Education in Heart
Heart: first published as 10.1136/heartjnl-2020-318553 on 6 September 2023. Downloaded from http://heart.bmj.com/ on September 7, 2023 at Bib Consejeria Sanidad SACYL Consortia.
Department of Cardiovascular
Sciences and NIHR Biomedical
Research Centre, University of
Leicester, Leicester, UK
Correspondence to
Shirley Sze, Department of
Cardiovascular Sciences and
NIHR Biomedical Research
Centre, University of Leicester,
Leicester LE3 9QP, UK;
​shirley.​sze@​nhs.​net
© Author(s) (or their
employer(s)) 2023. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Eltayeb M, Squire I,
Sze S. Heart Epub ahead of
print: [please include Day
Month Year]. doi:10.1136/
heartjnl-2020-318553
Biomarkers in heart failure: a focus on
natriuretic peptides
Mohamed Eltayeb, Iain Squire ‍ ‍, Shirley Sze ‍ ‍
ABSTRACT
While progress has been made in the management of
most aspects of cardiovascular disease, the incidence and
prevalence of heart failure (HF) remains high. HF affects
around a million people in the UK and has a worse
prognosis than most cancers. Patients with HF are often
elderly with complex comorbidities, making accurate
assessment of HF challenging. A timely diagnosis and
initiation of evidence-­based treatments are key to
prevent hospitalisation and improve outcomes in this
population. Biomarkers have dramatically impacted the
way patients with HF are evaluated and managed. The
most studied biomarkers in HF are natriuretic peptides
(NPs). Since their discovery in the 1980s, there has been
an explosion of work in the field of NPs and they have
become an important clinical tool used in everyday
practice to guide diagnosis and prognostic assessment
of patients with HF. In this article, we will review the
physiology of NPs and study their biological effects.
Then, we will discuss the role of NPs in the diagnosis,
management and prognostication of patients with
HF. We will also explore the role of NPs as a potential
therapeutic agent.
INTRODUCTION
Since the identification of the ‘atrial factor’—later
identified as atrial natriuretic peptide (ANP)—by
de Bold et al1 in 1981 to fill in a gap in the under-
standing of volume haemostasis in health and
disease, there has been an explosion in the field of
natriuretic peptides (NPs) and the understanding of
their role in the cardiovascular system.
The most studied NPs in heart failure (HF),
B-­type natriuretic peptide (BNP) and N-­ terminal
pro B-­type natriuretic peptide (NT-­proBNP), have
come to play a pivotal role in the diagnosis of HF
and in the understanding of an individual patient’s
disease trajectory and prognosis.
In this article, we will discuss (1) the mechanism
of release of NPs and their biological effects; (2)
their role in the diagnosis, management and prog-
nostication of patients with HF; (3) their poten-
tial role as therapeutic agents and (4) the effect of
recent advances in HF therapy on the clinical use
and interpretation of NP values.
BIOLOGICAL EFFECTS OF CARDIAC
NATRIURETIC PEPTIDES
ANP and BNP share similar biological effects,
modulating cardiovascular function at several levels.
ANP is predominantly secreted from, and stored in,
the atrium; it is also secreted from other tissues,
including the left ventricle (LV), in disease states.
BNP, on the contrary, is stored in small amounts
in atrial granules but is synthesised and released
Eltayeb M, et al. Heart 2023;0:1–10. doi:10.1136/heartjnl-2020-318553
Learning objectives
⇒ To understand the biological effects of
natriuretic peptides (NPs).
⇒ To understand the role of NPs in the diagnosis
of heart failure (HF).
⇒ To consider the cardiac and non-­cardiac factors
that may influence the interpretation of NP
values.
⇒ To understand the prognostic utility of NPs
across the spectrum of HF.
⇒ To understand the role of NPs in guiding HF
management.
as a result of increased myocardial wall stress and
filling pressure.2 Both hormones are released as
pre-­prohormones and after removal of the signal-
ling peptides, are then cleaved into an active
Protected by copyright.
peptide and a corresponding biologically inactive
peptide, N-­ terminal pro-­atrial natriuretic peptide
(NT-­ proANP) and NT-­ proBNP, respectively.3
They exert their physiologic effect via receptor-­
mediated cyclic guanosine monophosphate signal-
ling pathways and are degraded primarily through
receptor-­mediated internalisation and enzymatic
degradation3 (figure 1).
At the level of the kidneys, ANP and BNP stimu-
late natriuresis and diuresis. In the glomerulus, they
cause dilatation of the afferent and constriction of
the efferent renal arterioles, increasing the glomer-
ular filtration rate (GFR). In the collecting duct,
they inhibit sodium reabsorption. Both peptides
also inhibit the secretion of renin, angiotensin II
and aldosterone4 (figure 1).
NPs also have important central and peripheral
sympathoinhibitory effects3 (figure 1). Reduction
in cardiac and pulmonary chemoreceptor and baro-
receptor activity suppresses sympathetic outflow
to the heart and increases vagal efferent activity,
leading to a reduction in heart rate and improve-
ment in cardiac output. ANP also suppresses water
reabsorption by inhibiting vasopressin secretion
from the posterior pituitary. NPs also lower the
salt and water appetite, leading to a reduction in
extracellular fluid volume. NPs directly affect blood
vessel function by reducing vascular smooth muscle
tone and hence peripheral vascular resistance,
leading to vasodilatation; they also increase capil-
lary permeability.5 Cumulatively, these effects result
in significant increase in haematocrit.5
NPs also have growth suppressing and antiprolif-
erative properties; ANP has been shown to inhibit
vascular smooth muscle cell proliferation6 and the
growth-­ promoting effects of norepinephrine in
  1
 Education in Heart

Heart: first published as 10.1136/heartjnl-2020-318553 on 6 September 2023. Downloaded from http://heart.bmj.com/ on September 7, 2023 at Bib Consejeria Sanidad SACYL Consortia.
Protected by copyright.
