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Medicographia

The vulnerable phase of heart failure: a window of opportunity

C hance
favors only
the prepared mind

ISSN 0243-3397

Vol 37, No. 2, 2015

Medicographia
The vulnerable phase
of heart failure:
a window of opportunity

Pa s t e u r

Vol 37, No. 2


Pages 117-234

2015

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Medicographia

Vol 37, No. 2, 2015

123

Ser vier

publication

The vulnerable phase


of heart failure:
a window of opportunity
E DITORIAL
119

Hospitalization for heart failure: can we prevent it? Can we predict it?
Hospitalisation pour insuffisance cardiaque : pouvons-nous la prvenir ?
Pouvons-nous la prvoir ?
M. Komajda, France

T HEMED
125

ARTICLES
The changing landscape of heart failure outcomes
J. Lpez-Sendn, N. Montoro, Spain

135

The social and economic burden of hospitalization for heart failure


D. Farmakis, G. Filippatos, J. Parissis, J. Lekakis, Greece

139

Postdischarge outcomes of patients hospitalized for heart failure


M. Metra, V. Carubelli, I. Castrini, A. Ravera, E. Sciatti, C. Lombardi, Italy

144

Definition and characteristics of the vulnerable phase in heart failure


M. B. Yilmaz, A. Mebazaa, Turkey and France

149

Treatment optimization in heart failure patients from admission to discharge


P. Ponikowski, E. A. Jankowska, Poland

155

Postdischarge assessment and management of patients with heart failure


M. R. Cowie, United Kingdom

163

Impact of quality improvement initiatives in patients hospitalized


for heart failure
J. L. Zamorano, V. C. Lozano, Spain
Contents continued on next page

Medicographia

Vol 37, No. 2, 2015

123

C ONTROVERSIAL

Ser vier

publication

QUESTION

171 Can biomarkers guide the assessment and management of heart failure
patients after discharge from hospitals?
E. A. Bocchi, Brazil - D. A. Brito, Portugal - O. Chioncel, Romania A. Fong, Malaysia - M. Hlsmann, Austria - E. A. Jankowska, Poland M. Loutfi, Egypt - A. Lupi, Italy - Y. F. M. Nosir, Egypt - E. B. Reyes,
Philippines - S. N. Tereschenko, Russia - M. B. Yilmaz, Turkey B. Yoo, Republic of Korea

P ROCORALAN
185 Procoralan: new opportunities for vulnerable heart failure patients
I. Elyubaeva, France

I NTERVIEW
193 Therapeutic education: which tool for whom?
P. Jourdain, France

F OCUS
197 Challenges in predicting heart failure readmission: focus on heart rate
M. Bhm, Germany

U PDATE
202 Telemonitoring in heart failure management: what is needed to make it
fit for routine use?
C. Zugck, Germany

TOUCH OF

F RANCE

210 MuCEM, the pride of Marseille


M. Raive, France

221 The Medical Faculty of Montpellier: one thousand years of medicine


C. Rgnier, France

EDITORIAL

the burden of rehospitalizations remains an important issue:


it is associated with a very poor
quality of life and it puts health care
systems under considerable strain.
One of the major reasons for this
situation is underdosing of recommended medications and insufficient implementation of guidelines.
It results from nonmodifiable factors related to patient conditions
(age, comorbidities, and related
contraindications), but also from
the fragmented organization of
health care systems.

Hospitalization
for heart failure:
can we prevent it?
Can we predict it?
b y M . Ko m a j d a , Fra n c e
eart failure is a common condition associated with poor outcomes. Its
prevalence is increasing worldwide for several reasons, including aging
of the population, and this situation raises concerns about the growing
burden for health care systems. Significant progress has been made in
the pharmacological management of chronic heart failure over the last decades; this
is due to the introduction of angiotensin-converting enzyme (ACE) inhibitors, b-blockers, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and
more recently the If current blocker ivabradine. This has resulted in a significant reduction in heart failurerelated mortality. The annual death rate was approximately
20% before the era of ACE inhibitors, whereas in the most recent trials, this rate has
been reduced to 5% to 10%. Importantly, this is observed not only in clinical trials,
which include selected populations, but also in the general population.1

H
Michel KOMAJDA, MD, PhD
Department of Cardiology
Piti Salptrire Hospital
and University Paris 6
IHU ICAN
Paris, FRANCE

Address for correspondence:


Professor Michel Komajda,
GH Piti-Salptrire, Institut de
Cardiologie, 47-83 Boulevard de
lHpital, 75013 Paris, France
(e-mail: michel.komajda@psl.aphp.fr)
Medicographia. 2015;37:119-124
www.medicographia.com

However, the fact that the impact of modern therapies does not translate into a significant reduction in heart failurerelated hospitalizations is a cause for concern. Some
publications actually suggest a bidirectional trend in which there is a reduction in
mortality and an increase in hospitalizations.2 This is all the more worrisome as the
cost of heart failure hospitalizations accounts for approximately 70% of all the expenses incurred in the management of heart failure,3 since heart failure hospitalizations are both lengthy and recurrent. Several explanations can be put forward in
order to explain this apparent paradox. First, severely affected patients now survive
thanks to modern therapy at the expense of (re)hospitalizations with a particularly
critical phase in the first 30 days that follow an index hospitalization. Second, uptitration of lifesaving medications remains suboptimal. In fact, recent surveys suggest
that the rate of prescription of the medications recommended by international guidelines has improved, whereas the titration of these drugs is not performed in practice. For instance, a recent survey carried out across European Society of Cardiology countries shows that, overall, only 25% to 30% of patients reach the target
recommended dose of b-blockers in real-life situations.4 Multiple comorbidities are
frequent in elderly patients with heart failure, and they can result in contraindications
or poor tolerance of some of the recommended medications. This is, however, only
part of the explanation for the reluctance of health care professionals to uptitrate these
treatments in the context of polypharmacy, as complex uptitration schemes also play
a significant role. Third, patients who have recently been hospitalized for heart failure
decompensation are not appropriately monitored by health care professionals. There
is often a gap in follow-up care after discharge and many patients do not see any
health care professional (cardiologists, general practitioners, or specialized nurses)
at a time when the risk of being rehospitalized for decompensation is extremely high.

Hospitalization for heart failure: can we prevent it? Can we predict it? Komajda

MEDICOGRAPHIA, Vol 37, No. 2, 2015

119

EDITORIAL

In some surveys, less than one-third of patients hospitalized


for heart failure were found to have consulted a cardiologist in
the first 3 months after discharge.5 This poor coordination is
one of the major reasons why titration of lifesaving medications initiated in hospital during the decompensation phase
is not continued afterwards. A fundamental issue is, therefore,
to find solutions in order to improve this situation.

There is, therefore, no unique solution to improve the somewhat fragmented journey of the heart failure patient. However, it appears necessary to develop better communication
and coordination between stakeholders. Ideally, this can take
place in structured multidisciplinary networks as they have
been shown to improve (re)hospitalization rates.

Biomarkers monitoring and telemonitoring


Better education
In-depth information on the challenges and objectives of the
treatment of a chronic condition such as heart failure should
target the professionals in charge of its long-term management. This applies particularly to general practitioners who,
in many circumstances, are responsible for the uptitration of
medications outside the hospital. Here, the role of international guidelines is critical in order to provide clear guidance and
information in an abridged version and convince professionals of shifting the primary goal of treatment from symptom
relief to improvement of outcomes. Pocket versions of guidelines such as those developed by the European Society of
Cardiology are typically appropriate for this.
We have, however, to acknowledge the existence of gaps in
evidence in the field of heart failure. In particular, in heart failure
with preserved ejection fractionwhich represents a growing
proportion of heart failure patientsthere is scarce evidence
of benefits with any cardiovascular drug, and therefore, we
cannot provide evidence-based recommendations for these
patients. Patient education is also key for success: detailed
information on the disease, treatment objectives, warning signals of decompensation, side effects of medications, and dietary requirements should be provided by physicians as well
as nurses and nutritionists. This is the best way to make patients aware of the potential mistakes that can lead to decompensation such as poor compliance with medications or
excessive sodium intake.
Patient education is often provided individually in an unstructured manner. It is, however, preferable to adopt standardized strategies in specific structures where all the professionals mentioned above can interact with small groups of heart
failure patients using visual tools in lay language in order to
facilitate communication. Several national programs have been
successfully conducted in this way.6 The ultimate goal of this
strategy is to transform the relationship between the patient
and the health care professional(s) into a partnership where
the patient plays an active role.

Better cooperation between health care


professionals
Management of heart failure after discharge varies considerably between countries: cardiology departments, internal medicine divisions, and specialized heart failure clinics can all be
responsible for coordinating care management as well as private cardiologists, general practitioners, or specialized nurses.

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

Several studies suggest that serial measurements of natriuretic peptide plasma level can lead to a significant improvement
in outcomes. A recent meta-analysis of these studies shows
that natriuretic peptideguided strategies can reduce hospitalizations for heart failure by approximately 25% compared
with standards of care.7 Of note, although this natriuretic peptideguided strategy had beneficial effects on mortality in
younger patients <75 years, it did not in those >75 years, who
represent the majority of heart failure patients.
Another strategy is to use telemedicine. This generic term covers very different situations, from structured telephone support
to remote distance monitoring of biomarkers such as weight,
heart rate, blood pressure, oximetry, electrocardiogram, or
estimated pulmonary blood pressure through sophisticated
implantable devices. The results of published studies show
some divergence, but a meta-analysis of these trials suggests
nevertheless that telemedicine could improve outcomes and,
in particular, reduce heart failurerelated hospitalizations.8 In
many countries though, integration of this novel approach to
classic in-hospital existing structures is unresolved and reimbursement of the time spent by professionals for these activities remains an issue.

Conclusion
In summary, the management of chronic heart failure with reduced ejection fraction has significantly improved the rate of
mortality related to this condition. However, the burden of rehospitalizations remains an important issue: it is associated
with a very poor quality of life and it puts health care systems
under considerable strain. One of the major reasons for this
situation is underdosing of recommended medications and
insufficient implementation of guidelines. It results from nonmodifiable factors related to patient conditions (age, comorbidities, and related contraindications), but also from the fragmented organization of health care systems. In order to improve
the situation we need to recognize that the management of
this chronic condition is a continuum and that postdischarge
treatment and follow-up are as important as in-hospital management. A better global organization of medical care around
the heart failure patient is needed and health economic assessment of new initiatives is warranted in order to select optimal strategies.
This issue of Medicographia reviews all the scientific questions
related to the management of heart failure, and in particular, the
transition from hospital care to postdischarge management.

Hospitalization for heart failure: can we prevent it? Can we predict it? Komajda

EDITORIAL

References
1. Laribi S, Aouba A, Nikolaou M; GREAT Network. Trends in death attributed to
heart failure over the past two decades in Europe. Eur J Heart Fail. 2012;14(3):
234-239.
2. Heidenreich PA, Sahay A, Kapoor JR, Pham MX, Massie B. Divergent trends
in survival and readmission following a hospitalization for heart failure in the Veterans Affairs Health care system 2002 to 2006. J Am Coll Cardiol. 2010;56(5):
362-368.
3. Stewart S, Jenkins A, Buchan S, McGuire A, Capewell S, McMurray JJ. The current cost of heart failure to the National Health Service in the UK. Eur J Heart
Fail. 2002;4(3):361-371.
4. Maggioni AP, Dahlstrm U, Filippatos G, et al; Heart Failure Association of the
European Society of Cardiology (HFA). EURObservational Research Programme:
regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail. 2013;15(7):808-817.
5. Cohen Solal A, Leurs I, Assyag P, et al; French National College of Cardiologists.

Optimization of heart FailUre medical Treatment after hospital discharge according to left ventricUlaR Ejection fraction: the FUTURE survey. Arch Cardiovasc Dis. 2012;105(6-7):355-365.
6. Juillire Y, Jourdain P, Suty-Selton C, et al; ODIN Cohort Participants. Therapeutic patient education and all-cause mortality in patients with chronic heart failure:
a propensity analysis. Int J Cardiol. 2013;168(1):388-395.
7. Troughton RW, Frampton CM, Brunner-La Rocca HP, 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(23):
1559-1567.
8. Inglis SC, Clark RA, McAlister FA, Stewart S, Cleland JG. Which components of
heart failure programmes are effective? A systematic review and meta-analysis
of the outcomes of structured telephone support or telemonitoring as the primary
component of chronic heart failure management in 8323 patients: Abridged
Cochrane Review. Eur J Heart Fail. 2011;13(9):1028-1040.

Keywords: heart failure; hospitalization; prevention; postdischarge management

Hospitalization for heart failure: can we prevent it? Can we predict it? Komajda

MEDICOGRAPHIA, Vol 37, No. 2, 2015

121

DITORIAL

la charge des rhospitalisations constitue toujours un problme important : elle est associe
une qualit de vie trs dgrade
et elle exerce une charge considrable sur les systmes de soins de
sant. Lune des principales raisons
de cet tat de fait est le sous-dosage des mdicaments recommands et la mise en uvre insuffisante
des directives. Les raisons proviennent de facteurs non modifiables lis aux patients (ge, comorbidits et leurs contre-indications
inhrentes), mais galement de
lorganisation fragmente des systmes de soins de sant.

Hospitalisation pour
insuffisance cardiaque :
pouvons-nous la prvenir ?
Pouvons-nous la prvoir ?
p a r M . Ko m a j d a , Fra n c e

insuffisance cardiaque est une affection frquente dont lvolution est dfavorable. Sa prvalence augmente travers le monde pour plusieurs raisons, notamment le vieillissement de la population, et cette situation soulve
un certain nombre de problmes concernant la charge croissante assume par les systmes de soins de sant. Des progrs significatifs ont t accomplis dans la prise en charge pharmacologique de linsuffisance cardiaque chronique
au cours des dernires dcennies ; cette amlioration est due la mise sur le march des inhibiteurs de lenzyme de conversion de langiotensine (IEC), des btabloquants, des antagonistes des rcepteurs de langiotensine, des antagonistes des
rcepteurs des minralocorticodes et plus rcemment de livabradine, un inhibiteur
du courant If . Do une rduction significative de la mortalit lie linsuffisance cardiaque. Le taux de mortalit annuel tait dapproximativement 20 % avant lapparition des IEC, alors que les tudes les plus rcentes ont montr une rduction de
ce taux de 5 % 10 %. Il est important de souligner que ce rsultat a t observ
non seulement dans les tudes cliniques, qui portent sur des populations slectionnes, mais galement dans la population gnrale 1.

Cependant, le fait que limpact des traitements modernes ne se traduise pas en une
rduction significative des hospitalisations pour insuffisance cardiaque soulve un
certain nombre de problmes. Plusieurs publications suggrent mme une tendance bidirectionnelle, cest--dire une rduction de la mortalit et une augmentation des hospitalisations 2. Cette observation est particulirement proccupante, car
le cot des hospitalisations pour insuffisance cardiaque reprsente environ 70 % de
lensemble des dpenses lies la prise en charge de linsuffisance cardiaque 3,
dans la mesure o les sjours dus une insuffisance cardiaque sont la fois longs
et rcurrents. Plusieurs explications peuvent tre avances pour expliquer ce paradoxe apparent. Tout dabord, les patients svrement affects survivent dsormais grce aux traitements modernes aux dpens de (r)hospitalisations, une phase
particulirement critique intervenant au cours des 30 premiers jours suivant lhospitalisation initiale. Ensuite, laugmentation posologique des mdicaments essentiels reste sousoptimale. En fait, de rcentes enqutes suggrent que le taux de
prescription des mdicaments recommands par les directives internationales sest
amlior, mais que lajustement posologique de ces mdicaments nest pas effectu en pratique. Par exemple, une tude ralise rcemment dans les pays de la
Socit Europenne de Cardiologie montre que dune manire gnrale, seulement
25 % 30 % des patients atteignent la dose cible recommande pour les btabloquants en pratique relle 4. Les patients gs atteints dinsuffisance cardiaque prsentent frquemment de multiples comorbidits qui peuvent entraner des contre-

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

Hospitalisation pour insuffisance cardiaque : pouvons-nous la prvenir ? La prvoir ? Komajda

DITORIAL

indications ou une mauvaise tolrance certains des mdicaments recommands. Cependant, cela nexplique que partiellement les rticences des professionnels de sant augmenter la posologie de ces traitements dans le contexte dune
polymdicalisation ; en effet, la complexit des schmas daugmentation posologique peut galement jouer un rle significatif. Ensuite, les patients ayant rcemment t hospitaliss pour une insuffisance cardiaque dcompense ne sont
pas surveills de manire approprie par les professionnels
de sant. Les soins de suivi aprs la sortie de lhpital montrent souvent une discontinuit, et un grand nombre de patients ne consultent aucun professionnel de sant (cardiologue,
mdecin gnraliste ou infirmire spcialise) au cours dune
priode o le risque de rhospitalisation pour dcompensation est extrmement lev.
Dans certaines tudes, moins dun tiers des patients hospitaliss pour insuffisance cardiaque ont consult un cardiologue
au cours des 3 premiers mois ayant suivi la sortie de lhpital 5. Cette mauvaise coordination est lune des raisons majeures qui expliquent pourquoi laugmentation posologique
des mdicaments essentiels mise en uvre lhpital au
cours de la phase de dcompensation nest pas poursuivie
par la suite. Il est par consquent fondamental de trouver des
solutions permettant damliorer cette situation.

Une meilleure formation


Une information approfondie sur les difficults et les objectifs
du traitement dune affection chronique, comme linsuffisance
cardiaque, doit cibler les professionnels chargs de sa prise
en charge long terme. Cela est particulirement vrai pour
les mdecins gnralistes qui, dans de nombreuses circonstances, ont la charge de laugmentation posologique des mdicaments lorsque le patient nest plus hospitalis. Le rle
des directives internationales est cet gard essentiel, car
elles doivent fournir une orientation claire et des informations
concises destines convaincre les professionnels de changer lobjectif primaire du traitement, consistant soulager les
symptmes et amliorer les rsultats. Des versions des directives en format poche, comme celles dveloppes par la
Socit europenne de cardiologie, sont particulirement
adaptes cette situation.
Nous devons cependant reconnatre que les donnes sur linsuffisance cardiaque dont nous disposons prsentent certaines lacunes. En particulier, dans linsuffisance cardiaque
avec fraction djection prserve qui reprsente une proportion croissante des patients insuffisants cardiaques peu
de bnfices ont t mis en vidence avec les diffrents traitements cardio-vasculaires, et il est par consquent impossible de fournir des recommandations factuelles pour cette
population de patients. Lducation des patients est galement
essentielle la russite : des informations dtailles sur la maladie, les objectifs thrapeutiques, les signaux dalerte dune
dcompensation, les effets indsirables des mdicaments et

les recommandations alimentaires doivent tre dlivrs par


les mdecins, ainsi que par les infirmires et les nutritionnistes.
Cest la meilleure manire de faire prendre conscience aux
patients que certaines erreurs ventuelles peuvent conduire
une dcompensation, par exemple une mauvaise observance du traitement mdicamenteux ou une consommation
excessive de sodium.
Lducation des patients est souvent dlivre individuellement de manire non structure. Il serait pourtant prfrable
dadopter des stratgies standardises dans des structures
spcifiques, o tous les professionnels mentionns ci-dessus
pourraient interagir avec de petits groupes de patients insuffisants cardiaques, en utilisant des outils visuels dans un langage simple destins faciliter la communication. Plusieurs
programmes nationaux ont t mens avec succs dans cet
esprit 6. Lobjectif ultime de cette stratgie est de transformer
la relation entre le patient et le ou les professionnels de sant
en un partenariat dans lequel le patient joue un rle actif.

Une meilleure coopration entre


les professionnels de sant
La prise en charge de linsuffisance cardiaque aprs la fin de
lhospitalisation est extrmement variable selon les pays : les
services de cardiologie, les services de mdecine interne et
les cliniques spcialises dans linsuffisance cardiaque sont
tous susceptibles dassumer la responsabilit de la coordination des soins, de mme que les cardiologues privs, les mdecins gnralistes ou les infirmires spcialises. Il nexiste
donc aucune solution unique permettant damliorer le parcours quelque peu fragment du patient insuffisant cardiaque.
Cependant, il apparat ncessaire de dvelopper une meilleure communication et une coordination efficace entre les
diffrents intervenants. Dans lidal, cela pourrait tre mis en
uvre dans des rseaux multidisciplinaires structurs, dans
la mesure o il a t dmontr quils amlioraient les taux
de (r)hospitalisation.

Surveillance et tlsurveillance des biomarqueurs


Plusieurs tudes suggrent que des mesures en srie des
concentrations plasmatiques de peptide natriurtique pourraient entraner une amlioration significative des rsultats. Une
rcente mta-analyse de ces tudes a montr que les stratgies guides par le peptide natriurtique permettaient de
rduire les hospitalisations pour insuffisance cardiaque denviron 25 %, par rapport aux soins standard 7. Il faut souligner
que cette stratgie guide par le peptide natriurtique a des
effets bnfiques sur la mortalit des patients gs de moins
de 75 ans, mais non chez ceux gs de plus de 75 ans, qui
reprsentent pourtant la majorit des patients atteints dinsuffisance cardiaque.
Une autre stratgie repose sur lutilisation de la tlmdecine.
Ce terme gnral peut recouvrir des situations trs variables,
pouvant aller dun soutien tlphonique structur une sur-

Hospitalisation pour insuffisance cardiaque : pouvons-nous la prvenir ? La prvoir ? Komajda

MEDICOGRAPHIA, Vol 37, No. 2, 2015

123

DITORIAL

Conclusion

systmes de soins de sant. Lune des principales raisons de


cet tat de fait est le sous-dosage des mdicaments recommands et la mise en uvre insuffisante des directives. Les
raisons proviennent de facteurs non modifiables lis aux patients (ge, comorbidits et leurs contre-indications inhrentes),
mais galement de lorganisation fragmente des systmes
de soins de sant. Afin damliorer cette situation, nous avons
besoin de reconnatre que la prise en charge de cette affection chronique suit un continuum, et que le traitement et le
suivi post-hospitalisation sont aussi importants que la prise
en charge hospitalire. Une meilleure organisation globale des
soins mdicaux centrs sur le patient insuffisant cardiaque est
ncessaire, et une valuation pharmacoconomique des nouvelles initiatives doit tre effectue pour slectionner les stratgies optimales.

En rsum, la prise en charge de linsuffisance cardiaque


chronique avec rduction de la fraction djection a significativement amlior le taux de mortalit li cette affection. Cependant, la charge des rhospitalisations constitue toujours
un problme important : elle est associe une qualit de vie
trs dgrade et elle exerce une charge considrable sur les

Ce numro de Medicographia passe en revue lensemble des


questions scientifiques lies la prise en charge de linsuffisance cardiaque et, plus particulirement, la transition entre
les soins hospitaliers et la prise en charge du patient aprs
sa sortie de lhpital.

veillance distance des biomarqueurs, notamment le poids,


la frquence cardiaque, la pression artrielle, loxymtrie, llectrocardiogramme ou la pression artrielle pulmonaire estime
laide de dispositifs implantables sophistiqus. Les rsultats
des tudes publies montrent certaines divergences, mais
une mta-analyse de ces tudes suggre nanmoins que la
tlmdecine pourrait amliorer les rsultats et, en particulier, rduire les hospitalisations lies une insuffisance cardiaque 8. Toutefois, dans de nombreux pays, lintgration de
cette nouvelle approche aux structures existantes dhospitalisation classiques nest pas rsolue, et le remboursement du
temps pass par les professionnels pour ces activits constitue toujours un problme.

Mots cls : insuffisance cardiaque ; hospitalisation ; prvention ; prise en charge aprs la sortie de lhpital

124

MEDICOGRAPHIA, Vol 37, No. 2, 2015

Hospitalisation pour insuffisance cardiaque : pouvons-nous la prvenir ? La prvoir ? Komajda

THE

VULNERABLE PHASE OF HEART FAILURE:


A WINDOW OF OPPORTUNITY

For years, surrogates in heart


failure have been a deception. Many
therapies that improve symptoms,
ventricular function, arrhythmias
related to sudden cardiac death,
and even therapies that decrease
neurohormonal activation not only
failed to demonstrate a benefit, in
some cases they were associated
with an increase in mortality. The
lack of reliable surrogates is one
of the most important barriers to
identifying new therapies in heart
failure.

The changing landscape of


heart failure outcomes

b y J . L p e z - S e n d n
a n d N . Mo n t o ro , S p a i n

Jos LPEZ-SENDN, MD
Nieves MONTORO, MD
Hospital Universitario La Paz
IdiPaz Research Institute
Madrid, SPAIN

eart failure is a highly prevalent, lethal, and costly condition. For many
years, treatment was focused on improvement of symptoms. Sodium
restriction, diuretics, digoxin, and nitrates were the principal (and only)
therapies employed to alleviate symptoms and improve functional capacity.
Then, the CONSENSUS trial (COoperative North Scandinavian ENalapril SUrvival Study) demonstrated that medical therapy could also prolong life, a concept that changed clinical practice and research objectives in heart failure.
Since then, -blockers, angiotensin II receptor blockers, aldosterone antagonists, and If current blockers were included in the first-line treatment of patients with heart failure, along with nonmedical therapies such as implantable
defibrillators, resynchronization, and other therapeutic strategies that also
demonstrated a clear benefit in outcomes of selected populations. Research
has been intensive and fraught with failures. The majority of major clinical trials have yielded neutral or even negative results. Trials with inotropic drugs,
antiarrhythmic drugs, some vasodilators, and other drugs had to be prematurely discontinued because of an unexpected increase in mortality. Nevertheless, the landscape of heart failure treatment has changed completely. Guidelines have been prepared to recommend evidence-based therapies to improve
survival and reduce hospitalization. Research continues, but the immediate
challenge is to follow the guidelines recommendations for treatments that
prolong survival, reduce hospitalization, and improve ventricular function and
quality of life.
Medicographia. 2015;37:125-134 (see French abstract on page 134)

The increasing burden of heart failure


eart failure is one of the most important contemporary medical and social
problems. It is highly prevalent. It shortens life and greatly impairs quality of
life, and the management-related cost is very high (Table I, page 126). The
European Heart Failure Association estimates that 26 million people have heart failure worldwide and 3.6 million people are newly diagnosed with heart failure every
year in Europe alone.1 In the United States, heart failure may affect up to 3% of the
adult population.2 The absolute numbers are increasing due to the longer life expectancy of the population, a steady increase in risk factors related to ischemic heart
disease and heart failure (age, diabetes, obesity, sedentary lifestyle, etc), and the
longer survival of patients with heart diseases in general and after myocardial infarction in particular with modern therapy strategies.3 There are important differences
between countries regarding prevalence, hospitalizations, and mortality for heart fail-

H
Address for correspondence:
Jos Lpez-Sendn,
Hospital Universitario La Paz,
Instituto de Investigacin La PAZ, IdiPaz
Paseo de la Castellana 261. Planta 1,
28046 Madrid, Spain
(e-mail: jlopezsendon@gmail.com)
www.medicographia.com

The changing landscape of heart failure outcomes Lpez-Sendn and Montoro

MEDICOGRAPHIA, Vol 37, No. 2, 2015

125

THE
A

VULNERABLE

WINDOW

OF

PHASE

OF

HEART

FAILURE:

OPPORTUNITY

Figure 1. Hospitalizations for heart


failure in Europe and
the United States.
All data shown include
planned admissions.

Abbreviations: HF
(1 /2), number of hospitalizations for heart failure
as primary/secondary diagnosis; HF (any), number of hospitalizations for
heart failure as any diagnosis; HF/total, heart failure hospitalizations as a
proportion of all hospitalizations; LOS, average
length of hospital stay;
Total, total number of
hospitalizations.
After reference 3:
Cowie et al. Improving
care for patients with
acute heart failure
Before, during and after
hospitalization. London,
United Kingdom: Oxford
PharmaGenesis Ltd;
2014. 2014, Oxford
PharmaGenesis Ltd.
Available from:
http://www.oxfordhealthpolicyforum.org/
AHFreport.

Data provided by regional


health system representatives in Poland

ure.3 Indeed, generally speaking, in the United States, hospitalization is stable or decreasing while mortality remains stable4,5; however, in most European countries, the number of
hospitalizations is increasing and rehospitalization is becoming perhaps the major problem related with chronic heart failure (Figure 1),3 with a high impact on the increase in direct and
indirect costs associated with heart failure.6 Heart failure represents the greatest negative impact on quality of life as compared with other major chronic diseases, such as diabetes,
arthritis, and hypertension. Patients with heart failure, espe-

cially after the first hospitalization, suffer disabling symptoms


the most common being fatigue and dyspneaand the end
stage of the disease can only be compared to that of terminal cancer.
Table II shows the predicted projections of prevalence as well
as the direct costs (medical care, hospitalization, treatment)
and the indirect costs (loss of productivity) attributed to heart
failure for the years 2010 to 2030 in the United States.6 The
increase in prevalence will be relatively small, but within a 10Table I. Heart failure burden in numbers.

1 in 5 adults over the age of 40 will have heart failure in

Based on data from various sources.

their lifetime

1 in 5 heart failure patients will die within 1 year


3 major risk factors for heart failure are currently increasing:

age, diabetes, obesity

3% heart failure prevalence in Europe and the United States

in 2014 will increase to 3.5% by the year 2030

6- to 9-fold increase in sudden death in heart failure as

compared with the normal population

600 000 new heart failure cases per year in Europe.

500 000 new cases in the United States

Year

Prevalence (%)
of heart failure

2010
2015
2020
2025
2030
% Change

2.8
3.0
3.1
3.3
3.5
25.0

Direct costs
of heart failure

Indirect costs
of heart failure

24.7
32.4
42.9
57.5
77.7
215

9.7
11.3
13.0
15.1
17.4
80

6.5 million people with heart failure in Europe. 5 800 000

million in the United States

Table II. Projections of prevalence, and direct and indirect costs


of heart failure in the United States for the years 2010-2030.

26 million people with heart failure worldwide


$28 billion: heart failure cost in the United States in 2010;

will increase to $77.7 billion by the year 2030

126

MEDICOGRAPHIA, Vol 37, No. 2, 2015

Direct costs: medical care, hospitalization, treatments. Indirect costs: loss of


productivity. Cost is in billions 2008$.
After reference 6: Heidenreich et al. Circulation. 2011;123:933-944. Source: American Heart Association, Inc.

The changing landscape of heart failure outcomes Lpez-Sendn and Montoro

THE

VULNERABLE
A

year period will be equivalent to a 25% increase, a figure that


implies a terrible social and economic burden. These estimates may even be conservative; if there is a change in lifestyle leading to an increase in risk factors with a strong impact on heart failure, such as diabetes and obesity, we may
see a greater increase in cardiovascular diseases, heart failure, and associated costs.7,8 In countries with an economy in
transition, there may be more dramatic eventualities.9 The control of communicable diseases, the expected steep increase
in life expectancy, and the change in lifestyle mainly due to
a shift from rural to urban communities may lead to a steady
increase in cardiovascular diseases, such that the heart failure pandemic will be, simply, global. The only solution to prevent this growing epidemic is through control of risk factors.
Accurate diagnosis is one of the major issues in heart failure.1-3 Symptoms may be misleading. The diagnosis of heart
failure with depressed systolic ventricular function is elusive
and the correct diagnosis of diastolic heart failure is a real clinical challenge.10,11 This chapter focuses on outcomes in general, though the evidence in the literature mainly refers to heart
failure with depressed left ventricular ejection fraction.

Outcomes in heart failure


The aim of therapies in heart failure is to prolong life, reduce
hospitalization, and improve functional capacity. These main
outcomes have been the target and have served as measures of efficacy in therapies for clinical trials in heart failure.
Table III (page 128) details the most important outcomes in
heart failure, along with their advantages and drawbacks in
clinical practice and in clinical trials.
Mortality
The long-term prognosis associated with heart failure is poor.1-4
Half of all patients diagnosed with heart failure die within 4
years, and the 5-year survival rate is lower than that associated with myocardial infarction and the majority of key malignancies. Accordingly, mortality has been the most important outcome to be included in clinical trials. The importance
of total mortality is self-evident, but includes heart failurerelated as well as other cardiovascular and noncardiovascular
mortalities. This may be important in patients with heart failure and preserved systolic function, a clinical setting where
comorbidities have an important impact on outcomes, making the evaluation of therapy strategies very difficult in this
form of heart failure. Sudden death is the single most common form of death in heart failure, but decreasing sudden
death without improving overall prognosis simply implies a
change in the mode of death and is a useless achievement.
Mortality directly related to heart failure itself is probably the
best single outcome measure to evaluate the efficacy of new
therapies and should be included in all heart failure trials designed to explore outcomes. The main problem with this outcome measure is the need for adjudication, as comorbidities
often contribute to the cause of death.

PHASE

OF

WINDOW

HEART

OF

FAILURE:

OPPORTUNITY

Hospitalization
Hospitalization for heart failure is now recognized to be one of
the most important outcomes in cardiology.3 Worsening heart
failure resulting in hospitalization may be associated with cardiac and/or renal injuries that may contribute to progression
of heart failure, comorbidities, changes in lifestyle, and compliance with medication. Hospitalizations are associated with unacceptably high postdischarge mortality and rehospitalization
rates12 and are the single most important parameter related
to cost of care in heart failure patients. Besides, the need for
hospitalization objectively defines quality of life. However, hospitalization for heart failure itself is difficult to ascertain, and
is influenced by social, cultural, and economic reasons.

Nevertheless, hospitalization remains one of the principal outcome measures and should be included in all clinical trials
evaluating outcomes in this population. Comprehensive planning of hospital discharge, adequate patient education, and
initiation and continued optimization of disease-modifying therapies are crucial opportunities for improving postdischarge
outcomes and preventing repeated events in these patients.
Other clinical outcomes
Stroke and myocardial infarction are relatively frequent in patients with heart failure and have been included in some outcome trials, but the relationship with heart failure therapies is
uncertain. Undoubtedly, renal failure plays a key role in the
progression of the disease. It is associated with hospitalizations and prognosis and may be a target for treatment; however, some therapies may have an adverse influence on renal
function.1-3 Renal function is not a clinical outcome itself except when it forces hospitalization, dialysis, or other clinically relevant action, and this should be included as a clinical
outcome measure in patients with heart failure.
Symptoms and quality of life
Improvement in functional capacity and reduction in symptoms may be perceived as the most important target for many
patients with heart failure13 and will remain among the top priorities in the measurement of outcomes for this condition.

SELECTED

ABBREVIATIONS AND ACRONYMS

ACE

angiotensin-converting enzyme

ARB

angiotensin receptor blocker

BNP

B-type natriuretic peptide

CONSENSUS

COoperative North Scandinavian ENalapril


SUrvival Study

PARADIGM-HF Prospective comparison of Angiotensin


Receptorneprilysin inhibitor with ACE
inhibitors to Determine Impact on Global
Mortality and morbidity in Heart Failure
SHIFT

The changing landscape of heart failure outcomes Lpez-Sendn and Montoro

Systolic Heart failure treatment with the


If inhibitor ivabradine Trial

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FAILURE:

OPPORTUNITY

Cons

Pros
Major clinical
outcomes

Accepted and used in most major trials.


Reduction in major outcomes is still
needed in clinical practice.

Need to study large populations.


High cost.

Total mortality

Self-evident. Includes death possibly


related to secondary effects of therapies.

Mortality not related to heart failure difficult to attribute to


heart failure therapies.

Cardiovascular
mortality

Self-evident.

Needs adjudication in clinical trials. Mortality not related to


heart failure difficult to attribute to heart failure therapies.

Heart failure mortality

Self-evident.

Needs adjudication in clinical trials.

Sudden death

Self-evident.

Only relevant if total cardiovascular or heart failure mortality


is also demonstrated. Controversial benefit of sudden death
reduction in refractory heart failure.

Hospitalization and
rehospitalization

Probably best parameter for quality of


life assessment. High impact in cost.

Rehospitalization may be physician dependent.


Different criteria in different hospitals/countries.

Stroke, myocardial
infarction

Self-evident

Complication of heart failure.


No relationship with heart failure therapies.

Renal failure

Directly related with heart failure progression


and outcomes. Therapies may worsen
renal function.

Renal function is not a clinical outcome except when it


forces hospitalization, dialysis, or other clinically relevant
measures.

Other clinical
outcomes

Would reduce the population needed in


clinical trials.

May not be directly related to heart failure.

Symptom improvement, quality of life

May be the primary choice of the patient.

No clear relationship with major outcomes demonstrated.

Need of ventilator support, dialysis, ventricular assist device

Physician dependent.

No relationship with major outcomes demonstrated.

Surrogates for
outcomes

Use of surrogates (parameters related to


major outcomes) would greatly reduce the
number of patients needed to demonstrate
benefit of therapies in heart failure trials.

No surrogate identified as reliable to predict improvement in


outcomes.

Ventricular function,
eg, LVEF

Easy to measure.

No relationship with major outcomes demonstrated.

Hemodynamic
improvement

Related to symptom improvement.

No relationship with major outcomes demonstrated.


No relationship with major outcomes demonstrated.
Some antiarrhythmic drugs may increase mortality.

Arrhythmias
Number of days in ICU

Relevant, cost related.

No relationship with major outcomes demonstrated.


Physician dependent.

Need of ventilator support, dialysis, ventricular assist device

Physician dependent.

No relationship with major outcomes demonstrated.


Physician dependent.

BNP

Easy to measure, recommended for


diagnosis of heart failure.

Controversial relationship between decreasing BNP with therapy


and major clinical outcomes.

Diuresis and other


biomarkers

Relationship with symptom improvement.


Congestion considered as first cause for
hospitalization.

No demonstration of relationship with clinical outcomes.

Heart rate

Related to prognosis.

