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Contents lists available at ScienceDirect

Trends in Cardiovascular Medicine

journal homepage: www.elsevier.com/locate/tcm

Acute heart failureR,RR

Lauren Sinnenberg a,c, Michael M. Givertz b,c,∗
a
Department of Internal Medicine, Brigham and Women’s Hospital, Boston, MA, United States
b
Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, United States
c
Harvard Medical School, Boston, MA, United States

a r t i c l e i n f o a b s t r a c t

Keywords: Acute heart failure (AHF) is one of the most common causes for hospital admission and is associated
Acute heart failure with a high risk of mortality. Compared to chronic heart failure, there is less robust evidence to guide
Readmission
diagnosis, risk stratification and management of AHF. This state-of-the art review aims to summarize new
Congestion
developments in this field. We also highlight areas of ongoing work including novel vasoactive agents,
Vasodilators
Diuretics alternative models to traditional hospital admission and strategies to improve patient engagement.
© 2019 Elsevier Inc. All rights reserved.

Introduction is concern that these reductions may be accompanied by an in-

Acute heart failure (AHF) is a clinical syndrome characterized
by rapid onset or worsening of symptoms of heart failure [1].
While AHF is among the most common reasons for hospital admis-
sion, particularly in older patients, less is understood about patho-
physiology and management compared to chronic heart failure. In
this review, we aim to identify and summarize new developments
in diagnosing, risk stratifying and managing patients with AHF. A
comprehensive review of the field of AHF is beyond the scope of
this work.
Epidemiology, morbidity and mortality
The incidence of heart failure (HF) is estimated to be 5.7 cases
per 10 0 0 person years with the highest incidence rate in African
American men (9.1 cases per 10 0 0 person years), followed by
African American women (8.1), Caucasian men (6.0) and Caucasian
women (3.4) [2]. AHF is a common cause of hospital admission
with approximately 90 0,0 0 0 hospital discharges annually in the US
(Fig. 1) and 81,500 in the UK [3,4]. The median hospital length of
stay for an HF admission is 4.3 days with a 30-day readmission
rate of approximately 24% [5,6]. In the US, Medicare-driven finan-
cial penalties for hospital readmissions through the Hospital Read-
missions Reduction Program (HRRP) have achieved reductions in
readmission rates amongst Medicare beneficiaries; however there
R
Disclosures: None.
RR
Funding: None
∗
Corresponding author at: Cardiovascular Division, Brigham and Women’s Hos-
pital, Boston, MA, United States.
E-mail addresses: lsinnenberg@bwh.harvard.edu (L. Sinnenberg),
mgivertz@bwh.harvard.edu (M.M. Givertz).
crease in 30 day post-discharge mortality [7,8].
In-hospital mortality estimates for AHF range from 4–6% in the
US [5,9] and up to 9% in the UK [4]. Risk of mortality rises af-
ter hospital discharge with approximately 10% mortality at 30 days
and 22–27% mortality at 1 year [2,6]. Recent phase 3 clinical trials
(TRUE-AHF and RELAX-AHF-2) demonstrated similar post-discharge
mortality estimates for patients with AHF receiving standard of
care [10,11]. Interestingly, the recent Acute Study of Clinical Effec-
tiveness of Nesiritide in Decompensated Heart Failure (ASCEND-
HF) trial demonstrated a 30-day mortality of 4% in the placebo
group, raising the question of whether mortality after AHF hospi-
talization is decreasing [12].
In 2012, the total cost of HF care in the US was $30.7 billion.
Projections suggest that total costs will rise to $69.7 billion by
2030 (Fig. 2). 80% of these total costs will be for patients with AHF
rather than for chronic management [13].
Pathophysiology
In most patients hospitalized with heart failure and reduced
ejection fraction (HFrEF), end-systolic and end-diastolic volumes
and end-diastolic pressure are increased. These elevated end-
diastolic filling pressures are transmitted to the pulmonary venous
circulation, resulting in signs and symptoms of pulmonary conges-
tion [14]. In some patients, elevated right-sided filling pressures
result in systemic venous and hepatic congestion, leading to ab-
dominal discomfort, anorexia and bloating. Reduced contractility
may result in a fall in stroke volume, leading to signs and symp-
toms of systemic hypoperfusion. For patients admitted with heart
failure and preserved ejection fraction (HFpEF), the end-diastolic
pressure/volume relationship is also shifted upward leading to pul-
monary vascular and systemic venous congestion. Despite these

https://doi.org/10.1016/j.tcm.2019.03.007
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Fig. 1. Hospital discharges for heart failure by sex (United States: 1997–2014). Hospital discharges include people discharged alive, dead, and status unknown. Source: National
Hospital Discharge Survey/National Center for Health Statistics and National Heart, Lung, and Blood Institute. From Benjamin et al. [3] with permission.

