Download Aldosterone Receptor Antagonist and Heart Failure Following Acute

Aldosterone Receptor Antagonist in Heart FailureActa Cardiol Sin 2010;26:203-15
Review
Aldosterone Receptor Antagonist and Heart
Failure Following Acute Myocardial Infarction
Anil Verma,1† Bernard Bulwer,2† Ishita Dhawan,3 Hung-I Yeh4,5 and Chung-Lieh Hung4,5,6
The presence of heart failure or LV systolic dysfunction in the setting of acute myocardial infarction is associated
with poor prognosis. Aldosterone is an important downstream mediator of the renin-angiotensin-aldosterone system
which, in the post-acute myocardial infarction setting, promotes myocardial collagen deposition, myocardial
fibrosis, apoptosis, endothelial dysfunction, ventricular remodeling, and heart failure, with attendant increased
morbidity and mortality. Extending the findings from the Randomized Aldactone Evaluation Study (RALES) in
chronic heart failure patients, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival
Study (EPHESUS) demonstrated that the selective aldosterone blocker eplerenone offered a significant survival
benefit, attenuated the progression of heart failure, and prevented sudden cardiac death when used in addition to
optimal medical therapy. The current evidence-based guidelines suggest that aldosterone blockade should be an
integral component of heart failure therapy to improve outcomes in this high-risk population.
Key Words:
Acute myocardial infarction · Apoptosis · Heart failure · Renin-angiotensin-aldosterone
system · Ventricular remodeling
INTRODUCTION
tricular ejection fraction [LVEF] < 40%) and heart failure development are common sequelae of acute MI and
continue to be associated with increased mortality.2 The
renin-angiotensin-aldosterone system (RAAS) is upregulated in the setting of LV dysfunction or heart failure;3
thus, blocking RAAS has proven to be one of the most
successful therapeutic strategies for improving outcomes
in these patients. Pharmacologic inhibitors of this system
that have proven value in improving outcomes in patients following acute MI include angiotensin-converting
enzyme inhibitors (ACEIs), angiotensin receptor blockers
(ARBs) and aldosterone antagonists. Significant improvement in morbidity and mortality was demonstrated
with the addition of aldosterone blockers in the Randomized Aldactone Evaluation Study (RALES) 4 and the
Eplerenone Post-Acute Myocardial Infarction Heart
Failure Efficacy and Survival Study (EPHESUS).5 These
studies highlighted the role of aldosterone blockade in
ameliorating risk in patients with heart failure (Table 1).
Aldosterone is the major mineralocorticoid hormone secreted by the adrenal cortex in response to angiotensin II
Acute myocardial infarction remains a significant
public health problem worldwide.1 Therapies for acute
myocardial infarction (MI) continue to evolve, contributing to improved long-term survival benefits in patients
with MI. Despite improved therapies and process of
care, left ventricular (LV) systolic dysfunction (left ven-
Received: June 11, 2010
Accepted: October 7, 2010
1
Ochsner Medical Center, Ochsner Heart and Vascular Institute, New
Orleans, LA; 2Noninvasive Cardiovascular Research, Cardiovascular
Division, Brigham and Women’s Hospital, Boston, MA; 3Haverford
College, Haverford, PA; 4Mackay Medical College; 5Division of
Cardiology, Department of Internal Medicine, Mackay Memorial
Hospital; 6Mackay Medicine, Nursing and Management College,
Taipei, Taiwan.
Address correspondence and reprint requests to: Dr. Chung-Lieh
Hung, Division of Cardiology, Department of Internal Medicine,
Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd.,
Taipei City 10449, Taiwan. Tel: 886-2-2543-3535 ext. 2456; E-mail:
[email protected]
†Both authors contributed equally to this article.
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Table 1.
Study, year
Study design
RALES Trial Pitt B et al., 1999
Active therapeutic dosage
Other standard therapy (%)
Known medical history (%)
Multicenter, international spironolactone (25-50 mg/day)
ACEI: 94.5
Ischemic heart failure: 54.4
randomised, double-blind
Mean: 26 mg/day
BB: 10.5
Non-ischemic heart failure: 45.4
placebo-controlled trial
Baseline Information
Population
Age (years)
Sex
LVEF (%)
HF symptoms
Treatment group (N = 822)
65 ± 12
Female: 27%
25.6 ± 6.7 NYHA > = III: 99.5%
Placebo group (N = 841)
65 ± 12
Female: 27%
25.2 ± 6.8 NYHA > = III: 99.6%
Mean follow-up period
24 Months
Primary end-points
Death from any cause
Secondary end-points
Death from cardiac causes, hospitalization for cardiac causes
Combined incidence of death from cardiac causes or hospitalization for cardiac causes and a change in NYHA class
Results
Primary outcome: Risk of death from any cause: 30% reduction (RR = 0.70, 95% confidence intervals: 0.60-0.82, p < 0.001)
Secondary outcome: Death from cardiac causes or hospitalization for cardiac causes (combined end-points): 32% reduction (RR =
0.68, 95% confidence intervals: 0.59-0.78, p < 0.001)
Study, year
Study design
EPHESUS Trial Pitt B et al., 2003
Active therapeutic dosage
Other standard therapy (%)
Known medical history (%)
Multicenter, international
Eplerenone (25-50 mg/day)
ACEI or ARB: 86.5
Myocardial infarction: 27
randomised, double-blind
Mean: 43 mg/day
BB: 75
Diabetes: 32
placebo-controlled trial
Statins: 47
Heart failure: 14.5
Baseline Information
Population
Age (years)
Sex
LVEF (%)
HF symptoms
Treatment group
64 ± 11
Female: 28%
33 ± 6
HF symptoms: 90%
(N = 3,319)
Placebo group (N = 3,313)
64 ± 12
Female: 30%
33 ± 6
HF symptoms: 90%
Mean follow-up period
16 months
Primary end-points
Death from any cause
First hospitalization for a cardiovascular event, including heart failure, recurrent acute myocardial infarction, stroke, or ventricular
arrhythmia.