Figure 1 Physiology of NPs. Wall stretch triggers the production of proBNP which will then be cleaved into an active peptide (NP) and a biologically
inactive peptide (NT-­proANP or NT-­proBNP). The effects of circulating NPs are mainly mediated via NPR-­A. When NPR-­A is activated, the production
of cGMP is stimulated, this activates PKG which brings about different target tissue effects. NPs are cleared via three pathways: binding to clearance
receptor NPR-­C, resulting in its internalisation and lysosomal degradation. NPs are also cleaved by circulating endopeptidases, for example, neprilysin
or excreted via the kidneys. cGMP,cyclic guanosine monophosphate, GFR, glomerular filtration rate; GTP, guanosine triphosphate; NPR, natriuretic
peptide receptor; PKG, protein kinase G; proANP, pro-­atrial natriuretic peptide; proBNP, pro-B-­type natriuretic peptide; RAAS, renin–angiotensin–
aldosterone system.

cardiac myocytes and fibroblasts are also inhib-
ited by ANP.7 BNP has antifibrotic effects and is an
important regulator of cardiac interstitial remodel-
ling4 (figure 1)
ROLE OF NPS IN THE DIAGNOSIS OF HF
NPs reflect cardiac stress and dysfunction and
are markedly increased in patients with HF.
They have diagnostic value for different forms
of HF and are often used to evaluate HF severity.
Among the cardiac NPs, BNP and NT-­p roBNP
are preferred for diagnosis of HF compared
with ANP, for several reasons. First, although
the plasma level of BNP in healthy individuals
is much lower than that of ANP (3.5 pg/mL vs
20 pg/mL); in patients with HF, the concen-
tration of BNP is increased to a much greater
degree (up to 100-­f old increase) compared with
ANP. 8 Second, BNP and NT-­ p roBNP are less
labile and have a much longer half-­life (22 and
70 min, respectively) than ANP (2 min). 8
Acute heart failure (AHF)
Differentiating HF from alternative causes of
breathlessness can be challenging in the acute
setting. NPs can be useful in supporting or
excluding the diagnosis of HF when the aeti-
ology of dyspnoea is unclear. European Society
of Cardiology (ESC) guidelines recommend
BNP≥100 pg/mL, NT-­p roBNP≥300 pg/mL
and mid-­regional pro-­a trial natriuretic peptide
(MR-­p roANP)≥120 pg/mL for identification of
possible AHF. 9
A meta-­a nalysis of the diagnostic accuracy of
NPs for HF showed that BNP<100 pg/mL (sensi-
tivity: 0.95, negative predictive value (NPV):
0.94), NT-­ p roBNP<300 pg/mL (sensitivity:
0.99, NPV: 0.98) and MR-­p roANP≤120 pmol/L
(sensitivity: 0.95, NPV: 0.90) have excellent
ability to exclude the diagnosis of AHF. 10 Use
of NPs may enable streamlining of investigation
in patients presenting with suspected HF in the
acute setting. For example, NP levels below a
defined threshold can safely rule out HF and
focus investigations towards other potential
causes of the patient’s symptoms. A negative test
may also obviate the need to proceed to early
echocardiography, allowing more efficient use
of resources. In patients where clinical assess-
ment is difficult, an elevated NP level could raise
the suspicion of HF and instigate investigations

2 Eltayeb M, et al. Heart 2023;0:1–10. doi:10.1136/heartjnl-2020-318553

 Education in Heart

Heart: first published as 10.1136/heartjnl-2020-318553 on 6 September 2023. Downloaded from http://heart.bmj.com/ on September 7, 2023 at Bib Consejeria Sanidad SACYL Consortia.
Protected by copyright.
Figure 2 European Society of Cardiology diagnostic pathway for HF in the non-­acute setting. NP testing is recommended in those with suspected
HF, particularly to rule out the diagnosis. Recreated from the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure
by McDonagh et al.9 AF, atrial fibrillation; HF, heart failure; JVP, jugular venous pressure; LVEF, left ventricular ejection fraction; LVH, left ventricular
hypertrophy; MI, myocardial infarction; NP, natriuretic peptide; NT-­proBNP, N-­terminal pro-­B-­type natriuretic peptide;PND, paroxysmal nocturnal
dyspnoea.

to confirm or refute the diagnosis, allowing
appropriate treatment to be initiated in a timely
fashion.
At higher thresholds, the sensitivity of NPs
for diagnosing AHF decreases (ie, more cases
of AHF would be missed); although specificity
increases, the improvement is modest and vari-
able. 10 Therefore, in patients with NP values
above the rule-­o ut thresholds, it is important
to correlate such information with clinical and
imaging assessment to confirm a diagnosis of
HF. In any individual patient, cardiac and non-­
cardiac factors which may contribute to increased
NP levels should be considered; context is
everything. For instance, atrial fibrillation (AF)
is associated with approximately threefold
increase in circulating NP levels, taking levels to
the ‘abnormal’ range in a significant proportion
of cases. Other conditions associated with eleva-
tion of NPs include acute coronary syndrome,
myocarditis, pulmonary embolism, severe renal
impairment, sepsis, critical illness and age. 11 In
Eltayeb M, et al. Heart 2023;0:1–10. doi:10.1136/heartjnl-2020-318553
patients with elevated NPs, a careful clinical
review should be performed prior to further
investigations for HF (eg, echocardiogram). In
patients where there is a strong suspicion of
HF and other non-­H F contributing factors have
been considered, an echocardiogram should be
performed in a timely manner to look for struc-
tural abnormalities (eg, LV systolic or diastolic
dysfunction or valvular abnormality) that may
lead to AHF, so that targeted therapy can be
initiated.
Both BNP and NT-­p roBNP retain their diag-
nostic performance in AHF irrespective of left
ventricular ejection fraction (LVEF), 11 although
the sensitivity of NT-­p roBNP in diagnosing AHF
appears to be lower in cases of heart failure with
preserved ejection fraction (HFpEF) compared
with heart failure with reduced ejection fraction
(HFrEF) (84% vs 92%). 12 The level of NP does
not differentiate between HFpEF and HFrEF. As
with any test, the pretest probability is important
and results must be interpreted in the clinical
3
Education in Heart
context. If the clinical scenario is indicative of
HF, or conversely, points towards an alterna-
tive diagnosis, there is no indication to check
NP levels. The National Institute for Health and
Care Excellence (NICE) recommends the use of
NPs only in patients with ‘new, suspected HF’. 13
Chronic heart failure
There is less published literature regarding
the role of NPs for diagnostic evaluation in
the ambulatory setting. NPs maybe useful in
supporting evaluation of HF in an outpatient
setting, particularly when used to distinguish
cardiac versus non-­c ardiac causes of dyspnoea,
as in the acute setting. The Natriuretic Peptides
in the Community Study showed that in patients
with suspected HF, the addition of NT-­p roBNP
to standard clinical review resulted in a 21%
absolute improvement in achieving an accurate
HF diagnosis compared with only 8% improve-
ment in those with clinical review alone; the
improvement is mainly driven by general prac-
titioners correctly ruling out HF. 14 The ESC
recommends measurement of NPs as an initial
diagnostic test in patients with symptoms
suggestive of HF, particularly to rule out the
diagnosis 9 (figure 2). This emphasises the earlier
point regarding the low specificity of NPs for
the identification of HF and their greater clin-
ical utility for excluding the condition when not
elevated.
