Standards and new drugs in the treatment of heart

failure
escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-14/Standards-and-new-drugs-in-the-treatment-of-
heart-failure

Vol. 14, N° 39 - 01 Mar 2017

Dr. Ihab Ramzy , FESC

Heart failure (HF) is a major public health concern affecting as many as 23 million people
worldwide [1]. Furthermore, the hospitalisation rate and costs of care are enormous. The
goals of treatment in patients with HF are to improve their clinical status, functional
capacity and quality of life, prevent hospital admission and reduce mortality.

There has been substantial progress in the management of HF with drugs. One ongoing
challenge is to ensure that proven HF therapies are used at tolerated target doses.
Because of high morbidity and mortality, there is an overwhelming need for new therapies
that are safe in improving outcomes in HF patients.

Heart Failure

Abbreviations

ACE: angiotensin-converting enzyme

ACEI: angiotensin-converting enzyme inhibitor

ADHF: acute decompensated heart failure

AF: atrial fibrillation

AHF: acute heart failure

ANP: A-type natriuretic peptide

ARB: angiotensin receptor blocker

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ARNI: angiotensin receptor neprilysin inhibitor

BEAUTIFUL: morBidity-mortality EvAlUaTion of the If inhibitor Ivabradine in patients with

coronary disease and left ventricULar Systolic Dysfunction study

BNP: B-type natriuretic peptide

bpm: beats per minute

CKD: chronic kidney disease

EMA: European Medicines Agency

FDA: Food and Drug Administration

HARMONIZE: Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-

9) in heart failure patients study

HF: heart failure

HFrEF: heart failure with reduced ejection fraction

HR: heart rate

LV: left ventricular/left ventricle

LVEF: left ventricular ejection fraction

MRA: mineralocorticoid receptor antagonist

NP: natriuretic peptide

NT-proBNP: N-terminal pro-B type natriuretic peptide

NYHA: New York Heart Association

PARADIGM-HF: Prospective Comparison of ARNI with ACEI to Determine Impact on

Global Mortality and Morbidity in Heart Failure trial

RAAS: renin-angiotensin-aldosterone system

RCT: randomised controlled trial

SHIFT: Systolic Heart failure treatment with the If inhibitor ivabradine Trial

Introduction

Neurohormonal antagonists have been shown to improve survival in patients with heart
failure with reduced ejection fraction (HFrEF) and are recommended for the treatment of
every patient with HFrEF, unless contraindicated or not tolerated. A new compound
(LCZ696) that combines the moieties of an angiotensin receptor blocker (ARB; valsartan)

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and a neprilysin inhibitor (sacubitril) has recently been shown to be superior to an
angiotensin-converting enzyme inhibitor (ACEI;enalapril) in reducing the risk of death and
of hospitalisation for HF in a single trial with strict inclusion/exclusion criteria [2]. LCZ696
is therefore recommended to replace ACEIs in ambulatory HFrEF patients who remain
symptomatic despite optimal therapy. ARBs have not been consistently proven to reduce
mortality in patients with HFrEF, and their use should be restricted to patients intolerant of
an ACEI or those who take an ACEI but are unable to tolerate a mineralocorticoid
receptor antagonist (MRA). Ivabradine reduces the elevated heart rate often seen in
HFrEF and has also been shown to improve outcomes, and should be considered when
appropriate. The above medications should be used in conjunction with diuretics in
patients with symptoms and/or signs of congestion.

Pharmacological treatment of heart failure with reduced ejection fraction

Angiotensin-converting enzyme inhibitors (ACEI)

ACEIs have been shown to reduce mortality and morbidity in patients with HFrEF [3] and
are recommended unless contraindicated or not tolerated in all symptomatic patients.
ACEIs should be up-titrated to the maximum tolerated dose in order to achieve adequate
inhibition of the renin-angiotensin-aldosterone system (RAAS). ACEIs are also
recommended in patients with asymptomatic left ventricular (LV) systolic dysfunction to
reduce the risk of HF development, HF hospitalisation and death.

