Acute decompensated heart failure (adhf): A comprehensive contemporary

review on preventing early readmissions and postdischarge death

Bruno M.L. Rocha, Luiz Menezes Falcão

PII: S0167-5273(16)31654-0
DOI: doi: 10.1016/j.ijcard.2016.07.259
Reference: IJCA 23226

To appear in: International Journal of Cardiology

Received date: 15 May 2016

Revised date: 16 July 2016
Accepted date: 30 July 2016

Please cite this article as: Rocha Bruno M.L., Falcão Luiz Menezes, Acute decompen-
sated heart failure (adhf): A comprehensive contemporary review on preventing early
readmissions and postdischarge death, International Journal of Cardiology (2016), doi:
10.1016/j.ijcard.2016.07.259

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 ACCEPTED MANUSCRIPT

ACUTE DECOMPENSATED HEART FAILURE (ADHF): A COMPREHENSIVE

CONTEMPORARY REVIEW ON PREVENTING EARLY READMISSIONS
AND POSTDISCHARGE DEATH
Bruno ML Rocha1; Luiz Menezes Falcão2

1 – Faculty of Medicine, University of Lisbon, Lisbon, Portugal; [email protected]

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2 – Department of Internal Medicine , Hospital Santa Maria, Lisbon, Portugal; Faculty of Medicine,

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University of Lisbon, Lisbon, Portugal; [email protected]

Abstract

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Heart Failure (HF) is an increasingly prevalent syndrome and a leading cause of both first

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hospitalization and readmissions. Strikingly, up to 25% of the patients are readmitted within 30 to 60-
days, accounting for HF as the primary cause for readmission in the adult population. Given its poor
prognosis, one could describe it as a “malignant condition”. Acute decompensation is intrinsically
related to increased right heart tele-diastolic pressures and often related to congestive symptoms. In-

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hospital strategies to adequately compensate and timely discharge patients are limited. Conversely,
the fragile early postdischarge phase is a vulnerable period when one could potentially intervene
cost-effectively to improve survival and to reduce morbidity. Promising transitional hospital-to-home
programs may have a broader role in the near future, namely for selected higher risk patients.
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However, identifying patients at risk for hospital readmission has been challenging. Novel
approaches, such as ferric carboxymaltose and valsartan/sacubitril, and reemerging drugs,
particularly digoxin, may reduce hospitalizations. Despite this, optimizing the use of “older” therapies
is still warranted. Right heart pressures monitoring may provide novel insights into promptly
outpatient management. Unfortunately, randomized trials in the specific ADHF population are scarce.
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A novel paradigmatic approach is needed in order to suitably improve the currently poor prognosis of
ADHF. Both improving survival and reducing hospitalizations are, therefore, primordial therapy goals.
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Lastly, no single drug has consistently proved to improve survival in HF with preserved ejection
fraction (HFpEF); yet, some approaches may efficiently reduce hospitalizations. Awareness on
HFpEF management beyond the failing heart is imperative.
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Highlights
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- Identifying patients at risk for early readmission and timely plan discharge
- Emerging transitional hospital-to-home programs for postdischarge HF management
- Inpatient and outpatient management: older and novel approaches
- Early postdischarge outcomes in ADHF: which intervention to whom
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- The epidemic of comorbid conditions aggravating HF prognosis

Key Words

Acute Decompensated Heart Failure (ADHF); HFrEF; HFpEF; Post-Discharge Readmission and
Mortality; HF Management.

INTRODUCTION
Heart Failure (HF) is a worldwide prevalent debilitating syndrome and a leading cause of
hospitalization among the adult population. While the overall prevalence is estimated at 2%, HF
increases exponentially with age, affecting ≥10% of the elderly (≥65 years)1. Broadly speaking, one
could describe this disease as a “malignant condition” since its mortality rate exceeds those reported
in most cancer diseases.2,3 The median survival for those newly admitted with a HF is shortened and
the 10-year mortality rate is nearly 100%.4 Although clinical characteristics might include dyspnea,
congestion and fatigue following physical activity or at rest, one should also note that the HF
population is heterogeneous, broadly categorized into HF with a reduced ejection fraction (HFrEF)
and HF with a preserved EF (HFpEF).

Recent publications have determined that most rehospitalizations occur in the early postdischarge
period and the months preceding death4. Strikingly, the readmission rate may be as high as 15-25%
at 30-days.5,6 Early readmissions are mostly associated with volume overload, contrasting with later
readmissions, which seem to be the result of the natural history of this syndrome, i.e. progressive
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cardiac remodeling.7-10 As a consequence, the early postdischarge phase is a vulnerable period

when one could potentially intervene. Thus, we sought to review the precipitating factors for acute
decompensated HF (ADHF), the prognostic factors that predict higher rehospitalization, and the
interventions potentially influencing the early readmission and mortality rates. Updated guidelines
concerning HF and its treatment were also issued during the writing of this article. 11,12

ACUTE DECOMPENSATED HEART FAILURE (ADHF)

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Definition

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Acute HF syndromes (AHFS) is a broad term encompassing acute “unstable” presentations,
contrasting with chronic HF, which is said to be “stable”. Since AHFS vary in presentation and

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response to treatment, several subcategorizations have been proposed, including ADHF as a
separate entity. The proposed definition for ADHF is a sudden (“de novo”) or progressive (over a

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period of days or weeks) worsening HF, characterized by exacerbation of typical signs and
symptoms, often leading to hospitalization. Other forms of AHFS should be excluded.13-15

Furthermore, other designations, namely congestive HF (CHF), are still often used in the literature
and clinical practice, describing either acute or chronic HF with evidence of congestive signs.

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However, not all HF patients are congested, even during acute events.15 Also, one can use the terms
“wet” versus “dry” as a reference to the presence or absence of congestion, respectively, and “warm”
versus “cold” to distinguish patients adequately perfused from those who are not, respectively. 16
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Insights into transitioning from chronic compensated HF to ADHF have been brought by
outpatient implantable continuous hemodynamic monitoring studies.17,18 In the absence of primary
pulmonary conditions, an increase in estimated resting pulmonary artery diastolic pressure (ePAD)
seems to have a pivotal role in the underlying pathophysiology of acute decompensation,
independent of left ventricular ejection fraction (LVEF). On the other hand, patients without
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considerable changes in such pressure do not seem to be at increased risk for ADHF events.17,18
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Precipitating Factors

Patients with HF are susceptible to early hospital readmission. 4,6,19,20 Most patients are readmitted
due to cardiovascular (CV)-related causes. The leading mode of presentation is ADHF.21 A multi-
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center observational survey enrolling 1658 patients with AHFS showed that ADHF was the most
common scenario. In this subset, supraventricular arrhythmia (26.9%) and infection (25.3%) were the
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most prevalent precipitating factors for hospital admission, while ischemic events or hypertension
accounted for approximately 12% of admissions.21 An analysis of the Get With the Guidelines®–Heart
Failure (GWTG-HF) registry, including 54322 patients, has shown that non-adherence to either diet
or medication or both has been documented as the precipitating factor in >10% of the cases. 9
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Other frequent documented precipitants factors for ADHF include myocardial ischemia, worsening
renal function (WRF)9, overuse of over-the-counter drugs, such as nonsteroidal anti-inflammatory
drugs22, possibly dipeptidyl peptidase-4 inhibitors in type 2 diabetic patients23, and pulmonary
thromboembolism.24 Often, though, no main precipitant factor is identified or there are multiple
factors contributing to worsening HF7,9.

HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF)

Nowadays, approximately half of the HF population is diagnosed as having a preserved LVEF

(HFpEF) and this entity is increasingly documented.7,25,26 HFpEF patients are more often elderly,
women, hypertensive, and have multiple. Although the etiologic pathophysiological mechanisms
involved in HFrEF and HFpEF are distinctive25, those leading to ADHF in either situation seem to be
similar.