Cut-­o ff values for NPs used to diagnose HF
in an outpatient setting are much less investi-
gated than those used in the acute setting. There
is no clear consensus about the appropriate
threshold for diagnosing CHF using different
NPs. The ESC recommends a plasma BNP level
of <35 pg/mL, NT-­ p roBNP <125 pg/mL or
MR-­p roANP <40 pmol/L to exclude HF in the
non-­a cute setting, 9 while NICE recommends
an NT-­p roBNP level >400 ng/L for referral of
patients with suspected HF. 13
A recent meta-­ a nalysis looking at the diag-
nostic accuracy of point-­ o f-­
c are NP testing
for CHF in an ambulatory setting showed
that various NP thresholds have been used for
the index tests (5.1–412 pg/mL for BNP and
117–1000 pg/mL for NT-­p roBNP). 15 The most
used diagnostic threshold for BNP was 100 pg/
mL (threshold recommended by ESC and NICE
for acute setting 9 16) and for NT-­p roBNP was
125 pg/mL (threshold recommended by ESC
for non-­a cute setting 9). No study reported BNP
data at 35 pg/mL (threshold recommended by
ESC for non-­ a cute setting 9). The sensitivity
and specificity of BNP and NT-­p roBNP testing
were highly variable depending on the diag-
nostic threshold and the population studied.
At a threshold of 100 pg/mL, the pooled sensi-
tivity and specificity of BNP based on seven
studies were 0.95 and 0.64, respectively. At a
threshold of 125 pg/mL, the pooled sensitivity
and specificity of NT-­p roBNP, based on three
studies, were 0.99 and 0.60, respectively. Given
4 Eltayeb M, et al. Heart 2023;0:1–10. doi:10.1136/heartjnl-2020-318553
Heart: first published as 10.1136/heartjnl-2020-318553 on 6 September 2023. Downloaded from http://heart.bmj.com/ on September 7, 2023 at Bib Consejeria Sanidad SACYL Consortia.
the paucity of data in the ambulatory setting,
further trials in primary care are needed to
assess the role of point-­o f-­c are NP testing and
clarify appropriate thresholds to diagnose HF.
HFrEF versus HFpEF
Several studies have shown that NP levels are
higher in patients with HFrEF than in those
with HFpEF; however, head-­ t o-­
h ead compar-
ison between NP levels of patients with the two
different HF phenotypes in the same outpatient
population was rarely performed. A detailed
analysis of NT-­p roBNP levels in outpatients with
HFpEF (N=1811) versus HFrEF (N=5914)
enrolled in the Swedish Heart Failure Registry
confirmed previous observations that average
NP levels in patients HFrEF were higher than
those with HFpEF (median NT-­ p roBNP:
HFpEF=1428 pg/mL vs HFrEF=2288 pg/mL).
This might be due to higher end-­d iastolic wall
stress in patients with HFrEF than HFpEF. 17
According to a recent systematic review and
meta-­analysis, NPs have reasonable diagnostic
performance for the detection of HFpEF in a
non-­ a cute setting, with area under the curve
(AUC) values of approximately 0.80. 18 Both
NT-­ p roBNP and BNP have higher specificity
(NT-­p roBNP: 85%; BNP: 78%) than sensitivity
(NT-­ p roBNP: 69%; BNP: 68%) for detection
Protected by copyright.
of HFpEF, suggesting once again that NPs may
be more useful in ruling out HFpEF than for
making the diagnosis.
It is important to bear in mind that in patients
with early HF or in those with stable, well-­
treated HF, especially those with HFpEF, the
levels of BNP and NT-­p roBNP may be relatively
low. In this context, the signal-­to-­n oise ratio is
markedly diminished and factors influencing
NP concentration that are of little importance
in acute HF become major confounders and
should be considered. Therefore, as in all situa-
tions, NPs should be considered in context, and
used in conjunction with clinical assessment and
echocardiography for diagnosis of HFpEF.
Screening for asymptomatic left ventricular
systolic dysfunction (LVSD)
The use of NPs for detection of LVSD in asymp-
tomatic individuals has less utility. In 3177
asymptomatic individuals from the Framingham
study, the diagnostic performance of BNP and
NT-­A NP for detecting elevated LV mass or LVSD
(LVEF≤50%) was suboptimal, with AUC for
both peptides ≤0.75. 19 Comparing the perfor-
mance of different NPs in identifying significant
LVSD (LVEF≤35%), BNP (AUC: 0.96) may be
superior to NT-­ p roBNP (AUC: 0.90) or ANP
(AUC: 0.85). 20 The positive predictive value of
NPs for identification of previously undiagnosed
LVSD is markedly enhanced by consideration of
major ECG abnormalities (including patholog-
ical Q waves, left ventricular hypertrophy, AF
and left bundle branch block) and a history of

ischaemic heart disease. 20 Overall, the available
data do not support the use of NPs alone as a
mass screening tool for LVSD.
