Pharmacologic Trends of Heart Failure: Hector O. Ventura Editor

Current Cardiovascular Therapy
Series Editor: Juan Carlos Kaski
Hector O. Ventura Editor
Pharmacologic
Trends of
Heart Failure
Current Cardiovascular
Therapy
Series editor:
Juan Carlos Kaski
Cardiovascular and Cell Sciences Research Institute
St George's University of London
London
UK
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Hector O. Ventura
Editor
Pharmacologic Trends
of Heart Failure
Editor
Hector O. Ventura
Department of Cardiology
Ochsner Health System
New Orleans, LA
USA
Current Cardiovascular Therapy

ISBN 978-3-319-30591-2 ISBN 978-3-319-30593-6 (eBook)
DOI 10.1007/978-3-319-30593-6
Library of Congress Control Number: 2016941739
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Contents
1 The Established Therapies: HF-PEF

and HF-REF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Arthur Menezes, Selim R. Krim,
and Hector O. Ventura
2 Novel Therapies for the Prevention

and Management of Acute Decompensated
Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Patrick T. Campbell and Sepehr Saberian
3 A Comprehensive Transition of Care Plan

for a Patient Admitted with Acute
Decompensated Heart Failure . . . . . . . . . . . . . . . . . . . 73
Clement C. Eiswirth
4 Volume Assessment and Management:

Medical and Device Therapies. . . . . . . . . . . . . . . . . . . 125
Lauren B. Cooper and Robert J. Mentz
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
v
Contributors
Patrick T. Campbell, MD Heart Transplant Institute,

Baptist Health Transplant Institute, Little Rock, AR, USA
Lauren Cooper, MD Division of Cardiology,

Department of Medicine, Duke University Medical Center,
Durham, NC, USA
Clement C. Eiswirth, FACC, FASE Department of Cardiology

Section of Cardiomyopathy and Heart Transplantation,
Ochner Medical Center, New Orleans, LA, USA
Tulane University School of Medicine, New Orleans, LA, USA
Selim R. Krim, MD Department of Cardiology,

John Ochsner Heart and Vascular Institute,
Ochsner Clinic Foundation, New Orleans, LA, USA
Arthur Menezes, MD Department of Cardiology,

Robert J. Mentz, MD Division of Cardiology,

Department of Medicine, Duke University Medical Center,
Durham, NC, USA
Sepehr Saberian, MD Department of Cardiology,

University of Illinois College of Medicine at Peaoria,
Peoria, IL, USA
Hector O. Ventura, MD Division of Cardiology,

vii
Chapter 1
The Established Therapies:
HF-PEF and HF-REF
Arthur Menezes, Selim R. Krim, and Hector O. Ventura
Heart Failure with Reduced Ejection Fraction

(HFrEF)
Over the last few decades, our understanding of the patho-
physiology, and subsequently treatment, of chronic heart
failure with reduced ejection fraction (HFrEF) has grown
considerably. While diuretics and digoxin were once the pil-
lars of treatment for HFrEF, they did not offer any mortality
benefits. The discovery of beta blocker, angiotensin-converting
enzyme inhibitors (ACE-I), angiotensin-receptor blockers
(ARB’s), potassium-sparing diuretics, and their utility in the
setting of HFrEF has greatly improved outcomes among
these patients.
A. Menezes, MD • S.R. Krim, MD

Division of Cardiology, John Ochsner Heart and Vascular Institute,
Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans,
LA 70121, USA
H.O. Ventura, MD ()
Division of Cardiology, John Ochsner Heart and Vascular Institute,
Ochsner Clinic Foundation, 1514 Jefferson Highway,
New Orleans, LA 70121, USA
e-mail: hventura@ochsner.org
H.O. Ventura (ed.), Pharmacologic Trends of Heart Failure, 1

Current Cardiovascular Therapy,
DOI 10.1007/978-3-319-30593-6_1,
2 A. Menezes et al.
Diuretics
Sodium and water retention which result in systemic volume

overload are an inevitable sequelae of heart failure and are
associated with pulmonary and systemic venous congestion
[1]. In the setting of heart failure, alterations in the sympa-
thetic nervous system (SNS), the renin-angiotensin-
aldosterone system (RAAS), the vasopressin axis, and
vasodilatory/natriuretic pathways lead to sodium and water
retention at the level of the renal circulatory system [2].
Loop Diuretics
The use of diuretics among patients with HFrEF who have

evidence of fluid overload is recommended to restore and
maintain normal volume status [3]. Currently, loop diuretics
are the current preferred diuretic agent among most patients
with HFrEF. These agents (furosemide, bumetanide, and
torsemide) inhibit the reabsorption of sodium, potassium,
and chloride in the ascending loop of Henle. The diuretic
effects of these drugs depend on its tubular fluid concentration
[4, 5]. As a result, higher doses of loop diuretics are required
in the setting of severe renal insufficiency or low cardiac out-
put to ensure delivery of sufficient concentrations of the drug
to its site of action [6]. The efficacy of loop diuretics also
depends on gastrointestinal absorption which can decrease
due to bowel wall edema cause by sphlanchnic congestion in
the setting of decompensated heart failure. Decreased gastro-
intestinal absorption and/or insufficient delivery of sufficient
drug concentrations to site of action can lead to diuretic resis-
tance. Therefore, appropriate diuretic dosing is vital in main-
taining normal volume status among individuals with heart
failure.
Resistance to the effects of diuretics can also occur due to
post diuretic sodium retention and the braking phenomenon
[7]. Since diuretics such as furosemide are short acting, there
is a tendency for reabsorption of filtered sodium when there
is no longer a diuretic acting in the renal tubule, especially
Chapter 1. The Established Therapies 3
when salt intake is not restricted. Increasing the frequency of

diuretic administration reduces the drug-free interval and
may be an effective strategy to overcome post-diuretic sodium
retention [7]. The braking phenomenon is characterized by a
diminished response to loop diuretics over time due to chronic
administration. This can be explained in part due to adaptive
structural and functional changes in the epithelial cells of the
distal convoluted tubules which result in distal reabsorbtion of
sodium and decreased sodium excretion [8, 9].
In the setting of diuretic resistance, increasing the dose of
the loop diuretic will compensate for the pharmacokinetic
and pharmacodynamic changes that occur in CHF and may
be an effective strategy [10]. The use of intravenous loop
diuretics at a dose higher than the outpatient dose or oral
loop diuretics with a higher oral bioavailability than furose-
mide may be used [11]. Current evidence demonstrates no
significant difference in patient symptoms or changes in renal
function when loop diuretics were administered as a bolus
when compared to continuous infusion, or at a high dose
when compared to a low dose [12]. Furthermore, there does
not appear to be any difference in the safety and efficacy
between bolus injection when compared to continuous infu-
sion of loop diuretics [13].
Thiazide and Thiazide-Type Diuretics
While increasing the dose of the loop diuretic is an effective

strategy in overcoming diuretic resistance, there are instances
when this approach may not always be successful. The addition
of thiazides or thiazide-type diuretics to loop diuretics appear
to be highly effective in promoting diuresis among patient
resistant to high dose loop diuretics [14]. By decreasing sodium
reabsorption in the distal tubules, the addition of thiazides or
thiazide-type diuretics potentially antagonize post-diuretic
sodium retention and renal adaption to chronic loop diuretic
administration [15, 16]. While metolazone is more commonly
used in combination with loop diuretics, there is no evidence to
support its superiority over other thiazide diuretics [17]. The
4 A. Menezes et al.
use of thiazide or thiazide-type diuretics in addition to loop

diuretics can significantly increase natriuresis and help main-
tain a normal volume status [18]. However, there is an
increased risk of inducing severe hypokalemia, hyponatremia,
hypotension, and worsening renal function [19].
Potassium-Sparing Diuretics
Potassium-sparing diuretics (spironolactone and eplerenone)

function by competitively antagonizing the aldosterone
receptor. The use of aldosterone receptor antagonists in the
setting of HFrEF has been shown to provide a survival ben-
efit [20, 21]. Although only examined in a small number of
patients, there is evidence to suggest that the use of ACE-I or
ARB’s may not uniformly suppress the rennin-angiotensin-
aldosterone system. In fact, despite ACE inhibition, elevated
levels of plasma aldosterone were observed among 10–38 %
of individuals with congestive heart failure [22–24].. This phe-
nomenon is called “aldosterone breakthrough” and may have
important clinical consequences especially considering aldo-
sterone’s profibrotic action in non-epithelial tissue which
may result in cardiac hypertrophy and fibrosis [25]. This
would also explain the mortality benefit observed among
patients with HFrEF despite treatment with ACE-I or ARB’s.
In the Randomized Aldactone Evaluation Study (RALES),
the use of spironolactone in patients with HFrEF and NYHA
class III to IV demonstrated a 30 % decrease when added to
an ACE-I and loop diuretic therapy [26]. Similarly, in the
Eplerenone Post-Acute Myocardial Infarction Heart Failure
Efficacy and Survival Study (EPHESUS), the use of eplere-
none in patients with HFrEF after an acute myocardial
infarction (AMI) demonstrated a 15 % decrease in all-cause
mortality and a 21 % decrease in sudden cardiac death [27].
Most of the individuals in this study were on an ACE-I or
ARB, as well as a beta-blocker. Similar mortality benefits
were observed among HfrEF patients using eplerenone in
the Eplerenone in Mild Patients Hospitalization and Survival
Study in Heart Failure (EMPHASIS-HF) trial in which
patients treated eplerenone with HFrEF and mild symptoms

(NYHA II) had a reduced risk of death and hospitalization
[28]. Similar to RALES and EPHESUS, a majority of the
patients in the EMPHASIS-HF trial were concomitantly
treated with an ACE-I and/or ARB, and a beta blocker.
It is important to note an increased risk of hyperkalemia
among HFrEF patients treated with potassium-sparing diuret-
ics [29]. This risk is increased among individuals with renal
dysfunction and there is insufficient data to support the use of
potassium-sparing diuretics in patients with a serum creatinine
≥2.5 mg/dL (221 μmol/L) or eGFR <30 mL/min per 1.73 m2
since most of the available trials excluded these patients.
ACE-Inhibitors and ARB’s
In patients with HFrEF, maladaptive mechanisms lead to

increased RAAS activity, which cause cardiac remodeling
and increased sympathetic activation. RAAS activation is
sensitive to low cardiac output (CO) and/or low renal perfu-
sion [30]. In early heart failure, a reduced CO prompts
RAAS-activated fluid retention, which increases ventricular
preload and CO until sufficient CO and renal perfusion is
maintained. In the setting of HFrEF, RAAS is persistently
activated in an attempt to raise the chronically low CO [31].
Angiotensin I is cleaved by ACE to produce angiotensin II
which acts directly on vascular smooth muscle cells to cause
vasoconstriction [32]. Angiotensin II also causes vasoconstric-
tion by interacting with the sympathetic nervous system [33].
Angiotensin II also stimulates the production of aldosterone
[34] and antidiuretic hormone, [35] which in turn increases
volume expansion through sodium and water retention.
ACE-Inhibitors
Unless contraindicated, ACE-I’s are recommended in all

patients with HFrEF and have been shown to reduce morbid-
ity and mortality. ACE-I’s promote sodium excretion by
6 A. Menezes et al.
reducing the production of aldosterone and by increasing

renal blood flow. This class of drugs also decreases fluid
retention by indirectly decreasing circulating levels of antidi-
uretic hormone. By blocking the effects of ACE and other
growth factors on myocytes, ACE-I’s are also effective in
attenuating cardiac remodeling and left ventricular dysfunc-
tion [36, 37]. Finally, by indirectly influencing vascular smooth
muscle vasoconstriction and the sympathetic nervous system,
ACE-I’s reduce preload and afterload, thereby increasing
CO in patients with HFrEF [38, 39].
Over the last three decades, there have been multiple stud-
ies that have demonstrated a mortality benefit of ACE-I’s
among patient with HFrEF. The Cooperative North
Scandinavian Enalapril Survival Study (CONSENSUS) evalu-
ated the influence of ACE-I (enalapril) on patients with
HFrEF with overt CHF symptoms (NYHA class IV) [40].
Among individuals assigned to the treatment arm, there was a
significant decrease in mortality compared to the placebo
group. Similarly, patients treated with enalapril demonstrated
significant improvements in NYHA classification and a reduc-
tion in heart size. The Studies of Left Ventricular Dysfunction
(SOLVD) trial, unlike the CONSENSUS trial, evaluated the
effects of ACE-I (enalapril) on mortality and hospitalization
among patients with HFrEF and NYHA functional classes II
and III [41]. Treatment with ACE-I instead of placebo resulted
in significantly reduced mortality and hospitalization for heart
failure among individuals with HFrEF. In fact, even among
asymptomatic patients with HFrEF, the use of ACE-I reduced
the incidence of heart failure and heart failure related hospital-
izations and there was a trend towards fewer cardiovascular
deaths among patients receiving enalapril [42].
ARB’s
As mentioned earlier, due to the long-term deleterious

effects of RAAS in the setting of HFrEF, it remains a viable
target for therapy. While ACE-I’s have been shown to
improve morbidity and mortality, there is evidence to suggest
that circulating levels of angiotensin II return to ACE-I pre-

treatment levels with long term ACE inhibition. This may be
due to non-ACE pathways of angiotensin I metabolism and
is known as the “escape phenomenon” [43]. This partly
explains the logic behind the development of ARB’s. ARB’s
block the RAAS at the level of the receptors and thereby
enable kinin degradation. Moreover, ARB’s are theoretically
expected to provide the benefits of ACE-I’s with fewer of
their side effects such as angioedema and cough.
ACE-I’s currently remain the first choice for suppression
of the RAAS in patients with HFrEF. However, ARB’s are an
acceptable alternative to reduce morbidity and mortality in
patients with HFrEF who are ACE-I intolerant. The
Evaluation of Losartan In The Elderly (ELITE) I study was
among the first clinical trials to compare an ACE-I (capto-
pril) to an ARB (losartan) in patients with HFrEF [44]. While
there was no difference in the primary endpoint, which evalu-
ated increases in serum creatinine between the two groups,
the ARB treatment arm had significantly lower rates of all-
cause mortality when compared to the ACE-I treatment
group. However, it should be noted that the study was not
designed to detect a difference in mortality between the two
groups. A subsequent trial, the ELITE II study, attempted to
compare ACE-I (captopril) to ARB (losartan) with all-cause
mortality as the primary end point [45]. The data did not
demonstrate any statistically significant difference in all-
cause mortality between losartan and captopril among
patients with HFrEF with NYHA class II–IV.
While the Valsartan Heart Failure Trial (Val-HeFT)
demonstrated that complete blockade of the RAAS by
adding valsartan to ACE-I’s in patients with HFrEF reduced
the combined endpoint of morbidity and mortality, there
was no overall mortality benefit. Furthermore, post-hoc
analysis demonstrated adverse effects on morbidity and
mortality among the subgroup of patients who were already
on heart failure drug regimens containing ACE-I’s and beta
blockers and were started on valsartan [46]. The Candesartan
in Heart failure Assessment of Reduction in Mortality and
8 A. Menezes et al.
morbidity (CHARM) trial consisted of three simultaneous

parallel arms that evaluated the use of ARB (candesartan)
versus placebo in different settings of heart failure. The
CHARM-Alternative arm of the CHARM trial evaluated
efficacy of ARB use in patients with HFrEF who were not
receiving ACE-I due to a history of intolerance [47]. There
was a statistically significant reduction in cardiovascular
death and hospital admission for CHF among patients
treated with candesartan compared to those treated with
placebo. This suggests that ARB’s may be a good alterna-
tive to ACE-I’s in patients that are ACE-I intolerant.
CHARM-Added arm was the only trial to show a reduction
in cardiovascular mortality and congestive heart failure
hospital admission when candesartan was added to an
ACE-I [48]. However, there was no statistically significant
difference in deaths from any cause between the groups
treated with candesartan when compared to the placebo
group. Furthermore, patients treated with dual RAAS
therapy had higher rates of withdrawal from the study due
to renal dysfunction and hyperkalemia. Due to the lack of
evidence demonstrating consistent survival benefits with
dual RAAS therapy and an increase in adverse effects, cur-
rent data does not support concomitant use of ACE-I’s and
ARB’s for the treatment of HFrEF.
Beta-Blockers
The use of beta adrenoceptor blockers in the setting of heart

failure was first hypothesized in the 1970s and was widely met
with skepticism. However, today, beta blockade is the main-
stay therapy in patients with stable HFrEF. Along with the
RAAS, the SNS is chronically activated in the setting of heart
failure. In the acute setting, these compensatory systems help
maintain cardiac output and blood pressure. However, long-
term activation of these systems have been shown to have
detrimental effects which lead to remodeling of the myocar-
dium and worsening cardiac function [49]. Currently, one of
three beta-blockers (bisoprolol, carvedilol, metoprolol succi-

nate) are currently recommended to reduce morbidity and
mortality among patients with HFrEF.
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II)
investigated the efficacy of bisoprolol in reducing all-cause
mortality among patients with HFrEF who were receiving
diuretics and ACE-I’s [50]. The trial was stopped prema-
turely due to a significant decrease in all-cause mortality
observed among patients treated with bisoprolol com-
pared to placebo. Similarly, the Metoprolol CR/XL
Randomized Intervention Trial in Congestive Heart
Failure (MERIT-HF) evaluated the use of metoprolol con-
trolled release/extended release (CR/XL) in addition to
standard heart failure therapy in HFrEF patients [51].
Similar to the CIBIS-II trial, the MERIT-HF trial was
stopped prematurely due to a significant decrease in all-
cause mortality, as well as sudden deaths and deaths from
worsening heart failure in the group treated with metopro-
lol CR/XL when compared to the group treated with pla-
cebo. In addition to bisoprolol and metoprolol succinate,
when compared to placebo, carvedilol significantly reduced
the combined risk of death or hospitalization from HFrEF
in the Carvedilol Prospective Randomized Cumulative
Survival (COPERNICUS) trial [52].
In the early 1990s, the MDC trial evaluated the effects of
metoprolol tartrate on improvements in survival and mor-
bidity among patients with HFeEF secondary to idiopathic
dilated cardiomyopathy, when compared to placebo [53].
Patients were initially started at low doses of the beta
blocker and doses were gradually up-titrated. Individuals in
the treatment arm demonstrated better improvements in
ejection fraction, lower pulmonary wedge pressures, and
improved exercise times when compared to the placebo
group. Despite these results, the Carvedilol Or Metoprolol
European Trial (COMET) compared the efficacy of
carvedilol versus metoprolol tartrate on all-cause mortality
in patients with HFrEF [54]. At the end of the study, patients
treated with carvedilol demonstrated significantly lower
10 A. Menezes et al.
rates of all-cause mortality when compared to the patients

in the metoprolol tartrate arm. This suggests that while
metoprolol tartrate and carvedilol share many similar car-
diovascular effects, carvedilol is superior to metoprolol tar-
trate in extending survival in patients with HFrEF. Based on
the results from the MERIT-HF trial and the COMET trial,
metoprolol succinate, not metoprolol tartrate, is recom-
mended for patients with HFrEF.
Digoxin
Once, digoxin and diuretic therapy were the foundation of

heart failure therapy. However, the development of newer,
more effective therapies in addition to recent studies evaluat-
ing the efficacy of digoxin in the setting of HFrEF have
caused it to fall out of favor. Digoxin is a cardiac glycoside
that acts by inhibiting the Na-K-ATPase pump in myocardial
cells [55]. This results in an increase in intracellular sodium
which promotes sodium-calcium exchange and subsequently
increased concentrations of intracellular calcium [56]. This
increase in intracellular calcium improves myocyte contrac-
tility and, as a result, stroke volume and EF.
Digoxin has not been shown to provide any mortality ben-
efit when used in the setting of HFrEF [57]. However, digoxin
therapy has been shown to decrease hospitalizations for car-
diovascular causes primarily due to a decrease in HF hospi-
talizations. This is most likely due to it symptomatic benefits
in the setting of HF. As a result, current guidelines recom-
mend using digoxin in patients with HFrEF to decrease HF
hospitalizations [58].
Results from the Prospective Randomized study Of
Ventricular failure and the Efficacy of Digoxin (PROVED)
trial suggest that patients withdrawn from digoxin ther-
apy demonstrated worsening maximal exercise capacity
when compared to those that were continued on digoxin
[59]. Furthermore, in the Randomized Assessment of
Digoxin on Inhibitors of Angiotensin-Converting Enzyme
(RADIANCE) study, patients switched from digoxin to

placebo experienced worsening heart failure, decreased
functional capacity, lower quality-of-life scores, decreased
ejection fractions, increases in heart rate, and higher body
weights when compared to those individuals continuing to
receive digoxin therapy [60]. This suggests that withdrawal
of digoxin in patients with HFrEF may result in undesired
clinical consequences.
Finally, it should be noted that the narrow therapeutic
index of digoxin increase the risk of toxicity and adverse
effects. Digoxin is mainly excreted by the kidneys and as a
result, impaired renal function can lead to higher plasma con-
centrations [61]. Congestive heart failure and advanced age
can also reduce the volume of distribution of the drug and
increase the risk of toxicity. Other causes that can precipitate
digoxin toxicity include hypokalemia, hypomagnesemia,
hypocalcemia, medication interaction, as well as hypothy-
roidism [62, 63].
Hydralazine and Isosorbide Dinitrate

The simultaneous use of hydralazine and isosorbide dinitrate
(H-ISDN) in patients with HFrEF was first studied in 1977
[64]. The findings demonstrated a 36 % decrease in left ven-
tricular filling pressures, a 58 % increase in cardiac index, and
a 34 % decrease in systemic vascular resistance. These find-
ings lead to the formal evaluation of the effect of H-ISDN on
mortality in patients with HFrEF.
The first Vasodilator-Heart Failure Trial (V-HeFT I) com-
pared H-ISDN or prazosin to placebo in over 600 men with
HFrEF [65]. H-ISDN was associated with a trend towards
decreased mortality when compared to placebo. Additionally,
H-ISDN was associated with improvement in left ventricular
ejection at 8 weeks and 1 year. The V-HeFT II trial compared
H-ISDN and enalapril among patient with HFrEF [66]. After
2 years, there was significantly lower mortality in the enala-
pril arm. However, when compared to enalapril, treatment
with H-ISDN was associated with greater improvements in

body oxygen consumption at peak exercise and left ventricu-
lar ejection fraction.
The African-American heart failure trial compared treat-
ment with H-ISDN to placebo among black patients with
HFrEF and NYHA III or IV symptoms. The study was termi-
nated early due to significantly higher mortality rates in the
placebo group compared to the group treated with
H-ISDN. As a result, among African-American patients with
HFrEF and NYHA III or IV symptoms receiving optimal
therapy with ACE-I and beta-blockers (unless contraindi-
cated), H-ISDN is now recommended to reduce morbidity
and mortality [67, 68].
Conclusions
Current heart failure therapy is mainly targeted towards

HFrEF. While digoxin and diuretics were once the mainstay
therapy for HFrEF, newer classes of drugs have emerged that
have proven to confer mortality and morbidity benefits.
Advances in science and research impart promises of even
better future therapies for the management of HFrEF.
Heart Failure with Preserved Ejection

Fraction (HFpEF)
HF with preserved ejection fraction (HFpEF) represents
nearly half of the five million cases of HF in the United States
[69–71] and with the aging of the population its prevalence
will likely continue to rise. Unlike patients with HFrEF
where advances in therapy have led to significant improve-
ment of outcomes, owing to a lack of randomized trials
patient with HFpEF remain at a high risk with an estimated
five mortality of 65 % [70, 71]. Although not fully understood,
current available literature suggests that mortality in HFpEF

patients seem to be driven by the coexisting comorbidities. In
this regard, the Acute Decompensated Heart Failure National
Registry (ADHERE) study showed that 91 % of patients
with HFpEF had a diagnosis of hypertension, CAD, or
diabetes [72]. In addition, HFpEF patients are more likely to
be older, females and have atrial fibrillation when compared
to HFrEF patients [58, 73]. Most of the data for treating
HFpEF is derived from smaller studies and expert opinion.
This section will summarize available data focusing on
HFpEF therapy and recommended approach and rationale
for the management of HFpEF.
Diuretics
Similar to HFrEF, diuretics are commonly used to relieve

congestion with no mortality benefit. The Hong Kong
Diastolic HF study is the only randomized trial to date that
assessed the efficacy of diuretics in HFpEF patients [74].
Although no mortality benefit was shown, after 52 weeks of
therapy in 150 patients with HFpEF, diuretics significantly
improved symptoms, quality of life as assessed by 6-min walk
test. Interestingly no benefit was shown with the addition of
an angiotensin converting enzyme (Ramipril) or angiotensin
receptor blocker (Irbesartan). Another study showed that
chlorthalidone was associated with a reduction in the inci-
dence of new-onset hospitalization in patients with HFPEF
significantly compared to patients treated with calcium chan-
nel blockers or alpha receptor blockers [75]. The same study
also suggested that diuretics are associated with a reduction
in the incidence of new onset HFpEF when compared to
ACE’s. (ALLHAT).
In this regard, recent ACC/AHA HF guidelines give a
1C recommendation for diuretic use in patients with
HFPEF [58].
ACEI’s and ARB’s
Although inhibition of the RAAS system has shown to be

beneficial in the treatment of HFpEF associated comorbid
condition such as hypertension, diabetes and coronary artery
disease, ACEI’s and ARB therapy have failed to show any
mortality benefit in HFpEF. In the Candesartan in Heart
failure: Assessment of Reduction in Mortality and morbidity
(CHARM-Preserved), a multicenter, double-blind, interna-
tional trial, candesartan was compared to placebo in 3023
patients with HF-pEF (EF, ≥40 %; mean EF, 54 %) [76]. After
a mean follow-up duration of 36 months, no significant differ-
ence was found in composite outcome of cardiovascular
death or admission to hospital for HF between the two
groups (22 % in the candesartan group, 24 % in the placebo
group; HR, 0.89; 95 % CI, 0.77–1.03; P = 0.118). Likewise, the
Perindopril in Elderly People with Chronic Heart Failure
study randomized 850 HFpEF patients to either Perindopril
or placebo [77]. After a mean follow-up of 26 months, no dif-
ference in all-cause mortality or unplanned HF-related hos-
pitalization was found between the two groups. Finally, the
Irbesartan in Heart Failure with Preserved Ejection Fraction
Study (I-PRESERVE) randomized 4128 HFpEF patients to
either Irbesartan or placebo with a mean follow up duration
of 49 months [78]. Again no difference in the primary out-
come was seen between the two groups (composite of death
from any cause or hospitalization for cardiovascular causes).
Additionally, there were no differences in improvement of
quality of life at 6 months as assessed by the Minnesota
Living with Heart Failure scale between the two groups.
Beta Blockers
Beta blockers play an essential role in controlling tachycar-

dia, reducing myocardial oxygen demand, and regression of
LVH [79, 80]. In this regard, in the Swedish Doppler
Echocardiographic study, 113 symptomatic HF patients with

preserved left ventricular ejection fraction, and abnormal
diastolic function were randomized in a double blind fash-
ion to carvedilol or placebo with echocardiographic
assessment at baseline and 6 months [81]. Carvedilol
resulted in a significant improvement in the E/A ratio, but
no significant improvement in other echocardiographic
parameters of diastolic function such as deceleration time,
isovolumic relaxation time, or pulmonary vein flow velocity.
Two other important studies evaluating the clinical efficacy
of beta blockers in HFpEF showed mixed results. First, in
the Study of the Effects of Nebivolol Intervention on
Outcomes and Rehospitalisation in Seniors with Heart
Failure (SENIORS), 2128 patients ≥70 years of age with his-
tory of HF (with both HFpEF and HFrEF) were randomly
assigned Nebivolol or placebo [82]. After a mean follow-up
of 21 months, a statistically significant reduction in the pri-
mary outcome of all cause mortality or cardiovascular hos-
pital admission (31 % vs. 35 %; HR, 0.86; 95 % CI, 0.74–0.99;
P = .039) was shown in the Nebivolol group when compared
to placebo. Although a minority of patients included in this
study had preserved LV function, the effect of nebivolol on
the primary outcome was comparable in patients with pre-
served and impaired LVEF [83].
Conversely, in the Organized Program to Initiate
Lifesaving Treatment in Hospitalized Patients with Heart
Failure registry (OPTIMIZE-HF), 7,154 patients hospital-
ized with heart failure and eligible for beta-blockers, Beta
blockers were associated with reduced mortality (adjusted
hazard ratios of 0.77; 95 % CI: 0.68–0.87) for mortality and
rehospitalization rates (HR of 0.89 (95 % CI: 0.80–0.99) in
patients with HFrEF but no improvement in either mortal-
ity (HR of 0.94; 95 % CI: 0.84–1.07) or rehospitalization
(HR of 0.98; 95 % CI: 0.90–1.06) were shown in HFpEF
patients [84]. These results were corroborated by the
recently published Japanese Diastolic Heart Failure
(J-DHF) study where 245 patients with HF and LVEF
>40 % were randomly assigned to either carvedilol or pla-