Fig. 2. Costs of care for heart failure. The projected increase in direct and indirect costs attributable to HF from 2012 to 2030 is displayed. Direct costs (cost of medical care)
are expected to increase at a faster rate than indirect costs because of lost productivity and early mortality. From Heidenreich et al. [13] with permission.

similarities, recent studies suggest that pathophysiology differs on
a molecular level between HF phenotypes. Network analysis in
the Biology Study to Tailored Treatment in Chronic Heart Fail-
ure (BIOSTAT-CHF) demonstrated that biomarker profiles in HFrEF
are related to cellular proliferation and metabolism including N-
terminal pro-B-type natriuretic peptide (NT-proBNP), growth dif-
ferentiation factor-15 (GDF-15) and interleukin-1 receptor type 1,
whereas biomarker profiles for HFpEF are more closely related to
inflammation and extracellular matrix reorganization (e.g., integrin
subunit beta-2 and catenin beta-1) [15]. Furthermore, patients with
AHF and mid-range ejection fraction showed an intermediate pro-
file with biomarker interactions between both cardiac stretch and
inflammation markers [16].
Clinical assessment and risk stratification
Causes and precipitants
Of patients with AHF, 80% present with worsening chronic heart
failure while 20% are new cases of heart failure [1,14]. Initial work-
up should include identification of the precipitant(s) of the presen-
tation, including evaluation for myocardial ischemia, uncontrolled
hypertension, atrial or ventricular arrhythmias, worsening renal
function and nonadherence with medications or sodium and fluid
restriction. Acute bacterial or viral infection can also precipitate
worsening chronic heart failure, especially in older patients. Signs,
symptoms and initial laboratories can help to guide diagnosis of

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Table 1
Acute heart failure biomarkers.

Biomarker Labelled indication Comments

N-terminal pro-B-type natriuretic peptide
(NT-proBNP)
High sensitivity cardiac troponin T (hs-cTnT)
Soluble suppressor of tumorgenicity 2 (sST2)
Growth differentiation factor-15 (GDF-15)
Cystatin C
Galectin-3 (Gal-3)
High sensitivity C-reactive protein (hs-CRP)
Uric acid
HFrEF, heart failure with reduced ejection fraction.
Diagnosis and risk stratification of heart
failure
Diagnosis of acute coronary syndrome
Prognostication of heart failure
Investigational
Diagnosis of renal dysfunction,
investigational in heart failure
Prognostication of heart failure
Risk stratification of cardiovascular disease
Diagnosis and treatment of rheumatologic
disorders, investigational in heart failure
Prohormone produced in heart in response to
increased wall stress, associated with HFrEF
Regulatory protein integral to muscle contraction
Member of the interleukin-1 receptor family, produced
in response to myocardial stretch
Regulatory protein involved in inflammatory pathways,
associated with HFrEF
Inhibitor of lysosomal proteinases and cysteine
proteases
Protein factor involved in apoptosis and angiogenesis,
noted to promote ventricular remodeling
Pentameric protein produced in response to
inflammation
Breakdown product of purine metabolism cleared by
the kidney