Modest elevation in NP levels in patients
without a diagnosis of HF identifies individuals
at risk of developing HF. Wang and colleagues 21
prospectively studied the relations of plasma
BNP and NT-­p roANP in predicting incident HF
in 3346 persons without HF. During a mean
follow-­ u p of 5.2 years, after adjustment for
cardiovascular risk factors, the authors found
that each 1 SD increment in logBNP and logNT-­
proANP was associated with a 77% and 94%
increase in the risk of developing HF, respec-
tively. Peptide levels >80th percentile (BNP:
20 pg/mL for men, 23.3 pg/mL for women;
NT-­ p roANP 497 pmol/L for men, 351 pmol/L
for women) were associated with threefold
(BNP) and fivefold (NT-­ p roANP) increase in
risk, respectively. The American Heart Associ-
ation (AHA) guidelines for the management of
HF give a level 2a recommendation for the use
of NP to screen patients at risk of developing
HF, when utilised in the setting of subsequent
team based care. 22
Caveats to consider when using NPs in
diagnosing HF
Despite the proven value of NPs for diagnosis
across the spectrum of HF syndromes, it is
important to consider its limitations in specific
clinical contexts. One of the strongest stimu-
lants for myocardial NP production is myocar-
dial stretch due to increased intracardiac volume
or pressure. While acute or chronic HF strongly
stimulates NP production, many other cardio-
vascular diagnoses such as significant valvular
disease, infiltrative or hypertrophic cardiomy-
opathy, cor pulmonale and AF are very likely to
have a similar effect. 23
Multiple other non-­c ardiac factors may also
contribute to the synthesis and release of NPs.
Advanced age and comorbidities, such as renal
dysfunction, are associated with increased
plasma concentrations of NPs, irrespective of
left ventricular function or the presence of HF,
limiting their usefulness as a ‘rule in’ marker.
Ethnicity also influences plasma NP levels;
people of black and Hispanic ethnicities have
higher NP levels compared with Caucasians for
each corresponding NYHA class. 24
NP values are expected to be higher in the
elderly even in the absence of HF, possibly
as a result of reduction in natriuretic peptide
receptor (NPR)-­ C clearance receptors with
ageing. The predictive value of NPs for identi-
fication of LVSD has been shown to drop from
0.95 to 0.82 in patients over 75 years of age. 25
Therefore, age-­adjusted cut-­o ffs for NPs have
been suggested to improve their diagnostic accu-
racy in both AHF and CHF (AHF: NT-­p roBNP
>450 pg/mL for patients <50 years; 900 pg/
Eltayeb M, et al. Heart 2023;0:1–10. doi:10.1136/heartjnl-2020-318553
Education in Heart
Heart: first published as 10.1136/heartjnl-2020-318553 on 6 September 2023. Downloaded from http://heart.bmj.com/ on September 7, 2023 at Bib Consejeria Sanidad SACYL Consortia.
mL for those 50–75 years and 1800 pg/mL for
those >75 years 26; CHF: NT-­p roBNP >50 ng/L
for patients <50 years, 75 ng/L for those 50–75
years and 250 ng/L for those >75 years). 27
However, it is clear from the preceding text
that the use of simple dichotomisation of NP
levels based on age alone is simplistic. Failure to
consider confounding factors, such as the pres-
ence of AF, cor pulmonale and renal dysfunc-
tion, is likely to contribute to clinical confusion
and inaccurate labelling of patients as having/
not having HF.
The association between NP levels and renal
function is complex. Patients with chronic
kidney disease (CKD) tend to have higher atrial
pressure, systemic pressure and ventricular
mass, all of which are associated with elevated
NP levels. On the contrary, patients with CKD
have decreased renal filtration, decreased NP
clearance by NPR-­C and decreased renal respon-
siveness to BNP. NP levels begin to rise when
GFR decreases below 60 mL/min/1.7 m 2. 28 A
stronger relation appears to exist between GFR
and NT-­ p roBNP compared to that with BNP
levels. 29 NT-­p roBNP may be more sensitive to
reduced renal filtration and clearance than BNP,
as the clearance of NT-­p roBNP, unlike BNP, is
not mediated by NPR-­C . 30 A higher cut-­o ff of
Protected by copyright.
NT-­ p roBNP >1200 pg/mL has been proposed
for diagnosing HF in patients with CKD. 29
Conversely, NPs may be disproportionately
low in patients with high body mass index (BMI),
irrespective of volume status. 31 This appears to
be mediated through mechanisms other than
NPR-­C clearance, as both NT-­p roBNP and BNP
are closely associated with BMI; however, only
BNP, and not NT-­p roBNP, is cleared by NPR-­
C. 32 A lower BNP cut-­ o ff (eg, 50 pg/mL) has
been proposed for use in obese patients. This
is currently not reflected in the ESC guidelines
for management of HF. In patients with signs
and symptoms of HF who have risk factors for
developing HF, a lower-­than-­n ormal NP level
should not stop a physician from referring the
patient for specialist assessment. NPs should be
used in conjunction with clinical presentation
and other testing for diagnosis of HF. If a base-
line NP is available, then using the NP trend to
guide diagnosis may also be helpful.
Figure 3 summarises the factors influencing
the interpretation of NPs. While the ESC HF
guidelines 13 acknowledge that multiple cardio-
vascular and non-­ c ardiovascular factors could
impact on NP levels and reduce their accuracy
in diagnosing HF, there is currently no recom-
mendation that alternative NP cut-­o ffs should
be used when assessing patients with the above-
mentioned factors. The only exception is that for
the diagnosis of HFpEF, the ESC proposed using
a higher NP threshold in patient in AF versus
those in sinus rhythm (NT-­ p roBNP: 365 vs
125 pg/mL and BNP: 105 vs 35 pg/mL). Instead,
priority has been given to make guidelines
5
 Education in Heart

Heart: first published as 10.1136/heartjnl-2020-318553 on 6 September 2023. Downloaded from http://heart.bmj.com/ on September 7, 2023 at Bib Consejeria Sanidad SACYL Consortia.
Protected by copyright.
Figure 3 Factors influencing the interpretation of NPs. While acute and chronic heart failure strongly stimulates NP production, many other cardiac
and non-­cardiac factors also contribute to the synthesis and release of NPs and should be considered when interpreting NP levels. COPD, chronic
obstructive pulmonary disease; ICD, implantable cardioverter defibrillator; NP, natriuretic peptide.

simple and accessible to non-­ s pecialists, thus
increasing the likelihood of identifying patients
with suspected HF for specialist assessment.
PROGNOSTIC UTILITY OF NPS
NPs are well-­ e stablished prognostic markers
across a spectrum of HF severity. In patients with
chronic HFrEF (LVEF<45%), Tsutamoto and
colleagues 33 showed that BNP, but not ANP, was
a significant independent predictor of mortality.