Relationship of reduction in heart rate only clearly demonstrated


in sinus rhythm with ivabradine and b-blockers. Other heart
rate reduction therapies may worsen heart failure outcomes
(eg, verapamil, diltiazem, digoxin in atrial fibrillation).

Safety (EMA criteria)

Need for extra monitoring.

Mortality (over 6 months), arrhythmias, corrected QT interval (QTc), hypotension, ischemic events, renal function (over 6 months), bradycardia and atrioventricular (AV) conduction disturbances, exaggerated pharmacological response in special groups (children, women, elderly)

128

MEDICOGRAPHIA, Vol 37, No. 2, 2015

The changing landscape of heart failure outcomes Lpez-Sendn and Montoro

THE

VULNERABLE
A

However, neither functional capacity nor symptom improvement has been related to major outcomes, and symptoms are
subjective and difficult to evaluate. For these reasons, symptoms and functional capacity will probably remain to be considered important, but second-line, outcomes in the measurement of therapy efficacy.
No surrogates in heart failure?
Surrogates are parameters related to major outcomes. Improvements in these parameters would have a favorable impact on clinical outcomes. An example would be hypercholesterolemia and hypertension. Both are well-recognized
prognostic factors and reducing hypercholesterolemia and
hypertension levels improves outcomes.

For years, surrogates in heart failure have been a deception.


Many therapies that improve symptoms, ventricular function,
and arrhythmias related to sudden cardiac death, and even
therapies that decrease neurohormonal activation not only
failed to demonstrate a benefit, in some cases they were associated with an increase in mortality. The lack of reliable surrogates is one of the most important barriers to identifying
new therapies in heart failure.
More recently, it has been demonstrated that B-type natriuretic peptide levels (BNP and N-terminal proBNP) are increased
in heart failure and are closely related with prognosis. Changes
in BNP levels may represent a reliable surrogate, but this concept is still controversial.
Heart rate is clearly related to outcomes in heart failure14,15
and heart rate reduction has been associated with an improvement in outcomes. Furthermore, heart rate reduction induced with ivabradine, with no inotropic or vasoactive effects,
improved outcomes in the SHIFT trial (Systolic Heart failure
treatment with the If inhibitor ivabradine Trial), reducing heart
failure mortality and the need for hospitalization and recurrent hospitalizations as well as improving ventricular function
and quality of life.16-18 The information available supports the
concept of heart rate as a reliable surrogate for outcomes in
heart failure; in fact, it may be considered not only as a prognostic factor, but also as a therapeutic target.
Safety
With more aggressive therapies and multiple-drug combinations, safety becomes an issue in patients with heart failure
and different parameters must be monitored during follow-up.
These include all types of secondary effects previously reported in patients with heart failure; among others: mortality

Table III (left page). Desirable outcomes in heart failure clinical


trials.
Abbreviations: BNP, B-type natriuretic peptide; EMA, European Medicines
Agency; ICU, intensive care unit; LVEF, left ventricular ejection fraction.

PHASE

OF

WINDOW

HEART

OF

FAILURE:

OPPORTUNITY

(over 6 months) in trials not designed to measure outcomes,


arrhythmias, corrected QT interval (QTc) prolongation, hypotension, ischemic events, renal function (over 6 months), bradycardia and atrioventricular conduction abnormalities, and
exaggerated pharmacological response in special groups
(children, women, elderly) that may be related to single- or
multiple-drug therapy.
Impact of therapies designed to improve clinical
outcomes
Spurred on by a high prevalence, mortality, and morbidity, research in heart failure has been extraordinary through the
last 30 years. New pathophysiological mechanisms were identified and therapies with new drugs, devices, and management strategies have been tested with the aim to improve
clinical outcomes in different clinical settings.1,2 Some trials
demonstrated unequivocal benefit, including a reduction in
mortality, while others had to be prematurely discontinued because of unacceptable secondary effects or unexpected increase in mortality. Nevertheless, all yield important information to better understand the disease. Overall, the concept,
diagnosis, and management of heart failure have completely
changed the prognosis and quality of life in patients with heart
failure.
Therapies associated with an improvement in outcomes
in clinical trials
The first trial to demonstrate an improvement in survival was
the CONSENSUS trial (COoperative North Scandinavian
ENalapril SUrvival Study), adding enalapril to the standard
treatment of heart failure with digoxin and diuretics.19 This outstanding achievement changed the way physicians looked
at heart failure: prognosis could be improved with medical
therapy. Improving outcomes became a clear target in clinical practice and in the objectives of clinical research. After the
CONSENSUS trial, many other trials with angiotensin-converting enzyme (ACE) inhibitors, including captopril, lisinopril,
ramipril, and trandolapril, confirmed the benefit in different
clinical settings, including asymptomatic left ventricular dysfunction and postinfarction heart failure.20 Since then, ACE inhibitors have become the cornerstone of heart failure with reduced left ventricular function. Table IV (page 130) includes
a list of strategies showing clear evidence of improvement in
major clinical outcomes in such patients.1,2,14-19

After accepting that medical treatment could dramatically


change outcomes, the next huge change in the strategy of
heart failure management came from the clear demonstration that b-blockers (contraindicated in heart failure due to
the negative inotropic effect) further improve the outcomes.
Carvedilol, metoprolol, bisoprolol, and to some extent bucindolol were clearly associated with a further improvement in
outcomes when added to ACE inhibitors.21 The limitations
of the use of b-blockers are derived from some side effects, in
particular hypotension.

The changing landscape of heart failure outcomes Lpez-Sendn and Montoro

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129

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A

VULNERABLE

WINDOW

OF

PHASE

OF

HEART

Year first
evidence
published

Improved
outcomes

Clinical
setting

Medical
therapy

FAILURE:

OPPORTUNITY

Limitations

Guideline
recommendation

Reference

ACE
inhibitors

Systolic HF

Improved survival.
Reduced rehospitalization.

1987

Hypotension, renal failure,


hyperkalemia.

IA

1,2,18

ARBs

Systolic HF

Considered as alternative to
ACE inhibitors. Not superior to ACE inhibitors. No
extra reduction on mortality
on top of ACE inhibitors.

2000

Hypotension, renal failure,


hyperkalemia, in particular
when associated with ACE
inhibitors and aldo blockers.

IA

1,2

b-Blockers

Systolic HF

Improved survival. Reduced


rehospitalization. Reduced
sudden death. Reduced
reinfarction.

1999

Hypotension, bradycardia,
asthma, AV block.

IA

1,2

Aldosterone
blockers

Systolic HF

Improved survival.
Reduced rehospitalization.
Reduced sudden death.

1999

Renal failure, hyperkalemia.

IA

1,2

2004

Benefit demonstrated in
ethnic subgroups (African
Americans).

Improved heart failure


survival.
Reduced rehospitalization.

2011

Atrial fibrillation, bradycardia.

Improved survival. Reduced


rehospitalization as compared with ACE inhibitors.

2014

Hydralazine
Systolic HF in
and nitrates
selected ethnic groups
If inhibitors

Systolic HF,
sinus rhythm
and heart
rate >70 bpm

Neprilisil

1,2

IB

1,2
14-17

Hypotension, renal failure,


hyperkalemia.

Not
approved
yet.

19

Devices
ICD

Systolic HF

Reduced sudden death.

1996

Only applicable to selected


patients. Does not slow
progress of disease.

IA

1,2

CRT

Systolic HF and
LBBB

Improved survival.
Reduced rehospitalization.

2004

Only applicable to selected


patients (LBBB or QRS
duration >160 ms).

IA

1,2

Improved survival.

2004

Only applicable to few, selected


patients. Thrombosis.

1,2

Only applicable to few, selected


patients. Organ rejection.

1,2

LV assist devices
HeartMate

Refractory HF
Selected patients

Heart transplant
Refractory HF
Selected patients

Admitted improved survival.


No data from randomized
trials.

Table IV. Strategies with unequivocal evidence of major clinical outcomes improvement in patients with heart failure and reduced left ventricular ejection fraction.
Abbreviations: ACE, angiotensin-converting enzyme; aldo, aldosterone; AV, atrioventricular; bpm, beats per minute; CRT, cardiac resynchronization therapy; HF, heart
failure; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; LV, left ventricular; ms, milliseconds.
Based on references 1,2,14-19.

Angiotensin II receptor blockers (ARBs) were also extensively


investigated, but without the success needed to dramatically change clinical practice; the role of ARBs is currently perceived as an alternative to ACE inhibitors.1,2 Aldosterone blockers, spironolactone, and eplerenone were the third group of
drugs that demonstrated an extra benefit on top of ACE inhibitors and -blockers and are now recommended in all
patients without contraindication, mainly severe renal failure.
Heart rate is directly related to heart failure outcomes and selective heart rate reduction with ivabradine, an If current in-

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

hibitor, further improves outcomes, introducing a new concept in the heart failure management strategy.1,2,15-18 The last
achievement, yet to be implemented in clinical practice, comes
from the PARADIGM-HF trial (Prospective comparison of Angiotensin Receptorneprilysin inhibitor with ACE inhibitors to
Determine Impact on Global Mortality and morbidity in Heart
Failure).22 In this study, the new drug LCZ696 was superior
to enalapril in reducing the risks of death and of hospitalization for heart failure, challenging the accepted paradigm of
ACE inhibition as the cornerstone for heart failure treatment.

The changing landscape of heart failure outcomes Lpez-Sendn and Montoro

THE

VULNERABLE
A

Somehow, diuretics should be included in this selected list


of first-line medical therapies. There is not clear evidence of
clinical benefit using diuretics in heart failure. Certainly, no major trial could demonstrate an improvement in outcomes and
some large contemporary trials with new diuretic drugs were
a failure, including vasopressin inhibitors (tolvaptan) and adenosine inhibitors (rolofylline).

PHASE

OF

WINDOW

HEART

OF

FAILURE:

OPPORTUNITY

Failures of medical therapy in clinical research


More often than not, clinical trials in heart failure fail to demonstrate the hypothesis and yield neutral results. This includes
important groups of drugs with different mechanisms of action,
including levosimendan,23 vasopressin inhibitors (tolvaptan),24
statins,25 new antiarrhythmic drugs (celivarone),26 darbepoietin,27 dihydropyridines and other calcium channel blockers,28,29
Reference

Medical therapy

Clinical setting

Inotropes
Xamoterol
Vesnarinone
Enoximone
Pimobendan
Ibopamine
Levosimendan

Systolic HF

Antiarrhythmics
Propafenone
Flecainide
Sotalol
Dronedarone
Celivarone
Amiodarone

Systolic HF

Systolic HF+ICD
Systolic HF

Increased mortality.
Increased mortality.
Increased mortality.
Increased mortality.
Neutral.
Neutral on total mortality. May decrease sudden death.

Flosequinan

Systolic HF

Increased mortality.

Prostacyclins
Epoprostenol

Systolic HF

Calcium antagonists
Mibefradil
Amlodipine

Systolic HF

Endothelin antagonists
Bosentan, Tezosentan

Systolic HF

Vasopressin inhibitors
Tolvaptan

Systolic HF

Statins
Rosuvastatin

Systolic HF

Darbepoietin

Systolic HF+anemia

Neutral. Increased thrombosis.

27

Nesiretide

Acute HF

Neutral.

30

Adenosine A1 blockers
Rolofylline

Acute HF

Neutral. Increased stroke.

31

Inotropes
Dobutamine, Dopamine,
Milrinone, Epinephrine

Acute HF

Increased mortality. Neutral.

49-51

Inotropes
Milrinone

Acute HF

Neutral.

52,53

Digoxin

HF, general

Reduction in hospitalization. Some benefit in selected subgroups.


No evidence in association with contemporary treatments.

54

Diuretics

HF, general

Improved symptoms. No evidence of improved outcomes.

1,2

ARBs
Irbesartan

Diastolic HF

ACE inhibitors
Perindopril
Candesartan

Diastolic HF

Outcomes

23,32-36

Increased mortality.
Increased mortality.
Increased mortality.
Increased mortality.
Increased mortality.
Neutral; may increase arrhythmias.

26,37-42

43
44

Increased mortality.

28,29

May increase mortality.


Neutral.
May increase mortality and hospitalization. May induce hepatic
toxicity and myocardial ischemia.

45-48
24

Neutral. Benefit in hyponatremia.

25

Neutral.

55

Neutral.
Neutral.
Neutral.

56
57

Table V. Therapies with failure to demonstrate unequivocal evidence to improve outcomes in heart failure with reduced left ventricular
ejection fraction. Based on references 1,2,23-57.
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; HF, heart failure; ICD, implantable cardioverter defibrillator.

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nesiretide,30 adenosine inhibitors (rolofylline),31 and others. Furthermore, in many trials, new therapies were actually related
to an increase in mortality, including inotropes23,32-36 (xamoterol,
vesnarinone, enoximone, pimobendan, ibopamine), antiarrhythmic drugs37-41 (propafenone, sotalol, dronedarone), fluosequinan, prostacyclins (epoprostenol), calcium antagonists28
(mibefradil), and endothelin antagonists. Table V (page 131)
includes a list of therapies with neutral outcomes or negative
results in clinical trials well designed to explore the effect of
therapies on heart failure outcomes.1,2,23-57
The reasons for these failures are not completely clear (Table VI) and do not necessarily indicate that the tested drug
itself was the reason for failure.
Nonpharmacological therapies
Other management strategies have also demonstrated a significant clinical benefit, and have been included in the current
recommendations in heart failure guidelines. Some may be
applied universally; such is the case for exercise and team
work in heart failure clinics. Others, such as implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and implantable ventricular assist devices should
be reserved for very selected populations with specific characteristics.1,2
Lessons learned
Through this extraordinary research journey 2 important lessons should be recognized:
Heart failure outcomes may improve with a combination of
strategies. Guideline recommendations should be followed.
Well-defined hypotheses must be tested in outcomes trials before incorporating new treatments in clinical practice.
Future needs
New research

More research is needed as mortality and rehospitalizations


remain a major problem in heart failure. New mechanisms of
action and new drugs are currently being investigated58 and

Reasons for failure in


heart failure clinical trials

Components

Poor understanding of
pathophysiology

Etiology. Animal models may not


represent clinical heart failure.
Genotype, racial differences.

Incomplete understanding
of the drug

Secondary effects. Off-target effects.


Comorbidities. Dose response not
uniform in different populations
(age, sex, etc).

Wrong selection of
patients

Heterogeneous populations.
Comorbidities. Nonresponders.

Diagnosis of heart failure


uncertain

Diastolic dysfunction. LVEF and


dyspnea not specific.

Lack of reliable surrogates

LVEF, hemodynamics. Arrhythmias.


Improved symptoms.

Errors/difficulties in design
of clinical trials

Heterogeneous populations. Selection bias. Inadequate dosing,


timing, changes in dose. Lack of
standard background therapies.
Heterogeneous clinical practice.
Change of background medications through the study. Wrong
end point. No focus on primary
end point components. Difficulties
in obtaining information for primary
end points. Lack of standard definitions for adjudication of events.
Poor-quality investigators.
Crossover. Lack of compliance.
Inadequate statistical analysis.

Table VI. Reasons for failure in heart failure clinical trials.


Abbreviation: LVEF, left ventricular ejection fraction.

the results of ongoing clinical trials along with new management strategies and technology improvement of ventricular
assist devices will provide further evidence to modify the landscape of heart failure outcomes.
Two clinical settings are of particular interest for future research:
heart failure with preserved ventricular function and acutely decompensated heart failure where demonstrating evidence of
benefit remains a challenge.
Guideline implementation
However, implementation of what we have
learned so far is of paramount importance and
following the guideline recommendations improves outcomes. Figure 2 simplifies the current guideline recommendation for medical therapy in heart failure patients.59
Figure 2. Indications for first-line medical treatment
in patients with heart failure.
Abbreviations: ACE, angiotensin-converting enzyme; ARBs,
angiotensin receptor blockers; BP, blood pressure; contraindic,
contraindication; Cr: creatinine; HR, heart rate; inh, inhibitors;
K+, potassium ion; Na+, sodium ion; SR, sinus rhythm.
Based on reference 59: Lopez et al. Diagnstico y tratamiento
de la insufficiency cardiac. iPad application. 2014. CARDIOSESAMO.

132

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Redefining clinical research


Traditional components of efficacy measurement in clinical trials include mortality and hospitalization for cardiovascular reasons, but require a large number of patients to ensure the reliability of results. However, the size, duration, complexity, and

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costs associated with new, contemporary trials make clinical


research ever more difficult and challenging. A more pragmatic approach simplifying the trials and maintaining relevant
clinical outcome measures should be agreed upon between
the scientific community and health care authorities.60 n

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33. Feldman AM, Bristow MR, Parmley WW, et al. Effects of vesnarinone on morbidity and mortality in patients with heart failure. Vesnarinone Study Group. N Engl
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35. Lubsen J, Just H, Hjalmarsson AC, et al. Effect of pimobendan on exercise capacity in patients with heart failure: main results from the Pimobendan in Congestive Heart Failure (PICO) trial. Heart. 1996;76:223-231.
36. Hampton JR, van Veldhuisen D, Kleber FX, et al; Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators.
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39. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients
with left ventricular dysfunction after recent and remote myocardial infarction.
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40. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent
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43. Packer M, Rouleau J, Swedberg K, Pitt B, Fisher L, Klepper M; PROFILE Investigators and Coordinators. Effect of flosequinan on survival in chronic heart
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48. Anand I, McMurray J, Cohn JN, et al. Long-term effects of darusentan on leftventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebocontrolled trial. Lancet. 2004;364:347-354.
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51. Unverzagt S, Wachsmuth L, Kirch K, et al. Inotropic agents and vasodilator
strategies for acute myocardial infarction complicated by cardiogenic shock or
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53. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality
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56. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J; PEP-CHF
Investigators. The Perindopril in Elderly People with Chronic Heart Failure (PEPCHF) study. Eur Heart J. 2006;27:2338-2345.
57. Yusuf S, Pfeffer MA, Swedberg K, et al. CHARM Investigators and Committees
Effects of candesartan in patients with chronic heart failure and preserved leftventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777781.
58. Tamargo J, Lpez-Sendn J. Novel therapeutic targets for the treatment of heart
failure. Nat Rev Drug Discov. 2011;10:536-555.
59. Lpez-Sendon J, Lopez de S E, Moreno M, et al. Disnea. Diagnstico y tratamiento de la insufficiency cardiac. iPad application;2014.
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Keywords: heart failure; hospitalization; mortality; outcome

LE

PAYSAGE CHANGEANT DE L VOLUTION DE L INSUFFISANCE CARDIAQUE

Linsuffisance cardiaque est une pathologie prvalente, lthale et coteuse. Depuis de nombreuses annes, le traitement porte essentiellement sur lamlioration des symptmes. La restriction sode, les diurtiques, la digoxine et
les drivs nitrs taient les principaux (et seuls) traitements employs pour soulager les symptmes et amliorer
la capacit fonctionnelle. Puis ltude CONSENSUS (COoperative North Scandinavian ENalapril SUrvival Study) a
dmontr que les mdicaments pouvaient aussi prolonger la vie, ce qui a chang la pratique clinique et les objectifs
de recherche dans linsuffisance cardiaque. Depuis cette date, le traitement de premire intention des patients insuffisants cardiaques comprend des -bloquants, des antagonistes du rcepteur de langiotensine 2, des antagonistes de laldostrone et des inhibiteurs du courant If , paralllement des traitements non mdicaux comme les
dfibrillateurs implantables, la resynchronisation et dautres stratgies thrapeutiques qui ont aussi dmontr un bnfice vident chez des populations slectionnes. La recherche a t intensive et parseme dchecs. La plupart
des principales tudes cliniques ont donn des rsultats neutres ou mme ngatifs. Des tudes utilisant des mdicaments inotropes ou antiarythmiques, des vasodilatateurs et dautres mdicaments ont d tre arrts prmaturment cause dune augmentation inattendue de la mortalit. Le paysage du traitement de linsuffisance cardiaque
a nanmoins compltement chang. Des recommandations ont t prpares afin de conseiller des traitements bass sur les preuves pour amliorer la survie et rduire lhospitalisation. La recherche continue, mais le dfi immdiat
est de suivre les recommandations concernant les traitements qui prolongent la survie, rduisent lhospitalisation et
amliorent la fonction ventriculaire et la qualit de vie.

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VULNERABLE PHASE OF HEART FAILURE:


A WINDOW OF OPPORTUNITY

As hospitalization for heart


failure is the only major contributor
to the total heart failure cost, the
prevention of patients admission
seems to be the key to reduction
in costs and use of health care
resources, and thus reduction in
overall burden of the syndrome.
It has been postulated that up to
75% of readmissions are preventable and related to incomplete inhospital treatmentas well as to a
poor transition and postdischarge
follow-up plan.

The social and economic


burden of hospitalization
for heart failure
b y D . Fa r m a k i s , G . F i l i p p a t o s ,
J . Pa r i s s i s , a n d J . Le k a k i s , G re e c e

H
Dimitrios FARMAKIS, MD
FESC

eart failure (HF) affects 2% of the total population, a prevalence that


rises to over 10% in individuals aged over 65 years and is expected
to increase continuously over the following years given the aging of
the population. HF is the most common reason for hospital admission in the
elderly. Hospitalization for HF (HHF) is associated with adverse prognosis with
high in-hospital and postdischarge mortality as well as high postdischarge
rehospitalization rates. At the same time, HF leads to a huge financial burden
that accounts for 2% of the total health care expenditure for all medical conditions. The estimated total cost for HF in the United States in 2012 was $31
billion, and this amount is expected to rise to $70 billion in 2030. Approximately 70% of HF costs result from HHF, the main proportion of which represents
ward costs. Interestingly, most of HF readmissions seem to be preventable
as it is related to incomplete in-hospital therapy and a poor transition and follow-up plan. Thus, effective management of congestion, careful initiation and
titration of evidence-based therapies, and proper planning of follow-up are
the keys to prevention of HHF and thus reduction in the social and financial
burden of HF.
Medicographia. 2015;37:135-138 (see French abstract on page 138)

Heart failure in numbers

Gerasimos FILIPPATOS,
MD, FESC
John PARISSIS, MD, FESC
John LEKAKIS, MD, FESC
Heart Failure Unit
Department of Cardiology
Attikon University Hospital
Athens, GREECE

Address for correspondence:


Dr Gerasimos Filippatos,
Heart Failure Unit, Department of
Cardiology, Rimini 1, 12462 Haidari,
Athens, Greece
(e-mail: geros@otenet.gr)
www.medicographia.com

eart failure (HF) constitutes a major public health problem, affecting a total
of 26 million people worldwide.1 The incidence of HF, after 3 decades of
marked increase that was perceived as an alert of an upcoming epidemic,
currently seems to have reached a plateau.2 In the United States, the incidence of
HF in individuals aged 55 years or older is 870 000 new cases per year, reaching 10
per 1000 population after 65 years of age.3 The prevalence of HF in the United States
in 2012 was 5.7 million, representing 2.2% of the population.3 As HF is an age-related syndrome, its prevalence increases from less than 1% in individuals aged under 40 years to greater than 10% in those aged over 80 years.3 This increase is even
more profound in women, reaching 13.5% after 80 years of age.3 Thus, given the aging of the population as well as the prolongation of patients survival by modern drug
and device therapy, the overall prevalence of the syndrome is expected to rise. Accordingly, projections show that HF prevalence will increase by 46% up to the year
2030, resulting in more than 8 million adults with HF in the United States at that time.4
In addition, despite advances in therapy, HF is still associated with adverse prognosis, including a high mortality rate. In the United States in 2011, 1 in 9 death certificates mentioned HF and this number was approximately as high as in 1995.3

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Hospitalization for HF
Hospitalization for HF (HHF) represents the most common
cause of hospital admission in the elderly [acute heart failure chapter], with a total of approximately 1 million admissions per year in the United States and a similar number in
Europe.3 Hospital discharges with a diagnosis of HF clearly
increased from 1980 to 2000.3 In the subsequent decade,
2000-2010, although hospitalizations with a primary diagnosis of HF declined, those with HF as a secondary diagnosis
remained rather stable.5
Hospitalization occurs commonly after the diagnosis of HF. In
a population-based cohort, over a period of 5 years following the diagnosis of HF, 83% of patients were hospitalized at
least once and 43% of them at least 4 times.6 The majority
of patients hospitalized for HF have advanced age, usually
above 70 years, and a previous history of HF as de novo HF
represents less than one-third or one-fourth of cases.7 Left
ventricular ejection fraction is preserved in approximately half
of the patients, while the majority suffer from a wide range
of cardiovascular and noncardiovascular comorbidities, including arterial hypertension, coronary artery disease, atrial
fibrillation, diabetes mellitus, renal disease, chronic obstructive pulmonary disease, anemia, and depression. Comorbid
conditions, particularly noncardiovascular ones, affect significantly the prognosis of the syndrome, represent a frequent
cause of deterioration and readmission, and have a major impact on patients quality of life.8 The median duration of hospitalization ranges between 4 and 11 days.7
Pooled data from a number of acute HF registries carried out
in different parts of the world show that HHF carries an ominous prognosis.9-13 In-hospital mortality ranges between 4%
and 7%. Following discharge, mortality rates during the first 2
to 3 months are as high as 7% to 11%, and reach 36% within a year after discharge. Postdischarge readmission rates
are also high; about 25% to 30% of patients are rehospitalized during the first 2 to 3 months, while 66% are readmitted
within a year. Interestingly, those high event rates do not differ between patients with reduced and preserved left ventricular ejection fraction, except for a higher in-hospital mortality
rate observed in the former group.14 Postdischarge readmissions seem to follow a 3-phase pattern with an early peak
during the first 2 to 3 months, followed by a prolonged plateau
phase and a second late peak during the advanced and final stage.15

The financial burden of hospitalization for HF


The cost of HF represents 2% of the total health care expenditure for all medical conditions.16-18 The estimated total
cost for HF in the United States in 2012 was $30.7 billion,
68% of which was attributable to direct medical costs.3 As
a result of the projected rise in the prevalence of the syndrome, this cost is expected to increase almost by 127% to
$69.7 billion in 2030.4 The total health care expenditure that

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is attributable to HF, excluding the cost related to comorbidities, is expected to be 3-fold higher in 2030, summing a total of $160 billion.4
The huge financial burden associated with HF results from recurrent admissions, multiple-drug therapy, widespread use
of device and mechanical modalitiessuch as implantable
cardioverter-defibrillators or ventricular assist devicescombined with prolongation of patients survival. Of all those components, the one that contributes the most to the total cost
is hospital admissions. In the United Kingdom, the cost related to HHF in 1995 represented 69% of the total HF expenditure.16 The significance of the financial burden resulting
from HHF is stressed by the recently introduced Hospital
Readmission Reduction Program under President Obamas
Affordable Care Act (Sec. 3025), according to which hospitals with an excessive 30-day readmission rate of Medicare
patients face penalties of up to 3% of their total Medicare
reimbursement.
A study published in 2014 showed that the mean total cost
per patient of an episode of HHF in a Greek tertiary/teaching
hospital for a median hospital stay of 7 days reached 3200.18
This amount corresponded to hospitalization in the ward, laboratory investigations, and drug therapy, without taking into
account several other costly procedures such as hospitalization in an intensive/cardiac care unit, cardiac catheterization,
device implantation or other invasive diagnostic or therapeutic procedures, or the use of mechanical therapies such as
circulatory support or renal replacement therapy that increase
markedly the total expenditure. In an Irish teaching hospital,
the mean cost of HHF (study published in 2000) was estimated to be IR2146.19
Ward costs appear to represent the greatest proportion of the
total HHF cost, while medication contributes much less.17,20
In the aforementioned study from Greece, 79% of the total
expenditure was attributed to ward costs, while laboratory investigations and medical treatment accounted for 17% and
4% of the cost, respectively.18 Similarly, in Ireland, ward costs
represented 75% of the total HHF cost, while medications accounted for only 3.5%.19 Thus, the length of hospitalization is
a key factor that determines the HHF costs.21,22 In addition,
the expenditure seems to increase proportionally to the severity of the syndrome, as depicted by the New York Heart Association functional class, the extent of left ventricular systolic dysfunction, and the levels of natriuretic peptides upon
admission, all of which represent independent predictors of
the HHF cost.17,18
SELECTED

ABBREVIATIONS AND ACRONYMS

HF
HHF

heart failure
hospitalization for heart failure

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In addition, the presence of comorbid conditions such as


renal dysfunction also seems to affect the magnitude of the
expenditure resulting from HHF.20

Conclusions and key issues in preventing


hospitalization-related HF burden
The increasing prevalence of HF, the constantly high HHF
rates, the adverse prognosis associated with HHF, and the
huge health care expenditure resulting from HHF are the main
features that define the socioeconomic burden of HF. As HHF
is the only major contributor to the total HF cost, the prevention of patients admission seems to be the key to reduction
in costs and use of health care resources, and thus reduction in overall burden of the syndrome. It has been postulat-

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ed that up to 75% of readmissions are preventable and related to incomplete in-hospital treatmentcharacterized by
residual congestion and poor titration of chronic therapyas
well as to a poor transition and postdischarge follow-up plan.
According to recent evidence from the European Society of
Cardiology HF Long-term Registry, compliance with guidelines
remains suboptimal not only in ambulatory, but also in hospitalized HF patients.23 Proper titration of life-saving HF medications, complete decongestion, treatment and prevention of
exacerbating factors, education of patients, delineation of a
specific follow-up plan, as well as collaboration with the patients attending physician are important measures that may
contribute to a reduction in rehospitalization rates and thus
help limit the socioeconomic burden of HHF. n

References
1. Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart
failure registries. J Am Coll Cardiol. 2014;63:1123-1133.
2. Maggioni AP, Dahlstrm U, Filippatos G, et al; Heart Failure Association of the
European Society of Cardiology (HFA). EURObservational Research Programme:
regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail. 2013;15:808-817.
3. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2015 update: a report from the American Heart Association. Circulation.
2015;131(4):e29-e322.
4. Heidenreich PA, Albert NM, Allen LA, et al; American Heart Association Advocacy Coordinating Committee; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council
on Clinical Cardiology; Council on Epidemiology and Prevention; Stroke Council. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6:606-619.
5. Blecker S, Paul M, Taksler G, Ogedegbe G, Katz S. Heart failureassociated
hospitalizations in the United States. J Am Coll Cardiol. 2013;61:1259-1267.
6. Dunlay SM, Redfield MM, Weston SA, et al. Hospitalizations after heart failure
diagnosis: a community perspective. J Am Coll Cardiol. 2009;54:1695-1702.
7. Farmakis D, Parissis J, Filippatos G. Acute heart failure: epidemiology, classification, and pathophysiology. In: Tubaro M, Vranckx P, Price S, Vrints C,
eds. The ESC Textbook of Intensive and Acute Cardiac Care. 2nd ed. Oxford
University Press [in press].
8. Fonarow GC, Abraham WT, Albert NM, et al; OPTIMIZE-HF Investigators and
Hospitals. Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF. Arch Intern Med.
2008;168:847-854.
9. Cleland JG, Swedberg K, Follath F, et al. The EuroHeart failure survey programmea survey on the quality of care among patients with heart failure in
Europe. Part 1: patient characteristics and diagnosis. Eur Heart J. 2003;24:
442-463.
10. Komajda M, Follath F, Swedberg K, et al. Study Group on Diagnosis of the
Working Group on Heart Failure of the European Society of Cardiology. The EuroHeart failure survey programmea survey on the quality of care among patients with heart failure in Europe. Part 2: treatment. Eur Heart J. 2003;24:
464-474.
11. Nieminen MS, Brutsaert D, Dickstein K, et al: on behalf of the EuroHeart Sur-

vey Investigators. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J. 2006;
27:2725-2736.
12. Maggioni AP, Dahlstrom U, Filippatos G, et al. EURObservational Research
Programme: the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail.
2010;12(10):1076-1084.
13. Follath F, Yilmaz MB, Delgado JF, et al. Clinical presentation, management
and outcomes in the Acute Heart Failure Global Survey of Standard Treatment
(ALARM-HF). Intensive Care Med. 2011;37:619-626.
14. Fonarow GC, Stough WG, Abraham WT, et al. Characteristics, treatments, and
outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007;50:768777.
15. Desai AS, Stevenson LW. Rehospitalization for heart failure: Predict or prevent? Circulation. 2012;126:501-506.
16. Stewart S, Jenkins A, Buchan S, McGuire A, Capewell S, McMurray JJ. The
current cost of heart failure to the National Health Service in the UK. Eur J
Heart Fail. 2002;4:361-371.
17. Berry C, Murdoch DR, McMurray JJ. Economics of chronic heart failure. Eur
J Heart Fail. 2001;3:283-291.
18. Parissis J, Athanasakis K, Farmakis D, et al. Determinants of the direct cost of
heart failure hospitalization in a public tertiary hospital. Int J Cardiol. 2015;180:
46-49.
19. McGowan B, Heerey A, Ryan M, Barry M. Cost of treating heart failure in an
Irish teaching hospital. Ir J Med Sci. 2000;169:241-244.
20. Kourlaba G, Parissis J, Karavidas A, et al. Economic evaluation of ivabradine in
the treatment of chronic heart failure in Greece. BMC Health Serv Res. 2014;14:
631.
21. Braunschweig F, Cowie M, Auricchio A. What are the costs of heart failure?
Europace. 2011;13(suppl 2):ii13-ii17.
22. Wang G, Zhang Z, Ayala C, Wall HK, Fang J. Costs of heart failure-related hospitalizations in patients aged 18 to 64 years. Am J Manag Care. 2010;16:
769-776.
23. Maggioni AP, Anker SD, Dahlstrm U, et al; Heart Failure Association of the
ESC. Are hospitalized 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;
15:1173-1184.

Keywords: cost; expenditure; health care; heart failure; hospitalization

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LA

CHARGE SOCIALE ET CONOMIQUE DE L HOSPITALISATION


POUR INSUFFISANCE CARDIAQUE

Linsuffisance cardiaque (IC) touche 2 % de la population totale, une prvalence qui slve plus de 10 % chez les
personnes ges de plus de 65 ans et qui va augmenter constamment dans les futures annes cause du vieillissement de la population. LIC est la raison la plus courante dhospitalisation chez les personnes ges. Lhospitalisation pour IC (HIC) sassocie un mauvais pronostic, avec une forte mortalit hospitalire et post-hospitalire et
des taux levs de rhospitalisation aprs la sortie de lhpital. En mme temps, lIC conduit une norme charge
financire qui compte pour 2 % des dpenses totales des soins de sant pour toutes les pathologies mdicales. Le
cot total estim pour lIC aux tats-Unis en 2012 tait de 31 milliards de $, somme qui va atteindre 70 milliards de
$ en 2030. Fait intressant, la plupart des rhospitalisations pour IC semblent vitables, tant lies un traitement
hospitalier insuffisant et un mauvais plan de transition et de suivi. Une prise en charge efficace de la congestion,
une instauration et une augmentation soigneuses des doses des traitements bass sur les preuves ainsi quune planification adquate du suivi sont donc les cls de la prvention de lHIC et donc de la diminution de la charge sociale et financire de lIC.

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The social and economic burden of hospitalization for heart failure Farmakis and others

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VULNERABLE PHASE OF HEART FAILURE:


A WINDOW OF OPPORTUNITY

In its most extreme form, lack


of decongestion manifests as inhospital worsening heart failure,
and this event is an independent
predictor of increased mortality.
Clinical signs are poor surrogates
of the hemodynamic status, and
measurement of B-type natriuretic peptide (BNP) levels may identify persistent congestion even in
the presence of a seeming resolution of clinical signs. Lack of decrease in BNP levels during hospitalization is associated with poor
prognosis.