cebo [85]. After a median follow-up of 3.2 years, no signifi-
cant differences in the primary endpoint (composite of
cardiovascular death and hospitalization for HF) between
the carvedilol and the control group.
In summary, beta blockers are commonly used in the treat-
ment of atrial fibrillation, coronary artery disease and HTN
all contributing factors for HFpEF and given the limited data
on their efficacy in HFpEF, the current ACC/AHA guidelines
give a IIa recommendation (level of evidence C) recommen-
dation for their use in patient with HTN and HFpEF [58].
Calcium Channel Blockers (CCB)
The role of CCB in HFPEF has been very limited with no

large randomized clinical trials available. Moreover, most
published studies have focused on special populations such as
patients with hypertrophic cardiomyopathy (HCM) [86].
Nevertheless, most of the evidence suggests that in addition
to slowing the heart rate, CCB enhance left ventricular relax-
ation “lusitropic effect” and diastolic filling. In this regard, in
a study of 55 patients with HCM, treatment with verapamil
(360–480 mg/day) for 1–4 weeks was associated an increase in
peak LV diastolic filling rate and symptomatic improvement
on graded exercise testing [87]. Similarly, a small randomized
study of 20 patients with HFpEF, verapamil was associated
with significant improvement of symptoms of HF and
increased LV diastolic filling rate and treadmill exercise time
when compared to placebo [88].
Aldosterone Antagonists
Evidence from animal studies suggests that aldosterone

antagonists improve left ventricular diastolic dysfunction by
reducing left ventricular mass and fibrosis both major
factors contributing to myocardial stiffness and diastolic

dysfunction [89]. In a small randomized, double-blind, pla-
cebo-controlled trial of 44 patients with HFpEF, although a
significant reduction in serum markers of collagen turnover
and improvement in echocardiographic measures of dia-
stolic function was shown with eplerenone no significant
improvement in exercise capacity was observed when com-
pared to placebo [90].
Similarly, in the Aldo-DHF trial, a study that assessed the
efficacy of spironolactone in 422 patients with HFpEF, no
effects on maximal exercise capacity improvement, symp-
toms relief, or quality of life were seen [91]. The Treatment
of Preserved Cardiac Function Heart Failure with an
Aldosterone Antagonist (TOPCAT) trial is the largest study
to date assessing the clinical efficacy of spironolactone in an
exclusive cohort of HFpEF patients [92]. Hospitalization for
HF was less common in the spironolactone group when com-
pared to the placebo group (12 % vs. 14.2%; hazard ratio
0.83; 95 % CI, 0.69–0.99). Second, higher rates of hyperkale-
mia (18.7 versus 9.1%) and increased creatinine were
observed in the spironolactone group compared to the pla-
cebo group. Third, among patients in whom the diagnosis of
HF was confirmed by elevated BNP or NT-proBNP levels,
spironolactone was associated with a reduction in the pri-
mary outcome.
In summary, in contrast to HFREF where clear improved
survival has been shown, therapy aiming at neuro-hormonal
blockade failed to show mortality benefit in HFPEF patients.
Current ACC/AHA guidelines recommend treating associ-
ated comorbidities such as hypertension, CAD, diabetes, and
chronic kidney disease using current available evidence
based medicine (Tables 1.1 and 1.2).
Table 1.1 ACC/AHA recommendations for pharmacology therapy for HFrEF
18
Recommendation/
Therapy Indications/use level of evidence
Diuretics Diuretics are recommended in patients with HFrEF with fluid retention IC Class I/LOE C
Beta Use of 1 of the 3 beta blockers proven to reduce mortality is recommended Class I/LOE A
blockers for all stable patients IA
ACEI’s ACE inhibitors are recommended for all patients with HFrEF Class I/LOE A
A. Menezes et al.
IA
ARBs ARBs are recommended in patients with HFrEF who are ACE inhibitor Class I/LOE A
intolerant Class IIa/LOE A
ARBs are reasonable as alternatives to ACE inhibitor as first line therapy in HFrEF Class IIb/LOE A
The addition of an ARB may be considered in persistently symptomatic patients
with HFrEF on GDMT
Aldosterone Use in patients with NYHA class II-IV HF who have LVEF ≤35 % Class I/LOE A
antagonists Use in patients following an acute MI who have LVEF ≤40 % with symptoms Class I/LOE B
of HF or Diabetes mellitus
Hydralazine The combination of hydralazine and isosorbide dinitrate is recommended Class I/LOE A
and for African-Americans, with NYHA class III–IV HFrEF on GDMT Class IIa/LOE B
Isosorbide A combination of hydralazine and isosorbide dinitrate may be beneficial
Dinitrate in patients with HFrEF who cannot be given ACE inhibitors or ARBs
Digoxin Digoxin can be beneficial in patients with HFrEF Class IIa/LOE B
Adapted from 2013 ACCF/AHA Guideline for the Management of Heart Failure [58]
Table 1.2 ACC/AHA recommendations for pharmacology therapy

for HFpEF
Recommendation/level
Therapy Indication/use of evidence
Diuretics Use for relief of Class I, LOE C
symptoms due to volume
overload IC
Beta Use for hypertension in Class IIa, LOE C
blockers HFpEF IIa C
ARBs May be used for Class IIa/LOE C
hypertension in HFpEF Class IIb/LOE B
Can be considered to
decrease hospitalizations
in HFpEF patients
ACEI’s Can be used for Class IIa/LOE C
hypertension in HFpEF
Adapted from 2013 ACCF/AHA Guideline for the Management of
Heart Failure [58]
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failure with preserved ejection fraction. N Engl J Med.
2014;370(15):1383.
Chapter 2
Novel Therapies
for the Prevention
and Management of Acute
Decompensated Heart Failure
Patrick T. Campbell and Sepehr Saberian
Acute decompensated heart failure continues to be a leading

cause of hospital admissions in the U.S. and is the leading
cause of hospitalization in patients >65 years of age [1]. Over
the past three decades significant advances in understanding
the complex pathophysiology has lead to the development of
medical therapies that have improved outcome, unfortu-
nately the overall mortality rate remains staggeringly high,
50 % at 5 years [2]. Hospitalizations for acute decompensated
heart failure (ADHF) are a huge burden to the already over
taxed health care system. Even with the advances in the
medical therapies, the 30-day readmission rate for ADHF is
25 % [3]. While the management of chronic stable heart
P.T. Campbell, MD ()

Heart Transplant Institute, Baptist Health Transplant Institute,
Little Rock, AR, USA
e-mail: Patcamp32@hotmail.com
S. Saberian, MD
Department of Cardiology, University of Illinois College of
Medicine at Peaoria, Peoria, IL, USA

DOI 10.1007/978-3-319-30593-6_2,
30 P.T. Campbell and S. Saberian
failure has progressed, the management strategies and thera-

pies for ADHF have changed little in the same time period
[4]. The mainstay therapies for the management of ADHF
are focused on rapidly improving symptoms of dyspnea,
peripheral edema and decongesting the patient. Intravenous
diuretics are recommended for decongestion and volume
removal in all patients with evidence of significant volume
overload. Concomitant use of IV vasodilators (nitroprusside,
nitroglycerin and neseritide) in patients without evidence of
hypotension can aid in decongestion and improve symptoms.
In patients with reduced EF and evidence of decreased perfu-
sion and hemodynamic compromise, intravenous inotropes
can be used to improve and maintain cardiac output and end-
organ perfusion. However none of the therapies have been
shown to improve (and may actually increase) morbidity and
mortality [5].
The past decade has produced several promising novel
therapies for the prevention and treatment acute decompen-
sated heart failure including natriuretic peptides, inotropes
and vasodilators.
Modulators of Natriuretic Peptides and Renin

Angiotensin Aldosterone System (RAAS)
Vasopeptidase Inhibitors
Vasopeptidase inhibitors (VPIs) are agents that block the

activation of the angiotensin converting enzyme (ACE) and
neutral endopeptidases simultaneously. ACE, an enzyme that
converts angiotensin I into angiotensin II and degrades brady-
kinin, results in vasoconstriction, along with sodium and water
retention. ACE-inhibition decreases the conversion of ANG-I
to ANG-II and the degradation of bradykinin. Bradykinin
promotes of the vasodilators; NO and prostacyclins [6]. ACE
inhibitors are known to improve symptoms, quality of life and
reduce hospitalization in the management of patients with
congestive heart failure [7]. Neutral endopeptidase (NEP) is
Chapter 2. Novel Therapies for the Prevention 31
an endothelial; membrane-bound metallopeptidase which

catalyzes the degradation of vasodilator peptides, including
Atrial Natriuretic Peptide (ANP), Brain Natriuretic Peptide
(BNP), C-type Natriuretic Peptide (CNP), substance P, and
bradykinin [8].These agents act against the Renin-Angiotensin-
Aldosterone System (RAAS), cause vasodilation, promote
diuresis and natriuresis. NEP acts on both the vasodilatory
peptides and simultaneously on vasoconstrictor peptides such
as endothelin-1 and ANG-II [8].
Early trials using NEP inhibitors showed mixed results,
with certain formulations caused vasoconstriction rather than
vasodilation. The effect of NEP inhibition depends on the
substrate available, if ANG-II and ET-1 are predominant the
NEP inhibitor may result in vasoconstriction, as has been
shown in the vasculature of the forearm [9]. Furthermore, the
effects of increased natriuretic peptides (ANP) can be atten-
uated by upregulation of the RAAS and sympathetic nervous
system. In clinical trials evaluating the effect of NEP inhibi-
tion on vascular tone, Candoxatril showed inconsistent
results with no statistically significant benefit in lowering
blood pressure compare to placebo [10]. In patients with con-
gestive heart failure, similar results were observed despite
noted elevation of ANP and BNP levels [11]. In the advent of
ACE inhibitor agents backed by clinical trials, the potential
synergistic effects gained from combination of ACE and NEP
inhibition created new possibilities in treatment of congestive
heart failure by further additional down regulation of the
neurohormonal pathways (i.e. sympathetic nervous system
and the RAAS pathway).
Earlier trials using Vasopeptidase inhibitors in animal
models with hypertension showed significant long lasting
effect in reducing the systolic blood pressure in rat models
[12]. In hamster models with congestive heart failure, long-
term treatment with omapatrilat improved cardiovascular
outcomes compared to ACE inhibition with captopril [13].
The early human based trial; the OCTAVE (Omapatrilat and
enalapril in patients with hypertension: the Omapatrilat
Cardiovascular Treatment vs. Enalapril) trial enrolled 25,000
hypertensive patients who were randomly assigned to either

the NEP inhibitor Omapatrilat, or Enalapril. The study dem-
onstrated a greater reduction in systolic blood pressure in the
Omapatrilat treatment arm [14]. A smaller study comparing
Omapatrilat to Lisinopril found a similar comparison and
validated a dose dependent, long lasting effect of Omapatrilat
in reduction of blood pressure [15]. In a limited study
designed to evaluate the safety and efficacy of a combined
NEP-I and ACEI (Sampatrilat) in African American patients
with a history of decreased response to ACEI alone, demon-
strated improved blood pressure reduction compared to
ACEI mono-therapy [16]. The OVERTURE (Omapatrilat
Versus Enalapril Randomized Trial of Utility in Reducing
Events) trial, which enrolled patients with congestive heart
failure (NYHA II–III), demonstrated the beneficial clinical
and echocardiographic effects of Vasopeptidase inhibitors.
Omapatrilat therapy reduced cardiovascular death by 9 %
compared to enalapril, however the primary end-point of
death and heart failure hospitalization was not different
between the groups [17]. In the IMPRESS trial; a head to
head comparison between Omapatrilat and Lisinopril in a
randomized control trial, noted that Omapatrilat led to lower
incidence of hospitalization and reduction in symptoms while
being equally well tolerated within a 12 week period [18].
Despite encouraging results, FDA halted the approval of
Vasopeptidase Inhibitors due to the incidence of angioedema
in the studied patients. The rate of occurrence was noted to
be significantly higher in the OCTAVE trial (2.2 % vs. 0.7 %)
compared to ACE inhibitor therapy. The cause of angioedema
in patients with ACE inhibition and NEP inhibition was
evaluated in select studies and partly attributed to the enzy-
matic activity of other amino and dipeptidyl peptidases.
Further studies suggest the possibility of performing bio test-
ing in order to predict the probability of angioedema prior to
treatment [19]. Another factor contributing to lack of
approval for NEP inhibitors is a lack of sufficient data in dif-
ferent patient populations; accounting for race, gender, age
and medication formulations. Despite shown value in the
control of hypertension and clinical benefits in treatment of

patient’s with congestive heart failure, the risk of unpredict-
able life threatening angioedema caused a significant set
back in the studies and promotion of Vasopeptidase
inhibitors.
The concern for severe angioedema was addressed by
combining NEP inhibitors with an ARB rather than an
ACEI. The angioedema seen in early trials was related to
excessive inhibition of the enzymes that degrade bradykinin
including ACE and aminopeptidase P. ARB’s do not block
these enzymes and therefore reduce the risk of life-threatening
angioedema. Entresto (sacubitril/valsartan) a neprilysin
inhibitor and angiotensin receptor blocker (ARB) combina-
tion received FDA approval in July of 2015 after the
PARADIGM-HF [20] (Prospective Comparison of ARNI
[Angiotensin Receptor – Neprilysin Inhibitor] with ACEI
[Angiotensin-Converting–Enzyme Inhibitor to Determine
Impact on Global Mortality and Morbidity in Heart Failure)
trial was stopped early for overwhelming evidence of benefit
over standard ACEI therapy. PARADIGM-HF enrolled pri-
marily NYHA Class II-III FC heart failure patients with
elevated BNP levels. Patients were required to have been on
prior ACEI or ARB therapy and have an EF <40 %. After 2
years of therapy the NEPI-ARB combination demonstrated
significant reductions in the primary composite endpoint of
death from cardiovascular causes and heart failure hospital-
izations compared to enalapril therapy. The benefit was seen
in the individual components as well, it significantly reduced
death from cardiovascular causes and demonstrated a 21 %
reduction in hospitalization for heart failure. Patients on
Entresto had improved functional status, decreased heart
failure symptoms and better reported quality of life. The
angiotensin-neprilysin inhibitor did have higher rates of
symptomatic hypotension and non-serious angioedema, but
less cough, renal failure and hyperkalemia.
Sacubitril/valsartan has been approved for the treatment
of NYHA Class II–IV heart failure with reduced ejection
fraction. The recommended starting dose is 49/51 mg twice
daily and can be titrated to a recommended maximum dose

of 97/103 mg twice daily. There are recommendations to start-
ing at 24/26 mg twice daily for patients that have severe renal
dysfunction, moderate hepatic dysfunction or have never
been treated with ACEI/ARB. The significant benefit demon-
strated by the PARADIGM-HF study is encouraging for the
future of heart failure management. Its full benefits in rou-
tine clinical benefits remain to be seen, however ANRI ther-
apy will likely rapidly become standard therapy for the
management of chronic heart failure (Table 2.1).
Urodilatin/Ularitide
Natriuretic peptides (NP) have played a large role in the

management and understanding of heart failure. Brain-type
natriuretic peptide (BNP) and atrial natriuretic peptide
(ANP) are released in response to increased myocardial
stretch and BNP remains integral in the diagnosis of acute
decompensated heart failure (ADHF). Early studies of the
recombinant form of BNP (nesiritide) were encouraging,
however recent data has failed to demonstrate a significant
benefit in the treatment of ADHF [21] and controversy
regarding its safety remain [22]. Recent focus has been placed
on ANP and its potential therapeutic role in ADHF.
ANP is produced in the atrium primarily in response to
increased mycocyte stretch, however ANP can also be
released in response to several vasoactive and neurohor-
mones including; epinephrine, vasopression, norepinephrine,
angiotensin II and endothelin-1. ANP exerts its biological
effects primarily through interaction with the natriuretic pep-
tide receptor type A (NPR-A), the same receptor utilized by
BNP. However ANP has up to 70 times the affinity for
NPR-A and stimulates ten times greater activity of the
NPR-A cyclase [23]. NPR-A receptors are located in a vari-
ety of organs and tissues including: vascular smooth muscle,
endothelial cells, renal collecting ducts, adrenal glands, kid-
ney, lung, liver and the heart [24, 25]. The binding of ANP to
Table 2.1 Summary of clinical trials for neprilysin inhibitors
Study/trial Aim of study Dose Results
Octave To evaluate Omapatrilat 10–80 mg, Omapatrilat resulted in clinically significant
the efficacy of titrated to reach goal mean reduction of 3–4 mmHg in blood pressure
Omapatrilat in BP < 140/90 compared to Enalapril
patients with Enalapril 5–40 mg, Omapatrilat required less up titration of dosage
hypertension, titrated to reach goal to reach target blood pressure
Chapter 2.
compared to BP < 140/90 within 8 Use of adjuvant therapy post 8 weeks was higher
Enalapril weeks, followed for 24 in the Enalapril group
weeks with or without Risk of angioedema in the omapatrilat treated
addition of adjuvant patients was (2.17 %) compared to the enalapril
therapy to reach target treated group (0.68 %)
BP goal Death and all adverse outcomes were similar
between Omapatrilat and Enalapril
Overture To evaluate Enalapril 10 mg No statistically significant reduction in all cause
the efficacy of twice daily (n – mortality between Omapatrilat, compared to
Omapatrilat in 2884) compared to enalapril (hazard ratio 0.94, 95 % confidence
patients with heart Omapatrilat 40 mg daily interval 0.86–1.03, P = 0.187)
failure (NYHA class (n – 2886) Angioedema was more common with
II–IV), compared to Omapatrilat. N = 24 (0.8 %)
Novel Therapies for the Prevention
Enalapril
(continued)
35
Table 2.1 (continued)
36
Study/trial Aim of study Dose Results

Impress To evaluate Omapatrilat 40 mg once Week 12 exercise treadmill test results improved
the efficacy of daily (n – 289) compared similarly in the omapatrilat and lisinopril groups
Omapatrilat on to lisinopril 20 mg daily (p = 0.45)
functional capacity (n – 284) for 24 week Suggestive trend in favor of omapatrilat on
and clinical outcomes combined endpoints of death or admissions for
in patients with worsening heart failure (p = 0.052; hazard ratio
heart failure patients, 0.53, 95 % Confidence interval 0.27–1.02)
compared to lisinopril Omapatrilat significantly lowered combined
death, admission, or discontinuation of study
treatment due worsening heart failure (p = 0.035)
P.T. Campbell and S. Saberian
Omapatrilat improved NYHA class more than

lisinopril in patients who had NYHA class III
and IV (p = 0.035), but not if patients with NYHA
class II were included
Paradigm-HF To evaluate the ARB-NEP inhibitor Significant reduction in combined end-point of

efficacy of ARB-NEP titrated to 200 mg death from cardiovascular cause and heart failure
inhibitor on morbidity twice daily compared hospitalization in the ARB-NEP inhibitor group
and mortality in to enalapril titrated to 21 % (p < 0.001) reduction in heart failure
heart failure patients 10 mg twice daily hospitalizations with ARB-NEPI
compared to enalapril Improved symptoms and quality of life in ARB-
NEPI group
NPR-A results in increased intracellular concentrations of

cGMP [23], resulting in natriuresis, diuresis, vasodilation and
inhibition of the renal-angiotensin-aldosterone system
(RAAS). In the kidney ANP affects both the renal vascula-
ture and the medullary collecting ducts. ANP-NPR activation
in the kidney increases sodium excretion by the collecting
ducts enhancing natriuresis and diuresis. ANP acts directly on
the renal vasculature vasodilating the afferent and vasocon-
stricting the efferent arterioles. The increased pressure in the
glomerular capillaries results in increased glomerular filtra-
tion rate (GFR) [26]. The vasodilatory effects of ANP are
mediated through direct increase in cGMP in vascular
smooth muscle as well as antagonism of RAAS, vasopressin,
epinephrine, endothelin and cytokines [27, 28]. ANP causes
equal dilation of both the arterial and venous vasculature and
some data suggests that it may have a role in vasodilation of
the coronary arteries [24]. The metabolism and removal of
ANP is primarily through NPR Type C (clearance) and enzy-
matic degredation by the neutral endopeptidase (NEP) sys-
tem. In heart failure the effects of ANP are attenuated
compared to healthy individuals even in the setting of
increased circulating levels. Theories the attenuated effect of
ANP in chronic heart failure include: chronic upregulation of
ANP production results in the release of less biologically
active molecules [29], downregulation of NPR-A receptors
and increased NEP activity [30].
Carperitide is a recombinant form of ANP, currently
approved in Japan for the treatment of ADHF. A small ran-
domized controlled study (PROTECT) reported significant
reductions in death and rehospitalization in patients with
reduced EF (<35 %) treated with Carperitide [31], however
large scale trials confirming these outcomes are lacking. The
hemodynamic benefits of Carperitide are unclear, one study
[32] failed to demonstrate improved hemodynamics (PCWP,
RAP) with Carperitide compared to traditional intravenous
vasodilators, while a more recent study [33] reported
improved hemodynamic parameters compared with vasodila-
tor therapy. The conflicting data regarding the hemodynamic
benefits of Carpertide may be due to increased degredation

of ANP by the NEP system or the down regulation of NPR-A
receptors in chronic heart failure. The two largest observa-
tional studies of Carperitide for the treatment of ADHF [34,
35] demonstrated similar results. Caperitide improved dys-
pnea scores in younger patients (<65 years) with Heart
Failure with preserved EF (HFpEF) and mild/moderate
decompensation without acute ischemia. The most common
adverse event was hypotension, which occurred in 5–10 % of
patients. Carperitide was less effective and caused signifi-
cantly more hypotension in older patients, patients with acute
myocardial ischemia and reduced renal function. The limited
data regarding Carperitide seems to suggest a possible role in
the treatment of patients with ADHF in the setting of hyper-
tensive heart disease and/or HFpEF. Larger studies and more
robust data are required before Caperitide can be recom-
mended for routine treatment of ADHF.
Urodilatin is a modified pro-ANP produced in the kidneys,
first osilated from human urine [36]. Urodilation binds to
NPR-A receptors with equal affinity as ANP, and exerts simi-
lar hemodynamic effects as intravenous ANP [25]. Urodilatin
differs slightly from ANP in molecular confirmation, which
confers resistance to NEP degredation. Early studies of urodi-
lantin demonstrated similar yet sustained hemodynamic
effects compared to ANP, suggesting prolonged activity may
be due to its resistance to NEP degredation [37]. Ularitide is a
synthetic form of Urodilatin that has shown promising results
in the management of ADHF. Animal studies demonstrated
improved hemodynamic, natriuretic and diuretic effects from
Ularitide administration. Early trials in patients with ADHF,
both bolus [37] and infusions [38] of Ularitide resulted in
decreases in PCWP, systemic vascular resistance and right
atrial pressure (RAP). Ularitide favorably affected natriuresis
and diuresis. Results from SIRIUS I, a pilot trial [39] demon-
strated significant improvement in dyspnea and hemodynam-
ics when Ularitide was added to standard HF therapy
including diuretics. There was no difference in urine output
between the ularitide and placebo groups, however the
Ularitide group received less frequent and lower doses of

diuretics. The hemodynamic and possible diuretic benefits of
Ularitide occurred without negative impact on renal function.
Hypotension occurred in almost 17 % of the treatment group
without impact on clinical outcomes. The highest dose of
Ularitide was associated with greater hemodynamic benefits,
but resulted in significantly greater hypotension (−17 mmHg
in SBP). The follow-up, larger randomized SIRIUS II trial [40]
confirm the results of SIRIUS I. Ularitide resulted in favor-
able reductions in PCWP, right atrial pressure (RAP), sys-
temic vascular resistance (SVR) and improved dyspnea. The
effects of ularitide were observed throughout the entire 24 h
of infusion without deleterious effects on short-term outcome.
An important finding in the SIRIUS II trial was a dose depen-
dent decline in myocardial oxygen consumption in the treat-
ment group. Further analysis of the SIRIUS II [41] data
revealed the potential renal protective effects of the interme-
diate dose (15 ng/kg/min) of Ularitide in HF patients. Ularitide
resulted in a favorable effect on the MAP-RAP pressure
gradient (an estimate of renal perfusion) which improved
renal perfusion and may have contributed to short-term pres-
ervation of renal function. Ularitide resulted in sustained
MAP while simultaneously reducing RAP. Similar results
were not observed in the highest dose, likely due to more sub-
stantial reductions in MAP. In patients with ADHF infusions
of Ularitide seem to improve hemodynamic parameters,
antagonize neurohormonal activity, improve diuresis, preserve
renal function and reduce myocardial oxygen demand, how-
ever long-term clinical benefits have yet to be demonstrated.
Ularitide has not be approved for routine use, however data
from the SIRIUS trials suggest that the intermediate dose of
15 ng/kg/min may provide the desired benefits while poten-
tially limiting the incidence and severity of hypotension. With
concern regarding the efficacy and safety of other natriuretic
peptides, the ultimate role of Ularitide in the treatment of
heart failure remains to be seen. Future studies randomized
trials are required to assess the long-term risk and benefits
associated with natriuretic peptide therapy.
Vasodilator Therapies
Relaxin
Relaxin is a naturally occurring peptide that was first isolated

from pregnant guinea pigs and rabbits [42] and later found to
have cardiovascular effects including; increased cardiac out-
put, increased arterial compliance and reduced SVR, along
with increased renal blood flow, during human pregnancy [43].
Relaxin acts on multiple pathways with possible vasodilatory,
angiogenesis and anti-inflammatory effects (Fig. 2.1). Relaxin
exerts the majority of its effects through a g-protein coupled
receptor, LGR-7, which has been isolated in human systemic
vascular, renal vascular and cardiac tissues [46]. Relaxin acts
RELAXIN (serelaxin)
Relaxin family peptide receptors (RXFP) or LGR7 receptor
Direct stimulation of ET-BR Indirect effects of LGR7 stimulation
MMP stimulation
NOS Local systemic and
NO renal vasodilation
Conversion of
Indirect stimulation of ET-BR endothelin to ET-1
Arterial ↓ TNF-β ↓ TNF-α
compliance
VEGF
Angiogensis
NOS → NO production
↓ Fibrosis ↓ Inflammation
Vasodilation
Figure 2.1 Effect of Relaxin Receptor activation by Serelaxin.

