REVIEW

CME EDUCATIONAL OBJECTIVE: Readers will adhere to an evidence-based approach to managing heart failure with
CREDIT reduced ejection fraction
IKE S. OKWUOSA, MD OLUSEYI PRINCEWILL, MD, MPH CHIEMEKE NWABUEZE, MD LENA MATHEWS, MD STEVEN HSU MD
Division of Cardiology, The Johns Division of Cardiology, The Johns Hopkins Georgetown University School of Medicine, Division of Cardiology, The Johns Division of Cardiology, The Johns
Hopkins Hospital, Baltimore, MD Hospital, Baltimore, MD Washington, DC Hopkins Hospital, Baltimore, MD Hopkins Hospital, Baltimore, MD

NISHA A. GILOTRA, MD SABRA LEWSEY, MD, MPH ROGER S. BLUMENTHAL, MD STUART D. RUSSELL, MD
Director, Heart Failure Bridge Clinic, Advanced Division of Cardiology, The Johns Hopkins Division of Cardiology, The Johns Hopkins Division of Cardiology, The Johns
Heart Failure/Transplant Cardiology, Division Hospital, Baltimore, MD Hospital, Baltimore, MD Hopkins Hospital, Baltimore, MD
of Cardiology; Assistant Professor of Medicine,
The Johns Hopkins Hospital, Baltimore, MD

The ABCs of managing systolic

heart failure:
Past, present, and future
ABSTRACT
Heart failure management is complex and constantly
M anaging heart failure is a challenge.
To aid clinicians in this task, the Ameri-
can College of Cardiology Foundation (ACC)
evolving. The American College of Cardiology and the and the American Heart Association (AHA)
American Heart Association (ACC/AHA) last issued evi- publish evidence-based guidelines, most re-
dence-based guidelines in 2013, and since then, new drugs cently in 2013.1 Since then, new drugs and
and devices have been developed. This review presents an devices have been shown to improve survival
evidence-based approach to current heart failure manage- and reduce hospitalizations.
ment. See related editorial, page 766
KEY POINTS This paper reviews the ABCs of outpatient
Most patients with systolic heart failure (also called heart management of systolic heart failure (or heart
failure with reduced ejection fraction) should receive either failure with reduced ejection fraction), includ-
an angiotensin-converting enzyme inhibitor or an angio- ing the results of major trials and recommen-
tensin II receptor blocker. Most should also receive a beta- dations.
blocker (carvedilol, metoprolol succinate, or bisoprolol).
A common and serious condition

If symptoms persist or progress despite these treatments, A Angiotensin

Aldosterone
an aldosterone receptor antagonist (spironolactone or
eplerenone) is recommended. A common and serious condition
Heart failure is a debilitating syndrome that
takes a significant physical and mental toll on
Since the publication of the ACC/AHA guidelines in 2013, those affected.
the combination of sacubitril and valsartan has been ap- And it is common. An American age 40 or
proved, as has ivabradine. older faces a 20% lifetime risk of heart failure.1
An estimated 5.1 million Americans have
Patients with advanced heart failure should be identified clinical signs and symptoms of heart failure,
early for consideration of resynchronization therapy, an and 900,000 new cases are diagnosed each
implantable cardiac defibrillator, digoxin, a left ventricu- year.2 By 2030 the prevalence of heart failure
is projected to increase by 46%, and 9 million
lar assist device, or heart transplant.
Americans will have been diagnosed with it.2
The severity of heart failure can be de-
B-type natriuretic peptide levels can be used to guide scribed using either the functional classifica-
therapy. tion devised by the New York Heart Associa-
doi:10.3949/ccjm.83a.16006 tion (NYHA; Table 1) or the stages defined by
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 MANAGING SYSTOLIC HEART FAILURE

TABLE 1
Heart failure stages and functional classes
NYHA class I NYHA class II NYHA class III NYHA class IV
No physical limitations Slight limitation Marked limitation Symptoms at rest
of physical activity of physical activity
Stage A Stage B Stage C Stage D
Patients at risk for heart Structural disease Structural disease End-stage disease
failure No heart failure symptoms Heart failure symptoms
No structural disease
NYHA = New York Heart Association

