Pathophysiology and management of heart failure

pharmaceutical-journal.com/learning/cpd-article/pathophysiology-and-management-of-heart-
failure/20205742.cpdarticle
Clinical Pharmacist 6 DEC 2018 By Paul Wright , Martin
Thomas

Ensuring patients are optimised on maximum tolerated doses of

medicines to treat heart failure with reduced ejection fraction is
essential in minimising the burden of the condition.

Fluorescent micrograph of heart failure

Source: Sciencephotolibrary

Around 550,000 people in the UK are recorded as having heart failure (HF), which equates to
a prevalence of 0.8%[1] . The true number (including those with unrecorded/undiagnosed HF)
is likely to be much higher and estimated to be 920,000 in the UK[2] . Depending on the
definition applied, it is estimated that the prevalence of HF is around 1–2% of the adult
population, increasing to over 10% in people aged over 70 years[3] . Males are affected
slightly more than females, with an estimated lifetime risk of HF at the age of 55 years being
33% for men compared with 28% for women[4] .

Data from the 2015–2016 National Heart Failure Audit, which is carried out each year by the 1/21
Data from the 2015–2016 National Heart Failure Audit, which is carried out each year by the
National Institute for Cardiovascular Outcomes Research, highlights that patient prognosis
remains poor; mortality in patients admitted with HF is 8.9% during hospital admission, with
a third of those discharged dying within the following year. Following admission to hospital
for HF, survival rates are similar to those of colon cancer, and worse than those of breast or
prostate cancer.
HF is the cause of, or complicates, around 5% of all emergency admissions in adults and
consumes up to 2% of total NHS expenditure [5] . Unfortunately, it is predicted that hospital
admissions resulting from HF will continue to rise, mainly driven by an ageing population[2]
This article describes what happens to the heart during HF and how to treat it, as well as
how to determine ejection fraction (EF).

Definition
HF is a complex clinical syndrome whereby the heart is unable to meet the metabolic
demands of the body. Reasons for this mismatch can be multifactorial, and various
underlying pathological conditions make the management and treatment complex. Initially,
patients may tolerate small declines in output as various compensatory measures are
activated to redress the balance. Over time, however, these compensatory measures
become deleterious to heart function and lead to worsening cardiac output, resulting in
further activation and additional stress on a failing heart.
Given the multitude of causes of HF, it is difficult to give a precise classification and
definition compared with other common cardiac diseases, such as atrial fibrillation (AF),
ischaemic heart disease (IHD) or hypertension, where a diagnosis is relatively
straightforward. However, the European Society of Cardiology defines HF as a clinical
syndrome characterised by symptoms such as shortness of breath, persistent coughing or
wheezing, ankle swelling and fatigue, which may be accompanied by the following signs:
elevated jugular venous pressure; pulmonary crackles; increased heart rate; and peripheral
oedema[3] . In addition, patients with HF often have several pathologies that may potentiate
HF progression and symptoms. Diagnosis relies on clinical judgement based on a
combination of patient history, physical examination and appropriate investigations to
determine the likely underlying pathophysiology. Identification of the cause of HF is
essential in the diagnostic workup, as this may offer specific therapeutic opportunities (i.e. if
HF results from valvular causes, surgery may be curative).

Symptom classification
HF is a clinical syndrome characterised by a number of typical symptoms, such as
breathlessness, oedema and fatigue. HF can be categorised in a number of different ways,
although the underlying aetiologies are numerous. It is common practice in the UK to use
the New York Heart Association (NYHA) functional classification to document and assess
severity of symptoms and physical activity (see Table 1). It is also common to differentiate
between left and right-sided HF, although the failure of one side often leads to failure of the
other (biventricular failure). This is because the circulatory system works on a double pump
with blood from the left ventricle being pumped systemically, returning to the right side
where it is pumped towards the lungs for oxygenation; blood then returns to the left side
for distribution round the systemic circulation again. If there is a failing on one side, given
they are linked, failure on the other side will often follow.
2/21
 Class No limitation of physical activity. Ordinary physical activity does not cause undue
I breathlessness, fatigue or palpitations

Class Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity
II results in undue breathlessness, fatigue or palpitations

Class Marked limitation of physical activity. Comfortable at rest, but less than ordinary
III physical activity results in undue breathlessness, fatigue or palpitations

Class Unable to carry out any physical activity without discomfort. Symptoms at rest can be
IV present. If any physical activity is undertaken, discomfort is increased

Source: Reproduced with permission from the American Heart Association. Classes of heart
failure. 2017. Available at: http://www.heart.org/en/health-topics/heart-failure/what-is-heart-
failure/classes-of-heart-failure (accessed December 2018)

A further differentiation can be made on whether there is dysfunction with the active
pumping action in the ventricle (systolic dysfunction), or whether there is a problem with
the relaxation or filling of the ventricle (diastolic dysfunction).