The cutoff to consider a reduced, preserved, or borderline LVEF is not completely established,
even though most observational studies and randomized controlled trials (RCTs) consider HFrEF
when LVEF<35-40% and HFpEF when LVEF>40-50%.13,14 Updated ESC guidelines (2016) have
now considered patients with a LVEF in the range 40-49% representative of a “grey area” currently
defined as mid-range EF (HFmrEF).11 Moreover, HFpEF with previous reduced ejection may
represent a different subset of patients15. Patients with HFpEF have a slightly better lifetime
prognosis compared to their HFrEF counterparts20,27 The early postdischarge mortality rate is higher
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amongst HFrEF. On the contrary, there seems to be no difference between HFrEF or HFpEF and
early postdischarge readmissions rates.28

Atrial Fibrillation (AF)

Permanent AF is the most common arrhythmia in HF, occurring approximately in one-third of the
population. Its prevalence is even higher among those with HFpEF and ADHF hospitalized patients,
in whom new-onset AF may have contributed to acute decompensation.7,29,30 AF increases with

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progressive symptomatic HF, occurring in <10% of patients who are NYHA functional class I and
approaches 50% for those who are NYHA class IV; in other words, HF begets AF.30,31 Notoriously,

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the rate of conversion from sinus rhythm (SR) to AF may be as high as 22% per year.32 AF patients
are a subset of the HF population, ergo responding differently to usual management. For instance,

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once AF is established, beta blockade may not reduce HF hospitalizations nor mortality, contrasting
with HF patients in SR.33 Finally, conversely, AF also begets HF.31

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IDENTIFYING PATIENTS AT HIGHER RISK FOR REHOSPITALIZATION
The identification of those who are more likely to be readmitted due to anew acute
decompensation is challenging. A recent hospitalization event is a sentinel risk factor for worse

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outcomes.34,35 An analysis of the CHARM program showed that patients with a previous HF
admission were more likely to be women, to have a more symptomatically advanced and of longer
duration HF, and to have higher rates of hypertension, diabetes mellitus, and AF.20
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Resting Heart Rate

Several studies (table I) have proposed resting heart rate as an easily measurable and potentially
modifiable factor associated with higher overall and CV risk.27,30,32,36-41 In another analysis of the
CHARM program, which included 7599 patients with symptomatic chronic HF and any LVEF, it was
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shown that for each 5 bpm increment in heart rate there was a significantly higher all-cause mortality
as well as HF hospitalization in any of the following situation: baseline heart rate (HR=1.03; CI:1.01-
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1.05; p=0.002; HR=1.04; CI:1.02-1.06; p<0.001, respectively); heart rate at any visit (HR=1.09;
CI:1.07-1.11; p<0.001; HR=1.07; CI: 1.05-1.09; p<0.001; respectively); and heart rate variation
(HR=1.09; CI:1.07-1.11; p<0.001; HR=1.06; CI: 1.04-1,08; p<0.001; respectively). These findings
were similar in patients either with reduced or preserved EF, independently of β-blocker usage and
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dosage at any time during the study.36

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A retrospective analysis of the GWTG-HF program registry, which included an older population
than the CHARM program, showed an association between discharge heart rate (expressed as HR
per 10 beats-per-minute increment) and major outcomes. Specifically, patients with a heart rate
≥75bpm in the first 30-days after discharge had a higher mortality (SR: HR=1.300; CI:1.219-1.386;
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p<0.0001; AF: HR=1.128; CI:1.165-1.294; p<0,0001) and all-cause readmission rates (SR:
HR=1.128; CI:1.1089-1.168; p<0.0001; AF: HR=1.107; CI:1.073-1,143; p<0.0001).37 Both the
aforementioned studies found a weaker statistical correlation for those who presented with AF. Other
studies, which enrolled either patients with HFrEF32 or HFpEF38 have found such an association only
for those in SR but not for those with AF.

Worsening Renal Function (WRF)

Renal function is known to be often adversely affected during the course of ADHF. WRF has
often been defined differently since any serum creatinine (SCr) elevation seems to be associated
with worse outcomes13,14, and no cutoff is clearly set. In the last cardio-renal syndromes consensus
conference, the authors suggest that WRF should be diagnosed according to the RIFLE-AKIN
criteria42.

Acute kidney injury (AKI) that develops during the course of ADHF (also termed WRF) has been
labelled as acute cardiorenal syndrome type I and its occurrence is linked to worse outcomes.42-46
WRF, defined in one study as an increased SCr level ≥0.3mg/dL and ≥25% over the baseline value
at admission, occurred in 23% of the patients and was associated with a higher readmission rate
within 1-year (HR=2.38; CI:1.68-2.95; p=0.002) and longer hospital length of stay (median 9 days
versus 4 days, p<0.05).43 WRF has also been linked to higher mortality rate in several studies 34,45,47,48
and meta-analysis; moreover WRF severity is linked to greater mortality.46,49
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Although WRF has often been associated with worse outcomes in ADHF, a prospective
observational study from Italy, including 599 patients, has hypothesized that WRF would only have
such prognostic value in the presence of congestion. The main finding was that patients with WRF
and no congestion had similar outcomes compared to those with no WRF and no congestion. Such
findings led the authors to conclude that isolated WRF (in the absence of congestion) should not
influence HF treatment nor hospital length of stay.45 Another study, including 762 patients, has also
found a strong correlation between WRF and persistent congestion, and added that most death

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events occurred in persistent but not transient WRF (peak SCr ≥0.3 mg/dL higher than admission
SCr, later decreasing during hospitalization), implying that transient WRF does not adversely affect

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clinical outcomes.47

A sub-analysis of the OPTIMIZE-HF registry, which included 47 647 HF patients, found that

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hyponatremia was associated with higher in-hospital mortality (6.0% vs 3.2%, p<0.0001) and 60-90
days follow-up mortality (12.4% vs 7.1%, p<0.0001), but no association was found between

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hyponatremia and higher readmission rate.50

Body Temperature

Lower body temperature has been linked to worse outcomes in HF.51,52 In an analysis of the

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EVEREST trial, including HFrEF congested patients, for every 1ºC decrease in body temperature at
randomization (within admission), the risk of adverse outcomes (CV death or HF hospitalization)
increased by 16% (HR=1.16; CI:1.04-1.28).51 Also, a retrospective study that included a small
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population (N=198) has suggested that a decreasing temperature relative to baseline temperature is
associated with rehospitalization risk within 180 days (OR=4.01; CI:1.63-10,2; p=0.003).52

Cardiac Biomarkers

In PRIMA study, which enrolled 345 ADHF patients, even though NT-proBNP-guided therapy
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compared to symptom-guided therapy after discharge led to HF medication intensification (p=0.006),

particularly diuretics (p=0.02), and predicted HF-related events when there was an increase above
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each individual optimum (HR=4.17; CI:2.84-6.13; p<0.001), it did not improve primary nor secondary
endpoints.53 The PRIMA II study is assessing whether NT-proBNP-guided therapy during hospital
admission has an impact on early postdischarge outcomes (NTR3279). Other potential cardiac
biomarkers (e.g., neprilysin)54 and their combinations continue to be actively sought, in order to
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increase prognostic accuracy to detect higher rates of events.55

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Predictive Models of Postdischarge Outcomes

In order to predict postdischarge outcomes more accurately, one can hypothetically combine
different key prognostic factors. Such predictive models in HF often point out age, renal function,
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previous HF hospitalization, and comorbidities (e.g., diabetes) consistently correlated with major
outcomes40,56-58. For instance, an analysis of the ASCEND-HF trial, including 7141 ADHF patients,
showed that a multivariate model using key prognostic factors was predictive of 30-day mortality or
HF rehospitalization. The model included age, blood urea nitrogen (BUN), creatinine, sodium, chronic
obstructive pulmonary disease, dyspnea, systolic blood pressure, elevated jugular venous pressure,
and HF hospitalization within 1 year before admission (c-index=0.72). Notably, adding BNP or NT-
proBNP to this model did not significantly affect its discriminatory capacity. 56 Another study found that
BUN at admission was the single most strongly associated prognostic factor for 180-day mortality;
yet most variables, including BUN, had a weaker correlation with nonfatal events.58

Discharge Planning

Clinical congestion at discharge is associated with worse early postdischarge outcomes.59,60

Recently, a post hoc analysis of the DOSE-AHF and CARRESS-HF has shown that a simple
clinically determined score (orthodema score, which includes the severity of orthopnea and
peripheral edema) identifies patients at higher risk. This study included 496 HF patients regardless of
LVEF, of which only 52% were orthodema free (score=0) at discharge. These patients had a lower
60-day rates of death, rehospitalization or unscheduled visits (50%) compared to those with low-
grade or high-grade orthodema (52% and 68%, respectively; p=0.038). Approximately two-thirds of
those discharged free of orthodema developed some degree of congestion at 60-days, i.e., 27%
regressed to low-grade orthodema and 38% regressed to high-grade orthodema (patients with
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elevated ePAD may even be higher)59 Even so, it should be noted that patients discharged without
congestion still experience alarmingly high readmission and mortality rates.60

A prospective observational study, including 720 patients, has documented cognitive impairment
in 23% of the HF population. A poor Mini-Cog performance was an independent predictor of the
composite outcome – time to death or rehospitalization (HR=1.90; CI:1.47-2,44; p<0.0001) – and
was the greatest predictor of risk for events in the present study.61 Whether cognitive impairment is

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related to higher individual risk that calls for the need for specific decisions (e.g., discharge to
hospital-to-home transitional interventions) is not yet known and should be ascertained in a RCT.