the ACC and AHA.1,3 Though survival rates SOLVD (the Study of Left Ventricular
have improved, there is a direct correlation Dysfunction) extended the use of ACE inhibi-
between worsening symptoms and death.4 tors to all patients with heart failure, not just
Heart failure is the leading cause of hospi- those in NYHA class IV. It randomized 1,284
talizations annually. It accounts for $30 billion patients with heart failure of any NYHA class
in healthcare costs, with direct medical costs and an ejection fraction less than 35% to re-
accounting for 68% and another $1.8 billion ceive either enalapril or placebo, and demon-
associated with clinic visits, most often with strated a 16% relative risk reduction in mor-
primary care providers. By 2030, the cost is tality in the enalapril group, with mortality
projected to increase by 127% to $69.7 bil- rates of 36% vs 39.7% (P = .0036).11
lion—$244 per person in the United States.2 Recommendations. The benefits of ACE
inhibition have been demonstrated in pa-
ACE inhibitors tients with mild, moderate, and severe heart
An American The renin-angiotensin-aldosterone system has failure. Thus, the guidelines recommend ACE
been studied for over 100 years.5 inhibitors (Table 2) for all patients with heart
age 40 or older In heart failure with reduced ejection frac- failure with reduced ejection fraction.1
faces a 20% tion, this system is upregulated as an adaptive
lifetime risk mechanism to maintain hemodynamic ho- Angiotensin II receptor blockers
meostasis.6–8 However, prolonged activation of Angiotensin II receptor blockers (ARBs)
of heart failure the renin-angiotensin-aldosterone system can (Table 3) have been proven to be suitable al-
lead to deleterious cardiovascular effects such ternatives for patients with heart failure with
as myocyte hypertrophy, myocardial fibrosis, reduced ejection fraction who cannot tolerate
sodium conservation, and fluid overload.8,9 ACE inhibitors.
Angiotensin II is a potent vasoconstrictor and Val-HefT (the Valsartan HF Trial)12 ran-
plays a role in cardiovascular remodeling, lead- domized 5,010 patients in a double-blind fash-
ing to worsening progression of heart failure.6 ion to receive either valsartan or placebo, with
CONSENSUS (the Cooperative North background therapy that included beta-block-
Scandinavian Enalapril Survival Study) exam- ers, digoxin, diuretics, and ACE inhibitors.
ined the effect of the angiotensin-converting There was a 13% reduction of the combined
enzyme (ACE) inhibitor enalapril on survival primary end point of mortality and morbidity
in 253 patients with NYHA class IV heart fail- and a 24% reduction in heart failure hospital-
ure. Participants were randomized to receive izations in the valsartan group.12
either enalapril or placebo. At 6 months, the Subgroup analysis compared patients on
mortality rate was 26% in the enalapril group the basis of use of ACE inhibitors and beta-
vs 44% in the placebo group, an 18% absolute blockers at study entry. Valsartan had a favor-
risk reduction and a 41% relative risk reduc- able effect in the subgroups using beta-block-
tion (P = .002). At 12 months, the relative risk ers alone, ACE inhibitors alone, and neither
reduction in mortality was 30% (P = .001).10 drug. However, when patients received all
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 OKWUOSA AND COLLEAGUES

three (a beta-blocker, an ACE inhibitor, and

TABLE 2
valsartan), the mortality rate was significantly
increased (P = .009).12 This finding conflicted Angiotensin-converting enzyme
with those of other studies, which found a inhibitors for managing heart failure
small benefit of combining an ACE inhibitor
and an ARB. Generic name Dosing range
CHARM-Added (the Candesartan in HF Benazepril 5–40 mg once a day
Assessment of Reduction in Mortality and
Morbidity trial)13 investigated whether add- Captopril 6.5–50 mg three times a day
ing the ARB candesartan to an ACE inhibitor Enalapril 2.5–20 mg twice a day
would improve clinical outcomes. In the study,
2,548 patients in NYHA class II, III, or IV with Fosinopril 5–40 mg once a day
a left ventricular ejection fraction of less than Lisinopril 2.5–40 mg once a day
40% who were receiving ACE inhibitors were
randomized to either candesartan or placebo. Quinapril 5–20 mg once a day
The addition of candesartan resulted in a sig- Ramipril 1.25–10 mg once a day
nificant reduction in cardiovascular mortality
and heart failure hospitalizations, but with the Trandolapril 1–4 mg once a day
downside of higher rates of hyperkalemia and
serum creatinine elevation.13
Recommendations. The 2013 guidelines TABLE 3
recommend that ARBs be used in patients who Angiotensin II receptor blockers
cannot tolerate an ACE inhibitor due to cough.
However, routine combined use of ARBs, ACE
for managing heart failure
inhibitors, and aldosterone antagonists is not Generic name Dosing range
recommended and may cause harm.1
Candesartan 4–32 mg once a day
Aldosterone receptor antagonists
Losartan 25–150 mg once a day
Elevated levels of aldosterone lead to fluid re-
tention, loss of magnesium and potassium, and Valsartan 20–160 mg twice a day
myocardial fibrosis.
RALES (the Randomized Aldactone
Evaluation Study)14 tested the hypothesis that left ventricular systolic dysfunction was first
the aldosterone receptor antagonist spirono- established in postmyocardial infarction pa-
lactone (25 mg daily) would reduce deaths tients.15
from all causes in patients with severe heart EMPHASIS-HF (the Eplerenone in Mild
failure receiving standard medications includ- Patients Hospitalized and Survival Study
ing an ACE inhibitor. RALES included 1,663 in Heart Failure)16 broadened the applica-
patients in NYHA class III or IV with a left tion of eplerenone (and aldosterone antago-
ventricular ejection fraction of 35% or less, nists in general), investigating the effects of
randomized to receive 25 mg of spironolac- eplerenone in 2,737 NYHA class II patients,
tone or matching placebo. This study found regardless of ischemic etiology. The compos-
a 30% relative risk reduction and an 11% ab- ite end point of cardiovascular death or heart
solute risk reduction in all-cause mortality, a failure hospitalization occurred in 18.3% of
31% relative risk reduction and a 10% abso- the eplerenone group vs 25.9% of the placebo
lute risk reduction in cardiac mortality, and group (P < .001). A total of 12.5% of patients
30% fewer cardiac-related hospitalizations in in the eplerenone group died, compared with
the spironolactone group.14 15.5% in the placebo group (P = .008). Hos-
Eplerenone, an aldosterone receptor an- pitalizations were also fewer in the eplerenone
tagonist that lacks the antiandrogenic side ef- group.
fects of spironolactone, has also been shown Recommendations. The 2013 guidelines
to be beneficial. Its efficacy in patients with recommend aldosterone receptor antagonists
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 MANAGING SYSTOLIC HEART FAILURE