Diagnosis

Determining ejection fraction

The ‘gold standard’ tool for the assessment and diagnosis of HF is a transthoracic
echocardiogram (TTE). This test allows a thorough assessment of chamber dimensions,
valvular function and various estimates of heart function, including an estimation of EF (the
proportion of blood ejected from the heart during a heartbeat). EF, which is typically
between 55% and 70%, can be calculated using the following equation:
Ejection fraction = end diastolic volume – end systolic volume/end diastolic volume
HF is often classified based on the EF. HF with reduced ejection fraction (HFrEF) is identified
where the EF is less than 40%. HF with preserved ejection fraction (HFpEF) can be harder to
diagnose, and is defined as EF >50% with other markers of heart failure (e.g. diastolic
dysfunction or structural heart disease). This important as underlying pathologies are
distinct, with treatment in people with HFrEF having a strong evidence base in reducing
mortality and morbidity. This is not replicated in patients with HFpEF, although patients
typically exhibit similar clinical symptoms. Compared with HFrEF, patients with HFpEF are
often older, more often female, and more commonly have a history of hypertension and
valvular disease, while people with HFrEF tend to have a medical history that includes IHD[5] .
Table 2 represents the aetiology and comorbidity of patients with HF admitted to hospital in
the UK.

Medical history HFrEF (%) HFpEF (%)

Ischaemic heart disease 48.4 37.9

3/21
 Atrial fibrillation 49.1 40.0

Myocardial infarction 30.7 18.1

Valve disease 23.9 31.4

Hypertension 52.1 59.9

Diabetes 33.3 33.5

Asthma 8.4 9.4

Chronic obstructive pulmonary disease 16.7 18.9

HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection
fraction
Source: Reproduced with permission from the British Society for Heart Failure. National Heart
Failure Audit, April 2015 to March 2016. Available
at: http://www.ucl.ac.uk/nicor/audits/heartfailure/documents/annualreports/annual-report-
2015-6-v8.pdf (accessed December 2018)

To understand the differences and similarities in patients with HFrEF and HFpEF, it is
important to understand another measure of heart function — cardiac output. Cardiac
output can be defined as:
Cardiac output = stroke volume (amount of blood ejected in a heartbeat) x heart rate (beats per
minute [bpm])
Generally, this is 70mL x 70bpm, which gives a cardiac output of 4.9L/min and the end
diastolic volume is 110mL. Therefore, the EF will be 64% (110mL – 70mL / 110mL; see Figure
1A).
In a patient with HFrEF, stroke volume is typically reduced, which will therefore reduce
cardiac output. For example, the patient’s stroke volume reduces to 44mL. This would result
in an EF of 40% (44mL / 110mL) and a new cardiac output of 44mL x 70bpm = 3L/min (see
Figure 1B).
In a patient with HFpEF, although the EF is normal, diastolic dysfunction is often present,
lowering the end diastolic volume (either through ventricular hypertrophy, which reduces
the cavity size, or through ventricular stiffening, where blood is not allowed to fill the
ventricle). In either case, stroke volume ejected will be less because the initial volume is
lower, which again leads to a reduction in stroke volume and a decline in cardiac output. For
example, the patient’s end diastolic volume reduces to 70mL. As in the first case, the stroke
volume is reduced to 44mL but the EF remains ‘normal’. This would result in an EF of 63%
(44mL / 70mL) and a cardiac output of 3L/min (44mL x 70bpm; see Figure 1C).

4/21
5/21
 Figure 1: Representation of cardiac output in relation to ejection fraction
Source: Paul Wright & Martin Thomas

Biomarkers
Natriuretic peptides are released from the myocardium in response to ventricular wall
stress, hypertrophy and fluid overload, representing useful biomarkers in the workup to HF
diagnosis. B-type natriuretic peptide (BNP) and amino-terminal pro-B-type natriuretic
peptide (NT-proBNP) are the two main biomarkers used clinically.
The heart continuously produces small amounts of a precursor proBNP, which is cleaved to
release the active hormone BNP and an inactive fragment NT-proBNP. BNP and NT-proBNP
are increased in patients with HF; therefore, low levels are useful to rule out HF. It should be
noted that neprilysin inhibitors lead to an increase in circulating BNP and, therefore, BNP
should not be used to monitor treatment or to assess response to treatment if neprilysin
inhibitors are used. Instead, changes in NT-proBNP is still a useful reflection of the
reduction in wall stress[6] .
The latest National Institute for Health and Care Excellence (NICE) guidance for HF
recommends measuring NT-proBNP in people with suspected HF[2] . Since very high levels of
NT-proBNP carry a poor prognosis, people with suspected HF and an NT-proBNP level
>2,000 nanograms/L (236picomol/L) should be referred urgently for specialist assessment
and TTE within two weeks. Patients with a level of 400–2,000 nanograms/L (47–
236picomol/L) should also be referred for specialist assessment and TEE within six weeks. A
NT-proBNP of <400 nanograms/L (47picomol/L) in an untreated person makes a diagnosis
of HF less likely[2] .
Various factors can affect circulating BNP and NT-proBNP levels and, therefore, caution
must be taken when interpreting results (see Box 1).

Box 1: Factors that can affect circulating B-type natriuretic peptide and amino-
terminal pro-B-type natriuretic peptide
Factors that may lead to lower circulating levels:
Obesity;
African or Afro–Caribbean family origin;
Treatment with:
Diuretics;
Angiotensin-converting enzyme inhibitors;
Beta-blockers;
6/21
 Angiotensin II receptor blockers;
Mineralocorticoid receptor antagonists.