these entities, but at a minimum the work up should include an Biomarkers

electrocardiogram, B-type natriuretic peptide (BNP) level and chest
x-ray as well as consideration of a troponin level and transtho-
racic echocardiogram. If a clear, potentially reversible, underlying
precipitant is identified (e.g., acute coronary syndrome), diagnosis-
specific therapy should be initiated.
In addition to the trigger for the current presentation, knowl-
edge of the patient’s ejection fraction is crucial in determining ap-
propriate treatment. As discussed below, most therapies available
for AHF have been largely tested in patients with HFrEF. Less is
known about how therapies can be more uniquely tailored to the
HFpEF population.
Symptoms
Typically, patients with AHF and volume overload present with
symptoms of dyspnea on exertion, lower extremity edema, orthop-
nea and paroxysmal nocturnal dyspnea. Recently, a new symptom
of AHF, bendopnea or dyspnea on bending over, has been identi-
fied. Bendopnea is present in 25% of subjects with HFrEF referred
for hemodynamic assessment. In one study, the presence of ben-
dopnea was associated with higher supine right atrial pressure
[17]. Furthermore, right atrial and pulmonary capillary wedge pres-
sures increased in all patients when bending during right heart
catheterization.
Physical exam
The physical examination is a fundamental component in as-
sessing, risk stratifying and predicting outcomes in patients with
AHF. Patients with AHF can be characterized at the bedside as
falling into one of four broad hemodynamic profiles: dry-warm,
wet-warm, dry-cold or wet-cold. Clinical assessment of these pro-
files can predict death or urgent transplantation in patients with
AHF.
Patients with physical examination findings consistent with vol-
ume overload such as elevated jugular venous pressure (JVP) and
peripheral edema have higher body mass index, N-terminal pro B-
type natriuretic peptide (NT-proBNP) and BNP levels, more comor-
bid disease and lower ejection fraction compared to those without
these findings [18]. Furthermore, physical exam findings consistent
with volume overload can predict mortality. Patients with elevated
JVP and peripheral edema have a 24% increased risk of all-cause
mortality at 30 days compared to patients with elevated JVP only,
peripheral edema only or neither finding of volume overload.
Individual biomarkers can be utilized to predict outcomes in
patients with AHF, including risk of readmission and mortality
(Table 1). For example, BNP levels measured during hospitalization
for AHF are associated with 30-day HF readmission rate [19]. In
addition to BNP, studies have demonstrated that soluble suppres-
sor of tumorgenicity 2 (sST2), GDF-15, cystatin C, galectin-3, serum
uric acid, microRNAs and low serum chloride are predictors of out-
comes in AHF [20].
Biomarkers related to renal function can be used to identify
risk and monitor response to therapy in patients with AHF and
cardiorenal syndrome. Persistent worsening renal function as de-
fined by elevated creatinine and blood urea nitrogen (BUN) is as-
sociated with increased mortality and risk of readmission. Levels
of proenkephalin, a novel marker of kidney function, are also as-
sociated with worsening renal function, in-hospital mortality and
follow-up mortality in patients with AHF [21].
There is emerging interest in multi-marker strategies for clini-
cal assessment and risk stratification in patients with AHF. Studies
have demonstrated that models that account for multiple biomark-
ers have improved prognostic accuracy compared to those utilizing
individual biomarkers [22].
Imaging
Until recently, imaging, apart from chest radiography, has not
played a significant role in risk stratification of patients with AHF.
New studies are demonstrating the potential role of ultrasound in
this setting. In the emergency department (ED), lung ultrasound
can improve accuracy of AHF diagnosis [23]. Point-of-care ultra-
sound of jugular venous compliance has also shown promise with
strong correlation with invasive right atrial pressure measurement
and ability to predict 30-day readmission for AHF [24].
Management
Triage
While many patients with AHF are admitted to inpatient set-
tings, home hospitalization can be a safe alternative for elderly pa-
tients with no difference in mortality compared to traditional hos-
pitalization [25]. Studies are ongoing to assess when it is optimal
to discharge patients from an AHF hospitalization, and whether
short stay units (less than 24 h hospitalization) or discharge di-
rectly from the ED can be implemented effectively and safely for
selected patients [26–28].

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Table 2
Recent diuretic trials.