create the first angiotensin-neprilysin inhibi-

TABLE 4
tor (ARNI) (Table 5). The combination was
Aldosterone receptor antagonists selected to minimize the potential for angio-
for managing heart failure edema.
PARADIGM-HF (the Prospective Com-
Generic name Dosing range parison of ARNI With ACEI to Determine
Eplerenone 25–50 mg once a day Impact on Global Mortality and Morbidity in
Heart Failure trial)17 examined whether com-
Spironolactone 12.5–25 mg once or twice a day bined angiotensin-neprilysin inhibition was
superior to ACE inhibition alone with enala-
pril in patients with chronic heart failure.
TABLE 5 In PARADIGM-HF, 10,521 patients with
Angiotensin-neprilysin inhibition NYHA class II, III, or IV heart failure were
randomized to receive either sacubitril-valsar-
for managing heart failure tan or enalapril. The group receiving sacubi-
Generic name Dosing range tril-valsartan had significantly fewer deaths
from cardiovascular causes and heart failure
Sacubitril-valsartan 24–26 mg, 49–51 mg, or 97–103 mg twice hospitalizations.17 An improvement in qual-
daily
ity of life and NYHA functional class was also
If tolerated for 2–4 weeks, double the daily
dose until target dose of 97–103 mg twice observed in the sacubitril-valsartan group.17
daily is reached Sacubitril-valsartan underwent priority re-
For patients converting from an ACE inhibitor, view by the US Food and Drug Administra-
this medication should be started 36 hours tion and has been approved. Currently, it is in-
after discontinuation of the ACE inhibitor dicated for the treatment of heart failure with
reduced ejection fraction and NYHA class II,
III, or IV symptoms. It should be avoided in
(Table 4) for patients with NYHA class II, III, patients who have previously experienced an-
Routinely or IV heart failure who have an ejection frac- gioedema with an ACE inhibitor or ARB, in
tion of 35% or less, to reduce morbidity and patients receiving aliskiren for diabetes, and
combining mortality (class IA recommendation).1 The in patients with hypersensitivity reactions to
ARBs, guidelines also recommend that these agents either of its components. Simultaneous use
not be used in patients with renal insufficien- of sacubitril-valsartan and an ACE inhibi-
ACE inhibitors, tor should be avoided, and a washout period
cy (serum creatinine > 2.5 mg/dL in men or >
and aldosterone 2.0 mg/dL in women; an estimated glomerular is recommended when transitioning from an
antagonists is filtration rate < 30 mL/min/1.73 m2); or a se- ACE inhibitor to this combined agent.
not recom- rum potassium level above 5 mmol/L.1

mended Angiotensin-neprilysin inhibitor (the future) B Beta-blockers

BNP
Research has identified neprilysin as another Beta-blockers
potential target in the treatment of heart fail- In heart failure, there is increased sympathetic
ure and has sought to combine inhibition of activation and associated elevations in nor-
angiotensin and neprilysin. epinephrine levels, which may lead to del-
Neprilysin, a neutral endopeptidase, is as- eterious long-term effects on cardiac function
sociated with degradation of several natural and structure. Beta-adrenergic receptor block-
vasoactive peptides such as natriuretic pep- ade is now known to be cardioprotective, but
tide, bradykinin, and adrenomedullin. Nepri- it was not always so; beta-blockers used to be
lysin inhibition increases these substances and contraindicated in patients with heart failure.
counters the neurohormonal overactivation An early experience using beta-blockers
that leads to vasoconstriction, sodium reten- in heart failure was described in 1975.18,19 The
tion, and cardiac remodeling.17 first study to report a survival benefit of treating
The ARB valsartan has been combined systolic heart failure with a beta-blocker was
with the neprilysin inhibitor sacubitril to published in 1979.20 Later, small controlled tri-
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 OKWUOSA AND COLLEAGUES