Notes: ET-BR endothelin-B receptor, NOS nitric oxide synthase,
NO nitric oxide, MMP matrix metalloproteinase, VEGF vascular
endothelial growth factor, TNF tumor necrosis factor. (Adapted
from Teichman [44] and Teichman [45])
through multiple pathways that ultimately result in increased

nitric oxide (NO) production and vasodilation. One of the
predominant pathways utilized by Relaxin is the endothelin
system. The endothelin system comprises two major receptors,
Endothelin-A (ET-A) receptors and Endothelin-B (ET-B)
receptors. ET-A is responsible for vasoconstriction, while
ET-B is primarily responsible for vasodilation in the vascular
system. Relaxin has been shown to act both directly and indi-
rectly on the ET system and may increase ET-B receptor
expression [47]. The Relaxin-LGR-7 (RLX-7) ligand acts pri-
marily by stimulating matrix metalloproteins 2 and 9 (MMP)
which convert Endothelin (ET) into active ET1-32. The acti-
vated ET1-32 bind to ET-B receptors which then increase NO
production and result in vasoldilation. The increased NO
production results in vasodilation of both the systemic and
renal vasculature. In the systemic vasculature the RLX-7
ligand can also directly activate the ET-B receptor resulting in
increased NO production. There is evidence that RLX-7
increases local phosphatidylinositol 3-kinase and NO result-
ing in rapid vasodilation [48]. In the kidneys the RLX-7 ligand
inhibits the Na/K+ ATPase, which may be the mechanism of
the observed natriuresis and diuresis.
Few randomized clinical trials evaluating the efficacy and
safety of relaxin for the management of heart failure have
been published. The Pre-RELAX-AHF was a small, random-
ized pilot study that evaluated a 48 h infusion of escalating
doses of Relaxin compared to placebo for the treatment of
acute decompensated heart failure and mild to moderate
renal dysfunction. The study demonstrated reductions in the
composite endpoint of cardiovascular mortality, heart failure
hospitalization or hospitalization for renal failure [49].
The larger RELAX-AHF study enrolled 1161 patients
with acute decompensated heart failure with evidence of
congestion (pulmonary congestion on chest x-ray and ele-
vated BNP) and mild to moderate renal dysfunction (GFR
30–75 mL/min/m2). Patients were randomized to a 48 h infu-
sion of Serelaxin (30 μg/kg/day) versus placebo. Patients with
SBP <125 mmHg were excluded from the trial.
The administration of serealxin resulted in significant

declines in early worsening of heart failure, overall length of
stay and ICU length of stay. The treatment group reported
significantly greater mild reduction in dyspnea and earlier
improvement in symptoms. There was a 37 % reduction in
cardiovascular and all-cause mortality, however the study was
not powered to assess mortality. Serelaxin was associated
with greater rates of clinically significant hypotension requir-
ing dose adjustment but less worsening renal function [50].
The major criticism of the RELAX-AHF trial was the gener-
alizability of the data to the larger heart failure population.
Patients in the study had significantly higher BP compared to
most heart failure studies, almost half of the patients had
ejection fraction >40 % and the vast majority (95 %) were
Caucasian. While symptomatic improvement is important for
the treatment of patients with ADHF, future studies are
required to determine if the signal for improved mortality
seen is real.
Inotropic Agents
Istaroxime
Istaroxime (Istaroxime-(E,Z)-3-[(2-aminoethoxy)-imino]
androstane-6,17-dione is a novel drug with dual action that
while unrelated to cardiac glycosides (digoxin) shares one
similar mechanism of action. Istaroxime inhibits the Na+/K+
ATPase and simultaneously stimulates the sarcoplasmic
endoplasmic reticulum calcium ATPase isoform 2
(SERCA2a), thereby affecting both myocyte contraction and
relaxation [51]. The inhibition of Na+/K+ ATPase results in
increased cytosolic calcium concentrations during diastole
and intracellular Ca2+ concentrations is essential for sarco-
mere shortening and cardiac myocyte contractions. SERCA2a
stimulation results in rapid reuptake of Ca2+ into the sarco-
plasmic reticulum (SR) during diastole and enhances myo-
cyte relaxation and lusitropy. The efficient uptake of Ca2+
into the SR also results in sufficient SR Ca2+ concentrations

to facilitate subsequent cardiac contractions.
In the heart, calcium cycling is responsible for triggering
the interaction between actin and myosin, which result in
cardiac contraction. During systole, an action potential stimu-
lates the influx of Ca2+ through L-type Ca2+ channels and
the increase in intracellular Ca2+ induces release of Ca2+
from the SR through ryanodine receptor (RyR2) channels.
The increased intracellular Ca2+ concentrations is responsi-
ble for the contraction of cardiac myocytes [52]. During dias-
tole the RyR2 channels close, the Ca2+ dissociates from the
myofilaments and intracellular Ca2+ decline. The rapid
decline in intracellular Ca2+ concentrations result in myocar-
dial relaxation, also referred to as lusitropy. There are three
mechanisms by which the intracellular Ca2+ concentrations
are decreased during diastole, the first is through rapid reup-
take of Ca2+ into the SR by SERCA2a, which accounts for
approximately 70 %. SERCA2a activity is modulated by
phosphorylation of phospholamban (PLB), if unphosphory-
lated it inhibits the activity of SERCA, while phosphorylated
phopholamban activates SERCA. Thus phosphorylated PLB
is integral to lusitropy. The second is through the Na+/Ca2+
Exchanger (NCX), which moves Ca2+ extracellularly and is
responsible for approximately 28 % of the Ca2+ reuptake.
The final mechanism is through the plasma membrane Ca2+
ATPase [51, 53].
In the heterogeneity of heart failure calcium dysregulation
has been demonstrated to play a role in certain etiologies.
Calcium “leak” from the SR during diastole due to abnormal
RyR2 channels has been demonstrated. This “leak” results in
decreased Ca2+ availability during systole which decreases
the contractile force generated by the myocytes [54].
Abnormal function of the SERCA2a pump has also been
shown to impact both contraction and relaxation of the car-
diac myocyte. Reduced SERCA activity results in decreased
reuptake into the SR which results in creased concentrations
of Ca2+ available during systole and sustained levels of intra-
cellular Ca2+ during diastole results in decreased relaxation
and diastolic dysfunction [55]. Finally reduced phosphoryla-

tion of the PLB protein may also alter the efficiency of
SERCA2a in heart failure, affecting both lusitropy and inot-
ropy [56]. Istaroxime may improve cardiac calcium cycling
thereby improving relaxation, contraction and the oxygen
demand of the cardiac myocyte. In the mechanically chal-
lenged heart the reduction of SERCA2a activity results in
upregulation of the NCX channels, extracellular exchange of
Ca2+ for Na+. The increased NCX activity results in slower
reduction of intracellular Ca2+ concentrations, negatively
impacting cardiac relaxation and reducing the available Ca2+
for systole [57]. Furthermore it results in increased energy
demands, the NCX pathway requires twice as much energy as
the SERCA channels and requires increased Na+/K+ ATPase
activity to maintain intracellular Na+ levels, all at an increased
energy cost to the strained mycocardium [58].
Istaroxime has dual activity in the cardiac myocyte, it
inhibits the Na+/K+ ATPase, which results in increased cyto-
plasmic concentrations of Ca2+ and simultaneously stimu-
lates SERCA2a affinity for Ca2+. The increased SERCA2a
activity improves both cardiac relaxation and contraction.
The combined activity of Istaroxime, increasing systolic intra-
cellular Ca2+ concentration and rapid sequestration of Ca2+
during diastole, result in both increased contractility and
improved diastolic function. Early animal studies with
Istaroxime resulted in improved inotropy and lusitropy. In a
hamster model of dilated cardiomyopathy, long-term oral
administration demonstrated mortality benefits [59]. The
positive inotropic and lusitropic were observed without sig-
nificant side-effects including arrhythmia, heart rate, blood
pressure or myocardial oxygen demand. In a second animal
study [60] similar beneficial effects of Istaroxime were dem-
onstrated in hemodynamic and echocardiographic parame-
ters in dogs. Dose-dependent improvement was seen in left
ventricular ejection fraction (LVEF), End-diastolic pressures
(LVEDP), end-diastolic (EDV), end-systolic volumes (ESV),
stroke volume (SV), coronary blood flow (CBF) and
deceleration time (DT). The hemodynamic improvements
were obtained without significant increases in myocardial

oxygen consumption.
The HORIZON-HF was a large randomized, double-
blind, placebo controlled study evaluating the effects of
Istaroxime in patients admitted for decompensated heart
failure with reduced ejection fraction (HFrEF) [61, 62]. The
study included 120 patients between 18 and 85 years of age
with reduced EF (<35 %) and a pulmonary capillary wedge
pressure (PCWP) >20 mmHg on invasive hemodynamic
assessment.. Patients were randomized to an infusion of 0.5,
1.0, 1.5 μg/kg/min of Istaroxime or placebo for 6 h. The pri-
mary endpoint was change in pulmonary capillary wedge
pressure (PCWP) after 6 h infusion. Secondary endpoints
included change in cardiac index (CI), right atrial pressure
(RAP), systolic BP, diastolic BP, heart rate (HR), along with
echocardiographic assessment of systolic and diastolic func-
tion. Other parameters assessed included neurohormones,
renal function, and troponin. After the 6 h infusion Istaroxime
significantly reduced PCWP compared to placebo in a dose
dependent manner for all three doses. The greatest decline in
PCWP (−4.7 mmHg) was observed in the 1.5 μg/kg/min dose
compared to no change in the placebo group. Istaroxime also
significantly increased SBP in the highest dose by 15 mmHg
compared placebo. During infusion of the highest dose,
Istaroxime improved cardiac index (CI) but was not signifi-
cant at 6 h. Istaroxime improved regional and global myocar-
dial systolic and diastolic function, and LV compliance as
assessed by tissue-doppler echocardiography.
The improved PCWP and diastolic function were observed
without significant adverse events, changes in neurohor-
mones or increase in troponin. The lack of increase in tropo-
nin suggest that the inotropic and lusitropic effects of
Istaroxime occurred without significant increase in myocar-
dial oxygen consumption, these findings are consistent with
the findings in the animal studies. The only significant adverse
events noted were nausea, vomiting and injection site pain.
The data from current available evidence suggest Istaroxime
may provide beneficial effects in patients with ADHF, without
significant adverse effects. The combination of increased

SERCA2a activity and inhibition of the Na+/K+ ATPase chan-
nels results in improved energy balance, decreasing the myocar-
dial oxygen consumption in the failing heart. The increased
affinity of SERCA for Ca2+ improves both myocardial relax-
ation by increasing the rapid reuptake into the SR and improves
myocardial contraction through increased availability of Ca2+.
The data seems to suggest that Istaroxime improves cardiac
Ca2+ cycling and increases intracellular Ca2+ concentrations
without the risk of increased arrhythmogenesis [63]. In fact the
HORIZON-HF study demonstrated a significant shortening of
the QTc in patients treated with Istaroxime [61].
Although not currently FDA approved, recent literature
suggest that Istaroxime may be beneficial in patients admitted
for acute decompensated heart failure (NYHA Class II–III)
with reduced LVEF. Data from the HORIZON-HF suggest
doses between 0.5 and 1.5 μg/kg/min may be useful for the man-
agement of ADHF. Istaroxime has a 1 h half-life and reached
steady state levels at 4 h after of infusion. Istaroxime is metabo-
lized to three less active metabolites and is not excreted by the
kidneys [61]. While the most benefit was seen in the highest
dose, adverse events were more common at that dose. Future
studies focused on in-hospital and long-term clinical outcomes
are required to determine the future of this promising drug.
Levosimendan
Commonly used agents in patients with acute decompensated

heart failure with systolic dysfunction are intravenous inotropic
agents, of which B-adrenergic agonists and phosphodiesterase
inhibitors encompass the majority. β-adrenergic agents augment
the release calcium into the myocytes by increasing intracellular
cAMP levels. Phosphodiesterase inhibitors perform a similar
task by inhibiting the degradation of cAMP [64]. Increased intra-
cellular calcium increases contractility, but is also associated with
increased risk of arrhythmia and mortality [65]. Levosimendan is
a new agent, which acts by sensitizing cardiac troponin C to cal-
cium. This unique mechanism of action strengthens contraction
without increasing oxygen demand, cAMP or intracellular
calcium concentrations [66]. Levosimendan functions by binding

to the regulatory domain and the charged amino acids in the
hydrophobic pocket of the calcium saturated N-terminal domain
of the troponin C [67]. In a calcium dependent manner,
Levosimendan stabilizes the conformation of calcium–troponin
C complex through hydrophobic and electrostatic interactions.
This results in accelerated actin–myosin cross bridge formation
rate and reduces the speed of dissociation [68]. Levosimendan
has also been shown to improve both peripheral and coronary
vasodilation. The afterload reduction likely contributes to its
effectiveness and the coronary vasodilation may improve cardiac
myocyte oxygen mismatch [69].
The effect of Levosimendan is attenuated during diastole
due to reduced intracellular Ca2+ concentrations as a result
of active Ca2+ reuptake. This allows for appropriate left ven-
tricular relaxation, while maintaining its inotropic properties
during the systolic phase of the cardiac cycle [70]. Outside the
cardiac myocyte Levosimendan stimulates ATP-dependent
potassium channels in myocytes and vascular smooth muscle
cells, resulting in vasodilatation [71]. Levosimendan is gener-
ally well tolerated in all clinical trials to date. The most fre-
quent adverse effect is headache, hypotension, dizziness and
nausea. These side effects are largely attributed to the vaso-
dilatory effect of Levosimendan. Decrease in hemoglobin
and hematocrit in higher doses have been reported, as well a
mild hypokalemia without significant clinical outcomes.
Levosimendan is an infusion agent with a rapid onset of
action, a short half-life of 1.3 h and an active metabolite known
as OR-1986 [72]. OR-1986 is formed by the acetylation of
Levosimendan metabolites formed by colonic bacteria upon its
secretion. It is less plasma bound than its native parent and thus
more potent. The peak concentration of OR-1896 is reached
within 2–3 days post infusion and its effects may persist for 7–9
days [73]. The initial dosing recommended based on clinical
trial is a bolus infusion of 6–12 μg/kg over 10 min, followed by
a maintenance dose of 0.05–0.2 μg/kg/min over 24–48 h [74].
Several studies have evaluated the safety, efficacy and
hemodynamic outcomes of Levosimendan in humans. An
early randomized clinical trial in 146 patients with heart
failure NYHA class III–IV, with known cardiac index of
<2.5 L/min/m2 and elevated wedge pressure (PCWP)

showed favorable results. This study concluded that
Levosimendan was associated with a dose dependent
increase in stroke volume and cardiac index and decrease
in PCWP at various doses [75]. Clinical symptoms of dys-
pnea and fatigue were also improved without any clinical
adverse effects. The LIDO (Levosimendan Infusion vs
Dobutamine in Severe Low Output Heart Failure) study
compared the effect of Levosimendan to Dobutamine. It
was found that a significantly higher proportion of
Levosimendan patients showed improved cardiac output
(≥30 % increase) and a concomitant decrease in PCWP
(≥25 %). It was also found that 180-day mortality was lower
in the Levosimendan subgroup [76].
The CASINO (Calcium Sensitizer or Inotrope or None
in Low Output Heart Failure Study) trial, patients with
NYHA-IV classification and reduced left ventricular func-
tion showed statistically significant reduction in mortality
in a 6-month period compared to patients treated with
Dobutamine [77]. From a mortality perspective, The
SURVIVE study evaluated 1327 hospitalized patients with
acute decompensated heart failure found early benefits
from the use of Levosimendan but no difference in mortal-
ity and incidence of adverse effects [78]. The REVIVE II
study; which evaluated 600 patients with acute decompen-
sated heart failure, demonstrated that Levosimendan in
addition to standard therapy was superior to standard
therapy alone and resulted in a shorter duration of hospi-
talization. There was no significant difference in 90-day
mortality and concerns were raised regarding an increased
rate of arrhythmias [79].
Use of Levosimendan in patients with cardiogenic shock
has shown favorable results in those treated in conjugation
with catecholamines for restoration of hemodynamics. While
studied in a small sample size, Levosimendan treatment
resulted in a significant increase in cardiac output together
with a decrease in systemic vascular resistance and decreased
mortality at 6 months [80, 81]. The RUSSLAN (Randomized

Study on Safety and Effectiveness of Levosimendan in
Patients with Left Ventricular Failure due to an Acute
Myocardial Infarction) trial evaluated 504 patients with
reduced left ventricular ejection fraction due to recent myo-
cardial infarction. Use of Levosimendan was associated with
decrease in mortality and worsening heart failure compared
with placebo at 6 and 24 h after the infusion with lower all-
cause mortality at 14 days in the treatment group. This lower
mortality persisted at 180 days but without a statistically sig-
nificance [82]. On going large clinical trials including the
LION-Heart, LAICA and ELEVATE are underway evaluat-
ing the role intermittent dosing of Levosimendan in overall
mortality and hospitalization rate.
Major contraindications to Levosimendan include moder-
ate to severe renal impairment, severe hepatic impairment,
ventricular filling and outflow obstruction, hypotension,
tachycardia and a history of Torsades de pointes. No dose
change is required for mild renal or hepatic insufficiency.
Levosimendan is administered as loading dose of 6–12 μg/kg
over 10 min. It is followed by infusion 0.05–0.2 mcg/kg/min
for up to 24 h. Levosimendan administration has been well
tolerated when co-administered with standard heart failure
therapies; ACE inhibitor, B-blockers, Isosorbite mononitrate,
warfarin and digoxin, without significant drug-drug interac-
tions [83]. The European society of cardiology recommends
against the use of Levosimendan in patients with significant
hypotension (SBP < 85 mmHg). Use of Levosimendan is not
yet approved by the FDA. Levosimendan has since been
approved by many European countries and used when
indicated. Current clinical trails have largely been conducted
in European countries. Evidence supporting the role of
Levosimendan in improving and restoration of hemodynam-
ics in patients with decompensated heart failure are many. Its
role in reduction of mortality in long term follow up and
appropriate intermittent dosing are current topics in ongoing
clinical trials (Table 2.2).
Table 2.2 Summary of Levosimendan clinical trials
50
Study/study Aim Dose Results

LIDO To evaluate the effects 103 patients assigned to The primary hemodynamic endpoint
of Levosimendan on Levosimendan and given (30 % increase in cardiac output or 25 %
hemodynamic performance an infusion of 24 μg/kg decrease in pulmonary capillary wedge
and clinical outcomes over 10 min, followed by pressure) was achieved in 29 (28 %)
in heart failure patients, a continuous infusion of Levosimendan-group patients and 15
compared to Dobutamine 0.1 μg/kg/min for 24 h. (15 %) in the Dobutamine group (hazard
100 patients assigned to ratio 1.9, 95 % Confidence interval 1.1–
Dobutamine and infused 3.3, p = 0.022)
for 24 h at an initial dose of At 180 days, 27 (26 %) Levosimendan-
5 μg/kg/min group patients had died, compared with
38 (38 %) in the Dobutamine group
(hazard ratio 0.57, CI 0.34–0.95, p = 0.029)

Both Levosimendan and Dobutamine
increased heart rate by a modest and
similar amount
Renal and Liver dysfunction declined in
the Levosimendan group
Clinical symptoms of dyspnea and fatigue
improved more so with Levosimendan,
however not statistically significant
CASINO To evaluate the efficacy 299 patients with The study was designed to recruit 600
of Levosimendan on decompensated heart patients, but it was stopped after 299
composite of death or failure (Ejection fraction patients had been recruited due to clear
re-hospitalization in heart <35 %) receiving 24 h superiority of Levosimendan versus
failure patients compared infusion of Levosimendan, placebo or Dobutamine
to placebo or Dobutamine placebo or Dobutamine 6 months mortality was 18 % in the
Levosimendan treatment group, 42 % in the
Chapter 2.
Dobutamine group and 28.3 % for placebo

SURVIVE To evaluate the effect of 1327 patients with Mortality rates in patients treated with
Levosimendan on clinical heart failure (Ejection Levosimendan was not significantly
outcomes in patients with fraction <30 %) receiving superior to Dobutamine (26 vs. 28 %,
heart failure compared to Levosimendan (n – 664) respectively, Hazard ratio 0.91 (95 %
Dobutamine with bolus dose of 12 μg/kg Confidence interval 0.74–1.13, P = 0.401)
followed by dose increase Levosimendan use was attributed
of 0.1–0.2/kg/min for 24 h to higher rates of Atrial Fibrillation
or Dobutamine (n – 663) compared to Dobutamine (9.1 % vs. 6.1 %)
with a continuous dose of Levosimendan use was associated
5 μg/kg/min with lower incidence of heart failure
worsening (12.3 % vs. 17 %) compared
with Dobutamine
Incidence of hypotension and ventricular

arrhythmias were similar
51
(continued)
52
Study/study Aim Dose Results

REVIVE II To evaluate the effect of 600 patients with heart Levosimendan treatment was associated
Levosimendan on Clinical failure (Ejection fraction with improved outcomes (19.4 %
outcomes in patients with <30 %) receiving experienced improvement in clinical
heart failure as adjuvant Levosimendan with bolus findings vs. 14.6 % in placebo, p = 0.015),
therapy to standard therapy dose of 12 μg/kg followed Levosimendan use was associated with
by dose increase of decrease in duration of hospitalization by
0.1–0.2 μg/kg/min for 24 h. approximately 2 days ((7.9 vs. 8.9 days in
Patients were followed for placebo, p = 0.001)
up to 4 days post infusion No significant reduction in mortality was
completion observed within the follow up period
Levosimendan use was associated with

higher incidence of hypotension (50 %
vs. 36 %), Ventricular Arrhythmias (25 %
vs. 17 %) and Atrial Fibrillation (8 % vs.
2 %) compared to placebo
RUSSLAN To evaluate the effect of 504 patients treated with The incidence of ischemia with or
Levosimendan on clinical Levosimendan with four without hypotension was similar in all
outcomes in patients with different loading doses treatment groups (P = 0.319)
left ventricular failure due (0.1–0.4 μg/kg/min) for 6 h An increase in Incidence of myocardial
to as acute myocardial compared to placebo ischemia and/or hypotension was seen in
infarction the highest Levosimendan dose group
Levosimendan was associated with lower
Chapter 2.
risk of death and worsening heart failure,

compared to placebo during the 6 h
infusion (2.0 % vs. 5.9 %; P = 0.033) and
over 24 h (4.0 % vs. 8.8 %; P = 0.044)
Levosimendan was noted for decreased
mortality compared with placebo at
14 days (11.7 % vs. 19.6 %, hazard ratio
0.56, 95 % CI 0.33–0.95, P = 0.031) and
the reduction was maintained at the
180-day retrospective follow-up (22.6 %
vs. 31.4 %, Hazard ratio 0.67, 95 %
confidence interval 0.45–1.00, P = 0.053)
53
Omecamtiv Mecarbil
Myocardial contraction by the sarcomeres within the myo-

cytes is initiated through the transduction of chemical into
mechanical energy. The force generating structures within the
sarcomeres consist of actin and myosin, which are regulated
by regulatory proteins troponin and tropomyosin. Each myo-
sin complex consists of two myosin heavy chains and two
light chains. Each myosin heavy chain head consists of an
ATPase complex that cleaves ATP to produce energy, as well
as an actin-binding site. Cardiac troponin and tropomyosin
form a complex that regulates the interaction of myosin with
actin in a calcium dependent process [84]. Increased calcium
concentration via depolarization of the myocytes causes
binding of calcium to cardiac troponin and dissociation of the
troponin-tropomyosin complex. This process allows for actin-
myosin cross bridge formation and hydrolysis of ATP to
ADP + Pi. The subsequent release of the Pi results in bending
of the myosin head, producing a 10-nm stroke. Calcium is
then stored in the sarcoplasmic reticulum waiting for the next
cycle of myocardial activation. The actin-myosin cycle is
quintessential in generation of the myocardial force and con-
tractility [85]. The current drugs that influence the cardiac
contractility act by increasing intracellular cAMP and
Calcium. These agents have been associated with hypoten-
sion and increased myocardial demand due to the increased
myocardial oxygen demand. These agents, in the setting of
ongoing myocardial ischemia and decompensated heart fail-
ure, are associated with increased risk of arrhythmias and
mortality [86].
Omecamtiv Mecarbil, known as CK-1827452, is the fourth
candidate compound produced which increases the cardiac
myosin ATpase activity but not other muscle myosins. It has
a half-life that ranges from 17.1 to 21 h. It is the only com-
pound of its class that was studied in human populations and
is considered the successor to previous models that showed
favorable results in animal models only [87]. Omecamtiv
Mecarbil functions by improving energy mobilization and
Omecamtiv mecarbil
ATP Weak binding Strong binding
Pi
Myocyte contraction
= Myosin
= Actin
Figure 2.2 Mechanism of action: Omecamtiv Mecarbil. Pi phos-

phate (The mechanism of action of Omecamtiv Mecarbil; increas-
ing rate of strong binding through increased rate of phosphate
release from myosin, which is the rate limiting step of myocyte
activation)
enhancing the myosin-actin cross bridge formation and dura-

tion [88]. It also facilitates the release of the phosphate group
from myosin heads; thereby increasing the time spent con-
tracting without altering the velocity of the contraction [89].
Omecamtiv Mecarbil increases the rate of transition from
weakly bound myosin-actin filaments to the strongly bound
state, which enables the myocyte contraction (Fig. 2.2). There
are no changes in calcium concentrations within the sarco-
plasmic reticulum or the calcium made available for each
cycle [90]. Earlier animal studies in rat and dog models with
left ventricular hypertrophy and heart failure, utilizing
Omecamtiv Mecarbil showed a 20 % increase in left ventricu-
lar ejection fraction, systolic time, systolic wall thickening and
stroke volume [91]. Interestingly, the studies also showed a
reduction in left ventricular end diastolic pressure, mean left
atrial pressure and heart rate with no changes in blood flow
to the endocardium and myocardial oxygen demand.
In the first human study with Omecamtiv Mecarbil, 34
patients were randomized and received 6-h infusions weekly
for 4 weeks. Echocardiograms were obtained prior and post
administration of infusions. Researchers found a linear dose

dependent increase in left ventricular systolic time and statis-
tically significant changes in ejection fraction and fractional
shortening [92]. Doses that were well tolerated were infu-
sions at 0.625 mg/kg/h and below. Patients receiving higher
doses developed signs and symptoms of myocardial ischemia
due to severe prolongation of the systolic ejection time,
thereby decreasing the diastolic time and coronary perfusion.
A second randomized clinical trial evaluated 45 patients with
known heart failure with ejection fraction <40 %. This study
concluded that Omecamtiv Mecarbil was associated with
improved systolic ejection time, stroke volume and fractional
shortening in a concentration dependent manner with no
changes in the E/E′ or S′ [93]. Three patients were found to
have elevated cardiac biomarkers out of the 151 infusions
during this study. Two patients showed sign and symptoms of
myocardial ischemia; one due to accidental overdose while
the other was attributed to poor mechanisms of clearance
and therefore increased plasma concentrations beyond pre-
dicted values. A phase II clinical trial that evaluated the role
of Omecamtiv Mecarbil on patients with ischemic cardiomy-
opathy found no clinically significant deleterious effect in
patients with serum concentrations that improved cardiac
function [94]. The ATOMIC-AHF trial randomized 613
patients with left ventricular systolic dysfunction who were
admitted for worsening dyspnea. This study showed no sig-
nificant benefit at lower serum concentrations in improving
symptoms. Although the study did not reach clinical signifi-
cance in the primary end-point, there was improved dyspnea
in patients on the highest dose of omecamtiv mecarbil.
Interestingly there were also signals of decreases in worsen-
ing heart failure and ventricular arrhythmias [95].
Omecamtiv Mecarbil has shown a dose and concentration
dependent effect on cardiac function. The recommended ini-
tial infusion dosing based on early human studies was
0.125 mg/kg/h; in which increase in systolic ejection time,
fractional shortening and stroke volume are noted. Doses up
to 0.625 mg/kg/h were well tolerated during studies.
Improvement in ejection fraction was noted at doses of