Postdischarge outcomes
of patients hospitalized
for heart failure
b y M . Me t ra , V. C a r u b e l l i ,
I . C a s t r i n i , A . R a v e ra , E . S c i a t t i ,
a n d C . Lo m b a rd i , I t a l y

ospitalization of patients for heart failure is a landmark event in the clinical course of the disease. It reflects the prevalence of mechanisms
causing fluid overload and/or lung congestion with symptoms of severe dyspnea and/or fatigue and need of urgent treatment and hospitalization.
Despite relatively rapid relief of symptoms, hospitalizations for heart failure are
followed by an increased risk of death and rehospitalizations. The mechanisms
of these poor postdischarge outcomes are still incompletely understood and,
to date, no treatment has improved such outcomes. Comorbidities, persistent
congestion, and end-organ damage likely play a major role.
Medicographia. 2015;37:139-143 (see French abstract on page 143)

Marco METRA, MD
Valentina CARUBELLI, MD
Isotta CASTRINI, MD
Alice RAVERA, MD
Edoardo SCIATTI, MD
Carlo LOMBARDI, MD
Division of Cardiology
Department of Medical and
Surgical Specialties
Radiological Sciences and
Public Health
University and Civil Hospital
of Brescia
Brescia, ITALY

Address for correspondence:


Prof Marco Metra, Division of
Cardiology, Department of Medical
and Surgical Specialties,
Radiological Sciences, and Public
Health University and Civil Hospital
of Brescia, Italy
(e-mail: metramarco@libero.it)
www.medicographia.com

he prognosis of ambulatory patients with chronic heart failure and reduced


ejection fraction (HFREF) has substantially improved in recent years with a decrease in hospitalizations and a slightly lower, though still significant, reduction
in mortality.1-5 Annual mortality rates average 7%-8% for these patients.4,5 However, heart failure (HF) remains a progressive disease and the rate of episodes of
worsening HF is high, up to 20%-30% each year, in outpatients with chronic HF,4,5
with an increased risk even in patients showing ejection fraction (EF) recovery.6

Outcome rates after HF hospitalization


HF is the most important cause of hospitalization for subjects aged over 65 years
and HF hospitalizations are a landmark event in the clinical course of the disease.
Patients hospitalized for HF have an unacceptably high event rate, with up to 50%
possibly having further events with a 10%-15% mortality rate and a 30%-40% rehospitalization rate within the first 6 months after discharge.3,7,8 Unlike for acute
coronary syndromes and chronic HFREF, there is as yet no evidence of efficacy for
any new specific treatment for patients hospitalized for HF, thus no change in
treatment and prognosis has occurred in recent decades.
In the recent ESC-HF pilot survey (European Society of Cardiology Heart Failure pilot)
of the EURObservational Research Program, there were 2 patient groups: (i) ambulatory outpatients with chronic stable HF and (ii) patients hospitalized for acute HF.
Patients with chronic HF had an annual all-cause mortality of 7.2% with an annual
hospitalization rate of 31.9%. These rates increased to 17.4% and 43.9%, respectively, in the patients hospitalized for acute HF.5 Similarly, the annual mortality rates of
patients in the IN-HF survey (Italian Network on Heart Failure) were 5.9% in chronic
outpatients with HF, and 19.2% and 27.7% in the patients hospitalized for either

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new-onset or chronic decompensated acute HF, respectively.4


Longitudinal prospective clinical trials have shown similar results. Compared with patients who remain in stable clinical
condition, patients hospitalized for HF show a dramatic increase in their risk of dying and this is independent from baseline EF, with no difference between patients with HFREF and
those with preserved EF (HFPEF).9,10 This risk of death decreases exponentially in the months following discharge, but remains three- to fourfold higher even 12-18 months after the
initial hospitalization.9,11,12 HF hospitalizations are therefore associated with an increased risk of long-term death, and this
effect on patient prognosis is similar to that described for acute
coronary syndromes.11
Thus, improving postdischarge outcome in HF patients remains a major unmet need of current clinical practice. A better understanding of the mechanisms underlying the poor
prognosis of patients hospitalized for HF may help provide better care and improve postdischarge readmission and mortality.

some,13,19 but not all,9 studiesand the volume of HF patients


in the emergency department.20 An increase in body weight
after discharge, a marker of congestion, has been associated
with an increased risk of rehospitalization, but not of mortality.18

Major influences on postdischarge outcomes in HF


Three major causes seem to affect postdischarge outcomes
in HF patients: comorbidities, congestion, and end-organ damage, with the 2 latter causes likely related.
u Comorbidities
Comorbidities, cardiovascular and noncardiovascular, have a
major role in the postdischarge event rates of patients with
HF. As they are, or seem, less likely to be influenced by HF
treatment, they tend to be overlooked. Cardiovascular comorbidities that may precipitate rehospitalizations include myocardial ischemia, arrhythmiasnamely atrial fibrillationand
uncontrolled hypertension. They are all tightly related to the
clinical course of HF and may be potentially treated by targeted therapy at the time of first hospitalization.

Deaths and hospitalizations: is there a relation?


Rehospitalization and mortality are the most important outcomes in acute HF trials. However, they are not necessarily
related. Early rehospitalizations 30 days after discharge are an
important performance measurement for US hospitals.13 However, early rehospitalizations are poorly related to postdischarge mortality 8,14 and an inverse relationship between 30day rehospitalizations and mortality has even been shown.13,15
In the RELAX-AHF trial (RELAXin for the treatment of acute HF),
serelaxin was associated with a lower numerical incidence of
60-day mortality and a higher 60-day rehospitalization rate.16
Whereas hospitalizations in patients with chronic HF are an
index of HF severity and precede deaths,9-12 early postdischarge rehospitalizations may have a different meaning, as
shown by their poor relation to mortality. Social support, patient adherence to treatment, and relief from congestion at the
time of discharge may have a major role.17,18 Other factors influencing the early postdischarge rehospitalization rate are the
length of the initial hospitalizationwith an inverse relation in

SELECTED

ABBREVIATIONS AND ACRONYMS

BNP
EF
ESC-HF pilot
EVEREST
HF
HFREF
IN-HF
MI
NT-proBNP
RELAX-AHF
SCD

140

B-type natriuretic peptide


ejection fraction
European Society of Cardiology Heart Failure pilot
Efficacy of Vasopressin antagonism in hEart
failuRE: outcome Study with Tolvaptan
heart failure
heart failure with reduced ejection fraction
Italian Network on Heart Failure
myocardial infarction
N-terminal proB-type natriuretic peptide
RELAXin for the treatment of Acute Heart Failure
sudden cardiac death

MEDICOGRAPHIA, Vol 37, No. 2, 2015

The role of noncardiovascular comorbidities is extremely important, especially for rehospitalizations. In an analysis of the
causes of rehospitalizations in US hospitals, the proportion
of patients readmitted for the same condition was 35.2% after
a first HF hospitalization.21 Thus, the majority of readmissions
after a first HF hospitalization may not be due to HF itself.
In the EVEREST trial (Efficacy of Vasopressin antagonism in
hEart failuRE: outcome Study with Tolvaptan), among the 4133
randomized patients, there were 5239 rehospitalizations and
1080 deaths during a median of 9.9 months. Of all the rehospitalizations, 39.2% were noncardiovascular, 46.3% were due
to HF, and a minority due to stroke, myocardial infarction (MI),
arrhythmia, or other cardiovascular causes. Of all deaths,
13.2% were due to noncardiovascular causes, 41.0% to HF,
26.0% to sudden cardiac death (SCD), and the rest to MI
or stroke.22 Similar data were more recently obtained in the
RELAX-AHF trial, with 19 of the 107 deaths (18%) due to noncardiovascular causes, 37 (35%) due to HF, 25 (23%) due to
SCD, 15 (14%) due to other cardiovascular causes, and 11
(10%) classified as unknown.23
Patients enrolled in controlled trials generally have a lower
prevalence of comorbidities compared with those in the real
world. The impact of noncardiovascular causes of hospitalizations and death is therefore larger in observational studies.
In the ESC-HF pilot survey, diabetes, chronic kidney disease,
and anemia were independently associated with a higher risk
of mortality and/or HF hospitalization.24 Other noncardiovascular comorbidities that may cause rehospitalizations include
infections, chronic kidney dysfunction, and chronic pulmonary
disease.8,17,25 Elevated blood glucose levels on admission and
iron deficiency have also been shown to be independent prognostic factors in patients hospitalized for HF.26-29 In an analysis

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from the Cardiovascular Health Study of the risk


factors for all-cause hospitalizations among elderly patients with a new diagnosis of HF, the
only 2 cardiovascular variables related to outcomes were left ventricular EF and New York
Heart Association (NYHA) class, whereas many
noncardiovascular factors, namely diabetes mellitus, chronic kidney disease, weak grip strength,
slow gait speed, and depression had prognostic value.30 As previously pointed out, many other noncardiovascular factors related to patient
characteristics may affect early rehospitalizations. These include lack of adherence to treatment, dietary indiscretion, drug and alcohol
abuse, family and social support, and access
to care.8

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Heart failure
Neurohormonal activation
Inflammatory activation*

Fluid overload
Long-term changes
(days to weeks)

Fluid redistribution to the lungs


Short-term changes
(hours to days)

Venous congestion

Lung congestion

Peripheral edema

Cardiac, renal,
hepatic damage

Rehospitalizations

Dyspnea /
Pulmonary edema

Rehospitalizations

u Congestion

Mortality

Congestion is the main cause of HF hospital* The role of inflammatory activation is still less clear
izations.7,8,31 Most HF hospitalizations are her18,32
alded by a gain in body weight
and, when
Figure 1. Mechanisms of the increase in the risk of death and rehospitalizations in
this does not occur because of prevailing flu- patients hospitalized for heart failure decompensation.
id redistribution,33 other markers of congestion,
urements related to congestion, such as weight gain, or poor
such as pulmonary artery pressure or B-type natriuretic peptide (BNP) plasma levels are increased.34,35 Congestion also diuretic response, are associated with rehospitalizations and
short-term outcomes, but not with long-term mortality.18,47
has a major role as a cause of postdischarge deaths and rehospitalizations.
Secondly, risk of death after a HF hospitalization remains increased in the long-term, up to at least 12-18 months after
Lack of, or slower, resolution of signs and symptoms of conthe event.9,11,29 This is consistent with persistent organ damgestion during the first days of hospitalization for HF is assoage associated with the hospitalization, similar to what occiated with more adverse outcomes.31,36 In its most extreme curs after acute MI, rather than a mechanism more likely to
form, lack of decongestion manifests as in-hospital worsen- cause symptoms, eg, congestion. Thirdly, in addition to BNP
levels, other markers related to organ damage and/or funcing HF, and this event is an independent predictor of increased
mortality.36-40 Clinical signs are poor surrogates of the hemo- tion are independently related to outcomes, namely mortaldynamic status, and measurement of BNP levels may identi- ity, after a HF hospitalization.
fy persistent congestion even in the presence of a seeming
resolution of clinical signs.31 Lack of decrease in BNP levels The RELAX-AHF trial was particularly important with this reduring hospitalization is associated with poor prognosis.41 In spect, as biomarker measurements were repeated at basethe RELAX-AHF study, both worsening HF during the hos- line and during hospitalization and, differently from other caspital stay and a lack of decrease in N-terminal proBNP (NT- es,48 the study drug was not associated with untoward effects
proBNP) levels during hospitalization were associated with on outcomes. Changes in markers of myocardial damage
increased 180-day all-cause mortality.35
(serum troponins), renal function (cystatin C), and liver function (transaminases) were shown to have an independent reAssessment of signs of congestion, such as pulmonary rales, lation to 180-day mortality, which persisted after adjustment
for their baseline values.40
jugular venous pressure, peripheral edema, and weight gain,
is also important at the time of discharge or early after discharge.18,42 During hospitalization, better prognostic assessMultiple mechanisms may cause myocardial damage during
ment can be obtained by other measurements, such as pulacute HF.49 Consistently, an increase in plasma troponin levels
monary artery pressure monitoring or, more simply, by BNP is very common in patients hospitalized for HF and serum troor NT-proBNP levels.31,35,43-46
ponin levels are independent predictors of subsequent outcomes. In addition to baseline values and a rise in serum troponin levels during hospitalization, an index of an event-relatu Organ damage
There are reasons to hypothesize that congestion is not the ed myocardial necrosis, is a powerful predictor of outcomes.50,51
only determinant of the increase in cardiovascular events after
The relationship between chronic renal dysfunction and/or
discharge (Figure 1). Firstly, studies have shown that meas- worsening renal function and poor outcomes in patients with

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HF is well established.52,53 However, there are important exceptions, as an increase in serum creatinine may have a neutral, or even favorable, significance when it occurs after intensive diuretic treatment or after the initiation of renin angiotensin
inhibitors.53-56 Acute HF may cause kidney dysfunction through
multiple mechanisms.53 More recently, the role of hepatic dysfunction has been shown. The increase in inferior vena cava
pressure, caused by congestion, is transmitted backward
causing cholestasis and death of the hepatocytes, shown by
an increase in serum transaminases, and this has independent prognostic value.40,57

Conclusions
Hospitalization is a landmark event in the clinical history of HF
patients. It is caused by severe symptoms and their emergence is due to prevalence of the mechanisms causing fluid retention and congestion. Such an event is attended by
other mechanisms, which in addition to the untoward effects
of the hospitalization itself and to the effect of persistent congestion, cause organ damage with further deterioration of patient prognosis and increased mortality. This is the vicious cycle that new treatments for HF decompensation must try to
interrupt. n

References
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3. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force
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4. Tavazzi L, Senni M, Metra M, et al. Multicenter prospective observational study
on acute and chronic heart failure: one-year follow-up results of IN-HF (Italian
Network on Heart Failure) outcome registry. Circ Heart Fail. 2013;6: 473-481.
5. Maggioni AP, Dahlstrom U, Filippatos G, et al. EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure
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6. Basuray A, French B, Ky B, et al. Heart failure with recovered ejection fraction:
clinical description, biomarkers, and outcomes. Circulation. 2014;129:23802387.
7. Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes:
current state and framework for future research. Circulation. 2005;112:39583968.
8. Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization
for heart failure: problems and perspectives. J Am Coll Cardiol. 2013;61:391-403.
9. Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal hospitalization
for heart failure on subsequent mortality in patients with chronic heart failure.
Circulation. 2007;116:1482-1487.
10. Bello NA, Claggett B, Desai AS, et al. Influence of previous heart failure hospitalization on cardiovascular events in patients with reduced and preserved
ejection fraction. Circ Heart Fail. 2014;7:590-595.
11. Abrahamsson P, Swedberg K, Borer JS, et al. Risk following hospitalization in
stable chronic systolic heart failure. Eur J Heart Fail. 2013;15:885-891.
12. Ahmed A, Allman RM, Fonarow GC, et al. Incident heart failure hospitalization
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13. Kociol RD, Liang L, Hernandez AF, et al. Are we targeting the right metric for heart
failure? Comparison of hospital 30-day readmission rates and total episode
of care inpatient days. Am Heart J. 2013;165:987-994e1.
14. Krumholz HM, Lin Z, Keenan PS, et al. Relationship between hospital readmission and mortality rates for patients hospitalized with acute myocardial infarction, heart failure, or pneumonia. JAMA. 2013;309:587-593.
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N Engl J Med. 2010;363(3):297-298.
16. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebocontrolled trial. Lancet. 2013;381:29-39.
17. Fonarow GC, Abraham WT, Albert NM, et al. Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from
OPTIMIZE-HF. Arch Intern Med. 2008;168:847-854.
18. Blair JE, Khan S, Konstam MA, et al. Weight changes after hospitalization for
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19. Eapen ZJ, Reed SD, Li Y, et al. Do countries or hospitals with longer hospital

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stays for acute heart failure have lower readmission rates? Findings From ASCEND-HF. Circ Heart Fail. 2013;6(4):727-732.
20. Brar S MF, Youngson E, Rowe BH. Do outcomes for patients with heart failure
vary by emergency department volume? Circ Heart Fail. 2013;6(6):1147-1154.
21. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or
pneumonia. JAMA. 2013;309:355-363.
22. OConnor CM, Miller AB, Blair JE, et al. Causes of death and rehospitalization
in patients hospitalized with worsening heart failure and reduced left ventricular
ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program. Am Heart J. 2010;159:
841-849e1.
23. Felker GM, Teerlink JR, Butler J, et al. Effect of serelaxin on mode of death in
acute heart failure: results from the RELAX-AHF study. J Am Coll Cardiol. 2014;
64:1591-1598.
24. van Deursen VM, Urso R, Laroche C, et al. Co-morbidities in patients with heart
failure: an analysis of the European Heart Failure Pilot Survey. Eur J Heart Fail.
2014;16:103-111.
25. Metra M, Nodari S, Parrinello G, et al. Worsening renal function in patients hospitalised for acute heart failure: clinical implications and prognostic significance. Eur J Heart Fail. 2008;10:188-195.
26. Mebazaa A, Gayat E, Lassus J, et al. Association between elevated blood glucose and outcome in acute heart failure: results from an international observational cohort. J Am Coll Cardiol. 2013;61:820-829.
27. Jankowska EA, Kasztura M, Sokolski M, et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies
patients at the highest risk of death after an episode of acute heart failure. Eur
Heart J. 2014;35:2468-2476.
28. Yeo TJ, Yeo PS, Ching-Chiew Wong R, et al. Iron deficiency in a multi-ethnic
Asian population with and without heart failure: prevalence, clinical correlates,
functional significance and prognosis. Eur J Heart Fail. 2014;16:1125-1132.
29. Kristensen SL, Jhund PS, Kber L, et al. Comparison of outcomes after hospitalization for worsening heart failure, myocardial infarction, and stroke in patients with heart failure and reduced and preserved ejection fraction. Eur J Heart
Fail. 2015;17(2):169-176.
30. Chaudhry SI, McAvay G, Chen S, et al. Risk factors for hospital admission among
older persons with newly diagnosed heart failure: findings from the Cardiovascular Health Study. J Am Coll Cardiol. 2013;61:635-642.
31. Gheorghiade M, Follath F, Ponikowski P, et al. Assessing and grading congestion in acute heart failure: a scientific statement from the acute heart failure
committee of the heart failure association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine. Eur J
Heart Fail. 2010;12:423-433.
32. Chaudhry SI, Wang Y, Concato J, Gill TM, Krumholz HM. Patterns of weight
change preceding hospitalization for heart failure. Circulation. 2007;116:15491554.
33. Cotter G, Metra M, Milo-Cotter O, Dittrich HC, Gheorghiade M. Fluid overload
in acute heart failure--re-distribution and other mechanisms beyond fluid accumulation. Eur J Heart Fail. 2008;10:165-169.
34. Zile MR, Bennett TD, St John Sutton M, et al. Transition from chronic compensated to acute decompensated heart failure: pathophysiological insights obtained from continuous monitoring of intracardiac pressures. Circulation. 2008;
118:1433-1441.
35. Metra M, Nodari S, Parrinello G, et al. The role of plasma biomarkers in acute
heart failure. Serial changes and independent prognostic value of NT-proBNP

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A

and cardiac troponin-T. Eur J Heart Fail. 2007;9:776-786.


36. Metra M, OConnor CM, Davison BA, et al. Early dyspnoea relief in acute heart
failure: prevalence, association with mortality, and effect of rolofylline in the
PROTECT Study. Eur Heart J. 2011;32:1519-1534.
37. Torre-Amione G, Milo-Cotter O, Kaluski E, et al. Early worsening heart failure
in patients admitted for acute heart failure: time course, hemodynamic predictors, and outcome. J Card Fail. 2009;15:639-644.
38. Weatherley BD, Milo-Cotter O, Felker GM, et al. Early worsening heart failure in
patients admitted with acute heart failurea new outcome measure associated
with long-term prognosis? Fundam Clin Pharmacol. 2009;23:633-639.
39. Metra M, Teerlink JR, Felker GM, et al. Dyspnoea and worsening heart failure in
patients with acute heart failure: results from the Pre-RELAX-AHF study. Eur J
Heart Fail. 2010;12:1130-1139.
40. Metra M, Cotter G, Davison BA, et al. Effect of serelaxin on cardiac, renal, and
hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes. J Am Coll Cardiol. 2013;61:196-206.
41. Bettencourt P, Azevedo A, Pimenta J, Frioes F, Ferreira S, Ferreira A. N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge
in heart failure patients. Circulation. 2004;110:2168-2174.
42. Lucas C, Johnson W, Hamilton MA, et al. Freedom from congestion predicts
good survival despite previous class IV symptoms of heart failure. Am Heart J.
2000;140:840-847.
43. Stevenson LW, Zile M, Bennett TD, et al. Chronic ambulatory intracardiac
pressures and future heart failure events. Circ Heart Fail. 2010;3:580-587.
44. Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type natriuretic peptide
assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol. 2004;43:635-641.
45. Kociol RD, Horton JR, Fonarow GC, et al. Admission, discharge, or change
in B-type natriuretic peptide and long-term outcomes: data from Organized
Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) linked to Medicare claims. Circ Heart Fail. 2011;4:628-636.
46. Troughton R, Michael Felker G, Januzzi JL Jr. Natriuretic peptide-guided heart
failure management. Eur Heart J. 2014;35:16-24.

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47. Voors AA, Davison BA, Teerlink JR, et al. Diuretic response in patients with
acute decompensated heart failure: characteristics and clinical outcomean
analysis from RELAX-AHF. Eur J Heart Fail. 2014;16:1230-1240.
48. Gheorghiade M, Pang PS. Are BNP changes during hospitalization for heart
failure a reliable surrogate for predicting the effects of therapies on post-discharge mortality? J Am Coll Cardiol. 2009;53:2349-2352.
49. Januzzi JL Jr, Filippatos G, Nieminen M, Gheorghiade M. Troponin elevation
in patients with heart failure: on behalf of the third Universal Definition of Myocardial Infarction Global Task Force: Heart Failure Section. Eur Heart J. 2012;
33:2265-2271.
50. Metra M, Bettari L, Pagani F, et al. Troponin T levels in patients with acute heart
failure: clinical and prognostic significance of their detection and release during hospitalisation. Clin Res Cardiol. 2012;101:663-672.
51. OConnor CM, Fiuzat M, Lombardi C, et al. Impact of serial troponin release on
outcomes in patients with acute heart failure: analysis from the PROTECT pilot
study. Circ Heart Fail. 2011;4:724-732.
52. Damman K, Valente MA, Voors AA, O'Connor CM, van Veldhuisen DJ, Hillege
HL. Renal impairment, worsening renal function, and outcome in patients with
heart failure: an updated meta-analysis. Eur Heart J. 2014;35:455-469.
53. Metra M, Cotter G, Gheorghiade M, Dei Cas L, Voors AA. The role of the kidney
in heart failure. Eur Heart J. 2012;33:2135-2142.
54. Metra M, Davison B, Bettari L, et al. Is worsening renal function an ominous
prognostic sign in patients with acute heart failure? The role of congestion and
its interaction with renal function. Circ Heart Fail. 2012;5:54-62.
55. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364:797-805.
56. Testani JM, Kimmel SE, Dries DL, Coca SG. Prognostic importance of early
worsening renal function after initiation of angiotensin-converting enzyme inhibitor therapy in patients with cardiac dysfunction. Circ Heart Fail. 2011;4:685691.
57. Nikolaou M, Parissis J, Yilmaz MB, et al. Liver function abnormalities, clinical
profile, and outcome in acute decompensated heart failure. Eur Heart J. 2013;
34:742-749.

Keywords: heart failure; outcomes; postdischarge; prognosis

RSULTATS

POST- HOSPITALISATION DES PATIENTS HOSPITALISS


POUR INSUFFISANCE CARDIAQUE

Lhospitalisation des patients pour insuffisance cardiaque est un point de repre dans lvolution clinique de la maladie. Elle signe la prvalence des mcanismes provoquant une surcharge hydrique et/ou une congestion pulmonaire avec symptmes de dyspne svre et/ou fatigue et besoin dun traitement et dune hospitalisation urgents.
Malgr un soulagement relativement rapide des symptmes, les hospitalisations pour insuffisance cardiaque sont
suivies dun risque accru de dcs et de rhospitalisations. Les mcanismes de ces mauvais rsultats post-hospitalisation sont encore mal compris et, ce jour, aucun traitement na pu les amliorer. Les comorbidits, la congestion persistante et les lsions des organes cibles jouent probablement un rle majeur.

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

143

The mean duration of hospitalization in the United States is


4-5 days. In many cases, this is
too short for complete stabilization of the acute heart failure patients. Overall, system-induced
pressure encourages physicians
to discharge patients as early as
possible, which leads to the common practice in the United States
(unlike many European countries)
of using higher doses of diuretics
within a short period of time to
achieve decongestion.

THE

VULNERABLE PHASE OF HEART FAILURE:


A WINDOW OF OPPORTUNITY

Definition and characteristics


of the vulnerable phase
in heart failure
b y M . B . Y i l m a z a n d A . Me b a z a a ,
Tu r key a n d Fra n c e

H
Mehmet Birhan YILMAZ
MD, FESC, FACC
Cumhuriyet University
Faculty of Medicine
Department of Cardiology
Sivas, TUrKEY

eart failure (HF) is a disease with high morbidity and mortality in the
long run. Its course is not linear in nature, but characterized by spikes
and nadirs with a changing risk profile. It also includes a period called
the vulnerable phase, during which the patient is at an increased risk for
adverse outcomes. Here, vulnerability means that HF patients might experience unexpected outcomes, which could bring about windows of opportunity if addressed properly. This vulnerability is typically observed during the
periacute HF period, which extends from initiation of an index acute HF event
leading to admission, through a peridischarge period and up to 6 months after discharge. This vulnerable phase could potentially be divided into 3 overlapping phases. Of note, this relatively long-lasting phase is not based solely
on a single pathophysiological mechanism, because HF is a complex syndrome. Hence, an individual, but collaborative, approach is required. Whatever the driving mechanisms, tailoring of an individualized therapy by a multidisciplinary team might provide patients with better outcomes and see them
through to a stable phase of HF.
Medicographia. 2015;37:144-148 (see French abstract on page 148)

eart failure (HF) is a complex clinical syndrome. Acute HF (AHF) represents a


serious health problem with significant mortality and morbidity in-hospital despite contemporary therapy.1 Although survival of patients with chronic HF has
improved over time, postdischarge outcomes of patients with AHF remain unacceptably high. About half the patients with HF are readmitted within 1 year of discharge
and about 20% die in the following year, though geographical variations exist.2

H
Alexandre MEBAZAA
MD, FESC, FHFA
University Paris Diderot
Hpital Lariboisire
Paris, FrAnCE

Address for correspondence:


Prof. Dr. Mehmet Birhan Yilmaz, MD,
FESC, FACC, Cumhuriyet University
Faculty of Medicine, Department of
Cardiology, 58140, Sivas, Turkey
(e-mail: cardioceptor@gmail.com)
www.medicographia.com

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

The vulnerable phase of HF


The vulnerable phase, as typically defined for patients with AHF, is a period during
which microenvironmental changes in the cardiovascular milieu after an episode
of AHF impose an increased risk for adverse cardiovascular events, including increased risk of death or rehospitalization for HF. Patients who overcome this period successfully may transition into long-term stability. Of note, the vulnerable phase
exists whether or not the index attack is the first event. It can theoretically occur with
every episode of AHF.
Although the vulnerable phase of HF following an extensive myocardial infarction
is a relatively well-established clinical phenomenon, it has recently been noticed to
occur with each AHF episode, though the individual impact varies. An episode of

Definition and characteristics of the vulnerable phase in heart failure Yilmaz and Mebazaa

THE

VULNERABLE
A

PHASE

OF

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HEART

OF

FAILURE:

OPPORTUNITY

Figure 1.
The vulnerable phase
of heart
failure.
Abbreviations:
AHF, acute
heart failure;
WHF, worsening heart
failure.

AHF is by nature a period of vulnerability. However, physicians


can triage the patients according to disease severity and manage them accordingly, though referral to an intensive care unit
(ICU)/critical care unit (CCU) itself means increased vulnerability.1 On the other hand, after an AHF episode, patients enter a vulnerable phase that can lead to repeated hospitalizations within a short period. This vulnerable phase requires
accurate identification and management strategies.
With regard to risk prediction after discharge, several attempts
to predict rehospitalization have been described in the literature. Most of these models performed poorly, though some
of them may work in individual patients.3 The problem of poor
performance might be related to the multidimensional nature
of postdischarge management.
Typically, postdischarge adverse events peak up to 2 months
after discharge, and then gradually decrease until reaching
a plateau around month 6 of the postdischarge period. The
plateau may last as long as a year, and then deteriorations
may occur.4 Hence, the vulnerable phase of AHF could be considered to comprise 3 overlapping subphases (Figure 1): a
very early phase, an early phase, and a late phase.
u Very early vulnerable phase

The very early vulnerable phase is subdivided into further


overlapping periods and so could be regarded as a heterogeneous period. It extends from an index episode of AHF up
SELECTED

ABBREVIATIONS AND ACRONYMS

ACCF
ACE
AHA
AHF
HF
HFREF
MRA

American College of Cardiology Foundation


angiotensin-converting enzyme
American Heart Association
acute heart failure
heart failure
heart failure with reduced ejection fraction
mineralocorticoid receptor antagonist

to a few days post discharge. As an episode of AHF itself is a


vulnerable period, anyone experiencing one is subject to this
vulnerability, which is characterized by increased risk of morbidity and mortality.1 Following an initial stabilization of an AHF
episode, some patients, potentially up to 15% of the overall
population, might experience worsening in HF symptoms and
signs that require extra interventions.5 This has recently been
introduced into the literature as worsening HF.6 In-hospital
worsening of HF has been shown to be associated with an
increased risk for adverse outcomes.7
The very early vulnerable phase is typically expected in patients discharged before complete relief of congestion. The
mean duration of hospitalization in the United States is 4-5
days.8 In many cases, this is too short for complete stabilization of the AHF patients. Overall, system-induced pressure
encourages physicians to discharge patients as early as possible, which leads to the common practice in the United States
(unlike many European countries) of using higher doses of diuretics within a short period of time to achieve decongestion.
High-dose diuretics might provide more rapid relief of symptoms and congestion, but at a slightly increased cost of renal impairment,9 and many patients would potentially remain
relatively congested following such a discharge. Due to results of the rapidly changing tissue microenvironment, such
as an electrolyte disturbance in the form of hypokalemia, tissue ischemia in the form of organ dysfunction may be overlooked at this stage. Of note, organ dysfunction, possibly in
the form of renal or hepatic dysfunction, could determine the
prognosis of these patients in the very early vulnerable phase.10
Furthermore, anemia at admission might contribute to poor
outcomes in this phase if left untreated.
Long-term oral disease-modifying therapies are not easy to
initiate within a short hospitalization period. Therefore, patients might experience increased risk of rehospitalization or
fatality after discharge simply due to lack of administration
of these therapies. These patients require meticulous follow-

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A

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up by a multidisciplinary team, with short intervals as suggested by guidelines.11 The most recent American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)
guidelines recommend early telephone follow-up within 3 days
of discharge and an early follow-up visit within 2 weeks.
u Early vulnerable phase

The early vulnerable phase typically begins after the discharge


of a relatively well-decongested patient following an episode
of AHF. Hospitalization duration is typically 8-10 days in many
European countries.12 That is usually a sufficient period for
adequate decongestion and then stabilization of fluid balance
(dry weight). However, that might not be long enough for adequate control of accompanying problems. Predischarge,
when possible, specialist HF nurses should be involved in
educating the patient for nonpharmacological self-management of HF and for adjustment of diuretics in the outpatient
setting. This would be helpful, as many of these patients require outpatient management of diuretics for some time. Early referral for cardiac rehabilitation should also be considered.
These 2 factorsmanagement of diuretics and cardiac rehabilitationare important determinants of stability after AHF.
This phase of vulnerability is potentially secondary to a patients
attitude, ie, restricting lifestyle modifications to the honeymoon period following discharge. However, most of the
vulnerability is thought to be related to existing problems, ie,
comorbidities. As many AHF patients also suffer from renal
problems, anemia, hypertension, coronary artery disease,
diabetes mellitus, or chronic obstructive pulmonary disease
(though a cardiac problem could be relieved to an acceptable
level), it is possible that accompanying problems will be uncovered with an index AHF event. These accompanying problems, which typically increase with age, might hold the patient in a period of risk beyond discharge. Therefore, each of
the accompanying diseases is a potentially exacerbating factor and might require focused care unless well controlled. Patients with ischemic HF have been shown to be significantly
more likely to experience repeated hospital admissions,13 and
this theoretically means that repeated episodes of ischemia
might be an important contributor to vulnerability. Elevated levels of biomarkers before discharge, such as natriuretic peptides and cardiac troponins, could potentially predict readmission risk. Hence, management during the vulnerable phase
could be guided by biomarkers, though that remains to be
firmly established.
Thirty percent of all readmissions occur within the first 2
months of hospital discharge.13 Furthermore, cardiovascular
events are clustered before fatality.13 With a comprehensive
plan and collaborative work, many of these events are preventable. Furthermore, overcoming the problem of systemic
congestion does not mean relief of hemodynamic congestion in parallel. Patients in this phase might still require relatively higher doses of diuretics and vasoactive medications.

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They also require more careful and intimate follow-up. However, it has been shown that less than 50% of patients with HF
with reduced ejection fraction (HFrEF) are prescribed guideline-recommended therapies at discharge.14
Typically, b-blockers are recommended for most patients with
chronic HF, although such therapy may be discontinued or
reduced during hospitalizations. Long-term oral disease-modifying HF therapy should be continued on admission with
AHF, except in the case of hemodynamic instability. It has
been shown in severe, acutely decompensated HF patients
that continuing the existing b-blocker therapy yields the best
prognosis, while the worst belongs to those not prescribed
b-blockers at discharge though they had been on long-term
b-blocker therapy at admission.15 It has been demonstrated
that such discontinuation is not needed in patients with AHF
except in the case of cardiogenic shock.16 If heart rate remains elevated despite b-blockade in patients with HF, the
addition of ivabradine would be beneficial.17 Additionally, in
tachycardic AHF patients (in sinus rhythm) who cannot tolerate b-blockers, ivabradine remains an attractive option,
though further studies are needed for this indication.18
Prescription rates for these agents, namely, angiotensin-converting enzyme (ACE) inhibitors, b-blockers, and mineralocorticoid receptor antagonists (MrAs), were all higher when
patients were admitted to cardiology wards or seen by HF
specialists. Furthermore, patients with HFrEF who were discharged along with a prescription for these drugs have significantly better outcomes than those discharged without.14
notably, there is significant heterogeneity in the organization
of HF management.19 Transition from inpatient to outpatient
care can be very difficult in the vulnerable period due to the
complexity of the progressive nature of the disease state itself, accompanying diseases and associated long-term medications, as well as the patients perception of the disease.
Hence, collaborative care accounting for all variables is needed at every phase. readmission rates for HF in younger adults
are similar to those in elderly patients. Thus, a generalized risk
after hospitalization is present regardless of age.20 Therefore,
patients in this phase require closer clinical follow-up, typically within 1-2 weeks after discharge. Of note, a considerably
high percentage of HF readmissions occur before the first
scheduled ambulatory visit.21
u Late phase
The late phase typically extends up to 6 months. It is related
to reactivation of the renin-angiotensin-aldosterone axis and
the beginning of hemodynamic congestion before overt systemic congestion. Whatever the medical practice habits in different geographical areas, the overall prognosis of patients
from different continents is similar in this phase. Independent
of ejection fraction, HF-related rehospitalizations are typically preceded by a gradual rise in ventricular filling pressures
more than 2 weeks before the appearance of the overt clin-

Definition and characteristics of the vulnerable phase in heart failure Yilmaz and Mebazaa

THE

VULNERABLE
A

ical picture.22 Hence, a forthcoming episode should be thoroughly investigated according to symptoms and clinical signs,
and using any existing modalities, including biomarkers. As
AHF is mainly a condition of congestion,23 the accurate identification of signs of hemodynamic congestion is critical to the
eventual prognosis of the patient.
Poor prognosis in the late phase could be prevented through
fine-tuning (uptitration) of ACE inhibitors (or angiotensin receptor blockers), b-blockers, MrAs, and ivabradine. At this
stage, medication adherence is also important to prognosis.
Medication adherence should be achieved along with social
support.24 Up to this late phase, adverse events decrease
relatively over time and then reach a plateau, which could last

PHASE

OF

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OF

FAILURE:

OPPORTUNITY

several months. During this plateau, optimization of diseasemodifying therapies, including device therapy should be the
main target.

Conclusions
A vulnerable phase lasting up to 6 months following an episode
of AHF exists and is a critical determinant of prognosis. In order to avoid the poor outcomes related to this vulnerable
phase, patients should be discharged when they are hemodynamically stable for at least 24-48 hours, euvolemic, and
managed on long-term oral medication, and when they have
stable organ function, including the kidney and liver. It appears
that the best management of the vulnerable phase requires
a collaborative and multistep approach. n

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adherence, social support, and event-free survival in patients with heart failure.
Health Psychol. 2013;32(6):637-646.

Keywords: acute heart failure; outcome; peridischarge; postdischarge; vulnerable phase

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DFINITION

ET CARACTRISTIQUES DE LA PHASE VULNRABLE


DANS L INSUFFISANCE CARDIAQUE

Linsuffisance cardiaque (IC) est une maladie dont la morbimortalit est leve long terme. Cependant, le cours de
lIC nest pas linaire de nature, mais caractris par des pics et des creux avec un profil de risque changeant. Cette
volution comprend aussi une priode appele phase vulnrable , pendant laquelle le patient est risque lev
dvnements indsirables. La vulnrabilit signifie ici que les patients IC peuvent avoir des suites inattendues, qui
pourraient mettre en vidence des fentres dopportunits si elles sont utilises correctement. Cette vulnrabilit est
gnralement observe pendant la priode pri-aigu de lIC, qui stend du dbut de lvnement dIC aigu marquant conduisant lhospitalisation, jusqu une priode entourant la sortie de lhpital et allant jusqu 6 mois aprs.
Cette phase vulnrable peut ventuellement tre divise en trois phases qui se chevauchent. Il faut noter que cette
phase relativement longue nest pas seulement base sur un mcanisme physiopathologique unique, car lIC est un
syndrome complexe. Il faut donc une stratgie individuelle mais collaborative. Quels que soient les mcanismes dentranement, ladaptation dun traitement individualis par une quipe multidisciplinaire pourrait amliorer les suites
des patients et les amener une phase stable de lIC.

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A WINDOW OF OPPORTUNITY

Most importantly, all medical


professionals taking care of patients with acute heart failure
should have in mind that the major goal of applied therapies should
not be just a reduction in mortality.
Rather, they should make all available efforts to reduce the rate of
subsequent heart failure hospitalizations, along with a reduction in
days spent in hospitals, as well as
to alleviate heart failure symptoms
and to improve quality of life.

Treatment optimization in
heart failure patients from
admission to discharge
b y P. Po n i ko w s k i a n d
E . A . J a n ko w s k a , Po l a n d

C
Piotr PONIKOWSKI
MD, PhD, FESC

ardiac decompensation leading to hospital admission is a life-threatening condition, which always requires timely and accurate diagnostic
and therapeutic procedures. Due to the clinical heterogeneity of patients with acute heart failure (AHF) and the complexity of underlying pathophysiology, a uniform and simple diagnostic and therapeutic algorithm does
not exist. The entire in-hospital stay from emergency department to hospital
discharge should always be viewed as a continuum, with clearly defined and
prioritized therapeutic goals based on careful evaluation of the AHF patients
clinical status. This paper will discuss the strategies that can be applied at
each phase of in-hospital management in order to improve the outcomes of
patients with AHF.
Medicographia. 2015;37:149-154 (see French abstract on page 154)

ospitalization due to circulatory decompensation occurring either as an exacerbation of chronic heart failure (HF) or de novo HF should always be considered to be life threatening, requiring prompt and accurate diagnosis and
initiation of adequate therapy.1,2,3 In-hospital management of patients with acute HF
(AHF) should be viewed as a continuum with consecutive phases (immediate, intermediate, and predischarge phases), each comprising different goals of therapy.