als demonstrated a reduction in heart failure

TABLE 6
symptoms and improvement in left ventricu-
lar function and in NYHA functional class.21 Beta-blockers for managing heart failure
Larger clinical trials have demonstrated a tre-
mendous survival benefit with beta-blockers in Generic name Dosing range
heart failure, specifically carvedilol, extended- Bisoprolol 1.25–10 mg once a day
release metoprolol, and bisoprolol.
The US Carvedilol Heart Failure Study Carvedilol 3.125–50 mg twice a day
Group trial22 evaluated whether beta-blocker Metoprolol succinate 12.5–200 mg once a day
use in heart failure patients would reduce the
rates of morbidity and mortality.22 The trial
included 1,094 patients with symptomatic COMET (the Carvedilol or Metoprolol
heart failure for at least 3 months and a left European Trial)25 was the only head-to-head
ventricular ejection fraction of 35% or less randomized control trial evaluating clini-
on background therapy including vasodila- cal outcomes in patients receiving carvedilol
tors, ACE inhibitors, and digoxin. Patients or metoprolol tartrate (not metoprolol suc-
were randomized to receive either carvedilol cinate). In COMET, 1,511 patients with
or placebo. Carvedilol use was associated with NYHA class II, III, or IV heart failure with a
a dramatic 65% risk reduction in mortality left ventricular ejection fraction of 35% or less
(7.8% with placebo vs 3.2% with carvedilol, P were randomized to carvedilol or metoprolol
< .001) and a 27% risk reduction in hospital- tartrate. The primary end point of all-cause
izations (19.6% vs 14.1%, P = .036), leading mortality occurred in 34% of the carvedilol
to early trial termination. group and 40% of the metoprolol tartrate
CIBIS-II (the Cardiac Insufficiency Bi- group (P = .0017). There was no significant
soprolol Study II)23 investigated the effects difference with regard to the composite end
of beta-blockers on survival and morbidity. point of mortality and all-cause admissions.
CIBIS-II included 2,647 NYHA class III or Recommendations. The 2013 guidelines
IV patients with a left ventricular ejection give a class IA recommendation for starting a A washout
fraction less than 35% on background medi- beta-blocker (carvedilol, bisoprolol, or meto- period is
cal therapy that included diuretics and ACE prolol succinate, Table 6) in patients with
inhibitors. This trial was also terminated early, current or prior symptoms of heart failure.1
recommended
after demonstrating a significant survival ben- Beta-blockers should be initiated with caution when
efit with bisoprolol. or avoided in patients with acutely decompen-
MERIT-HF (the Metoprolol Extended transitioning
sated heart failure with evidence of fluid over-
Release Randomized Intervention Trial in load. from an
Congestive Heart Failure)24 evaluated if once- ACE inhibitor
daily metoprolol would lower mortality rates Brain-type natriuretic peptide
in patients with symptomatic heart failure. Brain-type natriuretic peptide (BNP) or its ami- to valsartan-
The study enrolled 3,991 NYHA class II–IV no-terminal cleavage product (NT-proBNP) sacubitril
patients with chronic heart failure and a left originates in cardiomyocytes and is released
ventricular ejection fraction of 40% or less. by several triggers, most commonly cardio-
Like the previous two beta-blocker trials, myocyte stretch in the setting of volume or
MERIT-HF was terminated early, as it demon- pressure overload.26 The biologic significance
strated a 34% reduction in all-cause mortality of BNP includes natriuresis and vasodilation,
(7.2% risk of death per patient-year vs 11.0%, renin-angiotensin system inhibition, and sym-
P = .00009). pathetic nervous system modulation.26
The beta-blocker trials have shown that TIME-CHF (the Trial of Intensified vs.
when added to background therapy, beta-block- Standard Medical Therapy in Elderly Patients
ers improve survival and reduce hospitalizations. With Congestive HF)27 investigated whether
However, when prescribing a beta-blocker, it is 18-month outcomes would be better if treat-
important to understand that not all beta-block- ment were guided by N-terminal BNP levels
ers are equal in the treatment of heart failure. rather than by symptoms. The BNP-guided
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 MANAGING SYSTOLIC HEART FAILURE

