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Management of Chronic Heart Failure: Biomarkers, Monitors, and Disease Management Programs


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The management of patients with heart failure has been evolving given the complex nature of the disease and the increasing number of patients. Biomarkers, and in particular the natriuretic peptides, have been studied to assist with diagnosis, chronic management, and prognosis in patients with heart failure. Several new biomarkers are emerging and may be used individually or in combination with the natriuretic peptides. The use of cardiac monitoring devices and disease management programs is being established to assist in the care of patients with chronic heart failure. Interventions using phone calls, telemedicine devices, intracardiac pressure monitors, and implantable cardioverter defibrillators have been investigated. The combination of biomarkers, monitoring devices, and disease management programs shows promise for improving care in this challenging patient population.
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Management of Chronic Heart Failure:
Biomarkers, Monitors, and Disease Management
Parul U. Gandhi, MD, and Sean Pinney, MD
The management of patients with heart failure has been evolving given the complex nature of the disease and the
increasing number of patients.
Findings: Biomarkers, and in particular the natriuretic peptides, have been studied to assist with diagnosis, chronic man-
agement, and prognosis in patients with heart failure. Several new biomarkers are emerging and may be used individually or in
combination with the natriuretic peptides. The use of cardiac monitoring devices and disease management programs is being
established to assist in the care of patients with chronic heart failure. Interventions using phone calls, telemedicine devices,
intracardiac pressure monitors, and implantable cardioverter defibrillators have been investigated.
Conclusions: The combination of biomarkers, monitoring devices, and disease management programs shows promise for
improving care in this challenging patient population.
Keywords: biomarkers, cardiac monitors, disease management programs, heart failure, natriuretic peptides
Annals of Global Health 2014;80:46-54
Heart failure is a growing pandemic affecting approxi-
mately 5.8 million people in the United States alone with
670,000 new cases diagn osed each year.
Even with the
development of several new therapies, approximately 30%
of patients with chronic heart failure are readmitted within
2 to 3 months.
Heart failure is a complex syndrome, and
both diagnosis and treatment therefore can be challenging.
Furthermore, although several evidence-based therapies
exist, achieving an appropriate regimen and target doses of
medications can be difficult, resulting in significant vari-
ability in treatment practices especially in older patients
and patients with renal dysfunction.
Use of guideline-
recommended therapies has been linked to an im prove-
ment in survival that only starts to plateau after 4 to 5
therapies have been initiated.
Biomarkers, intracardiac
monitors, and disease management programs are 3
im po rtant tools that can im prove the routine use of
guideline-based therapies and ultimately lead to an
improvement in clinical outcomes. The objective of this
review is to provide a foundation on the natriuretic pep-
tides, discuss some newer biomarkers, review some of the
intracardiac monitors that have been developed, and finally
to elucidate the data on disease management programs.
The term biomarker was initially used in 1989 as a Medical
Subject Heading (MeSH) term, and the definition was
standardized in 2001 by the National Institutes of Health
as a characteristic that is objectively measured and eval-
uated as an indicator of normal biologic processes, path-
ogenic processes, or pharmacologic responses to a
therapeutic intervention.
biomarker were previously defined as follows: 1) to provide
accurate and repeated measurements with short turn-
around times and reasonable cost, 2) to provide additional
information beyond what can be ascertained from a
thorough clinical assessment, and 3) to use results to aid in
making clinical decisions.
This review focuses on estab-
lished biomarkers, as well as some emerging biomarkers.
BNP was discovered in 1988, and was initially called
brain natriuretic peptide as it was isolated from porcine
ª 2014 Icahn School of Medicine at Mount Sinai
From the Massachusetts General Hospital, Boston, MA; Mount Sinai
School of Medicine, New York, NY. Address correspondence to P.U.G.;
No funding support was provided for this manuscript.
S.P. has clinical trial support from Thoratec, Inc and consulting fees from
XDX, Inc. P.U.G. states that they have no conicts of interest.
brain tissue. Once the primary source was found to be
ventricular cardiac myocytes, the name was changed.
BNP is 32 amino acids in length and is one of 2 prod-
ucts of the cleavage of the prohormone BNP, with the
second product being NT-proBNP (Fig. 1).
When BNP
is in the bloodstream, it binds to NP receptor A, leading
to activation of the cGMP-dependent cascade resulting in
diuresis, vasodilation, inhibition of renin and aldoste-
rone production, and inhibition of cardiac and vascular
cell myocyte growth. It is ultimately removed from the
bloodstream by either binding to the NP clearance re-
ceptor type C or degradation by neutral endopeptidase
and renal filtration.
Although BNP and NT-proBNP are
similar, they have important differences. For instance,
NT-proBNP has a longer half-life than BNP, and the
former also is more sensitive to renal function regarding
its clearance.
Table 1 highlights other features of BNP
and NT-proBNP.
In addition, both BNP and NT-
proBNP values tend to increase with age, are higher in
women, and are lower in obese individuals.
The Breathing Not Properly study, a landmark
clinical trial, established the importance of BNP in the
diagnosis of acute heart failure and led to its widespread
use. In this study, BNP was measured in 1586 patients
presenting to the emergency department (ED) with acute
dyspnea. The clinical diagnosis of heart failure was made
by 2 independe nt cardiologists, who were blinded to the
BNP results. The final diagnosis of dyspnea due to heart
failure occurred in 47% of the patients. BNP levels were
more accurate than any other physical exam or historical
finding with an odds ratio of 29.60.
Similar findings
were reported in the Pro-BNP Investigation of Dyspnea
in the Emergency Department (PRIDE) study using NT-
proBNP in 600 patients with cut-points differing with
age (> or <50).
Finally, BNP measured in the ED for
patients presenting with acute dyspnea also was found to
decrease time to discharge and total hospital cost.
Natriuretic peptides may be useful to guide heart
failure management. Several small, randomized trials
have compared a treatment strategy of optimizing medical
therapy with the guidance of natriuretic peptides
compared with usual care, but these trials have not been
adequately powered to find a mortality benefit. A meta-
analysis on the available data with a primary endpoin t
of all-cause mortality was previously performed.
Figure 1. Structure of BNP and NT-pro BNP. Reproduced with permission from Motiwala SR et al.