Trial Study design N Conclusion

Diuretic Optimization Strategies Evaluation
(DOSE)(30)
Comparison of metolazone versus
chlorothiazide in acute decompensated
heart failure with diuretic resistance(32)
Efficacy and safety of spironolactone in
acute heart failure (ATHENA-HF)(35)
Registry focused on very early presentation
and treatment in emergency department of
acute heart failure (REALITY-AHF)(29)
AHF, acute heart failure; IV, intravenous; RCT, randomized clinical trial.
Prospective, double-blind RCT, 2 × 2 factorial
design of IV diuretic bolus vs. infusion, as well
as high dose vs. low dose diuretic
Retrospective cohort study of metolazone vs.
chlorothiazide
Prospective, double blind RCT of high dose
spironolactone vs. placebo or low dose
spironolactone
Prospective observational cohort study
308 No significant differences in global symptoms or
change in renal function in patients who received
continuous or bolus diuretic therapy. High dose
diuretic therapy was associated with greater diuresis,
but transient worsening of renal function.
55 Metolazone and chlorothiazide are both safe in
patients with AHF and diuretic resistance
360 The addition of spironolactone to usual care for
patients with AHF was well tolerated but did not
improve mortality or rates of heart failure
hospitalization
1291 Earlier diuretic therapy is associated with lower
mortality in patients with AHF

Decongestion
Intravenous (IV) loop diuretics remain the mainstay of treat-
ment for patients with AHF. IV diuretics should be given at the
same dose as the patient’s chronic oral dose or greater, with esca-
lating doses if the patient does not respond. Earlier diuretic admin-
istration in AHF is associated with lower mortality when control-
ling for age, blood pressure, renal function and other independent
risk factors [29].
The Diuretic Optimization Strategies Evaluation (DOSE) trial
demonstrated that high dose loop diuretics were associated with
better symptom improvement and greater volume loss than low
dose loop diuretics; however higher doses transiently worsened
renal function [30]. Furthermore, the results from DOSE indicate
that diuretic infusions are no more effective or safe than inter-
mittent boluses of diuretics (Table 2). Recent pilot studies demon-
strate safety and efficacy of subcutaneous furosemide compared to
IV furosemide, raising the future possibility of home-based man-
agement of AHF with alternatives to oral diuretics [31].
Diuretic resistance can be a major obstacle in management of
AHF. Causes include inadequate diuretic dosing, gut edema hinder-
ing absorption, chronic kidney disease, hypotension and low renal
blood flow. Non-cardiac medications such as non-steroidal anti-
inflammatory agents can also inhibit diuretic effects. Strategies to
overcome diuretic resistance include use of a thiazide diuretic such
as IV chlorothiazide or oral metolazone which can increase urine
output when given along with a loop diuretic [32]. Positive in-
otropes can also be used to augment renal blood flow and improve
diuresis in the setting of resistance due to low cardiac output.
Studies using vasoactive agents like low-dose dopamine, low-
dose nesiritide, and tolvaptan to improve response to diuretic ther-
apy in AHF have been disappointing [33,34]. Similarly, the addition
of high-dose spironolactone (100 mg daily for 4 days) to the di-
uretic regimen in AHF was safe but did not improve outcomes, in-
cluding change in NT-proBNP, clinical congestion score or 30-day
death or readmission rate [35]. Finally, the potential role for ul-
trafiltration (UF) in the treatment of AHF has been investigated.
While small studies suggest that upfront use of UF can lower the
incidence of recurrent HF events compared to diuretics, the risk of
device-related complications raises concern. For patients with re-
fractory congestion who fail to respond to diuretic based-strategies,
rescue use of UF also remains controversial, with higher rates of in-
fection, bleeding and worsening renal function [36].
While guidelines suggest that fluid restriction is reasonable in
patients with heart failure, aggressive fluid and sodium restriction
has not been shown to effect weight loss or clinical stability at
3 days, and is associated with significant increase in thirst [37].
Marked fluid restriction should be reserved for patients with sig-
nificant hyponatremia [38].
Vasodilators
In patients presenting with AHF and pulmonary edema with-
out significant hypotension, guidelines recommend use of IV va-
sodilators including nitroglycerin and nitroprusside, however evi-
dence that these agents improve outcomes is lacking. [1,38] Several
newer vasodilators have been studied to assess safety and efficacy
in AHF on top of standard of care. Nesiritide, a recombinant form
of human BNP, was shown to have a small effect on patient dys-
pnea, but did not reduce mortality or hospitalization rates in 7141
patients with AHF (Fig. 3(A)) [12]. Similarly, serelaxin, a recom-
binant form of human relaxin-2, improved dyspnea compared to
placebo, but did not impact cardiovascular death or hospital read-
mission at 60 days (Fig. 3(B)) [39]. TRUE-AHF (Trial of Ularitide Ef-
ficacy and Safety in Acute Heart Failure) evaluated the use of ular-
itide, a synthetic form of urodilantin, in 2157 patients with AHF.
Despite greater early reductions in blood pressure and BNP levels,
ularitide did not reduce long-term cardiovascular or all-cause mor-
tality (Fig. 3C) [11].
Ongoing studies are evaluating the use of novel vasodilators,
such as BMS-986231 a nitroxyl donor, in AHF.
Inotropes
Guidelines recommend the use of positive inotropes including
dobutamine, dopamine, milrinone and levosimendan, for patients
with AHF and evidence of end organ hypoperfusion [1,38]. Levosi-
mendan, a calcium sensitizer, is an inotrope with vasodilator ef-
fects that is approved for use in Europe and Latin America but not
in the US or Japan. In the Survival of Patients With Acute Heart
Failure in Need of Intravenous Inotropic Support (SURVIVE) trial,
levosimendan did not demonstrate a mortality benefit when com-
pared to dobutamine [40]. In light of its vasodilatory properties,
the Hemodynamic Evaluation of Levosimendan in Patients with
PH-HFpEF study (HELP; NCT03541603) is evaluating the role of lev-
osimendan in patients with acute HFpEF and pulmonary hyperten-
sion.
All guideline-recommended inotropes act on adrenoreceptors,
and therefore result in dose-limiting adverse effects including
atrial and ventricular arrhythmias. Omecamtiv mecarbil (OM), an
activator of cardiac myosin, has raised interest due to its alterna-
tive inotropic mechanism that is less likely to cause these side ef-
fects. In the Acute Treatment with Omecamtiv Mecarbil to Increase
Contractility in Acute Heart Failure (ATOMIC-AHF) study, OM was

