Download Update on Aldosterone Antagonists Use in Heart Failure With

Journal of Cardiac Failure Vol. 18 No. 4 2012
Consensus
Update on Aldosterone Antagonists Use in Heart Failure With
Reduced Left Ventricular Ejection Fraction Heart Failure Society
of America Guidelines Committee
JAVED BUTLER, MD, MPH,1 JUSTIN A. EZEKOWITZ, MBBCh,2 SEAN P. COLLINS, MD, MSc,3
MICHAEL M. GIVERTZ, MD,4 JOHN R. TEERLINK, MD,5 MARY N. WALSH, MD,6 NANCY M. ALBERT, RN, PhD,7
CHERYL A. WESTLAKE CANARY, RN, PhD,8 PETER E. CARSON, MD,9 MONICA COLVIN-ADAMS, MD,10
JAMES C. FANG, MD,11 ADRIAN F. HERNANDEZ, MD, MHS,12 RAY E. HERSHBERGER, MD,13 STUART D. KATZ, MD,14
JOSEPH G. ROGERS, MD,12 JOHN A. SPERTUS, MD, MPH,15 WILLIAM G. STEVENSON, MD,4
NANCY K. SWEITZER, MD, PhD,16 W.H. WILSON TANG, MD,17 WENDY GATTIS STOUGH, PharmD,18 AND
RANDALL C. STARLING, MD, MPH17
Atlanta, Georgia; Edmonton, Alberta, Canada; Nashville, Tennessee; Boston, Massachusetts; San Francisco, and Azusa, California; Indianapolis, Indiana; Cleveland,
Ohio; Washington, DC; Minneapolis, Minnesota; Buies Creek, North Carolina; Miami, Florida; New York, New York; Kansas City, Missouri; and Madison, Wisconsin
ABSTRACT
Aldosterone antagonists (or mineralocorticoid receptor antagonists [MRAs]) are guideline-recommended
therapy for patients with moderate to severe heart failure (HF) symptoms and reduced left ventricular ejection
fraction (LVEF), and in postmyocardial infarction patients with HF. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial evaluated the MRA eplerenone in patients with mild HF symptoms. Eplerenone reduced the risk of the primary endpoint of cardiovascular death
or HF hospitalization (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.54e0.74, P ! .001) and allcause mortality (adjusted HR 0.76, 95% CI 0.62e0.93, P ! .008) after a median of 21 months. Based on
EMPHASIS-HF, an MRA is recommended for patients with New York Heart Association (NYHA) Class IIe
IV symptoms and reduced LVEF (!35%) on standard therapy (Strength of Evidence A). Patients with
NYHA Class II symptoms should have another high-risk feature to be consistent with the EMPHASIS-HF
population (age O55 years, QRS duration O130 msec [if LVEF between 31% and 35%], HF hospitalization
within 6 months or elevated B-type natriuretic peptide level). Renal function and serum potassium should be
closely monitored. Dose selection should consider renal function, baseline potassium, and concomitant drug
interactions. The efficacy of eplerenone in patients with mild HF symptoms translates into a unique opportunity to reduce morbidity and mortality earlier in the course of the disease. (J Cardiac Fail
2012;18:265e281)
Key Words: Aldosterone antagonists, eplerenone, heart failure, spironolactone.
and University of MissourieKansas City, Kansas City, MO; 16Department
of Medicine, University of Wisconsin, Madison, WI; 17Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH and 18Department
of Clinical Research, Campbell University College of Pharmacy and Health
Sciences, Buies Creek, NC.
Manuscript received February 12, 2012; revised manuscript accepted
February 15, 2012.
Reprint requests: Randall C. Starling, MD, MPH, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH
44195. Tel: þ1 216 444 2268. E-mail: [email protected]
This article was reviewed and approved by the HFSA Executive Council
on February 20, 2012. The HFSA Executive Council members are listed in
the Acknowledgment.
See page 278 for disclosure information.
1071-9164/$ - see front matter
Ó 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.cardfail.2012.02.005
From the 1Department of Medicine, Division of Cardiology, Emory
University, Atlanta, GA; 2Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada; 3Department of Emergency Medicine, Vanderbilt
University, Nashville, TN; 4Department of Medicine, Division of Cardiology
Brigham and Women’s Hospital, Boston, MA; 5Department of Medicine,
University of California San Francisco, San Francisco, CA; 6The Care
Group, Indianapolis, IN; 7Heart and Vascular Institute, Cleveland Clinic,
Cleveland, OH; 8School of Nursing, Azusa Pacific University, Azusa, CA;
9
Georgetown University and Washington DC Veterans Affairs Medical Center, Washington, DC; 10Cardiovascular Division, University of Minnesota,
Minneapolis, MN; 11Harrington-McLaughlin Heart and Vascular Institute,
University Hospitals Case Medical Center, Case Western Reserve University
School of Medicine, Cleveland, OH; 12Department of Medicine, Division of
Cardiology, Duke University Medical Center, Durham, NC; 13Department of
Medicine, Division of Cardiology, University of Miami, Miami, FL; 14Leon
H. Charney Division of Cardiology, New York University School of Medicine, New York, NY; 15Mid-America Heart Institute of St. Luke’s Hospital
265
266 Journal of Cardiac Failure Vol. 18 No. 4 April 2012
Aldosterone receptor antagonists, also referred to as mineralocorticoid receptor antagonists (MRA), are currently
guideline-recommended evidence-based therapy for select
patients with heart failure (HF) and reduced left ventricular
ejection fraction (LVEF).1 The contribution of aldosterone
to the development and progression of HF is wellestablished (Table 1).2e6 Further, large randomized, controlled clinical trials of aldosterone receptor antagonists
showed that spironolactone improved survival in patients
with severe HF with depressed EF,7 and eplerenone reduced
morbidity and mortality in postmyocardial infarction (MI)
patients with HF and LV dysfunction.8 The Heart Failure
Society of America (HFSA) and other national and international guidelines therefore recommend the use of aldosterone receptor antagonists in HF patients similar to the
populations studied in the Randomized Aldactone Evaluation study (RALES) and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study
(EPHESUS) trials (Table 2).1,7e10 These trials excluded patients with mild HF symptoms, rendering a knowledge gap
regarding the efficacy and safety of aldosterone receptor antagonists in this specific population.
The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial was designed to address this knowledge gap.11 The data generated
from this study necessitates a reexamination of the current
guideline recommendations. The purpose of this article is to
evaluate the existing and new evidence for aldosterone antagonism in patients across the spectrum of HF, and to provide
suggestions for how clinicians may incorporate this evidence
into their clinical practice. This document is not a formal
guideline update, but rather a document to communicate latest
results, cumulative evidence, highlight persistent knowledge
gaps, and provide care recommendations related to aldosterone antagonism in HF in accordance with emerging evidence.
Table 1. Pleiotropic Effects of Aldosterone in Heart
Failure*
Heart
Myocyte hypertrophy
Interstitial fibrosis
Coronary atherosclerosis
Decreased natriuretic peptide synthesis
Reduced norepinephrine uptake
Kidney
Sodium and water retention
Potassium and magnesium wasting
Glomerulosclerosis
Tubulointerstitial fibrosis
Podocyte apoptosis and proteinuria
Vasculature
Endothelial cell hypertrophy
Vascular smooth muscle cell hypertrophy
Atherosclerosis
Reduced nitric oxide bioavailability
Vasomotor dysfunction
Platelet aggregation
*Oxidative stress and inflammation have been shown to play a pathophysiologic role in all systems.20
Pathophysiology of Aldosterone in HF
More than 50 years ago, Luetscher and Johnson12 first
observed that adults and children with HF secrete a steroid
hormone in the urine with sodium-retaining properties. Using selective venous sampling and liquid chromatography,
Davis et al13 then identified this hormone as aldosterone
and found that it was produced in excess in the adrenal
gland in edematous states. Subsequent studies have shown
that plasma aldosterone levels are elevated in patients
with HF despite maximal renin-angiotensin system blockade (so-called aldosterone escape),14 correlate with disease
severity,15 and predict mortality.16 These data suggested
that aldosterone is not simply a biomarker of disease activity, but a potent mediator of ventricular and vascular remodeling and disease progression.