Table 1. Comparison of BNP and NT-proBNP
Amino acids 32 76
Molecular weight (kDa) 3.5 8.5
Half-life (min) 20 60-120
Hormonal activity Yes No
Clearance Renal, NPR-C Renal
Removal by hemodialysis w30% w10%
Clinical range (pg/mL) 0-5000 0-35,000
Approved cutoff value for
heart failure diagnosis in
normal renal function
100 Age <50 y: 450
Age >50 y: 900
NPR-C, neutral endopeptidase clearance receptors.
Adapted from Iwanaga Y et al.
Annals of Global Health 47
Table 2. Study Design Overview for Included Trials
N 69 137 220 499 364 345
Marker used NT-proBNP BNP BNP NT-proBNP NT-proBNP NT-proBNP
Randomization Yes Yes Yes Yes Yes Yes
Blinding No No No Single-blind Double-blind Single-blind
Strategy for intervention
Target NT-proBNP
level <200 pmol/L
(1692 pg/mL)
Target BNP value chosen
at hospital discharge,
therapy for values >2
discharge BNP
Target BNP <100 pg/mL Target NT-proBNP <400 pg/mL
is age <75, NT-proBNP <800
pg/mL if age 75
Target NT-proBNP <150
pmol/L (1270 pg/mL)
NT-proBNP at discharge
from hospital
Strategy for control
HF score Congestion score Usual care, BNP measurement
not allowed
Target symptoms <NYHA class II Usual care or intensive
clinical care based on
HF score
Usual care
Length of follow-up 9.6 mo 3 mo 15 mo 18 mo Minimum of 12 mo Minimum of 12 mo
Primary endpoint Death þ cardiovascular
hospitalization þ
outpatient HF event
Total days alive and out
of hospital at 90 d
HF death þ HF hospitalization Death þ all-cause hospitalization All-cause mortality Days alive and out of
Patient population
Age (y, mean) 70 61 66 77 76 72
Gender (% male) 76 70 64 66 62* 58
Ejection fraction (%,
27 20 31 30 37 33
HF etiology (% ischemic) 74 44 52 58 71* N/A
HF, heart failure; NYHA, New York Heart Association.
*Derived from design article
since data not presented in nal abstract.
Reproduced with permission from Felker GM et al.
48 Chronic Heart Failure Management
prospective, randomized trials were included in this
analysis with a total of 1,627 patients (Table 2).
The NT-proBNP-assisted Treatment to Lessen Serial
Cardiac Readmissions and Death (BATTLESCARRED)
and Can Pro-brain-natriuretic Peptide Guided Therapy
of Heart Failure Improve Heart Failure Morbidity and
Mortality? (PRIMA) trials included patients with both
systolic and diastolic dysfunction. The Strategies for
Tailoring Advanced Heart Failure Regimens in the
Outpatient Setting (STARBRITE) trial included more
younger patients with advanced disease, with the majority
having nonischemic cardiom yopathy, whereas the Trial of
Intensified vs Standard Medical Therapy in Elderly Pa-
tients With Congestive Heart Failure (TIME-CHF) and
BATTLESCARRED had primarily older patients with a
mean age >75. At baseline, use of evidence-based med-
ications in all of the studies was relatively high, except for
-blockers in one study that was performed before the
accepted use of
-blockers in heart failure.
therapy was optimized in both the biomarker-guided
group as well as in the control group in all of the
studies, but was significantly greater in the former with
regard to angiotensin-converting enzyme inhibitors/
angiotensin receptor blockers,
-blockers, and aldoste-
rone antagonists. Diuretic therapy was unchanged in the
intervention group of all of the studies. Of note, none of
the studies reported significant difference s in hypotension
or worsened renal function in the intervention group
compared with the control group, however, there was a
trend toward increasing creatinine in the biomarker
group of the PRIMA trial and a trend toward increase in
hypotension in the biomarker arm of the TIME-CHF
trial. Regarding all-cause mortality, the point estimate
favored biomarker-guided therapy in all of the studies,
with an estimated 30% improvement in survival,
although these trials individually had mixed outcomes
regarding their primary endpoints.
This may be due
to the greater use of guideline-recommended therapies in
the biomarker-guided therapy group. Another theme that
emerged from the TIME-CHF and the BATTLE-
SCARRED trials was the greater benefit of biomarker-
guided therapy in patients under the age of 75.
The most recent study investigating NT-proBNPe
guided care in patients with systolic dysfunction is the
ProBNP Outpatient Tailored Chronic Heart Failure
Therapy (PROTECT) trial. One hundred fifty-one patients
were randomized to either standard heart failure care or
standard care at a single, tertiary care center with a goal of
reducing NT-proBNP levels to 1000 pg/mL. The pri-
mary endpoint of total cardiovascular events was signifi-
cantly reduced in the biomarker-guided therapy group (58
vs 100 events), driven by a reduction in hospitalization and
worsening heart failure; quality of life was improved in the
biomarker group. Patients in the biomarker-guided arm
were seen more frequently (median, 6 vs 5 times), which
may have contributed to the difference in events.
A large,
randomized trial is still needed to investigate a difference in
survival, and this question will likely be answered by the
Guiding Evidence Based Therapy Using Biomarker
Intensified Treatment (GUIDE-IT) trial. This multicenter,
randomized controlled trial will compare the use of a
biomarker-guided treatment strategy with usual care in
patients with left ventricular systolic dysfunction with a
primary outcome of time to cardiovascular death or heart
failure hospitalization (
Natriuretic peptide measurement can provide
insight into prognosis in patients with chronic heart
failure, and the prognostic value of both baseline values
and changes in BNP and norepinephrine (NE) was
examined in more than 4000 patients from the Valsartan
Heart Failure (Val-HeFT) trial.
The incidence of all-
cause mortality and first morbid event was significantly
higher in patients with elevated baseline BNP and NE
levels, and BNP showed a stronger association with
morbidity and mortality than NE. Regarding changes in
BNP and NE over 4 months, patients with the highest
increase in BNP or NE had the highest mortality.
Twelve-month data were similar. Therefore, both base-
line values and trends in BNP are important predictors
of morbidity and mortality.
A similar study was done
with 1742 patients from the Val-HeFT trial to investigate
changes in NT-proBNP over 4 months.