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Fig. 3. Primary results from recent pivotal studies of vasoactive therapy in acute heart failure. Panel A. Changes in dyspnea at 6 and 24 h and the primary clinical end points at 30
days in patients treated with nesiritide or placebo for 1–7 days. From O’Connor et al. with permission. [12] Panel B. Cardiovascular death or hospital readmission of patients
with acute heart failure treated with serelaxin 30 μg/kg/day compared to placebo. From Teerlink et al. [39] with permission. Panel C. Effect of ularitide on cardiovascular
mortality in acute heart failure. From Packer et al. [11] with permission.

well tolerated, but did not improve the primary endpoint of dysp-
nea relief compared to placebo (Fig. 4) [41]. While dyspnea was
improved in those who received high-dose OM, plasma concen-
trations of troponin were higher in OM-treated patients. A pivotal,
phase 3 study (GALACTIC-HF; NCT02929329) is currently underway
to determine the effect of OM on morbidity and mortality in pa-
tients with chronic HFrEF.
Neurohormonal antagonists
In patients with HFrEF treated with guideline-directed medical
therapy, including angiotensin-converting enzyme (ACE) inhibitors,
angiotensin receptor blockers, angiotensin receptor neprilysin in-
hibitors (ARNI) and beta-blockers, outpatient medications should
be continued in the absence of hemodynamic instability or other
contraindications [38]. In patients not previously on beta-blockers,
providers should wait until patients are euvolemic and hemody-
namically stable prior to initiation. The PIONEER-HF (Comparison
of Sacubitril-Valsartan versus Enalapril on Effect on NT-proBNP
in Patients Stabilized from an Acute Heart Failure Episode) study
sought to determine whether initiation of ARNI is safe and ef-
fective in patients with AHF following hemodynamic stabilization
[42]. Patients receiving sacubitril-valsartan demonstrated a greater
reduction in NT-proBNP compared to those who received enalapril
(Fig. 5). The rates of worsening renal function, hyperkalemia and
symptomatic hypotension did not differ significantly between the
two groups. This study suggests that initiation of ARNI in patients
with AHF is safe and may improve outcomes.
Mechanical circulatory support
For patients with AHF and cardiogenic shock who cannot be
stabilized with medical therapy, temporary or durable mechanical
circulatory support may be considered. Intra-aortic balloon pumps
(IABP) have traditionally been used for patients with acute my-
ocardial infarction in cardiogenic shock, however the IABP-Shock
II Trial did not demonstrate a mortality benefit with IABP com-
pared to standard therapy [43]. Other forms of mechanical cir-
culatory support, including short-term percutaneous devices (e.g.,
Impella, TandemHeart) and veno-arterial extracorporeal membrane
oxygenation (ECMO), are being used more frequently at referral
centers despite lack of strong evidence to guide choice of ther-
apy [44,45]. In patients with refractory shock, these devices can
be used as “bridges” to decision, transplant or recovery [1,46].
Respiratory management
In patients with AHF presenting with hypoxia, oxygen supple-
mentation is recommended. In the absence of hypoxia, oxygen
supplementation should be avoided given evidence that high-
concentrations of inhaled oxygen can have detrimental hemody-
namic effects (reduced cardiac output, increased systemic vascular
resistance) in patients with HFrEF [47]. Non-invasive ventilation