Factors that can lead to higher circulating levels (other than heart failure):
Age over 70 years;
Left ventricular hypertrophy;
Ischaemia;
Tachycardia;
Right ventricular overload;
Hypoxaemia (including pulmonary embolism);
Kidney dysfunction (estimated glomerular filtration rate <60mL/minute/1.73m 2);
Sepsis;
Chronic obstructive pulmonary disease.

Source: National Institute for Health and Care Excellence. Chronic heart failure in adults:
diagnosis and management [NG106]. 2018. Available at:
https://www.nice.org.uk/guidance/ng106/resources/chronic-heart-failure-in-adults-
diagnosis-and-management-pdf-66141541311685 (accessed December 2018)

Impact of compensatory mechanisms

A reduction in cardiac output in both HFrEF and HFpEF leads to compensatory mechanisms
being activated to redress the imbalance. Initially, these may improve cardiac output but
they become detrimental in the longer term as they place excessive strain on the failing
heart. The main systems activated in response to a reduced systemic perfusion are the
renin-angiotensin-aldosterone system (RAAS), sympathomimetic nervous system (SNS) and
natriuretic peptide system (NPS). Other systems, such as parasympathetic activation,
vasopressin, endothelin and other pathways, are outside the scope of this article (most
therapeutic strategies to date are aimed at manipulating RAAS, SNS or NPS).
A reduction in cardiac output leads to reduced renal perfusion, which stimulates release of
renin in the kidneys. This stimulates conversion of angiotensinogen from the liver to
angiotensin I. This is promptly converted to angiotensin II on the surface of pulmonary and
renal endothelium. The actions of angiotensin II include activation of the sympathomimetic
pathway, arteriolar vasoconstriction and cardiac remodeling. Release of aldosterone leads
to increased salt and water retention. Activation of the RAAS leads to increased circulating
blood volume, which will increase pre-load with the aim to increase atrial pressure and,
ultimately, increase the stroke volume to improve cardiac output[7] .
The SNS is activated through release of catecholamines, such as noradrenaline and
adrenaline. Activation of beta 1, beta 2 and alpha receptors aim to raise the heart rate and
force of contraction with the aim to increase cardiac output. In addition, chronic activation
leads to stimulation of the RAAS system to further increase pre-load[6] .
Natriuretic peptides (NPs) have a wide range of effects on the kidneys, heart and central
nervous system. NPs are released in response to atrial and ventricular stretch and act to
oppose the effects of angiotensin II on systemic vascular resistance, vascular tone,
aldosterone and cardiac remodeling. Activation of this system aims to counteract the effects
of SNS and RAAS (see Figure 2). In addition, levels of NPs can be used to facilitate a diagnosis
of HF as they are released when the heart is under strain[8] .
7/21
 Figure 2: Activation of the renin angiotensin aldosterone system system
Source: Source: Drug Discovery Today: Therapeutic Strategies[8]

ANG II: angiotensin II; AT1: angiotensin type 1; cGMP: cyclic guanosine monophosphate; GTP: guanosine-
5’-triphosphate; NP: natriuretic peptide; NPR-A: neprilysin receptor A; RAAS: renin-angiotensin-aldosterone
system

The Frank–Starling law of the heart states that stroke volume increases in response to an
increase in volume of blood filling the heart (end diastolic volume) when all other factors
remain constant. This adaptive mechanism is crucial for normal physiological function and
allows rapid response to increased demands (e.g. when exercising). In chronic HFrEF, the
myocardium with impaired contraction is no longer able to increase the force of contraction
with increasing end diastolic volume and activation of RAAS and SNS become
counterproductive, as they lead to increased cardiac stress and pre-load with the heart
being unable to increase cardiac output.
Some have compared the Frank–Starling law with an analogy to an elastic band — as you
pull the elastic band further apart, the recoil is greater, but if over-stretched, the elastic
band can become weakened and you no longer get the recoil desired.

In HFpEF, the rise in left ventricular end diastolic pressure needed during exercise through 8/21
In HFpEF, the rise in left ventricular end diastolic pressure needed during exercise through
accommodation of more pre-load cannot be sustained before the left ventricular end
diastolic pressure rises to levels that usually result in significant rise in left atrial pressures,
and pulmonary venous pressure resulting in the development of pulmonary congestion and
breathlessness. This inability to increase cardiac output as the myocardium is unable to
stretch in the first instance, leads to the expression ‘stiff ventricle’, which is frequently used
to describe the physiology in HFpEF.
Depending on the underlying causes of HF, other adaptive processes can occur. Left
ventricular hypertrophy (LVH), which is an enlargement and thickening of the walls of the
heart, can occur in response to consistently raised ventricular pressure. This can commonly
occur owing to persistent high blood pressure or in response to aortic stenosis. As LVH
progresses, the increasing muscle mass reduces the end diastolic volume and will inevitably
reduce the cardiac output, while the EF remains “normal”.