0.5 mg/kg/h or greater. Adverse outcomes were attributed to
plasma concentrations exceeding 1200 ng/mL and were uni-
versally attributed to decreased diastolic filling time and
coronary perfusion. All research thus far in evaluating the
pharmacokinetics and effect of Omecamtiv Mecarbil has
provided guidelines for appropriate dosing selection and
monitoring for future trials. The role of Omecamtiv Mecarbil
in patients with acute decompensated heart failure with
NYHA III–IV with inadequate cardiac output remains under
evaluated with no answer in sight with regards to clinical
effects on quality of life, morbidity and mortality. Required
IV infusions and serum concentration monitoring may repre-
sent further challenges. Having established grounds regard-
ing appropriate dosing, concentration monitoring, tolerability,
and improved cardiac function, further studies are warranted
in the evaluation of this novel agent in the management of
decompensated heart failure with reduced ejection fraction.
Adjunctive Therapies
Tolvaptan
Vasopressin is a 9 amino acid peptide, which is produced by

the magnocellular neurosecratory cells of the supraoptic
nucleus and the paraventricular nucleus of the hypothalamus.
It is stored in the posterior pituitary and secreted into the
systemic circulation [96]. The release of Vasopressin is pri-
marily driven by changes in serum osmolality as detected by
specialized sensors in the brain, and changes in circulating
blood volume as perceived by baroreceptors in the carotid
sinus, the atria, pulmonary trunk and stretch receptors in
large veins [97, 98]. Vasopressin functions by acting on the
cells within the collecting ducts of the kidneys, where the
insertion of unique water channels (called aquaporin 2) into
the luminal membrane allow for free water reabsorption into
the systemic circulation [99]. Vasopressin receptors are
G-protein receptors of which three types are known, V1, V2

and V1B. V1 receptors are abundant in vascular smooth mus-
cles and cause vasoconstriction upon activation. V2 receptors
mediate the antidiuretic response in the collecting ducts of
the renal tubules while the V1B receptors in the anterior pitu-
itary mediate the release of adrenocorticotropic hormone
and endorphins [100, 101].
Tolvaptan is an oral Vasopressin antagonist first described
in 1998 [102] and approved by the FDA in 2009 for the treat-
ment of hypervolumic or euvolumic hypotonic hyponatremia
(Defined as serum sodium <125 mEq/L or less marked hypo-
natremia that is symptomatic and has persisted despite ade-
quate volume restriction). Tolvaptan antagonizes the V1 and
V2 receptors, thereby preventing free water reabsorption. It
binds V2 receptors with an affinity 1.8 times greater than
inherent Vasopressin and 29 times greater than V1. Tolvaptan
has a half-life of approximately 9.4 h. It is plasma protein
bound with a peak concentration of 2 h with no alteration in
effect by food intake [103]. The majority of the metabolism
occurs in the liver through the CYP3A4/5 enzymatic medi-
ated process, while a small fraction of its clearance is medi-
cated by the renal system. Vasopressin is primarily released in
response to a hypovolemia and hypotension. In a seemingly
paradoxical response vasopressin levels are not suppressed
and may even be elevated in heart failure. The up regulation
of vasopressin in heart failure results in increased vasocon-
striction, increased salt and fluid retention. These effects are
similar to the effects seen as a result of the up regulation of
the RAAS system, which has been associated with a poor
prognosis in patients with known systolic dysfunction via
retention of free water and resulting hyponatremia [104].
The SALT-1 and SALT-2 trials were the initial large ran-
domized clinical trials, which evaluated the effect of Tolvaptan
on euvolemic and hypervolemic, hyponatremic patients. Heart
failure patients comprised 33 and 29 % of enrolled patients in
the SALT-1, and 29 % in the SALT-2 trial, respectively [105].
Both trials concluded that Tolvaptan could be safely adminis-
tered in a 30-day period to increase serum NA+ concentrations
through removal of excess free water. The role of Tolvaptan in

heart failure patients has been analyzed in many clinical trials.
Early randomized studies in patients with heart failure symp-
toms showed weight reduction and normalization of sodium
concentrations without amendments in quality of life, reduc-
tion of systolic or diastolic blood pressures or negative impact
on renal function [106]. The ACTIV in CHF (Acute and
Chronic Therapeutic Impact of Vasopressin Antagonist in
Congestive Heart Failure) trial studied the effect of Tolvaptan
in hospitalized individuals with known LV dysfunction who
presented with worsening symptoms of their heart failure.
Gheorghiade M et al. showed a statistically significant reduc-
tion in weight and dyspnea in the treatment group compared
to placebo in a short-term analysis (up to 10 days) with no
significant difference in worsening HF between the two groups
during the outpatient follow up period of the study [107]. The
EVEREST (Efficacy of Vasopresin Antagonism in Heart
Failure Outcome Study With Tolvaptan) trial randomized 4133
patients presenting with HF symptoms and reduced EF to
either tolvaptan or placebo. The authors found improvements
in dyspnea, weight loss and edema in the treatment group.
Importantly these benefits occurred without significantly
higher incidence of adverse events including hypotension,
hypernatremia or renal failure [108]. The ECLIPSE (Effect of
tolvaptan on hemodynamic Parameters in Subjects with Heart
Failure) trial analyzed the hemodynamic effect of Tolvaptan in
heart failure patients with NYHA III & IV. It concluded that
no significant changes in cardiac index, pulmonary vascular
resistance, and systemic vascular resistance were noted in the
treatment group while a statistically significant decrease in
peak change in PCWP was noted from 3 to 8 h after Tolvaptan
administration [109]. The METEOR (Multicenter, random-
ized, double-blind, placebo-controlled study on the effect of
oral tolvaptan on left ventricular dilation and function in
patients with heart failure and systolic dysfunction) study sub-
sequently failed to show a significant change in LV ejection
fraction post 1 year of therapy with Tolvaptan 30 mg/daily in
240 patients with LV function <30 % [110].
While trials showcasing the effect of Tolvaptan in treat-

ment of heart failure are lacking clinical findings in reduc-
tion of mortality, quality of life and re-hospitalization; other
studies have evaluated its role as an adjuvant therapy in
patients with volume overload and hyponatremia. An inde-
pendent study in Japan showed favorable results, including
increased diuresis, using Tolvaptan in patients with conges-
tive heart failure in patients unresponsive to loop diuretics
without electrolyte abnormalities within 7 days of therapy
[111]. Another single center trial validated the role of
Tolvaptan in the treatment of acute decompensated heart
failure in addition to loop diuretics; in preventing renal
injury, decreasing the required doses of diuretics and reduc-
ing the time to achieve euvolemia [112]. The AVCMA trial
which studied the role of Tolvaptan vs. Carperitide (An
intravenous natriuretic peptide), showed favorable results
in maintaining electrolyte balance in conjunction with loop
diuretics without significant hypernatremia or hemody-
namic derangement [113].
The efficacy of Tolvaptan in patients with hyponatremia is
well defined. Hyponatremia has been evaluated as an inde-
pendent risk factor attributed to poor outcomes in patients
admitted for decompensated heart failure [114]. In an era
where the mainstay therapy for acute decompensated heart
failure are loop diuretics; of which the most profound side
effect is electrolyte abnormalities, Tolvaptan may offer a
novel strategy to alleviate hyponatremia while assisting in
diuresis. As mentioned before, several studies have shown the
benefit of Tolvaptan in addition to loop diuretics. These stud-
ies are performed in Japan and as such cannot necessarily be
generalized to other patient populations without further
studies. FDA has approved the use of Tolvaptan for durations
less than 30 days with recommendations against use in
patients with hepatic insufficiency. It is mandated that
Tolvaptan be initiated and or restarted in an inpatient setting
where serum electrolytes can be monitored closely as rapid
reversal of sodium concentrations can precipitate osmotic
demyelination, leading to seizures, coma and death.
It is available in 15, 30 and 60 mg dosing. The recom-

mended initial dose is 15 mg daily with titration to 30 mg
after 24 h and subsequently 60 mg daily as needed to reach
appropriate levels of sodium concentration. Tolvaptan is con-
traindicated in patients who are anuric, need an urgent rise in
serum sodium, in those unable to respond to thirst, hypovole-
mic hyponatremia and in patients with concomitant use of
strong CYP 3A inhibitors. The most common side effect of
Tolvaptan noted in all clinical trials included thirst, dry mouth
and polyuria. It is generally well tolerated with no significant
increase in adverse effects on renal function. There are cur-
rently no guidelines for the treatment of heart failure with
Tolvaptan; as such its use has been dependently driven on the
comfort level of individual providers. Its efficacy in conjunc-
tion with loop diuretics, duration of therapy and the appro-
priate dosing remain understudied in larger patient
populations within the United States. Given its relative safety
profile; it is imperative for randomized clinical trials to evalu-
ate the role of Tolvaptan from an inpatient perspective in
patients with heart failure to further evaluate its efficacy in
reducing symptoms, length of hospitalization, electrolyte
abnormalities, renal and hepatic dysfunction and all cause
mortality as an adjuvant therapy.
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Chapter 3
A Comprehensive Transition
of Care Plan for a Patient
Admitted with Acute
Decompensated Heart Failure
Clement C. Eiswirth
Introduction
Congestive heart failure (CHF) is a diverse syndrome
(Table 3.1) encompassing multiple disease states and marked
by variable rates of progression. The average hospitalized
patient with heart failure (HF) faces a 1 year mortality of
30 % and a readmission rate of 50 % at 6 months [1, 2]. Acute
exacerbations of chronic heart failure are common and fre-
quently result in hospitalizations which are costly for all par-
ties and subject hospitals to financial penalties for
re-admissions. This readmission penalty is imposed regardless
of the cause for the readmission and in fact, most patients are
readmitted for conditions other than recurrent CHF.
C.C. Eiswirth, MD, FACC, FASE

Department of Cardiology,
Medical Director, Cardiomyopathy and Heart Failure Program,
Section of Cardiomyopathy and Heart Transplantation,
Ochsner Medical Center, Jefferson, LA, USA
e-mail: clement.eiswirth@ochsner.org
DOI 10.1007/978-3-319-30593-6_3,
74 C.C. Eiswirth
Table 3.1 Heart failure (HF) in the U.S

The leading cause of hospitalizations with one million/year
Treatment of HF costs $33 billion/year
Prevalence: five million people; 1 % in those age 50–59 years &
10 % age >75 years
Incidence 500,000 new cases/year
Stable incidence but increasing prevalence, factors include:
Aging of the population
Improved survival of cardiovascular conditions predisposing to HF
Improved survival of patients treated for HF
Earlier recognition of HF
Subsequent lifetime risk for HF for a 40 years male is 21 % &
female 20 %
71 % of MI survivors over 65 years develop HF after infarct
hospitalization
67 % of these HF cases present during the first year following MI
It is incumbent upon the physicians caring for these patients

to implement guideline directed medical therapy (Tables 3.2) to
improve patient morbidity and mortality. Progress in these
efforts has translated into improvements in patient survival [3].
An effective, proven strategy to prevent readmissions remains
elusive. However, there are some generally accepted methods
that should be implemented including an early follow-up
appointment in clinic and educating the patient about medica-
tions, diet, activity, and the warning signs and symptoms to
report to the physician or their designee. One cannot empha-
size enough the importance of a smooth transition when dis-
charging a patient with congestive heart failure to the outpatient
clinic. One needs to remain cognizant of the changes in the
healthcare environment and the patient’s desire to see a physi-
cian of their choosing. Patients discharged may have been cared
for by Hospitalists or primary care physicians and may not have
seen a cardiologist. They are often sent home with instructions
Chapter 3. A Comprehensive Transition of Care Plan 75
Table 3.2 Discharge summary elements for acute CHF admission

Date of admission and date of discharge
Age, gender and ethnicity
Duration of CHF and document any other admissions for CHF
within the preceeding year
Type of CHF, systolic, diastolic or combined
Etiology (See Table 3.3?)
Social history to include alcohol intake, smoking, illicit drugs and
caregiver support available
Admission and discharge: BP, HR, body weight, orthopnea
and number of pillows used, level of JVD, degree of edema,
heart rhythm, cardiac murmur, S3, hepatic congestion (span,
hepatojugular reflux). If available included any change from
baseline prior to the admission for these values.
Precipitating factors for the CHF episode (See Table 3.3)
Diagnostic test results and compare to baseline if available:
EKG, CXR, CMP (especially Na, K, Cr, LFTs), Mg, CBC,
troponin, BNP/pro-NTBNP, urinalysis; include if performed the
results of thyroid tests, iron stores, lipids, A1c
2D ECHO-doppler (if not performed then results of last test
and whether one is planned as outpatient for follow-up)
Tests performed for ischemic heart disease and results if performed
Cardiac catheterization results if performed
List all cardiac devices whether implanted at this admission or previous
Pacemakers (single or dual chamber, bi-ventricular, implantable cardio-
defibrillator, loop recorder, wireless PA pressure or fluid monitor
Medications upon discharge and especially important to not any
changes made in the medications or their doses compared to
before the admission
Activity and diet restrictions
Disposition plan and include upcoming labs and date

anticipated, diagnostic tests to be performed and a comment on
condition upon discharge and probability of readmission
76 C.C. Eiswirth
to see a primary care physician and/or mid-level provider with

or without an outpatient cardiology appointment. There are
variations in the expertise of these providers in the evaluation
and treatment of patient afflicted with CHF. In some cases
those charged with assuming the care of the patient in the clinic
did not care for the patient in the hospital. This is compounded
when the medical record is not available, incomplete or not
optimally documented. As part of the transition to home we
must assure that these patients, who represent the sickest of the
sick, are not lost in the system. A complete and thorough
accounting of the hospital course and treatment plan must be
documented (Table 3.2). In so doing we can better assure that
these patients will continue their march to recovery in the out-
patient arena.
The Scope of the Problem

Congestive heart failure (CHF) is a diverse syndrome
encompassing multiple disease states and marked by variable
rates of progression. This disease (Table 3.1) afflicts more
than five million Americans and more than 600,000 new cases
are diagnosed each year [3, 4]. Heart failure with reduced
ejection fraction (HFrEF), defined as an ejection fraction
(EF) of <40 % accounts for approximately half of these cases
while heart failure with preserved ejection fraction (HFpEF)
accounts for the remainder. HFpEF is more prevalent in
women, irrespective of age and the elderly [5, 6]. Heart fail-
ure (HF) is not only the most common cause for hospital
admission and re-admission in the Medicare age group but it
adversely affects the quality of life of millions of Americans
with a substantial morbidity and mortality. The 65 year age
and sex adjusted survival for HF is lower than for most can-
cers including breast and prostate [7] though most patients
seem to fear these cancers more than HF in the mistaken
belief that HF is a more benign disease.
In the United States each year there are over 1.1 million
hospitalizations for HF at a cost exceeding $20 billion. Only
10 % of the total HF population is afflicted with advanced

Class D CHF. Despite this fact, 25 % of the total HF hospital-
izations are due to readmissions [8, 9]. The average hospital-
ized patient with heart failure (HF) faces a 1 year mortality
of 30 % and a readmission rate of 50 % at 6 months [1, 2, 10].
There are many factors contributing to the poor outcome
of these patients including the severity of the heart failure
syndrome and its etiology as well as co-morbid conditions
such as age, coronary artery disease, obesity, hypertension,
diabetes mellitus, chronic kidney disease, arrhythmias, ane-
mia, chronic lung disease and obstructive sleep apnea. The
complexity of the medical regimen required to care for these
patients and need for a detailed plan of care including daily
weights, the use of diuretics as needed based upon a body
weight range assigned to the patient, dietary restrictions of
salt and water all contribute to a patient’s difficulty in follow-
ing the treatment prescribed.
Heart failure may be aggravated by the failure of an indi-
vidual to care for oneself and is frequently contributed to by
the poor recognition or control of pre-existing medical prob-
lems. In many cases associated factors such as poor access to
healthcare, poor socioeconomic status and lower educational
levels are present. All of these contribute to the vicious cycle
of recurrent heart failure.
Are Readmissions Truly the Fault

of the Hospital or Physician?
Acute exacerbations of chronic heart failure are common
and frequently result in hospitalizations that are costly for all
parties and subject hospitals to financial penalties for re-
admissions. This readmission penalty is imposed regardless of
the cause for the readmission. In fact, most patients are read-
mitted for conditions other that recurrent CHF [11]. Following
the implementation of guideline directed medical therapy
(GDMT) improvements in patient’s morbidity and mortality
are realized and in fact, progress in these efforts has translated
78 C.C. Eiswirth
into improvements in patient survival, symptoms and

functional class [12].
Unfortunately, unadjusted, all cause readmission rates
have risen from 17 % in 1993 to 20 % in 2005 [12]. Discordance
between mortality and rehospitalization rates was note in the
Veterans Affairs Health Care System between 2002 and 2006
[13]. In that time frame the authors noted an increase in
co-morbid conditions but a stable rate of hospital admissions
for HF at 5 per 1000. They observed a reduction of the in-
hospital mortality rate from 4.7 to 2.8 % (p < 0.0001), a reduc-
tion in 30 day mortality from 7.1 to 5.0 % (p < 0.0001) and a
reduction in 1 year mortality from 27.7 to 24.3 % (p < 0.0001).
Despite these positive results, the 30 day risk for readmission
rose 21 % from 2002 to 2006. These facts, have been con-
firmed by other studies and should give pause to those advo-
cating all cause readmission for heart failure as a measure of
quality. The results of these studies have clearly cast doubt on
such a conclusion.
Steps That May Lessen Re-admission

While an effective, proven strategy to prevent readmissions
remains elusive at this point, there are some generally
accepted methods that should be implemented. These include
an early follow-up clinic appointment (within 3–7 days) and
educating the patient and caregivers. Education should thor-
oughly cover medications, diet and activity as well as the
warning signs and symptoms that should be reported to the
physician or their designee.
One of the most important measures one can perform in
the care of a patient with CHF is a succinct but informative
discharge summary (Table 3.2). This summary should include
the age, gender and ethnicity of the patient. It is important to
note how long the patient has suffered with CHF and any
admissions during the preceding year for CHF. The etiology
of the heart failure should be identified, e.g. ischemia, valvu-
lar, non-ischemic, etc. as well as the mechanism of HF
(systolic, diastolic or both). Pertinent social history such as
Table 3.3 Conditions that can precipitate acute decompensated HF

Coronary artery disease with ischemia and/or infarction
Atrial fibrillation, flutter, ventricular tachycardia, bradycardia
with or without AV block, etc)
Uncontrolled hypertension
Anemia
Infection
Exacerbation of chronic lung disease with or without
pneumonia
Pulmonary embolism
Adverse effects of medications (NSAIDs, calcium channel
blockers, prednisone, TZDs, etc.)
Non-compliance with medications and/or diet
Thyroid disorder
Anemia
Substance abuse
smoking, alcohol, illicit drug use as well as employment fac-

tors and caregiver support should be included.
Identified precipitating factors (Table 3.3) for the patient’s
hospitalization with ADHF should be included in the sum-
mary. The admission and discharge blood pressure, pulse and
body weight should be recorded. The presence of orthopnea
and the number of pillows required for comfortable breathing
is documented in the summary as well the level of jugular vein
distension (JVD), the grade of peripheral edema and evidence
of hepatic congestion. This should include a determination of
the liver size (finger-breadths below right costal margin or the
span by percussion) and the presence or absence of hepato-
jugular reflux. One should next document the presence or
absence of a heart murmur and/or S3. It is prudent to record
any changes in the admission exam compared to these findings
prior to admission (if known) as well as those physical exam
findings noted at the time of discharge.
80 C.C. Eiswirth
The results of all diagnostic tests such as EKG, CXR, ECHO,

stress testing, catheterization results, etc. should be listed and
compared to prior studies. The admission and discharge labs
should be listed for comparison as this will also assist in follow-
up care. A list of any cardiac devices present before or inserted
during the admission should be supplied in the summary. Most
importantly, a detailed list of medications to include the
strength of the pill and the prescribed dose along with any
changes in medications or dosing from prior to admit should be
documented. Activity, diet and disposition need to be included
along with any diagnostic testing planned for after the dis-
charge. A thorough discharge summary will help the physician
responsible for the care of the patient in their assumption of
care and assure a smooth transition in the outpatient arena.
Heart Failure Disease Management

In an effort to improve the morbidity and mortality associated
with HF and reduce readmission rates, heart failure disease
management (HFDM) programs have been developed and
introduced to hospitals across the country. These programs are
designed to improve the implementation of and compliance
with guideline directed medical therapy (GDMT). The suc-
cessful program works with patients to improve their compli-
ance with medications, diet and activity by identifying barriers
and addressing these with the patient and/or caregivers.
Through education one should increase the skills of the patient
and his caregiver for self directed management. These efforts
coupled with providing easy access to providers around the
clock should reduce the utilization rate of the emergency
department or hospital and reduce the cost of care.
While the results of individual studies of HFDM have been
mixed, published meta-analyses [14, 15] have demonstrated a
20–30 % reduction in hospital readmission rates at 3–6 months
and a 20 % improvement in survival. This is associated with
improved medication adherence, improvements in quality of
life and a reduction in the cost of care. While all patients with
HF should be approached with these general principles, the

patients most likely to benefit from a HFDM program would
be those at higher risk of morbidity, mortality or readmission.
These would include those patients at discharge with persistent
congestion, NYHA Class III or IV symptoms, those who have
experienced 2 hospitalizations in 6 months or 3 in 1 year, his-
tory of prior non-compliance with diet restrictions, medica-
tions and/or daily weights. Other risk factors include depression,
cognitive impairment or the presence of multiple co-morbidi-
ties especially chronic kidney (disease stage 3 or more), diabe-
tes mellitus and chronic pulmonary disease [16].
A typical HFDM program is composed of cardiologists,
mid-levels or registered nurses with specialized HF training.
It is imperative that the HFDM program have easy access to
social workers, dieticians, home health services, financial
counselors, physical and occupational therapists and pharma-
cists. This group is responsible for providing each patient with
a tailored medical program that optimizes GDMT. This pro-
gram must include instructions for the patient to follow
regarding management of dehydration (nausea, vomiting
and/or diarrhea), congestion (worsening dyspnea, edema
and/or orthopnea) or changes in body weight. This program
will provide the patient with around the clock support,
patient education, an updated list of medications and the
purpose of each medication as well as make suggestions on
ways to improve compliance. Some helpful actions include
the use of patient logs documenting changes in body weight,
symptoms and diuretic dosing adjustments as a result, pill
dispensers, and prescribing home health care if necessary.
How Can We Target the Development

of Heart Failure?
The most common cause for both admission and readmission
of the heart failure patient is congestion. Therefore, the relief
of congestion is the most important factor to target to achieve
patient comfort and lessen the risk of re-admission to the
82 C.C. Eiswirth
hospital [4, 17–19]. It is intuitive that one should maximize

the mobilization of fluid and relieve congestion in the hospi-
talized patient and assure the maintenance of this success in
the outpatient arena.
One of the most critical challenges facing physicians treat-
ing patients afflicted with HF is whether one can successfully
predict the occurrence of or detect the onset of decompen-
sated HF. If one identifies a group of patients at high risk for
developing decompensated heart failure that model should
also help predict those at risk for recurrent hospitalization.
Once these patients are identified then a specific program to
serve them should be implemented. A successful program
will improve the patient’s quality of life and prevent
readmissions.
If one could identify the onset of ADHF before the onset
of symptoms and implement a timely change in therapies that
should improve the patient’s condition such that hospitaliza-
tion can be avoided. A successful intervention may also
improve patient outcomes beyond hospitalization rates since
one knows that decompensated HF resulting in a first or
repeat hospitalization portends a worse prognosis [20]. While
one could argue an observational bias that the sickest
patients are the ones hospitalized and hence that is the rea-
son for the worse prognosis, troponin release associated with
decompensated heart failure may better explain this finding.
Clinically it has long been speculated that daily weights
would assist the patient and the clinician in identifying the
onset of acute decompensated heart failure. Unfortunately,
that has not been uniformly helpful in identifying and manag-
ing these patients. The author does not use the recommenda-
tion that patients call for a 3 pound weight gain overnight or
5 pounds in a week. Too many patients given this instruction
develop decompensated heart failure and present to the
clinic, emergency department or hospital after gaining more
than 10 pounds. They do not call as the weight is gained
slowly such that by following these instructions literally the
threshold to call is not reached. Instead, assigning the patient
a target dry weight with instructions in the use of a sliding

scale diuretic regimen is critical for successful management.
Patients should be instructed to weigh each morning upon
arising from sleep after voiding and prior to the oral intake of
medications, food or liquids. The weight should be obtained
while in underwear, light night clothing or naked. If they gain
3 or more pounds from their assigned dry weight then a self-
directed increase in oral diuretics and if appropriate potas-
sium supplementation should be implemented that morning.
If they fail to respond to this measure or gain more than 5
pounds over the assigned dry weight then a more aggressive
diuretic regimen should be undertaken. At that point one
might consider a further increase in the dose of the loop
diuretic, changing to a different loop diuretic (Table 3.6), add-
ing a thiazide diuretic or arranging for the administration of
a parenteral loop diuretic. The latter could be accomplished
with an intramuscular or intravenous route of administration
in the home or clinic.
Effectively Treating Congestive Heart Failure,

a Brief Overview for the Transition Phase
One can see that with over one million hospitalizations for
CHF in the United States [1] and recognizing a 25–30 % re-
hospitalization [11] rate, even a 10 % reduction in readmis-
sions would yield an estimated savings of $1 billion. The drug
treatment of heart failure (Table 3.5) is well established but
the treatment should also include the education of the patient
and caregiver in this disease. Instructions in the prompt rec-
ognition of symptoms, dietary restrictions, lifestyle modifica-
tions, abstinence from or judicious use of alcohol, smoking
cessation, immunization (influenza and pneumonia), activity,
exercise training and maintenance of body weight is critical.
In female patients, counseling regarding pregnancy in con-
junction with reasonable options for birth control requires a
thorough discussion.
84 C.C. Eiswirth
Table 3.4 Drug therapy for chronic heart failure

Beta-blockers
Angiotensin converting enzyme inhibitors (ACE)
Angiotensin receptor blockers (ARB)
Neprilysin inhibitor in combination with an ARBa
Digoxin
Hydralazine/nitrates
Diuretics
I-f channel blockersa
Anti-thrombotics
Statin therapy
Anti-arrhythmics only if mandatory
Limited to two agents, amiodarone and dofetilide
Drugs to avoid
Non-steroidal anti-inflammatory drugs
Thiazolidinediones
Aspirin, unless absolutely indicated
Calcium channel blockers
Except for amlodipine if mandatory for ischemia or hypertension

a
These agents have been recently approved in the U.S and are not
currently included in national guidelines for management of CHF
The initiation of an angiotensin converting enzyme inhibi-

tor (ACE) (Table 3.5) or angiotensin receptor blocker (ARB)
(Table 3.6) in those patients whom are ACE intolerant during
the index hospitalization is very important in the care of
these patients. Aldosterone antagonists (Table 3.7) should be
added either in the hospital or in the clinic during follow-up.
Beta blocker therapy with one of the approved agents
for CHF (Table 3.8) should be implemented in the hospital
setting once the patient is off intravenous diuretics and
Table 3.5 Recommended doses for ACE inhibitors in HF

ACE Intial Target
Captopril 6.25 mg TID 50 mg TID
Enalapril 2.5 mg BID 20 mg BID
Lisinopril 2.5–5 mg QD 20–40 mg QD
Benazepril 10 mg QD 80 mg QD
Ramipril 2.5 mg QD 10 mg QD
Quinapril 5 mg BID 20 mg BID
Fosinopril 5–10 mg QD 40 mg QD
Table 3.6 Recommended doses for ARB’S in HF

ARB Initial Target
Losartan 25–50 mg QD 50–100 mg QD
Losartan included in the guidelines however, the author
believes that the
Data for this drug is weaker than for the other listed ARB’S
If used suggest target dose of 150 mg
Valsartan 40 mg BID 160 mg BID
Do not use as add on therapy in patients already receiving a
beta blocker
With an ace due to higher mortality in this group
Candesartan 4–8 mg QD 32 mg QD
congestion has resolved. In a patient admitted with ADHF

who requires an inotrope, the beta-blocker should not be
initiated until the inotrope has been discontinued. In these
cases it is reasonable to delay initiating this therapy until
the first clinic visit to allow time to assure that they are
hemodynamically stable. The beta-blocker should be
titrated to the target dose with an incremental change no
sooner than 2 week intervals until a resting heart rate
86 C.C. Eiswirth
Table 3.7 Recommended aldosterone antagonista in HF

Drug Initial Target
Spironolactoneb 12.5 mg QD 50 mg QD
Eplerenoneb,c +25 mg QD 50 mg QD
a
Do not use if K > 5.0 or GFR <30; monitor K at 1 week, 1 month and
Q3 months
b
If patient not on ACE or ARB then consider doubling these doses
c
Gynecomastia occurred in 10 % of patients in rales trial; eplerenone
is less likely to cause this since it has a much lower affinity for the
sex hormone recpetors
Table 3.8 Recommended doses for beta blockers in HF

