European Heart Journal (2021) 42, 551–554 ISSUE @ A GLANCE

doi:10.1093/eurheartj/ehab044

New guidelines on adult congenital

heart disease, the fantastic four in
the treatment of heart failure, and
also what happened in the last year

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in heart failure and valvular heart
disease
1,2
Filippo Crea
1
Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy and 2Department of Cardiovascular and Pulmonary Sciences,
Catholic University of the Sacred Heart, Rome, Italy

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.

For the podcast associated with this article, please visit https://academic.
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oup.com/eurheartj/pages/Podcasts. ..
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This issue opens with the ‘2020 ESC Guidelines for the man- ..
..
agement of adult congenital heart disease: The Task ..
Force for the management of adult congenital heart dis- ..
..
ease of the European Society of Cardiology (ESC)’, auth- ..
ored by Helmut Baumgartner from the University Hospital
..
..
Muenster in Germany and colleagues from the ESC Scientific ..
..
Document Group.1 The population of adults with congenital heart ..
disease (CHD) has risen dramatically over the last 60 years, in ..
..
large part due to the success of cardiac surgery and paediatric car-
diac care. In most western civilizations, >85% of babies born with
CHD can now be expected to survive to adulthood.1–3 These
Guidelines address the many challenges regarding the management
of adults with congenital heart disease. The authors note that since
the previous version of the Guidelines on the management of
grown-up CHD was published in 2010, new evidence has accumu-
lated for this patient group, particularly on percutaneous interven-
tional techniques and risk stratification with regard to timing of
surgery and catheter intervention, as well as medical treatment.
This has made a revision of the recommendations necessary. Since
adult patients with CHD now present in increasing numbers at
advanced ages, including the elderly, the term grown-up CHD no
longer appears appropriate and has therefore been replaced with
adult CHD throughout the document. This is also in accordance
with the international literature.
The next article is from the ‘Year in Cardiovascular Medicine’ ser-
ies. In ‘The year in cardiovascular medicine 2020: valvular
heart disease’, Javier Bermejo from the Universidad Complutense
de Madrid and CIBERCV in Spain, and colleagues note that valvular
heart disease is one of the most rapidly changing disciplines in cardio-
vascular medicine.4 During the past year, important basic research
has provided new insight on disease mechanisms and identified new
potential targets for pharmacological treatment (Figure 1). Despite
the unequivocal impact of COVID-19, the results of landmark clinical
trials with percutaneous devices have become available. Aspects of
adjuvant medical therapies after device implantation have also been
.. clarified. Technical improvements in next-generation valvular medical
.. devices are taking place in parallel, showing promising preliminary
..
.. clinical results. As the risk related to intervention procedures and
..
.. their consequences is becoming lower, new opportunities for an ear-
.. lier treatment arise.
..
.. The issue continues with a focus on Heart Failure and
.. Cardiomyopathies. In the Special Article entitled ‘The year in car-
..
.. diovascular medicine 2020: heart failure and cardiomyopa-
.. thies’, Héctor Bueno from the Centro Nacional de Investigaciones
..
.. Cardiovasculares (CNIC) in Madrid, Spain, and colleagues,5 again
.. from the ‘Year in Cardiovascular Medicine’ series, highlights that
..
.. heart failure (HF) prevalence remains high worldwide, with significant
..
.. sex-related and regional differences in its presentation, management,
.. and outcomes. In 2020, advances in biomarkers and imaging techni-
..
.. ques were reported for the diagnosis and prognosis of diastolic dys-
.. function and HF with preserved ejection fraction (HFpEF), or