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NON-PHARMACOLOGICAL / NON-DEVICE INTERVENTIONS

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Pharmacological interventions are the mainstay of HF treatment. Nonetheless, novel targets are
troublesome and challenging to uncover such that drug development is both burdensome and takes

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several years to achieve market approval.62 Since available drug prescription and adherence are not
optimal7,63 and a handful of potential promising non-pharmacological therapies are emerging, interest
has been given to this approach. These include adherence to treatment and dosage optimization,
non-device telemonitoring, patient education, and transitional hospital-to-home care.

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Patient Education

A small case-control study (N=325) from Spain reported that readmission rates were significantly
higher within 180-days for patients with the following characteristics: no commitment to self-care
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management: no daily walk nor any daily physical activity; medical appointments skipping; failing to
take medication on scheduled time; to stop taking the medication; or failing to adhere to the
therapeutic regimen.64 A systematic review and meta-analysis, including 20 RCTs, showed that self-
management empowerment had a beneficial effect on both time to HF hospitalization or all-cause
death, and HF hospitalization alone (HR=0.80; CI:0.71-0.89; HR=0.80; CI:0.69-0,92; respectively).
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Self-management interventions were defined as those providing information to patients and at least
two of the following: self-monitoring; education; treatment adherence; physical activity; dietary intake;
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or smoke cessation.65

Transitional Hospital-To-Home Programs

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There is extensive literature supporting better outcomes with optimal pharmacological doses of
disease modifying therapy, specifically those proved in main RCTs.13,14 As a deduction, one would
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expect that interventions to improve treatment adherence and dose optimization would have a
positive impact on outcomes, crucial in those with more advanced disease. Unfortunately, since HF
severity is also linked to greater risk for other comorbidities 7,30,34, elderly patients and those with a
graver disease and who would potentially benefit the most are also less likely to be on optimal
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recommended therapy and optimal dosage prescriptions.30,66,67 Transitional programmes could

potentially permit safe interventions in the outpatient setting for such high risk patients.

A post-hoc analysis of a nurse-coordinated collaborative disease management showed that,

compared to usual care, the former was associated with an increase of beta-blocker prescription
(p<0.001), and target doses were more often achieved, both for angiotensin-converting enzyme
inhibitors and angiotensin receptor blockers (ACEI/ARB) (50% vs 25%; p<0.001) and beta-blockers
(39% vs 15%; p<0.001). Also, the former group had greater LVEF (+17% vs +14%; p=0.010) and
NYHA (-0.44 vs -0.22; p=0.002) improvement. Outstandingly, the magnitude of the changes in both
NYHA and LVEF were correlated to the magnitude of changes of mean ACEI/ARB and beta-blocker
equivalence doses between baseline and follow-up assessment at 18 months (p<0.05).68

A systematic review and meta-analysis of transitional programs has shown that home-visiting
programs reduced all-cause readmission [HR=0.75; CI:0.68-0.86; Number Needed to Treat (NNT)=9;
I2=0.0%] and HF-specific readmissions (HF=0.51; CI:0.31-0.82; NNT=7;) at 3-6 months. Also,
multidisciplinary-HF clinic also reduced all-cause readmission at 3-6 months (HR=0.70; CI:0.55-0.89;
NNT=8; I2=0,0%), but not HF-specific readmission, and reduced mortality at 3-6 months (HR=0.56;
CI:0.34-0.92; NNT=18; I2=0.0%). Lastly, structured telephone support reduced HF-specific
readmission at 3-6 months (HR=0.74; CI:0.61-0.90; NNT=14; I2=0,0%) but not all-cause
readmissions, and reduced mortality at 3-6 months (HR=0.74; CI:0.56-0.97; NNT=27; I2=0.0%). The
authors conclude that among transitional care, home-visiting programs and multidisciplinary clinic-
based interventions currently have the best evidence for reducing both all-cause readmission and
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mortality up to 6 months.69 Recently, a single-center hospital-to-home program, including a follow-up

visit within 7 days, has also been shown to significantly reduce costs and 30-day mortality compared
to usual care (both p<0.0001).70

We propose that identifying patients at higher risk and their management in potential evidence-
based transitional programs may increase the observed benefit. To our knowledge, no RCT has had
such design. Moreover, the number of ADHF patients is considerable in most referral hospitals and
available personnel for such interventions would not meet the demand, such that selection of those

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who would benefit the most is a reasonable allocation of resources.

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PHARMACOLOGICAL INTERVENTIONS

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The primordial goals of HF therapy are the following: mitigate symptoms and signs; prevent first
hospital admission and subsequent readmissions; and improve survival as well as quality of life.

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Since ADHF corresponds to worsening HF, the main goal is to compensate the patient, i.e. treat
volume overload and promote transition towards stabilization. On the other hand, the challenging
fundamental strategy in chronic HF is to maintain stability and avoid decompensation (figure I).13,14

Inpatient Management

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Diuretics

Acute decongestion is mainly obtained with inpatient diuretic therapy. Generally, loop diuretics
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are used at a dose equal or superior to that of the patient’s oral daily dose, often bridging from
intravenous to oral regimens as decongestion resumes.14,15 As for different diuretic regimens, no
single strategy has shown to be more advantageous or safer.71,72 Although these strategies are
recurrently unavoidable in congestion, large trials comparing different loop diuretics and different
diuretic strategies are lacking.
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Ultrafiltration
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Aside from diuretic treatment, ultrafiltration (UF) has been debated as a decongestion modality.
The following discussed trials (table II) compared UF to usual diuretic therapy during ADHF
admission. An analysis of the UNLOAD trial, enrolling 200 patients, showed that UF was superior
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compared to either regimen of diuretic therapy, reducing rehospitalization plus unscheduled visits at
90-days, despite similar fluid losses and no differences in SCr. 73 The CARRESS-HF enrolled 188
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ADHF patients with WRF and did not demonstrate any differences in efficacy outcomes. Actually, UF
was related to higher adverse events over a 60-day period (72% vs 57%; p=0.03).74 Since UF was
used as a rescue therapy in patients already having impaired renal function, some argue that this
accounts for the different results. The much awaited AVOID-HF, who could potentially clarify such
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disparities, was unfortunately underpowered (N=224) due to early termination by the sponsor. Even
so, similar in design to UNLOAD, UF only trended toward a longer time to first HF event within 90
days, even though patients experienced more adverse effects (p=0.018).75

A possible interpretation from the discussed results is that UF may be beneficial as an early
therapy in congestive HF but not as a rescue therapy in those with WRF. Yet, it is recommended and
mostly used as an alternative in patients presenting refractory congestion.

Disease-Modifying Drugs

Pharmacological therapy increasing survival in HFrEF includes renin-angiotensin-aldosterone

system (RAAS) inhibitors, beta blockers (i.e. bisoprolol, carvedilol, and metoprolol succinate), and
mineralocorticoid antagonists (MRAs). No single drug has consistently proved to reduce mortality in
HFpEF.