In patients hospitalised for HF, an elevated
NT-­p roBNP level was associated with increased
risk of rehospitalisation and mortality. 34 In
patients with advanced HF referred for consid-
eration of cardiac transplant, NT-­p roBNP has
been shown to be a better prognostic marker
than LVEF, maximum oxygen uptake and the HF
survival score in predicting death and the need
of urgent cardiac transplant. 35 However, the
study has a limited sample size and the results
have not altered the clinical guidance on assess-
ment of patients with advanced HF. Currently,
the ESC does not have specific recommenda-
tions on the use of NPs in prognosticating and
risk stratifying patients with advanced HF.
Instead, the Interagency Registry for Mechan-
ically Assisted Circulatory Support (INTER-
MACS) profiles should be used to determine the
ideal timing for referral to specialist centres for
advanced HF therapies. High-­r isk features such
as recurrent HF hospitalisations, progressive
end-­ o rgan failure and refractory congestion,
are often associated with persistently elevated
NP levels and should prompt urgent referral to
advanced HF centres.
Higher levels of NPs have also been shown to
be a significant prognostic marker in the general
population. The EchoCardiographic Heart of
England Screening study demonstrated that
NT-­ p roBNP >150 pg/mL was associated with
an 18-­f old increased risk of developing HF and
a 58% increased risk of death within 10 years. 36
Patients not known to have HF, but found to
have markedly high NP levels, should be assessed
urgently. Again, the contribution of concurrent
conditions, such as AF, should be considered.
A large contemporary community-­b ased study
showed that high NP levels (>2000 pg/mL) at
diagnosis was related to a twofold increased
risk of HF hospitalisation in the year following
diagnosis and 41% increased mortality in the
first 2 years. 37 NICE recommends patients with
NT-­ p roBNP >2000 pg/mL to be seen within
2 weeks of referral. 13 A specialist HF service
organised based on tiered NP thresholds may
facilitate rapid identification of patients with
HF. Timely initiation of disease-­ m odifying

6 Eltayeb M, et al. Heart 2023;0:1–10. doi:10.1136/heartjnl-2020-318553


treatment in such individuals may reduce risk
of hospital admission and potentially improve
survival.
NPS IN THE GUIDANCE OF HF THERAPY
The goals of therapy in the management of
HF are to reduce mortality and hospitalisa-
tions and to optimise patients’ symptoms and
quality of life. Pharmacotherapy with what has
become known as the ‘four pillars’ of HFrEF
treatment [ACE inhibitor (ACEi)/angiotensin
receptor-­n eprilysin inhibitor, beta-­b locker,
mineralocorticoid receptor antagonist (MRA)
and sodium-­g lucose co-­t ransporter-­2 inhibitors
(SGLT2i)], is the key element in HF therapy to
reduce the risk of hospitalisation and death. 9 In
its latest guideline for the diagnosis and manage-
ment of HF, the ESC adopts a clinically oriented
definition of HF, in which breathlessness and
ankle swelling are considered cardinal symp-
toms that may be associated with an elevated
jugular venous pressure, pulmonary crackles and
peripheral oedema as supporting signs in the HF
syndrome. This makes congestion an integral
part of the definition of HF and is recognised
as a leading cause of symptoms and admission in
AHF and CHF. 22 The utility of biomarkers as a
Key messages
⇒ Natriuretic peptides (NPs) are produced by cardiovascular, brain and renal
tissues in response to myocardial wall stress and have a wide range of
biological effects. NPs increase glomerular filtration and stimulate natriuresis
and diuresis. They also reduce vascular smooth muscle tone, leading to
vasodilation. NPs also suppress the sympathetic nervous system. They have
antifibrotic effect and are important regulators of cardiac remodelling. NPs
also have metabolic effects such as stimulation of lipolysis.
⇒ NPs have low specificity for the identification of heart failure (HF); their
greater clinical utility is for excluding the condition when not elevated.
⇒ NP levels should be interpreted with consideration to clinically relevant
parameters including age, body mass index, renal dysfunction and the
presence of AF.
⇒ NPs are well-­established prognostic markers for patients with HF across the
disease spectrum. In patients not known to have HF, a markedly high NP
level should prompt urgent referral for specialist assessment.
⇒ NPs may have utility as adjuncts to other parameters in guiding HF therapy
but should not be used in isolation as a guide to therapy.
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Eltayeb M, et al. Heart 2023;0:1–10. doi:10.1136/heartjnl-2020-318553
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potential guide for pharmacotherapy including
decongestion therapy has become a topic of
interest.
Congestion
As increased mechanical cardiac wall stress,
particularly in the LV, is the key driver for the
production and release of NPs, their utility in
guiding therapy in the setting of congestion has
been studied for over two decades. However,
NPs were found to have only weak to moderate
correlation with mean pulmonary artery pres-
sure and pulmonary artery wedge pressure. 38
Similarly, the correlation between NPs and right
atrial pressure was weak, which may explain
their weak performance in predominantly right-­
sided HF. 38 Moreover, a contemporary view on
congestion considers regional (pulmonary vs
systemic) and compartmental (intravascular vs
extravascular) distribution of congestion, 38 in
which LV wall stress and NPs might not be reflec-
tive of the entire clinical picture. Furthermore,
there is no strong correlation between NPs and
other indicators of decongestion. 38 39 There-
fore, NPs may be used as a surrogate marker,
but not a reliable predictor, of congestion and
decongestion. This is a crucial point; there is a
Protected by copyright.
perception among non-­s pecialists, in particular,
that elevated NP levels equate to congestion.
This is very much not the case, and elevated NP
levels should not trigger up-­t itration of diuretic
therapy without appropriate clinical assessment.
Pharmacotherapy
Multiple studies over the past 20 years have inves-
tigated the benefits of NP-­guided HF therapy,
with conflicting results. Many studies failed
to demonstrate any advantage to NP-­ guided,
compared with clinically guided therapy, while
others reported benefits of NP-­guided therapy in
certain subsets of patients, for example, younger
patients.40 It was noted that studies which
demonstrated benefit of NP-­ guided therapy
were more likely to have achieved significant
reduction in NP levels in the NP-­guided arm or
have low target NP values.41 This suggests that
these studies have examined NP-­guided therapy
more rigorously than those without significant
changes in the primary guiding target, that is,
NPs.