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552 Issue @ a Glance

monitoring cardiotoxicity; and a new definition of HF with recovered

left ventricular ejection fraction (LVEF) was released. Benefits of
renin–angiotensin–aldosterone system inhibitors and beta-blockers
may extend to patients with an LVEF up to 55%. Sacubitril/valsartan
improved LV remodelling, biomarker levels, and rates of sudden car-
diac death. Two studies investigating the sodium–glucose co-
transporter 2 (SGLT2) inhibitors empagliflozin and sotagliflozin in
patients with HF arereported. The EMPEROR Reduced trial in
patients with HF with reduced EF (HFrEF) with or without type 2 dia-
betes (T2DM) demonstrated a significant reduction of cardiovascular
death and HF hospitalizations (HFHs) in patients randomized to
empaglifozin. In patients with T2DM and HF across the whole EF

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spectrum after a recent HFH, the SOLOIST trial showed a reduction
of the primary endpoint of cardiovascular deaths, total HFHs, and ur-
gent visits for HF in patients randomized to sotaglifozin. In addition, in
patients with kidney disease with or without diabetes mellitus
(DAPA-CKD), dapagliflozin prevented deterioration of renal func-
tion. Two novel drugs, the activator of soluble guanylate cyclase veri-
ciguat, and the myosin activator omecamtiv mecarbil, in the large
outcome trials VICTORIA and GALACTIC-HF predominantly
reduced HFH in high-risk patients with worsening HF. In the
AFFIRM-AHF trial, intravenous ferric carboxymaltose reduced HFH
in patients with iron deficiency after HF decompensation (Figure 2).
As noted above, SGLT2s initially proposed for the treatment of
T2DM have then been found to improve the outcomes of HFrEF.6
The question remains, however, of whether the nominally ‘standard’
heart failure drug treatment in the SGLT2 inhibitor trials corre-
sponded to a ‘real’ modern guideline-directed medical therapy.7 In a
Fast Track clinical research article entitled ‘Influence of neprilysin
inhibition on the efficacy and safety of empagliflozin in
patients with chronic heart failure and a reduced ejection
fraction: the EMPEROR-Reduced Trial’,8 Milton Packer from
the Baylor University Medical Center at Dallas, Texas, USA, and col- ..
leagues evaluated the influence of background treatment with sacubi-
..
..
tril/valsartan on the effects of SGLT2 inhibition with empagliflozin in ..
patients with HFrEF. The EMPEROR-Reduced trial randomized
..
..
3730 patients with HF and an EF <_40% to placebo or empagliflozin ..
(10 mg/day), in addition to recommended treatment for HF, for a
..
..
median of 16 months. About 20% of patients were receiving sacubi-
tril/valsartan at baseline. Patients receiving a neprilysin inhibitor were
particularly well treated, as evidenced by lower systolic pressures,
heart rates, N-terminal probrain natriuretic protein (NT-proBNP),
and greater use of cardiac devices (all P < 0.001) when compared
with those not receiving sacubitril/valsartan. Nevertheless, when
compared with placebo, empagliflozin reduced the risk of cardiovas-
cular death or hospitalization for HF by 23% in the patients not taking
a neprilysin inhibitor (P = 0.0008) and by 36% in the patients taking a
neprilysin inhibitor (P = 0.009); interaction P = 0.31. In addition,
empagliflozin significantly and similarly slowed the rate of decline in
estimated glomerular filtration rate (eGFR) in patients not taking and
in patients taking a neprilysin inhibitor. Combined inhibition of an
SGLT2 and neprilysin caused minimal incremental changes in blood
pressure and was well tolerated.
The authors conclude that the effects of empagliflozin to favour-
ably affect the clinical course of HF and kidney function are not dimin-
ished in intensively treated patients who are receiving concurrent
therapy with sacubitril/valsartan. In contrast, combined treatment
Figure 1 Proposed framework for classifying coexisting mitral re-
gurgitation and severe LV systolic dysfunction. This framework is
based on ancillary analyses of randomized clinical trials and pro-
spective validation is pending. ERO: effective regurgitant orifice.
EDV: end-diastolic volume. TMVr: transcatheter mitral valve repair.
(from Bermejo J, Postigo A, Baumgartner H. The year in cardiovas-
cular medicine 2020: valvular heart disease. See pages 647–656).
with both SGLT2 and neprilysin inhibitors can be expected to yield
substantial additional benefits. The manuscript is accompanied by an
Editorial by Johann Bauersachs from the Medizinische Hochschule
Hannover in Germany.9 In his commentary, the author concludes
that the totality of evidence now suggests that patients with HFrEF
should be treated early with a combination of the four drugs [an
..
.. angiotensin receptor–neprilysin inhibitor, a beta-blocker, a mineralo-
.. corticoid receptor antagonist (MRA), and an SGLT2 inhibitor] to fully
..
.. benefit from substantial and sustained reductions of mortality and
..
.. HFHs. The important task now is to ensure access to this evidence-
.. based therapy for all HFrEF patients.
..
.. In a clinical research article entitled ‘The effect of spironolac-
.. tone on cardiovascular function and markers of fibrosis in
..
.. people at increased risk of developing heart failure: the heart
.. ‘OMics’ in AGEing (HOMAGE) randomized clinical trial’,
..
.. John Cleland from the University of Glasgow, and colleagues investi-
.. gated the effects of spironolactone on fibrosis and cardiac function in
..
.. people at increased risk of developing HF10 in a randomized, open-
..
.. label, blinded-endpoint trial comparing spironolactone (50 mg/day) or
.. control for up to 9 months in people with, or at high risk of coronary
..
.. artery disease and raised plasma BNPs. The primary endpoint was the
.. interaction between baseline serum galectin-3 and changes in serum
..
.. procollagen type-III N-terminal pro-peptide (PIIINP) in participants
.. assigned to spironolactone or control. Procollagen type-I C-terminal
Issue @ a Glance 553