The highest all-
cause mortality out of the 4 quartiles of patients was in
the group with both initial and 4-month NT-proBNP
values above the baseline value, as shown in Figure 2.
In patients who are hospitalized with heart failure,
those who had a <50% reduction in NT-proBNP had a
57% greater risk for readmission or death compared with
those who had a >50% reduction.
BNP also has been
demonstrated to be a good predictor of 1-year mortality
or rehospitalization in patients aged 65 from the
Organized Program To Initiate Lifesaving Treatment In
Hospitalized Patients With Heart Failure (OPTIMIZE-
HF) study.
The role of biomarker-guided therapy in the
inpatient setting still needs to be clarified.
Cardiac troponins T and I have been used for the diag-
nosis of myocardial injury for the past 20 years, and
detection is increasing with the development of highly
sensitive assays. Cardiac troponin I was found in half of the
patients with chronic heart failure, and the presence of
troponin I was an independent predictor of death even
after adjustment for other factors associated with poor
Troponin T was also investigated in 136
ambulatory patients with heart failure who were followed
for 14 months, and a level >0.02 ng/mL was found in 33
patients. The relative risks for death, hospitalization for
heart failure, and myocardial infarction were all signifi-
cantly higher in these patients.
The association of base-
line troponin T levels, all-cause mortality, and heart failure
hospitalization was studied in the patients with chronic
heart failure from the Val-HeFT trial.
With a highly
Annals of Global Health 49
sensitive assay, they were able to detect levels of troponin T
in 92% of these patients compared with 10% using the
standard assay. After baseline variables including BNP
levels were adjusted, the presence of elevated troponin T
using the highly sensitive assay was associated with an
increased risk for death.
The possible etiology of
troponin elevation is ongoing cardiomyocyte injury in heart
failure from myocardial strain or subendocardial ischemia.
Apoptosis also may be contributing, but this has not been
confirmed. Finally, troponin detected in the bloodstream
also may reflect degradation products from proteolysis or
turnover of myocardial contractile proteins, which may be
secondary to myocardial stretch, oxidative stress, neuro-
hormonal activation, or microvascular ischemia.
combined with the use of BNP, improved risk stratification
for these patients may be obtained.
The term cardiorenal syndrome has been used to describe
the complex pathophysiology of coexistent heart failure
and renal dysfunction. Renal dysfunction is prevalent in
patients with heart failure and effects prognosis. In a
review of 16 studies examining 80,098 patients with
heart failure, 63% had at least mild renal dysfunction,
and 20% had moderate to severe dysfunction. A 7%
increase in mortality with every 10 mL per minute
decrease in estimated glomerular filtration rate was
Serum creatinine has been consistently associ-
ated with poor prognosis in patients with heart failure
including prolonged hospital stay, increased read-
missions, and increased 6-month mortality.
Given the important link between these 2 organ
systems, 2 biomarkers of renal injury cystatin C (CysC)
and neutrophil gelatinase-associated lipocalin (NGAL)
have been studied in the context of heart failure. CysC is
produced at a constant rate by all nucleated cells and is
freely filtered through the glomerulus, reabsorbed, and
fully catabolized in the proximal tubule. CysC is
unaffected by age, sex, or muscle mass.
Compared with
creatinine, CysC is a stronger predictor of mortality and
cardiovascular events in patients over the age of 65.
acute heart failure, it has been demonstrated that
combining CysC with NT-proBNP further improved risk
stratification. In addition, in patients with normal
creatinine, elevat ed levels of CysC also were associated
with a significantly higher mortality at 1 year.
NGAL is a secretory glycoprotein that was originally
identified in mouse kidney cells and human neutrophil
granules. NGAL expression in the renal tubules is
rapidly induced by acute injury and is detected in the
bloodstream soon after acute kidney injury.
In a small
study of older patients with congestive heart failure,
higher levels of NGAL were found to parallel the severity
of heart failure symptoms with the highest levels seen in
New York Heart Association (NYHA) class IV patients
and were associated with a higher mortality.
In another
study including 150 patients with chronic heart failure,
NGAL levels correlated with clinical and neurohormonal
deterioration as well as NT-proBNP levels.
Along with creatinine, CysC, and NGAL, serum
sodium has been studied extensively in heart failure and
hyponatremia portends a poor prognosis.
In the
OPTIMIZE-HF registry, the relationship between serum
sodium on admission and clinical outcomes was
analyzed in more than 40,000 patients from 259 hospi-
tals. Patients with hyponatremia (Na < 135 mmol/L) on
admission had significantly higher rates of in-hospital
and follow up mortality and longer hospital lengths of
stay. In addition, for each 3 mmol/L decrease in serum
sodium < 140 mmol/L at admission, the risk for in-
hospital mortality and follow-up mortality increased by
19.5% and 10%, respectively.
Markers of hypertrophy and fibrosis
Soluble ST2 (sST2) is a protein that is formed secondary
to myocardial stretch and is associated with cardiac
remodeling and fibrosis. sST2 has been found to have
prognostic value in patients with acute decompensated
Figure 2. Kaplan-Meier curves for all-cause mortality in the 4 categories of patients. Reproduced with permission from Masson S et al.
50 Chronic Heart Failure Management
heart failure and the combination of sST2 and
NT-proBNP is a superior predictor of death than eith er
Galectin-3 is a marker of fibrosis and inflam-
mation that is elevated in many diseases, including renal
and heart failure. Given its lack of specificity, it is not
employed for diagnosis of heart failure, but can assist in
The role of galectin-3 in combination with
the natriuretic peptides is being clarified, however, one
study showed a loss of predictive value when combined
with NT-pro BNP.
Remote telemedical management of heart failure may be
an option to further improve outcomes, with the main-
stay of telemedicine being the early detection of disease
deterioration leading to prompt intervention. Both
noninvasive and invasive mo nitoring tools have been
developed from simple portable imaging devices and
digital assistants to intracardiac pressure monitoring and
use of parameters from implantable cardiac de-
A review from 2011 showed the overall
benefit achieved from telemonitoring with regard to all-
cause mortality, all-cause hospital admission, and hospi-
tal admission related to chronic heart failure.