Elevated plasma concentrations of aldosterone are due to
both increased adrenal production and decreased hepatic
clearance.17 In patients with HF, major triggers of aldosterone release include angiotensin II (especially when intravascular volume is reduced with diuretic therapy), serum
potassium concentration, and corticotropin.18 Additional
stimuli that play a minor role in normal adults but are upregulated in HF include circulating arginine vasopressin, catecholamines, and endothelin. Aldosterone has pleiotropic
effects on the heart, kidney and the vasculature (Table 1).
In the myocardium, aldosterone exerts growth-promoting
and pro-fibrotic effects on myocytes and the interstitium, respectively. Transgenic mouse models demonstrate that
cardiac-specific overexpression of 11b-hydroxysteroid
dehydrogenase type 2 with activation of mineralocorticoid
receptors leads to concentric ventricular remodeling, myocardial fibrosis and premature death.19 This phenotype can
be attenuated and survival enhanced with aldosterone receptor blockade. Reduction in dietary salt intake may also play
a key role in limiting aldosterone-mediated cardiovascular
damage.20
Beyond the adrenal cortex, aldosterone is produced by
vascular endothelial cells where it promotes inflammation
and fibrosis leading to endothelial dysfunction. Relevant
to patients with ischemic HF, stimulation of mineralocorticoid receptors in the coronary and peripheral arteries also
exerts proatherogenic effects, which are accelerated by
downregulation of the inhibitory enzyme 11b-hydroxysteroid dehydrogenase type 2.21 Numerous studies in animals
and humans have demonstrated salutary effects of aldosterone receptor blockade on vasomotor reactivity,22 baroreceptor responsiveness,23 and norepinephrine uptake.
Myocardial injury can be attenuated by inhibiting the development of coronary inflammatory lesions.24 These experimental data provide an explanation for reduction in both
HF and sudden death mortality demonstrated in RALES,
EPHESUS, and EMPHASIS-HF.7,8,11
In the kidney, aldosterone has long been understood to
promote reabsorption of sodium and water from tubular
fluid, an effect that is regulated by the a-subunit of the
Table 2. Aldosterone Antagonists in Heart Failure: Evidence From Randomized Controlled Trials
Trial
RALES
n
7
Primary Endpoint
Death or HF
Hospitalization, n
(%) RR (95% CI)
Serious
Hyperkalemia,
n (%)
CV death or CV hospitalization $6 mmol/L
0.68 (0.59e0.78), P ! .001 14 (2) S
10 (1) P.
P 5 .42
822 S
841 P
NYHA Class III/IV
(IV within 6 months
prior) (SCr O2.5
mg/dL or serum
potassium O5
mmol/L excluded)
All-cause mortality
24
95% S
94% P
11% S
10% P
284 (35) S
386 (46) P
0.7 (0.60e0.82),
P ! .001
3319 E
3313 P
AMI, LVEF #40,
and HF symptoms
(SCr O2.5 mg/dL
or serum potassium
O5 mmol/L
excluded)
Co-primary: Time to
death from any cause
Time to CV death
or first CV
hospitalization
16
86% E
87% P
75% E
75% P
478 (14.4) E
CV death or CV hospitalization
554 (16.7) P
885 (26.7%) E
0.85 (0.75e0.96),
993 (30%)
P 5 .008
P 0.87 (0.79e0.95),
P 5 .002
$6 mmol/L
180 (5.5) E
126 (3.9) P
P 5 .002
21 (median)
94% E
93% P
87% E
87% P
171 (12.5) E
CV death or HF hospitalization
213 (15.5) P
(primary endpoint)
0.76 (0.62e0.93), 249 (18.3) E
P 5 .008
356 (25.9) P
HR 0.63 (0.54e0.74),
P ! .001
O6 mmol/L
33 (2.5) E
25 (1.9) P, P 5 .29
O5.5 mmol/L
158 (11.8) E
96 (7.2) P, P ! .001
EMPHASIS-HF11 1364 E
1373 P
NYHA Class II
(NYHA III/IV, eGFR
!30 mL/min, serum
potassium O5
mmol/L excluded)
CV death or first
HF hospitalization
ACE, angiotensin-converting enzyme; AMI, acute MI; CV, cardiovascular; E, eplerenone; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; NYHA, New York
Heart Association; S, spironolactone; P, placebo; RALES, Randomized Aldactone Evaluation study; SCr, serum creatinine.
Update on Aldosterone Antagonists in HF
EPHESUS8
Population
Mean Length
All-cause
of Follow-up ACE inhibitor b-blocker, Mortality, n (%)
(Months)
or ARB, %
n (%)
RR (95% CI)
Butler et al
267
268 Journal of Cardiac Failure Vol. 18 No. 4 April 2012
epithelial sodium channel.25 More recent data suggest that
stimulation of mineralocorticoid receptors in the renal cortex can also contribute to ischemic injury, mesangial cell
proliferation, and nephrosclerosis.26 In kidneys isolated
from diabetic27 or spontaneously hypertensive rats,20 aldosterone activity is increased in glomeruli and proximal tubules, and is associated with podocyte apoptosis and
proteinuria. Notably, these effects can be reversed with spironolactone or eplerenone. In addition, aldosterone can alter the intrarenal hemodynamics regulating glomerular
filtration. As demonstrated in the myocardium, mechanisms
of renal damage likely involve induction of reactive oxygen
species and inflammatory molecules. Although the impact
of aldosterone-mediated renal damage in HF remains unclear, the growing population of patients with coexistent
cardiac and renal dysfunction (or cardiorenal syndrome)28
suggests that aldosterone antagonists may have renoprotective as well as cardioprotective effects.
Overview of Pharmacology
Aldosterone exerts its effects by binding to the mineralocorticoid receptor. In the United States, 2 pharmacologic
agents competitively inhibit aldosterone at the mineralocorticoid receptor sites, spironolactone and eplerenone.
Spironolactone is a nonselective MRA that is structurally
similar to progesterone. In addition to its aldosteroneblocking effects, spironolactone inhibits the effects of
dihydrotestosterone at the receptor site and increases the
peripheral conversion of testosterone into estradiol.29 As
a result, it is associated with antiandrogenic and progestogenic adverse effects including gynecomastia, impotence,
and menstrual irregularities.
Eplerenone is a selective MRA, with a 100- to 1000-fold
lower affinity for androgen, glucocorticoid, and progesterone receptors than spironolactone.30,31 As a result, eplerenone is not associated with the antiandrogenic side effects
observed with spironolactone therapy. Some data also suggest that eplerenone may influence other steroid receptors
to a lesser degree than spironolactone.32 In 1 study of 107 patients with mild HF, serum cortisol levels and hemoglobin
A1c increased from baseline in patients treated with spironolactone and did not change in those treated with eplerenone.32 Whether these effects are clinically relevant is not
known. Based on currently available data, the pharmacologic
differences between spironolactone and eplerenone appear
to be limited to tolerability (antiandrogenic or other
steroid-related side effects) rather than clinical efficacy, as
both drugs have been shown to improve outcomes in HF.
Eplerenone is extensively metabolized to inactive metabolites, whereas spironolactone is metabolized to the active
metabolite canrenone.31,33 In the distal tubule, aldosterone
promotes sodium reabsorption and potassium excretion.
Aldosterone antagonists block potassium excretion in the
renal distal tubule and collecting ducts, leading to the risk
of hyperkalemia.
Review of the Evidence
Several randomized controlled trials of aldosterone antagonists in patients with HF and reduced LVEF have
been conducted to date (Table 2). A systematic review of
these and other studies with aldosterone receptor antagonists included 10 trials that have specifically enrolled
New York Heart Association (NYHA) Class II patients
with reduced LVEF.34
NYHA Class III or IV
The RALES trial evaluated patients with NYHA Class
III/IV symptoms, LVEF #35%, and background
angiotensin-converting enzyme (ACE) inhibitor therapy.7
Patients with serum creatinine O2.5 mg/dL were excluded.
