Saturday, June 10, 2023
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Presenter: Bertram Pitt, MD (University of Michigan, Ann Arbor)
The results of the EPHESUS (Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trial, presented by Bertram Pitt, MD, at the 2003 American College of Cardiology (ACC) meeting in Chicago and published simultaneously in TheNew England Journal of Medicine,[1] were hailed as a new advance in the treatment of patients with myocardial infarction (MI) and heart failure. EPHESUS demonstrated that treatment with the selective aldosterone blocker, eplerenone (Inspra; Pharmacia), in patients with systolic left ventricular dysfunction (SLVD) and heart failure post-MI had a 15% relative risk reduction in all-cause mortality and a 13% relative risk reduction in cardiovascular mortality/cardiovascular complications compared with patients on current standard therapy.
Current evidence-based, guideline-mandated therapy for patients with acute MI (AMI) complicated with SLVD and heart failure post-MI is based on angiotensin-converting enzyme (ACE) inhibition and beta-blockade. Unfortunately, mortality/morbidity in these patients remains high, even when treated to standard. Recent strategies to further reduce mortality/morbidity in these patients -- such as tumor necrosis factor (TNF)-antibodies, endothelin antagonists, vasopeptidase inhibitors, and even angiotensin receptor blockers (ARBs), on top of ACE inhibitors and beta-blockers -- have not been proven effective in clinical trials. On the other hand, blockade of aldosterone with the nonselective aldosterone antagonist, spironolactone, was shown to reduce mortality/morbidity in patients with severe chronic heart failure due to SLVD in the RALES (Randomized Aldactone Evaluation Study) trial,[2] and this much-noted result led investigators to hypothesize that blockade of aldosterone with a more selective antagonist, eg, eplerenone, would reduce mortality/morbidity in patients with SLVD and heart failure post-AMI who were being treated with current "standard of care" therapy.
EPHESUS was an international trial carried out at 674 centers in 37 countries in patients with AMI, moderate LV dysfunction (LV ejection fraction ≤ 40%), and pulmonary rales (unless the patient had diabetes, in which case the requirement for rales was omitted). Patients with serum creatinine > 2.5 mg/dL or serum potassium > 5.0 mmol/L were excluded from the study.
Over 2 years, a total of 6642 patients were randomized 3-14 days after AMI to either eplerenone 25 mg/day or to matching placebo for 4 weeks, after which the doses of eplerenone were titrated to a target of 50 mg/day. An important component of the trial was that the trial drug was to be administered on top of optimal therapy, defined as ACE inhibitors or ARBs, beta-blockers, diuretics, and possible coronary reperfusion therapy.
The 2 primary endpoints were (1) death from any cause and (2) combined death from cardiovascular causes, or hospitalization for heart failure, AMI, stroke, or ventricular arrhythmia. Secondary endpoints included death from cardiovascular causes and death from any cause or any hospitalization. The study was stopped in August 2002, when the projected 1012 deaths had been reached, and unblinded the following December.
There were no significant differences in baseline patient characteristics between the placebo and eplerenone groups: mean age was 64 years, 71% were male, 90% were Caucasian, mean ejection fraction was 33%, and the mean time from onset of infarction was 7.3 days.
Per trial design, most patients were receiving optimal therapy for AMI complicated by LV dysfunction and heart failure: ACE inhibitors or ARBs (87%), beta-blockers (75%), diuretics (60%), and aspirin (88%). A number were also on statins, digitalis, and standard potassium supplements. About 45% of patients had undergone revascularization. The mean dose of eplerenone was 43 mg, and the mean patient follow-up time was 16 months (range, 0-33 months).
At 1 year, patients randomized to eplerenone had a significantly smaller rise in blood pressure compared with those on placebo and experienced no drop in blood pressure; most patients had a small but significant increase in both serum potassium and serum creatinine (Table 1). There was no significant increase in body weight.
Effects Placebo Eplerenone P Blood pressure (mm Hg) +8/4 +5/3 < .01 Heart rate (bpm) -6 -7 .32 Serum potassium (mmol/L) +0.2 +0.3 < .001 Serum creatinine (mg/dL) +0.02 +0.06 < .001
In the eplerenone group, statistically significant reductions were seen in both primary endpoints, with 15% reduction in total all-cause mortality and 13% fewer cardiovascular-related deaths and cardiovascular hospitalizations compared with the placebo group (Table 2).
Endpoints Eplerenone (%) Placebo
(%)Relative Risk
(95% CI)P Death from any cause* 478 (14.4) 554
(16.7)0.85
(0.78-0.96).008 Death from CV cause or hospitalization for CV events* 885 (26.7) 993
(30.0)0.87
(0.79-0.95).002 Death from cardiovascular causes 407 (12.3) 483
(14.6)0.83
(0.82-0.94).005
*Primary endpoints.
There was also a significant 17% reduction in deaths attributed to cardiovascular causes. The main cause of cardiovascular hospitalization was heart failure, which showed a 15% reduction in the eplerenone group (P < .05), and 23% fewer episodes of hospitalization for heart failure (P < .002) were seen in the eplerenone group compared with the placebo group.
Dr. Pitt noted that the earlier RALES trial with the nonselective aldosterone antagonist spironolactone had shown greater reductions -- 30% reduction in total mortality and 35% reduction in hospitalizations -- but the more moderate effects seen with the selective antagonist eplerenone may have been due to several factors, including a far greater use of beta-blockers (75% vs 11%) and a higher baseline LV ejection fraction (33% vs 25%) in the EPHESUS vs the RALES populations, respectively.