Secondary end-points
Death from cardiovascular causes
Death from any cause or any hospitalization
Results
Primary outcome: Risk of death from any cause: 15% reduction (RR = 0.85, 95% confidence intervals: 0.75-0.96, p = 0.008)
Primary outcome: Cardiovascular death or hospitalization for cardiovascular events: 13% reduction (RR = 0.87, 95% confidence
intervals: 0.79-0.95, p = 0.002)
Secondary outcome: Hospitalization for cardiovascular events: 13% reduction (RR = 0.85, 95% confidence intervals: 0.74-0.99, p =
0.002)
Secondary outcome: 41% improvement of NYHA in treatment group compared to 33% improvement in the placebo group, p < 0.001
by Wilcoxon test
ACEI, angiotensin-converting enzyme inhibitors; BB, beta-blocker; LVEF, left ventricular ejection fraction; HF, heart failure;
NYHA, New York Heart Association functional class; RR, relative risk.
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Aldosterone Receptor Antagonist in Heart Failure
Aldosterone and cardiovascular pathophysiology
in development of heart failure following acute
myocardial infarction
It is believed that aldosterone is produced in various
tissues, including the myocardium, brain, and vascular
tissue in addition to the adrenal cortex, and has paracrine
actions beyond the kidney (Figure 1). Aldosterone may
be a mediator of adverse vascular and myocardial remodeling6 and contributes to increased inhibition of nitric oxide synthesis, endothelial dysfunction and myocardial stiffness.10 Systemic and local cardiac activation
of RAAS promotes hypertrophy of cardiac myocytes,
marked increase in tissue aldosterone, increased perivascular interstitial fibrosis, and LV dilatation (Figure 2).11
Following acute MI, increased activity of matrix
metalloproteinases (MMPs) promotes the formation of
new collagen that is poorly cross-linked while breaking
down existing collagen.12 Poorly cross-linked collagen
stimulation, hyperkalemia, and corticotrophin (Figure 1).
It is an essential neurohormonal mediator of the RAAS
regulation of fluid and potassium balance. Additionally,
aldosterone stimulates fibroblast growth and synthesis of
fibrillar collagen 6 and may play a role in cardiac and
vascular fibrosis and ventricular remodeling. 7 Aldosterone blockers are a class I recommendation for patients with chronic heart failure and for patients with LV
systolic dysfunction or heart failure following MI in the
current American College of Cardiology/American Heart
Association (ACC/AHA) 1,8 and European Society of
Cardiology (ESC)9 guidelines.
Our review focuses on the possible mechanisms involved in the benefit of aldosterone blockade in patients
with heart failure and LV systolic dysfunction following
MI. In addition, practical approaches and precautions
will be discussed for the use of these agents to provide
optimal evidence-based care.
Figure 1. Aldosterone and the renin-angiotensin-aldosterone system (RAAS). Angiotensinogen from the liver is the precursor of angiotensin I and II
following consecutive cleavage by renin and angiotensin-converting enzyme (ACE). Aldosterone is produced by the zona glomerulosa cells of the
adrenal cortex in response to angiotensin II, hyperkalemia, and corticotrophin (ACTH). Aldosterone exerts its primary actions on the renal collecting
tubules, but its paracrine activities are far flung and are upregulated in the post-myocardial infarction setting, with deleterious consequences. ACE:
angiotensin converting enzyme; K +: potassium.
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Anil Verma et al.
contributes to the side-to-side slippage of myocytes and
thus purportedly contributes to LV remodeling after
acute MI12 (Figure 2). Activation of adrenergic mediators and RAAS plays an important contributory role in
the pathophysiology of post-MI LV remodeling. Increase
in myocardial angiotensin II increases the production of
reactive oxygen species and augments apoptosis via increased cytosolic calcium. 12 Raised concentrations of
circulating angiotensin II stimulates increased renal reabsorption of sodium and water subsequently leading to
an increased volume load on the heart and augmenting
stretch-induced abnormalities. Aldosterone is another
important component of the RAAS and its production is
partially mediated by angiotensin II via aldosterone
synthase. 13 The existence and upregulation of aldosterone synthase in the heart has been reported in rats
with MI, suggesting local cardiac production of aldosterone in patients with MI.14 It has also been shown
that plasma aldosterone is extracted by the heart following MI and correlates with increased LV end-diastolic
volume index at one month.15 Furthermore, high plasma
aldosterone levels were independently associated with
adverse clinical outcomes including heart failure and
mortality among patients referred for primary percutaneous intervention after acute myocardial infarction.16,17 The combination of fibrosis and increased cell
death post-MI leads to a disorganized, poorly contracting myocardium18 and may represent mechanisms by
which aldosterone promotes remodeling of the infarcted
heart (Figure 2).