Mean age of participants was 65 6 12 years, 73% were
male, 55% had ischemic cardiomyopathy, and mean
LVEF was 25.6 6 6.7%. While 95% of patients were on
an ACE inhibitor, only 11% were treated with a b-blocker.
The mean spironolactone dose achieved was 26 mg/day.
After a mean follow-up of 24 months, spironolactone reduced the primary endpoint of all cause mortality by 31%
compared with standard therapy (relative risk [RR] 0.69,
95% confidence interval [CI] 0.58e0.82, P ! .001).7 HF
hospitalizations, cardiovascular hospitalizations, and cardiac mortality rates were also lowered. Patients treated
with a b-blocker at baseline derived a similar benefit
from spironolactone as the overall population. The number
needed to treat (NNT) with spironolactone for 2 years to
save 1 life was 9 patients in this population with an annualized placebo mortality rate of w27%.
NYHA Class II
The EMPHASIS-HF trial was a randomized, doubleblind, placebo controlled trial of eplerenone or placebo in
addition to standard therapy in 2737 patients O55 years
old with NYHA Class II HF and LVEF #35%.11 Patients
with an estimated glomerular filtration rate (eGFR) !30
mL/min per 1.73 m2 or serum potassium O5.0 mmol/L
were excluded. Additionally, patients had to be enrolled
within 6 months of a cardiac hospitalization or have an
elevated BNP level O250 pg/mL or N terminal B-type
natriuretic peptide O500 pg/mL (men) or O750 pg/mL
(women). Patients with an LVEF between 31% and 35%
were additionally required to have QRS duration of $130
ms. Patients enrolled in EMPHASIS-HF had a mean age
of 68.7 6 7.7 years, 78% were male, 69% had an ischemic
cardiomyopathy, and mean LVEF was 26.2 6 4.6%. The
majority of patients received either an ACE-inhibitor or angiotensin receptor blocker (ARB) (94%), and b-blocker
(87%). Eplerenone reduced the risk of the primary endpoint
of cardiovascular death or HF hospitalization (hazard ratio
[HR] 0.63, 95% CI 0.54e0.74, P ! .001) and all-cause
mortality (adjusted HR 0.76, 95% CI 0.62e0.93, P !
.008) after a median of 21 months of follow-up. Additional
reductions were observed in all-cause, cardiac, and HF
Update on Aldosterone Antagonists in HF
hospitalizations. These findings were consistent across all
prespecified subgroups including those with the presence
of an implantable cardioverter defibrillator, cardiac resynchronization therapy, a prolonged QRS duration, or
LVEF above 30%. Overall, the NNT with eplerenone to
postpone 1 death per year of follow-up was 51 patients
(95% CI 32e180) in this population with an annualized
placebo mortality rate of 7.1%.
The anti-remodelling effect of canrenone in patients
with mild chronic heart failure (AREA IN-CHF) trial
was a randomized, double-blind, placebo-controlled trial
of 467 patients with NYHA Class II HF symptoms and
LVEF #45% on optimal background therapy, who were
randomized to canrenone (the active metabolite of spironolactone; not available in North America) or placebo.35
Patients enrolled had a mean age of 62 6 9.5 years, 84%
were male, 51% had an ischemic cardiomyopathy, and
mean LVEF was 40% 6 8.6%. Ninety-six percent were
on an ACE inhibitor or ARB, and 81% were on a b-blocker.
The mean dose of canrenone achieved was 44 mg/day. The
primary endpoint of reduction in left ventricular end diastolic volume at 12 months was not significantly different
between the 2 groups. However, LVEF improvement was
higher in the canrenone arm as compared with placebo
(canrenone 39.9 6 8.6 to 45.1 6 9.6 vs. placebo 39.7 6
8.6 to 42.9 6 9.7; P 5 .04). After 12 months, the canrenone group had a nonsignificant reduction in all-cause
mortality compared with placebo (2.8% vs. 5.4%, P 5
.17). Additionally, the composite of cardiac death or hospitalization was significantly lowered with canrenone (7.9%
vs. 15.1%, P 5 .02).35
Post-MI HF
In EPHESUS, patients 3 to 14 days post-MI with LVEF
#40 and HF signs (pulmonary rales, pulmonary venous
congestion, or S3) were randomized to eplerenone or placebo. Post-MI patients with diabetes and LVEF #40
were not required to have HF signs or symptoms. Mean
age of the patients was 64 6 11years, 70% were men,
and mean LVEF was 33 6 6%. Most patients received
background therapy with an ACE inhibitor or ARB
(86%) and b-blocker (75%). The mean dose of eplerenone
achieved was 43 mg/day. After a mean follow-up of
16 months, eplerenone reduced the coprimary endpoints
of all-cause mortality by 15% (RR 0.85, 95% CI
0.75e0.96) and cardiovascular death or cardiovascular
hospitalization by 13% (RR 0.87, 95% CI 0.72e0.94).
All-cause death or all-cause hospitalization (RR 0.92,
95% CI 0.86e0.98) and cardiovascular death (RR 0.83,
95% CI 0.72e0.94) were also reduced.8 In the diabetes cohort who were not required to have HF signs and symptoms, eplerenone reduced the relative risk of the
composite endpoint of cardiovascular mortality or any hospitalization by 17% (RR 0.83, 95 % CI 0.71e0.98; P 5
.031).36 Findings were consistent across multiple prespecified subgroups. The estimated NNT to save 1 life per year
Butler et al
269
was 50, and the NNT was 33 to prevent 1 cardiovascular
death or one cardiovascular hospitalization in this population with an annualized mortality of 13.6%.8
Impact of New Evidence on Guideline
Recommendations/Clinical Practice
The impact of the new evidence on guideline recommendations is summarized in Table 3.
Role of Eplerenone and Spironolactone
The European Society of Cardiology, American College
of Cardiology Foundation (ACCF)/American Heart Association (AHA), and HFSA all recommend the administration
of a low-dose aldosterone antagonist (spironolactone 12.5
to 25 mg or eplerenone 25 mg daily) in patients with an
LVEF #35% and NYHA Class IIIeIV symptoms in the absence of significant renal dysfunction or hyperkalemia.1,9,10
The ACCF/AHA also recommends eplerenone in patients
after an acute MI with clinical HF signs and symptoms
and a LVEF !40%.10 The HFSA suggests health care providers should consider using eplerenone in this clinical
scenario.1
On the basis of data from the RALES,7 EPHESUS,8 and
more recently EMPHASIS-HF11 trials, there are 3 clinical
scenarios where aldosterone antagonism in the absence of
significant renal dysfunction or hyperkalemia may be
used: 1) LVEF #35% and NYHA Class IIIeIV symptoms;
2) post-MI with signs and symptoms of acute HF and LVEF
#40%, or post-MI patients with diabetes and LVEF #40%
(regardless of HF symptoms); and 3) LVEF #30% (or if
LVEF O30 to 35 then QRS O130 ms should also be present), NYHA Class II symptoms and another high risk feature (eg, age O55 years, HF hospitalization within the
previous 6 months [or if no hospitalization, BNP O250
pg/mL, NT-proBNP O500 pg/mL (men) or O750 pg/mL
(women)]. Renal function and electrolytes should be evaluated before therapy initiation. Recommendations for dosing
and monitoring are shown in Table 4.
Order of Therapy
ACE inhibitors and b-blockers form the foundation of effective HF therapy.1 After optimization of these agents, clinicians may choose to initiate therapy with an ARB, an
aldosterone antagonist, or the combination of hydralazine
and isosorbide dinitrate. Specific recommendations for adding a third agent are included in the 2010 HFSA guidelines.
The EMPHASIS-HF trial results justify a reexamination of
the evidence-based approach to selecting add-on therapy in
patients with mild HF.
Background Therapy
In EMPHASIS-HF, the majority of patients were treated
with an ACE inhibitor or ARB and b-blocker. The magnitude of benefit for eplerenone was smaller in the subgroup
of patients not receiving a b-blocker at baseline, but there
was no statistical evidence of heterogeneity.11 A similar
Existing Recommendation (2010 Guideline)
7.14. Administration of an aldosterone antagonist is recommended for patients with
NYHA Class IV (or Class III, previously Class IV) HF from reduced LVEF (!