The effect of eplerenone was consistent over a number of predefined subgroups, but was particularly strong in patients on "recommended therapy," ie, ACE inhibitor/ARB and beta-blockade, who showed a 27% reduction in all-cause mortality (P < .004). Patients who received eplerenone on top of "optimal therapy" -- ie, an ACE inhibitor/ARB plus a beta-blocker, plus aspirin, and a statin, and who had undergone coronary reperfusion -- had a 26% reduction in all-cause mortality.
A small but significant increase was seen in minor gastrointestinal (GI) disorders with eplerenone, but importantly, in contrast to previous experience with the nonselective antagonist spironolactone, there was no increase in menstrual disorders, gynecomastia, or impotence (Table 3). A small but significant decrease seen in respiratory disorders probably reflected the effectiveness of eplerenone in heart failure, and a small but significant increase in metabolic disorders was probably attributable to significant reductions in hypokalemia and hypoglycemia.
Adverse Event Eplerenone (%) Placebo (%) P GI disorder 659 (19.9) 583 (17.7) .02 Menstrual disorder 0.4% 0.4% 1.0 Gynecomastia 12 (0.5) 14.0 (0.6) .70 Impotence 21 (0.9) 20 (0.9) 1.0 Respiratory disorder 729 (22.0) 803 (24.3) .03 Metabolic disorder
Hyperkalemia
Serious hyperkalemia*
Hypokalemia
Serious hypokalemia†568 (17.2)
113 (3.4)
180 (5.5)
15 (0.5)
273 (8.4)635 (19.2)
66 (2.0)
126 (3.9)
49 (1.5)
424 (13.1).03
<0.001
.002
<.001
<.001
*Serum potassium concentration ≥ 6.0 mmol/L; †serum potassium concentration < 4.5 mmol/L.
Serious hyperkalemia occurred in 5.5% of patients on eplerenone, compared with 3.9% of those on placebo, an absolute increase of 1.6% (P = .002). This occurred primarily in patients who had baseline creatinine clearance of < 50 mL/min and was offset by a 4.7% absolute decrease in hypokalemia (P < .001). This offsetting effect was particularly important, Dr. Pitt noted, because patients in the Systolic Hypertension in the Elderly Program (SHEP) trial[3] who developed hypokalemia lost all the benefit of blood pressure reduction.
Indicating that 1 life is saved per year for every 50 patients treated, and 1 episode of cardiovascular mortality/cardiovascular hospitalization is prevented for every 33 patients treated, the results of EPHESUS confirm the efficacy of aldosterone blockade in patients with systolic LV dysfunction, Dr. Pitt concluded. These findings have important implications not only for patients with AMI and heart failure, but also for a variety of cardiovascular diseases currently treated with an ACE inhibitor and a beta-blocker. However, Dr. Pitt also noted that since the EPHESUS population was mainly white male, he has called for follow-up studies in specialist populations to determine whether comparable effects of eplerenone are seen.
There was one further important implication of the EPHESUS results. In the eplerenone group, the reduction in cardiovascular mortality was mainly due to a significant 21% reduction in the rate of sudden cardiac death (SCD) (P < .03). Following the intense interest in MADIT II (the second Multicenter Automatic Defibrillator Implantation Trial), [4] which resulted in changing the heart-failure treatment guidelines to reflect the proven efficacy of implantable cardioverter defibrillator (ICD) therapy, SCD was retrospectively investigated in patients with an ejection fraction of ≤ 30%, the chief component of the so-called "MADIT II criteria." Among the "MADIT II" patients in EPHESUS, an even greater and highly significant 33% reduction in SCD was seen in the eplerenone group (P < .009). This led Dr. Pitt to declare, "The implications of this for me are that defibrillators will likely be effective in these patients, but . . . given these numbers -- the sudden death rate at 1 year is 6 % -- I just cannot believe that they are going to be cost-effective."
In an editorial[5] in TheNew England Journal of Medicine accompanying the publication of the EPHESUS results, Mariell Jessup, MD (University of Pennsylvania, Philadelphia), re-emphasizes that the greater reduction in mortality seen with spironolactone in RALES was probably due to differences in study populations (the RALES enrollees were sicker) and the additional background therapy (more beta-blockade) patients were on in EPHESUS. Dr. Jessup believes that the addition of aldosterone antagonists to the regimens of patients with SLVD and ongoing symptoms of heart failure, despite optimal treatment with ACE inhibitors, "can substantially reduce overall mortality in this vulnerable population."
At the same time, Dr. Jessup notes that current ACC/American Heart Association recommendations for the use of spironolactone -- low dose in patients with recurrent or current symptoms of systolic heart failure, despite the use of digoxin, diuretics, ACE inhibitors, and beta-blockade -- are often ignored. The guidelines also caution that spironolactone has not been tested in patients with mild-to-moderate heart failure and caution against its use in patients with elevated serum creatinine or potassium. Published and anecdotal data indicate that spironolactone has been widely used in patients without consideration of functional class or ejection fraction and without optimization of background treatment with ACE inhibitors and beta-blockers, and Dr. Jessup suggests that the lack of "cumbersome" adverse effects with eplerenone compared with spironolactone may result in increased inappropriate use of aldosterone blockade. She urges that patients under consideration for treatment with aldosterone blockers be screened as carefully as patients in RALES and EPHESUS, and she calls for further studies of aldosterone blockade in patients with less severe symptoms or in patients with heart failure due to primarily diastolic dysfunction.
On the basis of the results of EPHESUS, a supplemental New Drug Application will be submitted to the US Food and Drug Administration (FDA) for eplerenone in the treatment of post-MI heart failure later in 2003. Eplerenone was approved in the United States in September 2002 for the treatment of hypertension, but has not yet been made available on the market. Resolution of the marketing plans for eplerenone is believed to be under discussion between Pharmacia, which developed eplerenone, and Pfizer, which is due to acquire Pharmacia under an agreement signed by both companies in July 2002.