Aldosterone inhibition has been shown to reduce
post-infarction collagen synthesis and progressive LV
dilation in patients with MI and heart failure. 19 Aldosterone inhibition by spironolactone reduces the
plasma level of procollagen type III amino-terminal peptide (PIIINP), an indirect marker of myocardial collagen
Figure 2. Post-myocardial infarction aldosterone pathophysiology. In the post-myocardial infarction (MI) setting, aldosterone’s actions extend to
the fibroblast, the cardiac myocyte, and the endothelium, triggering a cascade that influences ventricular and arterial remodeling, cardiac myocyte
electrical stability, and atherothrombotic events - that can result increased cardiovascular morbidity and mortality. Aldosterone antagonists can
block several of these maladaptive responses, with measurable positive clinical impact. ACE: angiotensin-converting enzyme; K+, potassium; LV: left
ventricle; K+, potassium; NADPH: nicotinamide adenine dinucleotide phosphate; NE: norepinephrine.
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Aldosterone Receptor Antagonist in Heart Failure
turnover, in patients with heart failure.10 High levels of
plasma PIIINP, in relation to ventricular fibrosis, were
reportedly associated with poor LV function, remodeling, and prognosis.20 Suppression of such markers immediately following acute MI was also observed to be
associated with further prevention of ventricular remodeling.21 Zannad et al, in a substudy of RALES, emphasized this importance by demonstrating that the beneficial effects of aldosterone blockade with spironolactone
in RALES may be secondary to its ability to suppress
cardiac collagen synthesis.22
Some remodeling after myocardial infarction is independent of angiotensin-II blockade, probably because
of persistent cardiac aldosterone synthesis.23 Blockade of
the RAAS with ACEIs and ARBs have been shown to
incompletely suppress aldosterone levels over the longterm, termed as aldosterone escape.24,25 Aldosterone escape happens even with the use of higher doses of
ACEIs or ARBs or their use in combination.26 Although
the mechanisms of aldosterone escape are poorly understood, this phenomenon could be secondary to continued
production of aldosterone from angiotensin independent
pathways such as cardiac myoctes, due to production
from alternate chymase pathway, or by direct stimulation
by endothelin.27 Additive benefit in LV remodeling was
also reported when eplerenone was added to ACEIs in
post-MI animal model. 28 Given the significant role of
aldosterone in post-MI pathophysiology, its blockade
with agents such as spironolactone or eplerenone beyond
ACE inhibition is essential for continued benefit.
The endothelium plays an important role in regulating vascular tone, platelet aggregation, leukocyte adhesion and thrombosis. In experimental models aldosterone
has been implicated in endothelial dysfunction following
MI. Aldosterone has been shown to reduce nitric oxide
bioactivity by stimulating NADPH oxidase activity and
generating superoxide anions.29 It also attenuates acetylcholine-induced nitric oxide dependent relaxation in rats
with heart failure after MI and has been shown to upregulate vascular conversion of angiotensin I into angiotensin II in heart failure despite ACE inhibition.29 Aldosterone blockade with spironolactone in patients with
heart failure and ischemic cardiomyopathy inhibits vascular conversion of angiotensin I into angiotensin II, improving endothelial vasodilator function and nitric oxide
bioactivity while reducing thrombotic response to injury.30
In patients with chronic heart failure, aldosterone
blockade improves myocardial norepinephrine uptake,
baroreceptor function and cardiac sympathetic activity
concomitantly reducing QT dispersion and improving
heart rate variability.31 Mineralocorticoid receptor (MR)
activation by aldosterone plays an important pathophysiological role in cardiac arrhythmias and sudden
cardiac death as aldosterone alters myocyte electrical
properties, decreases tissue potassium and potentiates
the tendency for catecholamine-induced ventricular arrhythmias which is thought to be inhibited by aldosterone blockade.32,33 Aldosterone was also known to induce myocyte apoptosis and myocardial fibrosis.33 Resultant ventricular remodeling could promote electrical
inhomogeneity and the propensity for ventricular arrhythmia development as homogenous cardiac electrical
conduction requires extra cellular matrix and myocyte
integrity.33 These mechanisms may in part explain reduction of sudden cardiac death observed with aldosterone
blockade in the RALES4 and the EPHESUS5 trials. The
benefits of aldosterone blockade in terms of preventing
sudden cardiac death immediately following an acute MI
are more likely due to their effects on electrical remodeling of the myocardium whereas the effects on ventricular remodeling, and collagen formation may be of
equal or greater importance in preventing sudden cardiac death in patients with LV systolic dysfunction and
heart failure over the long term.33
The stimulation of the MR by aldosterone occurs
through a genomic pathway, resulting in transcription
and translation of effector proteins. These effects take
hours to days to generate a biological effect. 34 It has
been shown that aldosterone can actually induce a wide
range of effects through membrane receptors other than
traditional MR-dependent in epithelial (such as kidney)
and non-epithelial tissue (such as vasculature and heart)
in a nongenomic manner. 34 Regulation via classic genomic pathway by activating nuclear receptor directly
bound to a hormone response element (HRE) and other
non-HRE related pathways have been described more recently in non-epithelial cells (Figure 3).34-36 These nongenomic effects of aldosterone can occur within minutes
of aldosterone exposure, unlike the genomic pathway,
which demonstrates a lag time and some have been observed to occur via activation of the pertussis toxinsensitive heterotrimeric G proteins via Akt-signaling
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A
B
Figure 3. Aldosterone signaling in the primary epithelial cells (A) and cardiomyocytes (B). Left Panel of A: Aldosterone signaling in the primary
epithelial cell of the collecting duct via the classical genomic pathway. Aldosterone regulates sodium excretion through mineralocorticoid receptor
(MR)-dependent genomic effects in the distal nephron of the kidney. Aldosterone binds to the inactive cytosolic MR of the target cell, resulting in a
ligand-activated MR that is translocated to the nucleus. Here, it binds to hormone-response elements (HRE) within the regulatory region of target
gene promoters. MR induces serum- and glucocorticoid-inducible kinase-1 (sgk-1) gene expression and triggers a cascade involving epithelial
sodium channel (ENaC). This results in sodium and water absorption with concomitant potassium excretion, leading to volume expansion and
hypertension. Sgk-1 phosphorylates Nedd4-2, a ubiquitin-protein ligase that targets ENaC for degradation. In response to aldosterone, corticosteroid
hormone-induced factor (CHIF), a small transmembrane protein, enhances Na.K-ATPase activity and affinity of for sodium. Similarly, aldosterone is
necessary for the expression of small modulatory G protein (Ras) which promotes increased Na+ transport. Right Panel of A: Rapid signaling
through nongenomic MR-dependent and MR-independent mechanisms. Nongenomic aldosterone actions have been described for an increasing
number of epithelial and nonepithelial cell types. MR-dependent mechanisms can proceed through HRE-independent processes that generally involve
rapid activation of second messenger pathways. MR-independent pathways may be mediated via transmembrane receptors distinct from the cytosolic
MR. These may involve rapid flux of cytosolic calcium (Ca ++) and dose-dependent phosphorylation (P) via protein kinases downstream. B,
aldosterone-dependent pathways via MR as well as an MR-independent cellular signaling pathway exist within cardiac myocytes and fibroblasts.