35%) while receiving standard therapy, including diuretics (Strength of
Evidence A).
7.15. Administration of an aldosterone antagonist should be considered in patients
following an acute MI, with clinical HF signs and symptoms or history of diabetes
mellitus, and an LVEF !40%. Patients should be on standard therapy, including
an ACE inhibitor (or ARB) and a b-blocker (Strength of Evidence A).
7.16. Aldosterone antagonists are not recommended when creatinine is O2.5 mg/dL
(or creatinine clearance is !30 mL/min) or serum potassium is O5.0 mmol/L or
in conjunction with other potassium-sparing diuretics (Strength of Evidence A).
7.17. It is recommended that serum potassium concentration be monitored
frequently following initiation or change in an aldosterone antagonist. Monitoring
should reflect protocols followed in clinical trials (Strength of Evidence A).
7.18. In the absence of persistent hypokalemia (!4.0 mmol/L), supplemental
potassium is not recommended in patients taking an aldosterone antagonist
(Strength of Evidence A).
7.21. Additional pharmacologic therapy should be considered in patients with HF
and reduced LVEF who have persistent symptoms or progressive worsening
despite optimized therapy with an ACE inhibitor and b-blocker. The choice of
specific agent will be influenced by clinical considerations, including renal
function status, chronic serum potassium concentration, blood pressure, and
volume status. The triple combination of an ACE inhibitor, an ARB, and an
aldosterone antagonist is not recommended because of the high risk of
hyperkalemia (Strength of Evidence C).
Addition of an aldosterone antagonist:
for severe HF (Strength of Evidence A)
for moderate HF (Strength of Evidence C)
Addition of an ARB (Strength of Evidence A)
7.22. Additional pharmacological therapy should be considered in patients with HF
and reduced LVEF who are unable to tolerate a b-blocker and have persistent
symptoms or progressive worsening despite optimized therapy with an ACE
inhibitor. The choice of specific agent will be influenced by clinical
considerations, including renal function status, chronic serum potassium
concentration, blood pressure, and volume status. The triple combination of an
ACE inhibitor, an ARB, and an aldosterone antagonist is not recommended due to
the high risk of hyperkalemia (Strength of Evidence C).
Addition of an ARB (Strength of Evidence C)
Addition of an aldosterone antagonist
for severe HF (Strength of Evidence C)
for moderate HF (Strength of Evidence C)
Summary of Potential Change
Expand to include NYHA Class II
Potential Change Related to New Evidence
No change
7.14. Administration of an aldosterone antagonist is recommended for patients with
NYHA Class II*-IV HF from reduced LVEF (!35%) while receiving standard
therapy, including ACE inhibitor (or ARB if ACE inhibitor is not tolerated) and
b-blocker (Strength of Evidence A).
No change
No change
No change
No change
No change
No change
No change
Change to Strength of Evidence A
7.21 Additional pharmacologic therapy should be considered in patients with HF
and reduced LVEF who have persistent symptoms or progressive worsening
despite optimized therapy with an ACE inhibitor and b-blocker. The choice of
specific agent will be influenced by clinical considerations, including renal
function status, chronic serum potassium concentration, blood pressure, and
volume status (Strength of Evidence A).
No change
Change to ‘‘mild to moderate HF’’
Change to Strength of Evidence A
Change to ‘‘may be considered’’
Move statement regarding triple
combination to a stand-alone
recommendation highlight
importance
No change
7.21(a). The addition of an aldosterone antagonist is recommended in the following
clinical scenarios:
for severe HF (Strength of Evidence A)
for mild to moderate HF (NYHA Class II*-III) (Strength of Evidence A)
7.22 (b). The addition of an ARB may be considered in patients who do not meet
criteria for or who do not tolerate an aldosterone receptor antagonist (Strength of
Evidence A)
7.22 (c). The triple combination of an ACE inhibitor, an ARB, and an aldosterone
antagonist is not recommended because of the high risk of hyperkalemia or renal
impairment (Strength of Evidence A).
No change
No change
No change
No change
Change to include mild heart failure
No change
For mild* to moderate HF (Strength of Evidence C)
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; HF, heart failure; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association.
*For NYHA Class II, high-risk modifiers should also be present: LVEF #30% (if LVEF O30-35, then QRS O130 ms should also be present), age O55 years, HF hospitalization within 6 months (if no hospitalization within 6 months then BNP O250 pg/mL or NT-proBNP O500 pg/mL [men] or 750 pg/mL [women] should be present).
270 Journal of Cardiac Failure Vol. 18 No. 4 April 2012
Table 3. Impact of New Evidence on HFSA Guideline Recommendations1
Hold until K !5.0 mmol/L
Restart at 25 mg once daily
For K O6.0 mmol/L
Reassess after 72 hours,
and for K that returns
to !5.0 mmol/L
eGFR, estimated glomerular filtration rate; K, potassium.
*These dosing guidelines were used in the EMPHASIS-HF trial under the close supervision and monitoring typical of a randomized controlled, clinical trial. In clinical practice, a more conservative approach
may be warranted, such as holding the aldosterone antagonist until serum potassium is #5.5 mmol/L.
Restart at 12.5 mg once
daily or every other day
Restart at 12.5e25 mg
once daily
25 mg once daily
*For K 5.5e5.9 mmol/L
Restart at 25 mg once
every other day
12.5e25 mg once daily
or every other day
Hold until K !5.0 mmol/L
50 mg once daily
Maintenance dose after 4
weeks (if K #5 mmol/L)
25 mg once every
other day
Hold until K !5.0 mmol/L
25 mg once or twice daily
12.5e25 mg once
every other day
Hold until K !5.0 mmol/L
Monthly for first
3 months, then
regularly at 3- to
4-month intervals
Within 72 hours to 1 week
of the initial dose, with
any dose titrations, or with
any alterations in other
concomitant drugs, diseases,
or acute illnesses that may
influence potassium levels
25 mg once daily
Initial dose
25 mg once every
other day
25 mg once daily
12.5e25 mg once daily
12.5 mg once daily
or every other day
12.5-25 mg once daily
Routine
Interim
eGFR 30e49
mL/min/1.73 m2
eGFR $50
mL/min/1.73 m2
eGFR 30e49
mL/min/1.73 m2
eGFR $50
mL/min/1.73 m2
Spironolactone
Eplerenone
Table 4. Aldosterone Receptor Antagonist Recommended Dosing and Monitoring11,94
Time Points for Potassium and Serum
Creatinine Monitoring
Update on Aldosterone Antagonists in HF
Butler et al
271
result with regard to ARB add-on therapy was observed in
the subgroup of patients not receiving a b-blocker in the
CHARM-Added trial.37 These data suggest that ACEinhibitors and b-blockers should be initiated and optimized
as clinically appropriate before initiating therapy with an
aldosterone receptor antagonist or ARB.
Add-on Therapy
In the CHARM-Added trial, candesartan, added to background ACE inhibitor and b-blocker therapy, decreased the
risk of cardiovascular death or HF hospitalization (the primary endpoint) by 15%, but it did not significantly reduce
all-cause mortality (Table 5).37 In EMPHASIS-HF, eplerenone reduced the risk of cardiovascular death or HF hospitalization (the primary endpoint) by 37%, and it also decreased
the risk of all-cause mortality by 24% (Table 5).11 Both the
magnitude of benefit on the composite endpoint and the statistical certainty around the result were greater for eplerenone
than for candesartan.