Since this
review was released, 2 other trials have been published
with negative results. The Telemonitoring to Improve
Heart Failure Outcomes (Tele-HF) and Telemedical
Interventional Monitoring in Heart Failure (TIM-HF)
trials both employed noninvasive monitoring ap-
proaches. Tele-HF randomly ass igned more than 1600
patients who were recently admitted for heart failure
either to telemonitoring with a phone-based interactive
voice-response system to allow for daily evaluation of
symptoms and weight or to usual care. No significant
difference was noted in the primary endpoint of read-
mission or death from any cause at 180 days.
TIM-HF study also randomized chronic heart failure
patients with left ventricular ejection fraction (LVEF)
<35% and NYHA class II-III symptoms to usual care or
telemonitoring using a wireless Bluetooth device and
personal digital assistant that measured 3-lead electro-
cardiography, blood pressure, and weight, as well as
medical telephone support. No significant difference was
seen in the primary outcome of mortality between the 2
groups over a mean follow-up of 21.5 months.
Invasive monitoring also has been studied. The
Chronicle Offers Manage ment to Patients with Advanced
Signs and Symptoms of Heart Failure (COMPASS-HF)
study used a device to measure right ventricular pressure
in 274 patients with NYHA class III-IV symptoms who
were receiving optimal medical therapy. The patients were
randomized to device-guided management or the control
group. The device was found to be safe, but no significant
difference was detected in the number of heart failure-
related events.
The CardioMEMS Heart Sensor Al-
lows Monitoring of Pressure to Improve Outcomes in
NYHA Class III Patients (CHAMPION) study enrolled
patients with NYHA class III heart failure (regardless of
LVEF, however w80% had LVEF <40%) and previous
hospitalization for heart failure and randomized them to
usual care or a wireless implantable hemodynamic
monitoring system (W-IHM). The W-IHM involved the
implantation of a pulmonary artery pressure sensor and
patients in the intervention group had daily measurement
of pulmonary artery pressures. All patients were on
optimal medications at time of W-IHM implantation, and
medications were titrated based on pulmonary artery
pressure readings as well as patient symptoms. Patients in
the intervention group experienced a 39% reduction in
heart failure admissions over 15 months and also
benefitted from a greater number of medication changes
compared with the usual-care group.
However, the
W-IHM was not approved by the FDA secondary to the
difference in medical therapy between the 2 groups.
new left atrial pressure monitor called the HeartPod has
been developed and currently is being investigated in the
Left Atrial Pressure Monitoring to Optimize Heart Failure
Therapy (LAPTOP HF) trial.
Finally, the Diagnostic
Outcome in Heart Failure (DOT-HF) trial studied the use
of diagnostic features from implantable cardiac de-
fibrillators and cardiac resynchronization therapy such as
intrathoracic impedance (using OptiVol) to assist in
management of 355 patients with chronic heart failure.
Compared with the control arm, patients in the inter-
vention group did not experience a significant reduction
in the composite primary endpoint of all-cause mortality
and heart failure hospitalization.
This trial was termi-
nated early due to enrollment difficulties, and the Opti-
mization of Heart Failure Mana gement using OptiVol
Fluid Status Monitoring and CareLink (OptiLink-HF)
trial is currently under way to determine if OptiVol
monitoring with an automatic alert can reduce mortality
and hospitalization.
The definition of disease management program is highly
variable, and although many definitions have been pro-
posed, a universal definition does not exist. For this
reason in 2006, the American Heart Association orga-
nized the Disease Management Taxonomy Writing
The taxonomy defined the various components
of a disease management program, such as patient
population, intervention, communication method, and
outcome measures and was intended to assist in classi-
fication and understanding of the structure of these
various programs, which could then subsequently allow
for proper investigation of their effectiveness (Fig. 3).
The effectiveness of comprehensive heart failure
management programs was previously studied in non-
randomized trials, but showed a reduction in rehospi-
talization, health care costs, improved functional status
and symptoms, and better quality of life compared with
Annals of Global Health 51
patients receiving standard care.
The first random-
ized trial was published in 1995 from a single center and
used a nurse-directed multidisciplinary disease manage-
ment intervention to address risk factors for readmission
including dietary and medication noncompliance, failure
to recogn ize exacerbations of heart failure, and inap-
propriate medication prescribing. They found a 56%
reduction in 90-day readmissions for heart failure and a
reduction in costs of $460 per patient.
One systematic
review that included 29 trials with 5039 patients
confirmed that management strategies including follow-
up by a multidisciplinary team (either in a clinic or
nonclinic setting) reduced mortality, heart failure hospi-
talizations, and all-cause hospitalizations. Programs that
focused on self-care reduced heart failure hospitaliza-
tions, but did not affect mortality. Programs that used
telephone contact and recommended primary care
attention in the event of deterioration also reduced heart
failure hospitalizations, but did not have an effect on
mortality or all-cause hospitalization. Eighteen of the
reviewed trials studied cost, and 15 of these showed a
reduction in costs with multidisciplinary care.
As noted previously, phone-based interventions were
found to have variable results. In a trial with 1069 patients
who were randomized to telephone-based disease man-
agement or usual care, patients were enrolled for 18
months and all patients were assessed every 6 months by
history, physical, 6-minute walk test, and serum chemistry.
Patients in the disease management group were found to
have a reduction in mortality and an improvement in
NYHA class, however, there was no significant change in
6-minute walk data and total health care utilization,
including hospitalization.
Another phone-based inter-
vention was studied in the Randomized Trial of Phone
Intervention in Chronic Heart Failure (DIAL), which
included 1518 outpatients with stable chronic heart failure
who were randomized to routine care or an intervention
that included an explanatory booklet and periodic tele-
phone contact by a specialized nurse over 1 year. The
intervention resulted in a lower rate of death or hospital-
ization compared with the control group, driven by a
decrease in rehospitalization.
Follow-up of these patients
at 1 and 3 years showed the benefit persisted and was again
mostly due to a reduction in hospital admissions.