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Figure 2 During 2020, we learned new options to better stratify patients with heart failure and preserved left ventricular ejection fraction (HFpEF)
(A), the clinical benefit of three new drugs to improve prognosis of patient with heart failure and reduced left ventricular ejection fraction (HFrEF):
empagliflozin, vericiguat, and omecamtiv mecarbil (B), the potential benefit of a broader utilization of recommended drugs for HFrEF in patients with
left ventricular ejection fraction >40% (C), and the potential added clinical benefit of a comprehensive use of recommended drugs for HFrEF (D) in a
year marked by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic (central cartoon). (from Bueno H, Moura B,
Lancellotti P, Bauersachs J. The year in cardiovascular medicine 2020: heart failure and cardiomyopathies. See pages 657–680)

pro-peptide (PICP) and collagen type-1 C-terminal telopeptide

..
..
(CITP), reflecting synthesis and degradation of type-I collagen, were ..
also measured. In 527 participants, changes in PIIINP were similar for
..
..
spironolactone and control, but those receiving spironolactone had ..
greater reductions in PICP and the PICP/CITP ratio. No interactions
..
..
with serum galectin-3 were observed. ..
The authors conclude that galectin-3 does not identify greater
..
..
reductions in serum concentrations of collagen biomarkers in re-
sponse to spironolactone. However, spironolactone may influence
type-I collagen metabolism. The manuscript is accompanied by an
Editorial by Bertram Pitt and James Brian Byrd from the University
of Michigan School of Medicine in Ann Arbor, Michigan, USA.11 The
authors conclude that while the major use of MRAs currently is in
patients with HFrEF, it is reasonable to predict that on the basis of
HOMAGE and other recent findings, in the near future the use of
MRAs will be expanded, using new means to identify inappropriate
mineralocorticoid receptor activation, to prevent rather than to treat
HF, resistant hypertension, and chronic kidney disease.
While SGLT2 inhibition has consistently been found to improve
the outcome of patients with HFrEF regardless of the diabetic status,
its effects on symptoms in patients with HFrEF or HHpEF are poorly
known. The EMPERIAL programme was designed to prospectively
evaluate the effect of the SGLT2 inhibitor empagliflozin on exercise
ability and symptom burden in HF through two conceptually identical
randomized trials, enrolling patients with HFrEF or HFpEF, with or
without T2DM. Thus, in the clinical research article entitled
‘Effect of empagliflozin on exercise ability and symptoms in
heart failure patients with reduced and preserved ejection
.. fraction, with and without type 2 diabetes’, William Abraham
..
... from the the Ohio State University in Columbus, Ohio, USA and
.. colleagues enrolled patients with HFrEF (<_40%, n = 312, EMPERIAL-
.. Reduced) or HFpEF (>40%, n = 315, EMPERIAL-Preserved) who
..
.. were randomized to empagliflozin 10 mg or placebo for 12 weeks.12
