+-related mortality and eplerenone that may have been missed by the adjudication process, did not show any increased risk of death with the use of eplerenone. Mortality risk was significantly lower for eplerenone versus placebo, respectively, under worst-case assumption 1 (all deaths attributed to hyperkalemia by the independent committee and all sudden cardiac deaths were assumed to be due to increased serum K+; 4.9% versus 6.1%; P=0.022) and assumption 2 (all deaths attributed to hyperkalemia by the independent committee, all sudden cardiac deaths, and all deaths due to unknown causes were assumed to be due to increased serum K+; 5.3% versus 6.6%; P=0.016).
These post hoc analyses demonstrate that the selective aldosterone blocker eplerenone, when administered at a dose of 25 to 50 mg/d, is associated with a 4.4% absolute increase in the incidence of hyperkalemia (>5.5 mEq/L) and a 1.6% absolute increase in the incidence of more marked hyperkalemia (≥6.0 mEq/L). The major predictors of hyperkalemia (≥6.0 mEq/L) in the present study population, in which >80% of patients were administered either an ACE inhibitor or an angiotensin receptor blocker and 75% were administered a β-blocker, were an eGFR <60 · min−1 · 1.73 m−2, a baseline serum K+ above the median (4.3 mEq/L), the presence of diabetes mellitus, and prior use of antiarrhythmic drugs. Antiarrhythmic drug use was an unexpected risk factor. Although the use of an ACE inhibitor or an angiotensin receptor blocker in combination with an aldosterone blocker has previously been shown to increase the risk of hyperkalemia in similar patients,10,11 in the present analysis, the use of these agents in addition to eplerenone did not contribute to the risk independent of elevated baseline serum K+, low eGFR, or the presence of diabetes mellitus. Similarly, the use of a diuretic did not independently affect the risk for hyperkalemia (≥6.0 mEq/L) or the effectiveness of eplerenone in reducing either of the primary end points, all-cause mortality and the composite of cardiovascular mortality/cardiovascular hospitalization. Approximately one half of the episodes of hyperkalemia (≥6.0 mEq/L) occurred within 30 days of initiation of therapy, although sporadic episodes of hyperkalemia were observed throughout the 2-year follow-up period (Figure 3), which likely reflects changes in renal function or the use of pharmacological agents that affect K+ excretion, such as nonsteroidal antiinflammatory drugs. Overall, less than 1% of patients who were randomized to eplerenone had to discontinue therapy because of hyperkalemia. No relationship was found between either baseline serum K+ or the change in serum K+ from baseline and the benefit of eplerenone on all-cause mortality overall or in any subgroup, including those at risk for developing hyperkalemia.
Similar to the results from the Randomized Aldactone Evaluation Study (RALES) of spironolactone in patients with chronic severe HF due to left ventricular systolic dysfunction,12 no death was attributable to hyperkalemia in patients randomized to eplerenone in EPHESUS. These experiences in clinical trials contrast with several reports of serious hyperkalemia in patients given spironolactone for chronic HF in clinical practice, some of which were associated with increased hospital admissions and death.4–6,13,14 The occurrence of hyperkalemia in these trials may have been related to the higher doses used than what had been studied previously in the reference trials, EPHESUS and RALES. In clinical practice, patients are often older than in randomized trials such as EPHESUS and RALES and may have a reduced eGFR that is not reflected by serum creatinine. (Serum creatinine is an inaccurate metric of true of kidney function in the elderly.) Such patients may be given an aldosterone blocker regardless of baseline serum K+, serum creatinine, or estimated renal function. For example, in 1 report on the use of spironolactone in patients with chronic HF, a 15% incidence of hyperkalemia was found.6 However, in one third of these patients, no single measurement of serum K+ or creatinine occurred within the first 3 months of initiation of spironolactone. The lower incidence and risk of hyperkalemia associated with aldosterone blockade with eplerenone in EPHESUS and with spironolactone in RALES compared with that observed in clinical practice can be attributed to the fact that patients were excluded from randomization to the aldosterone blocker if they had a baseline serum K+ >5.0 mEq/L, a serum creatinine >2.5 mg/dL, or both in these clinical trials. Furthermore, in both EPHESUS and RALES, serum K+ was measured within 1 week of starting the aldosterone blocker and again at 4 weeks, as well as every 3 to 6 months thereafter. In addition to periodic K+ monitoring, it is recommended that whenever a change in electrolyte status is suspected, such as during an episode of vomiting or diarrhea or at initiation or dosage adjustment of concomitant diuretic therapy, serum K+ should be remeasured or the aldosterone blocker withheld until measurement of serum K+ is possible. The dose of aldosterone blocker should be adjusted according to serum K+ measurements as follows: The dose of the aldosterone blocker should be halved if serum K+ is >5.5 mEq/L, and if serum K+ is ≥6.0 mEq/L in a nonhemolyzed sample, the aldosterone blocker should be discontinued until serum K+ falls below 5.5 mEq/L (Table 1).1,12
Patients with risk factors for hyperkalemia, such as those with renal dysfunction or diabetes mellitus, may benefit by more frequent monitoring of serum K+. A recent study has suggested that the risk of hyperkalemia associated with aldosterone blockade in patients with HF and renal dysfunction, defined as creatinine clearance <60 mL/min, can be managed safely by the use of a low-K+ diet, adjustment of the dose of aldosterone blocker to renal function, and careful monitoring of serum K+.15 In the present small study, no deaths or hospitalizations related to hyperkalemia occurred. Although in EPHESUS and RALES, exclusion criteria were based on serum creatinine, serum creatinine may not adequately reflect renal function in the elderly, and one should determine an eGFR for these patients.