Decompensated heart failure

Also known as congestive HF, decompensated HF occurs in patients where there is
increased blood pressure resulting from weak pump in HFrEF and stiff pump in HFpEF. In
either case, there is a backfill of pressure in the lungs as the ventricle cannot eject enough
blood out of the left ventricle. This leads to increased pulmonary pressure that pushes fluid
out of capillaries and into aveolar space (causing pulmonary oedema). This additional fluid
in the aveolar spaces slows diffusion of oxygen and carbon dioxide, leading to dyspnoea
(shortness of breath).
Orthopnoea can also be present in decompensated HF; this is a feeling of breathlessness
when lying flat, which is caused as more venous blood flows back into the heart and into
pulmonary circulation when the patient assumes a supine posture, again leading to raised
pulmonary pressures and migration of fluid into aveolar space. Rales, or ‘crackles’, are heard
when listening to the chest through a stethoscope, at least in the lung bases. Similar to the
mechanism of pulmonary congestion, when there is either a rise in the pulmonary artery
pressure and/or impairment of the right ventricle, back pressure would lead to fluid
accumulation in the liver, legs, sacrum and peritoneal cavity, causing ascites.

Treatment

Diuretics to reduce congestion

Diuretics are used for HF of all causes to reduce congestion. While they relieve symptoms
associated with HF, they are generally regarded as not affecting the underlying disease
pathophysiology. In clinical practice, careful management of a patient’s fluid status with
diuretics can prevent or delay admission to hospital with acute decompensated HF. This
finding is echoed in a meta-analysis of diuretic use in congestive HF, suggesting a mortality
benefit with their use and a reduction of admission[9] .

In the UK, furosemide is commonly used as a first-line loop diuretic. Doses will be adjusted 9/21
In the UK, furosemide is commonly used as a first-line loop diuretic. Doses will be adjusted
according to symptoms and clinical status. Clinical examination of peripheral oedema,
pulmonary oedema and jugular venous pressure are used in this assessment. Typically,
doses of 40–80mg daily are used with doses up to 80mg twice daily in more severe cases.

10/21
Bumetanide, another loop diuretic, has a higher and more consistent bioavailability than
furosemide (>90%), whose bioavailability ranges from 10–90% with food intake delaying
absorption and reducing peak concentration[10].
In patients who are congested, absorption through an oedematous gastrointestinal tract is
affected less with bumetanide than with furosemide use, and some patients respond more
consistently to oral bumetanide than to furosemide.
In cases of diuretic resistance (i.e. lack of clinical effect despite large doses of loop diuretic),
a thiazide (e.g. bendroflumethiazide) or thiazide-like diuretic (e.g. metolazone, although this
is unlicensed in the UK) can be added that act synergistically to offload fluid. In general, the
response to adding metolazone is more potent than bendroflumethiazide, especially when
there is reduced kidney function. Therefore, much higher doses of bendroflumethiazide are
needed, whereas metolazone continues to work well even at lower estimated glomerular
filtration rates. Typically, doses of 2.5mg are used as a single dose or on alternate days.
Doses can be increased up to response or to 10mg daily, although electrolyte disturbance
generally means daily doses should not exceed 5mg. Owing to the potency of this
combination and the likelihood of kidney dysfunction and electrolyte disturbance, this
combination should be monitored very frequently with long-term use rarely seen in clinical
practice.
Aggressive use of diuretics can cause a dramatic reduction of circulating blood volume that
can lead to hypotension and kindey impairment. Patients should aim for weight loss not to
exceed more than 0.5–1.0kg a day while being treated with high-dose diuretics. Electrolyte
loss is also common with high-dose diuretics, which can limit their use, particularly
hyponatraemia (which can be difficult to treat). It should be noted that patients who have a
significant overload of fluid may have dilutional hyponatraemia, which is a poor marker of
response and can be difficult to treat. Failure to respond to combinations of loop and
thiazide diuretics, or hyponatraemia with accompanying fluid gain, would warrant advanced
HF input where other strategies such as intravenous diuresis, high-dose mineralocorticoid
receptor antagonists or extracorporeal ultrafiltration may be considered.

Treatment for heart fraction with preserved ejection fraction

No treatment has yet been shown to reduce morbidity or mortality in patients with HFpEF.
Management of HFpEF is directed towards managing the underlying comorbidities (e.g.
hypertension, IHD and diabetes) alongside diuretic use to manage symptoms of fluid
overload[2] .

Pharmacological management of heart failure with reduced ejection

fraction

There is clear evidence that initiation of disease-modifying drugs in HFrEF can lead to 11/21
There is clear evidence that initiation of disease-modifying drugs in HFrEF can lead to
significant reductions in mortality and morbidity. According to the National Heart Failure
Audit Report 2015–2016, patients admitted to hospital with left ventricular systolic
dysfunction that survived and were discharged with no prognostic medication had a one-
year mortality rate of 49.3%, compared with those that were discharged on an angiotensin-
converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARBs), and beta
blockers (BBs) and mineralocorticoid receptor antagonists (MRAs) who had a one-year

[5] 12/21
mortality rate of 23.4%[5] . This demonstrates the real-world value in ensuring patients are
medically optimised. Estimates for the individual reduction in mortality associated with the
disease-modifying agents are in HFrEF are presented in Figure 3.