Through such genomic and non-genomic pathways, aldosterone stimulates elastogenesis and degradation of the extracellular matrix. A: aldosterone;
Akt: a serine-threonine protein kinase encoded by the Akt gene; c-Src: cellular sarcoma family of proto-oncogenic tyrosine kinases; ET-1:
endothelin-1 isoform; Ga, Gb, and Gg: three main G-protein-mediated signaling pathways; GPCR: G-protein coupled receptor (transmembrane);
HRE: hormone-responsive element; IGF-1: insulin-like growth factor 1; IRS-1: insulin receptor substrate 1; MMPs: matrix metalloproteinases; MR:
mineralocorticoid receptor; PI 3-kinase: phosphatidylinositol 3-kinase; PTK: protein tyrosine kinases; TGF-b1: transforming growth factor beta 1.
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Aldosterone Receptor Antagonist in Heart Failure
pathway.37 Instead, involvement of amiloride-sensitive
epithelial sodium channel (ENaC), representing the principle rate-limiting step controlling for sodium flux (nuclear actions), 35 and some other rapid, non-genomic
(non-nuclear actions) pathways were observed in the
collecting duct of distal renal tubules (Figure 3). 35
Which biological effects of aldosterone are mediated
through a genomic or a non-genomic pathway in these
different tissues is not completely understood. The nongenomic effects of aldosterone are thought to be mediated by membrane receptors other than the traditional
MR and do not involve transcription or protein synthesis.
cardiac death in patients already receiving optimal adjunctive therapy including coronary reperfusion, aspirin,
statins, ACEI or ARB, and b-blocker.
Both aldosterone blockers, spironolactone and eplerenone, are approved for use in the United States in
patients with heart failure and LV systolic dysfunction
or in patients following MI and with symptomatic heart
failure. Eplerenone has greater selectivity for the MR
and has a lower affinity for androgen receptors compared to spironolactone.5 Due to the lower affinity for
the androgen receptors, the incidence of gynecomastia
and impotence among men in the eplerenone group was
no greater than that in the placebo group.5
BENEFICIAL EFFECTS AND CLINICAL
APPLICATIONS OF ALDOSTERONE
BLOCKADE
Clinical application and patient selection
The results from the EPHESUS trial provided a
strong rationale for routine incorporation of aldosterone
blocker in the management of patients following acute
myocardial infarction without significant renal dysfunction or hyperkalemia, who are receiving an ACEI or
ARB, have an LVEF £ 40%, and have either symptomatic heart failure or diabetes. The ACC/AHA guidelines
for patients with acute MI include a class IA recommendation for long-term aldosterone blockade in this population. 1 In RALES, 4 spironolactone was initiated at a
dose of 25 mg/day and then increased to 50 mg/day after
8 weeks if the patient showed signs or symptoms of progressive heart failure without hyperkalemia or renal insufficiency. In the EPHESUS5 trial, eplerenone therapy
was also begun at 25 mg/day and increased to a maximum
dose of 50 mg/day after 4 weeks. The significant beneficial effects of eplerenone were seen as early as thirty
days post randomization, although patients were not titrated to the target dose of 50 mg/day until after thirty
days, a 32% risk reduction in cardiovascular mortality
and a 36% risk reduction in sudden cardiac deaths were
observed with the use of eplerenone by 30 days.38 This is
particularly noteworthy as the risk for sudden death is
highest during the first thirty days after MI among
patients with LV dysfunction, heart failure or both.39
This underscores the importance of early initiation
of aldosterone blockade in patients following MI and
with heart failure. Although eplerenone’s target dose
specified in the EPHESUS trial was 50 mg/day, a recent
study by Banas et al.40 showed that patients unable to
achieve the specified target dose in the EPHESUS trial
A mortality benefit of aldosterone blockade was
demonstrated in two landmark trials, EPHESUS and
RALES (Table 1). In RALES,4 the aldosterone blocker
spironolactone was added to standard therapy in selected
patients with symptomatic chronic heart failure (New
York Heart Association class III-IV; mean LVEF, 25.6%
± 7%) who remained symptomatic despite optimal medical treatment. The dosage of spironolactone used was
low, at 25 mg/day, and could be increased to 50 mg/day
if there was progression of heart failure or decreased to
25 mg/day if hyperkalemia developed. Addition of
spironolactone reduced mortality by 30% (p < 0.001),
primarily due to a 29% (p = 0.02) reduction in sudden
cardiac deaths and a 35% reduction in hospitalization for
heart failure (p < 0.001). The reduction in mortality and
hospitalization for heart failure were observed after two
to three months of treatment and persisted throughout the
study (mean follow-up, 24 months).