Not all of the published studies have had positive
outcomes. The Coordin ating Study Evaluating Out-
comes of Advising and Counseling in Heart Failure
(COACH) trial was a multicenter, randomized trial that
evaluated 1023 patients who were enrolled after a heart
failure hospitalization and were assigned to a control
group (follow-up by a cardiologist), intervention with
basic support from a specialized nurse, or intervention
with intensive support from a specialized nurse. The
basic-support group included additional visits with a
heart failure nurse at the clinic, and the intensive group
consisted of additional visits with the nurse as well as
phone calls, home visits, and multidisciplinary advice
sessions with a physical therapist, social worker, and
dietitian. The patients were followed for 18 months and
the results showed no difference in the primary endpoint
of death and heart failure hospitalization.
The most recent meta-analysis from the Cochrane
group included 25 randomized trials with 5942 patients
and investigated types of disease management strategies
Figure 3. Disease Management Taxonomy. Reproduced with permission from Krumholz et al.
52 Chronic Heart Failure Management
after hospital discharge. The interventions were divided
into 3 groups: 1) case management interventions including
telephone and home visits, 2) clinic interventions, and
3) multidisciplinary interventions using a team approach.
Case management interventions demonstrated a reduction
in all-cause mortality after 1 year of follow-up and reduced
heart failure readmissions at 6 months. Clinic in-
terventions did not have a significant effect on mortality or
readmissions. The multidisciplinary approach reduced
heart failure and all-cause readmissions but did not
affect mortality; however, only 2 studies investigated this
The variable results of these trials are possibly sec-
ondary to differences in program design, but raise doubt
as to whether these results can be generalized. Despite
published recommendations to guide the structure of a
disease management program, it remains difficult to
predict efficacy. In addition, many of the details of the
intervention are not provided, which further limits
reproducibility. The most recent randomized trial of
disease management programs, HeartNetCare-HF
(HNC), used a well-defined nurse-coordinated disease
management program, which incorporated care from
nurses, general practitioners, cardiologists, and car egiver
training and used standardized questions and written
intervention templates.
Seven hundred fifteen patients
were randomized to either usual care or to HNC before
discharge. The patients in the usual-care group under-
went standard postdischarge planning with a follow-up
appointment 1 to 2 weeks after discharge with either a
general practitioner or cardiologist. The HNC group
patients were given scales and blood pressure monitors
and met with the specialty nurse before discharge. There
was no difference in the number of patients who reached
the combined primary endpoint of time to death or
rehospitalization; however, mortality was reduced in the
HNC group. HNC patients also improved more with
regard to NYHA class, drug adherence, and physical
This trial provided well-defined inter-
ventions, measured health care utilization, and had a
well-defined study population, which will ultimately assist
in further study of disease management programs.
In summary, biomarkers are valuable tools that can assist
in diagnosis, management, and determination of prog-
nosis for patien ts with heart failure. Although the natri-
uretic peptides are well established and widely used,
many new biomarkers are under investigation and may
further assist with the care of patients with chronic heart
failure. More studies are needed to elucidate the complex
disease mechanisms underlying these biomarkers, which
would allow this enhanced understanding to then be
combined with the technology of cardiac monitoring
devices and ultimately lead to new disease management
strategies to improve the use of guideline-ba sed therapies
and outcomes.
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54 Chronic Heart Failure Management
... With growing numbers and complexity of persons living with HF, the management heart failure (HF) challenges the whole health system globally [1]. HF affects nearly 64.3 million people worldwide, a roughly two-fold increase from 33.5 million since 1990 [2]. ...
... Although high-quality clinical guidelines can be a gold standard for practice [21], little is known about the content and consistency of HF guidelines relevant to homecare. To address these gaps, we conducted a systematic review with these aims: [1] to identify clinical home care guidelines in adult HF patients and their recommendations [2] to evaluate quality of the guidelines as well as to assess eight components of disease management at home in the guidelines. ...
... Data collection was divided into the three steps in our study: [1] to run a systematic search and selection of current evidence-based guidelines for HF patients that can be applied to home-based care (Fig. 1), [2] to evaluate of the methodological quality of the selected guidelines with the Appraisal of Guidelines for Research and Evaluation (AGREE-II) and [3] to compare recommendations of the guidelines with the eight components of disease management at home [19]. Two independent evaluators conducted data extraction. ...
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Background “Guidelines for the care of heart failure patients at home support safe and effective evidence-based practice. The aims of the present study were: [1] to identify guidelines addressing the care at home for adults with heart failure and [2] evaluate the quality of the guidelines and the extent to which they address eight components of home-based HF disease management.” Methods A systematic review was conducted of articles published between 1st of January 2000 to 17th of May 2021 using the databases of PubMed, Web of Science, Scopus, Embase, Cochrane, and nine specific websites for guideline development organisations. Clinical guidelines for HF patients with recommendations relevant to care provision at home were included. The results were reported according to the Preferred Reporting Items for Systematic Reviews (PRISMA-2020) criteria. The quality of included guidelines was evaluated using the Appraisal of Guidelines for Research and Evaluation-II (AGREE-II) by two authors independently. Guidelines were evaluated for their coverage of eight components of HF care at home, consisting of integration, multi-disciplinary care, continuity of care, optimized treatment, patient education, patient and partner participation, care plans with clear goals of care, self-care management and palliative care. Results Ten HF guidelines, including two nursing-focused guidelines and eight general guidelines were extracted from 280 studies. After evaluation of quality by AGREE-II, two guidelines obtained the highest score: “NICE” and the “Adapting HF guideline for nursing care in home health care settings. Five guidelines addressed all eight components of care at home while the others had six or seven. Conclusions This systematic review identified ten guidelines addressing care at home for patients with HF. The highest quality guidelines most relevant to the care at home of patients with HF are the “NICE” and “Adapting HF guideline for nursing care in home health care settings” and would be most appropriate for use by home healthcare nurses.
... • A marker of tubular damage that independently predicts CKD progression. 50,51 • Correlated with disease severity, independently of the coexistence of renal injury, and with NT-proBNP levels. 24,52 Kidney injury molecule-1 ...
... 43 Several new biomarkers are being studied aiming for the development of useful tools for early diagnosis and accurate prognosis in these patients. 4,50 Although there has been significant progress in the discovery of biomarkers, further trials are warranted to establish their exact role and to validate them in patients with type 4 CRS, before their translation into clinical practice. 7,32 Much remains to be elucidated about type 4 CRS: despite significant progress over the last decade, there are still significant questions regarding its pathophysiology and there is as yet no specific therapy. ...