During admission, as the patient is managed towards stabilization, disease-modifying drugs

should be introduced, uptitrated as tolerated. A post hoc analysis of COMET trial, enrolling 3029
patients, has shown that patients whose beta blocker was reduced or stopped during ADHF
admission were at significant risk for death compared to their counterparts, whose beta blocker dose
was maintained (HR=1.51; CI:1.22-1,89; p<0.001). Even though bias is possible, the correlation was
significantly maintained in the multivariate analysis.35

Outpatient Management
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Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors

WRF worsens prognosis in HF, both during admission and in outpatient setting. A systematic
review and meta-analysis enrolling >20 000 patients has shown that, even though WRF was
associated with increased all-cause mortality, such finding was less prominent, compared to placebo,
in those taking RAAS inhibitors [Rate Ratio (RR)=1.52; CI:1.37-1.69; p<0.00001]. These
pharmacological therapies not only significantly reduced mortality but also reduced HF
hospitalizations. The authors conclude that clinicians should not avert using RAAS inhibitors,

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especially in the presence of WRF.49

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Although WRF does occur more often upon RAAS inhibition42,76, its prognostic significance is
frequently debated. A post-hoc analysis of the HEAAL trial, which enrolled 3843 patients with stable

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chronic HFrEF, has shown that, compared to 50mg, an optimal 150 mg daily dose of losartan
improved significantly the outcomes. Particularly, it reduced the composite outcome of deaths or HF

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hospitalizations (HR=0.85; CI:0.77-0.93; p<0.0001). While WRF was more frequent with a higher
dose (50% vs 34%; p<0.0001), early WRF (defined as an increase in SCr > 0,3mg/dL within 4
months of randomization) was not associated with an increased risk for composite outcome.76
Therefore, high dose is as safe as low dose losartan and improves survival free of hospitalization.

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However, this trial enrolled a stable population, which means that no conclusion can be taken
regarding the optimal timing for drug titration and whether or not this is a safe approach during
ADHF.
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Mineralocorticoid Receptor Antagonists (MRAs)

MRAs (spironolactone and eplerenone) are currently recommended in patients with HFrEF
(LVEF≤35%) who remain symptomatic despite optimal medical treatment. 13,14 Although
recommended, MRAs prescription is low and decreases overtime after hospital discharge.7,77 A post
hoc analysis of the COACH study, which analyzed spironolactone intake in 534 ADHF patients with
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any LVEF, has shown that this drug reduced 30-day mortality or HF hospitalization (HR=0.45;
CI:0.24-0,83; p=0.011).78 A post hoc analysis of the EMPHASIS-HF study, which enrolled 2737
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patients with HFrEF, has shown that, even though both hyperkalemia and WRF were more frequent
amongst those in active intervention arm, careful titration of eplerenone still maintained its significant
efficacy in reducing death and/or hospitalizations. Also, this study documented worse prognosis only
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when hyperkalemia was defined as [K+] above 5,5mEq/L.79 In summary, when kidney function and
electrolytes are closely monitored, MRAs may have a benefit in the early postdischarge outcomes.
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Transitional hospital-to-home care could facilitate such monitoring.

As for HFpEF, the TOPCAT trial was a prospective double-blind RCT comparing spironolactone
to placebo in patients who had LVEF≥45% and a HF hospitalization within 1 year. The composite
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primary outcome did not reach statistical significance, even though there was a reduction in HF
hospitalizations in the active intervention arm compared to placebo (HR=0.83; CI:0.69-0,99; p=0,04)
as well as repeated HF hospitalizations (p=0.03).80 This international trial did denote marked regional
differences. Whether there were methodological or population discrepancies remains an open
question.

At last, the novel MRA, finerenone, was as safe as spironolactone in ARTS-HF Japan.81 The
results of the international ARTS-HF are yet to be published (NCT01807221), although they seem
promising.

Digoxin

A recent systematic review and meta-analysis, including mostly HFrEF patients, has shown that,
when moderate studies were considered, compared to placebo, digoxin did not increase mortality in
HF patients either with SR or AF. Moreover, digoxin was associated with a small but significant
reduction in all-cause hospital admission (RR=0.92; CI:0.89-0,95; p<0.001).82 A post hoc analysis of
the main DIG trial, enrolling 6800 HFrEF patients with SR, has shown that digoxin, in comparison to
placebo, significantly reduced 30-day all-cause readmission, as well as CV and HF hospitalization in
the same period (HR=0.66; CI:0.51-0,86; p=0,002; HR=0.53; CI:0.38-0.72; p<0.001; HR=0,40;
CI:0.26-0.62; p<0,001; respectively).83 In addition, such effect may be still observed after 2 years
taking digoxin.84 Conversely, a post hoc analysis of the ancillary DIG trial, enrolling 988 HFpEF
patients with SR, has documented an increased risk of 30-day all-cause readmission rate in those
taking digoxin compared to placebo (HR=2.46; CI:1.25-4.83; p=0.026).85 In summary, even though
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controversial, digoxin may have slight benefit in HFrEF care even in the absence of a mortality
benefit (figure II) but should be avoided in HFpEF.

Ivabradine

The pure heart rate-slowing agent ivabradine acts by selectively blocking the opened I F current,
slowing the firing rate of sinus node pacemaker cells. The main ivabradine study, SHIFT trial (table
III), enrolled 6558 patients with symptomatic HFrEF, SR and a heart rate of at least 70 bpm, admitted

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for HF within the previous year. Compared to placebo, patients taking ivabradine had a reduced
likelihood of CV death or HF hospitalization (HR=0.82; CI:0.75-0,90; p<0.0001). This effect was

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mainly driven by reduction of hospital admissions for worsening HF (HR=0.74; CI:0.66-0.83;
p<0.0001) and deaths due to HF (HR=0.74; CI:0.58-0.94; p=0.014). Interestingly, the treatment

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seemed to only have an effect on patients whose baseline heart rate was higher than 77 bpm.86 A
subsequent analysis of the SHIFT trial on recurrent hospitalizations, has strengthened ivabradine’s

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benefit on reducing HF hospitalization. Not only this intervention reduced recurrent HF
hospitalizations but also decrease risk of a second and third additional admissions.87

Two other analysis of SHIFT trial have concluded importantly that the effect of ivabradine was
independent of beta blockade.88 and that this intervention mainly reduced events due to heart rate

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reduction. In addition, patients presenting with higher heart rates at baseline had the greatest
reduction in both heart rate and primary composite endpoint41, gaining the most benefit from such
intervention.
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LCZ696 (Sacubitril/Valsartan)

ACEI are currently the cornerstone of HF treatment.13,14 A novel treatment, LCZ696

(sacubitril/valsartan), has shown great promise to change HF’s poor outcomes as we know it. The
original PARADIGM-HF trial, an international double-blind RCT enrolling 8442 symptomatic HFrEF
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patients (LVEF≤35%), NYHA classes II-IV, compared LCZ696 (200mg bid) to enalapril (10mg bid).
The novel drug reduced all adverse outcomes: composite outcome of CV death or HF hospitalization
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(HR=0.80; CI:0.73-0.87; p<0.001); CV death (HR=0.80; CI:0.71-0,89; p<0.001); HF hospitalization

(HR=0.79; CI:0.71-0.89; p<0.001); and death from any cause (HR=0.84; CI:0.76-0.93; p<0.001).
Patients taking LCZ696 had a 21% reduction in HF hospitalization. LCZ696 was as safe as enalapril
and fewer patients discontinued the former drug, both in the run-in phase and the follow-up phase of
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the trial, due to intolerance or adverse effects (p=0.03; p<0.001; respectively).89,90 Also, when repeat
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events were included, significantly fewer patients on LCZ696 arm were hospitalized for HF, CV
causes, and any cause (p<0.001).91

On the subject of LCZ696 in HFpEF patients, the PARAMOUNT study, a phase-2 trial, has
suggested a potential benefit of LCZ696, which significantly reduced NT-proBNP to a greater extent
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than valsartan at 12 weeks (but not at 36 weeks).92 The role of this therapy in such patients is
currently being studied in a larger phase 3 prospective RCT, the PARAGON-HF trial, which will
compare LCZ696 to valsartan (NCT01920711). Therapeutic targets to reduce mortality in those with
HFpEF continue to be actively sought.13,14

Despite the available drugs and eventual novel targets, disease modifying therapy prescription
and adherence is far from optimal. For instance, a survey showed that, at discharge, HFrEF patients
were not prescribed a RAAS blocker in nearly 25% of the cases, one-third had no beta-blocker, and
only one-fourth had a prescription for aldosterone antagonists.21 Optimization to recommended target
dose is also problematic.63