Immediate phase
Ewa Anita JANKOWSKA
MD, PhD, FESC
Department of Heart Diseases
Wroclaw Medical University
Wroclaw, POLAND
and
Centre for Heart Diseases
4th Military Hospital
Wroclaw, POLAND

During the initial (immediate) phase, beginning at admission, typically in the emergency department, major goals of management include4:
(i) clinical stabilization (restoration of peripheral oxygenation and optimal ventilation,
restoration of optimal hemodynamics and organ perfusion);
(ii) fast, effective, and sustainable relief of symptoms (most commonly dyspnea);
(iii) elimination of end-organ damage (including myocardium, kidneys, and liver);
(iv) reduction in the risk of early complications; and
(v) shortening of length of stay in intensive care.

Heterogeneity of patients with AHF


Address for correspondence:
Piotr Ponikowski, Department of
Heart Diseases, Wroclaw Medical
University, 4th Military Hospital,
Weigla 5, 50-981 Wroclaw, Poland
(e-mail: piotrponikowski@4wsk.pl)
www.medicographia.com

Difficulties in the management of HF decompensation are related to the complexity


of this syndrome, owing to various, often unidentified, causes that include distinct
clinical conditions with heterogeneous and often uncertain pathophysiology and
the fact that its clinical course is modified by numerous cardiovascular and noncardiovascular comorbidities. All these factors have significant effects on applied
therapeutic strategies. It should be emphasized that there is no uniform and simple
diagnostic and therapeutic algorithm for the management of patients with AHF.

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Prompt treatment and careful monitoring


All patients admitted with AHF should be promptly treated,
and diagnostic procedures should be implemented in parallel with respective treatment.4 Currently, therapeutic decisions are based on the initial presentation, clinical severity,
and changes in clinical status, particularly in the initial phase.
From the very beginning, monitoring of the patients vital functions is essential and many patients should be managed in an
intensive or coronary care unit, at least during the initial hours.

Identification of life-threatening conditions


Firstly, the following life-threatening conditions should be identified and, if present, they should be adequately treated immediately:
(i) inadequate ventilation and/or peripheral oxygenation (treatment: oxygen; in more severe cases, noninvasive ventilation,
or even endotracheal intubation and invasive ventilation);
(ii) life-threatening tachy- or bradyarrhythmias (treatment: electrical cardioversion or temporary pacing);
(iii) cardiogenic shock or symptomatic hypotension (treatment:
inotropic agents and vasopressors; in more severe cases,
mechanical circulatory support);
(iv) acute coronary syndrome as a potential cause of hemodynamic deterioration (treatment: coronary arteriography followed by revascularization); and
(v) acute mechanical cause as a potential cause of hemodynamic deterioration (treatment: imaging techniques followed
by either surgical or percutaneous interventions).

Management of patients with AHF based on


clinical profiles at admission
The clinical presentation of AHF ranges from a gradual worsening of chronic HF (ie, peripheral edema and dyspnea) to
life-threatening pulmonary edema or cardiogenic shock. In
clinical practice, a simultaneous assessment of congestion
and peripheral hypoperfusion allows the identification of 4 different hemodynamic profiles,5,6 which predict outcomes, but
most importantly pose several therapeutic consequences:
(i) wet and warm (congestion and adequate peripheral perfusion; the most common clinical profile of AHF);
(ii) wet and cold (congestion and peripheral hypoperfusion);
(iii) dry and cold (no congestion and peripheral hypoperfusion); and
(iv) dry and warm (no congestion and adequate peripheral
perfusion).
Importantly, there are 2 distinct clinical entities within a warm
and wet profile, which are triggered by different pathomechanisms and require different therapeutic strategies7,8:
(i) congestion due to fluid accumulation with concomitant
weight gain and peripheral edema; typically, rather slow deterioration, gradual (over several days) development of symptoms, and a previous history of chronic HF with systolic dysfunction; treatment should be based on diuretics in order to
remove fluid overload; and

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(ii) congestion due to fluid redistribution from splanchnic vasculature to the lungs without (or with minimal) weight gain; typically, rapid deterioration (sometimes flash pulmonary edema);
treatment should be based on vasodilators, sometimes combined with rather low doses of diuretics.7,8,9

Diuretic strategies
Diuretics are the most frequently used drugs in patients with
AHF.10 ESC guidelines recommend intravenous loop diuretics to reduce dyspnea and relieve congestion (class I, level
of evidence B).4 Symptoms, urine output, renal function, and
electrolytes should be carefully monitored to avoid hypovolemia, renal dysfunction, and hypokalemia.4 The optimal dose
and mode of intravenous diuretic administration (bolus or continuous infusion) are uncertain, but in general, high doses may
be deleterious. In patients admitted with pulmonary edema/
congestion already taking loop diuretics, an initial dose should
be 2.5 times the existing oral dose. In those with insufficient
diuretic response, a switch from furosemide to bumetanide
or torasemide or a combination of a loop diuretic and a thiazide (eg, bendroflumethiazide) may be considered after a
careful assessment of fluid status. In selected cases, venovenous isolated ultrafiltration can be used here. In patients with
AHF and cardiorenal syndrome, a standard stepped pharmacologic-therapy algorithm has been shown to be superior
to a strategy of ultrafiltration for the preservation of renal function, with a similar effect on weight loss with 2 approaches.11
Importantly, use of ultrafiltration has been associated with a
higher rate of adverse events.

Vasodilating strategies
For patients with fluid redistribution and/or high systemic vascular resistance, a combination of vasodilator (the most commonly used are nitrates, but sometimes also nitroprusside or
nesiritide) and diuretic should be used to relieve congestion
and alleviate symptoms.4 They affect hemodynamics, ie, they
reduce both a preload (and pulmonary capillary wedge pressure) and an afterload, and hence may increase cardiac output. Intravenous infusion of a vasodilator is recommended for

SELECTED

ABBREVIATIONS AND ACRONYMS

ACE

angiotensin-converting enzyme

AHF

acute heart failure

COPD

chronic obstructive pulmonary disease

ESC

European Society of Cardiology

EVEREST Efficacy of Vasopressin antagonism in hEart failuRE:


outcome Study with Tolvaptan
HF

heart failure

ID

iron deficiency

SHIFT

Systolic Heart failure treatment with the If inhibitor


ivabradine Trial

WRF

worsening renal function

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patients with pulmonary edema/congestion and preserved


systolic blood pressure (>110 mm Hg). Nitrate treatment
may cause significant hypotension when administered without careful blood pressure monitoring, and a tolerance to
prolonged nitrate use may occur. Nitrates should be used
with caution in patients with concomitant, clinically relevant
aortic or mitral stenosis. A recent study with nesiritide given
in the early phase of AHF demonstrated only a modest symptomatic improvement without any impact on outcomes as
compared with standard therapy.12

Inotropic and vasopressor strategies


In patients with low blood pressure, signs and symptoms of
peripheral hypoperfusion, and low cardiac output, there is
usually an indication to initiate inotropic support in order to
stabilize compromised hemodynamics and improve peripheral perfusion.4 In clinical practice, therapy usually starts with
dobutamine (a b1-adrenergic agonist producing dose-dependent positive inotropic and chronotropic effects), but phosphodiesterase III inhibitors (milrinone, enoximone) and levosimendan (calcium sensitizer improving cardiac contractility
by binding to troponin C in cardiomyocytes) are also available.
Dopamine is another often used inotropic agent, which stimulates b-adrenergic receptors (when used in moderate doses) and a-adrenergic receptors with subsequent vasoconstriction (when used in larger doses, exceeding 5 mg/kg/min).
If a combination of inotropic support and diuretic therapy is not
leading to clinical stabilization, adding a vasopressor (mainly
dopamine or norepinephrine) may be considered. In the most
severe cases, intra-arterial blood pressure monitoring should
also be considered; in some centers, pulmonary artery catheterization is applied in order to optimally treat severely compromised hemodynamics, which becomes the main goal of therapy. Another option that may be considered is temporary
mechanical support with either an intra-aortic balloon pump
or ventricular assist device, particularly if there are potentially reversible causes of acute deterioration (either as a bridge
to a final decision or as a bridge to treatment response).

Intermediate and predischarge phases


Once clinical conditions are stabilized and there is symptomatic improvement, a patient is transferred to the ward where
the next phasesintermediate and predischargeare initiated.4,13,14 This period constitutes the initiation of the transition from hospital to ambulatory outpatient setting with relevant implications on the long-term outcomes. From the health
care perspective, key recommendations should be initiated
here, due to patient receptivity and the opportunity to implement long-term intervention strategies. In this phase, the
following goals should be prioritized:
(i) maintenance of patient stabilization with optimized treatment;
(ii) initiation, uptitration, and optimization of disease-modifying pharmacological therapy;
(iii) identification of the underlying HF etiology and relevant
comorbidities;

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(iv) careful consideration of device therapy in appropriate patients;


(v) optimization of fluid and hemodynamic status (targeting
euvolemia);
(vi) predischarge risk stratification in order to identify high-risk
patients; and
(vii) enrollment in a disease management program, education
(regarding both a patient and relatives), and initiation of appropriate lifestyle adjustments.
Importantly, in addition to timely outlining of all these goals,
in each phase of AHF, management should be adjusted to
a patients clinical profile and the effects of therapy carefully
monitored. This strategy may result in further improvement of
long-term outcomes.

Management plan
In all patients hospitalized due to AHF, after stabilization and
transfer to the ward, a key element of effective management
should be a detailed, individualized management plan, which
should include the implementation of pharmacological interventions, devices, invasive procedures, and rehabilitation, obviously based on current recommendations.4 Most importantly, all medical professionals taking care of patients with AHF
should have in mind that the major goal of applied therapies
should not be just a reduction in mortality. Rather, they should
make all available efforts to reduce the rate of subsequent
HF hospitalizations, along with a reduction in days spent in
hospitals, as well as to alleviate HF symptoms and to improve
quality of life.

Serial clinical monitoring


An AHF patient transferred to the ward from the intensive care
unit still needs careful clinical re-evaluation and monitoring.
That should be based on simple, but clinically relevant, serial
measures from physical examination, such as blood pressure,
heart rate, body weight, severity of HF signs and symptoms
(peripheral edema, pulmonary congestion, dyspnea, and jugular venous dilatation), along with basic laboratory tests (renal
function, electrolytes). These clinical parameters on the one
hand provide important prognostic information, but on the
other hand, and most importantly, are crucial for further therapeutic decisions to be taken in patients with recent AHF.
Recently, Metra et al15 proposed that predischarge assessment should be based on the comprehensive, but simple,
evaluation of the following elements: clinical variables (signs of
congestion, blood pressure, heart rate, and orthostatic test),
electrocardiogram (duration of the QRS complex, presence of
atrial fibrillation), and selected laboratory examinations (natriuretic peptides, renal function, electrolytes, anemia, iron deficiency [ID], and myocardial viability). Among them, elevated
heart rate seems to be of particular interest as there is growing evidence that, similarly to chronic HF and also in patients
discharged after HF decompensation, it predicts an unfavorable outcome.16,17 In a study of patients hospitalized for HF

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Figure 1. High resting heart rate during an early postdischarge period (1-week and 4-week) after hospitalization due to acute heart failure
as a predictor of high mortality. Kaplan-Meier curves for all-cause mortality, by heart rate quartile. Log rank P<0.0001.
N=1947 patients with heart failure and left ventricular systolic dysfunction in sinus rhythm from the EVEREST study.
Abbreviations: bpm, beats per minute; EVEREST, Efficacy of Vasopressin antagonism in hEart failuRE: outcome Study with Tolvaptan; HR, heart rate; Q, quartile.
After reference 16: Greene et al. JACC Heart Fail. 2013;1:488-496. 2013, American College of Cardiology Foundation. Published by Elsevier, Inc. All rights reserved.

with a left ventricular ejection fraction 40% and who are not
in atrial fibrillation/flutter or pacemaker dependent (participants of the EVEREST trial [Efficacy of Vasopressin antagonism in hEart failuRE: outcome Study with Tolvaptan], an increased heart rate 70 beats per min (bpm) in both 1- and
4-week postdischarge assessment was associated with increased all-cause mortality (Figure 1).16 In order to reverse this
unfavorable phenomenon in such patients, it seems reasonable to consider pharmacological treatment to reduce resting heart rate during the early postdischarge phase using a
b-blocker and/or ivabradine.

chemia can contribute to HF progression and hemodynamic


decompensation, careful diagnostic procedures should be
implemented; in the case of proven ischemia, an individualized decision about coronary revascularization with optimal
mode and timing should always be discussed among the
experts. It is also important to verify the indications for implantation of devices (implantable cardioverter defibrillator [ICD],
cardiac resynchronization therapy [CRT]) as well as potential ablations of arrhythmias in patients with recent AHF.

Searching for comorbidities

Revascularization and anti-arrhythmic strategies

According to the ESC guidelines, active screening for comorbidities and their optimal treatment is crucial for patients with
HF and should constitute an element of a comprehensive
assessment also during the intermediate and predischarge
phases before the postdecompensation discharge. The
presence of certain comorbidities, as well as their number,
also contributes to the identification of particularly high-risk
patients with recent AHF. Data from the Heart Failure LongTerm Registry demonstrate that the prevalence of most comorbidities is more common in patients hospitalized for
worsening HF as compared with those with stable chronic
HF (respectively for these 2 groups: atrial fibrillation, 44% vs
38%; diabetes mellitus, 39% vs 32%; chronic obstructive pulmonary disease (COPD), 20% vs 14%; prior stroke/transient
ischemic attack (TIA), 13% vs 9%; renal dysfunction, 26% vs
18%; hepatic dysfunction, 8% vs 3%; all P<0.0001).10

In patients admitted with AHF, a potential ischemic trigger


should always be taken into consideration. For those with
co-incidence of AHF with acute coronary syndrome, immediate transfer to a catheterization laboratory with further urgent
revascularization should be considered. In all remaining patients, where on the basis of clinical evaluation myocardial is-

Screening for comorbidities would allow identification of certain ones and to optimize their treatment, as well as to modify the standard therapies applied in patients with HF based
on concomitant chronic diseases. Also, basic parameters
such as ferritin or transferrin saturation, reflecting iron status

Optimization of pharmacotherapy
Based on clinical status, diuretic therapy should be optimized
(a replacement of intravenous diuretics by oral diuretics, a
reduction in daily diuretic dose to a minimal adequate dose,
though still targeting euvolemia). At the same time, in patients
with systolic HF, life-saving therapies should be carefully implemented. These include angiotensin-converting enzyme
(ACE) inhibitors (or angiotensin receptor blockers if ACE inhibitors are not tolerated), b-blockers, and mineralocorticoid
receptor antagonists.4 Optimally, a triple combined therapy
with these agents needs to be initiated in the hospital (based
on clinical status and renal function permitting) and further
optimized during the postdischarge period.4

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and recommended by ESC guidelines to be assessed in HF


patients, allow diagnosis of ID and identify those who can
be effectively supplemented. Of AHF patients, 37% have ID,
which unfavorably affects their 12-month survival18 and could
constitute a potential therapeutic target.
The prime example of a comorbidity that may affect the applied HF treatment is COPD. COPD, occurring in 20% of patients with recent AHF,10 worsens the prognosis and constitutes an important barrier to optimal b-blocker therapy and
to an effective strategy for heart rate lowering (as COPD itself is accompanied by high resting heart rate). Data from
the SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) have shown that the primary composite end point of hospitalization for worsening HF or cardiovascular death, and its component, hospitalization for worsening
HF, were more common in patients with COPD.19 b-Blockers were prescribed to 69% of COPD patients and 92% of
non-COPD patients. The efficacy and safety profile regarding
the ivabradine treatment were similar in patients both with
and without COPD,19 hence this therapy could constitute an
alternative to b-blockers as a safe and effective heart rate
lowering strategy. Moreover, additional analyses from the SHIFT
trial demonstrated that worsening renal function (WRF), a
common problem in patients with recent AHF (defined here
as a creatinine increase of 0.3 mg/dL and 25% from the
baseline value), was directly proportionally related to baseline heart rate, with an incremental risk of 5% for every 5-

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bpm heart rate increment.20 WRF increased a risk of the primary composite end point of hospitalization for worsening
HF or cardiovascular death and of all-cause mortality, whereas ivabradine therapy was equally safe and effective regarding a reduction in the primary composite end point in patients
both with and without WRF.20 Similarly, recent evidence suggests that ivabradine therapy was equally safe and effective
regarding a reduction in the primary composite end point in
patients both with and without diabetes.21

Plan for postdischarge management


The final (predischarge) stage of management of patients hospitalized due to AHF should comprise the analysis and synthesis of all data that were obtained during the hospitalization,
including the clinical course during hospitalization, the applied
therapeutic interventions and their effectiveness regarding the
improvement in clinical status, and the comprehensive picture of cardiovascular and noncardiovascular status of the
patient with its effect on therapeutic decisions. Taken together, this evidence should form the basis for the plan for further
diagnostic and therapeutic steps during the postdischarge
stage in the management of a patient discharged after circulatory decompensation. A beneficial plan would be the enrollment of a patient in a long-term outpatient disease management program, associated with proper education (regarding
both a patient and his/her relatives), and an initiation of appropriate lifestyle adjustments, including a proper diet and exercise programs. n

References
1. Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart
failure registries. J Am Coll Cardiol. 2014;63:1123-1133.
2. Desai AS, Stevenson LW. Rehospitalization for heart failure: predict or prevent?
Circulation. 2012;126:501-506.
3. Mentz RJ, Felker GM, Ahmad T, et al. Learning from recent trials and shaping
the future of acute heart failure trials. Am Heart J. 2013;166:629-635.
4. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Committee for Practice
Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute
and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur
Heart J. 2012;33:1787-1847.
5. Nohria A, Tsang SW, Fang JC, et al. Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admitted with heart failure. J Am
Coll Cardiol. 2003;41:1797-1804.
6. Stevenson LW. Design of therapy for advanced heart failure. Eur J Heart Fail.
2005;7:323-331.
7. Metra M, Felker GM, Zac V, Bugatti S, et al. Acute heart failure: multiple clinical profiles and mechanisms require tailored therapy. Int J Cardiol. 2010;144:
175-179.
8. Cotter G, Metra M, Milo-Cotter O, Dittrich HC, Gheorghiade M. Fluid overload
in acute heart failurere-distribution and other mechanisms beyond fluid accumulation. Eur J Heart Fail. 2008;10:165-169.
9. Mentz RJ, Kjeldsen K, Rossi GP, et al. Decongestion in acute heart failure. Eur
J Heart Fail. 2014;16:471-482.
10. Maggioni AP, Anker SD, Dahlstrm U, et al; Heart Failure Association of the
ESC. Are hospitalized 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:
1173-1184.
11. Bart BA, Goldsmith SR, Lee KL, et al; Heart Failure Clinical Research Network.
Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl
J Med. 2012;367:2296-2304.

Treatment optimization in acute heart failure Ponikowski and Jankowska

12. OConnor 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.
13. Basoor A, Doshi NC, Cotant JF, et al. Decreased readmissions and improved
quality of care with the use of an inexpensive checklist in heart failure. Congest
Heart Fail. 2013;19:200-206.
14. Barnason S, Zimmerman L, Nieveen J, Schulz P, Young L. Patient recovery
and transitions after hospitalization for acute cardiac events: an integrative review. J Cardiovasc Nurs. 2012;27:175-191.
15. Metra M, Gheorghiade M, Bonow RO, Dei Cas L. Postdischarge assessment
after a heart failure hospitalization: the next step forward. Circulation. 2010;122:
1782-1785.
16. Greene SJ, Vaduganathan M, Wilcox JE, et al; EVEREST Trial Investigators. The
prognostic significance of heart rate in patients hospitalized for heart failure with
reduced ejection fraction in sinus rhythm: insights from the EVEREST (Efficacy
of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) trial. JACC Heart Fail. 2013;1:488-496.
17. Habal MV, Liu PP, Austin PC, et al. Association of heart rate at hospital discharge
with mortality and hospitalizations in patients with heart failure. Circ Heart Fail.
2014;7:12-20.
18. Jankowska EA, Kasztura M, Sokolski M, et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies
patients at the highest risk of death after an episode of acute heart failure. Eur
Heart J. 2014;35:2468-2476.
19. Tavazzi L, Swedberg K, Komajda M, et al; SHIFT Investigators. Clinical profiles
and outcomes in patients with chronic heart failure and chronic obstructive pulmonary disease: an efficacy and safety analysis of SHIFT study. Int J Cardiol.
2013;170:182-188.
20. Voors AA, van Veldhuisen DJ, Robertson M, et al; SHIFT investigators. The effect of heart rate reduction with ivabradine on renal function in patients with
chronic heart failure: an analysis from SHIFT. Eur J Heart Fail. 2014;16:426-434.
21. Komajda M, Tavazzi L, Swedberg K, et al; On behalf of the SHIFT Investigators.
Clinical profiles and outcomes of patients with chronic heart failure and diabetes: efficacy and safety of ivabradine. A SHIFT study analysis. Eur J Heart
Fail. 2014;16(suppl 2):42. Abstract P227.

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Keywords: acute heart failure; management plan; therapy optimization

OPTIMISATION

DU TRAITEMENT CHEZ LES PATIENTS INSUFFISANTS CARDIAQUES


ENTRE L HOSPITALISATION ET LA SORTIE DE L HPITAL

La dcompensation cardiaque conduisant lhospitalisation est une pathologie potentiellement mortelle, qui ncessite toujours un diagnostic et des procdures thrapeutiques justes et dans les dlais. tant donn lhtrognit clinique des patients en insuffisance cardiaque aigu (ICA) et la complexit de la physiopathologie sous-jacente, il nexiste pas de diagnostic simple et uniforme ni dalgorithme thrapeutique. La totalit du sjour lhpital,
du service des urgences la sortie de lhpital, devrait toujours tre regarde comme un continuum, dfinissant et
privilgiant clairement les buts thrapeutiques bass sur une valuation claire de ltat clinique des patients en ICA.
Cet article analysera les stratgies applicables chaque phase de lhospitalisation afin damliorer la survie des patients en ICA.

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Heart failurespecific disease


management programs are now
standard in many high-income
countries, at least for patients who
are seen by cardiologists. They
have evolved from nurse-led programs for drug titration and education, and have incorporated evidence from programs used to
manage other chronic conditions,
such as diabetes or asthma. The
structure of the programs varies,
but they usually start during the
hospital admission, and involve
multiple follow-up visits.

Postdischarge assessment
and management of
patients with heart failure

by M. R. Cowie, United Kingdom

A
Martin R. COWIE, MD, MSc
FRCP, FRCP (Ed), FESC
Professor of Cardiology
Imperial College London Royal Brompton Hospital
London, UNITED KINGDOM

fter discharge from hospital, patients with heart failure are at high risk
of mortality and rehospitalization: around 20% of patients are readmitted within 30 days, and 5% may die during that period. In most countries, only a minority of patients gain access to multiprofessional disease management programs, which can provide early and repeated contact between
the patient (and family) and the health care professional team. The evidence
for improved outcome and experience of care of such an approach is robust.
International guidelines clearly recommend this type of approach, with the
most recent US guideline stating that a follow-up visit within 7 to 14 days
and/or a telephone follow-up within 3 days of hospital discharge is reasonable. The key components of a disease management program include optimized medical and device management, patient education, involvement in
symptom monitoring and flexible diuretic dosing, follow-up after discharge,
facilitated access to care during periods of decompensation, access to advanced treatment options, and the provision of psychosocial support to patients and the family/carers. A person-centered approach is essential to ensure optimal adherence to treatment and lifestyle changes. Technology can
help support patient education, monitoring, and self-care. Increasingly, health
care systems are aligning payment systems to improve heart failure care, particularly in the transition from hospital care to longer-term care in the community, but the room for improvement remains huge.
Medicographia. 2015;37:155-162 (see French abstract on page 162)

fter discharge from hospital, patients with heart failure are at high risk of
mortality and rehospitalization. In the most recently available data from England, 9.4% of patients died during the hospitalization, a further 6.1% died
within 30 days of discharge, and readmission occurred in 19.1% by 30 days.1 In
other European countries, reported rehospitalization rates are typically around 25%
at 12 weeks.2 In the United States, 30-day readmission rates are similar: between
20% to 25%.3,4 Recurrence of heart failure is the single most common reason, accounting for 30% to 60% of all readmissions.4,5 More broadly, unscheduled contact
with the health service after hospital discharge is greatest in the first few weeks and
months, rising to 50% by 12 months.6

A
Address for correspondence:
Prof Martin R. Cowie, Royal
Brompton Hospital, Sydney Street,
London SW3 6HP, UK
(e-mail: m.cowie@imperial.ac.uk)
www.medicographia.com

International guidelines recommend that patients undergo a clinical review by a


clinician with experience in heart failure soon after discharge from hospital.7,8 The
2014 guideline from the National Institute for Health and Care Excellence (NICE) in

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ABBREVIATIONS AND ACRONYMS

COACH

Coordinating study evaluating Outcomes of Advising and Counseling in Heart failure

ESC

European Society of Cardiology

MAHLER

Medical mAnagement of chronic Heart faiLure in


Europe and its Related costs

NICE

National Institute for Health and Care Excellence

England also recommends early clinical review.9 The goal is


to provide a high-quality transition to outpatient and community care, supporting self-care where possible. Ideally, patients
should be enrolled in a disease management program, but in
the absence of such a structured multidisciplinary program,
review by a clinician with experience in heart failure is considered better than routine follow-up in a general clinic or only
in primary care.
The most recent US guideline suggests that it is reasonable
for patients to have a telephone follow-up within 3 days of discharge and/or a face-to-face clinical review within 1 to 2
weeks (Table I).7,10-27 Data from several countries suggest that
such early follow-up is the exception rather than the rule. In
the United Kingdom only 56% of hospitalized patients have
any follow-up organized with a multiprofessional heart failure team, and only 34% have such a follow-up within 2 weeks
of discharge,1 and in France only 28% of patients visited their
cardiologist within 3 months of discharge.28

Content of disease management programs


Heart failurespecific disease management programs are now
standard in many high-income countries, at least for patients
who are seen by cardiologists. They have evolved from nurseled programs for drug titration and education, and have in-

corporated evidence from programs used to manage other


chronic conditions, such as diabetes or asthma. The structure of the programs varies, but they usually start during the
hospital admission and involve multiple follow-up visits either at the clinic or at home. The European Society of Cardiology (ESC) has published guidelines on such programs,8,29
with emphasis on several key components (Table II).8
The evidence for the benefit of such disease management
programs is good, with reductions in rates of readmission and
mortality, and improvements in quality of life compared with
usual care.30-31 The nature of the interventions studied in randomized trials has varied, but most include inpatient contact
and then early follow-up, often with telephone support in addition to face-to-face visits either in a clinic or at home.
However, the evidence base for such recommendations is
largely confined to randomized trials from high-income countries. In a recent meta-analysis of disease management programs for heart failure, including 46 studies,32 30 (65%) were
based in the United States or Canada, 9 in Europe, 6 in Australia or New Zealand, and only 1 came from a middle-income country, Argentina. More recently, a small randomized
study of a nurse-based management program following discharge from hospital in Brazil reported an improved outcome
for patients with heart failure, even for those with a low background level of education.33 The program consisted of up to
4 home visits of an hours duration after discharge from hospital. The first occurred within 10 days of discharge (in keeping with the most recent North American guidelines), and
then at 1 month, 2 months, and 4 months after discharge.
In addition, there were telephone calls during the program
(4 calls of around 10 minutes) to reinforce the recommendations made during the home visits, to check the use of
prescribed medication, and to answer questions about the
condition and its treatment.

Table I. Summary
of recommendations for hospital
discharge in the
most recent US
guidelines on
heart failure
management.
Abbreviations: COR,
class of recommendation; HF, heart failure;
GDMT, guideline-directed medical therapy;
LOE, level of evidence
After reference 7:
Yancy et al. J Am Coll
Cardiol. 2013;62:e147e239. 2013 American
College of Cardiology
Foundation and American
Heart Association, Inc.

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Table II. Key components of a disease management program for patients with heart failure.
After reference 8: McMurray et al. Eur Heart J. 2012;33(14):1787-1847. 2012, The European Society of Cardiology. All rights reserved.

There may be an optimal amount of patient contact, particularly where the quality of usual care is high. In the COACH
study (Coordinating study evaluating Outcomes of Advising
and Counseling in Heart failure),34 there was no improvement
in patient outcome with an intensive support program provided by a nurse compared with either a moderate-intensity
program or usual follow-up by a cardiologist.
Patient (and family) education is a key component of all disease management programs. The guideline of the Heart Failure Association of the ESC gives an extensive list of items that
should be covered (Table III, page 158).8

A person-centered approach
It can be easy to lose sight of the individual when running a
disease management program: there can be a temptation
to let one size fit all, and to tick the boxes rather than tailor the speed and approach to the patient and their family.
Health policy has increasingly signaled a move away from an
emphasis on specific organs and disease, toward placing the
whole person at the center of medicine.35 The health professional must try to understand what the illness means for
the individual, within a social and psychological context. This
necessitates listening to that particular persons point of view,
with the ultimate goal of sharing responsibility with them.36
Clinicians should learn to ask not only what is the matter?
but what matters? In other words, what are the patients
interests, concerns, and fears about the specific conditions,
symptoms, or treatment options?37 This moves us from the
strictly biomedical view to a broader biopsychosocial and
spiritual view, with power shared between the health care professional and the patient.38

Clinical guidelines in cardiology are largely silent about the


person-centered approach, other than to state or imply that
the clinician must consider how best to apply the evidence
base to their patient. In the guidelines for chronic conditions
(such as heart failure), the multidisciplinary approach is strongly supported, with professionals working together (with the
patient and family) in a coordinated manner.8 An explicit discussion of the person-centered approach is not given, but
rather indicators of which type of patients might or might
not benefit from specific interventions. This approach is still
directivethe application of what the professionals consider
the best treatmentwithout a fuller discussion of the issues on
a more equal basis. Two key components of person-centered
care are collaborative goal setting and action planning: agreeing on what, when, where, and how often specific actions are
required and the barriers to such actions for that individual
patient.39 Such an approach helps foster self-efficacy and
may assist the person in moving from a position of dependence to that of being an expert, if that is what they wish.40
The evidence that this can make a difference is emerging,41
and is likely to be something that politicians and society will
increasingly expect of health care systems.

Self-care
Obviously, the individual with heart failure is key to the success
of long-term management after hospitalization for this condition. Even with frequent contact with health care professionals, active involvement of the patient and their family or carers is important to optimize outcomes and the experience of
care. Disease management programs aim to support selfcare, where this is wished by the patient. There are 3 key components to self-care: maintenance, monitoring, and management. Maintenance involves adherence to medication and

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life-style changes; monitoring includes keeping an eye on


signs and symptoms of heart failure and activities such as
daily weighing; and management implies making changes to
therapy (such as diuretic dose) in response to a fluctuation
in symptoms.

A large variation in adherence to self-management has been


reported.42,43 In a global study, most patients reported taking their medication as prescribed, but adherence to exercise
prescriptions was below 50%.43 Other studies report lower
adherence to medication, even after hospital discharge, with

Table III. Essential topics that should be covered during patient education and the skills and self-care behaviors that should be taught
in relation to these topics, according to the most recent European Society of Cardiology (ESC) guidelines.
After reference 8: McMurray et al. Eur Heart J. 2012;33(14):1787-1847. 2012, The European Society of Cardiology. All rights reserved.

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Figure 1. Adherence levels to self-care behaviors among patients with heart failure.
Good adherence is defined as patients reporting adherence to a given behavior all of the time or most of the
time over the past 4 weeks.
After reference 42: Marti et al. Congest Heart Fail.
2013;19:16-24. 2012, Wiley Periodicals, Inc.

adherence of only 80% at 1 month after discharge, and 60% to 65% between 3 months
and 1 year after discharge.44 One survey
suggested that a lack of understanding of
discharge instructions and confusion engendered by conflicting instructions from
the discharging physician and primary care
physician were the main reasons for nonadherence to medication.45 Many patients
continue to take previously prescribed medications, despite
them being discontinued in hospital.46 In a recent US study,
large variations in self-management were reported, even though
individuals received self-care education at regular clinic visits.42 Only 9% of patients showed good adherence to 8 key
behaviorssuch patients had the lowest risk of hospital admission, days in hospital, and emergency room visits, and better health status (Figure 1).42

analyses of small studies have suggested benefits on mortality and heart failure hospitalizations,55,56 large randomized trials have not confirmed such benefits.57,58 Many patients with
heart failure have an implanted cardiac device, such as cardiac resynchronization therapy, and/or an implantable cardioverter defibrillator. Remote monitoring of such devices may,
in some circumstances, improve the outcome for patients,59
although once again the evidence base is not consistent.60
Further studies are ongoing.61

Role of the family/carers


Higher levels of social support from friends and family are associated with increased medication and dietary adherence.47,48
High levels of support from a partner are also important and
improve self-care.49 Negative influence from family or friends
is also possible,50 suggesting that health care professionals
should work with the social network of patients where possible. Caring for a family member with heart failure can be a
physical, emotional, and financial strain on carers,51,52 and many
report a lack of social and emotional support and a lack of
information and advice.53

Who should be involved in postdischarge


follow-up?
Disease management programs are almost universally multiprofessional, and are typically coordinated by a heart failure
nurse specialist. Evidence from observational datasets suggests that any clinical follow-up improves outcomes in heart
failure, but there is incremental benefit from involvement of a
multiprofessional team over that of either a primary care physician or a cardiologist alone.54 The core team may be small, but
the skills of a wider range of health care professionals can be
drawn upon when appropriate, such as a nutritionist, physiotherapist, occupational therapist, palliative care service, psychologist, or pharmacist.

Remote monitoring
In theory, remote monitoring of patients after discharge should
allow remote decision making, facilitate patient self-care, and
improve outcome after discharge from hospital. Although meta-

Technology offers other opportunities to improve heart failure


management by both professionals and patients. Interactive
Internet-based education programs (such as heartfailurematters.org operated by the Heart Failure Association of the ESC),
and patient support groups can provide useful material for patients and their families. Smartphone applications (apps) are
also increasingly used to support lifestyle management, and
may be useful in supporting rehabilitation. Online consultations (by Skype or other systems), e-mail communication, and
transfer of data from home monitoring systems are changing
the way patients and their families interact with their health
care team. Concerns regarding legal liability, data confidentiality, and reimbursement are slowing implementation of
these technological changes in many countries.62

Palliative and end-of-life care


Traditionally, cardiac services have not embraced a palliative
care approach to end-of-life issues, although this has changed
dramatically in recent years, particularly where multiprofessional disease management programs and teams are involved
in care. In England, only 4% of heart failure patients were referred to palliative care services in 2012 after their admission,
despite 6% of patients dying within 30 days of discharge, and
25% by 6 months.1 Palliative care takes a broad approach to
disease management, addressing the physical, as well as psychological, social, and spiritual needs of patients and their families. Pain and symptom management are key elements of this
approach and are most useful when introduced early on in the
disease process so that patients and their families are famil-

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iar with the concepts and services available as the needs


arise. Organization and funding of palliative care services varies
from country to country.
Patient surveys suggest that the majority of patients with heart
failure do not feel that they have had an opportunity to adequately discuss end-of-life issues with their health care professionals, with unwillingness to tackle the subject found in
both the patients and the health care team.53

Driving change
In a survey published in 2006, only 7 of 26 European countries reported that heart failuremanagement programs were
being used in more than 30% of hospitals.63 Even when programs are in place, they are often underutilized. A survey in
Canada showed that only 15% of patients hospitalized for
heart failure were referred to a specialist clinic for follow-up.64
In France, a recent publication suggested that only 26% of
patients were seen by a cardiologist within 12 weeks of discharge,28 and in the United Kingdom only 56% of patients
were referred for heart failure follow-up at the time of discharge.1 In the United States, a Web-based survey reported
wide variation in the implementation of key practices in a quality improvement initiative to reduce preventable readmissions
after heart failure hospitalization: only 15% of hospitals employed all 4 recommended discharge and follow-up practices, and only 5% ensured all 3 classes of disease-modifying medication were in place.65
Health care systems have attempted to drive care toward multiprofessional and community care by a variety of means, including the introduction of performance metrics. Often, these
relate to process measures, such as the use of various drugs
or echocardiography, or evidence of delivery of education about
smoking cessation or exercise advice. Readmission within 30
days is penalized in several countries, including the United
States, Germany, and the United Kingdom. In the latter coun-

try, consideration is being given to the introduction of a payment by results tariff, so that reduced payment is made if certain procedures are not followed. There is good evidence that
the adherence of clinical teams to guideline-recommended
therapy is associated with better outcomes for patients. In
the MAHLER survey (Medical mAnagement of chronic Heart
faiLure in Europe and its Related costs), which was conducted in 6 European countries, after adjustment for potential confounding factors, patients that were seen by a clinical team
that was highly compliant with guideline-based therapy had
a 36% lower rate of cardiovascular rehospitalization over a
6-month period after discharge.66 Similar results have been
reported more recently from Germany.67 Recent data from the
national audit of heart failure admissions in the United Kingdom confirm that patients who see specialists, and those who
are given more guideline-recommended therapy, have a better outcome after discharge from hospital.1 This has supported NICE to mandate universal access to such specialist input
for patients admitted with heart failure to English hospitals
from 2014 onward.9

Conclusions
The evidence base strongly supports the international guideline recommendations that heart failure patients should be
followed-up by specialist services after discharge from hospital, ideally within the context of a multiprofessional disease
management program. The highest risk period is in the first
weeks to months after discharge, and input from the multiprofessional team during this period will help optimize the outcome and experience of care for the patient and their family/
carers. A patient-centered approach is essential to ensure
that support is tailored to the individuals needs. Increasingly,
health care systems are aligning payment mechanisms to incentivize best practice and better outcomes. Globally, the data
suggest that there is considerable room for improvement
the majority of patients with heart failure who are admitted to
hospital do not have access to good postdischarge followup and care, even in the wealthiest countries. n

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with the cardiology community. Eur Heart J. 2013;34:1864-1868.