An individual patient meta-­a nalysis studying
the effect of NP-­guided treatment of CHF on
mortality and hospitalisation,42 using data from
over 2000 patients across nine studies, showed
that NP-­guided CHF therapy was associated with
significant reduction in all-­c ause mortality (HR:
0.62; 95% CI: 0.45 to 0.86; p=0.004). This
survival benefit was only observed in younger
patients <75 years (HR: 0.62; 95% CI: 0.45
to 0.85; p=0.004) and not in those ≥75 years
7
Education in Heart
(HR: 0.98; 95% CI: 0.75 to 1.27; p=0.96).
NP-­g uided therapy was associated with a signif-
icant reduction in HF hospitalisation (HR:
0.80; 95% CI: 0.67 to 0.94; p=0.009) and the
combined outcome of all-­cause hospitalisation
and mortality (HR: 0.84; 95% CI: 0.71 to 0.99;
p=0.037) but not all-­cause hospitalisation alone
(HR: 0.94; 95% CI: 0.84 to 1.07; p=0.38). 42
In the Guiding Evidence Based Therapy Using
Biomarker Intensified Treatment in Heart Failure
(GUIDE-­ I T) study, 894 patients (of planned
1100 patient) were randomised to NP-­ guided
therapy or usual care with prioritisation of titra-
tion of neurohormonal modulators over diuretic
therapy unless there was a clinical need. 43 The
study was terminated early due to futility, as it
met prespecified inefficiency criteria. There was
no evidence that an NP-­g uided HF strategy is
superior to usual care, with no difference in
the primary outcome of first hospitalisation for
HF or cardiovascular death. Further, there was
no statistically significant difference between
the two groups in terms of all-­c ause mortality,
cardiovascular mortality, HF hospitalisation
and all-­cause hospitalisation.43 In GUIDE-­ I T,
there was a marginal numerical but not statis-
tically significant difference in the utilisation
and final doses achieved of individual compo-
nents of medical therapy (beta-­blockers, ACEi/
angiotensin receptor blocker (ARB) and MRA),
in favour of NP-­g uided therapy. Earlier studies
showed a numerically and often statistically
significant difference in that regard.41
There is an argument that GUIDE-­I T may not
have reflected a comparison between real-­world
usual care and NP-­g uided care, with expert HF
clinicians involved in participants’ management
and intense visit schedule, resulting in a marked
reduction in NT-­ p roBNP levels in both arms.
As such, this may reflect a comparison between
expert HF care, which may not benefit from
knowledge of NP levels per se, and NP-­guided
care.
On this background, it remains unclear how
NP-­g uided therapy might look in real-­world clin-
ical practice. As discussed, NP-­guided manage-
ment may have a role, when utilised by clinical
specialists with appropriate understanding of
the role of NPs. Conversely, there is no place
for random measurement of NPs in patients with
known LVSD.
Clinical perspective on the use of NP-guided
therapy in HF
The goal in HF management is to establish
patients on all evidence-­ b ased treatments as
early and as safely as possible, to achieve maxi-
mally tolerated (ideally study defined) target
doses and to relieve congestion, with the aims
of maximising quality of life and reducing the
risk of adverse outcomes. The evidence behind
routine use of NP-­ g uided HF therapy, which
8 Eltayeb M, et al. Heart 2023;0:1–10. doi:10.1136/heartjnl-2020-318553
Heart: first published as 10.1136/heartjnl-2020-318553 on 6 September 2023. Downloaded from http://heart.bmj.com/ on September 7, 2023 at Bib Consejeria Sanidad SACYL Consortia.
incurs additional costs, is not strong. Neither
the ESC nor AHA specifically recommend an
NP-­g uided treatment strategy in HF. However,
NPs should not be withdrawn from a physi-
cian’s armamentarium in the management of
patients with HF. If physicians find themselves
in a position where there is equipoise between
their desire to initiate or up-­ t itrate therapy
and possible undesirable side effects, then NP
measurements can be utilised to inform clin-
ical decision-­m aking, including a more aggres-
sive approach. Furthermore, primary care
physicians and HF clinics may adopt a policy
of NP measurement at specific times during
follow-­u p of patients with HF to stimulate a
review of therapy and break the so-­c alled ‘clini-
cian inertia’ in the treatment of HF and reduce
the risk-­treatment gap if possible—patients at
higher risk have lower use of evidence-­ b ased
therapy. 44 As for guiding decongestion, NPs can
be used as part of an integrated assessment of
congestion; experience in clinical assessment is
key to success in management of HF.
NPS AS THERAPEUTIC TARGETS AND THE
EFFECT OF SACUBITRIL–VALSARTAN ON NP
LEVELS
Protected by copyright.
Beyond their utility as biomarkers in HF,
attempts have been made to harness the benefi-
cial cardiovascular effects of NP. Almost 30 years
ago, recombinant ANP was approved in Japan
for use in AHF but the evidence supporting
its use was not sufficiently strong to attract
support in international HF guidelines. 45 Early
studies reported an improvement in patients’
symptoms and haemodynamics with the use
of nesiritide, a recombinant BNP, which was
approved by the FDA for the relief of dyspnoea
in AHF. 46 However, the ASCEND HF trial, a
large RCT which was preceded by a signal from
meta-­ a nalysis regarding deleterious effects on
mortality and renal dysfunction from nesiritide,
found no benefit of this agent on renal func-
tion, mortality or hospitalisation at 30 days in
patients with AHF. 47
An alternative approach to the modulation
of the NP system was to inhibit their degrada-
tion, thereby increase circulating levels with the
aim of enhancing their beneficial physiolog-
ical effects. Early attempts to do so combined
ACE inhibition with inhibition of neprilysin, an
enzyme which degrades NPs. While associated
with signals of benefit, this combination was
limited by increased risk of angio-­o edema (both
ACE and neprilysin degrade bradykinin). 48 The
PARADIGM-­H F study demonstrated clear clin-
ical superiority of the combination of sacubi-
tril (neprilysin inhibition) with valsartan (ARB)
compared with high-­d ose ACE inhibition. 49 Sacu-
bitril–valsartan therapy may be associated with
an increase in BNP values, but not NT-­p roBNP
(the former but not the latter being a substrate

for neprilysin). In this context, NT-­p roBNP is
the preferred biomarker for patients prescribed
sacubitril–valsartan in clinical practice. 50
SUMMARY
NPs have revolutionised the identification and
management of patients with suspected or
confirmed HF. They perform best in excluding
the diagnosis, particularly in the acute setting,
and are valuable in supporting a diagnosis of
HF as suggested by major HF management
guidelines. They are among the best predictors
of progressive disease, risk and the need for
specialist HF input. In the appropriate context,
NPs may have utility as adjuncts to other param-
eters in guiding HF therapy but should not be
used in isolation as a guide to therapy. Despite
their excellent performance in the diagnosis of
HF, NP levels should be interpreted with care
and with consideration to clinically relevant
parameters. Overall, NPs should be used as an
adjunct to a thorough clinical assessment and a
meticulous physical examination.