experience more comprehensive posthospital

TABLE 7
care by virtue of disease management clinics.
If inhibition for managing heart failure The name may vary by institution, but wheth-
er it is called a “diuresis clinic,” “bridge clinic,”
Generic name Dosing range
or “heart failure clinic,” the goal is to improve
Ivabradine 5–7.5 mg twice a day guideline-driven care, educate the patient, and
Initial dosing is 5 mg by mouth twice daily for 2 reduce heart failure hospitalizations. Heart
weeks failure clinics are designed to provide a smooth
Dose may be increased 5 mg to maintain a resting transition from inpatient to outpatient care
heart rate between 50 and 60 beats per minute and to encourage patient self-accountability
Maximum daily dose 15 mg/day in health maintenance thereafter.
Studies have shown that heart failure clin-
strategy was not associated with a reduction in ics are associated with better medication dos-
hospitalization or a survival benefit. ing, fewer hospitalizations, and lower health-
BATTLESCARRED (the NT-proBNP- care costs.30–32
Assisted Treatment to Lessen Serial Cardiac
Readmissions and Death trial)28 in 2009 Chronotropy: If inhibition
showed that a BNP-guided management strat- An elevated resting heart rate has been shown
egy significantly reduced mortality rates in pa- to be associated with increased cardiovascu-
tients under age 75 compared with standard lar morbidity and mortality.33 Studies have
medical therapy. shown that slowing the heart rate improves
PROTECT (the Use of NT-proBNP Test- myocardial contraction and energy supply and
ing to Guide HF Therapy in the Outpatient reduces energy expenditure.34 Ivabradine, a se-
Setting study)29 also showed that a BNP-guid- lective If (the f is for “funny”) channel inhibi-
ed strategy was superior to usual care and was tor, slows the heart rate without other known
associated with reduced cardiovascular events cardiovascular effects.
and improved quality of life.29 SHIFT (the Systolic Heart Failure Treat-
BNP testing is GUIDE IT-HF (the Guiding Evidence ment With the If Inhibitor Ivabradine Trial)35
Based Therapy Using Biomarker Intensified investigated whether isolated heart rate re-
recommended, duction with ivabradine would reduce adverse
Treatment in Heart Failure study), currently
especially in ongoing, is designed to assess the safety, effica- clinical outcomes in patients with symptomat-
cases of clinical cy and cost-effectiveness of a biomarker-guid- ic heart failure. SHIFT randomized 6,505 pa-
ed strategy in 1,100 high-risk patients with tients with a left ventricular ejection fraction
uncertainty heart failure with reduced ejection fraction. of 35% or less, in sinus rhythm, with a heart
Recommendations. The 2013 ACC/ rate of at least 70 beats per minute, on optimal
AHA guidelines give a class IA recommen- medical therapy, and hospitalized within 12
dation for the use of BNP to support clinical months of enrollment to receive ivabradine or
decision-making, particularly in cases of clini- placebo. The primary end point was a com-
cal uncertainty.1 BNP can also be used to es- posite of cardiovascular mortality and hospital
tablish prognosis or disease severity in chronic admission for worsening heart failure. Out-
heart failure and to achieve optimal dosage of comes varied by heart rates achieved, with the
goal-directed medical therapy for euvolemic best outcomes in those with the lowest heart
patients followed in a structured heart failure rates at trial conclusion.
program.1 Ivabradine (Table 7) is indicated for pa-
tients with symptomatic heart failure with

C Clinics
Chronotropy
a left ventricular ejection fraction less than
35%, in sinus rhythm, with a resting heart rate
of at least 70 beats per minute, and either on
Heart failure clinics a maximally tolerated beta-blocker or with a
Continuity of care upon discharge from the contraindication to beta-blockers.
hospital is currently in a state of evolution. Ivabradine should be avoided in patients
Those diagnosed with heart failure can now who are in acute decompensated heart failure
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 OKWUOSA AND COLLEAGUES

or are hypotensive (blood pressure < 90/50 mm

TABLE 8
Hg), as well as in patients with a significant
conduction abnormality (sick sinus syndrome, Diuretic dosing in heart failure
sinoatrial block, third-degree atrioventricular
block), hepatic impairment, or bradycardia Generic name Dosing range
(resting heart rate < 60 beats per minute). Bumetanide 0.5–10 mg daily in one or two doses