DEVICE THERAPY
Extension of indications for cardioverter defibrillator (ICD) and cardiac resynchronization therapy
(CRT) and selection of patients who benefit the most from such therapies is actively sought.93
Recently, the adaptive CRT device, which automatically adjusts atrioventricular and interventricular
delays, not only has shown safety but also reduced 30-day HF hospitalization readmission rate in
comparison to echocardiography guided adjustment. (19.1% vs 35.7%; OR=0.41; CI:0.19-0.86;
p=0.02).94

Other devices, either isolated or coupled with ICD/CRT-(D), may have a role in the future
management of selected patients. Particularly, pulmonary artery pressure (PAP) and intrathoracic
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impedance monitoring devices have been investigated. CHAMPION trial was a prospective RCT
enrolling 550 patients with HF and NYHA functional class III, regardless of LVEF, randomizing
patients to either PAP guided-therapy or symptom-guided. At 13 months, compared to placebo, there
was a significant 33% and 16% reduction in both HF and all-cause hospitalizations in the intervention
group, respectively (HR=0.67; CI:0.55-0.80; p<0.0001; NNT=4; and HR=0.44; CI:0.75-0.95;
p=0.0032; NNT=4; respectively). The follow-up study not only documented sustained efficacy in the
original randomized group but also, during open access, a significant reduction of the likelihood of

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the aforementioned outcomes in the original placebo group (who started receiving intervention during
follow-up), in a similar magnitude fashion.95 Two subsequent analysis of CHAMPION trial have a

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similar hospitalization reduction for both HFpEF and HFrEF96, either in the presence or absence of
comorbid chronic obstructive pulmonary disease (COPD). The latter analysis also documented a
62% reduction in respiratory hospitalizations only for those with comorbid COPD (HR=0.38; CI:0.21-

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0.71; p=0.0023).97

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COMORBIDITIES IN HEART FAILURE PATIENTS
Alarmingly, more than half of the HF population has more than two chronic comorbidities, and
most have at least one comorbidity.30,98 Comorbidities are particularly high among those with HFpEF,

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complicate HF treatment, and, broadly speaking, are harbingers of poor prognosis.14,98 Most
comorbidities may have a contributory or even a primary role in HF etiopathogenesis. In addition,
most risk factors for HF may also worsen once HF resumes.
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A prospective observational study, including 5118 HF patients, has documented that chronic
kidney disease (CKD) (41%), anemia (29%), and diabetes (29%) were the most prevalent
comorbidities. Intriguingly, even though patients with higher number of comorbidities had both
increased risk of mortality and HF hospitalizations, only CKD, anemia, and diabetes were associated
with these outcomes on multivariate analysis. Hypothyroidism, but not hyperthyroidism, was also
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associated with increased risk of HF hospitalization (HR=1.46; CI:1.06-2.01; p=0.0211).30

The double-blinded FAIR-HF trial enrolled 459 patients with chronic HFrEF and NYHA functional
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classes II-III. Half the patients taking intravenous ferric carboxymaltose reported being much or
moderately improvement in comparison to 28% of those receiving placebo (OR=2.51; CI:1.75-3.61;
p<0.001). Moreover, at week 24, there were more patients in lower NYHA functional classes in the
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active arm compared to placebo (p<0.001).99 Although FAIR-HF only showed a trend towards
reduction of first hospitalization for any CV cause, CONFIRM-HF trial has shown that ferric
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carboxymaltose kept its benefits over a period of 1-year and reduced risk of hospitalizations for
worsening HF compared to placebo (HR=0.39; CI:0.19-0.82; p=0.009).100 Currently, IRONOUT trial
(NCT02188784) is testing the hypothesis of a friendly approach with oral iron repletion in such iron
depleted patients. Contrasting with the previous trials, studies with erythropoietin analogues have
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been disappointing.101

FUTURE PERSPECTIVES
Acute decompensations are not all the same. We focused on ADHF, including a myriad of
precipitating factors and congested presentation, but this represents only a portion of AHFS. Either
way, acuteness in chronic morbid conditions needs to be addressed by multiple professionals,
beyond the hospital setting. Acute specialized care is not equal to hospital admission and HF
readmissions is not only a patient-centered issue but also a hazard of healthcare planning. Carefully
coordinated transitional programs, involving trained nurses and pharmacists, caregivers and family,
as well as primary care physicians and community resources, are clearly promising approaches.
Decentralization in favor of HF clinics and dedicated primary care institutions can additionally pose
as possible options.
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APPENDIX: TABLES

Study ID, Readmissions,

N Population Study Design Rhythm
Year Mortality

Analysis of an RCT: Higher risk as heart

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CHARM36, Chronic HF; SR=5516
N=7599 Candesartan vs rate increases; weaker
2015 any LVEF AF=2083
Placebo correlation in AF

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Higher risk as
Retrospective
GWTG-HF37, ADHF; SR=20020 discharge heart rate

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N=46217 analysis of a
2015 any LVEF AF=20197 increases; weaker
prospective cohort
correlation in AF

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Retrospective Higher risk as heart
Cullington et Chronic HF; SR=1551
N=2039 analysis of a rate increases in SR
al.32, 2014 HFrEF AF=488
prospective cohort but not in AF patients

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Analysis of an RCT: Higher risk as heart
I-PRESERVE38, Chronic HF; SR=3271
N=3967 Irbesartan vs rate increases in SR
2014 HFpEF AF=696
Placebo but not in AF patients
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HFrEF: higher risk for
DIG27, Chronic HF, Analysis of an RCT: SR=7780 all outcomes
N=7780
2012 Any LVEF Digoxin vs Placebo AF=0 HFpEF: higher HF
readmission rate

Analysis of an RCT: No association found in

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TIME-CHF39, Chronic HF; SR=327

N=327 BNP vs symptom- patients aged 75 years
2015 any LVEF AF=0
guided therapy or older.
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Table I: illustrative studies demonstrating an increased admission and/or mortality risk with increasing heart rate;
ADHF: acute decompensated heart failure; AF: atrial fibrillation; HF: heart failure; HFpEF: heart failure with
preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; LVEF: left ventricular ejection
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fraction; RCT: randomized controlled trial; SR: sinus rhythm.

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Study ID, Population Readmissions,

N Weight Loss, Symptoms Safety
Year Design Mortality

UF group had significantly UF reduced 90-day

ADHF patients
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UNLOAD73, more weight loss than bolus rehospitalizations and No

N=200 randomized to
2010 furosemide; no differences unscheduled visits; no difference
UF or usual care
in dyspnea score differences in mortality

ADHF plus WRF Greater

CARRESS74, patients increase
N=188 No difference No difference
2012 randomized to in SCr for
UF or usual care UF group

ADHF patients
with ≥4Kg UF was associated
CUORE102, estimated No difference; with lower 1-year
N=56 N/A
2014 weight gain N/A rehospitalization; no
randomized to differences in mortality
UF or usual care

Trending towards
ADHF patients
AVOID-HF75, longer time to first HF No
N=224 randomized to No difference
2015 hospitalization within difference
UF or usual care
90-days (p=0.06)
Table II: main studies comparing ultrafiltration to drug therapy (loop diuretics) strategy in acute decompensated
heart failure; ADHF: acute decompensated heart failure; N/A: Not Available; SCr: serum creatinine; UF:
ultrafiltration; WRF: worsening renal function.
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Study ID, Population

N Outcomes of Interest Statistical Analysis
Year Design

Primary Event HR=0.82; CI:0.75-0.90; p<0.0001

SHIFT, All-Cause Admissions HR=0.89; CI:0.82-0.96; p<0.003
2010 The SHIFT trial was a HF Admission HR=0.74; CI:0.66-0.83; p<0.0001

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double-blind HF Deaths HR=0.74; CI:0.58-0.94; p=0.014
international RCT

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enrolling patients with Total HF admissions RR=0.75; CI:0.68-0,87; p=0.0002
Borer et symptomatic HF and Second HF admission HR=0.66; CI:0.55-0.79; p=0.001
al., 2012 LVEF ≤35%. Patients Third HF admission HR=0.71; CI:0.54-0.93; p=0.012