Figure 3: Drugs that reduce mortality in heart failure with reduced ejection fraction
Source: SOLVD[11], AIRE[12], MERIT[13], CIBIS-II[14], CHARM[15], RALES[20], EMPHASIS[21]

ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta blocker; MRA:
mineralocorticoid receptor antagonist

The recently updated NICE guidance for HF includes a treatment algorithm (see Figure 4);
the following sections summarise this guidance[2] .

13/21
 Figure 4: National Institute for Health and Care Excellence therapeutic algorithm
*Please refer to CG180 for recommendations on the use of digoxin in patients with atrial fibrillationACEI:
angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BB: beta blocker; bpm: beats
per minute; CG180: NICE Clinical Guidance 180; CRT-P/D: cardiac resynchronisation therapy —
pacing/defibrillator; eGFR: estimated glomerular filtration rate; HR: heart rate; LVEF: left ventricular ejection
fraction; MRA: mineralocorticoid receptor antagonist; NICE: National Institute of Health and Care Excellence;
TA267: NICE Technology Appraisal 267; TA314: NICE Technology Appraisal 314; TA388: NICE Technology
Appraisal 388
If the person’s eGFR is 30–45mL/min/1.73m2, consider lower doses and/or slower titration of dose of ACEIs
or ARBs, MRAs, sacubitril valsartan and digoxin

If the person’s eGFR is <30mL/min/1.73m2, consider liaising with a renal physician

ACEIs together with BBs are considered first-line agents in the treatment of HFrEF, and both
have been demonstrated to reduce morbidity and mortality[11],[12],[13],[14]. Both agents
should be titrated up to maximum tolerated doses in order to replicate results from the
large randomised controlled trial that demonstrated their benefits. Where ACEIs are not
tolerated, an ARB can be considered[15]. Despite the strong evidence base, in clinical
practice the majority of patients receive sub-optimal doses of ACEIs and BBs, with around
30% of patients reaching target doses [16],[17].
Specific instructions for titration may vary slightly between different agents but a pragmatic
approach to initiating ACEIs or ARBs in a community setting would be to start low and
double the dose at no quicker than two-weekly intervals[2],[3] . Up-titration of ACEIs should
be continued, providing patients are tolerating this well and not suffering from symptomatic
hypotension. It is essential that kidney function is checked prior to initiation and rechecked
one to two weeks after and after any dose titrations to monitor for kidney dysfunction.
It has been suggested that in UK practice, only a tenth of patients initiating ACEI or ARB
therapy receive the guideline recommended creatinine monitoring[18]. In the community
setting, there are useful resources, such as the Think Kidneys position statement that offers
practical advice on monitoring and acting on changes to serum creatinine and potassium,
and what to do in patients with HF[19].

BBs licensed for the treatment of HF can be initiated together with ACEIs at low doses and 14/21
BBs licensed for the treatment of HF can be initiated together with ACEIs at low doses and
in a similar fashion, with doses doubled at intervals of no quicker than two weeks[2],[3] . It is
generally accepted that BBs should not be started in patients presenting with acute
decompensated HF, but can be initiated in clinically stable patients. Given the side effects of
BBs that can mimic symptoms of HF (particularly fatigue and, in some instances, shortness
of breath), titration should adopt a low and slow approach. The maximum tolerated dose
should be aimed for with both BBs and ACEIs. BBs should not be withheld because of age or
the presence of peripheral vascular disease, erectile dysfunction, diabetes, interstitial lung
disease or chronic obstructive pulmonary disease[2] .
In practice, although patients with HFrEF are commonly prescribed prognostic ACEIs and
BBs (a European registry suggested 92% and 93%, respectively), the proportion of patients
reaching target doses was only 29% and 18%, respectively; this is in stark contrast to clinical
trials in which 50–60% of patients achieve target doses[17].
The two available MRAs (spironolactone and eplerenone) are recommended in symptomatic
patients with an EF < 35%; both agents demonstrate a relative reduction in mortality of
around 30%[20],[21]. As they are added to ACEIs or ARBs, there is concern of hyperkalaemia.
Consequently, it is recommended to measure urea and electrolytes within one week of
initiation, or up-titration of spironolactone or epleronone monthly for the first three
months, three-monthly for one year and four-monthly thereafter[18].

Angiotensin receptor neprilysin inhibitors

More recently, a better understanding of the neurohormonal activation and pathways has
led to the successful development of a new class of agent in the management of patients
with HFrEF. Sacubitril, a neprilysin inhibitor has been combined with valsartan (an ARB) to
create a compound marketed as Entresto® (Novartis). Collectively, this compound is known
as an angiotensin receptor neprilysin inhibitor.
On their own, neprilysin inhibitors have failed to demonstrate adequate clinical outcomes in
HF, which is most likely a result of neprilysin inhibition leading to a rise in natriuretic peptide
levels but also in angiotensin II levels. For this reason, inhibition of neprilysin and dual
blockade of the RAAS system inhibitor was a logical next step in its development[6] . A
previous compound combining a neprilysin inhibitor with an ACEI (omapatrilat) was shown
to be non-inferior to enalapril but was associated with an increased risk (albeit low absolute
numbers) of life-threatening facial angioedema[22]. For this reason, it is essential that
sacubitril valsartan is not to be given within 36 hours after ACEI administration, likewise
ACEIs are not be given within 36 hours after sacubitril administration. This is not the same
for ARBs, where sacubitril valsartan can be initiated at the next due dose of ARB.