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The Acute Dialysis Quality Initiative consensus conference proposed a classification of cardiorenal syndrome (CRS), aiming for a better delineation of each subtype. Although the exact pathophysiology of type 4 CRS is not completely understood, the mechanisms involved are probably multifactorial. There is growing evidence that oxidative stress is a major connector in the development and progression of type 4 CRS. Giving its complexity, poor prognosis and increasing incidence, type 4 CRS is becoming a significant public health problem. Patients with chronic kidney disease are particularly predisposed to cardiac dysfunction, due to the high prevalence of traditional cardiovascular risk factors in this population, but the contribution of risk factors specific to chronic kidney disease should also be taken into account. Much remains to be elucidated about type 4 CRS: despite progress over the last decade, there are still significant questions regarding its pathophysiology and there is as yet no specific therapy. A better understanding of the mechanisms involved may provide potential targets for intervention. The present review will provide a brief description of the definition, epidemiology, diagnosis, prognosis, biomarkers and management strategies of type 4 CRS, and the pathophysiological mechanisms and risk factors presumably involved in its development will be particularly highlighted.
... [12][13][14] Apart from the in-hospital part of patient management, the complexity of HF as a clinical problem and the associated comorbidities contributing to the progression of the disease and thus higher hospitalization rates and polypharmacy, lead to a subsequent and continuous increase in expenditures attributed to HF. [15][16][17] A key objective in HF management is, therefore, to alleviate symptoms, reduce the occurrence and need for hospitalizations, and, subsequently, increase survival and improve the patients' quality of life. 5,18,19 Treatment options such as angiotensin-converting enzyme inhibitors and beta blockers, although effective in some aspects of the treatment, have not yet shown the desired outcomes in terms of clinical efficacy. 5,18,19 In this light, newer and emerging treatments could play a role in the future of patient management and improved clinical results. ...
... 5,18,19 Treatment options such as angiotensin-converting enzyme inhibitors and beta blockers, although effective in some aspects of the treatment, have not yet shown the desired outcomes in terms of clinical efficacy. 5,18,19 In this light, newer and emerging treatments could play a role in the future of patient management and improved clinical results. Among those, eplerenone, a selective mineralocorticoid-receptor antagonist, also known as an aldosterone antagonist, has been indicated for patients with New York Heart Association (NYHA) class II chronic heart failure (CHF) with reduced left ventricular ejection fraction (LVEF), in addition to standard therapy, on the basis of improved clinical outcomes, that is, reduced cardiovascular (CV) mortality and morbidity, in adult patients with NYHA class II CHF and left ventricular systolic dysfunction (LVEF ≤30%). ...
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Objectives: The aim of the study was to evaluate the cost-effectiveness (CE) of treatment with eplerenone versus standard care in adult patients with New York Heart Association class II chronic heart failure and reduced left ventricular ejection fraction from the perspective of the Greek national health care payer. Methods: A discrete-event model simulating the clinical course and respective outcomes of eplerenone as an add-on to standard therapy versus standard therapy alone based on the pivotal Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure (EMPHASIS-HF) trial was locally adapted for the Greek setting. Data on medications followed the resource use from eplerenone in mild patients hospitalization and survival study in heart failure and were estimated on a lifetime basis (or until discontinuation). Cost calculations were based on year 2014, event costs (cardiovascular hospitalizations, adverse events, and devices) were sourced from published diagnosis-related groups. A 3% discount rate was applied. In order to test the robustness of the model projections, a range of deterministic and probabilistic sensitivity analyses were carried out. Results: Over a patient’s lifetime, the addition of eplerenone to standard care compared to standard care alone led to an incremental gain of 1.33 quality-adjusted life-years (QALYs) (6.53 vs 5.20 QALYs, respectively) as well as an increase in the cost of treatment by €2,160; these outcomes produced an incremental CE ratio of €1,624/QALY for the Greek setting. On the basis of probabilistic sensitivity analysis, there was a 100% likelihood of eplerenone being cost-effective versus standard care at a threshold of €3,500/QALY. Conclusion: This analysis indicates that eplerenone may be a cost-effective option versus standard care accompanied by additional clinical benefits and an added incremental cost at an acceptable, if not low, CE ratio. The results are consistent with the previously published studies on the CE of eplerenone as an add-on therapy to standard care, such as those regarding the health care settings of Spain, the UK, and Australia.
... Conventional methods for detecting biomarkers are based on invasive blood sampling and relevant laboratory testing [4]. Sensors that can detect biomarkers in urine, tears, sweat, and saliva have been developed to solve the invasiveness of blood sampling [5][6][7]. Nevertheless, the concentration and dynamics of the biomarkers available in the mentioned bodily fluids are limited and poorly correlated with their existence in blood, making them typically of low diagnostic relevance [8,9]. Transdermal biosensors detect biomarkers by analyzing interstitial fluid (ISF) found in the dermis' lowermost skin layer [10][11][12]. ...
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To treat and manage chronic diseases, it is necessary to continuously monitor relevant biomarkers and modify treatment as the disease state changes. Compared to other bodily fluids, interstitial skin fluid (ISF) is a good choice for identifying biomarkers because it has a molecular composition most similar to blood plasma. Herein, a microneedle array (MNA) is presented to extract ISF painlessly and bloodlessly. The MNA is made of crosslinked poly(ethylene glycol) diacrylate (PEGDA), and an optimal balance of mechanical properties and absorption capability is suggested. Besides, the effect of needles’ cross-section shape on skin penetration is studied. The MNA is integrated with a multiplexed sensor that provides a color change in a biomarker concentration-dependent manner based on the relevant reactions for colorimetric detection of pH and glucose biomarkers. The developed device enables diagnosis by visual inspection or quantitative red, green, and blue (RGB) analysis. The outcomes of this study show that MNA can successfully identify biomarkers in interstitial skin fluid in a matter of minutes. The home-based long-term monitoring and management of metabolic diseases will benefit from such practical and self-administrable biomarker detection.
... Often caused by myocardial infarction, hypertension, valvular heart diseases, cardiomyopathy and other forms of chronic artery diseases, chronic heart failure (CHF) isa progressive and irreversible disease, which is commonly seen in the department of cardiology [1,2]. The treatment of CHF still depends on the severity and cause, and is often symptom relieving, though the pathogenesis of this disease is well investigated, which leads to a high rate of morbidity and a potentially dead condition [3][4][5]. ...