The combination of hydralazine and isosorbide dinitrate
is another option for add-on therapy. The majority of evidence supports this therapy for African American patients
with HF, but it may be considered in non-African Americans as well.1 The combination of hydralazine and isosorbide dinitrate is more relevant to the moderate to severe
HF population, because few patients (0.2%) in AfricanAmerican Heart Failure Trial (A-HeFT) had NYHA Class
II symptoms.38 Thus, in African Americans, aldosterone
antagonists may be used as add-on therapy in NYHA Class
II patients after ACE inhibitors and b-blockers, followed by
hydralazine and isosorbide dinitrate in patients who remain
symptomatic. However, it should be noted that only 2.7% of
patients in EMPHASIS-HF were African American. A retrospective analysis of A-HeFT suggested the morbidity and
mortality benefit of spironolactone in African Americans
was limited to those randomized to receive hydralazine
and isosorbide dinitrate (39% of A-HeFT patients were
treated with spironolactone), but these data require further
evaluation in a prospective study.39
Combination Add-on Therapy
In EMPHASIS-HF, a very small number of patients
(n 5 85) were treated with background combination of
beta-blocker, ACE-inhibitor, and ARB. In this subgroup,
the direction of eplerenone’s effect on the primary endpoint
was similar to the overall result. However, the confidence
interval was wide and conclusions about the safety and efficacy of this 4-drug combination cannot be drawn from this
subgroup analysis.11 The triple combination of an ACE inhibitor, ARB, and aldosterone antagonist is not recommended because of the high risk of hyperkalemia, although this
recommendation is based primarily on expert opinion rather
than prospective clinical trial data.1
Primary endpoint
HR 0.85 (0.75e0.96), P 5 .010
A-HeFT, African-American Heart Failure Trial; C, candesartan; CHARM, Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity; EMPHASIS-HF, Eplerenone in Mild Patients
Hospitalization And SurvIval Study in Heart Failure; HF, heart failure; H/I, hydralazine/isosorbide dinitrate; P, placebo; V, valsartan; Val-HeFT, Valsartan Heart Failure Trial.
Primary endpoint
HR 0.63 (0.54e0.74), P ! .001
77e78%
87%
19%
171 (12.5%) E
213 (15.5%) P
HR 0.76 (0.62e0.93), P 5 .008
69%
74%
17%
32 (6.2%) H/I
54 (10.2%) P
HR 0.57, P 5 .01
95% CI not given
Data not given
41%
55%
n/a
Primary endpoint
1398 (37%) C
1541 (41%) P
HR 0.9 (0.82e0.99), P 5 .032
HR 0.82 (0.77e0.91), P ! .0001
92.6%
34.5%
n/a
Coprimary endpoint
495 (19.7%) V
484 (19.4%) P
RR 1.02 (0.88e1.18), P 5 0.8
Co-primary endpoint (all-cause
mortality þ morbidity [resuscitated
cardiac arrest, HF hospitalization, or
IV inotrope/vasodilator])
723 (28.8%) V
801 (32.1%) P
RR 0.87 (0.77e0.97), P 5 .009
Mean age (SD), years
Mean LVEF (SD), %
NYHA Class II, %
Background therapy
ACEI
BB
ARB
All-cause
Mortality, n
Deaths
HR (95% CI)
CV death or HF
hospitalization
62 (11)
26.6 (7.3)
62.1%
66 (11)
38.8 (14.9)
44e45%
64 (11)
28 (7.5)
24%
100%
55e56%
n/a
377 (30%) C
412 (32%) P
HR 0.89 (0.77e1.02), P 5 .105
69 (8)
26 (5)
100%
Eplerenone
Hydralazine isosorbide
dinitrate (BiDil)
57 (13)
24 (7)
0.2%
ARB (candesartan)
Add-on drug class
ARB (valsartan)
ARB (candesartan)
A-HeFT
CHARM-Added
CHARM-Overall
Val-HeFT
Table 5. Comparison of Evidence Supporting Add-on Therapy
EMPHASIS-HF
272 Journal of Cardiac Failure Vol. 18 No. 4 April 2012
Individualization of Therapy
Although the totality of evidence is in favor of an aldosterone receptor antagonist as first-line add-on therapy, an
ARB may be preferable in some clinical situations. Patients
with renal impairment or serum potassium levels outside
the recommended range for an aldosterone antagonist
(eGFR !30 mL/min/1.73 m2 or potassium O5 mmol/L)
may be able to tolerate an ARB. In a pooled analysis of
ARB chronic HF trials, 3.5% of patients randomized to
the ARB arm (in addition to background ACE-inhibitor)
developed serum potassium levels O5.5 mEq/L.40 In comparison, 11.8% of patients randomized to eplerenone in
EMPHASIS-HF developed hyperkalemia (serum potassium
O5.5 mEq/L).11 The meta-analysis included Candesartan
in Heart Failure Assessment of Reduction in Mortality
and Morbidity (CHARM)-added, Val-HeFT, and Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD); the majority of these patients were
NYHA Class II (CHARM-added 24%, Val-HeFT 62%, RESOLVD 66%) or NYHA Class III (CHARM-added 73%;
Val-HeFT 36%; RESOLVD 33%).2,37,40,41 Thus, patients
should be closely monitored due to the risk of renal impairment and hyperkalemia that still exists with ARB therapy.
Recommended Clinical Approach
After ACE inhibitor and b-blocker therapy, the 2010
HFSA guideline recommendation supports the consideration of an ARB (Level of Evidence A) or an aldosterone
antagonist (moderate HF Level of Evidence C; severe HF
Level of Evidence A) as add-on therapy.1 Based on the totality of evidence, an aldosterone receptor antagonist
should now be considered as first-line add-on therapy for
patients who are eligible based on serum potassium and
creatinine levels. An ARB should be considered as firstline add-on therapy for patients who are not candidates or
who do not tolerate aldosterone blockade (Table 1).
Are Spironolactone and Eplerenone Interchangeable?
Few studies have evaluated the class effect of spironolactone and eplerenone. One 8-week, multicenter,
double-blind, placebo lead-in, parallel group, doseranging hypertension trial compared the efficacy, safety,
and tolerability of both drugs.42 During the double-blind
phase, patients were randomized to eplerenone 50, 100,
or 400 mg once daily; eplerenone 25, 50, or 200 mg twice
daily; spironolactone 50 mg twice daily; or placebo. The
primary endpoint was change in diastolic blood pressure.
The decrease in diastolic blood pressure among patients receiving eplerenone 100 mg was lower than that of patients
receiving spironolactone 100 mg, suggesting that eplerenone may be less potent than spironolactone. However,
eplerenone was never directly compared with spironolactone; both were compared with placebo only. Table 2 summarizes the characteristics of the 3 randomized controlled
trials of eplerenone and spironolactone with regard to their
Update on Aldosterone Antagonists in HF
use in patients with HF and post-MI left ventricular systolic
dysfunction. The eplerenone trials have included more patients (9369 eplerenone vs. 1663 spironolactone), and the
mean eplerenone doses were higher than the spironolactone
doses (43.5 mg/day and 39 mg/day vs. 26 mg/day).
Whether or not the 2 aldosterone antagonists can be interchanged is not known, particularly for a population in
which spironolactone has not been studied. Pharmacologic
differences and the lack of efficacy data make the substitution of one for the other problematic. Recent studies of
other drugs suggest that class effects are not universal.
For example, differential effects between statins, thiazolidinediones, and b-blockers have been well studied and documented.43-45 The substantial difference in cost between the
2 drugs makes the issue of using spironolactone instead of
eplerenone even more clinically relevant. The cost of generic eplerenone ranges from $1.34 to $2.59 for a 25-mg
dose, whereas a 25-mg dose of InspraÔ ranges from
$3.32 to $5.02. In contrast, generic spironolactone is available for between 15 and 42 cents per tablet and a 30-day
supply is available at large retail chain pharmacies for
approximately $4.00/month.46,47 This dramatic cost differential prompts the question of whether or not it is appropriate to use spironolactone in the care of patients with
conditions for which the drug has not yet been studied
(ie, those with post-MI LV systolic dysfunction and those
with LV systolic dysfunction and mild symptoms of HF).