63. Jaarsma T, Stromberg A, De Geest S, et al. Heart failure management programmes in Europe. Eur J Cardiovasc Nursing. 2006;5:197-205.
64. Gravely S, Ginsburg L, Stewart DE, Mak S, Grace SL. Referral and use of heart
failure clinics: what factors are related to use? Can J Cardiol. 2012;28:483-489.
65. Bradley EH, Curry L, Horwitz LI, et al. Contemporary evidence about hospital
strategies for reducing 30-day readmissions: a national study. J Am Coll Car-

diol. 2012;60:607-614.
66. Komajda M, Lapuerta P, Hermans N, et al. Adherence to guidelines is a predictor of outcome in chronic heart failure: the MAHLER survey. Eur Heart J.
2005;26:1653-1659.
67. Frankenstein L, Remppis A, Fluegel A, et al. The association between longterm longitudinal trends in guideline adherence and mortality in relation to age
and sex. Eur J Heart Failure. 2010;12:574-580.

Keywords: heart failure; hospitalization; postdischarge follow-up; postdischarge management

VALUATION ET PRISE EN CHARGE DES PATIENTS


INSUFFISANTS CARDIAQUES APRS LEUR HOSPITALISATION
Aprs la sortie de lhpital, les patients insuffisants cardiaques ont un risque lev de mortalit et de rhospitalisation : environ 20 % des patients sont rhospitaliss dans les 30 jours et 5 % peuvent dcder pendant cette priodel. Dans la plupart des pays, seule une minorit de patients sont admis dans des programmes multiprofessionnels
de prise en charge de la maladie offrant un contact prcoce et rpt entre le patient (et la famille) et lquipe soignante. Il a t montr que cette approche amliore les rsultats et la faon dont les patients vivent les soins. Les
directives internationales recommandent clairement ce type de suivi : daprs les directives amricaines internationales les plus rcentes, une visite de suivi dans les 7 14 jours et/ou un suivi tlphonique dans les 3 jours suivant
la sortie de lhpital sont raisonnables . Les points cls dun programme de prise en charge de la maladie consistent en une optimisation de la gestion mdicale et matrielle, une ducation des patients, une implication dans la surveillance des symptmes et un dosage flexible des diurtiques, un suivi aprs la sortie de lhpital, un accs aux
soins facilit pendant les priodes de dcompensation, un accs aux traitements de pointe et un soutien psychosocial aux patients et leur famille ainsi quaux proches qui soccupent deux. Une approche centre sur la personne
est essentielle pour une observance du traitement et des changements de style de vie optimaux. De son ct, la
technologie peut faciliter lducation, le suivi et lauto-prise en charge du patient. Les systmes de sant tendent de
plus en plus mettre en place des systmes de paiements coordonns, afin damliorer le traitement de linsuffisance
cardiaque, en particulier dans la transition des soins hospitaliers aux soins extrahospitaliers plus long terme, mais
des progrs importants restent faire.

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Postdischarge assessment and management of patients with heart failure Cowie

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A WINDOW OF OPPORTUNITY

Using something as simple


and inexpensive as a checklist
when patients are about to be discharged can greatly boost quality
of care and decrease patient readmissions. A checklist can be of
great help to attending physicians,
as well as nurse practitioners and
other house staff involved in patient care, reminding them about
the convenience of applying various evidence-based pharmacologic and nonpharmacologic therapeutic measures.

Impact of quality
improvement initiatives in
patients hospitalized
for heart failure
b y J . L . Z a m o ra n o
a n d V. C . Lo z a n o , S p a i n

H
Jos Luis ZAMORANO, MD, PhD
Head of Cardiology
University Hospital Ramn y Cajal
Madrid, SPAIN

eart failure has become a serious and expensive epidemic in the Western world, with hospitalization contributing to the greatest proportion
of spending. Many strategies to improve quality of care can be implemented during or after hospitalization to ensure optimal outcomes and reduce
readmission rates. In-hospital strategies include promoting the use of management protocols based on clinical practice guidelines and the use of checklists, as well as developing methods that deliver feedback to clinicians on care
provided and outcomes. A variety of follow-up measures can be planned on
hospital discharge. Patients who are seen early after hospitalization have better outcomes and fewer readmissions, and this benefit appears to be greater
if the follow-up is carried out by a familiar physician and shared between the
cardiologist and the primary care physician. Apart from the routine medical
follow-up, other effective strategies include referral to day hospitals or heart
failure clinics, structured telephone support, or telemonitoring of patient health
status by way of different telemedical solutions, and last, but not least, patient
empowerment through self-care activities that help them maintain physiological stability. All of the above can be effectively implemented through disease management programs aimed at improving the quality of care and patient outcomes while reducing health care expenditures.
Medicographia. 2015;37:163-169 (see French abstract on page 169)

Vanesa Cristina LOZANO, MD


University Hospital Ramn y Cajal
Madrid, SPAIN

Address for correspondence:


Prof Jos L. Zamorano,
Carretera de Colmenar Km 9.100,
28034 Madrid, Spain
(e-mail: zamorano@secardiologia.es)
www.medicographia.com

eart failure has become a severe and expensive epidemic in the Western
world, with an estimated prevalence of 1%-2% in Europeans, reaching over
10% in those aged 85 or older.1 Given the rapidly progressing aging of the
population, the need for complex pharmacotherapy, specific treatment procedures,
and frequent readmissions, it is not surprising that heart failure has long been considered a major public health problem and a growing burden on the health care system. Taking this into account, the American Heart Association published a policy
statement in which an estimated increase of 240% in direct cost burden of the disease by the year 2030 was foreshadowed.2 Hospitalization contributes to the greatest proportion of expenditure in heart failure, accounting for over 60% of the total
cost to the health service,3 which in turn represents between 1% and 2% of the total health care budget in developed countries.4

Readmission rates have been shown to be very high among patients with heart
failure, especially during the first months after diagnosis, with a quarter of patients returning within 30 days, a third of patients returning within 2 months, and more than

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half within 18 months after discharge from hospital.5,6 In addition, in the United States, a recently launched collaborative tool that provides information on how well hospitals perform in all-kind quality-of-carerelated statistical analysis shows
that the national 30-day readmission rate for heart failure has
had limited improvement in recent years.7 A reduction in this
carefully scrutinized hospital-performancerelated parameter is a desirable objective, as it not only helps decrease the
overall cost of medical care, but it also contributes to better
quality of life for our patients.
Many strategies regarding quality of care could be implemented during hospitalization to improve care and ensure optimal
patient outcomes (Figure 1), as it is well documented that a
substantial proportion of patients admitted with heart failure
receive less-than-optimal treatment, especially when they are
hospitalized for other causes.8

In-hospital strategies
u Management protocols
A written, updated, and shared document that clinicians can
consult when difficult decisions or clinical scenarios arise is
desirable. Management protocols can be an initial step in improving quality of care in hospitalized patients, providing for

list can be of great help to attending physicians, as well as


nurse practitioners and other house staff involved in patient
care, reminding them about the convenience of applying various evidence-based pharmacologic (medications that should
be prescribed or uptitrated during a patients stay, according
to guidelines) and nonpharmacologic therapeutic measures
(eg, the need to provide education, counseling, and followup instructions) (Figure 2).
Some studies have shown that the use of this kind of clinical tool can have a significant impact on improving quality of
care by leading to a higher proportion of patients being treated with evidence-based therapies and correctly uptitrated
drugs, which in turn leads to decreasing readmission rates
and better clinical outcomes.11
u Feedback
A critical element for improving quality of care lies in providing
clinicians with methods for monitoring care and outcomes of
patients. Each facility should have a quality assessment and
improvement program specific for heart failure where the extent to which clinicians practice in accordance with clinical
guidelines can be assessed. The most powerful method appears to be the sharing of feedback on data comparing clinicians with their colleagues and education
carried out at the local level by respected
fellows.12

A prospective registry, whether local or national, can be a useful tool. By collecting patient characteristics and performance measures during hospitalization and capturing
postdischarge outcomes during follow-up,
clinicians can receive feedback on their adherence to evidence-based guideline recommendations and quality of care provided.
Several national and local initiatives have
been undertaken in this field using a variety
Figure 1. Schematic showing various in-hospital and postdischarge follow-up strateof mechanisms, including national tracking
gies to ensure optimal patient outcomes.
and reporting of quality indicators through
standardized care and reducing undesired variation in clinical health plan claims and reviews of medical records. These initiatives provide feedback to practitioners on quality indicator
practice. Individual clinical expertise should only influence clinadherence through peer review, require hospitals to submit
ical management when scientific evidence is lacking or of inperformance measure data, and provide performance-imsufficient quality.
provement tools to enhance adherence.13,14
These management protocols should be based on the best
scientific evidence available, often found in clinical practice
SELECTED ABBREVIATIONS AND ACRONYMS
guidelines; it has been shown that their implementation re9,10
sults in significant improvement in outcome of care.
CI

confidence interval

u Checklists

HR

hazard ratio

Using something as simple and inexpensive as a checklist


when patients are about to be discharged can greatly boost
quality of care and decrease patient readmissions. A check-

OR

odds ratio

RR

relative risk

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Figure 2. Example of a simple, inexpensive heart failure checklist, which can have a significant impact on patient quality of care.

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Hospital discharge and follow-up strategies


u Early follow-up

The days following discharge are a vulnerable period for patients suffering from heart failure because of their advanced
age, the presence of comorbid conditions that could hinder
the complete resolution of episodes of decompensation (eg,
chronic kidney disease), the complexity of pharmacological
regimens employed, and the great number of physicians who
may be involved in their subsequent care. It is usually necessary to rely on new medical therapies or to make changes in
previous ones that could worsen their clinical condition, cause
secondary effects, or even destabilize other comorbidities. In
a retrospective cohort study conducted in Canada involving
patients discharged from acute care hospitals with the diagnosis of new-onset congestive heart failure, those who received a regular cardiovascular follow-up had fewer visits to
the emergency department (38% vs 80%; P<0.001), fewer
admissions to hospital (13% vs 94%; P<0.001), and showed
a lower 1-year mortality (22% vs 37%; P<0.001) compared
with those with no follow-up visit.15
Although aftercare tracking on a 6-monthly basis may seem
adequate for patients with stable disease, current guidelines
recommend an early follow-up after certain circumstances,
such as a recent hospital admission,16 given that prompt follow-up of patients hospitalized for heart failure has been associated with lower rates of death and readmission. In a study
carried out in 225 hospitals in the United States among
Medicare beneficiaries hospitalized for heart failure, patients
discharged from centers with a greater proportion of early follow-up (defined as an outpatient evaluation visit with a physician within 7 days after discharge) had lower rates of all-cause
30-day readmissions.17
u Physician continuity
Physician continuity has been demonstrated to positively influence postdischarge outcomes beyond the sole effect of an
early follow-up. In a recently published observational study
conducted in Canada regarding risk of death or urgent allcause readmission over 6 months in 24 373 patients discharged from hospital with a first-time diagnosis of heart failure, patients who had follow-up visits with a familiar physician
(defined as one who had seen the patient at least once during the index admission or at least twice in the year before
the index admission) had a lower risk of death or unplanned
readmission (hazard ratio [HR] 0.91; 95% confidence interval
[CI], 0.85-0.98) than those followed by an unfamiliar physician, whether specialist or not.18 Moreover, another observational study revealed that the benefit is not limited to patients
discharged from hospitalization, but has also been observed
to extend to patients treated and released from emergency
departments, a population known to have worse 30-day outcomes than those actually admitted.19 In a cohort of 12 285
patients treated and released directly from various emergency
departments in Canada, the risk of death or hospitalization

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was lower in patients followed by a familiar physician compared with those followed by an unfamiliar physician, at 3
months (HR 0.79; 95% CI, 0.71-0.89) as well as at 12 months
(HR 0.87; 95% CI, 0.80-0.96).20 The previous observations
raise the question of whether we could be achieving suboptimal outcomes by sacrificing physician continuity in order to
meet early follow-up deadlines.
u Collaborative care
Although many patients suffering from heart failure receive
care only by a primary care physician, being the gatekeeper
of referrals to specialist care, a lot of patients in the postemergency setting (that is, after discharge from hospital or after visiting the emergency department) are only seen by a cardiologist. However, patients who receive concurrent care by both
a primary care physician and a cardiologist show better results. In a population-based study including 10 599 patients,
those patients who visited both a primary care physician and
a specialist within 30 days from discharge showed a lower
rate of death at 1 year (7.2%) compared with those who only
visited a primary care physician (10.4%; P<0.001). Moreover,
patients with shared care had the highest rates of left ventricular ejection fraction evaluation, noninvasive testing for ischemia detection, and cardiac catheterization.21

Some studies suggest that collaborative care entails a tradeoff between lower mortality and higher rates of hospitalization,15 whereas others found no impact of specialist care.
u Day hospitals
Day hospitals allow evaluation and management of mild to
moderate decompensations by short therapeutic interventions, arising as an efficient alternative in maintaining continuity of care while preventing readmissions, improving accessibility, increasing patient comfort, and reducing costs.
Compared with other strategies, day hospitals or heart failure
clinic-based disease management models can deliver more
options in diagnostic tools and equipment, facilitating acute
care.22

In a study aimed at assessing and comparing the effectiveness and cost utility between a heart failure management program delivered by day hospital or usual care, patients referred
to one of these facilities (with a staff consisting of a cardiologist, 4 trained nurses, and 2 physiotherapists, as well as other part-time collaborators)where a series of interventions
including cardiovascular risk stratification, correction of causes of instability, and continuous optimization of therapy could
be appliedshowed better results in management outcomes
as well as in hard outcomes. A smaller percentage of patients
referred to day hospitals experienced readmission compared
with patients in the usual care group (8% vs 35%; P<0.05%)
or suffered cardiac death (2.7% vs 17.2%; P<0.05). This model also showed a better cost-utility ratio than community management.23

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u Structured telephone support


It is feasible to educate, monitor, and give support to patients
through self-management programs after discharge using simple telephone technology in a structured format. Through a
series of scheduled calls with a specific goal and thoughtful
questioning, a clinician can assess medication adherence, input-output balance, abrupt changes in body weight, and the
convenience of medication adjustment, among other things.
Although 2 large meta-analyses of randomized clinical trials24,25one meta-analysis focusing on telemonitoring and
structured telephone support and the other covering a broader range of transitional care interventionsshowed a reduction in congestive heart failurerelated hospitalizations and
a trend toward reduction in all-cause mortality, this did not
correlate with a reduction in all-cause hospitalizations. Furthermore, individual randomized clinical trials showed mixed
results.26 Therefore, the available evidence is insufficient to
support a clear recommendation.

Compared with other strategies, telephone-support disease


management models are low cost and time efficient, and have
been shown to be convenient for both the team and the patient. Nevertheless, it can be difficult to objectively assess
symptoms and signs of heart failure by this strategy and implementation of large adjustments in treatment can be challenging.
u Remote monitoring or telemedicine
Advances in telecommunication technologies have made possible the continuous care of patients at any place as an adjuvant to standard care, while contributing to the self-empowerment of patients. Through different telemedical solutions,
some of them based on the use of implantable devices, selected physiological measurements can be collected and analyzed to ensure an early detection of disease deterioration,
prompting medical intervention. The key to the effectiveness
of telemedical management hence relies on the predictive
value of the chosen monitored variables.26

As a noninvasive approach, body weight monitoring has been


considered for many years the cornerstone in traditional telemedicine. Although it may seem a simple measurement at first
glance, there are several shortcomings due to body weight
being easily influenced by clinical status or changes in food
or fluid intake. It is also possible to assess parameters such
as oxygen saturation, body impedance, and physical activity. Other monitoring strategies involve special drug containers that are able to send a signal when opened, thus helping assess adherence.
Minimally invasive approaches include measurement of serum
concentrations of certain biomarkers, such as blood glucose
or brain natriuretic peptide, or utilization of already in-use devices, like implantable cardioverter defibrillators or pacemakers, to monitor device function and usage or even some phys-

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iological variables, such as heart rate or type of rhythm. Moreinvasive approaches include the insertion of implantable devices specifically designed with telemonitoring purposes. Some
of these tools, such as a wireless pulmonary artery hemodynamics monitoring system, have been shown to reduce hospitalizations,27 although data on efficacy in improving outcomes
is still lacking.
u Self-care promotion
Self-care promotion, defined as the encouragement of a naturalistic decision-making process that patients use in the choice
of behaviors that maintain physiological stability and the response to symptoms when they occur, can be a very convenient ally for clinicians.28

In a systematic review of randomized trials of multidisciplinary


management programs in heart failure, those aimed at enhancing patient self-care activities effectively reduced heart
failurerelated hospitalizations (relative risk [RR] 0.66; 95%
CI, 0.52 -0.83) and all-cause hospitalizations (RR 0.73; 95%
CI, 0.57-0.93), without achieving an effect on mortality. The
interventions led in the publications analyzed included nursedelivered patient education, mailed patient education materials, home visits after discharge to reinforce education and
self-care, or regular telephone contact by a nurse educator
to monitor for deterioration.29,30 Similarly, on another systematic review of randomized clinical trials focusing specifically on
self-management interventions in which patients retained the
primary role in managing their health condition (which included education sessions or educational software providing information about signs and symptoms of heart failure, importance of daily weighing, dietary restrictions, and importance of
adherence to the medication prescribed), self-care activities
reduced heart failurerelated readmissions (odds ratio [OR],
0.44; 95% CI, 0.27-0.71) and all-cause hospital readmissions (OR 0.59; 95% CI, 0.44-0.80).31
Moreover, some studies show that self-care measures may
provide a benefit in terms of reduction in risk of death. In a
randomized controlled trial comparing a self-management
program (consisting of a 1-hour educational session in which
patients were given an educational booklet designed for lowliteracy patients and a digital scale, a personalized management plan centered on the patients ideal weight and modifications in dosage of diuretic medications, and scheduled
follow-up phone calls) with usual care among outpatients
with a diagnosis of heart failure, the intervention group had a
lower rate of hospitalization or death (adjusted incident rate
ratio [IRR] 0.52; 95% CI, 0.32-0.89).

Toward the era of integrated care and disease


management programs
All of the above quality-of-care strategies have been accepted to be useful tools that by themselves can have an impact
on patient outcomes, but this raises questions about which

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one would provide better outcomes, or to which one we


should pool our efforts. Disease management programs have
emerged in the past decade as a potential strategy to enhance the quality of care received by patients suffering from
chronic conditions by bringing together some of the above
components. It can not only increase the quality of care, the
adherence to guidelines and care protocols, and the access
to health services, but it can also be an effective way of improving the efficiency of health care services delivery by maintaining or improving quality while reducing costs.
Evidence regarding the characteristics and effectiveness of
various interventions often used in disease management programs has been published. Provider-centered components,
such as education and feedback, all of which can help to increase adherence to guidelines, as well as patient-centered
components, such as reminders and financial incentives, have
been associated with improvements in patient disease control.32 Moreover, a meta-analysis including 11 randomized clinical trials showed that disease management programs were
cost effective and patients cared for by these were more likely to undergo fewer hospitalizations.33
The American Heart Association recommends a series of
principles for guiding the development, implementation, and
evaluation of disease management strategies.34 First, the main
goal of disease management should be to improve the quality of care and patient outcomes, and should not be solely
based on their efficacy in reducing health care expenditures.
Second, these programs should be founded on scientifically

based guidelines, focusing on encouraging patients and caregivers to follow treatment plans based on the best available
evidence. Third, scientifically derived evaluations and consensus-driven performance measures should be included as
a crucial component of any disease management program,
to maximize benefit and facilitate its own refinement. Fourth,
these strategies should support and enhance the patientprovider relationship within an integrated and comprehensive
system of care. And lastly, these programs should address
potential handicaps, which include the complexity of medical
comorbidities, the challenges of the underserved and vulnerable populations, and the potential conflicts of interest of the
organizations involved.
A related and often inadvertently overlooked tool for improving quality of care and patient outcomes lies in providing our
health professionals with the best available information on
how to do so. In this regard, continuing medical education
and promotional education programs can help us maintain
competence and learn about old and new strategies in the
developing field of quality of care. Some studies suggest that
these kinds of activities can help improve physician performance, especially in resource utilization, counseling strategies,
and preventive medicine, and can have a positive impact on
patient health care outcomes.24
Although these programs are promising, there is a need for
testing and demonstrating best practices and for sharing information on successful components across a wide range of
scenarios and a variety of care settings. n

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disease management: principles and recommendations from the American
Heart Associations Expert Panel on Disease Management. Circulation. 2004;
109(21):2651-2654.

Keywords: heart failure, hospitalization, readmission, mortality, quality of care

IMPACT

DES INITIATIVES D AMLIORATION DE LA QUALIT DES SOINS


CHEZ LES PATIENTS HOSPITALISS POUR INSUFFISANCE CARDIAQUE

En Occident, linsuffisance cardiaque prend la forme dune pidmie svre aux cots importants gnrs en majeure partie par lhospitalisation. De nombreuses techniques damlioration de la qualit des soins peuvent tre mises
en uvre pendant ou aprs lhospitalisation pour optimiser les rsultats et diminuer les taux de radmission. Au sein
de lhpital, les stratgies utilises sont des protocoles de prise en charge bass sur les recommandations de pratique clinique, lutilisation de listes de points vrifier ainsi que des mthodes en cours dlaboration sur le retour
dinformation fait aux mdecins au sujet des soins dlivrs et des rsultats. la sortie de lhpital, plusieurs mesures
de suivi peuvent tre prvues. Les patients qui sont vus prcocement aprs lhospitalisation ont de meilleurs rsultats et sont moins rhospitaliss, dautant moins si le suivi est fait par un mdecin connu et partag entre le cardiologue et le mdecin traitant. ct du suivi mdical de routine, dautres mthodes efficaces comprennent lorientation vers lhpital de jour ou les tablissements spcialiss pour insuffisants cardiaques, le soutien tlphonique
structur ou la tlsurveillance de ltat de sant du patient par le biais de la tlmdecine sous diffrentes formes
et enfin, mais non des moindres, la responsabilisation du patient par des activits auto-thrapeutiques qui aident
au maintien dune stabilit physiologique. Toutes ces mthodes peuvent tre mises en place au sein de programmes
de prise en charge de la maladie dont le but est damliorer la qualit des soins et le suivi des patients tout en diminuant les dpenses de sant.

Quality improvement initiatives in heart failure Zamorano and Lozano

MEDICOGRAPHIA, Vol 37, No. 2, 2015

169

THE QUESTION
espite increasing evidence
on existing biomarkers and
constant discovery of new
biomarkers, their actual usefulness
in heart failure is not yet clear. Currently, they are mainly used to improve diagnostic performance or
for risk stratification and to determine prognosis. However, the value of biomarkers in daily practice
is less well described and surprisingly few data are available regarding their usefulness in clinical assessment and choice of therapy for
patients after hospital discharge.

CONTROVERSIAL

QUESTION

Can biomarkers guide the


assessment and management
of heart failure patients after
discharge from hospitals?

1.

E. A. Bocchi, Brazil

2.

D. A. Brito, Portugal

3.

O. Chioncel, Romania

4.

A. Fong, Malaysia

5.

M. Hlsmann, Austria

6.

E. A. Jankowska, Poland

7.

M. Loutfi, Egypt

8.

A. Lupi, Italy

9.

Y. F. M. Nosir, Egypt

10 .

E. B. Reyes, Philippines

11.

S. N. Tereschenko, Russia

12 .

M. B. Yilmaz, Turkey

13 .

B. Yoo, Republic of Korea

Biomarkerspostdischarge assessment and management of heart failure patients

MEDICOGRAPHIA, Vol 37, No. 2, 2015

171

CONTROVERSIAL

QUESTION

1. E. A. Bocchi, Brazil
Edimar Alcides BOCCHI, MD, PhD
Associate Professor, Head of the Heart
Failure Department and Heart Failure Team
at InCor (So Paulo)
So Paulo University Medical School
SHIFT National Coordinator
Rua Dr Melo Alves 690, apto 41, So Paulo
BRAZIL CEP 01417-010
(e-mail: dcledimar@incor.usp.br)

pidemiological data have shown 39.4% of total hospital admissions to be related to decompensated heart
failure (HF).1 Despite improvement during in-hospital
treatment, HF patients frequently present with severe events
after hospital discharge. It has been reported that over a period of 4.71.6 months, 36% of discharged decompensated
HF patients were readmitted.2 In the EVEREST trial (Efficacy
of Vasopressin antagonism in hEart failuRE: outcome Study
with Tolvaptan), of all rehospitalizations, 46.3% were for HF.
This immediate postdischarge risk period has been termed
the vulnerable phase of HF.
Early readmission of discharged patients with HF is challenging to predict. The focus has been primarily on quality improvement measures to assure patient education, checklist
discharge, physician adherence to evidence-based HF medications, follow-up appointments within 7 to 14 days of discharge and/or telephone follow-up within 3 days of discharge,
and use of clinical risk-prediction tools and/or biomarkers to
identify higher-risk patients.3

It is important to recognize that many patients after discharge


may be flying under the radar, without clinical congestion,
but with elevated left ventricular filling pressures or comorbidities leading to a high risk of hospital readmission. Aside
from residual clinical impairment with persistent signs and
symptoms of congestion, biomarkers have been examined
as potential predictors for HF readmission. Measurement of
circulating natriuretic peptide (NP) levels seems to add incremental prognostic information to standard clinical risk stratification algorithms for both ambulatory and hospitalized HF
patients, with a steady increase in the risk of mortality and recurrent HF hospitalization in relation to increment in NP levels.

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

Despite the widespread use of B-type NP (BNP) assays for diagnosis of HF, there remains a lack of well-defined and accepted diagnostic and prognostic cutoff values. Additionally,
elevations in NP levels can occur as a result of several cardiac
and noncardiac disease states, making the negative predictive value of the test most clinically helpful.
A plethora of candidate biomarkers now exist that reflect different aspects of HF pathology, with theoretical roles in diagnosis, risk assessment, and therapeutic tailoring, but data is
still required from testing within clinical trials. Serum sodium,
BNP levels, net reduction in N-terminal proBNP at discharge,
creatinine, albumin, hemoglobin, C-reactive protein, troponin,
systolic blood pressure, and heart rate seem to be predictive
of 30-day readmission for HF.4 In the EVEREST trial, heart rate
values 70 beats per minute (bpm) measured at either 1 or 4
weeks after discharge were independently associated with
all-cause mortality, with a 13% increase in risk of death for
every 5-beat increase in heart rate ( P=0.002) measured at
1 week or 12% for such increase in heart rate ( P=0.001) measured at 4 weeks. A discharge heart rate greater than 80 bpm
was associated with greater risk of all-cause mortality during
1 year of follow-up and an elevated risk of 30-day readmission for HF.5 Reducing heart rate with ivabradine is beneficial
in chronic HF, decreasing hospitalization and HF mortality.6

References
1. Bocchi EA, Guimares G, Tarasoutshi F, Spina G, Mangini S, Bacal F. Cardiomyopathy, adult valve disease and heart failure in South America. Heart. 2008;95:
181-189.
2. Bocchi EA, Vilas-Boas F, Moreira Mda C, et al. Levosimendan in decompensated heart failure patients: efficacy in a Brazilian cohort. Results of the BELIEF study.
Arq Bras Cardiol. 2008;90:182-190.
3. Bocchi EA, Cruz F, Guimares G, et al. Long-term prospective, randomized, controlled study using repetitive education at six-month intervals and monitoring for
adherence in heart failure outpatients: the REMADHE trial. Circ Heart Fail. 2008;
1:115-124.
4. Dunlay SM, Gheorghiade M, Reid KJ, et al. Critical elements of clinical follow-up
after hospital discharge for heart failure: insights from the EVEREST trial. Eur J
Heart Fail. 2010;12:367-374.
5. Habal MV, Liu PP, Austin PC, et al. Association of heart rate at hospital discharge
with mortality and hospitalizations in patients with heart failure. Circ Heart Fail.
2014;7:12-20.
6. Swedberg K, Komajda M, Bhm M, et al; SHIFT Investigators. Ivabradine and
outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
Lancet. 2010;376:875-885.

Biomarkerspostdischarge assessment and management of heart failure patients

CONTROVERSIAL

QUESTION

2. D. A. Brito, Portugal
Dulce Alves BRITO, MD, PhD, FESC
Professor, Department of Cardiology
Hospital Universitrio de Santa Maria
Lisbon Academic Medical Centre, CCUL
Av. Prof. Egas Moniz
1649-035 Lisboa
PORTUGAL
(e-mail: dulcebrito@spc.pt)

ost studies on biomarkers in heart failure (HF) report


their prognostic value, but their use in clinical practice is not well established and should be based
on clinical outcomes. Hospitalized HF patients have high postdischarge mortality and rehospitalization rates even when
treated with evidence-based therapies and early postdischarge
follow-up.1 The first 2 months after discharge are a particularly vulnerable period, with mortality and readmission rates
approaching 15% and 30%, respectively, 30 to 60 days postdischarge; 1 in 4 patients are readmitted within 30 days.2 Recurrent HF and related cardiovascular conditions account for
about half of readmissions and, overall, postdischarge readmission and mortality rates for HF remain similar whether ejection fraction (EF) is reduced or preserved. Measures to prevent
early readmission or death must begin during hospitalization
and extend through the early recovery period to reduce the
risk of adverse events.

Some biomarkers, including low serum sodium and high aldosterone and natriuretic peptide (NP) levels, at admission and
soon after discharge, help to predict early (within 90 days) readmission and death and to identify a subset of higher-risk
patients that may benefit from specific targeted therapies.3
Congestion is the single most important contributor to readmission and a crucial target for therapy. Subclinical congestion
(elevated left ventricular [LV] filling pressures in the absence
of clinical manifestations) may precede clinical congestion by
days to weeks or be present at discharge. Of the HF biomarkers, the B-type NPsBNP and N-terminal proBNPhave
been studied most. High levels of NPs at discharge reflect elevated LV filling pressures and correlate with readmissions
in the early postdischarge period.3 NPs are thus useful as a
marker for persistent congestion demanding further investigation and changes in diuretic dosing strategies.
Nevertheless, the role of NP levels in routine long-term HF
monitoring is still under debate, though meta-analysis of published data suggests that NP-guided treatment as compared
with intensive clinical management alone may indeed translate into better outcomes. In chronic HF patients (mainly with
reduced EF) receiving optimized pharmacologic HF therapy,
NP-guided treatment was associated with a significant and

consistent benefit in HF-related hospitalization, the main morbidity outcome in HF patients across all age groups.4 A mortality benefit was also observed, but was confined to younger
patients (<75 years of age).4
Overall, published studies tell us that individual tailoring of
therapy in chronic HF, guided by NP measurements, allows
better adjustment of recommended doses of drugs already
proven to favorably affect prognosis. However, close followup by trained HF practitioners able to interpret, integrate, and
react to peptide levels in the overall clinical contextparticularly in the older (and more vulnerable) patientmay itself
promote optimization of proven therapies and prevention of
adverse outcomes, independently of biomarker use to guide
HF therapy in the long term.5
Although NPs are the most extensively studied biomarkers
in HF, several others provide important insights into different
aspects of the pathophysiology of the syndrome. These others may provide additional prognostic information to that afforded by NPs and may also play a role in guiding treatment
and be useful for therapy selection.6 Galectin-3 (Gal-3), a fibrosis biomarker, is one example, potentially allowing the identification of HF patients who may benefit from specific therapies. Although not yet proven, mineralocorticoid receptor
antagonists (MRAs) may confer a greater benefit in HF patients with raised Gal-3 levels than in those with lower levels.
MRAs favorably affect prognosis in HF, in both the long and
short term, significantly reducing the early readmission rate
for HF.
The evaluation of multimarker strategies to guide therapy or
to provide a comprehensive understanding of how to select
therapy would certainly contribute toward better outcomes
in HF patients.
References
1. Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization
for heart failure: problems and perspectives. J Am Coll Cardiol. 2013;61:391403.
2. Epstein AM, Jha AK, Orav EJ. The relationship between hospital admission rates
and rehospitalizations. N Engl J Med. 2011;365:2287-2295.
3. Gheorghiade M, Pang PS, Ambrosy AP, et al. A comprehensive, longitudinal description of the in-hospital and post-discharge clinical, laboratory, and neurohormonal course of patients with heart failure who die or are re-hospitalized within 90 days: analysis from the EVEREST trial. Heart Fail Rev. 2012;17:485-509.
4. Troughton RW, Frampton CM, Brunner-La Rocca HP, 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;35:15591567.
5. Schlendorf KH, Kasper EK. Use of novel and conventional biomarkers for management of patients with heart failure. See comment in PubMed Commons. Curr
Treat Options Cardiovasc Med. 2011;13:475-488.
6. Schmitter D, Cotter G, Voors AA. Clinical use of novel biomarkers in heart failure:
towards personalized medicine. Heart Fail Rev. 2014;19:369-381.

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173

CONTROVERSIAL

QUESTION

3. O. Chioncel, Romania
Ovidiu CHIONCEL, MD, PhD
University of Medicine Carol Davila
Institute of Emergency for Cardiovascular
Diseases C.C. Iliescu, Bucharest
ROMANIA
(e-mail: ochioncel@yahoo.co.uk)

ollowing hospitalization for heart failure (HF), patients are


at a significantly increased risk for adverse outcomes,
with mortality rates as high as 10% to 15% and rehospitalization rates up to 30% 3 months after discharge.1 Identifying high-risk patients following hospitalization is essential,
given the opportunity to aggressively treat these patients and
to improve their outcomes.

Biomarkers may help identify patients at increased risk for


postdischarge adverse outcomes, and monitoring serial values in the outpatient setting may allow for early intervention
aimed at reducing deaths and readmissions. Natriuretic peptides (NPs)B-type NP and its N-terminal prohormone
are the most commonly used biomarkers with the potential
to guide therapy. Plasma NP concentrations reflect cardiac
structure and function and are prognostic in both acute and
chronic HF.2 NP variations generally parallel responses to antiHF therapies, and increasing concentrations are associated
with poorer outcomes.2 Using NP levels to guide therapy is
attractive, as it offers the possibility to individualize therapy
according to an objective measure of function and risk. This
strategy targets patients with high NP levels, at higher risk for
adverse events, to receive higher doses of medications
proven to increase survival.2
The concept of NPguided HF therapy has been examined in
recent trials.3-5 A majority of enrolled patients had a left ventricular ejection fraction (LVEF) under 45%, and patients with
significant comorbidities were excluded. Although the trial results suggest a potential benefit in the NP-guidedtherapy
arm, improving all-cause mortality and decreasing HF-related
readmissions, NP-guided care was ineffective in preventing
noncardiovascular readmissions.3,4 The target-peptide concentrations, the time point of measurement, and the aggressiveness of therapy adjustment, which varied substantially
across the trials, could contribute to the presence or absence
of a benefit. Current trial data have shown the benefit of NPguided therapy to be confined to patients under 75 years old.
However, with increasing age, a higher proportion of patients
with HF will have a preserved LVEF (HFPEF) and multiple associated comorbidities. Although the latest published metaanalysis6 did not report an interaction with LVEF, it should
be noted that only 10% of the patients had HFPEF at study

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enrollment. HFPEF has no pharmacotherapy proven to improve mortality rates and increasing doses of drugs that are
ineffective is probably harmful. Although NP-guided therapy
facilitates optimization of treatment and improves mortality
and HF-related readmissions in selected patients, there are no
convincing data to suggest that routine NP-guided therapy
should be applied to all HF patients. Serial changes in NPs
should be interpreted within the entire clinical context, including age, presence of comorbidities, and accounting for intrinsic biologic variability. Though well tolerated in the trial population, without excess risk of adverse outcomes related to
therapy intensification,3,5 safety of NP-guided care should be
considered in the broad HF population. NP-guided care appears to be cost effective by reducing HF hospitalization,7 but
that should be confirmed in different health care systems.
Future research will be needed to clarify the type and magnitude of therapeutic response to the release of biomarkers.
Most importantly, what should be done once patients at highest risk for postdischarge adverse events are identified? All
advocated interventionsintensification of oral therapies, addition of intravenous medications, follow-up visitsare generic measures, and no supporting evidence has demonstrated
any specific intervention to be more effective in lowering target NP levels. Secondly, what would be the most appropriate approach if NPs fail to decrease following intensification
of therapy? Thirdly, despite decreasing NP levels, some patients may have other elements of high risk such as high troponin or high cystatin C.
In HF, a single biomarker reflects only one pathophysiological
pathway. A multimarker panel investigating multiple pathological processes and probing therapeutic options would be
an ideal strategy, but will need further investigation.
References
1. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol.
2009;53:557-573.
2. Richards AM, Troughton RW. Use of natriuretic peptides to guide and monitor
heart failure therapy. Clin Chem. 2012;58:62-71.
3. Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided heart failure
therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With
Congestive Heart Failure (TIME-CHF) randomized trial. JAMA. 2009;301:383-392.
4. Eurlings LW, van Pol PE, Kok WE, et al. Management of chronic heart failure
guided by individual N-terminal proB-type natriuretic peptide targets: results of
the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart
failure IMprove heart fAilure morbidity and mortality?) study. J Am Coll Cardiol.
2010;56:2090-2100.
5. Januzzi JL Jr, Rehman SU, Mohammed AA, et al. Use of amino-terminal proBtype natriuretic peptide to guide outpatient therapy of patients with chronic left
ventricular systolic dysfunction. J Am Coll Cardiol. 2011;58:1881-1889.
6. Troughton R, Frampton CM, Brunner-La Rocca HP, 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;35:1559-1567.
7. Adlbrecht C, Huelsmann M, Berger R, et al. Cost analysis and cost-effectiveness
of NT-proBNP-guided heart failure specialist care in addition to home-based nurse
care. Eur J Clin Invest. 2011;41:315-322.