Beta blocker Initial Target
Carvedilol 3.125 mg BID 25–50 mg BID
Metoprolol succinate 12.5–25 mg 200 mg QD
QD
Bisoprolol 1.25 mg QD 10 mg QD
Nebivolol (not approved in U.S.) 1.25 mg QD 10 mg QD
below 70 bpm is achieved, the patient exhibits intolerance

to a higher dose or the maximal dose of the beta-blocker
has been reached.
If the patient has atrial fibrillation it is critical that rate
control be established prior to discharge. The optimal target
rate at rest for atrial fibrillation in heart failure has not been
determined though generally accepted to be below 80 bpm.
Whether patients with persistent or chronic atrial fibrillation
and heart failure with reduced ejection fraction attain a ben-
efit from the use of the beta-blockers currently approved in
the U.S. is unknown. This controversy arises from the results
of retrospective analyses of the trials leading to the approval
of these agents [21–24]. Nonetheless, beta-blockers are rec-
ommended and used in these patients as they are the most
effective agents to achieve rate control in patients with atrial
fibrillation. The dose should be adjusted to target the ven-
tricular rate to below 80 beats per minute.
Ivabradine [25], is a newly approved agent for the treatment

for HFrEF and acts to selectively inhibit the If current in the
sinoatrial (SA) node. Inhibition of this channel results in a slow-
ing repolarization of the SA node and thereby slowing the
heart rate. This agent has no effect on AV nodal conduction and
therefore should not be prescribed in patients with atrial fibril-
lation or flutter as it will not slow the ventricular rate in these
cases. Anticoagulation should be accomplished in patients with
HF and atrial fibrillation or flutter to lessen the risk of an
embolic event. An attempt to restore sinus rhythm should be
made in most patients with CHF in the absence of chronic atrial
fibrillation. If this is not performed during the index hospitaliza-
tion then arrangements should be made as an outpatient and
documented. If one elects to control the rate and maintain
atrial fibrillation as the rhythm of choice in these patients then
documentation supporting the rationale for this approach
should be clearly stated in the medical record.
Determining the diuretic dose for home can sometimes be
challenging. Higher doses are required at worse levels of
renal function. Dividing the total daily dose of the intrave-
nous loop diuretic by 3 and administering that amount twice
daily can be used as a rough estimate. For instance, a patient
on a furosemide infusion at 10 mg/h is receiving 240 mg/day.
The expected home dose for this patient is 80 mg twice daily.
If the patient was on a loop diuretic prior to admission a rea-
sonable consideration would be to increase the daily dose by
1.5–2.0 fold initially or consider changing to an alternative
loop diuretic. The patient should be observed at least 24 h on
the chosen oral diuretic regimen to assure stability of volume
status, renal function and electrolytes.
They should have assessment of renal function and elec-
trolytes within 3–7 days of discharge along with an outpatient
clinic visit. A simple question inquiring how dependent the
patient is on the presence of restroom facilities for 4–6 h
following an oral dose of a loop diuretic gives one a rough
guide as to the effectiveness of the chosen dose. If the dose
prescribed is not resulting in an effective dieresis it is likely
that the tubular threshold has not been reached and increasing
88 C.C. Eiswirth
Table 3.9 Commonly used diuretics for heart failure

Drug Initial Typical dose
Furosemide 20–40 mg per day 40–240 mg per day
Bumetanide 0.5–1.0 mg per day 1.0–5.0 mg per day
Torsemide 5–10 mg per day 10–20 mg per day
Ethacrynic acid 25–50 mg per day 200 mg per day
Metolazone 2.5 mg per day 2.5–10.0 mg per day
Chlorthalidone 12.5–25 mg per day 100–200 mg per day
Hctz 25–50 mg per day 200 mg per day
Indapamide 2.5 mg per day 5 mg per day
the dose, changing to a different loop diuretic or adding a

thiazide diuretic is required. A list of commonly used diuret-
ics and dose ranges is included in Table 3.9.
After Medical Treatment Is the Transition

Complete?
A discussion of additional strategies that one might implement
to accomplish the ultimate goal of improving the survival and
quality of life of these patients while avoiding recurrent hospi-
talizations is required. The physician must remember the scope
of this problem with over five million people in the United
States carrying a diagnosis of CHF and over 550,000 new cases
are diagnosed each year [3]. It is the most common Medicare
DRG and the cost of caring for this disease exceeds $30 billion
annually. Healthcare projections are that this cost will continue
to rise as the prevalence of HF is expected to continue to
increase as the population ages. This increased prevalence is
also fueled by improvements in the survival of victims of acute
myocardial infarction, more successful treatment of valvular
heart disease and improved survival into adulthood of patients
with complex congenital heart disease.
Work to End the Cycle of Heart Failure

as Part of the Transition
Heart failure begets heart failure and hospitalizations signal
a patient with a worsening prognosis especially in the face of
recurrent hospitalizations. This is likely fueled by the com-
plex interactions involving the renin-angiotensin-aldosterone
system (RAAS), the sympathetic nervous system (SNS),
adverse effects of an activated inflammatory state and oxida-
tive stress as well as adverse vascular adaptations. Elevated
troponin levels correlate with prognosis and likely reflect
ongoing myocardial necrosis that occurs in some patients
with chronic HF and those requiring admission for decom-
pensated HF. Hypertension, myocardial infarction and diabe-
tes mellitus contribute to 90 % of HF cases [26]. Effective
treatment of hypertension, diabetes mellitus, hyperlipidemia
and obesity as well as avoidance and cessation of tobacco
using established national guidelines can help prevent the
onset and recurrence of CHF [27].
The syndrome of HF is complex and the underlying etiol-
ogy as well as the presence of aggravating conditions influ-
ences the outcome of these patients. One should document
and address these conditions in the hospital and/or document
a plan to address them as part of the transition from inpatient
to outpatient care. It is critical that the etiology of the
patient’s HF (Table 3.10) be determined and documented
before discharge. A search for coronary artery disease, isch-
emia, valvular heart disease, congestive cardiomyopathy,
familial cardiomyopathy, myocarditis, arrhythmias, infiltrative
or hypertrophic cardiomyopathy is critical. One should also
evaluate for any aggravating conditions including anemia,
arrhythmias, sleep apnea, lung disease and/or hypoxemia,
infection and thyroid disorders. If they are identified effective
treatment should be initiated prior to discharge and a docu-
mented plan for outpatient care must be included in the dis-
charge summary.
90 C.C. Eiswirth
Table 3.10 Etiologies of cardiomyopathy/CHF

Coronary artery disease/prior MI
Hypertension
Idiopathic dilated cardiomyopathy
Familial cardiomyopathy
Hypertrophic cardiomyopathy
Left ventricular non-compaction
Arrhythmogenic right ventricular cardiomyopathy
Familial dilated cardiomyopathy
Endocrine related:
Hyopthyroidism
Hyperthyroidism
Diabetes mellitus
Pheochromocytoma
Peripartal cardiomyopathy
Tachycardia induced
Uncontrolled ventricular rate of atrial fibrillation
Uncontrolled ventricular rate of atrial flutter
Uncontrolled ventricular rate of atrial tahcycardia
Frequent premature ventricular contractions
Valvular heart disease
Toxic cardiomyopathy
Chemotherapy induced
Alcohol induced
Cocaine induced

Infectious
Chagas disease
HIV associated
Myocarditis
Amyloidosis
Familial TTR mutation
Wild type TTR
AL
Evaluations That Must Be Accomplished

as an Inpatient or Ordered for the Transition
to Outpatient Care
In the initial evaluation it is critical that the ejection fraction
be determined before formulating a long term treatment
strategy. The single most important test in the evaluation of
HF is an echocardiogram. Whether a patient has heart failure
with preserved ejection fraction (HFpEF) or reduced ejec-
tion fraction (HFrEF) is an important clinical distinction for
the implementation of GDMT though this distinction has a
minimal impact on prognosis. The 1 year mortality rate with
HFpEF is 22–29 % versus 30–50%with HFrEF while the
5 year mortality rate is 65 % versus 70–80 % respectively [5].
An EKG should be performed in all patients presenting with
HF to determine the cardiac rhythm, to assess for atrial or
ventricular hypertrophy, to assess for evidence of ischemia or
infarction, to identify any underlying conduction distur-
bances and to determine the QTc interval. In patients with
chest pain, EKG evidence of ischemia or infarction and/or
echo evidence of segmental wall motion abnormality the
performance of angiography should be entertained if the
patient is a suitable candidate for revascularization.
92 C.C. Eiswirth
Endomyocardial biopsy should be considered in patients

presenting with acute, fulminate HF of undetermined etiol-
ogy of less than 2 weeks duration who continue to deteriorate
despite conventional therapy. Endomyocardial biopsy is indi-
cated in patients with HF of 2–12 weeks duration associated
with left ventricular dilatation, complex ventricular arrhyth-
mias and/or second or third degree heart block who fail to
respond to standard care of HF in 2–3 weeks. Other indica-
tions include unexplained restrictive cardiomyopathy and if
eosinophilic myocarditis or anthracycline cardiotoxicity is
suspected [28]. Since this procedure is rarely indicated during
the initial hospitalization for ADHF, it is important to
remember its role in assessing these patients as the decision
to perform a biopsy will likely be made in the early phase of
outpatient care.
Methods to Determine the Prognosis

of Patients with ADHF
The patient’s prognosis should be determined prior to hospi-
tal discharge recognizing that in some this is difficult as it will
require a period of time on therapy before an accurate assess-
ment can be performed. Nonetheless, it is prudent that the
physician attempt to determine the prognosis upon admis-
sion and discharge, expounding upon this as the patient is
followed in the outpatient arena by observing their response
to therapy. Appropriate identification of patients who would
realize a functional and survival benefit from cardiac resyn-
chronization therapy (CRT) generally with the implantation
of a cardio-defibrillator is critical to the care of these patients.
If they meet the indication for the device and fail to respond
to medical therapy within 3 months then one should proceed
with implantation. Therefore this is another critical step to
document as one formulates the plan for the transitioning the
patient to the outpatient clinic.
Determing the Prognosis of Patients Admitted

with ADHF
Acute decompensated heart failure (ADHF) is a clinical pre-
sentation of heart failure necessitating care which is received
in an unscheduled clinic visit or an urgent care or emergency
room setting. In the vast majority of the cases the patient has
a prior history of CHF and the others represent new onset
heart failure most frequently caused by an acute coronary
syndrome. Other precipitating factors can be uncontrolled
hypertension, acute arrhythmias particularly atrial fibrillation,
acute valvular heart disease chiefly mitral insufficiency from
mitral valve prolapse with acute chordal rupture, peripartal
cardiomyopathy, myocarditis and stress induced (takaotsubo)
cardiomyopathy. The patient typically presents with acute
congestive symptoms such as dyspnea, orthopnea and/or
edema but can present with less obvious symptoms such as
abdominal discomfort, fatigue and easy satiety. Over the years
physicians have searched for reliable methods to determine
the prognosis of patients afflicted with ADHF as well as
chronic HF.
In keeping with this effort a large cohort of patients from
the Acute Decompensated Heart Failure National Registry
(ADHERE) [29] were reviewed to determine prognostic
features. In this effort it was noted that BUN, systolic blood
pressure (SBP) and serum creatinine (Cr) were all predictors
of survival. The best single predictor of mortality was an ele-
vated BUN ≥43 mg/dl and in these patients the 1 year mortal-
ity was 9.0 % versus 2.7 %. Further differentiation of the
mortality rate was possible by adding SBP to the analysis. To
interpret this data more easily it is important to note that in
patients admitted with ADHF, an elevated BP portends a
better prognosis for surviving the hospital stay while impaired
renal function portends a worse prognosis [30]. Therefore, as
expected in patients with a SBP ≥115 mmHg and a BUN
≥43 mg/dl, mortality rate fell to 6.4 %. If one had both BUN
94 C.C. Eiswirth
≥43 mg/dl and SBP <115 mmHg the mortality rate increased
to 15.3 %. In the subset with both high risk features of an
elevated BUN and lower SBP as defined, adding serum Cr
helped further define the mortality risk. In these cases if the
serum Cr was <2.75 mg/dl then the observed mortality was
slightly better at 12.4 %. On the other hand, the mortality
jumped to 21.9 % in those with Cr ≥2.75 mg/dl. In the lower
risk group of patients with BUN <43 mg/dl (mortality 2.7 %)
who had the higher risk feature of SBP <115 mmHg the mor-
tality rate rose to 5.5 % while in those whose SBP ≥115 mmHg
the mortality rate was only 2.1 %. In another large trial, The
Organized Program to Initiate Lifesaving Treatment in
Hospitalized Patients with Heart Failure (OPTIMIZE-HF)
[31] it was noted that the two most powerful predictors of
in-hospital mortality were systolic BP ≤100 mmHg and serum
Cr ≥2.0 mg/dl. These findings are consistent with the
ADHERE analysis and support the use of routinely mea-
sured admission data of SBP and renal function to identify
those at high risk for in-hospital mortality. Since the higher
risk patients surviving the hospitalization would likely repre-
sent a higher risk group of outpatients, these profiles have
implications for outpatient management and are important
to remember during the transition of care.
Defining Congestion in Heart Failure

There are additional clinical models that attempt to quantify
congestion that are important for the clinician to use in
patients with HF. The EVEREST trial [32, 33] enrolled
patients admitted to the hospital for worsening heart failure
with reduced ejection fraction. Enrollees had NYHA Class III
or IV symptoms plus two or more symptoms or signs of con-
gestion. Congestion was defined as dyspnea, edema or the
presence of jugular venous distension (JVD). Patients were
seen daily and assessed for dyspnea, orthopnea, fatigue, JVD,
rales and edema. Each of these was graded on a four point
scale (0–3) and a composite congestion score (CCS) was calcu-

lated by summing the scores for each finding. Dyspnea, orthop-
nea and fatigue were given a score of 0 = none, 1 = seldom,
2 = frequent and 3 = continuous. JVD was assessed in cm of
water and awarded 0 points for ≤6 cm, 1 point for 6–9 cm, 2
points for 10–15 cm, 3 points for ≥15 cm. A physical exam for
rales was performed and graded as 0 points = no rales, 1
point = only basal rales, 2 points = rales confined to lower half
of chest but more extensive than basal rales, 3 points = rales
extending into the upper half of the chest. The presence of
edema was graded as 0 points = absent/trace, 1 point = mild, 2
points = moderate and 3 points = marked. Patients were fol-
lowed for a median of 9.9 months. Patients with a CCS at dis-
charge of 0 versus a score of 3–9 experienced an increased rate
of hospitalizations for heart failure (HHF), 26.2 % versus
34.7 % and all cause mortality (ACM), 19.1 % versus 42.8 %.
After adjusting for potential confounders discharge CCS was
associated with an increased risk of ACM as well as ACM + HHF
at 30 days and for the study duration. The CCS was not associ-
ated with 30 day HHF but it was at completion of the study. A
discharge CCS of 0–2 points versus 3–9 points exhibited similar
reductions in body weight (2.2 kg versus 2.0 kg) but patients
with a discharge CCS of 3–9 points demonstrated higher levels
of BNP (423 versus 929) and NT-proBNP (2581 versus 4437)
at discharge. Scores at discharge of 0 correlated with the best
outcomes in terms of hospitalizations for heart failure (HHF)
26.2 %, all cause mortality (ACM) 19.1 % and the combination
of ACM + HHF 35.6 %. This contrasted sharply with outcomes
for scores of 3–9 which demonstrated rates for HHF 34.7 %,
ACM 42.8 % and ACM + HHF 60.0 % [34].
A similar evaluation known as the orthodema score was
formulated in an attempt to quantify and monitor congestion
in the hospital but should also be useful in the outpatient set-
ting [35]. A post hoc retrospective analysis of the Insights
From Diuretic Optimization Strategy Evaluation in Acute
Decompensated Heart Failure (DOSE-AHF) and the
Cardiorenal Rescue Study in Acute Decompensated Heart
96 C.C. Eiswirth
Failure (CARRESS-HF) demonstrated its value as a target

for therapy. The score is calculated using only edema and
orthopnea. It is easily determined by members of the health-
care team, the patients and/or family members. Edema is
graded as trace or mild (0 points), moderate (1 point) or
severe (3 points). Orthopnea is determined by inquiring if the
patient requires at least two pillows to be comfortable sleep-
ing (yes = 2 points; no = 0 points). Scores of 0 represent no
congestion, 1–2 represent low-grade congestion and 3–4 rep-
resent high grade congestion. While event rates were high for
all scores due to the poor prognosis of heart failure, the
higher the orthodema score the worse the outcome. The
authors observed a 50 % rate of death, rehospitalization or
unscheduled clinic visit with a score of 0, 52 % with score of
1–2 and 68 % with a score of 3–4, P = 0.038. The higher the
orthodema score on admission the longer the length of stay,
7.1 days (score 1–2) versus 8.9 days (score 3–4), P = 0.004.
Interestingly, there was no statistically significant difference
observed in the weight lost by the patient during the hospital
stay for an admission orthodema score of 1–2 versus 3–4. This
supports the contention that there are factors other than
solely fluid status contributing to the decompensated heart
failure state that force the patient to seek hospital care for
the relief of symptoms. These observations lend further
support to targeting congestion as a treatment endpoint as its
resolution portends a better survival [36, 37].
Clinical Scores Consistent with Invasively

Obtained Risk Models: The Prognosis
Determined Should Impact Therapeutic
Decisions in the Transition to Outpatient Care
Swan Ganz catheters are not routinely inserted for the man-
agement of heart failure patients since the publication of the
ESCAPE Trial [38]. Therefore it is incumbent upon the clini-
cian to rely on other clinical and laboratory assessments to
determine the risk the patient faces for mortality and mor-
bidity over the ensuing months. The clinician must also syn-
thesize the available information from the history, physical
exam and laboratory data on hepatic and renal function to
estimate cardiac filling pressures and the adequacy of sys-
temic perfusion. This information allows the clinician to
determine the best treatment options for the individual
patient, i.e. diuretics and/or vasodilators with or without the
initiation of an inotrope. These determinations will also help
the physician responsible for transitioning the patient to
home as they reflect upon the patient’s prognosis.
Determining this prognosis and relaying this information to
the patient and the physician assuming the responsibility for
the outpatient care is a critical step in the transition
process.
Proportional pulse pressure (PPP) can be used as a non-
invasive estimate of cardiac index (CI). It is calculated by
dividing the pulse pressure (systolic BP-diastolic BP) by the
systolic BP. The PPP correlates directly to the CI and lower
values correlate with worsening prognosis. This relationship
starts at PPP of ≤0.40 and is especially true at a value of ≤0.25
where it strongly correlates to CI ≤2.2 l/min/m2 [39–41].
Dr. Forrester and colleagues published invasive hemody-
namic subsets to guide the treatment of patients with an
acute myocardial infarction in the 1970’s using pulmonary
capillary wedge pressure (PCWP) and cardiac index (CI) [42,
43]. In 2003 Dr. Stevenson [44] validated a clinical assessment
that correlates with the Forrester hemodynamic profiles and
allows one to predict patient outcomes in acute heart failure
states non-invasively. This determination requires the clini-
cian to assess for the presence or absence of both congestion
and adequate perfusion. Congestion was considered present
if there was a recent history of orthopnea and/or neck vein
distension, rales, ascites, hepatojugular reflux, edema, left-
ward radiation of the pulmonic heart sound or demonstration
of a square wave blood pressure response to the Valsalva
maneuver. Inadequate perfusion was determined by any of
the following, a PPI ≤0.25, pulsus alternans, symptomatic
98 C.C. Eiswirth
hypotension (excluding orthostatic hypotension), cool

extremities or impaired mental status. Patients were consid-
ered to be dry and warm if there was no evidence of conges-
tion or impaired perfusion (Profile A), wet and warm if there
was congestion but normal perfusion (Profile B), dry and
cold if there was no congestion but evidence for impaired
perfusion (Profile L) and wet and cold if there was both con-
gestion and impaired perfusion (Profile C). As expected,
patients with Profile C had the worst survival followed by
Profile B. The best survival was in Profile A. While the
Kaplan Meir curve for Profile L was better than for Profiles
B & C, due to small number of patients in the profile the
authors were unable to conclude with certainty the signifi-
cance of this finding. The survival of these groups corre-
sponds well to those of Forrester using hemodynamic subsets
to identify similar groups of acute MI patients. In his work
patients were divided into four groups, warm and dry (CI
>2.2, PCWP ≤18 mmHg), warm and wet (CI >2.2, PCWP
>18), cool and dry (CI ≤2.2, PCWP ≤18 mmHg) and cool and
wet (CI ≤2.2, PCWP >18 mmHg). These profiles correspond
to Stevenson’s profiles A, B, L and C respectively.
Non-invasive Risk Scores That Help

in the Transition of Care by Assiting
the Physician in Determining Prognosis
The Heart Failure Survival Score (HFSS) [45] was developed
to assess the prognosis of patients referred for cardiac trans-
plantation. It uses seven clinical variables to define low,
medium and high risk subsets of patients. The variables are
resting heart rate, mean blood pressure, the presence of QRS
duration >120 ms regardless of cause, serum sodium level,
presence of ischemic heart disease, left ventricular ejection
fraction and peak oxygen consumption (VO2 max). The sur-
vival rates at 1 year were 93 %, 72 % and 43 % in the low,
medium and high risk groups.
The value of this model has been called into question

since it was developed before the wide spread implementa-
tion of beta-blocker and device therapy in clinical practice.
This group subsequently published data examining the
effects of beta-blocker use on the predictive value of the
HFSS [46]. As expected in this study, the patients receiving
beta-blockers had better 1 and 2 year survival (90.3 and
85.6 %) compared to those not receiving beta-blockers (75.7
and 63.7 %), p < 0.0001. For patients not on a beta-blocker
but with a low risk HFSS score the 1 and 2 year survival
rates were 88.5 and 84.5 % while those on beta blocker had
survival rates at 1 and 2 years of 95.1 and 94.1 %. For the
medium risk score without beta-blocker 1 and 2 year sur-
vival rates were 81.8 and 61.8 % while those on beta blocker
had survival rates at 1 and 2 years of 85.8 and 78.9 %. For
the high risk score without beta-blocker 1 and 2 year sur-
vival rates were 46.8 and 32.1 % while those on beta blocker
had survival rates at 1 and 2 years of 83.1 and 59.8 %. The p
values across all strata were highly significant, p < 0.0001. In
using the HFSS it is important for the reader to note that
these were ambulatory outpatients who were able to per-
form a cardiopulmonary stress exercise test and reach their
anaerobic threshold. Interested parties can access this calcu-
lator free of charge at http://handheld.softpedia.com/get/
Health/Calculator/HFSS-Calc-37354.shtml.
Another useful computer based model is the Seattle
Heart Failure Prognostication Model [47, 48] developed by
Levy and colleagues at the University of Washington Health
Sciences Center. The model has been updated to include all
GDMT options and device therapy. One can use this model
to project a patient’s 1, 2 and 3 year survival and the impact
of various interventions on these estimates. Of course it is
important to recognize the limitations of all predictive mod-
els and in the experience of this author, this model over-
estimates survival. Nonetheless, it is extremely useful in
demonstrating the relative risk reductions an individual
patient would be expected to realize if they underwent
100 C.C. Eiswirth
certain medical or device related therapeutic interventions.

One can use this model to educate the patient and caregiver
on the impact these therapies have in their case and in so
doing might improve compliance with the plan of care that
the physician is recommending. This model can be accessed
at http://SeattleHeartFailureModel.org and the service is
free of charge.
The Role of Biomarkers in the Transition

of Care and in Predicting Prognosis
Biomarkers are a diverse group of biological substances that
can be measured and reflect underlying pathologic or physi-
ologic states. To be a clinically useful biomarker three general
concepts must be fulfilled. First, the substance detected
should be accurately and reproducibly measured in a cost-
effective manner with the result readily available to the
attending physician; second, it should provide the clinician
with information not already available from the clinical
assessment; third, the result should assist the treatment team
in determining the medical care to be rendered [49]. There
are a variety of biomarkers identified for patients with HF
that reflect inflammation, oxidative stress, neurohormonal
activation, myocyte injury, myocyte stretch and macrophage
activation. A complete discussion of biomarkers is beyond
the scope of this chapter but interested parties might review
Dr. Braunwald’s paper, Biomarkers in Heart Failure pub-
lished in 2008 [50].
The natriuretic peptides generally available in practice are
B-type natriuretic peptide (BNP) and N-terminal pro-BNP
(NT-proBNP) levels. There is no debate that if the diagnosis of
CHF is in doubt measuring one of these markers can improve
the diagnostic certainty of CHF or alternatively assist the clini-
cian in excluding its presence [51, 52]. The release of these
compounds depends upon wall stress and mechanical stretch
thus levels for HFpEF are lower than with HFrEF. The abso-
lute levels are associated with the prognosis in patients with
HFrEF. Interpretation of these levels requires a knowledge of

conditions and factors that can impact the result. The levels of
these markers can be increased by acute or chronic kidney
disease, myocardial infarction, pulmonary embolism, cor pul-
monale and electrical cardioversion. The levels are also higher
in females than males and increase with advancing age. These
levels can be artificially low in overweight patients. Also, since
their release depends upon wall stress the observed values are
lower in HFpEF than HFrEF patients.
Using these markers to guide therapy has yielded mixed
results and the outcome changes noted are due to the attain-
ment of GDMT. In two meta-analyses of randomized con-
trolled trials using biomarker guided therapy, an increase in the
prescribed doses for ACE/ARB, aldosterone antagonists and
beta-blockers was seen when physicians had access to BNP and
NT-proBNP levels. Interestingly, in the six trials reviewed there
was no significant increase in diuretic dosages employed in
response to these biomarkers. Also, the changes in the drug
therapies mentioned above did not result in an increase in
adverse events including hypotension or renal impairment. The
patients in the control group were also well treated with similar
percentages of patients prescribed these agents though presum-
ably not on target doses. There was no explanation for the fail-
ure to prescribe target doses in these patients. There was a 31 %
improvement in mortality in the meta-analysis in the arm using
biomarker guided therapy in Felker’s paper and a 24 % reduc-
tion in the meta-analysis reported by Porapakkham [53].
Presumably the use of these markers emboldened the physician
and/or the patient to increase the dose of ACE or ARB, aldo-
sterone antagonist and/or beta blocker therapy. The studies
targeting biomarker guided therapy did not demonstrate an
improvement in the outcomes for patients over the age of 75.
Thus if one adopts this approach and follows these markers to
guide therapy in the clinical arena, it should probably be limited
to patients below the age of 75 [54].
Elevated troponin concentrations in acute heart failure in
the absence of a myocardial infarction or ischemia have been
observed even in patients without underlying CAD. The
102 C.C. Eiswirth
presence of troponin in the blood is consistent with myocyte

injury and/or necrosis and may help explain the poor progno-
sis associated with recurrent heart failure decompensations.
In the ADHERE registry patients with a positive troponin
had an 8.0 % mortality versus those without detectable tropo-
nin whose mortality was 2.7 % (P < 0.001) [55]. In addition, an
elevated troponin in the outpatient setting is a marker of a
worse prognosis [56] with higher mortality and morbidity for
both the patient with acute as well as chronic HF.
Uric acid is an inexpensive, readily available and easily
measured blood test that can serve as a biomarker of
impaired oxidative metabolism and cytokine activation.
These factors adversely impact the course of CHF. A meta-
bolic, functional and hemodynamic (MFH) score has been
proposed and subsequently validated [57, 58]. Uric acid is a
powerful, independent predictor of prognosis in patients with
HF. A serum level of ≥9.5 mg/dl correlates with 1 and 2 year
mortality rates of 48 and 64 % versus 8 and 14 % for patients
with uric acid levels below this value (P < 0.001). Uric acid
alone was found to be as predictive as the HFSS in the group
of patients studied.
Uric acid level ≥9.5 mg/dl, left ventricular ejection fraction
≤25 % and maximal oxygen consumption on stress testing of
≤14 cc O2/kg/min are each given 1 point. These values are
summed to calculate the MFH score which ranges from 0 to
3. A score of 0 defines a low risk group with predicted 1 and
3 year mortality rates of 2 % and 9 % respectively. The 1 year
mortality rates for scores of 1 and 2 are 23 % and 36 %
respectively. A score of 3 identifies a very high risk group
with a mortality rate of 69 % at 1 year and 88 % at 1.5 years.
How to Determine Who to Send

for Advanced Options During the Transition
of Care Phase
In hospitalized or ambulatory patients suffering with HF there
are several factors useful in identifying those patients in need
of advanced therapies. Patients with persistent NYHA Class
III-IV symptoms should be referred electively and this referral

becomes urgent in cases where there is a concern for low out-
put heart failure, the presence of refractory congestion or
dysfunction of the kidneys or liver. Patients requiring a reduc-
tion in the dose of beta-blockers, ACE or ARB therapy due to
symptoms or those with persistently low systolic blood pres-
sure below 90–100 mmHg represent another high risk group.
Any patient intolerant of beta-blockers or those exhibiting
persistent tachycardia should be referred since the presence of
an elevated heart rate is associated with a worse prognosis
even in patients treated with beta-blockers [59–61]. Though
not yet in the national guidelines for the management of con-
gestive heart failure one should consider adding ivabradine in
these cases. In the SHIFT trial ivabradine when added to
GDMT resulted in a 26 % reduction in deaths from heart fail-
ure and a 26 % reduction in heart failure admissions.
Echocardiography helps the physician define the high risk
patient who should be referred for advanced options. Findings
of a markedly dilated left ventricle on ECHO (LVEDD
>7.5 cm), increased left ventricular volume index (>120 cc/m2),
restrictive physiology, deceleration time ≤150 ms and mitral
regurgitation vena contract width >0.4 cm have all been asso-
ciate with a higher mortality rate [62]. Advanced right ven-
tricular dysfunction defined as RVEF <20 % measured by
nuclear ventriculography [63], ECHO features of right ven-
tricular dysfunction including fractional shortening <32 %,
right ventricular shortening <1.2 cm, tricuspid annular plane
systolic excursion <1.4 cm and right ventricular annular tissue
doppler index <10.8 cm/s have all been associated with an
increase in mortality as well [64].
Persistent hyponatremia reflects excessive stimulation of
the RAAS and is recognized as a major risk factor for adverse
cardiovascular events as is any level of renal dysfunction [65].
One should also send any patient failing to respond to cardiac
resynchronization therapy or experiencing ICD discharges,
appropriate or inappropriate for referral as these all are associ-
ated with a poor prognosis. Additional high risk patients are
those with a 6 min walk test distance of <300 m [66] or cardio-
pulmonary stress test demonstrating a VE/VCO2 slope >34 or
104 C.C. Eiswirth
a significant reduction in the peak oxygen consumption (pro-

vided anaerobic threshold obtained) defined as <12–14 cc O2/
kg/min or <50–55 % predicted for age [67–69].
Patients who remain hemodynamically unstable during a
hospitalization should be immediately transferred to a center
capable of performing advanced heart failure therapies such
as left ventricular assist device implantation and cardiac
transplantation. Some of these patients may require support
systems beyond intravenous inotropes and intra-aortic bal-
loon counter pulsation (IABP) not routinely available in
community hospitals. These devices include external corporal
membrane oxygenation (ECMO), Tandem Heart and Impella
2.5, CP and 5.0 support systems. At our institution [INSERT
REFERENCE] [70] we have enjoyed success using an
Impella 5.0 device inserted surgically via the right axillary
artery to reverse cardiogenic shock. This device is used as a
bridge to the implantation of a durable left ventricular assist
device or cardiac transplantation. We have found that using
this method of support allows for recovery and/or improve-
ment in the nutritional and functional status of the patient as
well as hepatic and renal function. An axillary access allows
the patient to remain mobile and capable of participating in
a physical rehabilitation program.
Initiating a Palliative Care Discussion:

An Important Step in the Transition
to Outpatient Care
Once a patient has developed symptoms of stage D heart
failure their mortality rate exceeds 50 % at 1 year. These
patients have marked symptoms at rest and typically exhibit
evidence of end organ hypoperfusion. In an effort to keep
them comfortable or out of the hospital they require advanced
options such as intravenous inotropes, circulatory support
systems and/or cardiac transplantation. All stage D patients
should undergo a palliative care discussion.
Planning for death is part of life and having a discussion

with one’s physicians and loved ones is as important as enact-
ing a financial plan, a will or purchasing life insurance.
Unfortunately, many people do not think of this and do not
have these discussions with those closest to them before they
become seriously ill. It is incumbent in such cases for the
physician and the health care team to remind the patient of
the importance of having these discussions and to assist the
patient and those of their choosing with the information
required to facilitate this effort. Due to the variable nature of
CHF many physicians find a palliative care discussion daunt-
ing or fear that it may be emotionally taxing for the patient
and family. The author has found that presenting this discus-
sion as a “what if” scenario should the patient fail to respond
to therapy is an effective way to introduce this topic. It is also
important to assure the patient and the family that having
this discussion is not an indication that there is no hope or
that one is surrendering to the disease process. Instead it is
simply an opportunity for the patient to reflect on their
wishes in the event that their functional status declines to the
point that they become incapacitated by their illness.
The opportunity to articulate their goals of care at that
point to their loved ones is instrumental in the long-term care
of these patients. As circumstances evolve the patient’s
desires will likely change over time and thus the palliative
care plan should be updated. In so doing the patient’s care
choices are known to both his physicians and loved ones. This
not only assures that the patients’ wishes are honored but
shields the loved ones from having to make emotionally dif-
ficult, trying and sometimes contentious decisions in an
attempt to guess what the patient would want.
If a patient has NYHA Class IV symptoms despite GDMT
and is not a candidate for advanced heart failure options then
palliative care options should be discussed. Palliative care
with continuous infusion of an inotrope may improve symp-
toms at the expense of shortening survival. This should be
discussed with the patient as many are willing to accept this
106 C.C. Eiswirth
outcome. Since there is no data to support the contention that

an ICD improves survival in these patients, one should not
feel that the ICD must remain active or that one has to be
placed in such patients if not already present or replaced if
the generator reaches end of life. In fact, whether or not an
inotrope is added at this time, the physician must discuss
deactivation of the ICD and do not resuscitate orders for the
hospital and ambulance/emergency transport vehicles in all
of these cases.
Palliation means to ease symptoms without curing the
underlying disease process. While code status certainly is
addressed in a palliative care encounter, the topics discussed
are much broader and extremely important in the care of a
patient with congestive heart failure. The author believes that
a discussion of the patient’s wishes should occur early in the
course of this disease, i.e., stage C due to the variable course
many of these patients demonstrate and the high morbidity
and mortality associated with CHF. When having this discus-
sion with the patient they should be encouraged to include
any loved ones, friends, religious associates or advisors that
they would like to participate. It is important to realize that
the patient is likely to consult with or lean on these sources
for emotional and physical support as well as counsel over
the coming days, weeks, months or even years.
It is appropriate to remind the patient to identify someone
to make decisions on their behalf if they become incapaci-
tated by enacting a medical power of attorney. Ideally, this
person should be present for most if not all of the palliative
care discussions. In cases where this is not possible a tele-
phone conference call with all parties is encouraged. One
should remind the patient that a medical and financial power
of attorney is not the same legal document so that execution
of the appropriate legal documents can be accomplished.
Simple forms or a note signed by the patient and witnessed
by an independent party is sufficient to declare this designa-
tion in most instances. If in doubt, one should always consult
with an attorney to assure that the appropriate format is
utilized. Many hospitals have legal staff available to assist the

patient and physician in these matters.
Hospice Care for CHF Patients

Hospice should be discussed for patients with an estimated
survival of <50 % at 6 months. Hospice agencies and the pay-
ors of these services must recognize the variability in the
course of patients with CHF. As a result, our ability to distin-
guish between 50 % survival at 6 months versus 12 months is
not always reliable. It is important to explain to the patient
and family that the role of hospice is to keep one comfortable
at home and to forego life sustaining care in the hospital set-
ting. Instead, this care is replaced with compassionate com-
fort care in the home.
It is critical that one not forget to discuss the deactivation
of an ICD in patients with end-stage heart disease as well as
those patients suffering with terminal non-cardiac diseases
such as cancer [71–75]. This should definitely be done by the
time a patient reaches Stage D CHF if advanced options are
not pursued.
It has been reported that only 50 % of patients entering
hospice care with an ICD have the device deactivated. This
omission can be particularly disturbing to both the patient
and the family when the device fires postponing the death
and prolonging the misery of the patient. Deactivation sim-
ply means discontinuing anti-tachycardia pacing and defi-
brillation. It does not require inactivation of either
bi-ventriuclar pacing or bradycardia pacing modalities. This
author routinely informs patients when discussing the
implantation of an ICD that they can elect to inactivate the
device at any time should their cardiac or general health
condition change such that they would no longer want this
resuscitative capability. This preparation makes any subse-
quent discussion of deactivating the device less traumatic
for everyone.
108 C.C. Eiswirth
Heart Failure Management Programs

and the Transition of Care
Transitioning care from the in-patient to the outpatient envi-
ronment is one of the most critical tasks facing physicians and
hospitals caring for patients diagnosed with CHF. The 2013
Guideline for the Management of Heart Failure: A report of
the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines, list the
following recommendations for coordinating care for patients
with chronic heart failure. Class I recommendations are:
1. Effective systems of care coordination with special atten-
tion to care transitions should be deployed for every
patient with chronic heart failure that facilitate and ensure
effective care that is designed to achieve GDMT and pre-
vent hospitalization [76–93]. (Level of Evidence: B)
2. Every patient with HF should have a clear, detailed, and
evidence based plan of care that ensures the achievement
of GDMT goals, effective management of co-morbid con-
ditions, timely follow-up with the healthcare team, appro-
priate dietary and physical activities, and compliance with
Secondary Prevention Guidelines for cardiovascular dis-
ease. This plan of care should be updated regularly and
made readily available to all members of each patient’s
healthcare team [94]. (Level of Evidence: C)
3. Palliative and supportive care is effective for patients with
symptomatic advanced HF to improve quality of life
[72, 95–98]. (Level of Evidence: B)
An institutional program for the management of heart
failure is important to reduce readmissions and improve
outcomes for CHF patients. The goals of such a program
include implementing GDMT with the subsequent titration
of these medications as an outpatient. In the hospital the
patient and his caregivers should be educated on the disease
as well as the myriad warning signs of incipient decompen-
sated heart failure. It is critical that they understand these
symptoms and report them to the care team. They should be

instructed on the importance of weighing daily and record-
ing the weights as opposed to trusting their memory. It is
critical that along with the weights a journal recording any
variations in diuretics necessitated by weight changes or
symptoms be included. There should also be a record of all
non-prescription and prescription medications on their per-
son at all times and this should include documentation of
when and why any medication was altered by themselves or
anyone else. This log should be brought to each clinic visit
along with the list of medications, all prescription bottles and
any pill dispensers used by the patient for ready access and
review by the healthcare team. This avoids conversations in
the clinic regarding, “the small, round white pill or was it the
yellow square one?,” that invariably occur and is a source of
frustration to the health care team as well as the patient. All
instructions should be given verbally and reinforced in writ-
ing to assure the patient’s comprehension as well as that of
the caregiver.
In the hospital or clinic a program of “teach back” is help-
ful in those patients whose cognitive and physical condition
allow. In this case the patient tells the nurse the name, dose,
frequency and purpose of the medication. Allowing the
patient to self administer medications in the hospital may
also benefit future compliance. The hospital setting is the
perfect place to stress the importance of daily weights, diet
and if appropriate fluid restriction.
Ideally the patient should perform and record the daily
weight with the supervision of the nursing staff. The author rec-
ommends that the patient bring their personal scale to the hos-
pital. This allows one to confirm not only that they indeed have
access to a reliable scale but also know how to zero and safely
use this important tool in their home care. The patient is allowed
to practice recording the weights and observe how the physician
uses this information in their care, including the adjustments of
diuretics. The patient and his caregiver should learn the
orthodema scale discussed earlier and report worsening of this
score even in the absence of a demonstrable weight gain.
110 C.C. Eiswirth
One of the goals of treating heart failure is to maintain

euvolemia using diuretics and dietary intervention to control
symptoms and lessen hospitalization. Overly aggressive
diuretic regimens can result in dizziness, dehydration, impair-
ment of renal function, electrolyte disturbances, fatigue and
lethargy. In some cases of severe HF, a fluid restriction must be
implemented though it should not be recommended as part of
the routine care of heart failure patients. When required, a
reasonable oral fluid restriction should be prescribed. An oral
allowance of 30 cc/kg for those weighing less than 85 kg and
35 cc/kg for those over 85 kg is reasonable [99, 100].
Sodium restriction is routinely advised though the data
supporting this is generally poor. A sodium restriction of
5–8 g of table salt per day is a reasonable target. Tighter salt
restrictions in conjunction with higher diuretic doses have
been associated with higher rates of re-admission. Perhaps
this is due to the development of diuretic resistance or stimu-
lation of the RAAS and SNS. Research to guide physicians in
this area is lacking and patient compliance with these efforts
is generally poor [101].
A successful transition should also assure that co-existent
medical conditions are optimally addressed and that the nec-
essary arrangements are made for ongoing outpatient care.
This includes evaluating and treating chronic kidney disease,
anemia, thyroid disorders, diabetes mellitus, obesity, orthope-
dic and ambulatory issues, sleep apnea, depression as well as
control of arrhythmias, ischemia, and hypertension.
The patient and caregiver should be questioned to assure
that adequate resources are available to purchase medica-
tions and for follow-up physician care. If the patient does not
possess these resources then consultation with a social
worker is indicated to determine eligibility for national, state
or local programs. At the time of discharge the patient and
the caregiver should be given contact numbers to access pro-
viders and the support team via telephone 24 h a day, 7 days
a week. An appointment within 3–7 days should be provided
at the time of discharge to assure compliance and adjust
therapies. Home health services may be of value in appropri-
ate patients but are not an adequate replacement for physi-
cian care and clinic visits.
Monitoring Options to Consider as Part

of a Heart Failure Disease Management Plan
Each institution and physician group will have to identify the
most cost effective post discharge support that they can offer
their patients. This could be something as simple as frequent
clinic visits with self-reported weights. It is important to note
that while the presence of weight gain over a couple of days
is predictive of hospitalization for ADHF most patients hos-
pitalized with ADHF do not experience a significant weight
gain [102]. If these steps are not practical and/or additional
resources are available one might consider adding telephone
management by an office medical assistant, nursing staff,
advanced practitioner or a clinical pharmacist.
A multi-disciplinary program targeting elderly patients
with CHF achieved a 56 % reduction in heart failure admis-
sions. However, this result is not proof of effectiveness since
the primary endpoint of the trial, survival at 90 days without
hospital readmission was negative [90]. The Specialized
Primary and Networked Care in Heart Failure (SPAN-CHF)
trial found a positive impact on 90 day readmissions by using
nurses to visit and educate the patient at home followed by
telephone contact once or twice a week to check on the
patient, answer any questions and reinforce the education
provided. Unfortunately this readmission benefit disap-
peared after the intervention ceased [103].
The DIAL (Randomized Trial of Phone Intervention in
Chronic Heart Failure) study achieved a 20 % reduction in
the combined endpoint of death or hospitalization 26.3 %
versus 31.0 %, P = 0.026. The effect of the intervention was
driven by a reduction in hospitalizations for HF, 16.8 % ver-
sus 22.3 % with no significant change in mortality. This
improvement was likely due to the observation that at the
end of the trial more patients in the intervention group were
taking ACE, beta-blockers and aldosterone antagonists as
well as diuretics and digoxin. In this trial nurses provided
the intervention group with an educational booklet and
performed phone calls every 2 weeks for 8 weeks though
the frequency of the phone calls were adjusted based upon
the nurses’ assessment of the patients’ needs. The
112 C.C. Eiswirth
improvement persisted for 3 years after the intervention

was completed.
The results of the Telemonitoring to Improve Heart
Failure Outcomes (Tele-HF) trial [104] utilizing telemonitor-
ing failed to demonstrate a benefit from the intervention. In
this study no improvement was observed in the combined
end point of all cause hospital readmissions and all cause
death rate nor was there any difference between the indi-
vidual components of the primary end point. All of the
secondary end points, hospitalizations for heart failure, num-
ber of hospitalizations or number of days in the hospital also
failed to demonstrate a benefit of telemonitoring.
The Telemedical Interventional Monitoring in Heart
Failure Study [105] enrolled ambulatory patients with NYHA
Class II–III symptoms and a severely reduced LVEF ≤25 %
or a LVEF ≤35 % in addition to a history of HF decompensa-
tion within 2 years. They were randomized to usual care ver-
sus telemedicine monitoring of weights, BP and ECG. The
information was connected to a personal digital assistant and
sent to the telemedicine system via an encrypted cell phone.
This trial failed to demonstrate a difference in all cause mor-
tality, cardiovascular death or HF hospitalizations at a
median follow-up of 26 months.
The results of these telemonitoring trials support a cau-
tious approach before one applies this strategy to all patients
with CHF. Instead, one might wish to tailor an approach for
the individual patient using these techniques in those whom
the clinician feels might achieve the greatest benefit from
such an intervention. This is especially prudent considering
the mixed results demonstrating a lack of efficacy as it is
unlikely that payors will reimburse physicians and hospitals
for these services.
With the widespread use of ICDs in patients with CHF,
companies have implemented various technologies to assist
the clinician in an effort to detect clinically meaningful
changes that may reliably detect the onset of ADHF. The
goal was that early detection of adverse clinically silent
events that predate the onset of ADHF would give the
clinician time to implement an intervention thereby pre-

venting an episode of ADHF resulting in hospitalization.
Heart rate variability (HRV) is one such measure. It is
derived from the pacemaker’s ability to measure the inter-
vals between successive atrial beats. HRV reflects the para-
sympathetic drive of the heart with higher degrees of HRV
representing a greater influence of the parasympathetic
system while loss of HRV reflects an increase in sympathetic
drive which is seen in ADHF. Using a device based calcula-
tion known as the standard deviation of the atrial-to-atrial
median (SDAAM) intervals one can predict the risk of hos-
pitalization for ADHF as well as mortality [106]. An SDAAM
of <60 ms compared to >100 ms was associated with a 3.2
fold increased 1 year mortality as well as higher risk of hos-
pitalization. This parameter is useful in predicting long term
events at 1 year as opposed short term events. There were
changes in the SDAAM present within 3 weeks of a hospital-
ization for ADHF but the differentiation is too narrow to be
of clinical use with current technology but if one observes a
loss of SDAAM from baseline then it is reasonable to have
the patient come to clinic for an assessment.
Intrathoracic impedance is reduced in the presence of
fluid within the lung or pleural spaces. Using an ICD or pac-
ing system allows measurement of the impedance between
the lead tip and the pulse generator which should be superior
to transthoracic measurements. Changes in impedance pre-
cede the onset of symptoms requiring hospitalization by an
average of 18 days [107]. Clinical trials using this technology
have been disappointing to date [108, 109]. There was one
small study of 27 patients [110] that gives proponents of this
technology hope for the future. However, at this time I would
not recommend using these monitoring systems for the rou-
tine management of HF patients.
In the United States in 2015 the FDA approved the use of
the CardioMEMMS device for reducing heart failure admis-
sions in patients with both HFrEF and HFpEF. This is a wire-
less system implanted via the femoral vein into a branch of
the left lower pulmonary artery. Data relaying the patient’s
114 C.C. Eiswirth
pulmonary artery pressure is sent wirelessly to the monitor-

ing center. The CardioMEMS Heart Sensor Allows
Monitoring of Pressure to Improve Outcomes in NYHA
Class III Heart Failure Patients, (CHAMPION) trial [111]
was a single blinded study (patients blinded but not the physi-
cian) that evaluated this technology and noted a 30 %
reduction in hospitalizations at 6 months associated with
lower PA pressure measurements in the group receiving the
implant. The group with the implant had observed changes in
PA pressure addressed at the discretion of the treating physi-
cian independent of symptoms. This generally involved
alterations in the doses of diuretic, ACE, ARB and/or hydral-
azine and nitrate medications. Outcomes were compared to
the control group that was treated only on the basis of symp-
toms or clinical findings. A 28 % reduction in heart failure
hospitalizations was observed over 6 months. This device was
equally effective in reducing hospitalizations due to HFrEF
as well as HFpEF.
Conclusion
The transition to outpatient care is critically important in the
successful management of patients with CHF. The hospital
physician must complete a detailed accounting of the hospital
stay including the results of pertinent details of the history
and physical exam and diagnostic tests. It is critical that the
responsible physician assure that any diagnostic testing not
performed in the hospital is performed expeditiously in the
outpatient setting. GDMT must be adjusted and laboratory
data collected as dictated by the circumstances of care.
A long-term management plan must be initiated during the
hospitalization for ADHF. Using as the foundation the prog-
nostic information obtained in the hospital the plan should be
continually refreshed as additional information is acquired in
the outpatient setting. Patients should be referred for device
therapies and advanced therapeutic options as their condition
and candidacy allows. Patient education of the disease process,
medications, dietary restrictions and activity are critical. A pal-

liative care discussion should be performed and a plan reflect-
ing the personal wishes of the patient regarding the care of his
disease documented with appropriate advanced directives.
A method to follow these patients with easy access to care
must be assured. Ultimately the program chosen should
assure the implementation of GDMT and a system to moni-
tor the clinical status and function of the patient. The precise
model one chooses is less important than adopting the
aforementioned concepts to achieve cost-effective, high qual-
ity care. In so doing these patients will attain the best func-
tional outcome and be afforded the best opportunity to
improve their prognosis for one of the most deadly medical
conditions in the world today.
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Chapter 4
Volume Assessment
and Management: Medical
and Device Therapies
Lauren B. Cooper and Robert J. Mentz
Introduction
The clinical syndrome of heart failure is a constellation of
signs and symptoms resulting from a reduced ability of the
heart to pump an adequate volume of blood, either due to
impaired ventricular filling or impaired ventricular pumping
[1]. Heart failure patients retain sodium and fluid and may
develop congestive symptoms of dyspnea, fatigue, and
peripheral edema. Congestion is associated with increased
morbidity and mortality in heart failure patients. Thus, the
clinician should routinely assess clinical congestion based on
history and physical examination. In addition, laboratory and
imaging modalities as well as more recently developed
implantable device technologies may assist with the diagnos-
tic evaluation of congestion. The management of congestion
has historically been based on loop diuretics, however, addi-
tional pharmacologic therapies such as thiazide diuretics,
vasodilators, vasopressin antagonists, and mineralocorticoid
receptor antagonists may provide additional decongestion
L.B. Cooper, MD () • R.J. Mentz, MD

Division of Cardiology, Department of Medicine,
Duke University Medical Center, Durham, NC, USA
e-mail: Lauren.B.Cooper@duke.edu

DOI 10.1007/978-3-319-30593-6_4,
126 L.B. Cooper and R.J. Mentz
benefits. If diuretic-based therapies are unsuccessful, ultrafil-

tration may be considered. In this chapter, we review the
assessment of clinical congestion and highlight recent device-
based diagnostic technologies. The approach to volume man-
agement is outlined including both pharmacologic and
mechanical fluid removal.
Epidemiology of Congestion
Heart failure is a considerable and costly public health
problem in the United States and worldwide, affecting more
the 5 million American adults, responsible for over 1 million
hospitalizations and costing over $30 million in 2012 [2]. Most
heart failure hospitalizations are due to volume overload,
with adequate decongestion therefore a major goal during
hospitalization [3]. Despite inpatient treatment, many patients
are discharged with persistent congestion, and congestion at
the time of discharge is associated with worse outcomes [3–5].
Therefore, adequate assessment and treatment of volume
overload are important factors in the management of patients
with heart failure.
Terminology and Pathophysiology

of Congestion
First described by Starling in 1914, as the normal heart fills
with blood during diastole, the filling pressure in the ventricle
increases, and the resultant stroke volume increases propor-
tionally [6]. In heart failure, the ventricle is unable to increase
stroke volume, either due to impaired contraction, impaired
relaxation, or both (Fig. 4.1). Typically, during diastole the
ventricle can accommodate large increases in volume with
small increases in pressure. However, as the ventricle fills to
capacity and becomes less distensible, the result is a significant
rise in end-diastolic pressure. Therefore, the ventricular
end-diastolic pressure is a marker of volume status. Congestion,
or volume overload, in the setting of left ventricular dysfunction
Chapter 4. Volume Assessment and Management 127
Normal
Stroke volume
LV dysfunction
LVEDP
Figure 4.1 Starling curve. The relationship between stroke volume

and left ventricular end-diastolic pressure in the setting of normal
cardiac function and left ventricular dysfunction
is defined in part based on high left ventricular end diastolic

pressure (LVEDp). LVEDp can be measured directly with a
catheter passed retrograde through the aortic valve into the
left ventricle or estimated via indirect measurements with a
pulmonary artery catheter. In the absence of mitral valve dis-
ease, the left atrial pressure (LAp) is equal to the LVEDp, and
the pulmonary capillary wedge pressure (PCWP) is a surro-
gate for the LAp and therefore for the LVEDp.
The mechanisms of congestion in heart failure are thought
to be a result of neurohormonal activation of the
renin-angiotensin-aldosterone system as well as increased
circulating levels of vasopressin (Fig. 4.2). Volume overload
may occur in isolation, or in conjunction with decreased
cardiac output. Causes of congestion and worsening cardiac
function can vary and may be multifactorial. Possible precipi-
tating factors including ischemia, infection, hypertension,
arrhythmia, and dietary or medication noncompliance [7].
Another proposed mechanism is that a reservoir of blood
from the splanchnic circulation gets abnormally distributed
to the effective circulating blood volume in the presence of
an abnormal hormonal milleau, as occurs in heart failure [8].
Congestion leads to further neurohormonal activation, and
Ischemia
Abnormal LV function lnfection
HTN
Arrhythmia
LVEDP
Third heart sound
LA pressures
Dyspnea
PND,Orthopnea
PCWP Pulmonary edema
Bendopnea
Rales
PA pressures
Peripheral edema
RV and RA pressures Hepatomegaly
Elevated JVP
Neurohormonal activation Systemic congestion
Redistribution of splanchnic circulation Ventricular remodeling

Pulmonary HTN
Renovascular pathology
Figure 4.2 Mechanisms of congestive heart failure. Abbreviations:

HTN hypertension, JVD jugular venous distension, LA left atrial, LV
left ventricular, LVEDP left ventricular end diastolic pressure, PA
pulmonary artery, PCWP pulmonary capillary wedge pressure, PND
paroxysmal nocturnal dyspnea, RA right atrial, RV right ventricular
results in ventricular remodeling, pulmonary hypertension,

and renovascular pathology, all of which contribute to wors-
ening heart failure [9, 10].
Volume Assessment
History and Physical Examination
Symptoms
The clinical assessment can provide important information
regarding volume status (Table 4.1). Patient reported
Table 4.1 Signs and symptoms of volume overload