In contrast, the EPHESUS study was conducted in
patients with acute MI complicated by evidence of LV
systolic dysfunction (LVEF < 40%) and signs of heart
failure (presence of pulmonary rales or congestion) or
the presence of a third heart sound. In the EPHESUS5
trial the addition of eplerenone, a selective aldosterone
blocker, resulted in a 15% (p = 0.008) reduction in total
mortality, a 17% (p = 0.005) reduction in cardiovascular
mortality and reduced mortality within one month,38 predominantly due to a 21% (p = 0.02) reduction in sudden
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Anil Verma et al.
experienced significant reductions in the endpoints with
a dose of 25 mg/day or even 25 mg every other day.
Although eplerenone and spironolactone both block
the binding of aldosterone to the MR and spironolactone
is less expensive than eplerenone, they are different drug
molecules and may not be completely interchangeable.
As discussed above, eplerenone has fewer endocrinerelated adverse effects due to its lower affinity for androgen receptors. The potency of the dose of eplerenone
(25-50 mg/day) in EPHESUS, with respect to aldosterone blockade, may be relatively less than the dose of
spironolactone (25-50 mg/day) in RALES.41 This may
lead to increased risk of hypotension or hypokalemia
with use of spironolactone at starting doses of 25 mg/day
in these patients. Regardless of the choice of aldosterone
blocker, current evidence-based guidelines coupled with
the results from the EPHESUS trial provide a strong
rationale for the routine incorporation of these agents in
management of patients with acute MI complicated with
heart failure and LV systolic dysfunction. These agents
should be used in conjunction with optimal conventional
therapy for patients with acute MI and heart failure including coronary reperfusion, aspirin, statins, ACEIs or
ARBs, and a b-blocker.5
For evidence-based therapies to have a wider applicability, it is desirable that they must be cost-effective. A recent cost-effective analysis by Weintraub et al.42 demonstrated that the use of eplerenone compared to placebo in
EPHESUS resulted in an incremental cost-effectiveness
ratio of $13,718 per quality-adjusted life-year gained.
This was well below the common benchmark ceiling ratio
of $50,000 per life-year gained and suggested that
eplerenone use compared with placebo in the treatment
of heart failure after acute myocardial infarction is effective in reducing mortality and is cost-effective in increasing years of life by commonly used criteria.
therapy will benefit patients with heart failure and normal ejection fraction. Although suppression of aldosterone seems like a logical therapeutic extension in this
population at the present time, this strategy cannot be
recommended because of lack of data from randomized
control trials. Patients with high-risk MI with heart failure or LV systolic dysfunction are at high risk for sudden cardiac death.39 Implantable cardioverter-defibrillators are effective in reducing long-term mortality in
chronic heart failure patients with severe LV systolic dysfunction, but are ineffective in reducing total mortality
when used early post MI. 43 Thus a combination approach of aldosterone blockade with implantable cardioverter defibrillators for more effective prevention of
sudden cardiac deaths in patients with persistent severe
LV systolic dysfunction post-MI seems intriguing which
will need evaluation in a prospective randomized trial.
RISK OF HYPERKALEMIA FROM
ALDOSTERONE RECEPTOR BLOCKERS
Both eplerenone and spironolactone may cause
hyperkalemia, and aldosterone blockade is contraindicated if the serum potassium level is greater than 5.5
mEq/L at initiation or if the estimated glomerular filtration rate is less than 30 mL/min. Aldosterone facilitates
sodium-potassium exchange by the cells of the cortical
collecting tubule, and its blockade decreases potassium
excretion. Aldosterone blockers may also reduce glomerular filtration rate and sodium delivery to distal
nephrons, further impairing sodium potassium exchange
and potassium excretion. Advancing age and diabetes
mellitus are associated with decreased aldosterone activity (hyporeninemic hypoaldosteronism state) and a
higher risk of renal impairment in which may predispose
them to develop hyperkalemia. The patients on spironolactone in the RALES trial experienced 1% absolute
increase in the risk of developing serious hyperkalemia
(2% in spironolactone group compared to 1% in placebo
group; statistically not significant). Patients who developed serious hyperkalemia were also more likely to
have a baseline potassium level greater than 5.5 mEq/L.