Sacubitril valsartan

In a large clinical trial where sacubitril valsartan was compared with enalapril, which is
considered a gold standard treatment, the trial was stopped early owing to favourable
effects of sacubitril valsartan. There was a 20% relative-risk reduction in the composite
outcome of cardiovascular death or hospitilisation for HF and a 16% reduction in death from
any cause. In addition, there were fewer heart failure symptoms in the sacubitril valsartan
group with improvements in NYHA class[23]. Despite this improvement, mortality rate from
cardiovascular causes in the treatment arm was 13.3% over the course of the trial that had a
median follow-up duration of 27 months.

NICE recommends that sacubitril valsartan is an option for treating symptomatic chronic 15/21
NICE recommends that sacubitril valsartan is an option for treating symptomatic chronic
HFrEF, only in patients:
With NYHA class II to IV symptoms;
With a left ventricular EF of 35% or less; and
Who are already taking a stable dose of ACEI or ARB[24].

Treatment with sacubitril valsartan should be started by HF specialists with access to a

multidisciplinary HF team. As recommended in the summary of product characteristics for
sacuitril valsartan, it should not be initiated in patients with systolic blood pressure
<100mmHg. In terms of monitoring, sacubitril valsartan can be thought of as being very
similar to ACEIs or ARBs, with initiation requiring monitoring of kidney function and
potassium in a similar manner as described above for ACEIs. However, it should be noted
that this is poorly done with ACEIs and ARBs in general practice[17].

Additional therapies for heart failure

Additional medical therapies that may be considered for patients with HFrEF groups include
ivabradine, digoxin and hydralazine in combination with isosorbide dinitrate. Use of these
agents is usually under direct supervision of HF specialists when other therapies are not
tolerated or in patients who remain symptomatic despite maximum tolerated titration of
other agents. It is outside the scope of this article, but device therapies, such as cardiac
resynchronisation therapy, can make significant symptomatic improvement in a selected
cohort with HFrEF and implantable cardioverter defibrillators can reduce sudden cardiac
death in appropriately selected patients.

Other considerations
AF is common to those presenting with HF. In part, this is owing to the prevalence of AF
increasing sharply aged over 70 years. Patients in AF are more likely to present with HF as
the coordinated atrial push of blood into the ventricles is lost, meaning cardiac output is
likely to decline. The reduction in cardiac output can be as high as 30%, which can have a
significant impact on patients whose hearts are already struggling owing to HF. A recent
study has suggested that catheter ablation for AF in patients with HFrEF can lead to
reductions in mortality and reduced admissions with HF [25]. However, it remains to be seen
if this trial will translate to wider clinical practice.
Optimisation of glucose control in patients with diabetes has been shown to reduce
microvascular but not macrovascular complications. More recently, empagliflozin, an
inhibitor of sodium–glucose cotransporter 2 (SGLT2), was the first to demonstrate a
reduction of cardiovascular mortality. It was also noted to reduce hospitilisations for HF[26].
While there are no results specifically looking at randomising patients with HF to a SGLT2
inhibitor, the signal that these agents may reduce hospitalisations and cardiovascular
mortality is attractive, especially if patients are failing to achieve blood glucose goals.

Summary

There is likely to be a considerable increase in patients presenting with HF over the next 16/21
There is likely to be a considerable increase in patients presenting with HF over the next
decade, as the population ages. Pharmacists can help minimise the burden of HF, both in
terms of NHS resources and patient morbidity and mortality, by not only ensuring that
patients with HFrEF are optimised on maximum tolerated doses of evidence-based
medication, but by helping patients implement appropriate lifestyle changes. These include
smoking cessation, making dietary changes, losing weight, increasing physical activity
(aiming for at least 30 minutes of exercise on most days of the week) and moderating
alcohol intake to below recommended limits.
Patients should also be counselled around self-care principles, so that they are able to
recognise worsening symptoms of dyspnoea, oedema, sudden weight gain and nocturnal
symptoms as worsening HF symptoms.
There is still a long way to go in improving outcomes for patients with HF, despite the
success of sacubitril valsartan. In addition, there is huge opportunity to improve dose
titrations of prognostic HF medication as many patients, despite being on ACEIs, BBs and
MRAs, are seldom titrated to evidence-based doses in practice.

Financial and conflicts of interest disclosure:

The authors have no relevant affiliations or financial involvement with any organisation
or entity with a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript. No writing assistance was used in the production
of this manuscript.