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Fig. 4. Effects of omecamtiv mecarbil on dyspnea in patients with acute heart failure. Although omecamtiv mecarbil (OM) did not improve the primary endpoint of dyspnea
relief when comparing the 3 OM dose groups with pooled placebo (A), OM did improve dyspnea response in the patients receiving the highest dose when compared with
the paired placebo groups (B). ∗ Ratio of response rate to pooled placebo. ∗ ∗ Ratio of response rate to placebo within each cohort. From Teerlink et al. [41] with permission.

can be used in patients with AHF and pulmonary edema, and has
been shown to induce a more rapid improvement in dyspnea and
metabolic disturbance compared to oxygen therapy alone [38].
Comorbidities
Once patients with AHF are stabilized, providers should con-
sider optimization of co-morbidities prior to discharge. In pa-
tients with type 2 diabetes, glugacon-like peptide-1 (GLP-1) re-
ceptor agonists can be used as an adjunct to diet and exercise to
improve glycemic control. In the Functional Impact of GLP-1 for
Heart Failure Treatment (FIGHT) study, liraglutide use was associ-
ated with reduction in weight and improved blood glucose control,
but did not improve post-hospitalization stability [48]. Sodium-
glucose cotransporter-2 (SGLT-2) inhibitors should be considered
in patients with diabetes and cardiovascular disease. In addition
to favorable effects on CV death, myocardial infarction and stroke,
reduction in HF hospitalizations has been observed [49].
For patients with chronic HFrEF and iron deficiency (with or
without anemia), IV iron can be administered to improve func-
tional status and quality of life [50]. For those with obstructive
sleep apnea, nocturnal continuous positive airway pressure (CPAP)
has been shown to improve EF, exercise capacity and quality of life
[38]. Conversely, adaptive servo-ventilation is not recommended in
patients with HFrEF and central sleep apnea because of increased
mortality [1].
Many patients with HF have comorbidities including atrial
fibrillation and venous thromboembolism for which full-dose
anticoagulation is indicated. Lower doses of rivaroxaban, an oral
direct factor Xa inhibitor, in combination with antiplatelet ther-
apy, has been shown to reduce the risk of cardiovascular death,
myocardial infarction and stroke in patients with acute coronary

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Fig. 5. Change in natriuretic peptide levels in PIONEER-HF. The time-averaged reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration was signifi-
cantly greater in the sacubitril-valsartan group than in the enalapril group (percent change −47% vs. −25%; P < 0.001). From Velazquez et al. [42] with permission.

Table 3
Recommendations for hospital discharge.

Before hospital discharge, at the first post discharge visit, and in subsequent follow-up visits, the following should be addressed:

Initiation of GDMT if not done or contraindicated

Causes of HF, barriers to care, and limitation in support
Assessment of volume status and blood pressure with adjustment of HF therapy
Optimization of chronic oral HF therapy
Renal function and electrolytes
Management of comorbid conditions
HF education, self-care, emergency plans, and adherence
Palliative or hospice carea

GDMT, guideline-directed medical therapy; HF, heart failure.

a
For patients with advanced heart disease. Adapted from Yancy et al. [38].