Similarly in the EPHESUS trial, a similar increased risk
of serious hyperkalemia was found in the eplerenone
group (5.5% in the eplerenone group compared to 3.9%
Further challenges and directions
It is possible although still unproven that the addition of aldosterone receptor blockers will be beneficial
in patients with asymptomatic LV systolic dysfunction
following MI or in patients with preserved systolic function heart failure. The ongoing NHLBI-sponsored Treatment of Preserved Cardiac function heart failure with an
Aldosterone anTagonist (TOPCAT) trial will determine
whether the additional of spironolactone to standard
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in the placebo group, p = 0.002). A recent report, however, indicated that with standard eplerenone therapy of
25-50 mg/day in post-MI patients, no excess risk of
hyperkalemia (³ 6.0 mEq/L) was seen when serum potassium level was periodically monitored.44
In the EPHESUS and the RALES trial, the reported
incidence of hyperkalemia was considerably low and no
deaths were attributed to hyperkalemia, however, the use
of spironolactone in clinical practice has been associated
with a relatively high incidence of serious hyperkalemia
resulting in renal failure, need for dialysis, and death.45
Higher rates of hyperkalemia in clinical practice observed after the publication of RALES could be attributed to patients being older than those entered into
RALES or EPHESUS, having higher pre-treatment creatinine levels, perhaps not having had serial potassium
monitoring with dose adjustment for serum potassium >
5.5 mmol/l or discontinuation for serum potassium > 6.0
mmol/l. Another possibility may be due to higher doses
of spironolactone exposure in clinical practice than in
RALES trial as larger doses of spironolactone may induce marked diuresis, volume depletion, and renal impairment.41 Serum creatinine poorly reflects renal function and is not, by itself, an accurate index of glomerular
filtration rate. Urinary creatinine excretion is lower in
patients with chronic kidney disease, and can lead to
systematic overestimation of glomerular filtration rate if
used as the sole estimate of renal function. Thus overreliance on creatinine levels in clinical practice to estimate renal function increases the risk of serious hyperkalemia when using aldosterone blockers. Other risk factors for hyperkalemia in patients receiving aldosterone
blockers include the concomitant use of nonsteroidal
anti-inflammatory drugs (NSAIDs), cyclooxygenase-2
enzyme inhibitors (both suppress renin release), volume
depletion status, concomitant usage of b-blockers (blocks
the action of renin), heparin preparations (impairs aldosterone secretion), ACEI or ARBs (blocks the action
of angiotensin II), cyclosporine and other potassium
sparing diuretics (amiloride, triamterene).27
blocker initiation, history of hyperkalemia or prevailing
hyperkalemia, renal function and current medication use
are all important factors to be considered in avoiding
serious hyperkalemia from aldosterone blockade and
affording optimal care to the post MI patient (Figure 4).
Careful attention should be paid to elderly patients,
those with a history of diabetes mellitus, and patients on
potassium supplements, ACEIs or ARBs before initiating therapy with aldosterone blockers.
For both RALES and EPHESUS, patients were excluded if serum creatinine levels exceeded 2.5 mg per
dL, but few patients were actually enrolled with serum
creatinine levels above 1.5 mg per dL. Since serum
creatinine is not an accurate index of renal function, we
recommend estimating the glomerular filtration rate using the four-component Modification of Diet in Renal
Disease (MDRD) study equation incorporating age, race,
sex, and serum creatinine level before initiating aldosterone blockade.46 For the MDRD equation: Estimated
glomerular filtration rate (mL/min per 1.73 m2) = 186 ´
(plasma creatinine [mg/dL])-1.154 ´ (age [years])-0.203 ´
(0.742 [if female]) ´ (1.210 [if African American]).
Serum potassium should be measured and aldosterone blockers should not be administered to patients
with baseline serum potassium in excess of 5.0 mEq/L or
estimated glomerular filtration rateless than 30 mL/min
per 1.73 m2 , particularly in the presence of insulinrequiring diabetes mellitus. Careful assessment of the
volume status is essential, and hypovolemia and hyperkalemia should be corrected before aldosterone blockade
is initiated. Nonsteroidal anti-inflammatory drugs or
cyclooxygenase-2 enzyme inhibitors and potassium
supplementation should be avoided, and patients should
be counseled to avoid high potassium-containing foods.8,9
An initial dose of spironolactone 12.5 mg or eplerenone
25 mg is recommended, after which the dose may be increased to spironolactone 25 mg or eplerenone 50 mg if
appropriate (Figure 4).8
Although both eplerenone and spironolactone have a
relatively weak diuretic effect, they may act synergistically with other diuretics to cause fluid depletion, further
increasing the risk of renal dysfunction and hyperkalemia. Close monitoring of serum potassium is required; potassium levels and estimated glomerular filtration rate should be rechecked within 3 days and again at
1 week after initiation of aldosterone blockers. Subse-
ALDOSTERONE BLOCKER THERAPY:
IMPORTANT ISSUES IN PATIENT CARE
Appropriate patient selection, timing of aldosterone
211
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Anil Verma et al.
Figure 4. Aldosterone blocker therapy. treatment with aldosterone receptor antagonists requires careful patient selection and assessment prior to
initiating therapy. Careful attention to drug dosage, renal function, and close monitoring of patient’s overall clinical status are important, especially
because of the need to minimize the risk of hyperkalemia. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker;
COX-2: cycloxygenase-2; CRI: chronic renal insufficiency; K+, potassium; NSAID, non-steroidal anti-inflammatory drugs.
and renal function and should occur one week after any
changes are made.8 The development of potassium levels
in excess of 5.5 mEq/L, hypotension or worsening renal
impairment should generally trigger either discontinuation or at least a 50% dose reduction of the aldosterone
blocker, and a review of concomitant medications, such
quent monitoring should be dictated by the general
clinical stability of renal function and fluid status but
should occur at least monthly for the first 3 months and
every 3 months thereafter. Any changes to the drug dose
or addition or change to the ACEIs and ARBs’ dosage
must prompt further monitoring of the potassium levels
Acta Cardiol Sin 2010;26:203-15
212
Aldosterone Receptor Antagonist in Heart Failure
4. Pitt B, Zannad F, Remme WJ, et al. Randomized aldactone
evaluation study investigators. The effect of spironolactone on
morbidity and mortality in patients with severe heart failure. N
Engl J Med 1999;341:709-17.