Beta-blockers

Beta-blockers reduce mortality and morbidity in symptomatic patients with HFrEF, despite
treatment with an ACEI and, in most cases, a diuretic [4], but have not been tested in
congested or decompensated patients. It is known that beta-blockers and ACEIs are
complementary, and can be started together as soon as the diagnosis of HFrEF is made.
There is no evidence favouring the initiation of treatment with a beta-blocker before an
ACEI has been started [5]. Beta-blockers should be initiated in clinically stable patients at
a low dose and gradually up-titrated to the maximum tolerated dose. In patients admitted
due to acute HF (AHF), beta-blockers should be cautiously initiated in hospital, once the
patient is stabilised. Beta-blockers should be considered for rate control in patients with
HFrEF and atrial fibrillation (AF), especially in those with a high heart rate.

Beta-blockers are recommended in patients with a history of myocardial infarction and

asymptomatic LV systolic dysfunction to reduce the risk of death.

Mineralocorticoid/aldosterone receptor antagonists (MRA)

MRA (spironolactone and eplerenone) block receptors that bind aldosterone and, with
different degrees of affinity, other steroid hormone (e.g., corticosteroids, androgens)
receptors. Spironolactone or eplerenone is recommended in all symptomatic patients
(despite treatment with an ACEI and a beta-blocker) with HFrEF and left ventricular
ejection fraction (LVEF) ≤35%, to reduce mortality and HF hospitalisation [6].

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Caution should be exercised when MRA are used in patients with impaired renal function
and in those with serum potassium levels>5.0 mmol/L. Regular checks of serum
potassium levels and renal function should be performed according to clinical status.

Treatments recommended in selected symptomatic patients with HFrEF

Diuretics

Diuretics are recommended to reduce the signs and symptoms of congestion in patients
with HFrEF, but their effects on mortality and morbidity have not been studied in
randomised controlled trials (RCTs). Loop diuretics produce a more intense and shorter
diuresis than thiazides, although they act synergistically and the combination may be
used to treat resistant oedema. However, adverse effects are more likely and these
combinations should only be used with care. The aim of diuretic therapy is to achieve and
maintain euvolaemia with the lowest achievable dose. The dose of the diuretic must be
adjusted according to individual needs over time. In selected asymptomatic
euvolaemic/hypovolaemic patients, the use of a diuretic drug might be (temporarily)
discontinued.

Angiotensin receptor neprilysininhibitor (ARNI)

Background
Currently, blockade of the RAAS is the cornerstone of the treatment of HF. However, the
combination of RAAS blockade with inhibition of neprilysin, an enzyme that degrades
natriuretic peptides (NPs), has recently emerged as a potentially superior treatment
strategy [2]. In July 2015, the Food and Drug Administration (FDA) approved
sacubitril/valsartan (previously known as LCZ696) for use in patients who have chronic
and stable but symptomatic HF and who have an LVEF of less than 40%. The drug
should be used in conjunction with other HF therapies but in place of ACE inhibitors or
ARBs, and is contraindicated in patients with a history of ACE inhibitor or ARB-induced
angioedema.

Mechanism of action
The first in class is LCZ696, which is a molecule that combines a neprilysin inhibitor
(sacubitril) and an ARB (valsartan) in a single substance. Neprilysin is a zinc-dependent
neutral endopeptidase that is responsible for the degradation of several vasoactive
peptides such as NPs, bradykinin, and adrenomedullin and contributes to the breakdown
of angiotensin II [7]. High circulating A-type natriuretic peptide (ANP) and B-type
natriuretic peptide (BNP) exert physiologic effects through binding to NP receptors and
the augmented generation of cGMP, thereby enhancing diuresis, natriuresis and
myocardial relaxation and anti-remodelling. ANP and BNP also inhibit renin and
aldosterone secretion. Selective AT1-receptor blockade reduces vasoconstriction, sodium
and water retention and myocardial hypertrophy [8].Neprilysin inhibition is thought to be
the therapeutic target for counteracting the neurohormonal activation and
complementarily inhibiting the RAAS.