syndromes. COMMANDER-HF [A Study to Assess the Effectiveness
and Safety of Rivaroxaban in Reducing the Risk of Death, Myocar-
dial Infarction, or Stroke in Participants with Heart Failure and
Coronary Artery Disease Following an Episode of Decompensated
Heart Failure) compared low dose rivaroxaban to placebo in pa-
tients with chronic HFrEF and coronary artery disease in sinus
rhythm following treatment of worsening HF [51]. There was no
difference in the rate of death, myocardial infarction or stroke
between the two groups, with more bleeding in patients receiving
rivaroxaban.
Work is also ongoing to clarify the benefits of virtual visits and
physical rehabilitation on patient outcomes post-discharge [53,54].
For patients with end-stage HF, hospice and palliative care refer-
rals should be strongly considered. In a large Medicare beneficiary
study, hospice referral at the time of discharge was associated with
lower 30-day readmission with no change in mortality [55]. De-
spite this, most patients with HF eligible for hospice are not re-
ferred.
Future directions

Discharge planning and follow-up
As patients with AHF approach discharge, providers should fo-
cus on patient and family engagement and transitions of care
(Table 3). Inadequate health literacy is shown to be an indepen-
dent risk factor for AHF re-hospitalization as well as all-cause mor-
tality [52]. Patient education is also key to avoiding unnecessary
hospitalizations and ED visits following a HF admission. In the
Care Optimization Through Patient and Hospital Engagement Clin-
ical Trial for Heart Failure (CONNECT-HF; NCT03035474), investi-
gators will assess the effect of a multifaceted, health system-level
quality-improvement program on HF outcomes and quality-of-care
metrics in over 70 0 0 patients. This study should help characterize
the magnitude of the effect of patient engagement on outcomes in
AHF.
Compared to chronic HFrEF, management of AHF is resource-
intense with much less data to guide clinical decision-making.
Moving forward, studies will help determine the safety, efficacy
and cost-effectiveness of shifting care away from traditional hos-
pitalizations towards alternative models of care (e.g., outpatient
management with subcutaneous loop diuretics, short stay units,
home hospitalizations) (Table 4). Meanwhile, risk stratification
tools will continue to evolve as new biomarkers are validated and
combined into multi-marker strategies. The increased use of point-
of-care ultrasound also shows promise as a method to improve di-
agnostic accuracy and risk-stratify patients with AHF. Finally, phar-
macologic management of AHF will continue to evolve as new
vasoactive agents including vasodilators and inotropes as well as
therapies targeting comorbidities such as diabetes, CKD and ane-
mia are studied.

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j.tcm.2019.03.007
JID: TCM
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Table 4
Selected ongoing clinical trials in acute heart failure.

Trial Study design Sample size Primary endpoint/duration

Rivaroxaban once daily versus dose-adjusted vitamin K Prospective, single center, open label 150 Change of high sensitivity troponin
antagonist on the biomarkers in acute decompensated RCT of rivaroxaban vs. warfarin plus from baseline to 72 h
heart failure and atrial fibrillation (ROAD HF-AF) enoxaparin
(NCT03490994)
Short stay unit vs. hospitalization in acute heart failure Prospective, multi-center, open label 534 Days alive and out of hospital at 30
(SSU-AHF) (NCT03302910) RCT days
Prospective comparison of metolazone versus Single center, randomized open label 48 Net urine output at 24 h
chlorothiazide for acute decompensated heart failure pilot study
with diuretic resistance (NCT03574857)
Acetazolamide in decompensated heart failure with Multicenter, randomized, double-blind, 519 Treatment success (decongestion
volume overload (ADVOR) (NCT03505788) phase 4 clinical trial achieved) at 4 days
Acetazolamide in patients with acute heart Single center, randomized, double blind 90 Diuresis and negative water balance at
failure (ACETA) (NCT03720288) study 72 h
Registrational study with omecamtiv mecarbil/AMG Double-blind, randomized, 80 0 0 Time to cardiovascular death or first
423 to treat chronic heart failure with reduced ejection placebo-controlled, multicenter study heart failure event (through study
fraction (GALACTIC-HF) (NCT02929329) completion, up to 4 years)
Mechanism and effects of manipulating chloride Prospective, double-blind, randomized 200 Change in blood volume over 7 days
homeostasis in acute heart failure (NCT NCT03446651) study of lysine chloride or placebo
From https://clinicaltrials.gov, accessed January 12, 2019. RCT, randomized clinical trial.

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