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.
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
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 conﬂicts 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).
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
Table 1 highlights other features of BNP
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.
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
level <200 pmol/L
Target BNP value chosen
at hospital discharge,
therapy for values >2
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
Strategy for control
HF score Congestion score Usual care, BNP measurement
Target symptoms <NYHA class II Usual care or intensive
clinical care based on
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
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
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 ﬁnal 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.
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 (http://clinicaltrials.gov/ct2/show/
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-
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.
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.
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.
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.
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-
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.
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
DISEASE MANAGEMENT STRATEGIES
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.
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,
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
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
1. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke
statistics—2010 update: a report from the American Heart Associ-
ation. Circulation. 2010;121:e46ee215.
2. Fonarow GC, Abraham WT, Albert NM, et al. Association between
performance measures and clinical outcomes for patients hospital-
ized with heart failure. JAMA. 2007;297:61e70.
3. Heidenreich PA, Zhao X, Hernandez AF, et al. Patient and hospital
characteristics associated with traditional measures of inpatient
quality of care for patients with heart failure. Am Heart J. 2012;163:
4. Fonarow GC, Albert NM, Curtis AB, et al. Incremental reduction in
risk of death associated with use of guideline-recommended thera-
pies in patients with heart failure: a nested case-control analysis of
IMPROVE HF. J Am Heart Assoc. 2012;1:16e26.
5. Biomarkers and surrogate endpoints: preferred deﬁnitions and con-
ceptual framework. Clin Pharmacol Ther. 2001;69:89e95.
6. Vasan RS. Biomarkers of cardiovascular disease: molecular basis and
practical considerations. Circulation. 2006;113:2335e62.
7. Morrow DA, de Lemos JA. Benchmarks for the assessment of novel
cardiovascular biomarkers. Circulation. 2007;115:949e52.
8. Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol.
9. Motiwala SR, Januzzi JL Jr. The role of natriuretic peptides as bio-
markers for guiding the management of chronic heart failure. Clin
Pharmacol Ther. 2013;93:57e67.
10. Iwanaga Y, Miyazaki S. Heart failure, chronic kidney disease, and
biomarkers—an integrated viewpoint. Circ J. 2010;74:1274e82.
11. Das SR, Drazner MH, Dries DL, et al. Impact of body mass and body
composition on circulating levels of natriuretic peptides: results from
the Dallas Heart Study. Circulation. 2005;112:2163e8.
12. Raymond I, Groenning BA, Hildebrandt PR, et al. The inﬂuence of
age, sex and other variables on the plasma level of N-terminal pro
brain natriuretic peptide in a large sample of the general population.
13. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of
B-type natriuretic peptide in the emergency diagnosis of heart fail-
ure. N Engl J Med. 2002;347:161e7.
14. Januzzi JL Jr, Camargo CA, Anwaruddin S, et al. The N-terminal Pro-
BNP investigation of dyspnea in the emergency department (PRIDE)
study. Am J Cardiol. 2005;95:948e54.
15. Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic
peptide in the evaluation and management of acute dyspnea. N Engl
J Med. 2004;350:647e
16. Felker GM, Hasselblad V, Hernandez AF, et al. Biomarker-guided
therapy in chronic heart failure: a meta-analysis of randomized
controlled trials. Am Heart J. 2009;158:422e30.
17. Januzzi JL Jr, Rehman SU, Mohammed AA, et al. Use of amino-
terminal pro-B-type natriuretic peptide to guide outpatient therapy
of patients with chronic left ventricular systolic dysfunction. J Am Coll
18. Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic
peptide and norepinephrine over time and mortality and morbidity in
the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2003;107:
19. Masson S, Latini R, Anand IS, et al. Prognostic value of changes in
N-terminal pro-brain natriuretic peptide in Val-HeFT (Valsartan Heart
Failure Trial). J Am Coll Cardiol. 2008;52:997e1003.
20. Michtalik HJ, Yeh HC, Campbell CY, et al. Acute changes in N-ter-
minal pro-B-type natriuretic peptide during hospitalization and risk of
readmission and mortality in patients with heart failure. Am J Cardiol.
21. Kociol RD, Horton JR, Fonarow GC, et al. Admission, discharge, or
change in B-type natriuretic peptide and long-term outcomes: data
from Organized Program to Initiate Lifesaving Treatment in Hospi-
talized Patients with Heart Failure (OPTIMIZE-HF) linked to Medicare
claims. Circ Heart Fail. 2011;4:628e36.
22. Horwich TB, Patel J, MacLellan WR, et al. Cardiac troponin I is
associated with impaired hemodynamics, progressive left ventricular
Annals of Global Health 53
dysfunction, and increased mortality rates in advanced heart failure.
23. Hudson MP, O’Connor CM, Gattis WA, et al. Implications of elevated
cardiac troponin T in ambulatory patients with heart failure: a pro-
spective analysis. Am Heart J. 2004;147:546e52.
24. Latini R, Masson S, Anand IS, et al. Prognostic value of very low
plasma concentrations of troponin T in patients with stable chronic
heart failure. Circulation. 2007;116:1242e9.
25. Wang TJ. Signiﬁcance of circulating troponins in heart failure: if these
walls could talk. Circulation. 2007;116:1217e20.
26. Braunwald E. Biomarkers in heart failure. N Engl J Med. 2008;358:
27. Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and
outcomes in heart failure: systematic review and meta-analysis. J Am
Coll Cardiol. 2006;47:1987e96.
28. Akhter MW, Aronson D, Bitar F, et al. Effect of elevated admission
serum creatinine and its worsening on outcome in hospitalized pa-
tients with decompensated heart failure. Am J Cardiol. 2004;94:
29. Shlipak MG, Sarnak MJ, Katz R, et al. Cystatin C and the risk of death
and cardiovascular events among elderly persons. N Engl J Med.