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N=6505 in SR with a heart rate
of at least 70 bpm, NNT to prevent one

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Rogers et admitted to hospital for first HF hospitalization NNT=27
al., 2015103 HF within the previous NNT to prevent one NNT=37
year were randomized first any hospitalization
to either ivabradine or
Primary endpoint

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Böhm et placebo.
(heart rate <60 bpm vs HR=0.69; CI:0.58-0.83; p<0.0001
al., 2010
>60bpm at 28 days)
Table III: SHIFT trial and main analysis of its population; Bpm: beats per minute; CI: confidence interval; HR: hazard
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ratio; LVEF: left ventricular ejection fraction; NNT: numbers needed to treat; RCT: randomized controlled trial; RR:
risk ratio; SR: sinus rhythm.
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APPENDIX: FIGURES

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Figure I: HF algorithmic treatment. Consider angiotensin receptor antagonists when angiotensin-converting enzyme
inhibitors are not tolerated; ACEi: angiotensin-converting enzyme inhibitor; ACS: acute coronary syndrome; ADHF: acute
decompensated heart failure; AHFS: acute heart failure syndrome; BB: beta blocker; CRT: cardiac resynchronization
therapy; HF: heart failure; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection
fraction; NYHA: New York heart association; NYHA: New York heart association; SR: sinus rhythm.
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Ivabradine Digoxin LCZ696 Hydralazine/Nitrate

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A-Heft104
SHIFT86 Main DIG trial83 PARADIGM-HF89
Study Hydralazine/Nitrate vs
Ivabradine vs Placebo Digoxin vs Placebo *LCZ696 vs Enalapril
Placebo

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Chronic HFrEF, SR, Self-identified blacks,
Chronic HFrEF, SR, Chronic HFrEF,
Population heart rate≥70bpm, Chronic HFrEF, NYHA
NYHA I-IV NYHA II-IV
NYHA II-IV III-IV

N 6558 6800 8442 1050

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Outcome Median follow-up 30-days after Median follow-up Median follow-up
measurement (22.9 months) randomization (27 months) (15 months)
Figure II: HF hospitalization rate reduction; HFrEF: heart failure with reduced ejection fraction; NYHA: New York heart
association; SR: sinus rhythm
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REFERENCES
1. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93(9):1137-1146.
2. Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJ. More 'malignant' than cancer? Five-
year survival following a first admission for heart failure. Eur J Heart Fail. 2001;3(3):315-322.

T
3. Stewart S, Ekman I, Ekman T, Odén A, Rosengren A. Population impact of heart failure and the
most common forms of cancer: a study of 1 162 309 hospital cases in Sweden (1988 to 2004).

IP
Circ Cardiovasc Qual Outcomes. 2010;3(6):573-580.
4. Chun S, Tu JV, Wijeysundera HC, et al. Lifetime analysis of hospitalizations and survival of
patients newly admitted with heart failure. Circ Heart Fail. 2012;5(4):414-421.

R
5. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after
hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA.

SC
2013;309(4):355-363.
6. O'Connor CM, Miller AB, Blair JE, et al. Causes of death and rehospitalization in patients
hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results

NU
from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan
(EVEREST) program. Am Heart J. 2010;159(5):841-849.e841.
7. Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic burden of
hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am
MA
Coll Cardiol. 2014;63(12):1123-1133.
8. Gheorghiade M, Filippatos G, De Luca L, Burnett J. Congestion in acute heart failure syndromes:
an essential target of evaluation and treatment. Am J Med. 2006;119(12 Suppl 1):S3-S10.
9. Ambardekar AV, Fonarow GC, Hernandez AF, et al. Characteristics and in-hospital outcomes for
nonadherent patients with heart failure: findings from Get With The Guidelines-Heart Failure
D

(GWTG-HF). Am Heart J. 2009;158(4):644-652.

10. Desai AS, Stevenson LW. Rehospitalization for heart failure: predict or prevent? Circulation.
TE

2012;126(4):501-506.
11. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of
acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and
P

chronic heart failure of the European Society of Cardiology (ESC)Developed with the special
contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016.
CE

12. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Focused Update on New
Pharmacological Therapy for Heart Failure: an Update of the 2013 ACCF/AHA Guideline for the
Management of Heart Failure: A Report of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
AC

J Card Fail. 2016.

13. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart
failure: a report of the American College of Cardiology Foundation/American Heart Association
Task Force on practice guidelines. Circulation. 2013;128(16):e240-327.
14. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment
of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of
Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in
collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J.
2012;33(14):1787-1847.
15. Weintraub NL, Collins SP, Pang PS, et al. Acute heart failure syndromes: emergency department
presentation, treatment, and disposition: current approaches and future aims: a scientific
statement from the American Heart Association. Circulation. 2010;122(19):1975-1996.
16. Thomas SS, Nohria A. Hemodynamic classifications of acute heart failure and their clinical
application: – an update –. Circ J. 2012;76(2):278-286.
17. Zile MR, Bennett TD, St John Sutton M, et al. Transition from chronic compensated to acute
decompensated heart failure: pathophysiological insights obtained from continuous monitoring
of intracardiac pressures. Circulation. 2008;118(14):1433-1441.
18. Stevenson LW, Zile M, Bennett TD, et al. Chronic ambulatory intracardiac pressures and future
heart failure events. Circ Heart Fail. 2010;3(5):580-587.
 ACCEPTED MANUSCRIPT

19. Dharmarajan K, Hsieh AF, Kulkarni VT, et al. Trajectories of risk after hospitalization for heart
failure, acute myocardial infarction, or pneumonia: retrospective cohort study. BMJ.
2015;350:h411.
20. Bello NA, Claggett B, Desai AS, et al. Influence of previous heart failure hospitalization on
cardiovascular events in patients with reduced and preserved ejection fraction. Circ Heart Fail.
2014;7(4):590-595.
21. Logeart D, Isnard R, Resche-Rigon M, et al. Current aspects of the spectrum of acute heart

T
failure syndromes in a real-life setting: the OFICA study. Eur J Heart Fail. 2013;15(4):465-476.
22. Feenstra J, Heerdink ER, Grobbee DE, Stricker BH. Association of nonsteroidal anti-

IP
inflammatory drugs with first occurrence of heart failure and with relapsing heart failure: the
Rotterdam Study. Arch Intern Med. 2002;162(3):265-270.

R
23. Li L, Li S, Deng K, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2
diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ.

SC
2016;352:i610.
24. Piazza G, Goldhaber SZ. Pulmonary embolism in heart failure. Circulation. 2008;118(15):1598-
1601.
25. Sharma K, Kass DA. Heart failure with preserved ejection fraction: mechanisms, clinical

NU
features, and therapies. Circ Res. 2014;115(1):79-96.
26. Silva-Cardoso J, Zharinov OJ, Ponikowski P, et al. Heart failure in patients with atrial fibrillation
is associated with a high symptom and hospitalization burden: the RealiseAF survey. Clin
Cardiol. 2013;36(12):766-774.
MA
27. Maeder MT, Kaye DM. Differential impact of heart rate and blood pressure on outcome in
patients with heart failure with reduced versus preserved left ventricular ejection fraction. Int J
Cardiol. 2012;155(2):249-256.
28. Nichols GA, Reynolds K, Kimes TM, Rosales AG, Chan WW. Comparison of Risk of Re-
D

hospitalization, All-Cause Mortality, and Medical Care Resource Utilization in Patients With
Heart Failure and Preserved Versus Reduced Ejection Fraction. Am J Cardiol. 2015;116(7):1088-
TE

1092.
29. Mendes FeS, Atié J, Garcia MI, et al. Atrial fibrillation in decompensated heart failure:
associated factors and in-hospital outcome. Arq Bras Cardiol. 2014;103(4):315-322.
30. van Deursen VM, Urso R, Laroche C, et al. Co-morbidities in patients with heart failure: an
P

analysis of the European Heart Failure Pilot Survey. Eur J Heart Fail. 2014;16(1):103-111.
31. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology,
CE

and rationale for therapy. Am J Cardiol. 2003;91(6A):2D-8D.