5. Pitt B, Remme W, Zannad F, et al. Eplerenone post-acute myocardial infarction heart failure efficacy and survival study investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction
[published correction appears in N Engl J Med 2003;348:2271]. N
Engl J Med 2003;348:1309-21.
6. Weber KT, Sun Y. Recruitable ACE and tissue repair in the
infarcted heart. J Renin Angiotensin Aldosterone Syst 2000;
1:295-303.
7. Weber KT, Brilla CG, Campbell SE, et al. Myocardial fibrosis:
role of angiotensin II and aldosterone [Review]. Basic Res
Cardiol 1993;88:107-24.
8. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart
Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines (Writing Committee to Update the 2001 Guidelines
for the Evaluation and Management of Heart Failure): developed
in collaboration with the American College of Chest Physicians
and the International Society for Heart and Lung Transplantation:
endorsed by the Heart Rhythm Society. Circulation 2005;112:
e154-235.
9. Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary
(update 2005): The Task Force for the Diagnosis and Treatment
of Chronic Heart Failure of the European Society of Cardiology.
Eur Heart J 2005;26:1115-40.
10. Struthers AD. Aldosterone blockade in cardiovascular disease
[Review]. Heart 2004;90:1229-34.
11. Lal A, Veinot JP, Ganten D, et al. Prevention of cardiac remodeling after myocardial infarction in transgenic rats deficient in brain
angiotensinogen. J Mol Cell Cardiol 2005;39:521-9.
12. Opie LH, Commerford PJ, Gersh BJ, et al. Controversies in ventricular remodeling [Review]. Lancet 2006;367:356-67.
13. Delcayre C, Silvestre JS, Garnier A, et al. Cardiac aldosterone
production and ventricular remodeling. Kidney Int 2000;57:
1346-51.
14. Silvestre JS, Heymes C, Oubenaissa A, et al. Activation of cardiac aldosterone production in rat myocardial infarction: effect of
angiotensin II receptor blockade and role in cardiac fibrosis. Circulation 1999;99:2694-701.
15. Hayashi M, Tsutamoto T, Wada A, et al. Relationship between
transcardiac extraction of aldosterone and left ventricular remodeling in patients with first acute myocardial infarction: extracting aldosterone through the heart promotes ventricular remodeling after acute myocardial infarction. J Am Coll Cardiol
2001;38:1375-82.
16. Beygui F, Collet JP, Benoliel JJ, et al. High plasma aldosterone
levels on admission are associated with death in patients present-
as ACEIs or ARBs, potassium supplements and nonsteroidal anti-inflammatory medications is warranted.
During hypovolemic states such as diarrhea, vomiting
and excessive diuretic use, therapy with aldosterone
blocker should be stopped until resolution.
CONCLUSION
Heart failure and LV systolic dysfunction complicating acute myocardial infarction are associated with
substantial morbidity and mortality. Blockade of aldosterone with eplerenone or spironolactone inhibits postmyocardial infarction collagen deposition, myocardial
fibrosis, apoptosis, ventricular remodeling and endothelial dysfunction. The results from landmark clinical trials
have demonstrated substantial survival benefits of aldosterone blockers and their role in the primary prevention of sudden cardiac death. Early and aggressive adjunctive treatment with aldosterone blockers offers significant incremental benefit for reducing mortality and
morbidity above and beyond standard proven therapies
for post-myocardial infarction heart failure and, as such,
should be incorporated into critical pathways for the care
of these patients. Although hyperkalemia is potentially a
serious threat, with appropriate patient selection and
close monitoring, the benefits of aldosterone blockade in
mitigating adverse outcomes should far outweigh its potential risks.
REFERENCES
1. Antman EM, Anbe DT, Armstrong PW, et al. American College
of Cardiology/American Heart Association Task Force on Practice Guidelines. ACC/AHA guidelines for the management of
patients with ST-elevation myocardial infarction — executive
summary: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines
(Writing Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation 2004;110:588-636.
2. Guidry UC, Evans JC, Larson MG, et al. Temporal trends in event
rates after Q-wave myocardial infarction: the Framingham Heart
Study. Circulation 1999;100:2054-9.
3. Haber E, George C. Griffith lecture. The role of renin in normal
and pathological cardiovascular homeostasis. Circulation 1976;
54:849-61.
213
Acta Cardiol Sin 2010;26:203-15
Anil Verma et al.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
ing with acute ST-elevation myocardial infarction. Circulation
2006;114:2604-10.
Palmer BR, Pilbrow AP, Frampton CM, et al. Plasma aldosterone
levels during hospitalization are predictive of survival post-myocardial infarction. Eur Heart J 2008;29:2489-96.
Hein S, Amon E, Kostin, et al. Progression from compensated
hypertrophy to failure in the pressure-overloaded human heart:
structural deterioration and compensatory mechanisms. Circulation 2003;107:984-91.
Modena MG, Aveta P, Menozzi A, et al. Aldosterone inhibition
limits collagen synthesis and progressive left ventricular enlargement after anterior myocardial infarction. Am Heart J 2001;141:
41-6.
Poulsen SH, Host NB, Jensen SE, et al. Relationship between
serum amino-terminal propeptide of type III procollagen and
changes of left ventricular function after acute myocardial infarction. Circulation 2000;101:1527-32.