30. Lassus J, Harjola VP, Sund R, et al. Prognostic value of cystatin C in
acute heart failure in relation to other markers of renal function and
NT-proBNP. Eur Heart J. 2007;2 8:1841e7.
31. Bolignano D, Basile G, Parisi P, et al. Increased plasma neutrophil
gelatinase-associated lipocalin levels predict mortality in elderly pa-
tients with chronic heart failure. Rejuvenation Res. 2009;12:7e14.
32. Yndestad A, Landro L, Ueland T, et al. Increased systemic and
myocardial expression of neutrophil gelatinase-associated lipocalin in
clinical and experimental heart failure. Eur Heart J. 2009;30:
33. Klein L, O’Connor CM, Leimberger JD, et al. Lower serum sodium is
associated with increased short-term mortality in hospitalized pa-
tients with worsening heart failure: results from the Outcomes of a
Prospective Trial of Intravenous Milrinone for Exacerbations of
Chronic Heart Failure (OPTIME-CHF) study. Circulation. 2005;111:
34. Gheorghiade M, Abraham WT, Albert NM, et al. Relationship be-
tween admission serum sodium concentration and clinical outcomes
in patients hospitalized for heart failure: an analysis from the
OPTIMIZE-HF registry. Eur Heart J. 2007;28:980e8.
35. Gaggin HK, Januzzi JL Jr. Biomarkers and diagnostics in heart failure.
Biochim Biophys Acta. 2013;1832:2442e50.
36. Ahmad T, Felker GM. Galectin-3 in heart failure: more answers or
more questions? J Am Heart Assoc. 2012;1:e004374.
37. Felker GM, Fiuzat M, Shaw LK, et al. Galectin-3 in ambulatory pa-
tients with heart failure: results from the HF-ACTION study. Circ
Heart Fail. 2012;5:72e8.
38. Anker SD, Koehler F, Abraham WT. Telemedicine and remote man-
agement of patients with heart failure. Lancet. 2011;378:731e9.
39. Chaudhry SI, Mattera JA, Curtis JP, et al. Telemonitoring in patients
with heart failure. N Engl J Med. 2010;363:2301e9.
40. Koehler F, Winkler S, Schieber M, et al. Impact of remote
telemedical management on mortali ty and hospitalizations in
amb ulatory patients with chroni c heart failure: the telemedical
interventional monitoring in heart failure study. Circulation.
41. Bourge RC, Abraham WT, Adamson PB, et al. Randomized controlled
trial of an implantable continuous hemodynamic monitor in patients
with advanced heart failure: the COMPASS-HF study. J Am Coll
42. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary
artery haemodynamic monitoring in chronic heart failure: a rando-
mised controlled trial. Lancet. 2011;377:658e66.
43. Singh B, Russell SD, Cheng A. Update on device technologies for
monitoring heart failure. Curr Treat Options Cardiovasc Med.
44. van Veldhuisen DJ, Braunschweig F, Conraads V, et al. Intrathoracic
impedance monitoring, audible patient alerts, and outcome in pa-
tients with heart failure. Circulation. 2011;124:1719e26.
45. Krumholz HM, Currie PM, Riegel B, et al. A taxonomy for disease
management: a scientiﬁc statement from the American Heart
Association Disease Management Taxonomy Writing Group. Circu-
46. Fonarow GC, Stevenson LW, Walden JA, et al. Impact of a compre-
hensive heart failure management program on hospital readmission
and functional status of patients with advanced heart failure. J Am
Coll Cardiol. 1997;30:725e32.
47. West JA, Miller NH , Parker KM, et al. A comprehensive man-
agement system f or heart failure improves clinical outcomes and
reduces medical resource utilization. Am J Cardiol. 1997;79:
48. Rich MW, Beckham V, Wittenberg C, et al. A multidisciplinary inter-
vention to prevent the readmission of elderly patients with conges-
tive heart failure. N Engl J Med. 1995;333:1190e5.
49. McAlister FA, Stewart S, Ferrua S, et al. Multidisciplinary strategies for
the management of heart failure patients at high risk for admission:
a systematic review of randomized trials. J Am Coll Cardiol. 2004;44:
50. Galbreath AD, Krasuski RA, Smith B, et al. Long-term healthcare and
cost outcomes of disease management in a large, randomized,
community-based population with heart failure. Circulation.
51. Randomised trial of telephone intervention in chronic heart failure:
DIAL trial. BMJ. 2005;331:425.
52. Ferrante D, Varini S, Macchia A, et al. Long-term results after a
telephone intervention in chronic heart failure: DIAL (Randomized
Trial of Phone Intervention in Chronic Heart Failure) follow-up. J Am
Coll Cardiol. 2010;56:372e8.
53. Jaarsma T, van der Wal MH, Lesman-Leegte I, et al. Effect of mod-
erate or intensive disease management program on outcome in
patients with heart failure: Coordinating Study Evaluating Outcomes
of Advising and Counseling in Heart Failure (COACH). Arch Intern
54. Takeda A, Taylor SJ, Taylor RS, et al. Clinical service organisation for
heart failure. Cochrane Database Syst Rev. 2012;9:CD002752.
55. Angermann CE, Stork S, Gelbrich G, et al. Mode of action and ef-
fects of standardized collaborative disease management on mortality
and morbidity in patients with systolic heart failure: the Interdisci-
plinary Network for Heart Failure (INH) study. Circ Heart Fail. 2011;5:
54 Chronic Heart Failure Management