32. Cullington D, Goode KM, Zhang J, Cleland JG, Clark AL. Is heart rate important for patients with
heart failure in atrial fibrillation? JACC Heart Fail. 2014;2(3):213-220.
AC

33. Rienstra M, Damman K, Mulder BA, Van Gelder IC, McMurray JJ, Van Veldhuisen DJ. Beta-
blockers and outcome in heart failure and atrial fibrillation: a meta-analysis. JACC Heart Fail.
2013;1(1):21-28.
34. Tavazzi L, Senni M, Metra M, et al. Multicenter prospective observational study on acute and
chronic heart failure: one-year follow-up results of IN-HF (Italian Network on Heart Failure)
outcome registry. Circ Heart Fail. 2013;6(3):473-481.
35. Metra M, Torp-Pedersen C, Cleland JG, et al. Should beta-blocker therapy be reduced or
withdrawn after an episode of decompensated heart failure? Results from COMET. Eur J Heart
Fail. 2007;9(9):901-909.
36. Vazir A, Claggett B, Jhund P, et al. Prognostic importance of temporal changes in resting heart
rate in heart failure patients: an analysis of the CHARM program. Eur Heart J. 2015;36(11):669-
675.
37. Laskey WK, Alomari I, Cox M, et al. Heart rate at hospital discharge in patients with heart failure
is associated with mortality and rehospitalization. J Am Heart Assoc. 2015;4(4).
38. Böhm M, Perez AC, Jhund PS, et al. Relationship between heart rate and mortality and
morbidity in the irbesartan patients with heart failure and preserved systolic function trial (I-
Preserve). Eur J Heart Fail. 2014;16(7):778-787.
39. Zurek M, Maeder MT, Rickli H, et al. Differential prognostic impact of resting heart rate in older
compared with younger patients with chronic heart failure--insights from TIME-CHF. J Card Fail.
2015;21(4):347-354.
 ACCEPTED MANUSCRIPT

40. Kaneko H, Suzuki S, Goto M, et al. Incidence and predictors of rehospitalization of acute heart
failure patients. Int Heart J. 2015;56(2):219-225.
41. Böhm M, Swedberg K, Komajda M, et al. Heart rate as a risk factor in chronic heart failure
(SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled
trial. Lancet. 2010;376(9744):886-894.
42. Ronco C, McCullough P, Anker SD, et al. Cardio-renal syndromes: report from the consensus
conference of the acute dialysis quality initiative. Eur Heart J. 2010;31(6):703-711.

T
43. Belziti CA, Bagnati R, Ledesma P, Vulcano N, Fernández S. Worsening renal function in patients
admitted with acute decompensated heart failure: incidence, risk factors and prognostic

IP
implications. Rev Esp Cardiol. 2010;63(3):294-302.
44. Komukai K, Ogawa T, Yagi H, et al. Decreased renal function as an independent predictor of re-

R
hospitalization for congestive heart failure. Circ J. 2008;72(7):1152-1157.
45. Metra M, Davison B, Bettari L, et al. Is worsening renal function an ominous prognostic sign in

SC
patients with acute heart failure? The role of congestion and its interaction with renal function.
Circ Heart Fail. 2012;5(1):54-62.
46. Damman K, Navis G, Voors AA, et al. Worsening renal function and prognosis in heart failure:
systematic review and meta-analysis. J Card Fail. 2007;13(8):599-608.

NU
47. Wattad M, Darawsha W, Solomonica A, et al. Interaction between worsening renal function and
persistent congestion in acute decompensated heart failure. Am J Cardiol. 2015;115(7):932-
937.
48. Fonarow GC, Abraham WT, Albert NM, et al. Factors identified as precipitating hospital
MA
admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF. Arch Intern
Med. 2008;168(8):847-854.
49. Clark H, Krum H, Hopper I. Worsening renal function during renin-angiotensin-aldosterone
system inhibitor initiation and long-term outcomes in patients with left ventricular systolic
D

dysfunction. Eur J Heart Fail. 2014;16(1):41-48.

50. Gheorghiade M, Abraham WT, Albert NM, et al. Relationship between admission serum sodium
TE

concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from
the OPTIMIZE-HF registry. Eur Heart J. 2007;28(8):980-988.
51. Payvar S, Spertus JA, Miller AB, et al. Association of low body temperature and poor outcomes
in patients admitted with worsening heart failure: a substudy of the Efficacy of Vasopressin
P

Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial. Eur J Heart Fail.
2013;15(12):1382-1389.
CE

52. Ahmed A, Aboshady I, Munir SM, et al. Decreasing body temperature predicts early
rehospitalization in congestive heart failure. J Card Fail. 2008;14(6):489-496.
53. Eurlings LW, van Pol PE, Kok WE, et al. Management of chronic heart failure guided by
AC

individual N-terminal pro-B-type natriuretic peptide targets: results of the PRIMA (Can PRo-
brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure
morbidity and mortality?) study. J Am Coll Cardiol. 2010;56(25):2090-2100.
54. Bayés-Genís A, Barallat J, Galán A, et al. Soluble neprilysin is predictive of cardiovascular death
and heart failure hospitalization in heart failure patients. J Am Coll Cardiol. 2015;65(7):657-665.
55. Jungbauer CG, Riedlinger J, Block D, et al. Panel of emerging cardiac biomarkers contributes for
prognosis rather than diagnosis in chronic heart failure. Biomark Med. 2014;8(6):777-789.
56. Khazanie P, Heizer GM, Hasselblad V, et al. Predictors of clinical outcomes in acute
decompensated heart failure: Acute Study of Clinical Effectiveness of Nesiritide in
Decompensated Heart Failure outcome models. Am Heart J. 2015;170(2):290-297.
57. Eurlings LW, Sanders-van Wijk S, van Kraaij DJ, et al. Risk stratification with the use of serial N-
terminal pro-B-type natriuretic peptide measurements during admission and early after
discharge in heart failure patients: post hoc analysis of the PRIMA study. J Card Fail.
2014;20(12):881-890.
58. Cleland JG, Chiswell K, Teerlink JR, et al. Predictors of postdischarge outcomes from
information acquired shortly after admission for acute heart failure: a report from the Placebo-
Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for
Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess
Treatment Effect on Congestion and Renal Function (PROTECT) Study. Circ Heart Fail.
2014;7(1):76-87.
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59. Lala A, McNulty SE, Mentz RJ, et al. Relief and Recurrence of Congestion During and After
Hospitalization for Acute Heart Failure: Insights From Diuretic Optimization Strategy Evaluation
in Acute Decompensated Heart Failure (DOSE-AHF) and Cardiorenal Rescue Study in Acute
Decompensated Heart Failure (CARESS-HF). Circ Heart Fail. 2015;8(4):741-748.
60. Ambrosy AP, Pang PS, Khan S, et al. Clinical course and predictive value of congestion during
hospitalization in patients admitted for worsening signs and symptoms of heart failure with
reduced ejection fraction: findings from the EVEREST trial. Eur Heart J. 2013;34(11):835-843.

T
61. Patel A, Parikh R, Howell EH, Hsich E, Landers SH, Gorodeski EZ. Mini-cog performance: novel
marker of post discharge risk among patients hospitalized for heart failure. Circ Heart Fail.

IP
2015;8(1):8-16.
62. Sacks CA, Jarcho JA, Curfman GD. Paradigm shifts in heart-failure therapy--a timeline. N Engl J

R
Med. 2014;371(11):989-991.
63. Moran D, Buckley A, Daly K, et al. Heart rate awareness in patients with chronic stable heart

SC
failure. A multi-center observational study. Int J Cardiol. 2014;177(2):380-384.
64. Rodríguez Artalejo F, Guallar-Castillón P, Montoto Otero C, et al. [Self-care behavior and
patients' knowledge about self-care predict rehospitalization among older adults with heart
failure]. Rev Clin Esp. 2008;208(6):269-275.