Sponsored by:
Novartis provided financial support in the production of this content. Clinical Pharmacist
retains sole editorial responsibility. CVM18-E025

References:
[1]British Heart Foundation. Cardiovascular disease statistics 2018. Available at:
https://www.bhf.org.uk/what-we-do/our-research/heart-statistics/heart-statistics-
publications/cardiovascular-disease-statistics-2018 (accessed December 2018)
[2]National Institute for Health and Care Excellence. Chronic heart failure in adults:
diagnosis and management. NICE guideline [NG106]. 2018. Available at
https://www.nice.org.uk/guidance/ng106/resources/chronic-heart-failure-in-adults-
diagnosis-and-management-pdf-66141541311685 (accessed December 2018)
[3]Ponikowski P, Voors AA, Anker SD et al. 2016 ESC Guidelines for the diagnosis and
treatment of acute and chronic heart failure. Eur Heart J 2016;37(27):2129–2200. doi:
10.1093/eurheartj/ehw128
[4]
Bleumink GS, Knetsch AM, Sturkenboom MCJM et al. Quantifying the heart failure
epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The
Rotterdam Study. Eur Heart J 2004;25(18):1614–1619. doi: 10.1016/j.ehj.2004.06.038

[5] British Society for Heart Failure. National Heart Failure Audit: April 2015 to March 2016. 17/21
[5]British Society for Heart Failure. National Heart Failure Audit: April 2015 to March 2016.
2017. Available at:
http://www.ucl.ac.uk/nicor/audits/heartfailure/documents/annualreports/annual-report-
2015-6-v8.pdf (accessed December 2018)
[6]
Jhund PS & McMurray JJV. The neprilysin pathway in heart failure: a review and guide on
the use of sacubitril/valsartan. Heart 2016;102(17):1342–1347. doi: 10.1136/heartjnl-2014-
306775
[7]
Jackson G, Gibbs CR, Davies MK et al. ABC of heart failure. BMJ 2000;320:167–170. doi:
10.1136/bmj.320.7228.167
[8]
Langenickel TH & Dole WP. Angiotensin receptor-neprilysin inhibition with LCZ696: a
novel approach for the treatment of heart failure. Drug Discov Today Ther Strateg
2012;9(4):e131–139. doi: 10.1016/j.ddstr.2013.11.002
[9]
Faris R, Flather M, Purcell H et al. Current evidence supporting the role of diuretics in
heart failure: a meta analysis of randomised controlled trials. Int J Cardiol 2002;82(2):149–
158. doi: 10.1016/S0167-5273(01)00600-3
[10]
Ellison DH & Felker GM. Diuretic treatment in heart failure. NEJM 2017;377:1964–1975.
doi: 10.1056/NEJMra1703100
[11]
The SOLVD investigators. Effect of enalapril on survival in patients with reduced left
ventricular ejection fractions and congestive heart failure. NEJM 1991;325:293–302. doi:
10.1056/NEJM199108013250501
[12]
The AIRE study investigators. Effect of ramipril on mortality and morbidity of survivors of
acute myocardial infarction with clinical evidence of heart failure. Lancet
1993;342(8875):821–828. doi: 10.1016/0140-6736(93)92693-N
[13]
MERIT HF study group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol
CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet
1999;353(9169):2001–2007. doi: 10.1016/S0140-6736(99)04440-2
[14] CIBIS-II investigators and committees. The cardiac insufficiency bisoprolol study II (CIBIS
II) a randomised trial. Lancet 1999;353(9146):9–13. doi: 10.1016/S0140-6736(98)11181-9
[15]
Young JB, Dunlap ME, Pfeffer MA et al. Mortality and morbidity reduction with
candesartan in patients with chronic heart failure and left ventricular systolic dysfunction:
results of the CHARM low-left ventricular ejection fraction trials. Circulation
2004;110(17):2618–2626. doi: 10.1161/01.CIR.0000146819.43235.A9
[16]
Russell SJ, Oliver M, Edmunds L et al. Optimised beta blocker therapy in heart failure: is
there space for additional heart rate control? Br J Cardiol 2012;19:21–23. doi:
10.5837/bjc.2012.001
[17]
Maggioni AP, Anker SD, Dahlström U et al. Are hospitalised or ambulatory patients with
heart failure treated in accordance with European Society of Cardiology guidelines?
Evidence from 12,440 patients of the ESC Heart failure long-term registry. Eur J Heart Fail
2013;15(10):1173–1184. doi: 10.1093/eurjhf/hft134
[18]
Schmidt M, Mansfield KE, Bhaskaran K et al. Adherence to guidelines for creatinine and
potassium monitoring and discontinuation following renin-angiotensin system blockade; a
UK general practice based cohort study. BMJ Open 2017;7(1):e012818. doi:
10.1136/bmjopen-2016-012818
[19] Think Kidneys, The Renal Association & The British Society for Heart Failure. Changes in 18/21
[19]
Think Kidneys, The Renal Association & The British Society for Heart Failure. Changes in
kidney function and serum potassium during ACEi/ARB/diuretic treatment in primary care.
2017. Available at: https://www.thinkkidneys.nhs.uk/aki/wp-
content/uploads/sites/2/2017/10/Changes-in-Kidney-Function-FINAL.pdf (accessed
December 2018)
[20]
Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and
mortality in patients with severe heart failure. NEJM 1999;341:709–717. doi:
10.1056/NEJM199909023411001
[21]
Zannad F, McMurray JJ, Krum H et al. Eplerenone in patients with systolic heart failure
and mild symptoms. NEJM 2011;364:11–21. doi: 10.1056/NEJMoa1009492
[22]Packer M, Califf RM, Konstam ME et al. Comparison on omapatrilat and enalapril in
patients with chronic heart failure: the omapatrilat versus enalapril randomized trial of
utility in reducing events (OVERTURE). Circulation 2002;106:920–926. PMID: 12186794
[23]McMurray JJV, Packer M, Desai A et al. Angiotensin – neprilysin inhibition versus enalapril
in heart failure. NEJM 2014;371:993–1004. doi: 10.1056/NEJMoa1409077
[24] National
Institute for Health and Care Excellence. Sacubitril valsartan for treating
symptomatic chronic heart failure with reduced ejection fraction. Technology appraisal
guidance [TA388]. 2016. Available at:
https://www.nice.org.uk/guidance/ta388/resources/sacubitril-valsartan-for-treating-
symptomatic-chronic-heart-failure-with-reduced-ejection-fraction-pdf-82602856425157
(accessed December 2018)
[25]
Marrouche NF, Brachmann J, Andresen D et al. Catheter ablation for atrial fibrillation
with heart failure. NEJM 2018;378:417–427. doi: 10.1056/NEJMoa1707855
[26]
Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular outcomes and
mortality in type 2 diabetes. NEJM 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720