Biomarkerspostdischarge assessment and management of heart failure patients

CONTROVERSIAL

QUESTION

4. A. Fong, Malaysia
ing strategy accordingly, thus adopting a more aggressive
strategy in those patients with the highest cardiac event risk
in the outpatient clinic setting.
Alan FONG, MD
Clinical Research Centre, Sarawak General
Hospital,
Jalan Hospital, 93586 Kuching, Sarawak
MALAYSIA
(e-mail: alanfong@crc.gov.my)

ven in the era of advanced therapeutics, hospital readmission rates for patients admitted with heart failure remain high. Approximately 22% of patients are readmitted within 30 days, and more than 50% are readmitted within
6 months.1,2 The cost of rehospitalization and the clinical morbidity associated with hospitalization generate demand for
strategies to improve the management of patients discharged
with heart failure. Heart failure clinics in the community have
already made a positive impact on improving patient outcomes,3 but with rising numbers of patients being hospitalized
with heart failure, quantifiable blood biomarkers are increasingly used to discriminate those at greatest risk of rehospitalization and cardiac death after discharge.
In the last decade, the principle biomarkers that have aided
clinical decision making in patients with heart failure were the
natriuretic peptides (NPs)B-type NP (BNP) and N-terminal
proBNP. In patients admitted with heart failure, NPs have been
shown to be useful in identification of those at highest risk for
rehospitalization.4,5 High NP levels, eg, a predischarge BNP
level >700 ng/L has been associated with a death or readmission rate of approximately 50% 30 days postdischarge and
roughly 80% at 6 months.
Conversely, a predischarge BNP level <350 ng/L was associated with a death or readmission rate of less than 5% 30
days postdischarge and <20% at 6 months. As NPs reflect
the physiological status associated with myocardial strain,
this information can enable clinicians to adapt the monitor-

NPs can now be reliably measured using validated point-ofcare devices. These can be placed in hospital wards or in the
clinics, allowing the health care professional to obtain a timely
result so that a management strategy can be more carefully
constructed. In addition to the predischarge NP reading, serial monitoring of NPs provides clinicians with a biochemical
monitoring system facilitating titration of treatment for heart
failure patients. In this way, treatment can be optimized before
patients experience decompensation and require subsequent
hospital admission. Extending this concept further, a homemonitoring program for natriuretic testing is now under investigation, although pilot studies showing encouraging results are already available.6
Of all blood biomarkers in clinical practice, the positive role of
NP assessment in patients with heart failure is now clearly defined. The additional information it provides to both the health
care provider and the patient empowers all parties to optimize
the postdischarge management of heart failure patients.
References
1. Krumholz HM, Merrill AR, Schone EM, et al. Patterns of hospital performance in
acute myocardial infarction and heart failure 30-day mortality and readmission.
Circ Cardiovasc Qual Outcomes. 2009;2:407-413.
2. Chun S, Tu JV, Wijeysundera HC, et al. Lifetime analysis of hospitalizations and
survival of patients newly admitted with heart failure. Circ Heart Fail. 2012;5(4):
414-421.
3. Ducharme A, Doyon O, White M, Rouleau JL, Brophy JM. Impact of care at a multidisciplinary congestive heart failure clinic: a randomized trial. CMAJ. 2005;173
(1):40-45.
4. Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type natriuretic peptide
assay for identifying patients at high risk of re-admission after decompensated
heart failure. J Am Coll Cardiol. 2004;43(4):635-641.
5. Salah K, Kok WE, Eurlings LW, et al. A novel discharge risk model for patients hospitalised for acute decompensated heart failure incorporating N-terminal proB-type natriuretic peptide levels: a European coLlaboration on Acute decompeNsated Heart Failure: ELAN-HF Score. Heart. 2014;100(2):115-125.
6. Maisel A, Barnard D, Jaski B, et al. Primary results of the HABIT Trial (heart failure
assessment with BNP in the home). J Am Coll Cardiol. 2013;61(16):1726-1735.

Biomarkerspostdischarge assessment and management of heart failure patients

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175

CONTROVERSIAL

QUESTION

www.mediendienst.com/Foto Wilke

5. M. Hlsmann, Austria
Martin HLSMANN, MD
Univ-Dozent, Medical University of Vienna
Department of Cardiology
Whringer Grtel 18-20
A-1090 Vienna
AUSTRIA
(e-mail: martin.huelsmann@meduniwien.ac.at)

atients admitted for decompensation are very heterogeneous in respect to underlying cause and to severity of disease. More importantly, in-hospital treatment
success is a prerequisite of postdischarge outcome. Therefore, risk assessment at discharge is necessary for decision
making in the vulnerable phase afterwards. In a time of limited economic resources, there are competing interests between care of high- and low-risk patients. Relatedly, length of
hospital stay (LOS), which differs up to threefold between various countries, has already become an end point marker of
treatment.1
Currently, LOS correlates neither with the severity of heart failurereflected by N-terminal proB-type natriuretic peptide
(NT-proBNP) at entrancenor with postdischarge outcome,
implying that the time of discharge might be more influenced
by cost effectiveness than evidence. Thus, there is an imminent need to change LOS policy. NT-proBNP is an excellent
surrogate for treatment success, especially in acute heart failure. Bettencourt and colleagues2 proved that NT-proBNP level over time is the most favorable variable to detect treatment
success. Compared with a >30% decrease in NT-proBNP
during hospital stay, there is a 6-fold increase in worse outcome if NT-proBNP increases more than 30%. These results
show the importance of using NT-proBNP monitoring to guide
treatment and, consecutively, hospital stay. If there is no significant decrease in NT-proBNP following intervention, treatment should be scrutinized as to the expense of hospital stay.
On the other hand, a rapid decrease in NT-proBNP level allows a safe and rapid discharge. Consequently, an uncritical
discharge policy influences postdischarge outcome and decreases the cost effectiveness of care, something that can be
optimized by a biomarker-guided approach.

Predischarge stability can directly affect postdischarge management. After discharge, there is a need for optimization of
oral therapy, which has to be done during postdischarge care.
A multidisciplinary approach during this period could be attractive.3 Such an approach would include, in particular, an
educational program, aside from intensified collaborative care
by nurses and doctors. Just after discharge, patients and their

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families are open to self-care education, hoping to avoid rehospitalization. Data on the effectiveness of such programs
are conflicting and appear to depend on duration of the program and severity of the disease. Predischarge NT-proBNP
is directly correlated with postdischarge outcome.2 Thus, preselection of patients according to NT-proBNP level might be
useful in this context, to identify those patients most likely to
gain the greatest benefit. Biomarker-guided therapy is shown
to be effective in various settings.4 Some studies did not prove
efficacy, but meta-analysis was very noisy. Thus, data from an
ongoing large, randomized trial by Felker et al (NCT01685840)
are awaited for final answers. One of those studies combined
a multidisciplinary approach and guided therapy in patients
following discharge.5 The investigator used NT-proBNP at discharge as a selection parameter to identify high-risk patients
and used it to guide intensity of care and treatment during the
following vulnerable phase. Depending on the NT-proBNP
level, measured at discharge and over time, consultations by
the nurse and by the heart failure specialist were initiated if
the level remained elevated or, in the event of a low level at
discharge, reduced. This strategy significantly reduced event
rates compared with controls and with pure multidisciplinary care, but also had cost-saving effects despite increasing
numbers of consultations and drug prescriptions.6 It appears
that such a risk-selected treatment approach matches the
right intervention to the right patient, thus avoiding under- and
overtreatment.
In conclusion, NT-proBNP levels indicate the right moment
for discharge following decompensation, which is crucial to further disease management. Furthermore, treatment guided by
NT-proBNP levels can ensure the patient receives an appropriate intensity of care, which might save lives and money.

References
1. Mentz RJ, Cotter G, Cleland JG, Stevens SR, et al. International differences in
clinical characteristics, management, and outcomes in acute heart failure patients: better short-term outcomes in patients enrolled in Eastern Europe and
Russia in the PROTECT trial. Eur J Heart Fail. 2014;16(6):614-624.
2. Bettencourt P, Azevedo A, Pimenta J, et al. N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation. 2004;110(15):2168-2174.
3. Sochalski J, Jaarsma T, Krumholz HM, et al. What works in chronic care management: the case of heart failure. Health Aff (Millwood). 2009;28(1):179-189.
4. Felker GM, Hasselblad V, Hernandez AF, O'Connor CM. Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials. Am
Heart J. 2009;158(3):422-430.
5. Berger R, Moertl D, Peter S, et al. N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic
heart failure: a 3-arm, prospective, randomized pilot study. J Am Coll Cardiol.
2010;55(7):645-653.
6. Adlbrecht C, Huelsmann M, Berger R, et al. Cost analysis and cost-effectiveness
of NT-proBNP-guided heart failure specialist care in addition to home-based nurse
care. Eur J Clin Invest. 2011;41(3):315-322.

Biomarkerspostdischarge assessment and management of heart failure patients

CONTROVERSIAL

QUESTION

6. E. A. Jankowska, Poland
Ewa Anita JANKOWSKA, MD, PhD, FESC
Laboratory of Applied Research on
Cardiovascular System, Department of
Heart Diseases, Wroclaw Medical University
and
Cardiology Department, Centre for
Heart Diseases, Military Hospital
Weigla 5, 50-981 Wroclaw
POLAND
(e-mail: ewa.jankowska@umed.wroc.pl)

ecurrent hospitalization among patients with heart failure (HF) is unanimously considered the clinically crucial
issue in both cardiovascular and general medicine today. Recent years have seen numerous attempts to develop optimally targeted treatment strategies aiming to relieve
symptoms and improve in-hospital and long-term prognosis.
Unfortunately, most have failed, providing no breakthrough in
the management of acute HF.
Despite optimal treatment with life-saving drugs and devices,
on discharge from hospitalization for circulatory decompensation, HF patients have an extremely high cardiovascular risk
and are characterized by an enormous risk of recurrent hospitalization due to HF progression. Most importantly, the history of HF and related prognosis in these patients is very heterogeneous, and available diagnostic tools are imperfect with
regard to precise individualized risk stratification.
Therefore, biomarkers have been put forward as potential additional, measurable (objective) indicators of clinical status and
its dynamic changes in patients with acute HF.1,2 In this context,
a comprehensive assessment (comprising clinical features
and a set of biomarkers) performed after preliminary circulatory stabilization and directly before discharge is a particularly attractive concept.

For the last 20 years, biomarker research has garnered a huge


amount of attention.1,2 The vast majority of related publications
have concerned different aspects of the potential clinical applicability of various biomarkers in HF patients, including the
natriuretic peptides (NPs) and numerous others.1,2 Along with
the many publications in this field, a huge amount of scientific
data on biomarkers in acute HF has been generated. Several
biomarkers were shown to be related to HF severity and to
predict short- and long-term outcomes; however, most of
these papers provided no unequivocal and practically applicable evidence. Although the concept of the biomarker-guided diagnosis and treatment of patients with HF has been theoretically proposed, particularly for acute HF, there is as yet
no hard evidence that any classical biomarker (including the
NPs) can be used to guide future therapeutic decisions.

On the other hand, biomarkers allow diagnosis of some comorbidities. According to the European Society of Cardiology
guidelines, active screening for comorbidities and their optimal treatment is crucial for patients with HF and could constitute an element of a comprehensive assessment before
postdecompensation discharge. For example, biomarkers of
iron status allow diagnosis of iron deficiency (ID) and identify
those who can be effectively supplemented. Of acute HF patients, 37% have ID, which unfavorably affects their 12-month
survival3 and could constitute a potential therapeutic target.
Notably, the definition of a biomarker is somewhat open. For
example, consider the following 2 approaches. According to
the traditional, strict definition, a biomarker is a molecule measured in various samples (blood, urine, etc), which provides
a certain specificity and sensitivity for the diagnosis of any
pathology and/or for the prediction of a particular event, success/failure in therapy, etc. However, from a broader perspective, a biomarker can be considered a measure of any quantifiable biological signal/sign.
In this context, a measure of body weight, blood pressure, or
heart rate during circulatory decompensation, at discharge,
and during follow-up potentially offers prognostic information, but could also be considered a therapeutic target. The
prime example here could be resting heart rate. In a study
of patients hospitalized for HF with a left ventricular ejection
fraction 40% and who are not in atrial fibrillation/flutter or
pacemaker dependent (participants of the EVEREST trial [Efficacy of Vasopressin antagonism in hEart failuRE: outcome
Study with Tolvaptan]), an increase in heart rate 70 beats
per min in both 1- and 4-week postdischarge assessment
was associated with increased all-cause mortality.4 In order
to reverse this unfavorable phenomenon in such patients, it
seems reasonable to consider pharmacological treatment to
reduce resting heart rate during the early postdischarge phase
using a -blocker and/or ivabradine.

References
1. Troughton R, Michael Felker G, Januzzi JL Jr. Natriuretic peptide-guided heart
failure management. Eur Heart J. 2014;35(1):16-24.
2. Ahmad T, Fiuzat M, Pencina MJ, et al. Charting a roadmap for heart failure biomarker studies. JACC Heart Fail. 2014;2(5):477-488.
3. Jankowska EA, Kasztura M, Sokolski M, et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients
at the highest risk of death after an episode of acute heart failure. Eur Heart J.
2014;35(36):2468-2476.
4. Greene SJ, Vaduganathan M, Wilcox JE, et al; EVEREST Trial Investigators. The
prognostic significance of heart rate in patients hospitalized for heart failure with
reduced ejection fraction in sinus rhythm: insights from the EVEREST (Efficacy
of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) trial.
JACC Heart Fail. 2013;1(6):488-496.

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QUESTION

7. M. Loutfi, Egypt
of serum CA125, a marker of congestion that indicates the degree of volume overload, have been documented in patients
with HF.6 Finally, the biomarker hs-CRP can be used to evaluate progression of HF, due to the inflammatory etiology of
the condition. Patients with acute HF and increased levels of
both hs-CRP and NT-proBNP had worse clinical outcomes.7

Mohamed LOUTFI, MD
Assistant Professor of Cardiology
Department of Cardiology
Faculty of Medicine
University of Alexandria
EGYPT
(e-mail: drmloutfi@gmail.com)

eart failure (HF) is a chronic disease associated with


a high symptom burden, and poor health status is
common.1 Cardiac biomarkers, which are objective,
reproducible, and accessible, are excellent adjuncts to physical examination and imaging studies in HF diagnosis and risk
stratification. With a high prevalence of comorbidities associated with HF, an integrated approach utilizing multiple biomarkers has shown promise in better risk stratification, prediction of mortality, and reduction in rehospitalizations, thus
lowering health care costs.
The number of biomarker studies in HF is exploding. Currently, among the available biomarkers, 5 could be used for assessment of HF prognosis, as single markers or clustered in
a panel: B-type natriuretic peptide (BNP), N-terminal proBNP,
(NT-proBNP), high-sensitivity cardiac troponin (hs-cTn), cystatin C, the tumor marker carbohydrate antigen 125 (CA125),
and high-sensitivity C-reactive protein (hs-CRP).

BNPs provide independent prognostic information regarding


estimated risk of disease progression, hospital readmission,
and mortality.2 Bayes-Genis et al reported that among patients
hospitalized with acute HF, those who experienced complications had a smaller percentage reduction in NT-proBNP
during admission.2 Apart from the BNPs, hs-cTn assays will
improve risk stratification in HF compared with conventional
Tn tests. In patients with decompensated HF, serial increases in TnI during the course of hospitalization were associated
with higher mortality than stable or decreasing TnI levels.3,4
Cystatin C, aside from its use in estimation of renal function,
could also be used as a cardiac marker, as it reflects extracellular matrix pathology of ventricles.5 Recently, increased levels

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It is possible that the combination of neurohumoral and inflammatory markers could provide a better strategy for risk stratification of patients with acute HF. Moreover, use of a single
biomarker reflects only 1 ongoing pathophysiological pathway.
The combination of biomarkers in a multimarker panel reflects
several ongoing pathological processes, providing an increasingly clearer risk profile for HF patients.
Biomarkers not only serve as traditional predictors of prognosis, they can also help to identify high-risk patients who need
closer monitoring and more aggressive therapy. An integrated approach utilizing multiple biomarkers has shown promise in predicting mortality, in risk stratification, and in reducing rehospitalizations, with subsequent improvement in the
effectiveness of HF therapy and patient outcomes.
References
1. Heidenreich PA, Spertus JA, Jones PG, et al. Health status identifies heart failure outpatients at risk for hospitalization or death. J Am Coll Cardiol. 2006;47:
752-756.
2. Bayes-Genis A, Santalo-Bel M, Zapico-Muniz E, et al. N-terminal probrain natriuretic peptide (NT-proBNP) in the emergency diagnosis and in-hospital monitoring of patients with dyspnoea and ventricular dysfunction. Eur J Heart Fail.
2004;6:301-308.
3. Xue Y, Clopton P, Peacock WF, Maisel AS. Serial changes in high-sensitive troponin I predict outcome in patients with decompensated heart failure. Eur J Heart
Fail. 2011;13:37-42.
4. Pascual-Figal DA, Manzano-Fernandez S, Boronat M, et al. Soluble ST2, highsensitivity troponin T- and N-terminal pro-B-type natriuretic peptide: complementary role for risk stratification in acutely decompensated heart failure. Eur J Heart
Fail. 2011;13:718-725.
5. Diez J. Altered degradation of extracellular matrix in myocardial remodelling: the
growing role of cathepsins and cystatins. Cardiovasc Res. 2010;87:591-592.
6. Nez F, Chorro FJ, Bod V, et al. Clinical utility of antigen carbohydrate125 in
heart failure. Heart Fail Rev. 2014;19(5):575-584.
7. Park JJ, Choi DJ, Yoon CH, et al. Prognostic value of C-reactive protein as an
inflammatory and N-terminal probrain natriuretic peptide as a neurohumoral marker in acute heart failure (from the Korean Heart Failure Registry). Am J Cardiol.
2014;113(3):511-517.

Biomarkerspostdischarge assessment and management of heart failure patients

CONTROVERSIAL

QUESTION

8. A. Lupi, Italy
Alessandro LUPI, MD, FSCAI
Chief of the Hospital Cath Lab
Maggiore della Carit University Hospital
Cso Mazzini 18, 28100 Novara,
ITALY
(e-mail: lupialessandro1@gmail.com)

eart failure (HF) is a clinically challenging syndrome,


with different etiologies according to patient age and
coexisting comorbidities. Such heterogeneity is associated with different HF stages, affecting patient prognosis
and therapeutic response.1 However, diagnosis and prognostic stratification based purely on clinical features has shown
limited accuracy, often accounting for suboptimal therapy and
high rates of hospital readmission and mortality. Thus, the efforts of clinical researchers have been polarized toward the
development of more reliable HF laboratory markers.
This research has profoundly benefited from increased knowledge in the pathophysiology of cardiac failure: myocyte derangement caused by oxidative stress, injury and apoptosis,
inflammation, neurohumoral upregulation, and excessive proliferation of the extracellular matrix are phenomena that can
all be tracked with a multitude of biomarkers. However, despite the recent hyperbolic increase in published studies on
HF biomarkers, their actual clinical usefulness is still unclear,
accounting for the need of convenient frameworks in which
these markers might be used in a cost-effective manner.2
Among the numerous biomarkers proposed for guiding therapeutic optimization and postdischarge management of HF
patients, only a few have been extensively studied and can
currently be assessed with reasonable practicality. B-type
natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are by-products of the myocardial endocrine secretion
of mediators in response to left ventricular dysfunction and
mechanical stress. Increased levels of NPs at discharge have
been associated with higher readmission rates for HF,3 thus
measurement of such markers after clinical resolution of HF
has been proposed for guidance of therapeutic optimization
before and after discharge.
Guided therapy was addressed by a few nonrandomized
studies that produced contrasting results. Moreover, these
studies did not present enough statistical power to detect
any significant difference in hard end points. To overcome
these limitations, these studies were pooled into 2 metaanalyses, which suggested a mortality reduction in patients
treated with NP-guided therapy (NP-GT),4,5 but no apparent
reduction in rehospitalization rates.5

These results cannot be directly translated into daily clinical


practice for several reasons. First of all, NP-GT studies preferentially enrolled patients with systolic dysfunction of ischemic origin, excluding HF cases with preserved ejection
fraction and nonischemic cardiomyopathies. Moreover, different NP goals influenced the final results of NP-GT studies,
with better outcomes in those aiming to lower NP levels. In
many patients, NP levels did not respond to NP-GT, generally
in subjects aged over 75 years. Actually, no randomized trial
with sufficient statistical power using NP guidance in acute HF
treatment has been published thus far and we currently do
not have firm evidence from prospectively-defined published
trials that the addition of NP-GT is beneficial.2 However, taking
all the evidence into account, the American Heart Association
(AHA)/American College of Cardiology (ACC) 2013 guidelines
placed NP-GT in class 2a with a level of evidence B.6 From
a practical point of view, it seems reasonable to routinely collect baseline and predischarge NP samples in hospitalized HF
patients, with those showing a <30% reduction in NP level from
baseline considered to be at higher risk of hospital readmission and thus treated with more aggressive management.2
Other available biomarkers, such as high-sensitivity C-reactive protein (hs-CRP), the tumor marker carbohydrate antigen
125 (CA125), and high-sensitivity cardiac troponins, are increased in HF patients, but their role in optimizing HF therapy
and guiding hospital discharge seems to be limited.
In conclusion, HF biomarkers could potentially guide therapy
in HF patients after hospital discharge on an outpatient basis,
but the few studies conducted in this area have conflicting results. A large, prospective, controlled study, statistically powered to look at hard end points such as mortality is warranted
before the scientific community can reach any consensus on
this approach.
References
1. von Scheidt W, Zugck C, Pauschinger M, et al. Characteristics, management
modalities and outcome in chronic systolic heart failure patients treated in tertiary care centers: results from the EVIdence based TreAtment in Heart Failure
(EVITA-HF) registry. Clin Res Cardiol. 2014;103:1006-1014.
2. Thygesen K, Mair J, Mueller C, et al. Recommendations for the use of natriuretic
peptides in acute cardiac care: a position statement from the Study Group on
Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care.
Eur Heart J. 2012;33:2001-2006.
3. Bettencourt P, Azevedo A, Pimenta J, Frioes F, Ferreira S, Ferreira A. N-terminalpro-brain natriuretic peptide predicts outcome after hospital discharge in heart
failure patients. Circulation. 2004;110:2168-2174.
4. Felker GM, Hasselblad V, Hernandez AF, OConnor CM. Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials. Am
Heart J. 2009;158:422-430.
5. Porapakkham P, Porapakkham P, Zimmet H, Billah B, Krum H. B-type natriuretic
peptide-guided heart failure therapy: a meta-analysis. Arch Intern Med. 2010;
170:507-514.
6. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll
Cardiol. 2013;62:e147-e239.

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179

CONTROVERSIAL

QUESTION

9. Y. F. M. Nosir, Egypt
60 to 74 years (400 pg/mL). Some significant clinical benefit was shown with biomarker-guided management, at least
in younger patients.4
Youssef Fathy Mohamed NOSIR
MD, MSc, PhD
Consultant Cardiologist KFAFH, Jeddah, KSA
Professor of Cardiology, Al-Azhar University
Cairo, EGYPT
(e-mail: ynosir@hotmail.com)

eart failure (HF) prevalence is increasing and remains


the leading cause of death worldwide, causing a significant burden on health care systems across the
globe. Currently, there is no reliable objective guide to optimal pharmacotherapy in HF. Despite clear treatment guidelines, target doses for medications are often not achieved.
Clinical assessment is insensitive and frequently does not identify hemodynamic decompensation.
Biomarkers, with their objectivity and widespread availability,
have a promising role in improving HF management. The natriuretic peptides (NPs) are the most widely used biomarkers
of myocardial strain. These include B-type NP (BNP) and the
N-terminal fragment of its prohormone (NT-proBNP), as well
as atrial NP (ANP), and the mid-regional fragment of its prohormone (MR-proANP), and adrenomedullin.1 Cardiac troponin (cTn) levels and their assays (cTnI vs cTnT) have also
been evaluated in ambulatory patients with stable coronary
artery disease (CAD).2 In many studies, there is a >10-fold increase in the proportion of subjects with detectable cTn levels when utilizing a high sensitivity (hs) assay.2 In randomized
controlled trials of statins and angiotensin-converting enzyme
inhibitors versus placebo, NPs consistently and independently identified subjects with increased risk. The same was
found true of cTnI and cTnT.2

The PRIMA study (Can PRo-brain-natriuretic peptide guided


therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?)5 looked at an individualized NT-proBNP
target in 345 patients who had been hospitalized with decompensated HF. The target NT-proBNP level was 1700 pg/mL.
Additionally, subjects had to achieve a >10% decrease and
at least a 850 pg/mL reduction in NT-proBNP during hospitalization. For the 174 subjects randomized to the NT-proBNPguided group, an individualized target NT-proBNP level
was identified based on the lowest NT-proBNP level obtained
at discharge or within 2 weeks after discharge. Uptitration of
treatment was triggered if the NT-proBNP level at scheduled
3-monthly visits was more than 10% and at least 850 pg/mL
above their individual baseline level. For the 171 subjects in
the comparator clinically guided group, treatment was uptitrated on the basis of standard clinical assessment. After a
median follow-up of 702 days, there was greater uptitration
of treatment in the NT-proBNPguided group at 1-year followup. The investigators observed fewer deaths in the NT-proBNPguided group, particularly in patients under 75 years of
age and in those with reduced ejection fraction below 45%.5,6
Currently available data showed usefulness of biomarkers in
HF management through achieving target dosage of medication with a trend in reducing mortality. Further data are needed from more robust, adequately powered trials before guidelines can confidently endorse a biomarker-guided strategy in
HF management.

References

Tailoring HF treatment to achieve a target level of BNP was


first tested in the late 1990s.3 Since then, a series of studies
using a variety of study designs have addressed this strategy.4 To date, there is little evidence to support using elevated
levels of either NPs or cTns to guide therapy. It may be that
no 1 biomarker fits all in this heterogeneous population with
known CAD.2 However, plasma levels of both peptides reflect
cardiac function and filling pressures and are powerful predictors of mortality.4
Serial peptide measurements provide incremental prognostic
value in both the in- and outpatient setting, with a fall in peptide levels being associated with better outcomes.4-6 In the
largest of these studies, TIMECHF (Trial of Intensified vs standard Medical therapy in Elderly patients with Congestive HF),
a higher NT-proBNP level was used as a target for subjects
over 75 years of age (800 pg/mL) compared with those ages

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1. Lenzen MJ, Boersma E, Reimer WJ, et al. Under-utilization of evidence-based


drug treatment in patients with heart failure is only partially explained by dissimilarity to patients enrolled in landmark trials: a report from the Euro Heart Survey on Heart Failure. Eur Heart J. 2005;26:2706-2713.
2. Beatty AL, Ku IA, Christenson RH, DeFilippi CR, Schiller NB, Whooley MA. Highsensitivity cardiac troponin T levels and secondary events in outpatients with coronary heart disease from the Heart and Soul Study. JAMA Intern Med. 2013;173:
763-769.
3. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards
AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic
peptide (N-BNP) concentrations. Lancet. 2000;355:1126-1130.
4. Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided heart failure
therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients
With Congestive Heart Failure (TIMECHF) randomized trial. JAMA. 2009;301:
383-392.
5. Eurlings LW, van Pol PE, Kok WE, et al. Management of chronic heart failure
guided by individual N-terminal proB-type natriuretic peptide targets: results of
the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart
failure IMprove heart fAilure morbidity and mortality?) study. J Am Coll Cardiol.
2010;56:2090-2100.
6. Rogers RK, Stoddard GJ, Greene T, et al. Usefulness of adjusting for clinical covariates to improve the ability of B-type natriuretic peptide to distinguish cardiac
from noncardiac dyspnea. Am J Cardiol. 2009;104:689-694.

Biomarkerspostdischarge assessment and management of heart failure patients

CONTROVERSIAL

QUESTION

10. E. B. Reyes, Philippines


Eugenio Borja REYES, MD
Associate Professor
Department of Medicine
University of the Philippines College
of Medicine
Taft Avenue, Manila, 1000
PHILIPPINES
(e-mail: eugenereyes@yahoo.com)

eart failure (HF) is a syndrome with a wide spectrum


of clinical manifestations: from asymptomatic to fullblown congestive failure; from normal ejection fraction (EF), ie, HF with preserved EF (HFPEF), to very low EF, ie,
heart failure with reduced EF (HFREF); from acute onset to
gradual onset and chronic conditions. Etiologies and comorbidities are also diverse, and there can be puzzling differences in response to therapies.
At the end of the spectrum is severe symptomatic systolic
HF, which is quite easy to diagnose and prognosticate, with
clinical assessment as a key basis for choosing diagnostics
and treatment. However, gray zones are found in mild disease (New York Heart Association functional classes I or II), in
HFPEF, and in treated patients who have stabilized and are
feeling better after discharge.1
Left ventricular EF (LVEF), is a useful parameter in assessing
LV pump performance, especially now that echocardiography
is readily accessible. When LVEF is reduced (<45%), it is a
powerful and useful prognostic and monitoring parameter.1
However, LVEF plateaus over time and has limited utility in
HFPEF.
In the last 2 decades, an explosion in research paved the way
to the use of biomarkers as clinical guidance in the management for HFan example of knowledge translation from clinical evidence to patient careto close the gap emanating from
the limitations of using pure clinical assessment in making
therapeutic decisions.2 One such gap is the low utilization of
guideline-directed therapy to optimize patient care, which may
be due to low awareness or competence in applying such
therapy.
Biomarkers for HF include markers for myocyte stretch (eg, Btype natriuretic peptide [BNP] and atrial NP), myocyte remodeling (eg, ST2 protein and galactin), inflammation (eg, interleukin 6 and Fas), neurohormonal activation (eg, endothelin),
and comorbidities (eg, procalcitonin for infection, and neutrophil gelatinase-associated lipocalin for kidney failure).2 All

of these are elevated in clinical HF and can define the presence of HF or other diseases that may mimic HF. The best
studied markers are BNP and N-terminal proBNP.
There are at least 11 randomized controlled studies that compared NP-guided therapy vs therapy guided by pure clinical
assessment.3 The studies were all small (ranging from 69 to
499 included patients) and results of individual trials, though
positive, were not convincing. A meta-analysis showed that
the hazard ratio for total mortality was 0.82 (95% confidence
interval [CI], 0.62-1.00), with the CI touching the line of unity.
However, the hazard ratio for rehospitalization was reduced
significantly by 26% (0.74; 95% CI, 0.60-0.90). This reduction
could be attributed to a 7% absolute increase in the proportion
of patients who received target doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (41%
vs 34%), a 2% increase in those that received target-dose
aldosterone antagonists (28% vs 26%), and no difference for
-blockers (19% vs 19%) and loop diuretics in patients under
NP-guided treatment.3
Clearly, biomarker-guided therapy in HF is possible, but the
findings from randomized trials are not convincing enough to
recommend its routine use. Its weakness lies in the fact that
it does not tell you which medications to adjust and so we go
back to clinical assessment. Furthermore, NP testing is costly and target levels and frequency of testing have not been
standardized. The latest guidelines on HF recommend the
use of biomarkers for risk stratification. The recommendations
on the use of biomarkers as a guide in maximizing medical
therapy are weak, but do not prohibit physicians from using
them as guides.4,5 A large randomized trial is needed to address this gap.
References
1. De Keulenaer GW, Brutsaert DL. The heart failure spectrum: time for a phenotype-oriented approach. Circulation. 2009;119(24):3044-3046.
2. Iqbal N, Wentworth B, Choudhary R, et al. Cardiac biomarkers: new tools for heart
failure management. Cardiovasc Diagn Ther. 2012;2(2):147-164.
3. Troughton RW, Frampton CM, Brunner-La Rocca HP, 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(23):
1559-1567.
4. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/
AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.
5. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Committee for Practice
Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic
heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and
Chronic Heart Failure 2012 of the European Society of Cardiology. Eur Heart J.
2012;33:1787-1847.

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181

CONTROVERSIAL

QUESTION

11. S. N. Tereschenko, Russia


Sergey Nikolaevich TERESCHENKO, MD
Chief of Heart Failure Department
Tretya Cherepkovskaya ul. 15a
Research Institute for Clinical Cardiology
named after A. L. Myasnikov
Russian Cardiology Research and
Production Complex
121552 Moscow, RUSSIA
(e-mail: stereschenko@yandex.ru)

oday, maximum personalization of risk assessment in


heart failure (HF) patients is important in order to identify those most vulnerable, in whom intensified therapeutic approach is the most warranted. To this end, great attention is paid to biomarkers.
To date, the B-type natriuretic peptide (BNP) and N-terminal
proBNP (NT-proBNP) are among the most studied biomarkers. An increased level of NP is directly associated with hemodynamic stress. In HF, a high NP level at hospital discharge
is an independent marker of poor prognosis (death and HF
decompensation).

The significance of NPs for risk stratification in HF patients has


been shown in both inpatients and outpatients. These biomarkers represent a gold standard in prognostic evaluation.
According to Val-HeFT (the Valsartan in Heart Failure Trial),
the cutoff values for BNP and NT-proBNP in stable HF patients
are 125 pg/mL and 1000 pg/mL, respectively.1 More prognostic information can be obtained by serial measurements. In general, a reduction in NP levels below a specified value predicts
fewer hospital admissions or reduced mortality risk. According to a study by Doust et al, each 100 pg/mL increase in BNP
level is associated with a 35% increase in mortality risk.2
A study by Berger et al3 included 278 patients with decompensated HF, who were randomized at discharge using the
NT-proBNP cutoff value of >2200 pg/mL into 3 groups: (i) personalized treatment (with NT-proBNP level reduction below
2200 pg/mL), (ii) intensive patient management using the multidisciplinary care (MC) approach, and (iii) conventional treatment. Once the target NT-proBNP level was achieved, patients were treated according to standards of the MC group.
However, in case of an increase in NT-proBNP level, patients
received NP-guided treatment. Main end points included HF
hospitalization, time to death or HF rehospitalization, time to
first HF rehospitalisation, and death. During follow-up, the NPguided group received more aggressive therapy than the

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other 2 groups: a higher proportion of patients were on triple


therapy, and doses were 50% of target doses. As a result,
this group showed the greatest reduction in NT-proBNP level
by the end of follow-up. In general, these patients remained
clinically more stable throughout the study and had significantly fewer days of hospitalization due to decompensated
HF (P=0.0001). Moreover, with the NP-guided approach, risk
of the combined end point of death/HF rehospitalization at
18 months was reduced by 37% (vs 50% in the MC group
and 65% in the conventional treatment group; P<0.05). The
mortality rate in the NP-guided group was the same as in
the MC group (22%) and was significantly lower than in the
conventional treatment group (39%; P=0.02).
This study is of extreme value. It is well known that HF patients
with persistently high NP concentrations at discharge after
hospitalization due to decompensated HF have a higher risk
of death and HF rehospitalization. Thus, these patients require
a particular approach to treatment and control that presupposes, among other things, the reduction in NP level as a result of successful therapy.
Limiting factors include the relatively low stability of the BNP
molecule, biological variability, a large gray zone, as well as
the influence of age, sex, and body weight. Comorbidities can
cause mistaken risk stratification of HF patients. In this regard,
a multimarker strategy (with copeptin, galectin-3, MR-proadrenomedullin, soluble ST2 receptor, high-sensitivity [hs]-troponin, etc) is attractive, due to potential for better risk stratification of HF patients.
Will these multimarker panels have a real advantage? Will the
predictive value from a combination of markers exceed that
obtained from each individually and to what extent? How many
markers are required, and what combination is optimal for
prognostic assessment in HF patients? Nowadays, there are
still many more questions than answers.
References
1. Masson S, Latini R, Anand IS, et al; Val-HeFT Investigators. Direct comparison of
B-type natriuretic peptide (BNP) and amino-terminal proBNP in a large population of patients with chronic and symptomatic heart failure: the Valsartan Heart
Failure (Val-HeFT) data. Clin Chem. 2006;52:1528-1538.
2. Doust JA, Pietrzak E, Dobson A, et al. How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic
review. BMJ. 2005;330:625.
3. Berger R, Moertl D, et al. N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure. J Am Coll Cardiol. 2010;55:645-653.

Biomarkerspostdischarge assessment and management of heart failure patients

CONTROVERSIAL

QUESTION

12. M. B. Yilmaz, Turkey


Mehmet Birhan Yilmaz, MD, FESC
Professor, Cumhuriyet University
Faculty of Medicine
Department of Cardiology
Sivas, 58140
TURKEY
(e-mail: mehmet.birhan.yilmaz@tkd.org.tr)

an biomarkers guide the assessment and management of heart failure patients after discharge from
hospitals? In the presence of an ideal biomarker, the
answer would be Yes, they can. What is a biomarker? A
biomarker is defined as a characteristic that is objectively
measured and evaluated as an indicator of normal biologic
processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.1 Hence, anything could be
a biomarker. However, in the clinical sense, measurement of a
biomarker usually refers to a simple blood or urine test in most
cases. Biomarkers could be used in diagnosis, prognostication, monitoring of a therapeutic response, stratification and
also for some other reasons.
Heart failure (HF) is a complex, fatal disease, characterized by
2 overlapping subtypes, ie, acute and chronic HF.2 Acute HF
represents a major challenge both to the physician and to
the hospital and has a high risk of mortality and morbidity in
the short term. Patients hospitalized for an attack of acute HF
enter a vulnerable period after hospital discharge, during which
many patients need close follow-up management.3 After discharge, biomarkers can be used to guide physicians. For example, choice of therapy is already guided by safety biomarkers, such as creatinine or potassium, as in the case of
mineralocorticoid-receptor antagonist therapy.