Clinical efficacy

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The PARADIGM trial

The PARADIGM-HFtrial was conducted in 8,399 patients who had New York Heart
Association (NYHA)Class II-IV HF and an LVEF of not more than 40% (this was changed
to ≤35% during the study) and who were randomly assigned to LCZ696 or enalapril [2].
The trial was stopped early because of an overwhelming benefit with LCZ696 therapy.
The composite primary endpoint, including cardiovascular mortality and hospitalisation for
HF, occurred significantly more often in patients receiving LCZ696 compared with those
receiving enalapril (hazard ratio [HR] 0.80, 95% confidence interval [CI]: 0.73-0.87,
p<0.001). LCZ696 was also associated with significant reductions in all-cause mortality,
cardiovascular mortality, and hospitalisation for worsening HF. Furthermore, those
patients who received LCZ696 had lower levels of the biomarkers NT-proBNP and
troponin compared with those receiving enalapril. These differences were apparent within
four weeks of treatment and were maintained when patients were assessed again eight
months later. Interestingly, levels of BNP actually increased: this is consistent with the
mechanisms of action of neprilysin inhibition [9]. This trial provided strong evidence for
superiority of the ARNI in patients with HFrEF [2].

Despite the superiority of LCZ696 over enalapril in the PARADIGM-HF trial, some
relevant safety issues remain when initiating therapy with this drug in clinical practice.
Symptomatic hypotension was more often present in the sacubitril/valsartan group (in
those ≥75 years of age, it affected 18% in the sacubitril/valsartan group vs. 12% in the
enalapril group), although there was no increase in the rate of discontinuation [2]. The risk
of angioedema in the trial was reduced by recruiting only those who tolerated therapy with
enalapril 10 mg b.i.d. and sacubitril/valsartan during an active run-in phase of five to nine
weeks (it resulted in a 0.4% rate of angioedema in the sacubitril/valsartan group vs. 0.2%
in the enalapril group). Also, the number of African American patients, who are at a higher
risk of angioedema, was relatively small in this study. To minimise the risk of angioedema
caused by overlapping ACE and neprilysin inhibition, the ACEI should be withheld for at
least 36 hrs before initiating sacubitril/valsartan. Combined treatment with an ACEI (or
ARB) and sacubitril/valsartan is contraindicated.

If-channel inhibitor
Background
One novel potential therapeutic option for HF is heart rate (HR) control. An elevated HR,
probably reflecting activation of the sympathetic nervous system, is associated with worse
cardiovascular outcomes. Although beta-blockers are used mainly for reducing HR in HF
treatment, up-titration of beta-blockers can be associated with an increased risk of
adverse reactions [10]. Ivabradine, which acts by directly and selectively inhibiting the If
current in the sinoatrial node and therefore should only be used for patients in sinus
rhythm, has potential benefits of pharmacologic modification of HR in HF. The European
Medicines Agency (EMA) approved ivabradine for use in Europe in patients with HFrEF
with LVEF ≤35% and in sinus rhythm with a resting heart rate ≥75 bpm, because in this
group ivabradineconferred a survival benefit [11] based on a retrospective subgroup
analysis requested by the EMA.

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Mechanisms of action
Ivabradine lowers HR by inhibiting a specific sinus node pacemaker If current without
affecting the myocardial contractility or relaxation, ventricular repolarisation, or
intracardiac conduction. This is rather different from the mechanism induced by beta-
blockers, which acts wherever beta-adrenergic receptors are present, causing negative
inotropism and vasoconstriction in the bronchi; and calcium channel blockers act on the
calcium channels of the heart and smooth muscle, causing negative inotropism,
hypotension, and constipation.

Clinical trials
The BEAUTIFUL trial

The BEAUTIFUL trial was an RCT to test the efficacy of ivabradine in 10,917 patients with
stable coronary disease and an LVEF of less than 40% and an HR of more than 60 beats
per minute (bpm) [12]. In this trial, ivabradine reduced HR but had no effect on the
primary endpoint of cardiovascular death or admission to a hospital for new-onset or
worsening HF. However, in a subgroup of patients with an HR of at least 70 bpm,
ivabradine revealed a clear benefit with respect to the secondary endpoints of admission
to a hospital for a fatal or non-fatal myocardial infarction and coronary revascularisation
[12].