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Background Appetite loss is one complication of chronic heart failure (CHF), and its association with pancreatic exocrine insufficiency (PEI) is not well investigated in CHF. Aim We attempted to detect the association between PEI and CHF-induced appetite. Methods Patients with CHF were enrolled, and body mass index (BMI), left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) cardiac function grading, B-type natriuretic peptide (BNP), serum albumin, pro-albumin and hemoglobin were evaluated. The pancreatic exocrine function was measured by fecal elastase-1 (FE-1) levels in the enrolled patients. Appetite assessment was tested by completing the simplified nutritional appetite questionnaire (SNAQ). The improvement of appetite loss by supplemented pancreatic enzymes was also researched in this study. Results The decrease of FE-1 levels was found in patients with CHF, as well as SNAQ scores. A positive correlation was observed between SNAQ scores and FE-1 levels (r = 0.694, p < 0.001). Pancreatic enzymes supplement could attenuate the decrease of SNAQ scores in CHF patients with FE-1 levels <200 μg/g stool and SNAQ < 14. Conclusions Appetite loss is commonly seen in CHF, and is partially associated with pancreatic exocrine insufficiency. Oral pancreatic enzyme replacement therapy attenuates the chronic heart failure-induced appetite loss. These results suggest a possible pancreatic-cardiac relationship in chronic heart failure, and further experiment is needed for clarifying the possible mechanisms.
... Cardiac biomarkers have been recommended as prognostic and diagnostic tools in the clinical management of HF, and American College of Cardiology/American Heart Association guidelines have suggested the use of 4 biomarkers-B-type natriuretic peptide (BNP), troponin, galectin-3, and suppression of tumorigenicity 2 (ST2)-to guide the prognosis of patients with HF (4). Management of HF with routine biomarkers as part of the follow-up was shown to increase the survival benefi t for these patients (5). We incorporated the 4 recommended biomarkers into the Myocardial Injury Summary Score (MISS) (6), a novel score to measure the severity of HF. ...
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We propose a novel Myocardial Injury Summary Score (MISS) integrating the 4 biomarkers suggested by the 2013 American College of Cardiology/American Heart Association guidelines for management of heart failure. In this case series, we examined 4 heart failure patients who received treatment guided by the biomarker results and 4 patients who received routine clinical management with no information about the biomarkers. Most of the patients receiving biomarker-guided management had medications adjusted based on the biomarker values, while no changes were recommended for patients in the biomarker-blinded category. This case series suggests that biomarker-guided therapy with serial biomarker values leads to timely therapeutic adjustment and that biomarker values as a composite score can be used effectively to measure the severity of heart failure.
Skin Interstitial Fluid (ISF) is an alternative source for biomarkers. Herein, a highly swellable microneedle patch (MNP) to rapidly extract ISF painlessly and bloodlessly is presented. The MNP is made of crosslinked methacrylated hyaluronic acid (MeHA) and dissolvable hyaluronic acid (HA) with the optimal balance of mechanical strength (0.6 N/MN) and absorption capability (16.22 μL in 20 minutes). Incorporated with wax-patterned and sensing-reagent-decorated test paper (TP) for multiplexed colorimetric detection of metabolites (glucose, lactate, cholesterol, and pH), this TP-MNP biosensor gives rapid color change in biomarker concentration-dependent manner based on specific enzymatic reactions, whereby allowing diagnosis by the naked eye or quantitative RGB analysis. Both the in vitro and in vivo experiments demonstrate the feasibility of TP-MNPs to detect multiple biomarkers in skin interstitial fluid within minutes. Such convenient and self-administrable profiling of metabolites shall be instrumental for home-based long-term monitoring and management of metabolic diseases.
Study objectives: Subjective versus objective sleepiness in heart failure (HF) remains understudied; therefore, we sought to examine the association of these measures and interrelationships with biochemical markers. Methods: Participants with stable systolic HF recruited from a clinic-based program underwent attended polysomnography, Multiple Sleep Latency Testing, questionnaire data collection including Epworth Sleepiness Scale (ESS), and morning phlebotomy for biochemical markers. Linear regression was used to assess the association of mean sleep latency (MSL) and ESS (and other reported outcomes) with adjustment of age or body mass index or left ventricular ejection fraction (LVEF) (beta coefficients, 95% confidence interval) and also with biochemical markers (beta coefficients, 95% confidence interval). Results: The final analytic sample comprised 26 participants: 52 ± 14 years with apnea-hypopnea index (AHI): 34 ± 27, LVEF: 34 ± 12%, MSL: 7 ± 5 minutes and ESS: 7 (5, 10). There was no significant association of MSL and ESS (-0.36, -0.81 to 0.09, P = .089), AHI, or other questionnaire-based outcomes in adjusted analyses. Although statistically significant associations of ESS and biomarkers were not observed, there were associations of MSL and cortisol (μg/dL) [-0.05: -0.08, -0.01, P = .012] and interleukin-6 (pg/mL) [-0.11: -0.18, -0.04, P = .006], which persisted in adjusted models. Conclusions: In systolic HF, although overall objective sleepiness was observed, this was not associated with subjective sleepiness (ie, a discordance was identified). Differential upregulation of systemic inflammation in objective sleepiness was observed, findings not observed with subjective sleepiness. These findings suggest that underlying mechanistic pathways of inflammation may provide the explanation for dissonance of objective and subjective sleepiness symptoms in HF, thus potentially informing targeted diagnostic and therapeutic approaches.
While the practice of taking blood pressure readings at the physician’s office continues to be valid, home blood pressure monitoring is being increasingly used to enhance diagnostic accuracy and ensure a more personalized follow-up of patients. In the case of white coat hypertension and resistant arterial hypertension, ambulatory blood pressure monitoring is indispensable. Recent studies attach great importance to nocturnal blood pressure patterns, with a reduction in these becoming a treatment goal, a strategy known as chronotherapy. Home blood pressure monitoring is useful for both diagnosis and follow-up of arterial hypertension. Its use, particularly if combined with other patient-support interventions, serves to improve blood pressure control. Telemonitoring is associated with a decrease in blood pressure values and an increase in patient satisfaction. All studies highlight the importance of patients being supported by a multidisciplinary health care team, since blood pressure telemonitoring with a support team is more effective than simple data telemonitoring. Further studies are called for, especially on the illiterate population, with difficulties posed by technological accessibility and transcriptions into different languages. More cost-effectiveness studies and long-term results are needed to ascertain the true benefit of blood pressure telemonitoring.