Contributors SS and ME performed literature review and wrote
the manuscript. IS reviewed the manuscript.
Funding This research was supported by the NIHR Leicester
Clinical Research Centre.
Disclaimer The views expressed are those of the authors and not
necessarily those of the NHS, the NIHR or the Department of Health
and Social Care.
Competing interests None declared.
Patient consent for publication Not applicable.
Ethics approval Not applicable.
Provenance and peer review Commissioned; internally peer
reviewed.
Author note References which include * are considered to be key
references.
ORCID iDs
Iain Squire http://orcid.org/0000-0002-6282-4318
Shirley Sze http://orcid.org/0000-0002-0226-5083
REFERENCES
1 de Bold AJ, Borenstein HB, Veress AT, et al. A rapid and potent
natriuretic response to intravenous injection of atrial myocardial
extract in rats. Life Sci 1981;28:89–94.
2 Yasue H, Yoshimura M, Sumida H, et al. Localization and
mechanism of secretion of B-­type natriuretic peptide in
comparison with those of A-­type natriuretic peptide in
normal subjects and patients with heart failure. Circulation
1994;90:195–203.
3 Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J
Med 1998;339:321–8.
4 Vanderheyden M, Bartunek J, Goethals M. Brain and other
natriuretic peptides: molecular aspects. Eur J Heart Fail
2004;6:261–8.
5 McGrath MF, de Bold MLK, de Bold AJ. The endocrine function of
the heart. Trends Endocrinol Metab 2005;16:469–77.
6 Abell TJ, Richards AM, Ikram H, et al. Atrial natriuretic factor
inhibits proliferation of vascular smooth muscle cells stimulated
by platelet-­derived growth factor. Biochem Biophys Res Commun
1989;160:1392–6.
7 Calderone A, Thaik CM, Takahashi N, et al. Nitric oxide, atrial
natriuretic peptide, and cyclic GMP inhibit the growth-­promoting
effects of norepinephrine in cardiac myocytes and fibroblasts. J
Clin Invest 1998;101:812–8.
Eltayeb M, et al. Heart 2023;0:1–10. doi:10.1136/heartjnl-2020-318553
Education in Heart
Heart: first published as 10.1136/heartjnl-2020-318553 on 6 September 2023. Downloaded from http://heart.bmj.com/ on September 7, 2023 at Bib Consejeria Sanidad SACYL Consortia.
8 Baba M, Yoshida K, Ieda M. Clinical applications of natriuretic
peptides in heart failure and atrial fibrillation. Int J Mol Sci
2019;20:2824:11.:.
*9 Authors/Task Force Members, McDonagh TA, Metra M, et al. 2021
ESC guidelines for the diagnosis and treatment of acute and
chronic heart failure: developed by the task force for the diagnosis
and treatment of acute and chronic heart failure of the European
Society of Cardiology (ESC). with the special contribution of
the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail
2022;24:4–131.
*10 Roberts E, Ludman AJ, Dworzynski K, et al. The diagnostic accuracy
of the natriuretic peptides in heart failure: systematic review
and diagnostic meta-­analysis in the acute care setting. BMJ
2015;350:h910.
11 Richards AM, Januzzi JL, Troughton RW. Natriuretic peptides
in heart failure with preserved ejection fraction. Heart Fail Clin
2014;10:453–70.
12 Januzzi JL, van Kimmenade R, Lainchbury J, et al. NT-­proBNP testing for
diagnosis and short-­term prognosis in acute destabilized heart failure:
an international pooled analysis of 1256 patients: the International
collaborative of NT-­proBNP study. Eur Heart J 2006;27:330–7.
*13 NICE. Chronic heart failure in adults: diagnosis and management.
2018. Available: https://www.nice.org.uk/guidance/ng106
14 Wright SP, Doughty RN, Pearl A, et al. Plasma amino-­terminal pro-­
brain natriuretic peptide and accuracy of heart-­failure diagnosis
in primary care: a randomized, controlled trial. J Am Coll Cardiol
2003;42:1793–800.
15 Taylor KS, Verbakel JY, Feakins BG, et al. Diagnostic accuracy of
point-­of-­care natriuretic peptide testing for chronic heart failure
in ambulatory care: systematic review and meta-­analysis. BMJ
2018;361:k1450.
16 NICE. Acute heart failure: diagnosis and management Clinical
guideline [CG187]. 2021.
17 Savarese G, Orsini N, Hage C, et al. Associations with and
Protected by copyright.
Prognostic and discriminatory role of N-­terminal pro-­B-­type
natriuretic peptide in heart failure with preserved versus mid-­range
versus reduced ejection fraction. J Card Fail 2018;24:365–74.
18 Remmelzwaal S, van Ballegooijen AJ, Schoonmade LJ, et al.
Natriuretic peptides for the detection of diastolic dysfunction and
heart failure with preserved ejection fraction-­a systematic review
and meta-­analysis. BMC Med 2020;18:290.
19 Vasan RS, Benjamin EJ, Larson MG, et al. Plasma natriuretic
peptides for community screening for left ventricular hypertrophy
and systolic dysfunction: the Framingham heart study. JAMA
2002;288:1252–9.
20 Ng LL, Loke I, Davies JE, et al. Identification of previously
undiagnosed left ventricular systolic dysfunction: community
screening using natriuretic peptides and electrocardiography. Eur J
Heart Fail 2003;5:775–82.
21 Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide
levels and the risk of cardiovascular events and death. N Engl J
Med 2004;350:655–63.