Symptoms/signs Etiology/hemodynamics
Left sided
Dyspnea Fluid accumulation in the lungs causing
reduced lung compliance
Orthopnea Increased ventricular preload: ≥2 pillows
(dyspnea when is consistent with a pulmonary capillary
supine) wedge pressure ≥28 mmHg
Paroxysmal Fluid shifts from peripheral circulation
nocturnal dyspnea
Bendopnea Increasing right and left sided filling
(dyspnea when pressures
bending)
Rales Pulmonary edema
3rd heart sound Rapid ventricular filling during diastole
Right sided
Edema Increased venous pressures causing fluid to
shift to interstitium
Hepatomegaly Elevated right-sided filling pressures
Jugular venous Elevated right atrial pressure
distension
Bendopnea Increasing right and left sided filling
(dyspnea when pressures
bending)
symptoms of congestion include dyspnea, dyspnea on

exertion, orthopnea, paroxysmal nocturnal dyspnea, bendop-
nea, and edema [11].
The symptom of dyspnea is frequently reported by patients,
and is one of the most common reasons they seek treatment
for heart failure. Cardiogenic dyspnea is caused by fluid accu-
mulation in the lungs that reduces lung compliance. Pulmonary
edema is a result of high pressure in the pulmonary capillaries
causing transudation of fluid into the alveolar walls and the
alveolar spaces [12]. In the early stages of volume overload,
dyspnea may only occur with exertion, but as congestion

worsens, dyspnea can occur with progressively less exertion
and even occur at rest. Shortness of breath may also present
suddenly, as in “flash pulmonary edema,” caused by acute
increases in LVEDp caused by acute ischemia, acute aortic or
mitral regurgitation, or severe hypertension. While the symp-
tom of dyspnea is neither sensitive nor specific for volume
overload, it can be used to subjectively assess response to
therapy and characterize a patient’s clinical course.
Orthopnea—dyspnea when supine—is due to the changes
in blood distribution to the pulmonary circulation and
increased ventricular pre-load when lying flat. Patients may
describe this symptom in terms of the number of pillows
required to sleep without experiencing shortness of breath.
More severe orthopnea has been shown to correlate with
higher pulmonary capillary wedge pressures [13]. A related
symptom that occurs in the supine position is paroxysmal
nocturnal dyspnea (PND). PND is acute shortness of breath
that awakens a patient from sleep and results in an urge to sit
upright and breathe cool air. PND is also thought to occur
due to fluid shifting from the peripheral circulation.
Bendopnea—dyspnea when bending over—occurs when
there are elevated right- and left-sided cardiac filling pres-
sures. Compared to patients without bendopnea, patients
with bendopnea have higher supine right atrial and pulmo-
nary capillary wedge pressures, and both right and left sided
filling pressures increase when bending over [14].
Physical Exam
Physical exam signs of congestion include peripheral edema,

hepatomegaly, a third heart sound, rales, and jugular venous
distention. Jugular venous distention and pulmonary rales
are the most specific findings, and a third heart sound is the
most sensitive finding [11].
Peripheral edema is the result of high right heart filling
pressures which increases hydrostatic pressure in the
venous circulation, causing fluid to shift into interstitial

tissues. Like many signs and symptoms, the exam finding of
dependent edema is not sensitive, but can be used to
monitor response to treatment [11]. In addition to edema,
marked elevation in right-sided filling pressures can also
result in congestion of the liver, causing the liver to be
enlarged and pulsatile. Prolonged congestive hepatopathy
can result in irreversible liver damage, termed cardiac
cirrhosis.
A third heart sound, termed an S3 gallop, is caused by
rapid ventricular filling during the passive ventricular filling
in diastole. The presence of an S3 is associated with elevated
left atrial and left ventricular end diastolic pressures and is
associated with a poor prognosis. As filling pressures decrease
with diuresis, the S3 may diminish.
Pulmonary rales are due to fluid accumulation in the
alveoli due to transudation of fluid due to increased pres-
sures in the pulmonary veins. Volume overload causes ele-
vated pressure in the left ventricle which leads to elevated
pressures in the left atrium and pulmonary veins. While rales
on the examination of the lungs may be heard, this finding
can be found with other conditions. Additionally due to a
compensatory increase in lymphatic drainage from the lungs
in chronic heart failure, rales are often notably absent in
many chronic heart failure patients despite significant patient-
reported dyspnea [15].
Jugular venous pressure reflects right atrial pressure which
typically correlates with pulmonary capillary wedge pressure.
However, in approximately 20 % of patients, right atrial pres-
sure and PCWP are discordant, with low RA pressure despite
elevated PCWP, or, less commonly, high RA pressure despite
low or normal PCWP [16, 17]. Therefore, JVP assessment is
an important component of the evaluation of volume status
in heart failure patients, but this should not be used in
isolation.
Despite low sensitivity and specificity of individual patient-
reported symptoms and physical exam findings, taken
together, health care providers are commonly able to use
these findings to diagnose decompensated heart failure,

distinguish it from other disease processes and characterize
the severity of congestion. Furthermore, changes in symp-
toms and exam findings can aid both patients and health care
providers in monitoring volume status and response to ther-
apy. Physician assessment of hemodynamics has been shown
to correlate with invasive hemodynamic measurements, with
clinical findings of congestion correlating with higher PCWP
by invasive hemodynamic measurements [18].
Pulmonary Artery Catheters
In addition to noninvasive evaluations, pulmonary artery

(PA) catheters can aid in the evaluation and monitoring of
volume status. The Evaluation Study of Congestive Heart
Failure and Pulmonary Artery Catheterization
Effectiveness (ESCAPE) trial, studied heart failure
patients hospitalized with congestion, and compared ther-
apy tailored by clinical assessment versus invasive hemo-
dynamic monitoring [13]. In this study, 433 patients were
randomized to one of the two strategies with an endpoint
of resolution of clinical congestion. While the trial did not
show a difference in survival or hospitalization between
patients who were treated with the aid of a PA catheter
and those who were treated based on clinical assessment
alone, the patients whose diuresis was adjusted based on
the invasive hemodynamics had greater diuresis and less
renal dysfunction with therapy [13, 19]. Furthermore, a
review of patients excluded from the trial confirmed they
were often more severely decompensated than those
included in the trial [20]. Because physical exam findings
can be confounded by factors such as discordant hemody-
namics or valvular disease, PA catheters are recommended
for patients with uncertain clinical pictures such as those
with symptoms out of proportion to clinical exam findings
and those not responding to therapy as expected based on
clinical assessment alone [21].
Biomarkers: Natriuretic Peptides

Serum biomarkers, most notably the natriuretic peptides, can
also be used to assess volume status and differentiate
between signs and symptoms caused by heart failure versus
other etiologies.
Brain Natriuretic Peptide (BNP)
Natriuretic peptides are neurohormones involved in natri-

uresis and diuresis. Brain natriuretic peptide (BNP) was
originally identified in the brain, but is primarily released
from the cardiac ventricles in response to volume overload
and cardiac wall stress. Pre-proBNP is synthesized in the
myocardium, cleaved first to pro-BNP, then cleaved to the
biologically active BNP and the inactive NT-proBNP frag-
ment. BNP causes myocardial relaxation and counteracts the
effects of the renin-angiotensin-aldosterone system resulting
in vasodilation, natriuresis, and diuresis [22].
In two prospective studies of patients presenting to the
emergency department with complaints of dyspnea, the
Breathing Not Properly (BNP) study and the N-terminal Pro-
BNP investigation of dyspnea in the emergency department
(PRIDE) study, natriuretic peptides were shown to accurately
differentiate between dyspnea due to congestive heart failure
versus dyspnea due to other causes [23, 24]. Elevated levels of
BNP (>100 pg/mL) and NT-proBNP (>450 pg/mL for patients
<50 years of age, >900 pg/mL for patients >50 years of age)
were shown to have a high positive predictive value for short-
ness of breath due to congestive heart failure, while low levels
of BNP (<50 pg/mL) and NT-proBNP (<300 pg/mL) had a
high negative predictive value indicating dyspnea due to non-
cardiac causes [23]. Furthermore, BNP and NT-proBNP levels
were superior to other history, physical exam or laboratory
findings for diagnosing acute heart failure [23–25].
BNP has been shown to correlate with high LVEDP, with
decreases in BNP correlating with decreases in LVEDP [26, 27].
Furthermore, elevated BNP levels have been shown to correlate

with heart failure severity and prognosis [24, 28, 29]. It is impor-
tant to note, however, that BNP is influenced by a number of
factors, with the elderly, females, and patients with renal dysfunc-
tion have been shown to have higher BNP levels, while obese
patients typically have lower BNP levels [30–33]. It has been
suggested that the change in BNP level for a particular patient
compared to the baseline BNP or the admission BNP may be
more accurate than the use of a fixed value for all patients [34].
Furthermore, BNP may not correlate with hemodynamics in
patients with advanced heart failure [35], possibly due to
changes in BNP clearance in patients with advanced disease
[36]. Multiple studies with modest sample sizes have assessed
the utility of using natriuretic peptides to guide therapeutic deci-
sions in heart failure patients (Table 4.2). These studies have had
variable results and a large-scale clinical trial, Guiding Evidence
Based Therapy Using Biomarker Intensified Treatment
(GUIDE-IT), is ongoing (clinicaltrials.gov, NCT01685840).
Atrial Natriuretic Peptide (ANP)

ANP is released from cardiomyocytes primarily in the atria.
ANP has similar actions as BNP, acting as a vasodilator and
increasing natriuresis and diuresis by reducing renal sodium
reabsorption and decreasing the activity of the renin-
angiotensin-aldosterone system [37, 38]. Despite the similari-
ties, ANP has been shown to be inferior to BNP at predicting
volume status and prognosis, and is therefore not used in the
clinical setting [34].
Imaging
Chest Radiography
Chest radiographs can provide important clinical informa-

tion and confirmation of physical exam findings for patients
with heart failure and volume overload. The heart size can
Table 4.2 Summary of randomized controlled trials of biomarker guided therapy in heart failure
Results for
Trial name or Follow-up primary
first author N Marker Target (months) Primary endpoint endpoint
Troughton 69 NTproBNP 1692 pg/ml 9.6 CV death + CV +
hospitalization +
Chapter 4.
worsening HF
STARS-BNP 220 BNP 100 pg/ml 15 HF death + HF +
hospitalization
TIME-CHF 499 NTproBNP 400 pg/ml (age 18 All-cause death or Neutral
<75) or 800 pg/ hospitalization
ml (age ≥75)
BATTLE 364 NTproBNP 1270 pg/ml 12 All-cause death Neutral
SCARRED
SIGNAL-HF 252 NTproBNP 50 % 9 Days alive and out Neutral
reduction of hospital
PRIMA 345 NTproBNP D/C level 12 Days alive and out Neutral
of hospital
Volume Assessment and Management
(continued)
135
136
Results for
Trial name or Follow-up primary
first author N Marker Target (months) Primary endpoint endpoint
Berger 278 NTproBNP 2200 pg/ml 15 Total days of HF +
hospitalization
STARBRITE 137 BNP <2× D/C level 3 Days alive and out Neutral
of hospital
UPSTEP 279 BNP 150 ng/L 4 All-cause Neutral
(age <75) or death + hospitali-
300 ng/L zation + WHF
L.B. Cooper and R.J. Mentz
(age ≥75)
PROTECT 151 NTproBNP 1000 pg/ml 10 Total CV events +
GUIDE-IT 1100 NTproBNP 12 Time to CV In progress
death or first HF
hospitalization
Abbreviations: BNP B-type natriuretic peptide, CV cardiovascular, D/C discharge, HF heart failure, NTproBNP
N-terminal peptide fragment
be evaluated on chest imaging. Cardiomegaly, identified as

the cardiac silhouette >50 % of the chest width, is an impor-
tant clue in the diagnosis of new onset heart failure.
Pulmonary findings including evidence of pulmonary
hypertension, pulmonary edema, and pleural effusions can
also aid in the assessment of patients with volume overload
and are helpful in monitoring the efficacy of treatment for
volume overload. Furthermore, chest radiographs can often
identify other possible sources of the patient’s symptoms.
Echocardiography
Echocardiography is considered the gold standard in identi-

fying depressed ventricular function. Echocardiography is
also a tool to assess volume status noninvasively. Size and
respirophasic movements of the inferior vena cava (IVC)
reflect right atrial pressure. Imaging of the inferior vena cava
in the subcostal echocardiogram view can estimate right
atrial pressure. A normal sized IVC of 1.5–2.5 cm diameter
which collapses completely with inspiration corresponds to a
right atrial pressure of 5–10 mmHg. Elevation of right atrial
pressure leads to dilation of the vessel and loss of the normal
inspiratory collapse. A nondilated IVC (1.5–2.5 cm) with
<50 % collapse during inspiration corresponds to a right
atrial pressure of 10–15 mmHg, and a dilated IVC (>2.5 cm)
with <50 % collapse corresponds to a right atrial pressure of
15–20 mmHg. A dilated IVC of >2.5 cm with no respiratory
collapse corresponds to a right atrial pressure of >20 mmHg
[39]. As previously stated, right atrial pressure typically
corresponds with pulmonary capillary wedge pressure, but
can be discordant in some patients [16, 17].
Implantable Devices
Table 4.3 provides a summary of implantable fluid monitor-
ing devices as well as several relevant clinical trials.
Table 4.3 Summary of trials of implantable fluid monitoring devices
138
Device name Location/measurement Study name Trial design Results

OptiVol Right ventricle/ MID-HeFT Prospective, Correlation between
(Medtronic) Intrathoracic impedance observational, impedance and
double-blinded PCWP: r = −0.61
N = 33 (p < 0.001)
NYHA Class Correlation between
III/IV impedance and
fluid loss: r = −0.70
(p < 0.001)
Impedance decreases
15.3 ± 10.6 days before
symptom onset
Detection of
decreased impedance
is 76.9 % sensitive in
detecting HFH with
1.5 false-positive
detections per
patient-year
FAST Prospective, Comparison
double-blind of changes in
N = 156 intrathoracic
NYHA Class impedance (fluid
I–IV index, FI) and
changes in weight
Chapter 4.
At 537 ± 312 days:

Sensitivity for
detection of HFE:
FI 76.4 % vs Weight
22.5 %, (p < 0.001)
Unexplained
detection rate
(changes in
impedance NOT
associated with
an HFE) per
patient-year: FI
1.9 vs Weight 4.3
(p < 0.001)
(continued)
139
140
Device name Location/measurement Study name Trial design Results
DOT HF Prospective, Death or HFH at

randomized, 14.9 ± 5.4 months:
unblinded TG 29 % vs CG
N = 335 (TG 168, 20 % (p = 0.063)
CG 167)
NYHA Class
II-IV
Chronicle Right ventricle/RV COMPASS-HF Prospective, At 6 months:
(MedTronic) pressure randomized, Freedom from DSC
single-blind 92 %
N = 274 (TG 134, Freedom from DF
CG 140) 100 %
NYHA Class HFE event rate:
III/IV TG 0.67 vs CG 0.85
(p = 0.33)
HeartPOD (St. Left atrium/LA pressure HOMEOSTASIS Prospective, At 6 weeks:
Jude) observational, Freedom from
open label MACE/MANE:
N = 40 100 %
NYHA Class Freedom from DF:
III/IV 95 %
Chapter 4.
Rate of HFE or
death:
0.72 at 1 year
0.69 at 2 years
61 % at 3 years
CardioMEMS Pulmonary artery/PA CHAMPION Prospective, At 6 months:
(CardioMEMS) pressure randomized, Freedom from
single-blind DSC: 98.6 %
n = 550 (TG 270, Freedom from DF:
CG 280) 100 %
NYHA Class III Rate of HFH: TG
0.32 vs CG 0.44
(p = 0.0002)
Abbreviations: HFH heart failure hospitalizations, HFE heart failure events (hospitalizations, ER visits, urgent clinic
visits), TG treatment group, CG control group, DSC device or system complications, DF device failure, MACE major
adverse cardiovascular events, MANE major adverse neurological events
141
Impedance Monitors
Another way to assess fluid status is through devices that mea-

sure intrathoracic impedance, which correlates with volume
status. Electricity traveling between two points conducts better
(i.e. decreased impedance) through water than through air
(Fig. 4.3). As fluid accumulates in the lungs, the impedance
across the lungs decreases [40, 41]. Devices that monitor
impedance and record changes in impedance over time are
included on some implantable cardioverter defibrillators.
OptiVol [42] (Medtronic, Inc., Minneapolis, MN) measures
intrathoracic impedance between the tip of the right ven-
tricular lead and the implanted device. The utility of the
OptiVol device was studied in the Medtronic Impedance
Diagnostics in Heart Failure Trial (MIDHeFT) [42], showing
a decrease in intrathoracic impedance approximately 2 weeks
prior to hospitalization for decompensated heart failure, and
more than 1 week prior to the onset of symptoms. Furthermore,
Figure 4.3 Measurement of intrathoracic impedance via an implant-

able device
with diuresis, there was a correlation with an increase in

intrathoracic impedance. This concept was further tested in
the Fluid Accumulation Status Trial (FAST) which showed
that impedance monitoring was more sensitive than changes
in weight for detecting fluid overload and worsening heart
failure [43]. Additional studies have demonstrated that
OptiVol monitoring can predict heart failure hospitalizations
[44, 45], rehospitalizations [46, 47], and mortality [48].
However, when patients were given access to impedance
information, via an automated alert for possible fluid
accumulation, the result was more outpatient visits and hos-
pitalizations, and no improvement in mortality compared
with usual care [49]. OptiVol monitoring is currently avail-
able as a diagnostic feature on certain implantable defibrilla-
tors, and is being used as an additional diagnostic component
in the overall volume assessment of patients.
While impedance monitors measure use algorithms to
characterize volume status, there are also direct pressure sen-
sors that can be implanted in the right ventricle, left atrium,
or pulmonary artery.
Right Ventricular Pressure Monitor
Similar to an RV pacemaker lead, a right ventricular pressure

monitor can be implanted in the right ventricle and continu-
ously measure ventricular filling pressures [50]. The RV pres-
sure monitor, Chronicle (Medtronic, Inc., Minneapolis, MN)
was tested in the Chronicle Offers Management to Patients
with Advanced Signs and Symptoms of Heart Failure
(COMPASS-HF) study. While the hemodynamic data
obtained from the device correlates with right heart catheter-
ization data [51], compared to standard care, treatment with
the Chronicle device did not reduce hospitalizations and it
did not reduce emergency or urgent care visits requiring
intravenous therapy [52]. In both the treatment group and
the standard of care groups, there was a lower than expected
event rate, which may have been due to regular and frequent
contact with medical professionals which has previously been
shown to improve heart failure outcomes [53, 54]. Thus, the

role for RV pressure monitoring devices for the routine
assessment of volume status in heart failure patients requires
further study.
Left Atrial Pressure Monitor
A left atrial pressure monitor, the HeartPOD (St. Jude Medical

Inc., Minneapolis, MN), measures left atrial pressure and is
implanted surgically or transvenously via a transseptal punc-
ture [55, 56]. In the Hemodynamically Guided Home Self-
Therapy in Severe HF patients (HOMEOSTASIS) trial [57],
the use of this device improved patient’s functional status and
ejection fraction, and allowed for up titration of heart failure
medications and decreases in diuretic doses. The left atrial
pressure monitor is currently being further studied in the Left
Atrial Pressure Monitoring to Optimize Heart Failure Therapy
(LAPTOP-HF) for safety and efficacy in reducing worsening
heart failure and hospitalization (clinicaltrials.gov,
NCT01121107). It will be necessary to demonstrate the effi-
cacy of these devices to improve outcomes compared with
current usual care prior to broad clinical application.
Pulmonary Artery Pressure Sensor
A pulmonary artery pressure monitor can be deployed in a

pulmonary artery branch during right heart catheterization
and provides accurate pulmonary pressure measurements
[58]. A pulmonary artery pressure sensor, CardioMEMS
(CardioMEMS, Atlanta, Georgia), was studied in the
CardioMEMS Heart Sensor Allows Monitoring of Pressure
to Improve Outcomes in NYHA Class III HF Patients
(CHAMPION) trial [59, 60]. Use of this device resulted in a
reduction in heart failure hospitalizations, pulmonary artery
pressures, and an improvement in quality of life and medica-
tion utilization. The CardioMEMS device was approved by
the FDA in October 2013.
The official practice guidelines for the management of

heart failure recognize the advances in technology in the
diagnostic evaluations of heart failure [21]. While initial
studies suggest that implantable devices can provide accurate
measurements that correlate with filling pressures, some of
these devices are still being evaluated in larger clinical trials
to determine the degree to which they impact outcomes. As
these devices are adopted into routine clinical practice, they
may be able to provide additional information in the evalua-
tion of patients and the overall assessment of volume status.
Volume Management
Medical Therapy/Diuretics
Diuretics work by limiting sodium reabsorption in the kidney,

resulting in increased urinary sodium and water excretion.
The mechanism of action and the location of action in the
kidney differ between classes of diuretics. Due to a positive
charge, sodium can only cross the lipid luminal membrane
into the cell by a transmembrane carrier or sodium channel.
Sodium is transported out of the cell by Na-K-ATPase pumps
in the basolateral cell membrane which return reabsorbed
sodium to the systemic circulation. In the kidney, approxi-
mately 65–70 % of sodium is reabsorbed in the proximal
tubule, 25 % is reabsorbed in the loop of Henle, and the
remainder reabsorbed in the distal and collecting tubules [61].
Figure 4.4 presents the sites of diuretic action in the nephron.
Loop Diuretics
Loop diuretics include furosemide, torsemide, and

bumetanide, and their mechanism of action is in the loop of
Henle. The transmembrane carrier in the thick ascending
limb of the loop of Henle is a Na+ K+ 2CL− cotransporter,
which is dependent on chloride delivery. Loop diuretics
compete for the chloride site on the transporter, thereby
Distal
Mannitol, Thiazide, convoluted
acetazolamide metolazone tubule
Amiloride,
spironolactone,
Proximal triamterene
Cortex convoluted tubule
Medulla Collecting
Proximal
duct
straight tubule
Bumetanide,
ethacrynic acid,
furosemide
Thick ascending
limb of Henle’s
loop
Figure 4.4 Sites of diuretic action in the nephron. Proximal tubular

diuretics such as mannitol and acetazolamide, have a modest net
negative effect on sodium balance because downstream nephron
sites reabsorb much of the sodium that is not reabsorbed in the
proximal tubule. Loop diuretics dose-dependently decrease sodium
reabsorption in the thick ascending limb of the loop of Henle.
Thiazides and metolazone inhibit sodium reabsorption in the early
portion of the distal convoluted tubule. Triamterene, amiloride, and
spironolactone are potassium-sparing diuretics that work at the late
portion of the distal convoluted tubule and the cortical collecting
duct. (Reproduced with permission)
limiting the transporter and blocking sodium reabsorption

[62]. The pharmacology differs between the loop diuretics.
Bumetanide and torsemide have a higher and more predict-
able bioavailability than furosemide. Torsemide has the lon-
gest half-life, but the half-lives of all of the loop diuretics
increase with renal or hepatic dysfunction. The onset of
action for loop diuretics is similar, 30–60 min if given orally
and within minutes if given intravenously [63].
Loop diuretics are often the first line for treatment of vol-
ume overload in heart failure and are typically given
intravenously in the setting of decompensation due to the

need for a rapid onset of action. A pharmacologic review of
loop diuretics highlights favorable outcomes in patients with
heart failure treated with torsemide over furosemide, with
respect to mortality, hospitalization, and functional class [63].
Additionally, in outpatients with heart failure, bumetanide has
been shown to be more effective than furosemide at reducing
dyspnea [64]. While continuous dosing of loop diuretics has
theoretical advantages over intermittent bolus dosing, with a
steady delivery of the drug to maintain a constant effect, the
Diuretic Optimization Strategies Evaluation (DOSE) trial did
not show a significant difference between the two approaches
for the co-primary endpoints assessing patients’ symptoms
and creatinine change [65, 66]. The DOSE trial was a prospec-
tive, randomized trial to evaluate diuretic dosing strategies in
patients hospitalized with decompensated heart failure. Three
hundred eight patients were randomized in a 2 × 2 factorial
design to IV furosemide given as twice daily boluses or con-
tinuous infusion, and to either low dose (equivalent dose to
home dose) or high dose (2.5 times home dose). There was no
significant difference between the bolus versus continuous
infusion groups. However, compared to the low dose group,
the high dose group had more favorable outcomes in terms of
dyspnea relief, weight loss, and net fluid loss. The high dose
group, however, had worsening renal function, though this was
found to be transient and resolved by the 60-day follow up
[65]. Thus, an evidence-based initial approach to congestion
management involves high-dose intravenous diuretics, admin-
istered as bolus or continuous infusion dosing.
Thiazide Diuretics
Sequential nephron blockade with thiazide-type diuretics

may be used in combination with loop diuretics to augment
diuresis [67]. Thiazide diuretics including hydrochorothiazide,
chlorothiazide, chlorthalidone, and metolazone, act in the
distal tubule by inhibiting the Na+ Cl− cotransporter in this
location. Because the distal tubule reabsorbs less sodium
than the loop of Henle, thiazide diuretics are less potent than
loop diuretics. However, if sodium is not absorbed proximally,
as during administration of loop diuretics, there is a compen-
satory response for the excess sodium and water to be
absorbed distally [62]. Under normal physiologic conditions,
the distal tubule absorbs approximately 5 % of the filtered
sodium; the capacity for reabsorption can more than double
in response to increased flow to the distal tubule due to the
effects of a loop diuretic [62]. Giving a thiazide diuretic in
conjunction with a loop diuretic may increase effectiveness of
the loop diuretic by preventing distal reabsorption of sodium
[68]. Because thiazide diuretics have a longer half-life than
loop diuretics, the effect on the distal tubule will continue
even after the loop diuretic has worn off [67]. Thus, patients
who take loop diuretics chronically may be instructed to take
thiazide diuretics on an “as needed” basis for worsening vol-
ume overload, though this strategy has not been rigorously
evaluated in a clinical trial. Furthermore, the use of thiazide
diuretics has been associated with increased arrhythmia risk
due to hypokalemia [69, 70].
Potassium Sparing Diuretics
Potassium sparing diuretics include sodium channel blockers

and aldosterone antagonists. These groups of medications act
at the collecting tubule via different mechanisms. In the
collecting tubule, the luminal membrane contains sodium and
potassium channels, not transporters. Sodium channel block-
ers, amiloride and triamterene, directly block the sodium
channels in the luminal membrane.
Aldosterone acts as a diuretic by increasing the number of
open sodium channels in the collecting tubule. In the setting
of loop diuretic use, when sodium is not absorbed proximally
in the loop of Henle, it can be absorbed distally via an upreg-
ulation of aldosterone-sensitive sodium channels in the
collecting tubule. The aldosterone antagonists (also referred
to as mineralocorticoid receptor antagonists [MRAs]), spi-
ronolactone and eplerenone, block the action of aldosterone
resulting in decreased sodium reabsorption in the collecting

tubule; therefore, the addition of an MRA to a loop diuretic
may result in increased natriuresis and diuresis. Aldosterone
antagonists are recommended for patients with heart failure
and reduced left ventricular ejection fraction ≤35 % and
New York Heart Association class II–IV symptoms, based on
several studies which demonstrated a reduction in mortality
in patients taking aldactone or eplerenone [71–73]. While the
MRAs have both diuretic and potassium-sparing effects, they
also offer additional cardiovascular benefits beyond these
properties [74]. Heart failure patients taking only non-
potassium sparing diuretics without concomitant use of a
potassium-sparing diuretic have been shown to have an
increased risk of progressive heart failure and death, likely
due to deleterious effects of neurohormonal activation that
occurs with diuretic use in heart failure [75, 76].
Diuretic Resistance and RAAS Activation