NU
65. Jonkman NH, Westland H, Groenwold RH, et al. Do Self-Management Interventions Work in
Patients With Heart Failure? An Individual Patient Data Meta-Analysis. Circulation.
2016;133(12):1189-1198.
66. Yancy CW, Fonarow GC, Albert NM, et al. Influence of patient age and sex on delivery of
MA
guideline-recommended heart failure care in the outpatient cardiology practice setting:
findings from IMPROVE HF. Am Heart J. 2009;157(4):754-762.e752.
67. Sanders-van Wijk S, Maeder MT, Nietlispach F, et al. Long-term results of intensified, N-
terminal-pro-B-type natriuretic peptide-guided versus symptom-guided treatment in elderly
D

patients with heart failure: five-year follow-up from TIME-CHF. Circ Heart Fail. 2014;7(1):131-
139.
TE

68. Güder G, Störk S, Gelbrich G, et al. Nurse-coordinated collaborative disease management

improves the quality of guideline-recommended heart failure therapy, patient-reported
outcomes, and left ventricular remodelling. Eur J Heart Fail. 2015;17(4):442-452.
69. Feltner C, Jones CD, Cené CW, et al. Transitional care interventions to prevent readmissions for
P

persons with heart failure: a systematic review and meta-analysis. Ann Intern Med.
2014;160(11):774-784.
CE

70. Welch T, Bilchick K, Reigle N, et al. Cost analysis of heart failure readmission intervention
program. American College of Cardiology 2016 Scientific Sessions; Chicago, IL. Abstract 1285M-
01; April 4, 2016.
AC

71. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated
heart failure. N Engl J Med. 2011;364(9):797-805.
72. Triposkiadis FK, Butler J, Karayannis G, et al. Efficacy and safety of high dose versus low dose
furosemide with or without dopamine infusion: the Dopamine in Acute Decompensated Heart
Failure II (DAD-HF II) trial. Int J Cardiol. 2014;172(1):115-121.
73. Costanzo MR, Saltzberg MT, Jessup M, Teerlink JR, Sobotka PA, Investigators UVIDfPHfADHFU.
Ultrafiltration is associated with fewer rehospitalizations than continuous diuretic infusion in
patients with decompensated heart failure: results from UNLOAD. J Card Fail. 2010;16(4):277-
284.
74. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with
cardiorenal syndrome. N Engl J Med. 2012;367(24):2296-2304.
75. Costanzo MR, Negoianu D, Jaski BE, et al. Aquapheresis Versus Intravenous Diuretics and
Hospitalizations for Heart Failure. JACC Heart Fail. 2016;4(2):95-105.
76. Kiernan MS, Gregory D, Sarnak MJ, et al. Early and late effects of high- versus low-dose
angiotensin receptor blockade on renal function and outcomes in patients with chronic heart
failure. JACC Heart Fail. 2015;3(3):214-223.
77. Schou M, Gislason G, Videbaek L, et al. Effect of extended follow-up in a specialized heart
failure clinic on adherence to guideline recommended therapy: NorthStar Adherence Study. Eur
J Heart Fail. 2014;16(11):1249-1255.
78. Maisel A, Xue Y, van Veldhuisen DJ, et al. Effect of spironolactone on 30-day death and heart
failure rehospitalization (from the COACH Study). Am J Cardiol. 2014;114(5):737-742.
 ACCEPTED MANUSCRIPT

79. Rossignol P, Dobre D, McMurray JJ, et al. Incidence, determinants, and prognostic significance
of hyperkalemia and worsening renal function in patients with heart failure receiving the
mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical
therapy: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in
Heart Failure (EMPHASIS-HF). Circ Heart Fail. 2014;7(1):51-58.
80. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection
fraction. N Engl J Med. 2014;370(15):1383-1392.

T
81. Sato N, Ajioka M, Yamada T, et al. A Randomized Controlled Study of Finerenone vs. Eplerenone
in Japanese Patients With Worsening Chronic Heart Failure and Diabetes and/or Chronic Kidney

IP
Disease. Circ J. 2016;80(5):1113-1122.
82. Ziff OJ, Lane DA, Samra M, et al. Safety and efficacy of digoxin: systematic review and meta-

R
analysis of observational and controlled trial data. BMJ. 2015;351:h4451.
83. Bourge RC, Fleg JL, Fonarow GC, et al. Digoxin reduces 30-day all-cause hospital admission in

SC
older patients with chronic systolic heart failure. Am J Med. 2013;126(8):701-708.
84. Gheorghiade M, Patel K, Filippatos G, et al. Effect of oral digoxin in high-risk heart failure
patients: a pre-specified subgroup analysis of the DIG trial. Eur J Heart Fail. 2013;15(5):551-559.
85. Hashim T, Elbaz S, Patel K, et al. Digoxin and 30-day all-cause hospital admission in older

NU
patients with chronic diastolic heart failure. Am J Med. 2014;127(2):132-139.
86. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure
(SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875-885.
87. Borer JS, Böhm M, Ford I, et al. Effect of ivabradine on recurrent hospitalization for worsening
MA
heart failure in patients with chronic systolic heart failure: the SHIFT Study. Eur Heart J.
2012;33(22):2813-2820.
88. Swedberg K, Komajda M, Böhm M, et al. Effects on outcomes of heart rate reduction by
ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?:
D

findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial)
study. J Am Coll Cardiol. 2012;59(22):1938-1945.
TE

89. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in
heart failure. N Engl J Med. 2014;371(11):993-1004.
90. McMurray J, Packer M, Desai A, et al. A putative placebo analysis of the effects of LCZ696 on
clinical outcomes in heart failure. Eur Heart J. 2015;36(7):434-439.
P

91. Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared
with enalapril on the risk of clinical progression in surviving patients with heart failure.
CE

Circulation. 2015;131(1):54-61.
92. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in
heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled
AC

trial. Lancet. 2012;380(9851):1387-1395.

93. Biton Y, Moss AJ, Kutyifa V, et al. Inverse Relationship of Blood Pressure to Long-Term
Outcomes and Benefit of Cardiac Resynchronization Therapy in Patients With Mild Heart
Failure: A Multicenter Automatic Defibrillator Implantation Trial With Cardiac
Resynchronization Therapy Long-Term Follow-Up Substudy. Circ Heart Fail. 2015;8(5):921-926.
94. Starling RC, Krum H, Bril S, et al. Impact of a Novel Adaptive Optimization Algorithm on 30-Day
Readmissions: Evidence From the Adaptive CRT Trial. JACC Heart Fail. 2015;3(7):565-572.
95. Abraham WT, Stevenson LW, Bourge RC, et al. Sustained efficacy of pulmonary artery pressure
to guide adjustment of chronic heart failure therapy: complete follow-up results from the
CHAMPION randomised trial. Lancet. 2016;387(10017):453-461.
96. Adamson PB, Abraham WT, Bourge RC, et al. Wireless pulmonary artery pressure monitoring
guides management to reduce decompensation in heart failure with preserved ejection
fraction. Circ Heart Fail. 2014;7(6):935-944.
97. Krahnke JS, Abraham WT, Adamson PB, et al. Heart failure and respiratory hospitalizations are
reduced in patients with heart failure and chronic obstructive pulmonary disease with the use
of an implantable pulmonary artery pressure monitoring device. J Card Fail. 2015;21(3):240-
249.
98. Moe G. Heart failure with multiple comorbidities. Curr Opin Cardiol. 2016;31(2):209-216.
99. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure
and iron deficiency. N Engl J Med. 2009;361(25):2436-2448.
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100. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term
intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure
and iron deficiency†. Eur Heart J. 2015;36(11):657-668.
101. Swedberg K, Young JB, Anand IS, et al. Treatment of anemia with darbepoetin alfa in systolic
heart failure. N Engl J Med. 2013;368(13):1210-1219.
102. Marenzi G, Muratori M, Cosentino ER, et al. Continuous ultrafiltration for congestive heart
failure: the CUORE trial. J Card Fail. 2014;20(5):378.e371-379.

T
103. Rogers JK, Kielhorn A, Borer JS, Ford I, Pocock SJ. Effect of ivabradine on numbers needed to
treat for the prevention of recurrent hospitalizations in heart failure patients. Curr Med Res

IP
Opin. 2015;31(10):1903-1909.
104. Anand IS, Win S, Rector TS, Cohn JN, Taylor AL. Effect of fixed-dose combination of isosorbide

R
dinitrate and hydralazine on all hospitalizations and on 30-day readmission rates in patients
with heart failure: results from the African-American Heart Failure Trial. Circ Heart Fail.

SC
2014;7(5):759-765.

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