The work of Hayashi et al supports the extension of spironolactone use to the post-MI setting.48 These investigators used intravenous canrenoate, a metabolite of
spironolactone, in a randomized controlled study of 134 patients with a first acute anterior myocardial infarction. All
patients received an ACE inhibitor along with study drug
immediately after revascularization, and the drug was continued daily for 1 month. LVEF was significantly improved
in the group that received study drug and LV end-diastolic
volume index did not increase, suggesting prevention of
post-MI left ventricular remodeling. The AREA-IN-CHF
trial randomized 467 patients with NYHA Class II HF
symptoms and LVEF #45% on optimal background therapy to canrenone or placebo.35 Patients randomized to canrenone had a greater improvement in LVEF and a decreased
risk of cardiovascular death or rehospitalization.35
Until such time as the effectiveness of these 2 drugs in
several different patient groups are compared in a welldesigned clinical trial, it seems most reasonable for the
clinical use of these agents to be consistent with their use
in clinical trials. Thus, in patients with severe HF and left
ventricular dysfunction, spironolactone should be the
choice. If male patients develop gynecomastia, breast
pain, or impotence or female patients develop menstrual
irregularities or other spironolactone-related side effects,
eplerenone may be substituted. The initiation of eplerenone
should be considered in patient populations paralleling
those studied in EPHESUS and EMPHASIS-HF. If cost
or insurance reimbursement is an issue, as it will be for
many, a reasonable choice is to substitute spironolactone.
Butler et al
273
Severe HF and Post-MI HF
The recommendations for aldosterone antagonist use in
NYHA Class III/IV HF and post-MI HF are unaffected by
the new data generated in EMPHASIS-HF. Thus, clinical
practitioners should follow the recommendations in the current guideline.1 However, it should be noted that in an analysis of a large quality improvement registry, only 32.5% of
12,565 eligible patients hospitalized for acute decompensated heart failure (those meeting guideline criteria without
contraindications) received an aldosterone antagonist at the
time of hospital discharge.49 Focused efforts to reduce this
treatment gap are warranted, although the safety of initiating
MRAs during a heart failure admission has not been tested.
Safety: Monitoring and Follow-up
As with all medical therapy, there are risks to be considered with aldosterone receptor antagonists, especially in
conjunction with other medications that block the reninangiotensin system, alter volume status, or influence potassium levels. The principal risks of aldosterone receptor
antagonists are hyperkalemia, renal dysfunction, and
gynecomastia.40,50e52
Hyperkalemia
Hyperkalemia resulting from aldosterone receptor antagonism has been extensively studied in single-center case-control53 or cohort studies,51 and within the context of clinical
trials. In a systematic review including 19 randomized controlled trials (n 5 10,807 patients), the rate of serious hyperkalemia was 5.9% in the aldosterone antagonist arm and 3%
in the placebo arm.34 Subsequently, in EMPHASIS-HF, the
rate of serum potassium concentration O5.5 mmol/L was
11.8% in the eplerenone group and 7.2% in the placebo group
(P ! .001). Serum potassium O6.0 mmol/L was observed in
2.5% of the eplerenone group, and 1.9% of the placebo group
(P 5 .29). Wei et al conducted an analysis of spironolactone
use in a large nonrandomized cohort of HF patients and reported a 2.9% incidence of hyperkalemia (O6 mmol/L); patients with higher baseline creatinine or potassium levels
were at a higher risk.51
It is important to recognize that the risks of hyperkalemia among patients enrolled in the major randomized controlled trials were limited by the study eligibility criteria.
In general, these patients had baseline serum creatinine
of !2.5 mg/dL (!221 umol/L), serum potassium concentration of !5 mmol/L, and were largely already on a maximally tolerated dose of an ACE inhibitor or ARB. Patients
also underwent frequent laboratory assessment at the time
of study drug initiation or titration, and in the setting of
other illnesses (eg, influenza, diarrhea) or medications
(eg, nonsteroidal anti-inflammatory drugs) that could increase the risk for hyperkalemia or renal impairment. In
the analysis of a community-based population, an increased frequency of potassium and serum creatinine
274 Journal of Cardiac Failure Vol. 18 No. 4 April 2012
monitoring may have contributed to the lower incidence of
serious hyperkalemia.51
When initiating an aldosterone antagonist, the following
patient characteristics should be considered: NYHA Class
IIeIV symptoms, serum potassium concentration !5.0
mmol/L, and eGFR O30 mL/min/1.73 m2. Concomitant
use of potassium sparing diuretics should be avoided. The
frequency of serum creatinine and potassium monitoring
is between 72 hours and 1 week after initiation or uptitration of aldosterone antagonists, then monthly for the first
3 months, followed by every 3 to 4 months thereafter, or
at any time a concurrent disease or other medication could
influence potassium homeostasis (Table 4).
Renal Impairment
Renal dysfunction associated with these drugs is more
difficult to quantify because the cohort and randomized trials have used varying definitions. Within randomized trials,
the overall rate of renal failure (using the definitions from
within each trial) was 8.9% in the aldosterone antagonist
arm and 1.6% in the placebo arm.34 However, in the
EMPHASIS-HF trial, this adverse event was not significantly different between the eplerenone and placebo groups
(2.8% and 3.0%, respectively).11
Gynecomastia
Gynecomastia is an uncommon side effect of spironolactone, and when present, is due to its activity as an
androgen receptor blocker, inhibiting the effects of dihydrotestosterone at the receptor site and increasing the peripheral conversion of testosterone to estradiol.29 The
incidence of gynecomastia in clinical trials of spironolactone was 4% (compared with 0.6% of controls),34 but it
was higher if breast tenderness was included. Eplerenone
is a selective aldosterone receptor antagonist that has a reduced affinity for endocrine receptors. In clinical trials, the
incidence of gynecomastia with eplerenone was similar to
placebo.
potassium and creatinine should be implemented. A lower
eplerenone dose is recommended if these drugs are
used concomitantly. Although grapefruit juice is typically
considered a potent inhibitor of CYP 3A4, it has been shown
to increase eplerenone AUC only to a minor degree (25%).54
Patients should be educated to maintain consistency in their
dietary intake of grapefruit juice. Starfruit is a tropical fruit
that is also a potent inhibitor of CYP 3A4, and although
there are no published studies documenting an interaction
between ingestion of starfruit and eplerenone, avoidance
may be warranted on the basis of its potent inhibitory properties.58 Inducers of the CYP3A4 isoenzyme may lower
eplerenone levels, but the clinical relevance of this interaction has not been established.
Spironolactone is a potent inhibitor of P-glycoprotein.59
Digoxin is a substrate for P-glycoprotein transport, and spironolactone can reduce the renal clearance of digoxin. This
interaction is sometimes difficult to quantify since spironolactone can also cross react with some digoxin assays and
give falsely elevated digoxin concentrations. The need to
reduce digoxin dose when used concomitantly with spironolactone has been documented in the literature, but it
may not be necessary in all patients.60
Pharmacodynamics
Concomitant use of other agents that block potassium excretion or otherwise raise serum potassium levels should be
avoided, with the exception of an ACE inhibitor or ARB.
Thus, concomitant use of potassium-sparing diuretics (amiloride, triamterene), nonsteroidal anti-inflammatory drugs,
pentamidine, and drospirenone (antimineralocorticoid activity similar to spironolactone) should be avoided. Potassium supplements are commonly used among patients
receiving loop diuretics. In many patients, potassium supplementation will not be needed when aldosterone receptor
antagonists are used; however, some patients may still require oral potassium replacement to avoid hypokalemia
and should be monitored closely.
Dietary Considerations
Drug Interactions
Pharmacokinetic
Eplerenone is a substrate of the cytochrome P-450 3A4
isoenzyme.54,55 Thus, the serum concentration of eplerenone is affected by concomitant use of CYP 3A4 inhibitors
or inducers (Table 6). Concomitant use of a CYP 3A4 inhibitor inhibits eplerenone metabolism, thereby increasing
eplerenone serum concentrations, enhancing the risk for hyperkalemia. Drugs that are potent inhibitors of CYP 3A4
(ketoconazole) increase the eplerenone area under the curve
(AUC) by 5-fold and should be avoided in patients treated
with eplerenone.54e57 Erythromycin is a moderate inhibitor
of CYP 3A4, and concomitant administration with eplerenone resulted in a 2- to 3-fold increase in eplerenone
AUC. Moderate to weak inhibitors of CYP 3A4 should be
used cautiously, and more frequent monitoring of serum
Patients should be educated to avoid using potassium
containing salt substitutes (eg, Nu-SaltÔ, No SaltÔ). In patients with a history of hyperkalemia, avoidance of high
potassiumecontaining foods may be reasonable. Patients
should be screened for the use of nutraceuticals, over-thecounter vitamins, or other dietary sources of potassium.