With regard to biomarkers in HF, considerable progress has


already been made. Natriuretic peptides (NPs), as quantitative
biomarkers of ventricular and/or atrial loading, can serve as
near-perfect biomarkers in the diagnosis of HF. Nevertheless, their performance in daily practice is limited 4 despite recent efforts and well controlled studies (eg, GUIDE-IT [GUIDing

Evidence based therapy using biomarker Intensified Treatment in heart failure]). First of all, quantitation of NPs is limited by test accuracy.5 Secondly, though a decrease/increase
in NPs is linked to improvement/progression of the disease,
there is considerable room for biological variation, particularly
in patients with mild disease or in patients with recent acute
HF.6 Thirdly, an ideal biomarker should either be disease specific or organ specific. However, there is a sizeable list of reasons that lead to elevation of NPs in the absence of HF.7 Furthermore, right ventricular function, independent from left
ventricular function, adds complexity to the interpretation of elevated NPs. Last, but not least, in order for information from
a biomarker to be meaningful, it should not overlap significantly with otherwise obtained basic clinical information. In the
case of NPs, they may provide additional information which
is useful for diagnostic purposes; however, their use in guiding therapy during follow-up has not been well established.
In conclusion, there is an unmet need for a biomarker that can
help physicians tailor therapy of HF patients after discharge.
Despite progress in this area, there are obstacles to overcome
before integrating biomarkers into clinical decision making in
the HF setting.
References
1. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints:
preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;
69(3):89-95.
2. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013
ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force
on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.
3. Metra M, Gheorghiade M, Bonow RO, Dei Cas L. Postdischarge assessment
after a heart failure hospitalization: the next step forward. Circulation. 2010;122
(18):1782-1785.
4. Savarese G, Trimarco B, Dellegrottaglie S, et al. Natriuretic peptide guided therapy in chronic heart failure: a meta-analysis of 2,686 patients in 12 randomized
trials. PloS One. 2013;8:e58287.
5. Morrow DA, Cook NR. Determining decision limits for new biomarkers: clinical
and statistical considerations. Clin Chem. 2011;57:1-3
6. Wu AH, Smith A. Biological variation of the natriuretic peptides and their role in
monitoring patients with heart failure. Eur J Heart Fail. 2004;6(3):355-358.
7. Zakynthinos E, Kiropoulos T, Gourgoulianis K, Filippatos G. Diagnostic and prognostic impact of brain natriuretic peptide in cardiac and noncardiac diseases.
Heart Lung. 2008;37(4):275-285.

Biomarkerspostdischarge assessment and management of heart failure patients

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183

CONTROVERSIAL

QUESTION

13. B. Yoo, Republic of Korea


or diuretic adjustment. BNP level measured in the outpatient
clinic may be a reliable monitoring marker, taking into consideration the following advantages: results are obtained quickly, it is not affected by eating or exercise, it facilitates diuretic
adjustment early after discharge, and it reflects exacerbation
or success of treatment.1

ByungSu YOO, MD, PhD


Professor, Chief of Cardiology Division
Department of Internal Medicine
Wonju College of Medicine
Yonsei University
Wonju, 220-701
REPUBLIC OF KOREA
(e-mail: yubs@yonsei.ac.kr)

ecently, natriuretic peptide (NP) measurements after


discharge from hospital have been used to provide incremental information over clinical presentation or as
an end point to assess the efficacy of heart failure therapy, and
as a prognostic marker in heart failure.1 However, although
commercial assays are currently approved for diagnosis of
heart failure, use of NPs in monitoring the success of congestive heart failure (CHF) therapy or as a therapeutic target
in heart failure has not as yet been submitted for regulatory
approval.2
The first question is whether B-type NP (BNP) or N-terminal
proBNP (NT-proBNP) can be a treatment target in HF management. BNP levels correlate positively with cardiac filling
pressures and volumes and are inversely related to left ventricular ejection fraction. After treatment, recovery of neurohormonal balance means stabilization of HF status. BNP in
follow-up of heart failure patients was considered as a biochemical Swan-Ganz catheter, such as glycated hemoglobin
(HbA1c ) in patients with diabetes mellitus or alpha-fetoprotein
(AFP) in patients with hepatocellular carcinoma. Because BNP
levels correlate with atrial and ventricular filling pressures, it
is reasonable to ask whether changes in BNP mirror the effectiveness of therapies designed to reduce filling pressures.
Therefore, it is possible to accept BNP or NT-proBNP as a
good target for treatment of heart failure, one that is objective, reliable, practical, and inexpensive.1

The final question is about BNP- or NT-proBNPguided therapy in HF. The dynamic nature of BNP and NT-proBNP relative to therapeutic intervention in HF has led to the concept
of using the biomarkers as a guide for intensification of HF
care. The aim would be not only to achieve guideline-directed medical therapy goals, but to target NP itself, suppressing it below prognostic thresholds.4 During the last decade
or more, the concept of biomarker-guided management of
HF based on NP targets has been an intriguing and controversial topic.2 Nevertheless, in certain studies of this BNP- or
NT-proBNPguided approach, patients treated with biomarker-guided care had superior outcomes when compared with
standard heart failure management alone. This was the case
particularly in younger study populations, in patients with left
ventricular systolic dysfunction, and when substantial reductions in NPs were achieved in association with biomarkerguided care.1
BNP and NT-proBNP can provide significant prognostic information and it is possible that adjustment of antiheart failure therapy according to serial measurements of BNP (in addition to standard clinical assessment) may lead to improved
outcomes.4 However, randomized controlled trials have yielded inconsistent results. A better understanding of unresolved
issues, including test variation, cutoff values, acceptable times
for check-up, and cost effectiveness is needed before we can
effectively use this valuable test in the clinical setting.

References

The second question is how results of serial measurements


of BNP or NT-proBNP should be interpreted in the outpatient
clinic. In the Val-HeFT study (Valsartan in Heart Failure Trial),
high baseline values of BNP were related to high mortality, and
after 4 months, patients with a large reduction (% change) in
BNP had a relatively lower risk than other groups.3 In the outpatient setting, symptoms that suggest early decompensation and a rising BNP level should trigger either a clinic visit

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1. Troughton R, Michael Felker G, Januzzi JL Jr. Natriuretic peptide-guided heart


failure management. Eur Heart J. 2014;35:16-24.
2. De Vecchis R, Esposito C, Cantatrione S. Natriuretic peptide-guided therapy:
further research required for still-unresolved issues. Herz. 2013;38:618-628.
3. Anand IS, Fisher LD, Chiang YT. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2003;107:1278-1283.
4. Writing Committee Members. 2013 ACCF/AHA guideline for the management
of heart failure: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on practice guidelines.
Circulation. 2013;128:e240-e327.

Biomarkerspostdischarge assessment and management of heart failure patients

PROCORALAN

As opposed to other heart


ratelowering agents, Procoralan
(ivabradine) expresses unique action on pacemaker activity in the
sinoatrial node of the heart, which
results in important differences between ivabradine and nonselective
heart ratereducing agents such as
b-blockers. Ivabradine inhibits If, an
ionic current that modulates pacemaking activity, lowering heart rate
without directly affecting cardiac
conduction or contractility.

Procoralan:
new opportunities
for vulnerable
heart failure patients
b y I . E l y u b ae va , Fra n c e

O
Irina ELYUBAEVA, MD, PhD
Servier International
Division of Medical Information
Suresnes, FRANCE

nce a relatively short-term, quickly fatal condition, systolic heart failure (HF) today is a chronic disease characterized by recurrent nonfatal events (hospital admissions). With the burden of hospitalizations
for HF continuing to grow, prevention of rehospitalization has become the most
urgent need in cardiology. Hospital discharge is an opportunity to identify modifiable prognostic factors and to optimize patient therapy. The clinical profile
of HF patients is complex, mainly due to aging and the frequent presence of
noncardiovascular and cardiovascular comorbidities. These conditions not
only complicate management of HF patients, but also increase risk of in-hospital and postdischarge mortality and morbidity. The important role of Procoralan (ivabradine) in the management of patients with chronic HF is well established and supported by its benefits in prevention of morbidity and mortality.
Efficacy and tolerability of ivabradine in patients with HF, including those with
different clinical profiles (elderly; severe disease; low blood pressure; comorbidities, including renal dysfunction, diabetes, chronic obstructive pulmonary
disease) make ivabradine particularly pertinent for achievement of all targets
in the treatment of HF, including improvement of symptoms and well-being,
as well as outcomes. This offers the promise of a better prognosis and improved quality of life for millions of patients with chronic HF.
Medicographia. 2015;37:185-192 (see French abstract on page 192)

eart failure (HF) hospitalizations are a tremendous burden in terms of costs


and patient outcomes. The huge burden of HF-related hospitalization makes
its prevention the most urgent unmet need in cardiology.1 While patients hospitalized for worsening HF experience relatively low in-hospital mortality, they are at
much higher risk for early postdischarge readmission and mortality.2 These early
postdischarge mortality and readmission rates have remained largely unchanged
and may even be worsening in all countries. Thus, clear predischarge planning is
crucial to reduce preventable readmissions. Predischarge medications with proven
prognostic benefits for long-term use is critical to reduce high early postdischarge
risk and prevent readmission for HF.1

H
Address for correspondence:
Dr Irina Elyubaeva, MD, PhD,
Servier International, 50 rue Carnot,
92284 Suresnes Cedex, France
(e-mail:
irina.elyubaeva@fr.netgrs.com)
www.medicographia.com

Elevated heart rate to predict the risk of readmission and mortality


in patients with HF
The risk for postdischarge adverse events can be predicted with a high degree of
fidelity by a small number of widely available clinical variables. In this regard, such
a simple and standard clinical assessment as resting heart rate (HR) at discharge

Procoralan: new opportunities for vulnerable HF patients Elyubaeva

MEDICOGRAPHIA, Vol 37, No. 2, 2015

185

PROCORALAN

Figure 1. Mechanisms potentially


involved in the untoward effects of
elevated heart rate in heart failure.

Elevated resting heart rate

Abbreviation: O2 , oxygen.
After reference 5: Metra. JACC Heart Fail.
2013;1(6):497-499. 2013, American
College of Cardiology Foundation.
Published by Elsevier Inc. All rights
reserved.

Endothelial
dysfunction
Plaque rupture

Diastolic
phase duration
Coronary
blood flow

Energy
expenditure
Myocardial O2
consumption

Arterial
stiffness
Afterload

Myocardial
efficiency
& contractility

or early postdischarge provides important prognostic information. The


recent analysis of a cohort of 9097
patients with HF discharged from
hospital demonstrated that disHypertrophy,
Myocardial ischemia,
ventricular remodeling
charge HR was significantly assonecrosis, apoptosis
Heart failure
ciated with 30-day HF readmissionwith adjusted hazard ratios
Mortality &
of 1.26 (95% confidence interval,
rehospitalizations
1.04-1.54; P=0.021) in patients with
the highest HR group (HR>90 beats
per minute [bpm]) compared with
the reference group with a HR of 61-70 bpm.3 There was a risk of 1-year HF mortality (1.26; P=0.023) compared with the
trend in patients with HR below 60 bpm toward the lowest reference group with a HR lower than 60 bpm. The recent
risk with an adjusted hazard ratio of 0.87. The trend was con- analysis from the EVEREST trial (Efficacy of Vasopressin ansistent for 30-day cardiovascular (CV) readmission, mortal- tagonism in hEart failuRE: outcome Study with Tolvaptan)4
ity, and long-term outcomes. For example, the group with the demonstrated that the survival curves of the patients, subdihighest HRabove 80 bpmwas associated with higher vided according to the HR measured 1 or 4 weeks after discharge, started to diverge relatively early, and continued to
diverge during follow-up. These results are consistent with
SELECTED ABBREVIATIONS AND ACRONYMS
a long-lasting persistent effect of elevated HR on prognosis
(Figure 1).5 This causal role is also consistent with the imACE
angiotensin-converting enzyme
provement in outcomes observed with pure HR reduction
bpm
beats per minute
with ivabradine in patients with chronic HF on optimal medical
CARVIVA
Effect of CARVedilol, IVAbradine or their combination on exercise capacity in patients with
treatment.
CHF
COPD
CV
DM
ESC
EVEREST
HF
HR
INTENSIFY

KCCQ
LV
NYHA
RAAS
RR
RRR
SBP
SHIFT

186

Heart Failure
chronic heart failure
chronic obstructive pulmonary disease
cardiovascular
diabetes mellitus
European Society of Cardiology
Efficacy of Vasopressin antagonism in hEart
failuRE: outcome Study with Tolvaptan
heart failure
heart rate
PractIcal daily effectiveNess and TolEraNce of
Procoralan in chronic SystolIc heart Failure in
GermanY
Kansas City Cardiomyopathy Questionnaire
left ventricular
New York Heart Association
renin-angiotensin aldosterone system
relative risk
relative risk reduction
systolic blood pressure
Systolic Heart failure treatment with the If inhibitor
ivabradine Trial

MEDICOGRAPHIA, Vol 37, No. 2, 2015

Pure HR reduction with procoralan (ivabradine):


anti-ischemic effect and dual cardiac and vascular
protection in coronary artery disease and HF
Procoralan (ivabradine) is a specific HR-lowering agent, and
is the first agent of this type to be approved for therapeutic
use.6 As opposed to other HR-lowering agents, ivabradine expresses unique action on pacemaker activity in the sinoatrial node of the heart, which results in important differences between ivabradine and nonselective HR-reducing agents such
as b-blockers. Ivabradine inhibits If, an ionic current that modulates pacemaking activity, lowering HR without directly affecting cardiac conduction or contractility.7 Myocardial perfusion, particularly in the subendocardium, takes place almost
entirely during diastole. Physiological changes in HR affect
mainly the duration of diastole leading to prolongation in diastolic time at lower HR, both in absolute terms and as a fraction of the cardiac cycle, facilitating myocardial perfusion.8
Ivabradine, in common with physiological HR reduction, lowers HR essentially by prolonging diastole.9 By reducing HR,
ivabradine decreases myocardial oxygen consumption and
increases myocardial perfusion, both explaining the preserved

Procoralan: new opportunities for vulnerable HF patients Elyubaeva

PROCORALAN

cardiac energy metabolism, which is profoundly depleted during HF. Sustained HR reduction with ivabradine improves
cardiac function by significantly decreasing left ventricular (LV)
systolic diameter and increasing fractional shortening.10 Ivabradine preserves cardiac output due to increased stroke volume, reduced LV collagen density, and increased LV capillary
density. Similar cardiac benefits have also been observed in
rats when ivabradine was given immediately after myocardial infarction, highlighting both the preventive and curative
benefits of ivabradine in HF.11
These experimental data show that long-term HR reduction
with ivabradine optimizes energy consumption, reverses remodeling, and prevents disease progression in HF.12 Beneficial effects of ivabradine on LV volumes have been further
documented by assessing its effects on the global cardiac
remodeling process involved in HF. This adaptation following
myocardial injury is defined as a series of biochemical and
cellular modifications, such as fibrosis and local renin-angiotensin aldosterone system (RAAS) stimulation, and electrophysiological modifications, such as alteration of sarcoplasmic reticulum calcium cycling. Nonclinical data have shown
that ivabradine has a marked beneficial effect on these remodeling parameters. At the cellular level, ivabradine reduces
fibrosis and local RAAS stimulation (decrease in cardiac angiotensin II type 1 receptor).13 Ivabradine reduces triggered
ventricular premature complexes in chronic HF (CHF) rats in
addition to a decrease in ventricular fibrosis and sympathetic drive.14
These preclinical findings show that, in several models of HF,
a pathological condition in which a series of phenotypic cardiac maladaptations is progressively induced, the long-term
HR-reducing properties of ivabradine prevent progression of
cardiac dysfunction and optimize energy consumption. In the short term, this is
associated with increased diastolic time,
improved myocardial perfusion, and reduced oxygen consumption. In the long
term, ivabradine induces a global reversal of remodeling and prevents endothelial dysfunction. All these mechanisms
contribute to the prognostic benefits of
ivabradine in patients with HF.

Clinical benefits of pure HR reduction by ivabradine


in patients with LV dysfunction and HF
The results of clinical trials are consistent with the importance of HR in the pathophysiology of HF, supporting the
place of ivabradine as an important part of management of
patients with LV systolic dysfunction (LVSD) and HF.
Improvement of symptoms and exercise capacity, and
reduction in signs of decompensation in patients with HF
SHIFT (the Systolic Heart failure treatment with If inhibitor ivabradine Trial) found that ivabradine significantly improved the
New York Heart Association (NYHA) class (29.0% vs 24.2%
in the placebo group; P<0.0156) and patient-reported global
assessment (65.9% vs 61.3% in placebo; P<0.0345) in the
overall SHIFT population.15

In the randomized, open, blinded end point CARVIVA study


(Effect of CARVedilol, IVAbradine or their combination on exercise capacity in patients with Heart Failure), after 3 months of
therapy with ivabradine, the NYHA class was significantly more
improved in patients receiving ivabradine and combination
therapy compared with those allocated to carvedilol.16 Ivabradine alone or in combination was also more effective in improvement of exercise capacity compared with carvedilol alone.
The results of the recent INTENSIFY study (PractIcal daily effectiveNess and TolEraNce of Procoralan in chronic SystolIc
heart Failure in GermanY) confirmed the clinical efficacy of
ivabradine in daily practice over a 4-month period in 1956 patients with CHF.17 After 4 months, ivabradine reduced HR by
18.112.3 bpm to 67.18.9 bpm, accompanied by symptomatic improvement with a shift in NYHA classification of patients toward lower gradings (Figure 2)17 and a reduction in
signs of decompensation from 23% to 5% of patients.

Figure 2. Proportion of patients in


different NYHA classes over 4 months of
therapy with ivabradine in patients with
chronic heart failure participating in the
INTENSIFY trial.
Abbreviations: INTENSIFY, PractIcal daily effectiveNess and TolEraNce of Procoralan in chronic SystolIc
heart Failure in GermanY; n, number of patients;
NYHA, New York Heart Association.
After reference 17: Zugck et al. Adv Ther.
2014;31(9):961-974. 2014, The Author(s).

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PROCORALAN

Improvement of health-related quality of life in patients

with HF
A substudy of the SHIFT trial in 1944 patients demonstrated
that in parallel to a reduction in outcomes in the SHIFT trial,
ivabradine improved health-related quality of life (HQOL) in
patients with HF, assessed by the specific Kansas City Cardiomyopathy Questionnaire (KCCQ).18 Treatment with ivabradine significantly improved both scores measured with the
KCCQ: the overall summary score (OSS) and the clinical summary score (CSS). The OSS, which includes the physical limitation, total symptom, QOL, and social limitation scores, was
improved by ivabradine by 6.7 points vs 4.3 in the placebo

ume index (LVESVI), as compared with 0.9 mL/m2 in the placebo group.19 The LV end-diastolic volume index (LVEDVI) was
reduced by 7.9 mL/m2 as compared with 1.8 mL/m2 in the
placebo group; LVEF was improved by 2.4%, whereas there
was no change in the placebo group at all. Moreover, these
results occurred despite treatment with b-blockers and
RAAS inhibitors, each used in more than 90% of patients.
Further analysis from SHIFT demonstrated that HR reduction with ivabradine can directly affect the vascular system
and that the reported reduction in afterload was mainly triggered by a decrease in vascular pulsatile load, whereas sys-

Figure 3. Change
in stroke volume
and cardiac output
over 8 months in
patients with systolic chronic heart
failure participating
in the SHIFT trial.
Abbreviation: SHIFT,
Systolic Heart failure
treatment with the If inhibitor ivabradine Trial.
After reference 21:
Ferrari. Cardiology.
2014;128(2):226-230.
2014, S. Karger AG,
Basel.

group (P<0.001) by 12 months. The CSS, which includes the


physical limitation and the total symptom domain scores, was
improved by 5.0 points with ivabradine vs 3.3 in the placebo
group (P=0.018) after 12 months. Qualitatively, similar benefits were found with ivabradine vs placebo at 4 months and
were maintained throughout study follow-up.
The improvement of QOL was demonstrated in the randomized, open, blinded end point CARVIVA study.16 After 3 months
of therapy, ivabradine improved QOL compared with no change
with carvedilol alone.
In the recent INTENSIFY study, scores from the European
quality of life-5 dimensions (EQ-5D) index and the EQ-5D visual analog scale (EQ-5D-VAS) were improved from 0.640.28
to 0.790.21 and from 0.550.18 to 0.700.16, respectively, over 4 months of therapy with ivabradine.17
Reversing ventricular remodeling in patients with HF
Reversal of LV remodeling has important clinical implications
as cardiac remodeling is a central feature of the progression
of HF and is an established prognostic factor in patients
with this condition. An echo substudy in 611 patients from
SHIFT demonstrated that 8 months of therapy with ivabradine resulted in a 7 mL/m2 reduction in LV end-systolic vol-

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

temic resistance remained constant.20 Better arterial compliance appears to result in improved ventricular arterial coupling
with a significant increase in LVEF and stroke volume, without changes in LV contractility and cardiac output (Figure 3).21
The beneficial impact of ivabradine on LV remodeling and function may contribute to the reduction in cardiac morbidity and
mortality found in patients with HF.
Prevention of hospital admissions and mortality in
patients with HF
The effect of ivabradine to improve prognosis in HF has been
successfully tested in the SHIFT trialthe randomized, placebo-controlled clinical trial in 6558 patients with moderate to
severe chronic HF and LV systolic dysfunction (LVEF<35%;
HR70 bpm; with median follow-up of 22.9 months).15 The
SHIFT trial clearly demonstrates that ivabradine offers major
prognostic benefits for patients with HF on top of the best
possible recommended therapy. The primary composite end
point (CV death or hospital admission for worsening HF) was
significantly reduced by 18% (P<0.0001). Ivabradine significantly reduced HF death (relative risk reduction [RRR], 26%;
P=0.014) and hospitalization for HF (RRR, 26%; P<0.0001).
Results were consistent across all subgroups, including patients with HF of ischemic and nonischemic origin (Figure 4).15
On the strength of the absolute RR of the primary end point,

Procoralan: new opportunities for vulnerable HF patients Elyubaeva

PROCORALAN

hospitalization and a 29% (P<0.012) reduction in risk of third


hospitalization (Figure 5).24 Similar results for HF hospitalization were seen in the higher-risk subgroup of patients with
a HR of at least 75 bpm (27% reduction; P=0.0006). Ivabradine also reduced hospitalizations for any cause (by 15%;
P=0.001) and CV hospitalizations (by 16%; P=0.002).
Improvement of prognosis in patients with HF with
different clinical profiles
Patients with HF are characterized by the presence of multiple comorbidities or conditions, including old age and low
systolic blood pressure (SBP), which not only complicates
treatment strategies, but also increases the risk of undesirable side effects and worsens prognosis. Therefore, it is imperative to analyze efficacy and tolerability of medications in
patients with HF with different clinical profiles.
Figure 4. Reduction in cardiovascular death or hospitalization for
worsening heart failure (primary composite end point) in the prespecified patients with systolic chronic heart failure of ischemic or
nonischemic etiology in the SHIFT trial.
Abbreviations: CI, confidence interval; HF, heart failure; SHIFT, Systolic Heart
failure treatment with the If inhibitor ivabradine Trial.
Based on data from reference 15: Swedberg et al. Lancet. 2010;376(9744):
875-885.

26 patients would need to be treated for 1 year to prevent 1


CV death or HF-related hospital admission. CV death and
all-cause death diminished by 9% and 10%, respectively,15
and achieved statistical significance in patients with a HR of
at least 75 bpm, with 17% reduction in all-cause mortality
(P=0.0109) and 17% reduction in CV mortality (P=0.0166).22
Prevention of HF readmission is identified today as the most
urgent unmet need in cardiology. Such admissions are not
only distressing for patients and their families, but are also
implicated in disease progression and drive the huge economic burden of HF.23 The analysis from SHIFT showed that
ivabradine substantially reduces the total number of HF hospitalizations by 25% (P=0.0002).24 Over 2 years of follow-up,
ivabradine substantially reduced the risk of recurrent HF hospitalization: with a 34% (P<0.001) reduction in risk of second

Patients with severe HF


Severe HF, ie, NYHA class IV, is associated with relatively poorer survival than patients with NYHA classes II and III. Moreover, patients with severe HF are the most difficult to treat.
The analysis from the SHIFT trial explores the efficacy and
safety of ivabradine in 712 patients with severe HF (NYHA
class IV and/or LVEF20%).25 The results indicated that the
effect of ivabradine to reduce outcomes, including the primary
outcome (CV mortality or hospitalization for HF), HF death, and
hospitalization for worsening HF, is consistent in patients with
severe and less-severe HF, with no significant statistical interaction between the results in the 2 groups. Treatment with
ivabradine was also associated with improvement in NYHA
functional status in patients with severe disease. Importantly,
therapy with ivabradine was safe in these severe patients with
no unexpected adverse events and no impact on blood pressure (BP).

The recently published study in patients with severe systolic


HF who were hospitalized for worsening HF explored the use
of ivabradine in the hospital setting. Ivabradine treatment was
started within 6 days of admission on average.26 The mean

Figure 5.
Estimate of the
effect of ivabradine on recurrence
of hospitalizations
for worsening
heart failure.
Abbreviation: n, number of patients.
After reference 24:
Borer et al. Eur Heart
J. 2012;33(22):28132820. Published on
behalf of the European
Society of Cardiology.
All rights reserved.
2012, The Author.

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PROCORALAN

dosage at discharge was 9.52.8 mg/day. The HR decreased


by 10.77.2 bpm 24 hours after ivabradine administration.
The maximum HR decrease was 16.38.2 bpm, at discharge.
A HR under 70 bpm was achieved in 50% and 80% of patients 24 hours after administration and at discharge, respectively. Thus, the decrease in HR was rapid, but sustained.
There was no significant variation in BP, which explains the
hemodynamic stability. Moreover, HR had a significant association with N-terminal proB-type natriuretic peptide (NTproBNP) and NYHA class improvement.
Patients with renal dysfunction

Renal dysfunction, even transient, is common in HF patients


and is a known predictor of CV outcomes and mortality in patients with cardiac disease. Worsening renal function has been
associated with adverse outcomes in patients with HF, underuse of proven agents, and even discontinuation of beneficial medication.27 The analysis from SHIFT demonstrated that
renal dysfunction defined as an estimated glomerular filtration rate (eGFR) under 60 mL/min was present in 24% of patients (n=1579).28 Ivabradine use was associated with a reduction in the primary composite end point of CV mortality or
hospitalization for HF both in patients with (by 18% of RRR;
P=0.023) or without renal dysfunction (by 19% of RRR;
P<0.001) at baseline (P for interaction=0.89), and tolerability
of ivabradine was comparable in the 2 groups.28 There were
no differences in changes in renal function over time between
ivabradine- and placebo-treated patients.
Patients with chronic pulmonary obstructive disease

Up to one-third of HF patients are affected with chronic obstructive pulmonary disease (COPD) and vice versa.29 Thus,
it is important to know of the potential interference of COPD
with any therapy in HF. Analysis from the SHIFT trial showed
that COPD was present in 11% of HF patients (n=730).30 The
primary end point (CV mortality or HF hospitalization) and its
component, hospitalization for worsening HF, were more frequent in COPD patients (hazard ratios 1.22, P=0.006; and
1.34, P<0.001; respectively), but relative risk (RR) was reduced similarly by ivabradine in both COPD (14% and 17%)
and non-COPD (18% and 27%) patients (P interaction=0.82
and 0.53, respectively). Ivabradine was similarly safe in chronic HF patients with or without COPD.
Patients with low BP

Of HF patients, 15% to 25% have low SBP (ie, <120 mm Hg),


and are at greater risk of in-hospital and postdischarge mortality and morbidity.31 Moreover, the presence of low SBP complicates the management of HF, as many guideline-recommended HF medications also lower SBP, such as b-blockers
and angiotensin-converting enzyme (ACE) inhibitors. The analysis from the SHIFT trial assessed the efficacy of ivabradine
in patients with different baseline levels of SBP.32 The results
of this analysis demonstrated that baseline SBP did not affect the impact of HR reduction with ivabradine on clinical out-

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comes in HF. There was a similar beneficial effect on both the


primary composite end point of CV mortality or hospitalization
for HF and on the selected secondary end points whatever
the baseline SBP, including patients in the low-SBP group
(<115 mm Hg). The safety profile of ivabradine was also similar in the 3 groups, and there was no difference compared
with the global SHIFT population. The BP variation over 24
months was similar in ivabradine- and placebo-treated patients in the low-SBP group.
Patients with diabetes mellitus
Recent analysis from the European Society of Cardiology
(ESC) Heart Failure Pilot Survey demonstrated that 29% of
patients with HF have diabetes mellitus (DM), which was independently associated with a higher risk of mortality and/or
HF hospitalization.33 The preliminary data reported at the last
European HF congress showed that 31% of patients with DM
enrolled in SHIFT showed similar benefits from ivabradine in
patients with or without DM.34 The RR of the primary composite end point of CV mortality or hospitalization for HF was
decreased significantly by ivabradine in both groups: by 19%
(P=0.012) in patients with DM and by 17% (P=0.002) in patients without. There was no significant difference in the impact of ivabradine in the 2 groups (P value for interaction=
0.864). The RR of HF hospitalization was reduced similarly
by ivabradine in patients with (27%; P=0.001) or without DM
(17%; P<0.001) (P for interaction=0.784).
Elderly patients
The analysis from the SHIFT trial demonstrated that age does
not limit the benefits of ivabradine in patients with chronic HF
and systolic dysfunction, with comparable safety and efficacy across all age groups.35 In a subgroup of 722 very elderly
patients aged at least 75 years, end points also occurred less
frequently with ivabradine than with placebo. The rate of CV
deaths was lower (16% vs 22%; P=0.048), as was the rate of
HF death (4% vs 8%; P=0.019).

Good tolerability profile and ease of use in practice


Ivabradine was well tolerated in patients with CHF. In the
SHIFT trial, bradycardia led to study withdrawal in only 1%
of the overall population, which is remarkable considering that
89% were receiving b-blockers.15 Based on the SHIFT trial,
a starting dosage of 5 mg twice daily is recommended, and
can be increased up to 7.5 mg twice daily according to tolerability and if resting HR is above 60 bpm. In patients aged
75 years or more, a lower starting dosage should be considered (2.5 mg twice daily with further uptitration if necessary).
Ivabradine should not be used with moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors.
Due to its pharmacological properties and supported by clinical evidence, ivabradine is a particularly pertinent therapy to
achieve all treatment targets in HF patients: the improvement
of symptoms, well-being, and outcomes. Pharmacological

Procoralan: new opportunities for vulnerable HF patients Elyubaeva

PROCORALAN

therapy of HF patients is becoming increasingly complex as


patients are older and increasingly develop noncardiac and
CV comorbidities and disabilities. These conditions not only
complicate the management of HF patients, but also increase
the risk of in-hospital and postdischarge mortality and mor-

bidity. The efficacy and tolerability of ivabradine in patients with


HF and different clinical profiles (elderly, severe disease, low
BP, presence of comorbidities including renal dysfunction, DM,
COPD) make ivabradine an essential therapeutic modality for
the management of patients with HF.

References
1. Gheorghiade M, Shah AN, Vaduganathan M, et al. Recognizing hospitalized
heart failure as an entity and developing new therapies to improve outcomes:
academics', clinicians', industry's, regulators', and payers' perspectives. Heart
Fail Clin. 2013;9(3):285-290.
2. Solomon SD, Dobson J, Pocock S, et al; Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Investigators. Influence
of nonfatal hospitalization for heart failure on subsequent mortality in patients
with chronic heart failure. Circulation. 2007;116(13):1482-1487.
3. Habal MV, Liu PP, Austin PC, et al. Association of heart rate at hospital discharge with mortality and hospitalizations in patients with heart failure. Circ Heart
Fail. 2014;7(1):12-20.
4. Greene SJ, Vaduganathan M, Wilcox JE, et al; EVEREST Trial Investigators.
The prognostic significance of heart rate in patients hospitalized for heart failure with reduced ejection fraction in sinus rhythm: insights from the EVEREST
(Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With
Tolvaptan) trial. JACC Heart Fail. 2013;1(6):488-496.
5. Metra M. Tachycardia after a heart failure hospitalization: another piece of the
puzzle? JACC Heart Fail. 2013;1(6):497-499.
6. DiFrancesco D. Cardiac pacemaker If current and its inhibition by heart ratereducing agents. Curr Med Res Opin. 2005;21(7):1115-1122.
7. Berdeaux A. Preclinical results with If current inhibition by ivabradine. Drugs.
2007;67(suppl 2):25-33.
8. Heusch G. Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br J Pharmacol. 2008;153(8):1589-1601.
9. Colin P, Ghaleh B, Monnet X, et al. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol. 2003;284(2):H676-H682.
10. Simon L, Ghaleh B, Puybasset L, Giudicelli JF, Berdeaux A. Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther. 1995;275(2):659-666.
11. Mulder P, Barbier S, Chagraoui A, et al. Long-term heart rate reduction induced by the selective If current inhibitor ivabradine improves left ventricular
function and intrinsic myocardial structure in congestive heart failure. Circulation. 2004;109(13):1674-1679.
12. Ceconi C, Cargnoni A, Francolini G, Parinello G, Ferrari R. Heart rate reduction
with ivabradine improves energy metabolism and mechanical function of isolated ischaemic rabbit heart. Cardiovasc Res. 2009;84(1):72-82.
13. Dedkov EI, Zheng W, Christensen LP, Weiss RM, Mahlberg-Gaudin F, Tomanek
RJ. Preservation of coronary reserve by ivabradine-induced reduction in heart
rate in infarcted rats is associated with decrease in perivascular collagen. Am
J Physiol Heart Circ Physiol. 2007;293(1):H590-H598.
14. Milliez P, Messaoudi S, Nehme J, Rodriguez C, Samuel JL, Delcayre C. Beneficial effects of delayed ivabradine treatment on cardiac anatomical and electrical remodeling in rat severe chronic heart failure. Am J Physiol Heart Circ
Physiol. 2009;296(2):H435-H441.
15. Swedberg K, Komajda M, Bhm M, et al; SHIFT Investigators. Ivabradine and
outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled
study. Lancet. 2010;376(9744):875-885.
16. Volterrani M, Cice G, Caminiti G, et al. Effect of Carvedilol, Ivabradine or their
combination on exercise capacity in patients with Heart Failure (the CARVIVA
HF trial). Int J Cardiol. 2011;151(2):218-224.
17. Zugck C, Martinka P, Stckl G. Ivabradine treatment in a chronic heart failure
patient cohort: symptom reduction and improvement in quality of life in clinical
practice. Adv Ther. 2014;31(9):961-974.

18. Ekman I, Chassany O, Komajda M, et al. Heart rate reduction with ivabradine
and health related quality of life in patients with chronic heart failure: results from
the SHIFT study. Eur Heart J. 2011;32(19):2395-2404.
19. Tardif JC, O'Meara E, Komajda M, et al; SHIFT Investigators. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy. Eur Heart J. 2011;32
(20):2507-2515.
20. Reil JC, Tardif JC, Ford I, et al. Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients. J Am Coll Cardiol. 2013;62(21):
1977-1985.
21. Ferrari R. Ivabradine: heart rate and left ventricular function. Cardiology. 2014;
128(2):226-230.
22. Bhm M, Borer J, Ford I, et al. Heart rate at baseline influences the effect of
ivabradine on cardiovascular outcomes in chronic heart failure: analysis from
the SHIFT study. Clin Res Cardiol. 2013;102(1):11-22.
23. Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic
burden of hospitalizations for heart failure: lessons learned from hospitalized
heart failure registries. J Am Coll Cardiol. 2014;63(12):1123-1133.
24. Borer JS, Bhm M, Ford I, et al; SHIFT Investigators. Effect of ivabradine on
recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study. Eur Heart J. 2012;33(22):2813-2820.
25. Borer JS, Bhm M, Ford I, et al; SHIFT Investigators. Efficacy and safety of
ivabradine in patients with severe chronic systolic heart failure (from the SHIFT
study). Am J Cardiol. 2014;113(3):497-503.
26. Sargento L, Satendra M, Longo S, Lousada N, dos Reis RP. Heart rate reduction with ivabradine in patients with acute decompensated systolic heart failure.
Am J Cardiovasc Drugs. 2014;14(3):229-235.
27. Tonelli M, Bohm C, Pandeya S, Gill J, Levin A, Kiberd BA. Cardiac risk factors
and the use of cardioprotective medications in patients with chronic renal insufficiency. Am J Kidney Dis. 2001;37(3):484-489.
28. Voors AA, van Veldhuisen DJ, Robertson M, et al; on behalf of the SHIFT investigators. The effect of heart rate reduction with ivabradine on renal function in
patients with chronic heart failure: an analysis from SHIFT. Eur J Heart Fail. 2014
Feb 7. Epub ahead of print. doi:10.1002/ejhf.59.
29. Hawkins NM, Petrie MC, Jhund PS, Chalmers GW, Dunn FG, McMurray JJ.
Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and
epidemiology. Eur J Heart Fail. 2009;11(2):130-139.
30. Tavazzi L, Swedberg K, Komajda M, et al; SHIFT Investigators. Clinical profiles
and outcomes in patients with chronic heart failure and chronic obstructive
pulmonary disease: an efficacy and safety analysis of SHIFT study. Int J Cardiol. 2013;170(2):182-188.
31. Gheorghiade M, Vaduganathan M, Ambrosy A, et al. Current management and
future directions for the treatment of patients hospitalized for heart failure with
low blood pressure. Heart Fail Rev. 2013;18(2):107-122.
32. Komajda M, Bhm M, Borer JS, et al; SHIFT Investigators. Efficacy and safety
of ivabradine in patients with chronic systolic heart failure according to blood
pressure level in SHIFT. Eur J Heart Fail. 2014;16(7):810-816.
33. van Deursen VM, Urso R, Laroche C, et al. Co-morbidities in patients with heart
failure: an analysis of the European Heart Failure Pilot Survey. Eur J Heart Fail.
2014;16(1):103-111.
34. Komajda M, Tavazzi L, Swedberg K, et al. Clinical profiles and outcomes of patients with chronic heart failure and diabetes: efficacy and safety of ivabradine.
Eur J Heart Fail. 2014;16(suppl 2):42.
35. Tavazzi L, Swedberg K, Komajda M, et al; SHIFT Investigators. Efficacy and safety of ivabradine in chronic heart failure across the age spectrum: insights from
the SHIFT study. Eur J Heart Fail. 2013;15(11):1296-1303.