The SHIFT trial

The SHIFT trial was an RCT in 6,558 patients with stable symptomatic HF and an LVEF
of not more than 35% in sinus rhythm with an HR of at least 70 bpm [14]. In this trial,
ivabradine significantly reduced the primary endpoint of a composite of cardiovascular
death or hospital admission for worsening HF and deaths due to HF [13]. The effect was
consistent across all pre-specified subgroups, including the elderly [13]. Further analyses
proved that high HR as a risk factor in HF and lowering HR improve outcomes [13]. Other
analyses showed that ivabradine reduces the risk of rehospitalisation for HF and is
associated with an improvement in quality of life. HR targeted below a threshold rather
than HR reduction itself has demonstrated potential benefits. One problem with
interpreting the results of the SHIFT trial is that many patients were not on target doses of
beta-blockers. If indeed these patients were intolerant of higher doses of beta-blockers,
then these results are quite important for clinical care. Given its promising therapeutic
value, ivabradine is clearly desirable in patients with symptomatic LV systolic dysfunction,
elevated HR, and an intolerance to beta-blockers.

Angiotensin II type I receptor blockers (ARB)

ARB are recommended only as an alternative in patients intolerant of an

ACEI.Candesartan has been shown to reduce cardiovascular mortality [14].Valsartan
showed an effect on hospitalisation for HF (but not on all-cause hospitalisations) in
patients with HFrEF receiving background ACEIs. The combination of ACEI/ARB for
HFrEF was reviewed by the EMA, which suggested that the benefits are thought to
outweigh the risks only in a select group of patients withHFrEF in whom other treatments
are unsuitable. Therefore, ARBsare indicated for the treatment of HFrEF only in patients

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who cannot tolerate an ACEI because of serious side effects. The combination of
ACEI/ARB should be restricted to symptomatic HFrEF patients receiving a beta-blocker
who are unable to tolerate an MRA, and must be used under strict supervision.

Combination of hydralazine and isosorbide dinitrate

There is no clear evidence to suggest the use of this fixed-dose combination therapy in all
patients with HFrEF. Evidence on the clinical utility of this combination is scanty and
comes from one relatively small RCT conducted exclusively in men and before ACEIs or
beta-blockers were used to treat HF.

Additionally, a combination of hydralazine and isosorbide dinitrate may be considered in

symptomatic patients with HFrEF who can tolerate neither ACEI nor ARB (or they are
contraindicated) to reduce mortality. However, this recommendation is based on the
results of the Veterans Administration Cooperative Study, which recruited symptomatic
HFrEF patients who received only digoxin and diuretics [15].

Table 1 summarises the above recommended treatments in selected patients with

symptomatic heart failure with reduced ejection fraction.

Table1. Pharmacological treatments recommended in selected patients with

symptomatic (NYHA Class II-IV) heart failure with reduced ejection fraction.

Class of Level of
Recommendations recommendation evidence

Diuretics

Diuretics are recommended in order to improve I B

symptoms and exercise capacity in patients with signs
and/or symptoms of congestion.

Diuretics should be considered to reduce the risk of IIa B

HF hospitalisation in patients with signs and/or
symptoms of congestion.

Angiotensin receptor neprilysin inhibitor

Sacubitril/valsartan is recommended as a replacement I B

for an ACEI to reduce further the risk of HF
hospitalisation and death in ambulatory patients with
HFrEF who remain symptomatic despite optimal
treatment with an ACEI, a beta-blocker and an MRAa.

If-channel inhibitor

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 Class of Level of
Recommendations recommendation evidence

Ivabradine should be considered to reduce the risk of IIa B

HF hospitalisation and cardiovascular death in
symptomatic patients with LVEF ≤35%, in sinus rhythm
and a resting heart rate ≥70 bpm despite treatment
with an evidence-based dose of beta-blocker (or
maximum tolerated dose below that), ACEI (or ARB),
and an MRA (or ARB).

Ivabradine should be considered to reduce the risk of IIa C

HF hospitalisation and cardiovascular death in
symptomatic patients with LVEF ≤35%, in sinus rhythm
and a resting heart rate ≥70 bpm who are unable to
tolerate or have contraindications for a beta-blocker.
Patients should also receive an ACEI (or ARB) and an
MRA (or ARB).

ARB

An ARB is recommended to reduce the risk of HF I B

hospitalisation and cardiovascular death in
symptomatic patients unable to tolerate an ACEI
(patients should also receive a beta-blocker and an
MRA).

An ARB may be considered to reduce the risk of HF IIb C

hospitalisation and death in patients who are
symptomatic despite treatment with a beta-blocker
who are unable to tolerate an MRA.