22 Heidenreich PA, Bozkurt B, Aguilar D, et al. AHA/ACC/HFSA
guideline for the management of heart failure: A report of the
American College of Cardiology/American Heart Association
joint committee on clinical practice guidelines. Circulation
2022;145:e895–1032.
*23 Baggish AL, van Kimmenade RRJ, Januzzi JL Jr. The differential
diagnosis of an elevated amino-­terminal pro-­B-­type natriuretic
peptide level. Am J Cardiol 2008;101:43–8.
24 Daniels LB, Bhalla V, Clopton P, et al. B-­type natriuretic peptide (BNP)
levels and ethnic disparities in perceived severity of heart failure: results
from the rapid emergency department heart failure outpatient trial
(REDHOT) multicenter study of BNP levels and emergency department
decision making in patients presenting with shortness of breath. J Card
Fail 2006;12:281–5.
*25 Brunner-­La Rocca HP, Sanders-­van Wijk S. Natriuretic peptides in chronic
heart failure. Card Fail Rev 2019;5:44–9.
26 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;95:948–54.
27 Hildebrandt P, Collinson PO, Doughty RN, et al. Age-­dependent values
of N-­terminal pro-­B-­type natriuretic peptide are superior to a single
cut-­point for ruling out suspected systolic dysfunction in primary care.
Eur Heart J 2010;31:1881–9.
28 Tsutamoto T, Wada A, Sakai H, et al. Relationship between renal
function and plasma brain natriuretic peptide in patients with heart
failure. J Am Coll Cardiol 2006;47:582–6.
9
Education in Heart
29 Anwaruddin S, Lloyd-­Jones DM, Baggish A, et al. Renal function,
congestive heart failure, and amino-­terminal pro-­brain natriuretic
peptide measurement: results from the proBNP investigation of
dyspnea in the emergency department (PRIDE) study. J Am Coll Cardiol
2006;47:91–7.
30 Lamb EJ, Vickery S, Price CP. Amino-­terminal pro-­brain natriuretic
peptide to diagnose congestive heart failure in patients with
impaired kidney function. J Am Coll Cardiol 2006;48:1060–1;
31 Madamanchi C, Alhosaini H, Sumida A, et al. Obesity and
natriuretic peptides, BNP and NT-­proBNP: mechanisms
and diagnostic implications for heart failure. Int J Cardiol
2014;176:611–7.
32 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;112:2163–8.
33 Tsutamoto T, Wada A, Maeda K, et al. Attenuation of
compensation of endogenous cardiac natriuretic peptide
system in chronic heart failure: prognostic role of plasma
brain natriuretic peptide concentration in patients with
chronic symptomatic left ventricular dysfunction. Circulation
1997;96:509–16.
34 Molvin J, Jujic A, Bachus E, et al. Cardiovascular biomarkers
predict post-­discharge re-­hospitalization risk and mortality among
Swedish heart failure patients. ESC Heart Fail 2019;6:992–9.
35 Gardner RS, Ozalp F, Murday AJ, et al. N-­terminal pro-­brain natriuretic
peptide. A new gold standard in predicting mortality in patients with
advanced heart failure. Eur Heart J 2003;24:1735–43.
36 Taylor CJ, Roalfe AK, Iles R, et al. The potential role of NT-­proBNP
in screening for and predicting prognosis in heart failure: a survival
analysis. BMJ Open 2014;4:e004675.
37 Taylor CJ, Lay-­Flurrie SL, Ordóñez-­Mena JM, et al. Natriuretic peptide
level at heart failure diagnosis and risk of hospitalisation and death in
England 2004-­2018. Heart 2022;108:543–9.
38 Núñez J, de la Espriella R, Rossignol P, et al. Congestion in heart failure:
a circulating biomarker-­based perspective. A review from the biomarkers
working group of the Heart Failure Association, European Society of
Cardiology. Eur J Heart Fail 2022;24:1751–66.
10
Heart: first published as 10.1136/heartjnl-2020-318553 on 6 September 2023. Downloaded from http://heart.bmj.com/ on September 7, 2023 at Bib Consejeria Sanidad SACYL Consortia.
39 Haag S, Jobs A, Stiermaier T, et al. Lack of correlation between different
congestion markers in acute decompensated heart failure. Clin Res
Cardiol 2023;112:75–86.
40 Bayes-­Genis A, Aimo A, Jhund P, et al. Biomarkers in heart failure clinical
trials. A review from the biomarkers working group of the heart failure
Association of the European Society of Cardiology. Eur J Heart Fail
2022;24:1767–77.
41 Troughton R, Michael Felker G, Januzzi JL. Natriuretic peptide-­guided
heart failure management. Eur Heart J 2014;35:16–24.
42 Troughton RW, Frampton CM, Brunner-­La Rocca H-­P, et al. Effect of
B-­type natriuretic peptide-­guided treatment of chronic heart failure on
total mortality and hospitalization: an individual patient meta-­analysis.
Eur Heart J 2014;35:1559–67.
43 Felker GM, Anstrom KJ, Adams KF, et al. Effect of natriuretic peptide–
guided therapy on hospitalization or cardiovascular mortality in
high-­risk patients with heart failure and reduced ejection fraction: a
randomized clinical trial. JAMA 2017;318:713–20.
44 Verhestraeten C, Heggermont WA, Maris M. Clinical inertia in the
treatment of heart failure: a major issue to tackle. Heart Fail Rev
2021;26:1359–70.
45 Saito Y. Roles of atrial natriuretic peptide and its therapeutic use. J
Cardiol 2010;56:262–70.
46 Young JB, Abraham WT, Stevenson LW, et al. Results of the VMAC trial:
vasodilation in the management of acute congestive heart failure.
Circulation 2000;102:2794.
47 O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide
in patients with acute decompensated heart failure. N Engl J Med
2011;365:32–43.
48 Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat
and enalapril in patients with chronic heart failure: the omapatrilat
versus enalapril randomized trial of utility in reducing events
(OVERTURE). Circulation 2002;106:920–6.
*49 McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin
inhibition versus enalapril in heart failure. N Engl J Med
Protected by copyright.
2014;371:993–1004.
50 Bayes-­Genis A, Lupón J, Jaffe AS. Can natriuretic peptides be used to
guide therapy EJIFCC 2016;27:208–16.
Eltayeb M, et al. Heart 2023;0:1–10. doi:10.1136/heartjnl-2020-318553