Knowledge Gaps/Research Needs
HF With Preserved Ejection Fraction
HF with preserved ejection fraction (HFPEF) accounts
for approximately half of the overall HF burden in the community.61 Over the past 2 decades, the prevalence growth
rate for HFPEF has exceeded that of HF with reduced
EF.62 This trend may be related to the aging of the population and the age-related changes in cardiac structure and
Table 6. Potential Interactions With Aldosterone Receptor Antagonists
Relevant to Eplerenone Only
Potent inhibitors of
CYP3A4
Avoid concomitant use
Moderate to weak inhibitors of CYP3A4
P-glycoprotein substrates
Avoid concomitant use, or if medically
necessary to use concomitantly, reduce
eplerenone dose and increase monitoring
Fluconazole
Saquinavir
Verapamil
Amiodarone
Diltiazem
Fluoxetine
Fluvoxamine
Zafirlukast
Efavirenz
Indinavir
Ranolazine
Voriconazole
Nilotinib
Aprepitant
Cimetidine
Ciprofloxacin
Norfloxacin
Spironolactone is a inhibitor of P-glycoprotein
and may influence the systemic exposure
of drugs transported by P-gp*
Digoxin (reduction in renal clearance,
prolongation of half-life; also may
produce false increases in serum
digoxin assays)
Alvimopan
Amprenavir
Cimetidine
Colchicine
Cyclosporine
Dexamethasone
Diltiazem
Doxorubicin
Erythromycin
Estradiol
Etoposide
Fexofenadine
Indinavir
Itraconazole
Ivermectin
Loperamide
Methylprednisolone
Morphine
Nelfinavir
Paclitaxel
Quinidine
Ranitidine
Saquinavir
Tetracycline
Verapamil
Vinblastine
Relevant to Both Aldosterone Antagonists
Pharmacodynamic interactions with other drugs that raise serum potassium
Avoid concomitant use
If medically necessary to use concomitantly,
reduce aldosterone antagonist dose and
increase monitoring
Potassium-sparing diuretics
Trimethoprim95
Potassium salts or supplements Heparin
IV penicillin G potassium
NSAIDs
Potassium iodide
Pentamidine
Tolvaptan
Drospirenone
Cyclosporine
Tacrolimus
Butler et al
IV, intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs.
*These interactions have the potential to influence the P-glycoprotein substrate’s systemic exposure. These interactions do not increase the systemic exposure of spironolactone, and therefore would not be
expected to enhance the risk of hyperkalemia associated with spironolactone.
Adapted from references 56,57,59
Update on Aldosterone Antagonists in HF
Ketoconazole
Itraconazole
Erythromycin
Clarithromycin
Imatinib
Nefazodone
Nelfinavir
Ritonavir
Conivaptan
Grapefruit Juice
Telithromycin
Conivaptan
Delavirdine
Relevant to Spironolactone Only
275
276 Journal of Cardiac Failure Vol. 18 No. 4 April 2012
function.63 No interventions tested to date have been shown
to reduce all-cause mortality in this patient population. Patients with HFPEF have a mortality and morbidity burden
that is comparable to patients with HF and reduced EF.62
The RALES, EMPHASIS-HF, and EPHESUS trials of aldosterone antagonists in HF were exclusively conducted
in patients with reduced EF.7,8,11 Extracellular matrix fibrosis plays a major role in ventricular stiffness and relaxation,
and in turn the development of HF.64 Aldosterone promotes
myocardial fibrosis, enhances ventricular stiffness, and
worsens diastolic function. Hypertension potentiates diastolic dysfunction by enhancing myocyte hypertrophy and
interstitial fibrosis.65 Therefore, evaluating aldosterone antagonists in patients with HFPEF is important. Indeed, early
data are promising in this respect,66 and a large scale randomized controlled trial of spironolactone versus placebo,
the Treatment Of Preserved Cardiac Function Heart Failure
with an Aldosterone anTagonist (ie, TOPCAT) in patients
with HFPEF is ongoing.67
LVEF 35% to 45%
The LVEF inclusion criteria in the RALES trial was !
35%. In EMPHASIS-HF, it was !30% or 30% to 35%
with a QRS duration of O130 ms, and in the EPHESUS trial
it was !40%. Although it may appear mostly semantic, the
LVEF cutoff ranges for inclusion in clinical trials have significant impact on the subsequent drug or device approval by the
Food and Drug Administration, and in turn, on practice
guidelines and quality and performance measures. Most trials with HF and systolic dysfunction have included patients
with LVEF !40%, but this criterion has not been uniform.
For example, all studies with cardiac resynchronization therapy and implantable cardioverter defibrillators for primary
prevention included patients with LVEF !35%,68e71 making this cutoff an approved indication for these devices. Similarly, there has been no uniform definition of HFPEF. The
CHARM preserved EF arm included patients with LVEF
O40%,72 whereas I-PRESERVE included patients with
LVEF O45%,73 and Perindopril in Elderly People with
Chronic Heart Failure (PEP-CHF) study included patients
with LVEF 40% to 50%.74
Data for aldosterone antagonism are lacking in patients
with LVEF between 35% and 45%. This is compounded
by the fact that there is modest inter- and intra-observer variability in LVEF assessment.75 If the TOPCAT trial is positive, it is likely, though not certain, that there will be a low
threshold to use aldosterone antagonists in HF across the
spectrum, including patients with LVEF between 35%
and 45%. This supposition is based on an extension of pathophysiologic logic because of consistent positive trials
among patients with LVEF #35 and O45%. If, however,
the TOPCAT trial is negative or neutral, uncertainty will remain regarding the efficacy of using these agents in patients
with LVEF 35% to 45%.
The totality of evidence supports the efficacy of aldosterone receptor antagonists in all symptomatic heart failure
patients, from patients with NYHA Class IV through
NYHA Class II symptoms and the EMPHASIS-HF
enrollment qualifiers (LVEF #30% [if LVEF O30 to 35,
then also QRS O130 ms], age O55 years, HF hospitalization
within 6 months [if no hospitalization within 6 months, then
BNP O250 pg/mL or NT-proBNP O500 pg/mL [men] or
750 pg/mL [women]). It may be reasonable to consider aldosterone antagonists in patients with low LVEF and NYHA
Class II symptoms who do not have the EMPHASIS-HF enrollment qualifiers, but a gap in the evidence currently exists
for this patient population.
HF Prevention: Asymptomatic LV Dysfunction and
Stage B HF
One in 5 Americans will be over the age 65 by 2030.
The incidence and prevalence of HF is highest in the elderly.76 If the current epidemiologic trends continue,
then by 2030 the prevalence of HF will increase by 25%,
as opposed to the estimated 16.6% and 9.9% rise in coronary heart disease and hypertension prevalence, respectively. The economic impact will be a rise in direct and
indirect cost of care to $95 billion annually.77 These trends
underscore the importance of furthering HF prevention
efforts. Subclinical changes in cardiac structure and function, including LV hypertrophy, enlargement, wall motion
abnormalities, diastolic dysfunction, or reduced EF, and
left atrial enlargement, often precede the development of
Stage C HF.10 In cohort studies, LV changes have been
strongly associated with increased HF risk after adjustment for clinical characteristics.78,79 Prevalence of asymptomatic left ventricular dysfunction (ALVD) is up to 16%
in some populations.80e83 Patients with ALVD represent
a group with a distinct opportunity to reduce incident
HF. Patients with ALVD have half the mortality rate (5%
annualized) of those with overt HF; however, the risk of
death is 5 to 8 times higher than a normal age-matched
population.1 In the SOLVD Prevention Study, patients
with untreated ALVD developed overt HF at a 10% annual
rate, with a further 8% annual risk of death or hospitalization for HF.1,84
Both ACE inhibitors and b-blockers reduce the risk of
new-onset HF in patients with ALVD.1,84 Considering the
role of the renin angiotensin aldosterone system in LV dysfunction, it is possible that individuals with ALVD may
benefit from aldosterone antagonists. However, this hypothesis needs to be tested. Similarly, to further prevention efforts, the ACCF/AHA guidelines include LV hypertrophy
in their criteria for Stage B HF.10 Stage B HF is associated
with adverse outcomes among men.85 If the TOPCAT trial
is positive, new questions will emerge as to whether aldosterone antagonists could be used to prevent HF in patients
with certain Stage B clinical characteristics.