Hydralazine and isosorbide dinitrate

Hydralazine and isosorbide dinitrate should be IIa B

considered in self-identified black patients with LVEF
≤35% or with an LVEF <45% combined with a dilated
LV in NYHA Class III-IV despite treatment with an
ACEI, a beta-blocker and an MRA, to reduce the risk
of HF hospitalisation and death.

Hydralazine and isosorbide dinitrate may be IIb B

considered in symptomatic patients with HFrEF who
can tolerate neither an ACEI nor an ARB (or they are
contraindicated) to reduce the risk of death.

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 Class of Level of
Recommendations recommendation evidence

Other treatments with less certain benefits

Digoxin

Digoxin may be considered in symptomatic patients in IIb B

sinus rhythm despite treatment with an ACEI (or ARB),
a beta-blocker and an MRA, to reduce the risk of
hospitalisation (both all-cause and HF-
hospitalisations).

a
Patient should have elevated natriuretic peptides (plasma BNP ≥150 pg/mL or plasma
NT-proBNP ≥600 pg/mL, or, if HF hospitalisation within the last 12 months, plasma BNP
≥100 pg/mL or plasma NT-proBNP ≥400 pg/mL) and be able to tolerate enalapril 10 mg
b.i.d.

ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BNP:

B-type natriuretic peptide; bpm: beats per minute; HF: heart failure; HFrEF: heart failure
with reduced ejection fraction; LVEF: left ventricular ejection fraction; MRA:
mineralocorticoid receptor antagonist; NT-proBNP: N-terminal pro-B type natriuretic
peptide; NYHA: New York Heart Association. OMT: optimal medical therapy (for HFrEF
this mostly comprises an ACEI or sacubitril/valsartan, a beta-blocker and an MRA).

Other treatments with less certain benefits in symptomatic patients with

heart failure and reduced ejection fraction

Digoxin and other digitalis glycosides

Digoxin may be considered in patients in sinus rhythm with symptomatic HFrEF to reduce
the risk of hospitalisation (both all-cause and HF hospitalisations),although its effect on
top of beta-blockers has never been tested. The effects of digoxin in patients with HFrEF
and AF have not been studied in RCTs, and recent studies have suggested a potentially
higher risk of events (mortality and HF hospitalisation) in patients with AF receiving
digoxin.

In patients with symptomatic HF and AF, digoxin may be useful to slow a rapid ventricular
rate, but it is only recommended for the treatment of patients with HFrEF and AF with
rapid ventricular rate when other therapeutic options cannot be pursued. Of note, the
optimal ventricular rate for patients with HF and AF has not been well established, but the
prevailing evidence suggests that strict rate control might be deleterious. A resting
ventricular rate in the range of 70-90 bpm is recommended based on current opinion.

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Digitalis should always be prescribed under specialist supervision. Given its distribution
and clearance, caution should be exerted in females, in the elderly and in patients with
reduced renal function. In the latter patients, digitoxin should be preferred.

Newer agents to prevent hyperkalaemia during RAAS inhibition

Patiromer and zirconium cyclosilicate

Background
As the use of RAAS inhibitors and MRA in patients with HF increases, hyperkalaemia has
become a more common electrolyte disturbance in clinical practice, especially in patients
with chronic kidney disease (CKD). Moreover, hyperkalaemia is a major limiting factor to
titrate these drugs fullyin these patients who are most likely to benefit from treatment.
Currently, non-invasive treatment of hyperkalaemia is limited by a lack of safety, efficacy,
and tolerability. Thus, agents to control reliably the plasma concentration of potassium
while maintaining the use of RAAS inhibitors or MRA are needed. Now, there are two
novel potassium absorbents, patiromer calcium and zirconium silicate (ZS-9), that are
designed to increase potassium loss via the gastrointestinal tract. Although they have not
yet been approved by the FDA, both have demonstrated efficacy and safety in recent
trials.

Mechanism of action
1. Patiromer

Patiromer is a non-absorbable polymer that binds potassium in exchange for calcium

throughout the gastrointestinal tract. This agent, which is an orally administered drug,
increases faecal excretion of potassium and consequently decreases plasma potassium
levels. Prior patiromer clinical trials have also demonstrated the drug’s utility in treating
hyperkalaemia in at-risk populations for periods ranging from a few days to up to 12
weeks [16].