CPD Questions:
1. Sacuitril valsartan, as recommended in the summary of product characteristics as a
treatment option for heart failure with reduced ejection fraction, should be initiated in
patients with systolic blood pressure <100mmHg. True or false?
2. Furosemide is commonly used as a first-line loop diuretic to relieve the symptoms
associated with heart failure in the UK. Doses of 40–80mg daily are typically used, and
doses up to 80mg twice daily in more severe cases. True or false?
3. When other therapies are not tolerated, patients with heart failure with reduced ejection
fraction (HFrEF) may receive ivabradine, digoxin and hydralazine in combination with
isosorbide dinitrate, under the direct supervision of heart failure specialists. True or false?
4. As per the National Institute for Health and Care Excellence (NICE) guidelines, people
suspected of heart failure with an amino-terminal pro-B-type natriuretic peptide (NT-
proBNP) level >3,000 nanograms/L should be referred urgently for specialist assessment
and transthoracic echocardiogram (TTE) within three weeks. True or false?

5. As per the New York Heart Association functional classification, a patient with marked 19/21
5. As per the New York Heart Association functional classification, a patient with marked
limitation of physical activity, who is comfortable at rest, but less than ordinary physical
activity results in undue breathlessness, fatigue or palpitations, can be classified as having
class II heart failure. True or false?
6. An increase in cardiac output leads to reduced renal perfusion, which stimulates release
of renin in the kidneys. True or false?
7. Biomarkers such as B-type natriuretic peptide (BNP) and amino-terminal pro-B-type
natriuretic peptide (NT-proBNP) can be used to help diagnose heart failure. However,
factors such as age over 70 years, ischaemia and tachycardia may also lead to higher
circulating levels of BNP and NT-proBNP. True or false?
8. Bumetanide, a loop diuretic that is used to relieve the symptoms associated with heart
failure, has a lower and less consistent bioavailability than furosemide, which is commonly
used as a first-line loop diuretic in these patients. True or false?
9. The National Institute for Health and Care Excellence (NICE) recommend offering
angiotensin-converting enzyme inhibitors (ACEI) and beta blockers (BB) as first line
treatment for heart failure with preserved ejection fraction (HFpEF). True or false?
10. Biomarkers such as B-type natriuretic peptide (BNP) and amino-terminal pro-B-type
natriuretic peptide (NT-proBNP) can be used to help diagnose heart failure. However,
factors such as obesity and treatment with beta-blockers may lead to lower circulating
levels of BNP and NT-proBNP. True or false?
11. It is recommended that titration of angiotensin-converting enzyme inhibitors (ACEIs) in a
community setting should start low and the dose to be doubled at no quicker than two-
weekly intervals; up-titration is recommended providing patients are tolerating this well and
are not suffering from symptomatic hypotension. True or false?
12. It is generally accepted that beta blockers (BBs) can only be initiated in patients
presenting with acute decompensated heart failure. True or false?
13. The National Institute for Health and Care Excellence (NICE) recommend replacing
angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs)
with sacubitril valsartan if the left ventricular ejection fraction (LVEF) is >35%, for patients
with heart failure with reduced ejection fraction whose symptoms persist despite optimal
first-line therapy. True or false?
14. On their own, neprilysin inhibitors have failed to demonstrate adequate clinical
outcomes in patients with heart failure. True or false?
15. Sacubitril valsartan, as recommended by The National Institute for Health and Care
Excellence (NICE), is an option for treating symptomatic chronic heart failure with reduced
ejection fraction only in patients already taking a stable dose of angiotensin-converting
enzyme inhibitors (ACEIs) or angiotensin receptor blocker (ARBs). True or false?
Citation: Clinical Pharmacist, December 2018, Vol 10, No 12, online | DOI:
10.1211/CP.2018.20205742

Test your knowledge

Closing date: 6 December 2019

Required score to pass: 70% 20/21

Required score to pass: 70%
Sign in to take this article's CPD module.
CPD modules and learning certificates are only available to RPS members and subscribers.
Sign in here

21/21