Digoxin Furosemide 20–600 mg daily in one or two doses

D Diuretics
Devices
Torsemide 10–200 mg once daily

Digoxin with heart failure with reduced ejection frac-

Digoxin has been used in treating systolic tion who have evidence of fluid retention, un-
heart failure for more than 70 years.36,37 less contraindicated, to improve symptoms.1
DIG (Digoxin Investigative Group trial)38
evaluated the long-term effect of digoxin on Devices: ICDs
rates of mortality and hospitalization for heart Patients with heart failure are at increased risk
failure over a 3-year period. In patients with of sudden death and ventricular arrhythmias.39
a left ventricular ejection fraction less than Previously, antiarrhythmic drugs were con-
45%, digoxin had no effect on overall mortal- sidered the standard of care for nonsustained
ity when combined with diuretics and ACE ventricular tachycardia after myocardial in-
inhibitors. However, the risk of hospitaliza- farction.
tion for worsening heart failure was signifi- MADIT (the Multicenter Automatic
cantly reduced with digoxin treatment.38 Defibrillator Implantation Trial) investigat-
Recommendations. Digoxin should be ed whether prophylactic implantation of an
considered when patients are on guideline- internal cardiac defibrillator would improve
recommended therapy but heart failure symp- 5-year survival rates in patients with heart
toms persist. It is commonly initiated at a dose failure. Eligible patients had had a Q-wave or Heart failure
of 0.125 to 0.25 mg. The target therapeutic enzyme-positive myocardial infarction within clinics promote
range for digoxin is 0.5 to 0.9 ng/mL.1 Digoxin 3 weeks of study entry. They also had had an
toxicity can occur in patients with renal im- episode of asymptomatic nonsustained ven- better
pairment, hypokalemia, hypomagnesemia, tricular tachycardia unrelated to an acute medication
and hypothyroidism. myocardial infarction. Additionally, the pa-
The 2013 ACC/AHA guidelines give a tients had a left ventricular ejection fraction
dosing, reduce
class IIA recommendation (treatment is “rea- less than 35%, and inducible, sustained, non- hospitalizations,
sonable”) for digoxin in patients with heart suppressible ventricular tachyarrhythmia on and lower
failure with reduced ejection fraction unless electrophysiologic testing.40
contraindicated, to decrease hospitalizations During the study, 15 patients in the defi- healthcare costs
for heart failure.1 brillator group died vs 39 in the conventional
therapy group (P = .009).40
Diuretics MADIT II evaluated the potential surviv-
Clinical manifestations of volume overload al benefit of a prophylactically implanted de-
in patients with heart failure are from excess fibrillator in the absence of electrophysiologic
salt and water retention leading to inappro- testing to induce arrhythmias.41 MADIT II
priate volume expansion in both the vascular included 1,232 patients with prior myocardial
and extravascular space. Diuretics (Table 8) infarctions and a left ventricular ejection frac-
are the foundation of heart failure treatment. ton of 30% or less. Patients were randomized
Most patients are first initiated on a combina- to receive an implanted cardioverter-defibril-
tion of a loop diuretic and a low-sodium diet lator or conventional medical therapy. The
to improve symptoms. primary end point was death from any cause.41
The 2013 ACC/AHA guidelines give a The mortality rate was 19.8% in the con-
class I recommendation for diuretics in patients ventional therapy group vs 14.2% in the defi-
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 MANAGING SYSTOLIC HEART FAILURE

brillator group (hazard ratio 0.69, P = .016).41 mality,43,44 which can result in abnormalities
Thus, MADIT-II confirmed the benefits of of systolic and diastolic function. Biventricu-
prophylactic implantable cardioverter-defi- lar pacing, in which a pacing lead is placed
brillator therapy seen in the original MADIT, in the coronary sinus in addition to the right
and additionally eliminated the need for an atrium and right ventricle, optimizes synchro-
electrophysiology test prior to device implan- nization of ventricular contraction.43,44
tation. MUSTIC (the Multisite Stimulation
SCD-HeFT (the Sudden Cardiac Death in Cardiomyopathies study) was a random-
in Heart Failure Trial) evaluated whether ized trial designed to assess the efficacy of
amiodarone or a conservatively programmed biventricular pacing (also known as cardiac
shock-only, single-lead implanted cardio- resynchronization therapy) in heart failure
verter-defibrillator would decrease the risk of patients.44 Entry criteria included NYHA
death (all-cause) in a population with mild class III heart failure for at least 1 month,
to moderate heart failure with ischemic and left ventricular ejection fraction less than
nonischemic causes.42 In this trial, 2,521 pa- 35%, left ventricular end-diastolic diameter
tients with an ejection fraction of 35% or less, greater than 60 mm, and QRS duration lon-
in NYHA class II or III, and with stable heart ger than 150 ms. Patients were followed up
failure were randomized to receive a single- at 9 and 12 months with 6-minute walking
chamber implantable cardioverter-defibrilla- distance, peak oxygen consumption, changes
tor, amiodarone, or placebo. in NYHA class, and left ventricular systolic
There were 244 deaths in the placebo function by echocardiography or radionu-
group, 240 deaths in the amiodarone group (P clide testing. Quality of life was assessed by
= .53 compared with placebo), and 182 deaths the Minnesota Living With Heart Failure
in the defibrillator group (P = .007 compared Questionnaire.
with placebo).42 At 12 months, patients could walk signifi-
Recommendations. The 2013 ACC/ cantly farther in 6 minutes, and their peak
AHA guideline1 gives implantable defibrilla- oxygen consumption had increased. They also
Ivabradine tor therapy a class IA recommendation for the reported significant improvement in quality
slows the heart primary prevention of sudden cardiac death in of life, and NYHA class improved by 25%.
selected patients with nonischemic cardiomy- MUSTIC was the first study to show a benefit
rate without opathy or ischemic cardiomyopathy at least in exercise tolerance, quality of life, improve-
other known 40 days after a myocardial infarction and 90 ment in cardiac performance, and reduction
cardiovascular days after percutaneous coronary interven- in heart failure symptoms with the use of bi-
tion or coronary artery bypass grafting; with ventricular pacing at 1 year.
effects a left ventricular ejection fraction of 35% or MIRACLE (the Multicenter InSync Ran-
less; and NYHA class II or III symptoms on domized Clinical Evaluation) validated the
chronic goal-directed medical management. findings seen in MUSTIC by using a larger
This therapy receives a class IB recommen-
population size and a double-blinded meth-
dation for primary prevention of sudden car-
od.45 Compared with a control group, patients
diac death to reduce total mortality in selected
who underwent cardiac resynchronization
patients at least 40 days after myocardial infarc-
therapy could walk farther in 6 minutes and
tion with a left ventricular ejection fraction of
scored better in NYHA class, quality of life,
30% or less and NYHA class I symptoms while
and left ventricular ejection fraction.45
receiving goal-directed medical therapy.
Recommendations. The 2013 ACC/AHA
Implantable cardioverter-defibrillators are
guidelines1 give cardiac resynchronization
not recommended in patients who otherwise
have a life expectancy of less than 1 year. therapy a class IA/B indication for NYHA
class II, III, or IV patients on goal-directed
Devices: medical therapy in sinus rhythm with left
Cardiac resynchronization therapy ventricular ejection fraction 35% or less, left
From 25% to 30% of heart failure patients bundle branch block, and QRS duration of
have an intraventricular conduction abnor- 150 ms or more.1
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 OKWUOSA AND COLLEAGUES