2. Zirconium cyclosilicate (ZS-9)

ZS-9 is a high-specificity inorganic crystal that entraps potassium in the intestinal tract.
Instead of exchanging calcium, ZS-9 exchanges sodium and hydrogen ions for
potassium. Dose-dependent excretion of potassium occurs in the faeces, whereas urinary
excretion decreases with dose.

Clinical trial
The HARMONIZE study

The HARMONIZE study was an RCT evaluating the long-term efficacy and safety of ZS-9
in 258 patients with hyperkalaemia [17]. Patients achieving normokalaemia (3.5 to 5.0
mEq/l) were randomly assigned to different doses of ZS-9 (5, 10, or 15 g) or placebo for
28 days in the maintenance phase. Mean baseline potassium was 5.6 mEq/l and declined
to 4.5 mEq/l after 48 hours of 10g ZS-9 treatment in the acute phase. A significant

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reduction in potassium was observed within one hour of ZS-9 administration, and 84% of
patients achieved normokalaemia at 24 hours and 98% at 48 hours [17]. Furthermore,
studies assessing the long-term efficacy and safety profile of this novel drug are ongoing.

Relaxin
Background
Serelaxin is a recombinant form of the human hormone relaxin, which is a naturally
occurring hormone that is produced by the corpus luteum and placenta in pregnancy.
Recent studies have shown that relaxin is also produced by the vasculature and failing
myocardium.

Mechanism of action
Relaxin interacts with a G protein-coupled receptor, leading to increased cyclic adenosine
monophosphate (cAMP). As a result, nitric oxide production is increased. Additionally,
relaxin upregulates the activity of vascular matrix metalloproteinase-2 (MMP-2), which
can activate endothelin-1, leading to endothelin-B receptor activation and subsequent
nitric oxide production. Activation of the endothelin-B receptor is probably involved in the
relaxin-mediated increases in renal blood flow [18]. Thus, relaxin increases cardiac
output, arterial compliance, and renal blood flow, supporting important physiological
changes during pregnancy. Given its potent vasodilator properties as well as its ability to
increase renal perfusion, relaxin became of interest as a potential therapy for acute HF.

Ularitide
Background
Decongestion is an important part of managing both acute and chronic HF, and retention
of fluid and sodium metabolism play a fundamental role in this. NPs are activated in HF
and exert compensatory effects by inhibiting the RAAS and inducing vasodilation and
natriuresis. Therefore, NPs have received much interest as a potential therapy in acute
decompensated heart failure (ADHF). NPs consist of ANP, BNP, C-type NP (CNP), D-type
NP (DNP), and urodilatin.

Mechanism of action
Urodilatin was first isolated from human urine in 1988 as a modified version of pro-ANP. It
is produced mainly by distal renal tubule cells and is secreted into urine and is involved in
renal sodium handling [19]. Synthetic NPs such as carperitide (a recombinant form of
ANP) and nesiritide (a recombinant form of BNP) are currently used to treat congestive
HF (carperitide is available only in Japan). When it is administered to patients with ADHF,
a rapid reduction of pulmonary capillary pressure and consequent relief of dyspnoea often
result because of natriuresis, diuresis, and venous and arterial dilation. In contrast to ANP
and BNP, urodilatin is effective in more distal parts of the renal tubular system because of
its slower elimination rate.

Conclusion

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The treatment of heart failure has evolved rapidly over the past few years and many
aspects of this are considered in this article. Patients are often complex, with multiple
comorbidities, and being under specialist care has been shown to be associated with
greater use of evidence-based therapies and improved survival. Future clinical trials with
adequately powered, more appropriate study designs, optimal clinical endpoints, and
proper patient selection are mandatory to assess the true efficacy of these treatments.

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Notes to editor

Author:

Dr Ihab S.Ramzy, MD, PhD, FESC

Northwick Park Hospital, London, United Kingdom

Address for correspondence:

Dr Ihab S. Ramzy

Specialty Doctor in Cardiology,Cardiology Department, Northwick Park Hospital,

Watford Road, Harrow, London, HA1 3UJ, United Kingdom

E-mail:ihab.ramzy@nhs.net

Author disclosures:

The author has no conflicts of interest to declare.

The content of this article reflects the personal opinion of the author/s and is not
necessarily the official position of the European Society of Cardiology.

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