.. The primary endpoint was the 6-min walk test distance change to
..
.. week 12. Key secondary endpoints included the Kansas City
.. Cardiomyopathy Questionnaire Total Symptom Score and the
..
.. Chronic Heart Failure Questionnaire. Empaglifozin failed to improve
.. the primary endpoint and the secondary endpoints.
..
.. Abraham et al. conclude that the primary outcome for both trials
.. was neutral. Nevertheless, they found hypothesis-generating
..
.. improvements in exploratory analyses of secondary endpoints with
.. empagliflozin in HFrEF. The manuscript is accompanied by an
554 Issue @ a Glance

..
Editorial by Mark C. Petrie from the University of Glasgow, and col- .. MC, Schou M, Verma S, Vinh PN, Solomon SD, McMurray JJV. Effects of dapagli-
leagues.13 The authors note that the 6-min walk distance does not ap- .. flozin in DAPA-HF according to background heart failure therapy. Eur Heart J
.. 2020;41:2379–2392.
pear to be the optimum ‘patient-centred’ outcome. Indeed, the 6- .. 7. Butler J, Zannad F, Filippatos G, Anker SD, Packer M. Totality of evidence in tri-
min distance can be affected by many HF-related comorbidities such .. als of sodium–glucose co-transporter-2 inhibitors in the patients with heart fail-
.. ure with reduced ejection fraction: implications for clinical practice. Eur Heart J
as arthritis, previous stroke, obesity, and lung disease, and is therefore ..
not an optimal measure of improvement in patients’ HF status. The .. 2020;41:3398–3401.
.. 8. Packer M, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, Kimura K, Zeller
impact of these comorbidites may be even more relevant in HFpEF .. C, George J, Brueckmann M, Anker SD, Zannad F. Evaluation of the effect of so-
where comorbidities are more prevalent and more severe. .. dium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and
.. mortality of patients with chronic heart failure and a reduced ejection fraction:
The issue is further complemented by one Discussion Forum con- .. rationale for and design of the EMPEROR-Reduced trial. Eur J Heart Fail 2019;21:
tribution, a manuscript entitled ‘On risk stratification and its par-
.. 1270–1278.
..
adoxes: the physician as a risk factor?’ by Pedro Brugada from .. 9. Bauersachs J. Heart failure drug treatment: the fantastic four. Eur Heart J 2021;

the Free University of Brussels (UZ Brussel) VUB in Belgium.14

.. 42:681–683.
.. 10. Cleland JGF, Ferreira JP, Mariottoni B, Pellicori P, Cuthbert J, Verdonschot JAJ,
..

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The editors hope that this issue of the European Heart Journal will Petutschnigg J, Ahmed FZ, Cosmi F, Brunner La Rocca HP, Mamas MA, Clark AL,
be of interest to its readers.
.. Edelmann F, Pieske B, Khan J, McDonald K, Rouet P, Staessen JA, Mujaj B,
.. González A, Diez J, Hazebroek M, Heymans S, Latini R, Grojean S, Pizard A,
.. Girerd N, Rossignol P, Collier TJ, Zannad F. The effect of spironolactone on car-
..
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