A recent subanalysis from EPHESUS16 showed that although the benefit of eplerenone on all-cause mortality decreased with worsening levels of kidney function, no evidence was found of an increased risk of all-cause mortality even in patients with stage 4 nephropathy (ie, creatinine clearance ≤30 mL/min). Moreover, in the present analysis, no significant interaction of eGFR with the ability of eplerenone to reduce all-cause mortality was present, with a hazard ratio of 0.52 for eplerenone compared with placebo in patients with eGFR <60 · min−1 · 1.73 m−2 (P for interaction=0.13). This suggests that eplerenone can be used safely in patients with this degree of renal dysfunction provided they are monitored appropriately, as was done in the present trial.
Although we recommend discontinuing an aldosterone blocker in patients with serum K+ ≥6.0 mEq/L, recent studies have pointed out that serum K+ may not accurately reflect tissue K+ in patients with HF. For example, patients with HF have been found to have a serum K+ >7.0 mEq/L without any ECG changes or clinical manifestations of hyperkalemia because their tissue K+ was normal or low, as reflected by the red blood cell K+ concentration.17 In patients with HF, an increase in oxidative stress may result in a defect in Na/K ATPase and transport of K+ into tissues.
In EPHESUS, a significant absolute decrease of 4.7% was found in the incidence of hypokalemia (serum K+ <3.5 mEq/L), and the incidence of hypokalemia was greater than that of hyperkalemia (serum K+ ≥6.0 mEq/L; Figure 1). Although many clinicians become concerned about the risk of hypokalemia only when serum K+ <3.5 mEq/L, a recent analysis of the National Heart, Lung, and Blood Institute’s Digitalis Investigation Group trial showed an increased risk of both sudden cardiac death and progressive HF in patients with a serum K+ <4.5 mEq/L regardless of the use of K+ supplements.18 This relationship of decreased serum K+ (<4.4 mEq/L) as an independent predictor of sudden cardiac death in patients with HF has been demonstrated previously in other studies,19 and thus, it has been suggested that serum K+ should be maintained between 4.5 and 5.5 mEq/L in patients with HF.20 As mentioned previously, patients with HF may have difficulty in transporting K+ into the tissues, and therefore, tissue levels of K+ may be considerably less than serum levels, which would place them at increased risk for myocardial fibrosis, hypertrophy, and sudden cardiac death. However, although eplerenone reduced the incidence of hypokalemia (<3.5 mEq/L), no significant relationship was found between the change in serum K+ from baseline and the effectiveness of eplerenone in reducing total mortality in the present study.
In conclusion, these results demonstrate a beneficial effect of eplerenone on all-cause mortality regardless of baseline risk factors for the development of hyperkalemia (≥6.0 mEq/L). However, to obtain this beneficial effect on mortality, it is necessary to ensure the safe use of the agent, which involves measuring both serum K+ and either eGFR or estimated creatinine clearance before therapy is instituted; excluding patients with serum K+ greater than 5.0 mEq/L, serum creatinine >2.5 mg/dL, and/or an estimated creatinine clearance ≤30 mL/min or below; periodically monitoring serum K+; and adjusting the dose of eplerenone as necessary, according to serum K+ and changes in renal function. This view is reflected in major therapeutic guidelines in the United States2 and Europe,3 which, based on the results from EPHESUS, recommend that all eligible post-AMI patients with concomitant HF be treated with an aldosterone blocker in addition to an ACE inhibitor (or an angiotensin receptor blocker) and a β-blocker.
Sources of Funding
This subanalysis of EPHESUS was funded by Pfizer Inc. Editorial support was provided by Mark Poirier of PAREXEL and was funded by Pfizer Inc.
Dr Pitt is a consultant for Pfizer Inc. Dr Ruilope has served as a consultant for Pfizer Inc. Drs DiCarlo and Robin Mukherjee are employees of Pfizer Inc.
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Aldosterone blockade is effective in reducing all-cause mortality in patients after myocardial infarction complicated by left ventricular dysfunction and heart failure. The use of aldosterone blockade in these patients has been recognized as a class 1 indication in both US and European guidelines; however, many clinicians have been reluctant to adopt this strategy because of the fear of inducing serious hyperkalemia (K+ ≥6.0 mEq/L). We analyzed the relationship between serum K+ and clinical outcomes in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) and found a 1.6% absolute increase in serious hyperkalemia and a 4.7% absolute decrease in hypokalemia (K+ <3.5 mEq/L). The baseline predictors of serious hyperkalemia were a K+ level >4.3 mEq/L; an estimated glomerular filtration rate ≤60 mL · min−1 · 1.73 m−2; a history of diabetes mellitus; and prior use of antiarrhythmic agents. No relationship was found between either baseline serum K+ or change in serum K+ from baseline and the benefit of eplerenone on all-cause mortality, even in those at risk of developing hyperkalemia. These data support the further use of aldosterone blockade with eplerenone at a dose of 25 to 50 mg/d early after myocardial infarction in patients with left ventricular dysfunction and heart failure who are treated with standard therapy when periodic monitoring of serum K+ is instituted and when patients with a baseline serum K+ level >5.0 mEq/L, a creatinine level >2.5 mg/dL, or an estimated glomerular filtration rate <30 mL · min−1 · 1.73 m−2 are excluded.
Clinical trial registration information—URL: http://www.clinicalstudyresults.org. Unique identifier: IE3-99-02-035.