Devices: Implantable sensors outcomes (cardiopulmonary exercise time, left

The future of ambulatory heart failure man- ventricular ejection fraction, atrial fibrillation,
agement may include implantable pulmonary and depression), exercise training was found to
artery pressure sensors. reduce the incidence of all-cause mortality or
The CardioMEMS is a permanently im- all-cause hospitalization by 11% (P = .03).49
plantable pressure measurement system de- Recommendations. Based on the results of
signed to provide daily pulmonary artery pres- HF-ACTION and several smaller studies, the
sure measurements in an ambulatory setting ACC/AHA guidelines give exercise training a
with a goal of reducing heart failure-related class IA recommendation as a safe and effec-
hospitalizations. Through a transvenous deliv- tive activity for patients with heart failure who
ery system, an implantable, battery-free sensor are able to participate, to improve functional
is positioned in the distal pulmonary artery.46,47 status.1 A class IIA recommendation is given
CHAMPION (the CardioMEMS Heart to cardiac rehabilitation for the improvement
Sensor Allows Monitoring of Pressure to Im- of functional capacity, exercise duration, qual-
prove Outcomes in NYHA Class III Patients ity of life, and mortality rates.1
trial) was one of the first major trials to assess
End-stage heart failure: Recognition
the safety and efficacy of implantable pulmo-
Despite adequate titration of goal-directed
nary artery pressure monitoring systems.46 The
study device was associated with a significant medical therapy, a portion of patients with
reduction in mean pulmonary artery pressures, heart failure with reduced ejection fraction ul-
fewer heart failure hospitalizations, and bet- timately progress to stage D, also termed “ad-
ter quality of life. The length of stay for heart vanced” heart failure. The 5-year survival rate
failure-related hospitalizations was also signifi- for patients with heart failure overall is 50%,
cantly shorter in the CardioMEMs group.46 but the 1-year mortality rate for those with ad-
vanced heart failure exceeds 50%.50
Because the high rates of morbidity and
E Exercise
End-stage heart failure mortality can potentially be lowered, recog-
nition of heart failure disease progression is Diuretics are
Exercise imperative so that patients can be promptly
referred for therapies such as inotropic infu-
the foundation
Patients with heart failure routinely experi-
ence a decline in functional capacity. This de- sion, mechanical circulatory support, and car- of heart failure
cline manifests as reduced exercise tolerance diac transplant, as well as end-of-life care such treatment
and poor quality of life, usually resulting in a as hospice.1
physician recommendation to rest and para- The ACC/AHA1 have published clinical
doxical deconditioning and possible progres- events and findings useful in identifying pa-
sion of symptoms. tients with advanced heart failure:
Several studies have shown that cardiac • Two or more hospitalizations or emergency
rehabilitation has improved outcomes in heart department visits for heart failure in the
failure patients.48 Cardiac rehabilitation is a past year
supervised program that helps patients with • Progressive deterioration in renal function
exercise training, healthy living, education, (eg, elevation in creatinine or blood urea
and psychosocial counseling. nitrogen)
HF-ACTION (Heart Failure: A Con- • Weight loss without other cause
trolled Trial Investigating Outcomes of Exer- • Intolerance to ACE inhibitors due to hy-
cise Training) is the largest randomized trial potension or worsening renal function
performed to determine whether aerobic ex- • Inability to tolerate beta-blockers due to
ercise training reduces all-cause mortality or worsening heart failure or hypotension
all-cause hospitalization and improves quality • Systolic blood pressure often below 90 mm Hg
of life in patients with stable heart failure.49 • Persistent dyspnea with dressing or bath-
Although the reduction in end points was ini- ing requiring rest
tially not statistically significant, after adjust- • Inability to walk one block on level ground
ing for highly prognostic predictors of poor due to dyspnea or fatigue
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 MANAGING SYSTOLIC HEART FAILURE

Diuretics for congestive symptoms

Angiotensin-converting enzyme inhibitor,

angiotensin-neprolysin inhibitor, or
angiotensin II receptor blocker

Add a beta-blocker

No
New York Heart Association (NYHA) class II, III,
or IV?
Yes

Add an aldosterone receptor antagonist

No
NYHA class II, III, or IV?
Yes

No
Left ventricular ejection fraction < 35%?
Yes

No
Sinus rhythm and heart rate > 75 beats per
minute?