Niche HF
HF is a syndrome composed of various etiologies that
all present with a common set of symptoms and signs. Although many patients with nonischemic cardiomyopathy
Update on Aldosterone Antagonists in HF
may not have an identifiable underlying etiology, a distinct
minority have specific causes (eg, amyloidosis, hypertrophic cardiomyopathy, sarcoidosis). These conditions
are not common and patients with these diseases are typically either excluded from trials or represent a distinct
minority of patients enrolled. The use of typical HF
drugs in these clinical scenarios, including aldosterone
antagonists, may be chosen based on a clinical and
pathophysiologic rationale; however, definitive data do
not exist.
In-hospital Initiation and Continuation
Use of aldosterone antagonists is associated with renal
dysfunction and hyperkalemia, especially in conjunction
with the use of agents that effect renal function or
potassium levels. Of significant concern is the coadministration of aldosterone antagonist therapy with an
ACE inhibitor, ARB, diuretic, or potassium supplementation.52 Recently, Albert et al assessed data from the AHA
Get with the Guidelines database and showed a substantial
gap in aldosterone antagonist prescription in eligible patients with acute HF at discharge.49 In-hospital initiation
of medications has been shown to be 1 of the best predictors
of long term adherence.86,87 Concerns with in-hospital initiation of HF medications have also been raised previously,
for example, with b-blocker therapy. However, in several
observational studies, in-hospital initiation of b-blockers
was not only safe (once patients were diuresed), but it
was associated with improved outcomes.87,88 These observational data led to a randomized control trial of b-blocker
initiation at the time of discharge among patients with acute
HF that confirmed the earlier positive observational data.89
Currently, there are no randomized trials of in-hospital initiation of aldosterone antagonists. Data from Get with the
Guidelines are encouraging in this respect. However, in
the absence of randomized trials, the safety of this approach
should not be assumed, and it is prudent to only start this
therapy in patients who have been reliable in terms of close
medical follow-up.
Another related issue is the continuation of aldosterone
antagonists when patients present with acute HF. Acute
HF may be associated with significantly altered renal function because of the primary cause of acute HF (high systemic vascular resistance, high central venous pressure, or
low cardiac output), treatment (diuretics), or to in-hospital
procedures using radiocontrast.90 Close to one third of
acute HF patients develop worsening renal function.91
Thus, the continuation of aldosterone antagonists needs to
be individualized based on the clinical scenario. If these
agents are stopped due to renal concerns, it is important
to consider the safety of restarting them after renal function
stabilizes.
Duration of Therapy in the Setting of Normalized LVEF
One common issue for all HF medications is whether to
discontinue their use if the LVEF normalizes over time.
Butler et al
277
Reverse remodeling and substantial improvement in
LVEF was uncommon before use of b-blocker therapy.
However, ACE inhibitors, b-blockers, and cardiac resynchronization therapy promote reverse remodeling leading to
a substantial minority of patients who normalize their
LVEF on therapy,92 especially those with a nonischemic
etiology.93 As a result, clinicians are faced with a dilemma
of how long multidrug therapy should be continued. Although there are no specific data to help guide this issue,
it may be reasonable to discontinue single-therapies gradually on a trial basis for patients with distinct etiologies
(eg, peripartum cardiomyopathy) provided they can be
closely monitored).
Conclusion
In earlier trials, aldosterone receptor antagonists, or
MRAs, demonstrated clinically meaningful improvements
in rehospitalizations and survival and are now an established, though underused, part of the standard therapy of
selected patients with HF or post-MI LV dysfunction.
The results of the EMPHASIS-HF trial have filled a prominent knowledge gap and support the addition of an MRA
to standard therapy in selected patients with mild HF with
reduced EF. Although formal revisions to established
guidelines will follow, these data suggest that clinicians
should strongly consider the expansion of their use of
MRAs to patients similar to those enrolled in
EMPHASIS-HF and should continue to use these lifesaving agents in patients where current guidelines already
have recommended their use. Large-scale clinical trials are
currently enrolling patients to address additional knowledge gaps regarding MRA therapy in patients with HF as
well as other potential therapeutic targets. Clinicians
should strongly consider the addition of an ARB or
MRA for patients with symptomatic HF already on an
ACE inhibitor and b-blocker. In most situations, an MRA
will be an appropriate addition, proven to provide additional reductions in morbidity and mortality.
Acknowledgments
The HFSA Guideline Committee acknowledges the administrative support of Cheryl Yano, Executive Director,
HFSA and Bart Galle, PhD. We also acknowledge the
HFSA Executive Council for their careful review of this
manuscript, and their contributions to the document: Barry
M. Massie, MD; Thomas Force, MD; Hani N. Sabbah,
PhD; Mandeep R. Mehra, MD; Douglas L. Mann, MD; Inder S. Anand, MD, PhD; John C. Burnett, Jr., MD; John
Chin, MD; Steven R. Houser, PhD; Sharon A. Hunt,
MD; JoAnn Lindenfeld, MD; Sara C. Paul, RN, MSN,
DNP; Mariann Piano, RN, PhD; Heather J. Ross, MD;
James E. Udelson, MD; Michael R. Zile, MD.
Name
Consulting
Fees/Honoraria
Randall C. Starling,
MD, MPH
Biocontrol, Medtronic,
Novartis, Novella,
Thoratec
William G. Stevenson, MD
None
Adrian F. Hernandez, MD
None
Peter E. Carson, MD
None
James C. Fang, MD
Boston Scientific, Medtronic
Stuart D. Katz, MD
Amgen, Inc., BristolMyers
Squibb, Terumo
John A. Spertus, MD, MPH None
Nancy K. Sweitzer, MD, PhD None
W. H. Wilson Tang, MD
Medtronic, St. Jude’s
Medical
Nancy M. Albert, RN, PhD None
Javed Butler, MD
Bayer Healthcare,
Cardiomems, Takeda,
Trevena
Events Committee:
Corthera
Cheryl A. Westlake Canary, None
RN, PhD
Sean P. Collins, MD, MSc
Abbot Point-of-Care, PDL
BioPharma, Astellas,
Otsuka Pharmaceuticals,
Bayer, Trevena, Novartis,
The Medicines
Company, Corthera
Monica Colvin-Adams, MD None
Justin A. Ezekowitz, MBBCh None
Michael M. Givertz, MD
None
Ray E. Hershberger, MD
None
Joseph G. Rogers, MD
Thoratec
John R. Teerlink, MD
Amgen, CardioMEMS,
Corthera, Cytokinetics,
Geron, Momentum
Research, Novartis,
Scios/Johnson &
Johnson, St. Jude
Mary N. Walsh, MD
Wendy Gattis Stough,
PharmD
Medtronic, United
Health Care
HFSA
Speaker’s
Bureau
None
Research Grants
Other
Financial
Benefit
CardioMEMS
None
None
None
None
None
None
Medtronic (fellowship)
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
Medtronic, site investigator
Abbott Laboratories
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
Site investigator for
Medtronic, Amgen, NIH
None
None
None
None
None
None
None
None
None
None
None
Biosignetics , Inovise
Medical Inc, Abbott
Point-of-Care, NIH/NHLBI,
Corthera, BRAHMS
None
None
None
None
None
None
None
None
None
None
None
None
None
Amgen, CardioMEMS,
Corthera, Cytokinetics,
Momentum Research,
National Institutes of
Health, Novartis, Scios/
Johnson & Johnson,
St. Jude
None
None
None
None
None
None
None
Otsuka
Biotronik (paid to
Cleveland Clinic)
Equity
Interests/
Stock/Stock Equity Royalty Non-Royalty
Options Interests Income Payments
Intellectual
Property Fellowship
Support
Salary Rights
UNOS Board None
Member
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
KCCQ
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
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278 Journal of Cardiac Failure Vol. 18 No. 4 April 2012
Disclosures
Update on Aldosterone Antagonists in HF
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