Hayashi M, Tsutamoto T, Wada A, et al. Immediate administration of mineralocorticoid receptor antagonist spironolactone
prevents post-infarct left ventricular remodeling associated with
suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation
2003;107:2559-65.
Zannad F, Alla F, Dousset B, et al. RALES Investigators. Limitation of excessive extracellular matrix turnover may contribute to
survival benefit of spironolactone therapy in patients with congestive heart failure. Circulation 2000;102:2700-6.
Katada J, Meguro T, Saito H, et al. Persistent cardiac aldosterone
synthesis in angiotensin II type 1A receptor-knockout mice after
myocardial infarction. Circulation 2005:111:2157-64.
Staessen J, Lijnen P, Fagard R, et al. Rise in plasma concentration
of aldosterone during long-term angiotensin II suppression. J
Endocrinol 1981;91:457-65.
Borghi C, Boschi S, Ambrosioni E, et al. Evidence of a partial escape of renin-angiotensin-aldosterone blockade in patients with
acute myocardial infarction treated with ACE inhibitors. J Clin
Pharmacol 1993;33:40-5.
Tang WH, Vagelos RH, Yee YG, et al. Neurohormonal and
clinical responses to high- versus low-dose enalapril therapy in
chronic heart failure [published correction appears in J Am Coll
Cardiol 2002;39:746]. J Am Coll Cardiol 2002;39:70-8.
Tang WH, Parameswaran AC, Maroo AP, et al. Aldosterone receptor antagonists in the medical management of chronic heart
failure. Mayo Clin Proc 2005;80:1623-30.
Fraccarollo D, Galuppo P, Hildemann S, et al. Additive improvement of left ventricular remodeling and neurohormonal activation
by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction. J Am Coll Cardiol
2003;42:1666-73.
Bauersachs J, Heck M, Fraccarollo D, et al. Addition of spironolactone to angiotensin-converting enzyme inhibition in heart
failure improves endothelial vasomotor dysfunction: role of vascular superoxide anion formation and endothelial nitric oxide
Acta Cardiol Sin 2010;26:203-15
synthase expression. J Am Coll Cardiol 2002;39:351-8.
30. Farquharson CA, Struthers AD. Spironolactone increases nitric
oxide bioactivity, improves endothelial vasodilator dysfunction,
and suppresses vascular angiotensin I/angiotensin II conversion
in patients with chronic heart failure. Circulation 2000;101:
594-7.
31. Barr CS, Lang CC, Hanson J, et al. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in
chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 1995;76:1259-65.
32. Dyckner T, Wester PO, Widman L. Effects of spironolactone on
serum and muscle electrolytes in patients on long-term diuretic
therapy for congestive heart failure and/or arterial hypertension.
Eur J Clin Pharmacol 1986;30:535-40.
33. Pitt B, Pitt GS. Added benefit of mineralocorticoid receptor
blockade in the primary prevention of sudden cardiac death.
Circulation 2007;115:2976-82.
34. Cohn JN, Colucci W. Cardiovascular effects of aldosterone and
post-acute myocardial infarction pathophysiology. Am J Cardiol
2006;97:4F-12F.
35. Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action.
Hypertension 2005;46:1227-35.
36. Marney AM, Brown NJ. Aldosterone and end-organ damage.
Clin Sci (Lond) 2007;113:267-78.
37. Bunda S, Wang Y, Mitts TF, et al. Aldosterone stimulates elastogenesis in cardiac fibroblasts via mineralocorticoid receptorindependent action involving the consecutive activation of
Galpha13, c-Src, the insulin-like growth factor-I receptor, and
phosphatidylinositol 3-kinase/Akt. J Biol Chem 2009;284:
16633-47.
38. Pitt B, White H, Nicolau J, et al. EPHESUS Investigators.
Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol
2005;46:425-31.
39. Solomon SD, Zelenkofske S, McMurray JJV, et al. Sudden death
in patients with myocardial infarction and left ventricular dysfunction, heart failure or both. N Eng J Med 2005;352:2581-8.
40. Banas J, White H, Parkhomenko A, et al. Favorable outcomes
with 25 mg of eplerenone in patients with post-AMI heart failure:
results from the EPHESUS trial. J Cardiac Fail 2005;11:S156.
41. Pitt B, Ferrari R, Gheorghiade M, et al. Aldosterone blockade in
post-acute myocardial infarction heart failure [Review]. Clin
Cardiol 2006;29:434-8.
42. Weintraub WS, Zhang Z, Mahoney EM, et al. Cost-effectiveness
of eplerenone compared with placebo in patients with myocardial
infarction complicated by left ventricular dysfunction and heart
failure. Circulation 2005;111:1106-13.
43. Hohnloser SH, Kuck KH, Dorian P, et al. DINAMIT Investigators. Prophylactic use of an implantable cardioverter-defibrillator
after acute myocardial infarction. N Engl J Med 2004;351:
2481-8.
44. Pitt B, Bakris G, Ruilope LM, et al. EPHESUS Investigators.
214
Aldosterone Receptor Antagonist in Heart Failure
Serum potassium and clinical outcomes in the Eplerenone PostAcute Myocardial Infarction Heart Failure Efficacy and Survival
Study (EPHESUS). Circulation 2008;118:1643-50.
45. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia
after publication of the Randomized Aldactone Evaluation Study.
N Engl J Med 2004;351:543-51.
46. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to
estimate glomerular filtration rate from serum creatinine: a new
prediction equation. Ann Intern Med 1999;130:461-70.
215
Acta Cardiol Sin 2010;26:203-15