Add ivabradine
No
Yes NYHA class II, III, or IV?

QRS duration > 150 ms? No

Yes

Cardiac resynchronization therapy Implantable cardiac defibrillator

with pacing or with defibrillator
No
Recurrent heart failure hospitalizations?

Yes

Consider digoxin No further therapy

recommended
If end-stage, consider left ventricular assist device
or transplant

FIGURE 1. An algorithm for managing heart failure with reduced ejection fraction.

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 OKWUOSA AND COLLEAGUES

• Recent need to escalate diuretics to main- The next generation of continuous-flow

tain volume status, often reaching daily dose left ventricular assist devices are currently in
equivalent to furosemide more than 160 mg/ clinical trials in the United States and include
day or use of supplemental metolazone the axial flow MVAD (Heartware) and cen-
• Progressive decline in serum sodium, usu- trifugal flow Heartmate III (Thoratec).
ally to below 133 mmol/L We emphasize the importance of early iden-
• Frequent shocks from implanted cardiac tification of patients with advanced disease who
defibrillator. may qualify for and benefit from such therapies.
End-stage heart failure:
Left ventricular assist devices
For patients with refractory heart failure de-
F Failure (less of it)

spite optimal medical management, advanced The management of heart failure is evolving.
therapies such as heart transplant or ventricu- In the 1960s, the standard heart failure medi-
lar assist devices have been proven to be du- cal regimen included digoxin, diuretics, and the
rable options. These mechanical circulatory recommendation of rest. This contrasts with
support devices “unload” the diseased ven- the current era, in which medical regimens in-
tricle and maintain cardiac output to vital or- clude neurohormonal blockade, diuretics, and
gans.51 They were initially designed as tempo- the promotion of physical activity.55 Since the
rary support to allow ventricular recovery or as publication of the 2013 heart failure guidelines,
a bridge to cardiac transplant. However, they new medical and device options have emerged
have also evolved into permanent (“destina- that have been proven to either improve sur-
tion”) therapy.52 vival or reduce hospitalizations. The develop-
REMATCH (the Randomized Evaluation ment of clinical guidelines promotes evidence-
of Mechanical Assistance for the Treatment of based practice and overcomes the inertia of
Congestive HF trial) was the landmark study practice patterns based on anecdotal evidence.
that showed that left ventricular assist device Several approaches to the management of
heart failure have been recommended. A ma-
implantation resulted in a survival benefit and
jor effort should be made to identify those at The future
an improved quality of life in patients with
advanced heart failure ineligible for cardiac
risk for heart failure (stage A) and to imple- of ambulatory
ment risk factor modification. Treatment of heart failure
transplant, compared with medical manage-
hypertension, diabetes mellitus, and dyslipid-
ment.50 Implantation of a left ventricular as- management
emia decreases the risk of heart failure.1
sist device was associated with a 27% absolute
For patients with evidence of structural may include
reduction in the 1-year mortality rate.50
heart disease with and without symptoms,
Since the National Institutes of Health’s
Figure 1 summarizes a guideline approach to implantable
artificial heart program was launched in 1964,
there has been tremendous progress in the
the management of heart failure. It should be pulmonary
stressed that guidelines are meant to guide
development of mechanical circulatory de- management, but do not serve as a substitute
artery pressure
vices.50 The results of REMATCH were prom- for sound clinical judgment. sensors
ising, but the 2-year survival rate was still only Heart failure is the common final pathway
23%, leaving a lot to be desired. of all cardiac pathology, and understanding
The HeartMate II (Thoratec) trial com- the neurohormonal response and maladaptive
pared an axial continuous-flow device vs the physiology has led to the development of novel
previously established pulsatile left ventricu- therapeutics and devices. At present, the field
lar assist device, and noted a 2-year survival of of cardiology may not be able to remove the
58% with the continuous flow device vs 24% “failure” from heart failure, but we can make
with the pulsatile device (P = .008).53 every effort to prevent failure of treatment de-
ADVANCE (Evaluation of the HeartWare livery and reduce resource utilization and mor-
Left Ventricular Assist Device for the Treatment bidity associated with this syndrome. ■
of Advanced Heart Failure) showed similar ef-
ficacy of the HVAD (Heartware), a centrifugal ACKNOWLEDGMENTS: We would like to thank Chankya Da-
hagam and Cynthia Obenwa for their valuable contribution in
continuous-flow LVAD currently in use.54 the preparation of this manuscript.

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 MANAGING SYSTOLIC HEART FAILURE

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