The efficacy of a diuretic depends on many factors: the dose
of the drug, the rate of delivery of the drug to the renal
tubule, and patient factors including sodium and fluid intake
and co-morbidities including heart failure and renal dysfunc-
tion [62]. There is a dose response curve that differs between
drugs and between oral and intravenous administration. A
certain concentration of the drug is required before diuresis
occurs. Once that threshold level is reached, the response
increases with increasing dose of the drug. There is a ceiling
on the dose responsiveness. Once the transporter or channel
is saturated, the maximum rate of diuresis is reached, and
further dose increases will not result in increased diuresis
[62]. The goal with diuresis is to find an effective dose that
results in an effect on the ascending portion of the dose-
response curve (Fig. 4.5). In patients with heart failure, the
dose response curve is shifted downward and to the right and
patients become less responsive to diuretics, thus higher dose
are often required to achieve effective diuresis [77]. While
Normal
Fractional excretion of sodium
Diminished
maximal
responsiveness
Heart failure
Higher doses
required to
achieve same
diuretic effect
Diuretic concentration
Figure 4.5 Dose response curve of loop diuretics. Schematic of

dose‐response curve of loop diuretics in heart failure patients com-
pared with controls. In heart failure patients, higher doses are
required to achieve a given diuretic effect and the maximal effect is
blunted (Reproduced with permission from Felker [77])
some observational studies have shown an association

between high dose loop diuretics and poor outcomes, these
results are cofounded given that patients receiving higher
doses of diuretics were likely more sick with more volume
overload and possibly more diuretic resistance, requiring
higher doses of diuretics to achieve a diuretic response [78].
Impaired renal function affects the bioavailability of
diuretics. If the reduced glomerular filtration rate (GFR) is
due to chronic kidney disease, there is impaired delivery of
the drug to the kidney. A higher dose of the drug promotes an
increased rate of delivery to the tubule and thus may be
necessary in order to achieve efficacy in the setting of chronic
kidney disease. If the reduced GFR is due to low cardiac out-
put, improving hemodynamics can improve renal perfusion
and diuretic efficacy [67]. Additionally, with volume overload
resulting in intestinal edema, intestinal absorption of oral

drugs may be impaired, therefore intravenous administration
is preferred to overcome this issue [62].
In addition to adequately dosing and optimizing delivery
of the drug, diuretic resistance may occur in patients being
treated for volume overload. Several mechanisms contribute
to diuretic resistance with loop diuretics: reduced diuretic
efficacy with repeated dosing, rebound sodium retention due
to increased sodium reabsorption in the distal nephron, and
with chronic use, renal adaptation in the distal tubule result-
ing in hypertrophy and increased sodium reabsorption [66,
67]. One way to overcome diuretic resistance, in addition to
increasing the dose of the drug, is to block sodium reabsorp-
tion in the distal tubule by giving a thiazide diuretic in con-
junction with a loop diuretic (i.e., dual nephron blockade).
However, treatment with combination diuretics can result in
electrolyte disturbances, particularly hypokalemia, so electro-
lytes must be closely monitored and repleted during diuresis.
Similarly, blocking downstream sodium reabsorption in the
collecting tubule by administering an aldosterone antagonist
can help overcome diuretic resistance. Reduced diuretic effi-
cacy can be caused by neurohormonal activation, as diuretics
may activate the renin-angiotensin-aldosterone system, which
increases sodium reabsorption. This issue can be overcome
with concomitant use of other medications that block the
cascade, including ACE inhibitors, ARBs, and MRAs [67].
Vasopressin Receptor Antagonists
Vasopressin, or antidiuretic hormone, which is increased in

the setting of heart failure has many systemic effects includ-
ing vasoconstriction, cardiac hypertrophy, platelet aggrega-
tion, adrenocorticotropic hormone release, and uterine
contraction [79]. Activation of the V2 receptor in the renal
collecting tubule effects the aquaporin channels resulting in
increased permeability to water which leads to water reten-
tion and hyponatremia [80]. Unlike diuretics that promote
natriuresis and diuresis, vasopressin receptor antagonists, like
tolvaptan, inhibit vasopressin, resulting in selective free water

diuresis without natriuresis.
Treatment with tolvaptan has been shown to reduce
weight, decrease dyspnea and edema, and normalize serum
sodium levels in patients with hyponatremia [81–83]. Weight
loss and symptom relief appears to be more significant in
patients with hyponatremia. However, in heart failure
patients, it has not yet been shown that treatment with
tolvaptan improves long term mortality or cardiovascular
morbidity [83]. Tolvaptan is approved for the treatment of
severe or symptomatic hyponatremia in patients with heart
failure.
Ultrafiltration
Ultrafiltration is an alternate strategy for volume removal.
During the process of ultrafiltration, plasma water is removed
from whole blood across a semipermeable membrane due to
a pressure gradient across the membrane. Until recently,
ultrafiltration has required central venous, but current devices
allow for ultrafiltration through peripheral venous access
[84]. In this technique, two peripheral intravenous catheters
are placed, one for blood withdrawal and one for blood
return, with ultrafiltration through a single-use extracorpo-
real blood circuit achieving fluid removal of up to 500 mL/h
[66, 84]. Anticoagulation is typically required to prevent mal-
function of the filter. Contraindications to ultrafiltration
include hemodynamic instability, acute renal insufficiency,
hypercoagulability, and poor venous access [66].
An advantage of ultrafiltration over diuretics is that ultra-
filtrate is isotonic compared with urinary output with diuret-
ics which is hypotonic. Thus, ultrafiltration removes more
sodium and less potassium for the same volume compared
with diuretics and may offer benefits related to maintain elec-
trolyte balance [85]. Additionally, the rate of fluid removal
can be titrated so that it does not does not exceed the inter-
stitial fluid mobilization rate, preserving intravascular volume
and avoiding the acute renal insufficiency the may occur with
diuretic therapy [66, 86].
The first prospective, randomized, multicenter study com-
paring ultrafiltration with intravenous diuretic therapy in
patients with heart failure and volume overload, the
Ultrafiltration versus Intravenous Diuretics for Patients
Hospitalized for Acute Decompensated Congestive Heart
Failure (UNLOAD) trial, randomized 200 patients within 24
hours of hospital admission to either ultrafiltration or stan-
dard care with intravenous diuretics administered via con-
tinuous infusion or bolus injections [87]. At 48 hours, both
groups had similar relief of dyspnea, but the ultrafiltration
group had greater net fluid loss and greater weight loss. Both
groups had similar length of hospital stay. At 90 days, the
ultrafiltration group had fewer rehospitalizations and
unscheduled clinic or emergency department visits. There
were no differences in serum creatinine changes between the
groups, and both groups had a similar number of deaths [87].
Further analysis comparing ultrafiltration to continuous
intravenous diuretic therapy and to bolus intravenous diuretic
therapy revealed similar degree of weight and fluid loss
between the ultrafiltration and continuous infusion groups
and between the continuous infusion and bolus dosing
groups, but a greater degree of weight and fluid loss in the
ultrafiltration group compared to the bolus dosing group [85].
However, despite similar weight and volume loss in the ultra-
filtration and continuous infusion groups, there were fewer
rehospitalizations and unscheduled visits to the clinic or
emergency room in the ultrafiltration group [85]. Notably, the
number of events was low and these findings warrant further
validation in larger adequately powered studies.
Despite the favorable outcomes for ultrafiltration in
patients with heart failure and volume overload, the outcomes
may be different in patients with worsening renal function in
the setting of decompensated heart failure and volume over-
load, as assessed in the Cardiorenal Rescue Study in Acute
Decompensated Heart Failure (CARRESS-HF) study [88].
In this prospective randomized study, 188 patients with acute
decompensated heart failure, worsening renal function with a

rise in serum creatinine ≥0.3 mg/dL from baseline, and per-
sistent congestion were randomized to ultrafiltration or a
stepped pharmacologic therapy to maintain a urine output of
3–5 l/day. While the weight loss was similar between the
groups at 96 h, the ultrafiltration group experienced a greater
increase in serum creatinine. Furthermore, the ultrafiltration
group had a higher rate of serious adverse events over the
follow-up period of 60 days. At 60 days, there were no signifi-
cant differences in weight loss, mortality, or rehospitalizations
between the groups, and both groups had lower creatinine
levels compared to baseline levels [88]. The difference in out-
comes in these two trials highlights the complexity of imple-
menting this novel technique to treat patients with volume
overload. Current guidelines recommend consideration of
ultrafiltration for relief of volume overload or for refractory
congestion not responding to medical therapy [21].
Summary
Volume overload occurs in heart failure because of pathologic
changes in hemodynamics and neurohormonal activation.
Congestion is a major cause of morbidity and mortality in
patients with heart failure, and thus it must be accurately rec-
ognized and adequately treated. The diagnosis of volume over-
load is often made based on patient and clinician assessments,
though radiographic and echocardiographic findings and
serum biomarker measurements can help confirm the diagno-
sis and monitor the effectiveness of treatment. Implantable
devices to measure filling pressures are being developed and
tested to provide additional information to incorporate into
the overall clinical picture of congestion. Invasive hemody-
namic monitoring can be pursued for cases in which noninva-
sive assessments are inadequate or confounded.
Treatment of volume overload consists of pharmacologic
and mechanical strategies (Fig. 4.6) [89]. Diuretics increase
urinary sodium and water excretion, with different classes of
AHF with congestion
High dose IV loop

diuretics
Relief of symptoms and Yes Focus on evidence based

adequate decongestion HF medications
No
Potential alternatives·
Consider thiazide diuretic
Vasopressin antagonist
Natriuretic dose of MRA Relief of symptoms and Yes Focus on evidence based
adequate decongestion HF medications
No
Consider vasodilators if Consider inotropes if

SBP allows SBP low
Ultrafiltration
Relief of symptoms and

adequate decongestion
Figure 4.6 Management of volume overload in heart failure

(Modified and reproduced with permission from Mentz et al. [89])
diuretics acting at different sites in the kidneys—loop diuret-

ics at the loop of Henle, thiazide diuretics at the distal tubule,
and potassium sparing diuretics and vasopressor receptor
antagonists at the collecting tubule. When escalating doses of
diuretics are ineffective, volume removal may be achieved
with ultrafiltration, a process in which plasma water is
removed from whole blood across a semipermeable mem-
brane. Ultrafiltration, which once require central venous
catheter placement, can now be performed through periph-
eral venous access.
Conclusions
Heart failure is a considerable public health problem world-
wide. In this chapter, we reviewed the diagnosis and treat-
ment of volume overload, one of the major sources of
morbidity and mortality in heart failure. Despite the current

assessment and management tools available to clinicians, the
burden of heart failure remains high, highlighting the need
for development of novel tools and strategies to improve
outcomes in this patient population.
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Index
A Acute myocardial
ACE. See Angiotensin infarction
converting enzyme (AMI), 4
(ACE) ADHF. See Acute
Acute decompensated heart decompensated heart
failure (ADHF). failure (ADHF)
See also Transition African-American heart
of care plan, ADHF failure trial, 12
adjunctive therapies, 57–61 “Aldosterone breakthrough”
hospitalizations, 29 phenomenon, 4
inotropic agents All cause mortality
Istaroxime, 42–46 (ACM), 94
Levosimendan, 46–53 Angiotensin converting
Omecamtiv Mecarbil, enzyme (ACE),
54–57 1, 4–9, 12, 30, 84, 85, 110
intravenous diuretics, 29 Angiotensin receptor
natriuretic peptides and blockers (ARB’s),
RAAS 1, 4–8, 14, 33, 84,
urodilatin/ularitide (see 85, 101, 113
Urodilatin/ularitide) Atrial natriuretic peptide
VPIs (see Vasopeptidase (ANP), 31, 34, 37, 38,
inhibitors (VPIs)) 134
vasodilator therapies, 40–42
Acute Decompensated
Heart Failure B
National Registry Bendopnea, 129, 130
(ADHERE), Bisoprolol, 9, 86
13, 92 Brain natriuretic peptide (BNP),
Acute heart failure (AHF), 31, 34, 99, 133–134
41, 42, 56, 94 Bumetanide, 2, 146, 147

DOI 10.1007/978-3-319-30593-6,
166 Index
C Chlorthalidone, 13, 147

Calcium channel blockers Chronicle Offers Management
(CCB), 13, 16 to Patients with
Calcium Sensitizer or advanced Signs
Inotrope or None and Symptoms
in Low Output of Heart Failure
Heart Failure Study (COMPASS-HF)
(CASINO) trial, 48 study, 143
Candesartan in Heart failure Composite congestion score
Assessment of (CCS), 93, 94
Reduction in Congestion, 81, 93–95
Mortality and biomarkers
morbidity (CHARM) ANP, 134
trial, 7–8 BNP, 133–134
Captopril, 7, 31 randomized controlled
Cardiac index (CI), trials, 135–136
11, 45, 47, 48, 59, 96 diuretic-based therapies, 126
Cardiac Insufficiency diuretic resistance and
Bisoprolol Study II RAAS activation,
(CIBIS-II), 9 149–152
Cardiac resynchronization epidemiology of, 126
therapy (CRT), 91 imaging
Cardiogenic dyspnea, 129 chest radiography,
Cardiomegaly, 137 134, 137
CardioMEMS Heart Sensor echocardiography, 137
Allows Monitoring implantable devices
of Pressure to impedance monitors,
Improve Outcomes 142–143
in NYHA Class III left atrial pressure
Heart Failure Patients monitor, 144
(CHAMPION) trial, pulmonary artery pressure
112, 144 sensor, 144–145
Cardiorenal Rescue Study in right ventricular
Acute Decompensated pressure monitor,
Heart Failure 143–144
(CARRESS-HF), trials of, 138–141
94, 153 morbidity and mortality, 125
Carperitide, 37, 38, 60 terminology and
Carvedilol, 9, 10, 15, 16 pathophysiology,
Carvedilol Or Metoprolol 126–128
European Trial ultrafiltration, 126, 152–154
(COMET), 9 volume assessment
Carvedilol Prospective physical exam, 130–132
Randomized pulmonary artery
Cumulative Survival catheters, 132
(COPERNICUS) symptoms, 128–130
trial, 9 volume management, 145
Index 167
Congestive heart failure (CHF) readmission penalty,

admission and discharge labs, 73, 77
80 therapeutic decisions,
biomarkers, 99–101 95–97
congestion, 81, 93–95 transition phase
decompensated HF, 82 ACE inhibitors, 85
discharge summary elements, aldosterone
75 antagonist, 86
disease management plan anticoagulation, 87
CardioMEMMS device, ARB’S, 85
112 atrial fibrillation, 86
HRV, 111 beta blocker therapy,
intervention group, 110 84, 86
intrathoracic impedance, diuretics, 88
112 drug therapy, 84
PA pressure, 113 echocardiography, 102
post discharge support, hyponatremia, 102
109 IABP, 103
SDAAM, 112 inotrope, 85
SPAN-CHF, 110 intravenous
usual care vs. telemedicine inotropes, 103
monitoring, 111 ivabradine, 87
early follow-up clinic NYHA Class III-IV
appointment, 78 symptoms, 101
education, 78 patient and caregiver
etiology, 89 education, 83
evaluation, 90–91 renal function and
GDMT, 77 electrolytes
healthcare projections, 88 assessment, 87
heart murmur/S3, 79 sinoatrial (SA)
HFDM, 80–81 node, 87
hospice care, 105–106 tachycardia, 102
hospital course and treatment United States, 74
plan, 76 Cooperative North
hospitalizations, 76 Scandinavian Enalapril
management programs and Survival Study
transition of care, (CONSENSUS), 6
106–109 Coronary blood flow (CBF), 44
non-invasive risk scores, C-type natriuretic peptide
97–98 (CNP), 31
outpatient care, 89
palliative care, 103–105
patient morbidity and D
mortality, 74 Deceleration time (DT), 44
patient’s prognosis, ADHF Diuretic Optimization
determination, 92–93 Strategy Evaluation
methods, 91 (DOSE), 94, 147
168 Index
Diuretics External corporal membrane

loop diuretics, 2–3 oxygenation
potassium-sparing (ECMO), 103
diuretics, 4–5
thiazide and thiazide, 3–4
Dyspnea, 30, 38, 39, 42, 48, 56, F
59, 81, 92, 93, 125, Fluid Accumulation Status
129, 130, 133, 147 Trial (FAST), 143
Furosemide, 2, 3, 87, 145–147
E
Effect of Tolvaptan on G
hemodynamic Glomerular filtration rate
Parameters in (GFR), 37, 150
Subjects with Heart Guideline directed medical
Failure trial, 59 therapy (GDMT),
Efficacy of Vasopresin 77, 80, 90, 100, 102
Antagonism in Guiding Evidence
Heart Failure Outcome Based Therapy
Study With Tolvaptan Using Biomarker
(EVEREST) trial, 59 Intensified Treatment
Enalapril, 6, 11, 32, 33 (GUIDE-IT), 134
Endomyocardial biopsy, 91
Endothelin (ET), 31, 34, 37, 41
End-systolic volumes (ESV), 44 H
Eplerenone in Mild Patients HCM. See Hypertrophic
Hospitalization and cardiomyopathy
Survival Study in (HCM)
Heart Failure Heart failure disease
(EMPHASIS-HF) management
trial, 4 (HFDM),
Eplerenone Post-Acute 80–81
Myocardial Infarction Heart Failure Survival Score
Heart Failure Efficacy (HFSS), 97
and Survival Study Heart failure with
(EPHESUS), 4 preserved ejection
“Escape phenomenon,” 7 fraction (HFpEF),
Evaluation of Losartan In 90
The Elderly (ELITE) I ACEI’s and ARB’s, 14
study, 7 aldosterone antagonists,
Evaluation Study of Congestive 16–19
Heart Failure and atrial fibrillation, 13
Pulmonary Artery beta blockers, 14–16
Catheterization CCB, 16
Effectiveness diuretics, 13
(ESCAPE) trial, 132 mortality, 12
Index 169
Heart failure with reduced ryanodine receptor (RyR2)

ejection fraction channels, 43
(HFrEF), 90 SERCA2a, 42
ACE-inhibitors, 5–6 IVC. See Inferior vena cava
ARB’s, 6–8 (IVC)
beta-blockers, 8–10
digoxin, 10–11
diuretics (see (Diuretics)) J
hydralazine and isosorbide Japanese Diastolic Heart
dinitrate, 11–12 Failure (J-DHF)
Heart rate variability (HRV), 111 study, 15
Hemodynamically Guided Home Jugular vein distension
Self-Therapy in Severe (JVD), 79, 93
HF patients
(HOMEOSTASIS)
trial, 144 L
HFDM. See Heart failure Left atrial pressure
disease management (LAp), 127
(HFDM) Left Atrial Pressure
Hospitalizations for heart failure Monitoring to
(HHF), 94 Optimize Heart
Hydralazine and isosorbide Failure Therapy
dinitrate (H-ISDN), 11 (LAPTOP-HF), 144
Hyperkalemia, 5, 8, 17, 33 Left ventricular ejection
Hypertrophic cardiomyopathy fraction (LVEF),
(HCM), 16 15, 44, 46, 111
Left ventricular end diastolic
pressure (LVEDp),
I 44, 127, 130
Inferior vena cava (IVC), 137 Levosimendan
Intra-aortic balloon counter β-adrenergic agents, 46
pulsation (IABP), 103 clinical trials, 50–53
Intrathoracic impedance Dobutamine, 48
measurement, 142 LIDO, 48
Irbesartan in Heart Failure with mortality, 49
Preserved Ejection PCWP, 48
Fraction Study peripheral and coronary
(I-PRESERVE), 14 vasodilation, 47
Istaroxime phosphodiesterase
calcium dysregulation, 43 inhibitors, 46
HORIZON-HF study, 46 Levosimendan Infusion vs
inotropy and lusitropy, 44 Dobutamine in
Na+/Ca2+ Exchanger, 43, 44 Severe Low Output
PCWP, 45 Heart Failure (LIDO)
phosphorylation of study, 48
phospholamban, 43 Losartan, 7
170 Index
M Lisinopril, 32
Medical therapy/diuretics NEP inhibitors, 31
loop diuretics, 145–147 neprilysin inhibitors,
potassium sparing diuretics, 35–36
148–149 Omapatrilat, 32
thiazide diuretics, 147–148 Nebivolol, 15
Medtronic Impedance Neutral endopeptidase (NEP),
Diagnostics in Heart 30–33, 37, 38
Failure Trial Nitric oxide (NO), 40, 41
(MIDHeFT), 142
Metabolic, functional and
hemodynamic O
(MFH), 101 Omapatrilat and enalapril in
Metolazone, 3 patients with
Metoprolol controlled release/ hypertension: the
extended release, 9 Omapatrilat
Metoprolol CR/XL Randomized Cardiovascular
Intervention Trial in Treatment vs. Enalapril
Congestive Heart (OCTAVE) trial, 31
Failure (MERIT-HF), 9 Omapatrilat Versus Enalapril
Metoprolol succinate, 9, 10 Randomized Trial of
Mineralocorticoid receptor Utility in Reducing
antagonists (MRAs), Events (OVERTURE)
148 trial, 32
OptiVol device, 142, 143
Organized Program to Initiate
N Lifesaving Treatment
Natriuretic peptides (NP) in Hospitalized
urodilatin/ularitide Patients with Heart
ADHF, 38 Failure
ANP, 34 (OPTIMIZE-HF),
BNP, 34 15, 93
Carperitide, 37 Orthopnea, 79, 81, 93–96,
hemodynamics, 37 129, 130
hypotension, 39
NPR-A receptors, 34
SIRIUS II trial, 39 P
VPIs PA. See Pulmonary artery (PA)
ACE inhibitors, 30 Paroxysmal nocturnal
angioedema, 32 dyspnea (PND), 130
ANRI therapy, 34 PCWP. See Pulmonary
bradykinin, 30 capillary wedge
endothelin-1 and ANG-II, pressure (PCWP)
31 Pharmacology therapy
Entresto, 33 HFpEF, 19
hamster models, 31 HFrEF, 18
Index 171
Potassium-sparing diuretics, urodilatin/ularitide

1, 4–5, 149 ADHF, 38
Proportional pulse pressure ANP, 34
(PPP), 96 BNP, 34
Prospective Randomized study Carperitide, 37
Of Ventricular failure hemodynamics, 37
and the Efficacy of hypotension, 39
Digoxin (PROVED), NPR-A receptors, 34
10 SIRIUS II trial, 39
Pulmonary artery (PA), vasopressin receptor
112, 127, 132, 143, 144 antagonists, 151–152
Pulmonary capillary wedge VPIs
pressure (PCWP), ACE inhibitors, 30
37–39, 45, 48, angioedema, 32
59, 96, 127, 131 ANRI therapy, 34
bradykinin, 30
endothelin-1 and ANG-II,
R 31
Ramipril, 13 Entresto, 33
Randomized Aldactone hamster models, 31
Evaluation Study Lisinopril, 32
(RALES), 4, 5 NEP inhibitors, 31
Randomized Assessment of neprilysin inhibitors, 35–36
Digoxin on Inhibitors Omapatrilat, 32
of Angiotensin- Right atrial pressure (RAP),
Converting Enzyme 37–39, 45
(RADIANCE) study,
10–11
Randomized Study on Safety S
and Effectiveness of SBP. See Systolic blood
Levosimendan pressure (SBP)
(RUSSLAN), 49 SDAAM. See Standard deviation
Randomized Trial of Phone of the atrial-to-atrial
Intervention in median (SDAAM)
Chronic Heart Failure Seattle Heart Failure
(DIAL) study, 110 Prognostication Model,
RAP. See Right atrial pressure 98
(RAP) Serelaxin, 40, 42
Relaxin, 40–42 SNS. See Sympathetic nervous
Renin-angiotensin-aldosterone system (SNS)
system (RAAS), 2, 5–8, Specialized Primary and
14, 31, 37, 58, 133 Networked Care
diuretic efficacy, 149 in Heart Failure
GFR, 150 (SPAN-CHF),
loop diuretics, 150 110
sodium reabsorption, 151 Spironolactone, 4, 17, 148
172 Index
Standard deviation of the Transition of care plan, ADHF

atrial-to-atrial median admission and discharge
(SDAAM), 112 labs, 80
Stroke volume (SV), 44 biomarkers, 99–101
Studies of Left Ventricular congestion, 81, 93–95
Dysfunction (SOLVD) congestive heart failure
trial, 6 ACE inhibitors, 85
Study of the Effects of Nebivolol aldosterone antagonist, 86
Intervention on anticoagulation, 87
Outcomes and ARB’S, 85
Rehospitalisation atrial fibrillation, 86
in Seniors with beta blocker therapy,
Heart Failure 84, 86
(SENIORS), 15 diuretics, 88
Swedish Doppler drug therapy, 84
Echocardiographic echocardiography, 102
study, 14–15 hyponatremia, 102
Sympathetic nervous system IABP, 103
(SNS), 2, 8, 89, 109 inotrope, 85
Systemic vascular resistance intravenous inotropes, 103
(SVR), 39, 40 ivabradine, 87
Systolic blood pressure (SBP), NYHA Class III-IV
39, 41, 92, 93 symptoms, 101
patient and caregiver
education, 83
T renal function and
Telemedical Interventional electrolytes assessment,
Monitoring in Heart 87
Failure Study, 111 sinoatrial (SA) node, 87
Telemonitoring to Improve tachycardia, 102
Heart Failure decompensated HF, 82
Outcomes (Tele-HF) discharge summary elements,
trial, 110 75
Tolvaptan, 152 disease management plan
adjuvant therapy, 61 CardioMEMMS device,
ECLIPSE trial, 59 112
EVEREST trial, 59 HRV, 111
hypervolumic/euvolumic intervention group, 110
hypotonic intrathoracic impedance,
hyponatremia, 58 112
hyponatremia, 60 PA pressure, 113
SALT-1 and SALT-2 trials, 58 post discharge support,
Vasopressin, 57 109
Torsemide, 2, 146 SDAAM, 112
Index 173
SPAN-CHF, 110 U
usual care vs. telemedicine Ultrafiltration versus
monitoring, 111 Intravenous Diuretics
early follow-up clinic for Patients
appointment, 78 Hospitalized for Acute
education, 78 Decompensated
etiology, 89 Congestive Heart
evaluation, 90–91 Failure (UNLOAD)
GDMT, 77 trial, 153
healthcare projections, 88 Uric acid, 101
heart murmur/S3, 79 Urodilatin/ularitide
HFDM, 80–81 ADHF, 38
hospice care, 105–106 ANP, 34
hospital course and treatment BNP, 34
plan, 76 Carperitide, 37
hospitalizations, 76 hemodynamics, 37
management programs and hypotension, 39
transition of care, NPR-A receptors, 34
106–109 SIRIUS II trial, 39
non-invasive risk scores,
97–98
outpatient care, 89 V
palliative care, 103–105 Valsartan Heart Failure Trial
patient morbidity and (Val-HeFT), 7
mortality, 74 Vasodilator Heart Failure Trial
patient’s prognosis, (V-HeFT), 11
ADHF Vasopeptidase inhibitors (VPIs)
determination, 92–93 ACE inhibitors, 30
methods, 91 angioedema, 32
readmission penalty, ANRI therapy, 34
73, 77 bradykinin, 30
therapeutic decisions, endothelin-1 and ANG-II, 31
95–97 Entresto, 33
United States, 74 hamster models, 31
Treatment of Preserved Lisinopril, 32
Cardiac Function NEP inhibitors, 31
Heart Failure with neprilysin inhibitors, 35–36
an Aldosterone Omapatrilat, 32
Antagonist (TOPCAT) Vasopressin receptor antagonists,
trial, 17 151–152

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Current Cardiovascular Therapy

Series Editor: Juan Carlos Kaski

Hector O. Ventura Editor

More information about this series at

Current Cardiovascular Therapy

Library of Congress Control Number: 2016941739

© Springer International Publishing Switzerland 2016

Printed on acid-free paper

This Springer imprint is published by Springer Nature

1 The Established Therapies: HF-PEF

2 Novel Therapies for the Prevention

3 A Comprehensive Transition of Care Plan

4 Volume Assessment and Management:

Patrick T. Campbell, MD Heart Transplant Institute,

Lauren Cooper, MD Division of Cardiology,

Clement C. Eiswirth, FACC, FASE Department of Cardiology

Tulane University School of Medicine, New Orleans, LA, USA

Selim R. Krim, MD Department of Cardiology,

Arthur Menezes, MD Department of Cardiology,

Robert J. Mentz, MD Division of Cardiology,

Sepehr Saberian, MD Department of Cardiology,

Hector O. Ventura, MD Division of Cardiology,

Heart Failure with Reduced Ejection Fraction

A. Menezes, MD • S.R. Krim, MD

H.O. Ventura (ed.), Pharmacologic Trends of Heart Failure, 1

Sodium and water retention which result in systemic volume

The use of diuretics among patients with HFrEF who have

when salt intake is not restricted. Increasing the frequency of

Thiazide and Thiazide-Type Diuretics

While increasing the dose of the loop diuretic is an effective

use of thiazide or thiazide-type diuretics in addition to loop

Potassium-sparing diuretics (spironolactone and eplerenone)

patients treated eplerenone with HFrEF and mild symptoms

ACE-Inhibitors and ARB’s

In patients with HFrEF, maladaptive mechanisms lead to

Unless contraindicated, ACE-I’s are recommended in all

reducing the production of aldosterone and by increasing

As mentioned earlier, due to the long-term deleterious

that circulating levels of angiotensin II return to ACE-I pre-

morbidity (CHARM) trial consisted of three simultaneous

The use of beta adrenoceptor blockers in the setting of heart

three beta-blockers (bisoprolol, carvedilol, metoprolol succi-

rates of all-cause mortality when compared to the patients

Once, digoxin and diuretic therapy were the foundation of

(RADIANCE) study, patients switched from digoxin to

Hydralazine and Isosorbide Dinitrate

with H-ISDN was associated with greater improvements in

Current heart failure therapy is mainly targeted towards

Heart Failure with Preserved Ejection

current available literature suggests that mortality in HFpEF

Similar to HFrEF, diuretics are commonly used to relieve

ACEI’s and ARB’s

Although inhibition of the RAAS system has shown to be

Beta blockers play an essential role in controlling tachycar-

Echocardiographic study, 113 symptomatic HF patients with

>40 % were randomly assigned to either carvedilol or pla-

Calcium Channel Blockers (CCB)

The role of CCB in HFPEF has been very limited with no

Evidence from animal studies suggests that aldosterone