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Objective To determine whether a centralised telephone intervention reduces the incidence of death or admissions for worsening heart failure in outpatients with chronic heart failure. Design Multicentre randomised controlled trial. Setting 51 centres in Argentina (public and private hospitals and ambulatory settings). Participants 1518 outpatients with stable chronic heart failure and optimal drug treatment randomised, stratified by attending cardiologist, to telephone intervention or usual care. Intervention Education, counselling, and monitoring by nurses through frequent telephone follow-up in addition to usual care, delivered from a single centre. Main outcome measure All cause mortality or admission to hospital for worsening heart failure. Results Complete follow-up was available in 99.5% of patients. The 758 patients in the usual care group were more likely to be admitted for worsening heart failure or to dic (235 events, 31%) than the 760 patients who received the telephone intervention (200 events, 26.3%) (relative risk reduction = 20%, 95% confidence interval 3 to 34, P = 0.026). This benefit was mostly due to a significant reduction in admissions for heart failure (relative risk reduction = 29%, P = 0.005). Mortality was similar in both groups. At the end of the study the intervention group had a better quality of life than the usual care group (mean total score on Minnesota living with heart failure questionnaire 30.6 v 35, P = 0.001). Conclusions This simple, centralised heart failure programme was effective in reducing the primary end point through a significant reduction in admissions to hospital for heart failure.
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Objective: To identify potentially confounding variables for the interpretation of plasma N-terminal pro brain natriuretic peptide (NT-proBNP). Design: Randomly selected subjects filled in a heart failure questionnaire and underwent pulse and blood pressure measurements, ECG, echocardiography, and blood sampling. Setting: Subjects were recruited from four Copenhagen general practices located in the same urban area and were examined in a Copenhagen University Hospital. Patients: 382 women and 290 men in four age groups: 50–59 years (n = 174); 60–69 years (n = 204); 70–79 years (n = 174); and > 80 years (n = 120). Main outcome measures: Associations between the plasma concentration of NT-proBNP and a range of clinical variables. Results: In the undivided study sample, female sex (p < 0.0001), greater age (p < 0.0001), increasing dyspnoea (p = 0.0001), diabetes mellitus (p = 0.01), valvar heart disease (p = 0.002), low heart rate (p < 0.0001), left ventricular ejection fraction ⩽ 45% (p < 0.0001), abnormal ECG (p < 0.0001), high log10[plasma creatinine] (p = 0.0009), low log10[plasma glycosylated haemoglobin A1c] (p = 0.0004), and high log10[urine albumin] (p < 0.0001) were independently associated with a high plasma log10[plasma NT-proBNP] by multiple linear regression analysis. Conclusions: A single reference interval for the normal value of NT-proBNP is unlikely to suffice. There are several confounders for the interpretation of a given NT-proBNP concentration and at the very least adjustment should be made for the independent effects of age and sex.
Chronic heart failure (CHF) is a serious, common condition associated with frequent hospitalisation. Several different disease management interventions (clinical service organisation interventions) for patients with CHF have been proposed. To update the previously published review which assessed the effectiveness of disease management interventions for patients with CHF. A number of databases were searched for the updated review: CENTRAL, (the Cochrane Central Register of Controlled Trials) and DARE, on The Cochrane Library, ( Issue 1 2009); MEDLINE (1950-January 2009); EMBASE (1980-January 2009); CINAHL (1982-January 2009); AMED (1985-January 2009). For the original review (but not the update) we had also searched: Science Citation Index Expanded (1981-2001); SIGLE (1980-2003); National Research Register (2003) and NHS Economic Evaluations Database (2001). We also searched reference lists of included studies for both the original and updated reviews. Randomised controlled trials (RCTs) with at least six months follow up, comparing disease management interventions specifically directed at patients with CHF to usual care. At least two reviewers independently extracted data and assessed study quality. Study authors were contacted for further information where necessary. Data were analysed and presented as odds ratios (OR) with 95% confidence intervals (CI). Twenty five trials (5,942 people) were included. Interventions were classified by: (1) case management interventions (intense monitoring of patients following discharge often involving telephone follow up and home visits); (2) clinic interventions (follow up in a CHF clinic) and (3) multidisciplinary interventions (holistic approach bridging the gap between hospital admission and discharge home delivered by a team). The components, intensity and duration of the interventions varied, as did the 'usual care' comparator provided in different trials.Case management interventions were associated with reduction in all cause mortality at 12 months follow up, OR 0.66 (95% CI 0.47 to 0.91, but not at six months. No reductions were seen for deaths from CHF or cardiovascular causes. However, case management type interventions reduced CHF related readmissions at six month (OR 0.64, 95% CI 0.46 to 0.88, P = 0.007) and 12 month follow up (OR 0.47, 95% CI 0.30 to 0.76). Impact of these interventions on all cause hospital admissions was not apparent at six months but was at 12 months (OR 0.75, 95% CI 0.57 to 0.99, I(2) = 58%). CHF clinic interventions (for six and 12 month follow up) revealed non-significant reductions in all cause mortality, CHF related admissions and all cause readmissions. Mortality was not reduced in the two studies that looked at multidisciplinary interventions. However, both all cause and CHF related readmissions were reduced (OR 0.46, 95% CI 0.46-0.69, and 0.45, 95% CI 0.28-0.72, respectively). Amongst CHF patients who have previously been admitted to hospital for this condition there is now good evidence that case management type interventions led by a heart failure specialist nurse reduces CHF related readmissions after 12 months follow up, all cause readmissions and all cause mortality. It is not possible to say what the optimal components of these case management type interventions are, however telephone follow up by the nurse specialist was a common component.Multidisciplinary interventions may be effective in reducing both CHF and all cause readmissions. There is currently limited evidence to support interventions whose major component is follow up in a CHF clinic.