Keywords: heart failure; heart rate reduction, hospitalization; If current; ivabradine; Procoralan

Procoralan: new opportunities for vulnerable HF patients Elyubaeva

MEDICOGRAPHIA, Vol 37, No. 2, 2015

191

PROCORALAN

PROCORALAN :

NOUVELLES OPPORTUNITS POUR LES INSUFFISANTS CARDIAQUES FRAGILES

Autrefois pathologie relativement brve, rapidement mortelle, linsuffisance cardiaque systolique (IC) est aujourdhui
une maladie chronique caractrise par des vnements rcurrents non mortels (hospitalisations). La charge des
hospitalisations pour IC tant croissante, la prvention des rhospitalisations devient le besoin le plus urgent en
cardiologie. La sortie de lhpital est un moment privilgi pour identifier les facteurs pronostiques modifiables et optimiser le traitement du patient. Le profil clinique des patients IC est complexe, principalement en raison de lge et
de la prsence frquente de comorbidits cardiovasculaires et non cardiovasculaires qui, non seulement compliquent
la prise en charge des patients IC mais aussi augmentent le risque de morbi-mortalit lhpital et la sortie de lhpital. Le rle important de Procoralan (ivabradine) dans la prise en charge des patients atteints dIC chronique est
bien tabli et confort par ses effets bnfiques dans la prvention de la morbidit et de la mortalit. Lefficacit et
la tolrabilit de livabradine chez les patients IC, y compris ceux aux profils cliniques diffrents (sujet g, maladie
grave, pression artrielle basse, comorbidits dont une dysfonction rnale, un diabte, une bronchopneumopathie
chronique obstructive), en font un traitement particulirement pertinent de lIC sous tous ses critres, dont lamlioration des symptmes et du bien-tre comme des rsultats. Cest la promesse dun meilleur pronostic et dune qualit de vie amliore pour des millions de patients souffrant dIC chronique.

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Procoralan: new opportunities for vulnerable HF patients Elyubaeva

INTERVIEW

Compliance is not the lone


determinant of patients involvement in their own medical disease
management. While compliance
is mandatory, it is in itself insufficient. The concept of therapeutic
patient education includes an improvement in patient knowledge
and in patient involvement in follow-up (identification of symptoms;
identification of warning signs;
analysis of usual biochemistry results). However, the crucial point
is the patients capacity to be involved in self-management.

Therapeutic education:
which tool for whom?

I n t e r v i e w w i t h P. J o u rd a i n , Fra n c e

I
Patrick JOURDAIN, MD, FESC
Head, Therapeutic Patient
Education Department
School of the Heart Team
Heart Failure Unit
Paris Descartes University
Paris, FRANCE

mproving patient competencies through therapeutic education of patients,


relatives, and caregivers is a key point in heart failure (HF) management. It
can be considered the first step toward a real partnership between health
care professionals and patients. Despite all guidelines, recommendations, and
convincing evidence, HF therapeutic education is rarely implemented, which
may contribute in large part to the inefficacy of therapy and the overuse of
emergency department facilities by poorly involved and -informed patients.
In real life, it is difficult to improve patient self-management because of its dependency on patient willingness and due to the lack of time that health care
professionals in most countries can invest in such an endeavor. However, HF
therapeutic education tools are very useful, helping doctors, nurses, dieticians,
and physiotherapists to quickly develop patients skills and competencies that
improve life with the disease. This is especially pertinent in HF, due to the 5day delay between the emergence of clinical signs and hospital admission in
the majority of patients. Such tools should be flexible and adaptable to the
health care professional and patient type, with different tools possibly more
suitable for different situations. Such tools should not be stressing, but realistic, fostering autonomy in patients and their relatives. Some tools already
exist, helping nurses and doctors train patients in difficult environments while
facing time constraints. Try these tools or create your own to help your patients
improve their everyday life with chronic HF.
Medicographia. 2015;37:193-196 (see French abstract on page 196)

In heart failure today, what are some of the challenges to optimal


management?
eart failure (HF) is a severe chronic condition. Management of chronic HF implies an adaptation of daily life, salt consumption, and physical activity and
also involves many different medications. Furthermore, there are many issues
that contribute to the nonoptimal HF management seen in real life. Some are patient related, involving for example therapy adherence or comorbidities, and some
are doctor related, such as medical inertia.

H
Address for correspondence:
Dr Patrick Jourdain
Chef du Dpartement dEducation
Thrapeutique du Patient
Universit Paris Descartes
12 rue de lcole de Mdicine
75006 Paris, France
(e-mail:
patrick.jourdain-mantel@wanadoo.fr)
www.medicographia.com

Compliance with medical therapy is crucial to therapy effectiveness, as shown in a


post hoc analysis of the CHARM study (Candesartan in Heart failure: Assessment
of Reduction in Mortality and morbidity). In this study, poor compliance, defined as
the intake of less than 80% of prescribed protocol therapy, was associated with an

Therapeutic education: which tool for whom? Jourdain

MEDICOGRAPHIA, Vol 37, No. 2, 2015

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INTERVIEW

increase in risk of death or HF rehospitalization. Poor compliance is common in real life, especially in the oldest patients
with many comorbidities and more than 5 different therapies.
The difference between prescribed therapy and actual intake of therapy is often underestimated by doctors, despite
the number of publications attesting to this discrepancy. This
is particularly well analyzed in noninsulin-dependent diabetic
patients. In those patients, a study determined that patients
receiving a combination of 2 drugs (sulfamid and metformin)
received only 266 days of therapy per year. This lack of compliance is comparable in chronic severe cardiac diseases such
as myocardial infarction and HF. For example, 1 month after
acute myocardial infarction, one-third of the patients have
stopped at least 1 of the recommended BASI therapies (bblockers, aspirin, statins, and angiotensin-converting enzyme
inhibitors).

What influences compliance with medical therapy


and how can it be improved?
eterminants of compliance differ greatly from patient
to patient. Some are related to the therapy itself: form,
taste, texture, name of medication, and side effects
(real or not). Some are related to the patient: social and financial autonomy, dementia, perception of the disease and the
usefulness of medical therapy, clinical evidence of usefulness,
etc. Some are related to doctors: level of support of therapy
(strong or weak) and the link between pharmacist and doctor.
Compliance is mainly based on the confidence among doctors, pharmacists, and patients and is mandatory for an effective medical therapy. Considering optimal therapy to mean
100% compliance, a mean compliance higher than 80% is
acceptable according to most publications. Improving compliance is a crucial, but difficult, target in everyday practice.
The first step is to systematically analyze compliance during
the medical visit. Rather than asking directly, it is more effective to ask patients indirectly how they analyze the impact of
their therapy, what they are doing to avoid forgetting to take
their tablets, etc. Most of the tools proposed to patients are
based on tablet boxes and on connected tablet boxes (eg,
they can ring phones to send reminders, are connected to
the Internet, or can send e-mails to relatives), an approach to
medical therapy focusing on close surveillance, which can
seem intrusive. Though the short-term impact may be positive, the advantage in the long term is questionable.

Are there other ways to improve HF management


through active involvement of the patient?
ndeed, compliance is not the lone determinant of patients
involvement in their own medical disease management.
While compliance is mandatory, it is in itself insufficient. The
concept of therapeutic patient education (TPE) includes an
improvement in patient knowledge and in patient involvement
in follow-up (identification of symptoms; identification of warn-

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

ing signs; analysis of usual biochemistry results, eg, renal


function, natremia, kalemia, and sometimes natriuretic peptides). However, the crucial point is the patients capacity to
be involved in self-management. This self-management can
be split into 2 different dimensions. One is more focused on
patient ability to identify the risk of decompensation (analyzing clinical signs) and to contact the general practitioner or
the cardiologist rather than going later on to the emergency
department. The second dimension is focused more on selfmedication and adaptation of diuretic therapy, which diabetics are doing with insulin. Involving patients not only in regards
to compliance with medical therapy, but also in everyday follow-up or management is crucial and substantially changes
the relationship between patients and doctors. This cooperation implies that the patient takes on the role of equal partner and is no longer only a patient, signifying that the patient
and relatives can play an active role in daily follow-up.

How do we reach this partnership between


patient and health care professional?
n order to obtain this holy grail, it is first necessary to
train patients and to improve their reactivity, not only their
knowledge. Take as an example, the driving of a car. To be
able to drive that car, one must first learn the road code. However, that isnt enough to drive safely; the driver must practice and learn to adapt trajectory and speed to the environment. In HF, patients need to adapt their alimentation and their
reactions to the disease, their clinical signs, and to the health
resources available. TPE regroups all these concepts and
has proven its effectiveness to limit hospitalization, duration
of stay, and even all-cause mortality in meta-analysis and in
real-life analysis in France. European Society of Cardiology
(ESC) guidelines and US guidelines recommend to the highest degree multidisciplinary TPE due to its impact on patient health and on health resource expenditures. Despite all
guidelines and evidence-based medicine, TPE is actually only
carried out with few patients in real life (eg, estimated to be
5% in France) and is highly dependent on the motivation of
local health professionals, thus not implemented equally in
all places. Some specific tools are already in existence and
are extremely useful to encourage doctors and nurses and
to provide support to local teams and patient associations.

What are the important characteristics of these


kinds of tools?
PE tools or systems should be: -----------------------c
Simple. The system should be easily understood by
health care professionals. Its concept and use should
be as near as possible to what is familiar in usual practice and
not require long and complex explanations.

Adaptive. The system should be adaptable to all medical

practices. In some countries, it could be used by nurses and

Therapeutic education: which tool for whom? Jourdain

INTERVIEW

doctors outside usual practice sites. Also, a high percentage


of the population in some countries may not be fluent readers and so the tool should avoid long and complex chapters. Similarly, the systems should be adapted to the key
messages used by the user center as opposed to focusing
solely on guidelines. The system should also be in the native
language.
Useful. The system should be easy to use in many centers

and focus on the key points of HF. The messages should be


chosen by the medical teams and could emphasize specific objectives (eg, self-adjustment of diuretics). Furthermore,
the system should undergo regular evaluation by the medical team.
Educative. The system should aim to usher patients from
a role of simple patient to that of key partner, leading them to
take an active part in their medical management. To do this,
the focus must not rest only on improving knowledge, but on
reactivity as well.
Flexible (In terms of health care expenditure). If the system

is managed by the patients themselves, its degree of complexity is more important than the time involved; however, if
the medical team is involved, the system should use as little medical and nursing time as possible due to health systems restrictions. The system should be flexible in terms of
time consumption and rooms used. Depending on the country, this could concern hospitals only or hospitals and outpatient settings. A very complex and strict system may be used
in studies, but would be difficult to use in real life.

What type of tool or system is best for different


situations?

he type of tool depends on the goal defined at the beginning of the educational process, be it improving compliance, knowledge, or self-management.

Improving compliance. For this goal, we have 2 main options. One focuses on patient follow-up and is related to warning systems (eg, connected watch, smartphones, short message service [SMS], e-mails), but could be based on nonnumeric systems (eg, sticky notes, a diary, posters on the
fridge). The second one focuses more on patient motivation
and is based on the patients perception of the benefit/risk
ratio of taking his/her tablets. Remember that from a patients

SELECTED

ABBREVIATIONS AND ACRONYMS

CHARM Candesartan in Heart failure: Assessment of Reduction


in Mortality and morbidity
HF
heart failure
TPE
therapeutic patient education

Therapeutic education: which tool for whom? Jourdain

point of view, a side effect is certain and has a short-term perspective, while therapy benefit is uncertain and has a longterm perspective. TPE improves compliance and motivates
the patients to take all their medical therapy during all their
life. Proactive patients could themselves indicate their compliance, using simple declarative tools (eg, on a smartphone,
similar to patient medical passports). It is easy to estimate
patient motivation in the first month using this type of tool,
but it is difficult to maintain this kind of self-estimation every
day for years.
Improving knowledge. Information for patients is sometimes scarce and leads to extensive use of the Internet in
search of clear information about their disease or lifestyle
modifications it imposes. However, they may also find confusing or false information in this manner. The more we provide
correct and useful information about daily life with their disease, the less inclined patients will be to search for it elsewhere. Specific Internet sites focusing on specific diseases
are interesting solutions, but require the patient to access
these Internet sites. Another promising solution is the development of specific applications that send daily text messages
to a patients smartphone. One such application is MyHF,
which relays key messages based on real preoccupations of
patients. If doctors are aware of these solutions, they might
find them helpful to relay information from the doctor or pharmacist to the patient.
Improving self-management. This is considered the main
target, because it is the main objective behind equipping the
patient with information. When the patient is not only informed,
but also reactive and involved in his/her follow-up with the
optimization of lifestyle and the awareness of what to do in
case of the most frequent warning signs or complications, the
patient becomes a real nonmedical partner.

Changing patient competencies and not only improving patient knowledge is the main objective of TPE. TPE involves a
multidisciplinary teamincluding nurses, dieticians, doctors,
and sometimes a physiotherapistand it needs time. In real
life, few patients benefit from TPE (less than 5% in France,
for example), despite its being highly recommended in all international guidelines. The 2 mandatory elements are (i) an
educational diagnostic at the beginning of TPE in order to
adapt the program to the patients current knowledge and
perception of the disease and to the therapy and (ii) the setting of a common goal, together with the patient, for the next
visit (improvement of lifestyle, improvement in ability to identify warning signs, improvement of follow-up, etc). Aside from
these 2 elements there are different tools that could be helpful. Some focus on serious games (Internet, apps, gamepads,
etc). These serious games appear to be dynamic, are reallife based and interactive, but are costly and have low flexibility for the patients. Some focus on real-life clinical cases
or may be board games like the HF toolbox game now avail-

MEDICOGRAPHIA, Vol 37, No. 2, 2015

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INTERVIEW

able in 32 countries with the help of a Servier partnership.


These are more adaptive to the entire spectrum of patient
ages and available health care resources (no need for Internet or computer access). This is particularly pertinent in HF
due to the old age of patients (78 years old in Europe). The
tools have to adapt to the patient, not vice versa.

Any final comments on incorporating TPE into


HF management?
o sum up, optimal management of HF should include
TPE to improve patient knowledge, compliance, and reactivity, and such initiatives are enhanced using adapted tools. These tools have to be flexible and adjusted to each
patients level of motivation, beliefs, and limitations. All these
tools should be adapted to local key messages and health
care resources. These tools already exist and could support
the deployment of education programs. Therapeutic education is not simply education, but is intrinsically a therapeutic
act, which we propose to the patient as we would medical
therapy or device treatment. Indeed, TPE is changing how
patients see themselves: from obedient patients to active lifelong partners. It is also changing the doctors relation with the
patient, with the doctor becoming an ever more attentive caregiver.

Who should TPE be offered to and when?


nformation should be given to all patients and their relatives regardless of age and social status. TPE is crucial at
the beginning of the disease especially for less-involved or
-informed patients. Using relaying tools like the MyHF app
or using diaries could be helpful to maintain patient motivation and compliance. The tools should be adapted to a patients limitations (visual, hearing, age, comorbidities, etc), but
all patients except those that refuse should be included in
local or national self-management programs.

Keywords: compliance; heart failure; knowledge; self-management; therapeutic patient education

LDUCATION

THRAPEUTIQUE

QUEL OUTIL ET POUR QUI

Lamlioration des comptences du patient par son ducation thrapeutique, celle de ses proches et des soignants
est un point cl de la prise en charge de linsuffisance cardiaque (IC). Cest la premire tape vers un vritable partenariat entre les professionnels de sant et les patients. Malgr toutes les directives, recommandations et donnes
convaincantes, lducation thrapeutique de lIC est rarement mise en uvre, ce qui contribue en grande partie
linefficacit du traitement et la sur-utilisation des services durgence par des patients mal informs et peu impliqus. Il est difficile dans la vraie vie damliorer lauto-prise en charge du patient, car elle dpend de son bon vouloir et, dans la plupart des pays, du manque de temps que les professionnels de sant peuvent investir dans un tel
effort. Cependant, les outils dducation thrapeutique de lIC sont trs utiles, aidant les mdecins, les infirmires,
les ditticiens et leur kinsithrapeutes dvelopper rapidement les comptences et les capacits des patients pour
mieux vivre avec la maladie. Cest particulirement vrai dans lIC, cause du dlai de 5 jours entre la survenue des
signes cliniques et lhopitalisation chez la majorit des patients. Ces outils doivent tre flexibles et adaptables aux
professionnels de sant et au type de patients, avec des outils probablement plus adapts diffrentes situations.
Ces outils ne doivent pas tre source de tension mais ralistes, encourageant lautonomie des patients et de leurs
proches. Des outils existent dj, aidant infirmires et mdecins former les patients dans des environnements difficiles, tout en faisant face des contraintes de temps. Essayez-les ou crez les vtres pour aider vos patients amliorer leur vie quotidienne avec une IC chronique.

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

Therapeutic education: which tool for whom? Jourdain

FOCUS

Since heart rate is related


to cardiovascular death and heart
failure hospitalization in stable patients, it is also predictive of outcome early at discharge. Heart rate
is also closely associated with
symptoms, being in turn associated with outcomes. Therefore, the
determination of heart rate in accordance with well-being of the patients at discharge might provide
important information helping clinicians to identify those at high
risk for future complications.

Challenges in predicting
heart failure readmission:
focus on heart rate

by M. Bhm, Germany

hronic heart failure is characterized by a high readmission rate, in particular in patients with advanced syndrome. Shortly after discharge,
neuroendocrine activation is particularly evident, resulting in elevated
heart rate and low blood pressure. Both of these vital signs are closely associated with high morbidity and mortality. The open question is whether early
treatment to achieve heart rate reduction with an If -channel inhibitor like ivabradine could reduce the high readmission rate. As heart rate is associated
with hospital admissions and mortality, this approach is worthwhile to study
in a prospectively randomized trial.
Medicographia. 2015;37:197-201 (see French abstract on page 201)

Michael BHM, MD
University Hospital of Saarland
Department of Internal Medicine III
Cardiology, Angiology, and
Intensive Care Medicine
Homburg/Saar
GERMANY

espite intensive multidrug therapy, patients with heart failure are often readmitted to hospital, resulting in an annual rehospitalization rate for heart failure in the United States of 1 million patients per year.1 Despite evidence-based
treatments, often initiated in the hospital, these individuals face high postdischarge
mortality and rehospitalization rates: 15% and 30%, respectively, within 60 to 90
days.2-4 Mechanistically, during this vulnerable phase, an excess of neuroendocrine
activation likely contributes to the high event rate. To take one example, the escape
phenomenon of the renin-angiotensin-aldosterone system (RAAS) provides the basis for a combined inhibitor therapy for heart failure5-7 in stable patients, but such
therapy during the postdischarge vulnerable phase has failed to show benefits.8,9
The treatment of these patients is limited due to the fact that they quite often have
low blood pressure and high heart rates, preventing physicians from treating with
adequate doses of neuroendocrine antagonists.10

Association of heart rate and blood pressure

Address for correspondence:


Michael Bhm, MD,
Universittsklinikum des Saarlandes,
Klinik fr Innere Medizin III,
Kardiologie, Angiologie und
Internistische Intensivmedizin,
Kirrberger Str. 1, DE 66424
Homburg/Saar, Germany
(e-mail: michael.boehm@uks.eu)
www.medicographia.com

Elevated heart rates in heart failure increase oxygen consumption11 and might reduce cardiac contractility due to the inverse force-frequency relationship in vitro12,13
and in vivo.14 In patients with stable heart failure with a heart rate above 70 beats
per minute (bpm) included in the SHIFT trial (Systolic Heart failure treatment with
the If inhibitor ivabradine Trial), heart rate was associated with an increased risk of
cardiovascular death and heart failure hospitalizations,15 which translates into a 3%
increase in risk for every 1-bpm increase from baseline heart rate and 15% increase
in risk for every 5-bpm increase. Consistently, heart rate reduction with ivabradine
in stable patients with heart failure was able to reduce the composite outcome of
cardiovascular death and heart failure hospitalization in individuals with a heart rate
above 70 bpm16 and even cardiovascular death and total mortality in the subgroup

Challenges in predicting heart failure readmission: focus on heart rate Bhm

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Figure 1. Baseline heart rate (left) and 1-week postdischarge heart rate (right) in patients acutely admitted for acute heart failure.
In particular, heart rate 1-week postdischarge is strongly predictive of death after acute hospitalization for heart failure.
Abbreviation: Q, quartile.
After reference 18: Greene et al. JACC Heart Fail. 2013;1:488-496. 2013, American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

of patients with a heart rate above 70 bpm.17 For the postdischarge phase, there are no data on treatment effects of
heart rate reduction. However, a substudy for the EVEREST
trial (Efficacy of Vasopressin antagonism in hEart failuRE:
outcome Study with Tolvaptan) has shown that early after
discharge, a heart rate above 75 bpm was associated with an
increase in mortality, while heart rate at admission showed
no association (Figure 1).18 Furthermore, in a large hospital
registry, the threshold heart rate for an increased risk was
70 to 80 bpm in determining 30-day and 1-year cardiovascular death.19 This observation provides the basis for the hypothesis that heart rate reduction early after discharge might
improve outcome. However, this has to be closely examined
in prospective randomized trials.
After discharge from heart failure hospitalization, undertreatment of patients with b-blockers and angiotensin-converting enzyme (ACE) inhibitors occursin particular, in high-risk
patients with presumably low blood pressure (Figure 2)
and this does not change over the year following discharge.20

SELECTED
bpm

ABBREVIATIONS AND ACRONYMS

beats per minute

EVEREST Efficacy of Vasopressin antagonism in hEart failuRE:


outcome Study with Tolvaptan
RAAS

renin-angiotensin-aldosterone system

SHIFT

Systolic Heart failure treatment with the If inhibitor


ivabradine Trial

SOLVD

Studies Of Left Ventricular Dysfunction

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

Therefore, early initiation (even in hospital) of heart ratereducing therapies such as ivabradine, which is not accompanied by blood pressure reduction,16 might lead to a higher
proportion of patients receiving evidence-based treatment,
which includes heart rate reduction, in the year after discharge.
In the long run, this could improve outcomes.

Heart ratereducing therapy after discharge


The problem in the treatment of the postdischarge vulnerable patient is that about 15% to 25% of patients present with
low blood pressure (ie, <120 mm Hg), which puts them at
a particularly high risk for poor outcomes.10,21,22 Interestingly,
in SHIFT, high heart rates and low blood pressure, in particular the combination thereof, further increased event rates in
heart failure patients.23 In this heart failure population at particularly high risk, the heart rate reducer ivabradine showed no
heterogeneity of treatment effects whether blood pressure
was low or high.23 Furthermore, ivabradine treatment in stable patients did not reduce blood pressure, but even slightly
increased it.16,17
Patients with low blood pressure are more likely to suffer from
multiple cardiovascular and noncardiovascular comorbidities.10 In the SOLVD (Studies Of Left Ventricular Dysfunction)
population, the cumulative load of comorbidities was accompanied by a strong increase in cardiovascular morbidity and
mortality.24 Also, in SHIFT, there was no heterogeneity of the
treatment effects in the elderly,25 in patients with particularly
severe heart failure or low ejection fraction,26 impairment of
renal function,27 intensive treatment with mineralocorticoid antagonists,28 chronic obstructive pulmonary disease,29 or left
bundle branch block.30

Challenges in predicting heart failure readmission: focus on heart rate Bhm

FOCUS

Figure 2. Drug treatment at hospital discharge in patients with chronic heart failure.

in heart failure treatment, because hospitalizations markedly worsen the prognosis in


heart failure patients.36-38 Interestingly, ivabradine was shown not only to reduce those
heart failure hospitalizations occurring as
first events, but also recurrent hospitalizations, with a similar risk reduction as for first
events for patients on ivabradine compared
with placebo.39 Thus, a prospective trial in
postdischarge patients is needed to show
whether heart rate reductionin particular,
in vulnerable patients with low blood pressure early after discharge, in the context of
guideline-based therapies for heart failure
might improve clinical outcomes in patients
with this disabling condition.

These numbers document the risk paradox indicating that those patients with high and average risk
have lower treatment intensity while the same patients exhibit an increased risk concerning 1-year
mortality with or without cerebrovascular events.
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
Data from reference 20: Lee et al. JAMA. 2005;294:1240-1247.

Though still to be proven whether heart rate reduction is safe


in this condition, in the critically ill patient, like in patients with
multiple organ dysfunction syndrome, high heart rate was related to poor outcome.31 Thus, one ongoing trial is looking
at the effect of heart rate reduction with ivabradine in septic
shock.32 The association of heart rate and outcome also holds
true in acutely admitted patients with hypertensive crisis.33
Early experiences with patients in cardiogenic shock provide
evidence that this drug has potential to be applicable in critical cardiac disease34 and, thus, also in patients in a fragile
postdischarge situation. Again, the treatment effect from lowering heart rate has to be carefully examined in prospective
randomized trials to validate these hypotheses-generating
associations.
u Perspectives and future research
While the effect of heart rate reduction is established and such
treatment has been introduced in the heart failure guidelines
of the European Society of Cardiology35 in stable heart failure
patients, data on the postdischarge situation are not available.
Reduction in rehospitalization for heart failure is a crucial goal

u Practical considerations
Despite some deficits in scientific knowledge, heart rate measurement is a very
simple tool to predict future outcomes in
chronic heart failure patients. Since heart rate is related to
cardiovascular death and heart failure hospitalization in stable patients,15,17,23 it is also predictive of outcome early at discharge.9,18,19 Heart rate is also closely associated with symptoms, being in turn associated with outcomes.40

Therefore, the determination of heart rate in accordance with


well-being of the patients at discharge might provide important information helping clinicians to identify those at high risk
for future complications. Those patients would require special attention, such as uptitration of the doses of heart failure
medications and initiation of ivabradine to reduce heart rate
when heart rate stays above 70 bpm. Heart rate should be
calculated as in clinical trials, by an electrocardiogram (ECG)
following sufficient rest time and, as recommended by guidelines, in the sitting position, counting heart beats for 30 seconds and then multiplying the value by 2.41 Altogether, high
heart rate has been identified as a risk marker and in heart
failure has been determined to be a modifiable risk factor for
outcomes that are amenable to heart ratereducing therapy.
In chronic heart failure, the normal or beneficial heart rate is
to be newly defined as below 70 bpm.42

References
1. Blecker S, Paul M, Taksler G, Ogedegbe G, Katz S. Heart failureassociated hospitalizations in the United States. J Am Coll Cardiol. 2013;61:12591267.
2. Gheorghiade M, Abraham WT, Albert NM, et al; OPTIMIZE-HF Investigators
and Coordinators. Systolic blood pressure at admission, clinical characteristics,
and outcomes in patients hospitalized with acute heart failure. JAMA. 2006;
296:2217-2226.
3. Blair JE, Zannad F, Konstam MA, et al; EVEREST Investigators. Continental differences in clinical characteristics, management, and outcomes in patients hospitalized with worsening heart failure results from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) program.

J Am Coll Cardiol. 2008;52:1640-1648.


4. Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization for heart failure: problems and perspectives. J Am Coll Cardiol. 2013;61:
391-403.
5. Zannad F, McMurray JJ, Krum H, et al; EMPHASIS-HF Study Group. Eplerenone
in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;
364:11-21.
6. McMurray JJ, Ostergren J, Swedberg K, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme
inhibitors: the CHARM-Added trial. Lancet. 2003;362:767-771.

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7. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized


trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl
J Med. 2001;345:1667-1675.
8. Gheorghiade M, Bhm M, Greene SJ, et al; ASTRONAUT Investigators and
Coordinators. Effect of aliskiren on postdischarge mortality and heart failure
readmissions among patients hospitalized for heart failure: the ASTRONAUT
randomized trial. JAMA. 2013;309:1125-1135.
9. Maggioni AP, Greene SJ, Fonarow GC, et al; ASTRONAUT Investigators and
Coordinators. Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the
ASTRONAUT trial. Eur Heart J. 2013;34:3117-3127.
10. Gheorghiade M, Vaduganathan M, Ambrosy A, et al. Current management and
future directions for the treatment of patients hospitalized for heart failure with
low blood pressure. Heart Fail Rev. 2013;18:107-122.
11. Colin P, Ghaleh B, Monnet X, Hittinger L, Berdeaux A. Effect of graded heart
rate reduction with ivabradine on myocardial oxygen consumption and diastolic
time in exercising dogs. J Pharmacol Exp Ther. 2004;308:236-240.
12. Bhm M, La Rose K, Schmidt U, Schulz C, Schwinger RH, Erdmann E. Forcefrequency relationship and inotropic stimulation in the nonfailing and failing
human myocardium: implications for the medical treatment of heart failure.
Clin Investig. 1992;70:421-425.
13. Mulieri LA, Hasenfuss G, Leavitt B, Allen PD, Alpert NR. Altered myocardial
force-frequency relation in human heart failure. Circulation.1992;85:1743-1750.
14. Hasenfuss G, Holubarsch C, Hermann HP, Astheimer K, Pieske B, Just H. Influence of the force-frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated
cardiomyopathy. Eur Heart J. 1994;15:164-170.
15. Bhm M, Swedberg K, Komajda M, et al; SHIFT Investigators. Heart rate as a
risk factor in chronic heart failure (SHIFT): the association between heart rate
and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376:
886-894.
16. Swedberg K, Komajda M, Bhm M, et al; SHIFT Investigators. Ivabradine and
outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled
study. Lancet. 2010;376:875-885.
17. Bhm M, Borer J, Ford I, et al. Heart rate at baseline influences the effect of
ivabradine on cardiovascular outcomes in chronic heart failure: analysis from
the SHIFT study. Clin Res Cardiol. 2013;102:11-22.
18. Greene SJ, Vaduganathan M, Wilcox JE, et al; EVEREST Trial Investigators.
The prognostic significance of heart rate in patients hospitalized for heart failure
with reduced ejection fraction in sinus rhythm: insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) trial. JACC Heart Fail. 2013;1:488-496.
19. Habal MV, Liu PP, Austin PC, et al. Association of heart rate at hospital discharge
with mortality and hospitalizations in patients with heart failure. Circ Heart Fail.
2014;7:12-20.
20. Lee DS, Tu JV, Juurlink DN, et al. Risk-treatment mismatch in the pharmacotherapy of heart failure. JAMA. 2005;294:1240-1247.
21. Meredith PA, Ostergren J, Anand I, et al. Clinical outcomes according to baseline blood pressure in patients with a low ejection fraction in the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity)
Program. J Am Coll Cardiol. 2008;52:2000-2007.
22. Cheng RK, Horwich TB, Fonarow GC. Relation of systolic blood pressure to
survival in both ischemic and nonischemic systolic heart failure. Am J Cardiol.
2008;102:1698-1705.
23. Komajda M, Bhm M, Borer JS, et al; SHIFT Investigators. Efficacy and safety
of ivabradine in patients with chronic systolic heart failure according to blood
pressure level in SHIFT. Eur J Heart Fail. 2014;16:810-816.
24. Bhm M, Pogue J, Kindermann I, Pss J, Koon T, Yusuf S. Effect of comorbidities on outcomes and angiotensin converting enzyme inhibitor effects in patients

with predominantly left ventricular dysfunction and heart failure. Eur J Heart
Fail. 2014;16:325-333.
25. Tavazzi L, Swedberg K, Komajda M, et al; SHIFT Investigators. Efficacy and
safety of ivabradine in chronic heart failure across the age spectrum: insights
from the SHIFT study. Eur J Heart Fail. 2013;15:1296-1303.
26. Borer JS, Bhm M, Ford I, et al; SHIFT Investigators. Efficacy and safety of
ivabradine in patients with severe chronic systolic heart failure (from the SHIFT
study). Am J Cardiol. 2014;113:497-503.
27. Voors AA, van Veldhuisen DJ, Robertson M, et al; on behalf of the SHIFT Investigators. The effect of heart rate reduction with ivabradine on renal function in patients with chronic heart failure: an analysis from SHIFT. Eur J Heart
Fail. 2014 Feb 7. Epub ahead of print. doi:10.1002/ejhf.59.
28. Borer JS, Bhm M, Ford I, et al; SHIFT Investigators. Effect of ivabradine on
recurrent hospitalization for worsening heart failure in patients with chronic
systolic heart failure: the SHIFT Study. Eur Heart J. 2012;33:2813-2820.
29. Tavazzi L, Swedberg K, Komajda M, et al; SHIFT Investigators. Clinical profiles and outcomes in patients with chronic heart failure and chronic obstructive pulmonary disease: an efficacy and safety analysis of SHIFT study. Int J
Cardiol. 2013;170:182-188.
30. Reil JC, Robertson M, Ford I, et al. Impact of left bundle branch block on heart
rate and its relationship to treatment with ivabradine in chronic heart failure.
Eur J Heart Fail. 2013;15:1044-1052.
31. Hoke RS, Mller-Werdan U, Lautenschlger C, Werdan K, Ebelt H. Heart rate
as an independent risk factor in patients with multiple organ dysfunction: a
prospective, observational study. Clin Res Cardiol. 2012;101:139-147.
32. Nuding S, Ebelt H, Hoke RS, et al. Reducing elevated heart rate in patients
with multiple organ dysfunction syndrome by the If (funny channel current) inhibitor ivabradine: MODIfY trial. Clin Res Cardiol. 2011;100:915-923.
33. Al Bannay R, Bhm M, Husain A. Heart rate differentiates urgency and emergency in hypertensive crisis. Clin Res Cardiol. 2013;102:593-598.
34. De Santis V, Vitale D, Santoro A, et al. Ivabradine: potential clinical applications
in critically ill patients. Clin Res Cardiol. 2013;102:171-178.
35. McMurray JJ, Adamopoulos S, Anker SD, et al; Task Force for the Diagnosis
and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology; ESC Committee for Practice Guidelines. ESC guidelines for
the diagnosis and treatment of acute and chronic heart failure 2012: The Task
Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
of the European Society of Cardiology. Developed in collaboration with the Heart
Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14:803-869.
36. Solomon SD, Dobson J, Pocock S, et al; Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Investigators. Influence
of nonfatal hospitalization for heart failure on subsequent mortality in patients
with chronic heart failure. Circulation. 2007;116:1482-1487.
37. Liao L, Allen LA, Whellan DJ. Economic burden of heart failure in the elderly.
Pharmacoeconomics. 2008;26:447-462.
38. Abrahamsson P, Swedberg K, Borer JS, et al. Risk following hospitalization in
stable chronic systolic heart failure. Eur J Heart Fail. 2013;15:885-891.
39. Borer JS, Bhm M, Ford I, et al; SHIFT Investigators. Effect of ivabradine on
recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study. Eur Heart J. 2012;33:2813-2820.
40. Ekman I, Chassany O, Komajda M, et al. Heart rate reduction with ivabradine
and health related quality of life in patients with chronic heart failure: results from
the SHIFT study. Eur Heart J. 2011;32:2395-2404.
41. Palatini P, Benetos A, Grassi G, et al; European Society of Hypertension. Identification and management of the hypertensive patient with elevated heart rate:
statement of a European Society of Hypertension Consensus Meeting. J Hypertens. 2006;24:603-610.
42. Palatini P. Need for a revision of the normal limits of resting heart rate. Hypertension. 1999;33:622-625.

Keywords: heart failure; heart rate reduction; If -channel inhibitor; ivabradine; postdischarge; rehospitalization

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Challenges in predicting heart failure readmission: focus on heart rate Bhm

FOCUS

LA

RHOSPITALISATION DANS L INSUFFISANCE CARDIAQUE


INTRT DE LA FRQUENCE CARDIAQUE

Linsuffisance cardiaque chronique se caractrise par un taux lev de rhospitalisation, surtout pour les patients
un stade avanc. Lactivation neuro-endocrinienne est particulirement vidente juste aprs la sortie de lhpital, se
manifestant par une frquence cardiaque leve et une pression artrielle basse. Ces deux signes vitaux sont troitement associs une mortalit et une morbidit leves. Reste savoir si un traitement prcoce pour diminuer la
frquence cardiaque par un inhibiteur du canal If comme livabradine pourrait rduire le taux lev de rhospitalisation. La frquence cardiaque tant associe aux hospitalisations et la mortalit, cest une question qui mrite de
faire lobjet dune tude prospective randomise.

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201

U P DAT E

Current data of the German


population estimate there are
more than 1.8 million inhabitants
suffering from chronic heart failure. Put in other numbers, every
tenth inhabitant over 65 years of
age is affected and approximately
200 000 to 300 000 cases are newly diagnosed every year. Other
population-based statistics such
as those for the United States reveal similarly increasing numbers.
In Germany alone, the cost of heart
failure treatment is approximately
3 billion per year.

Telemonitoring in
heart failure management:
what is needed to make it fit
for routine use?
by C. Zugck, Germany

I
Christian ZUGCK, MD
Specialist in Internal Medicine
Cardiology, Angiology, and
Intensive Care Medicine
and Medical Director of the
Cardiac Catheterization
Laboratory at Bogen Hospital
and Fellow of the European
Society of Cardiology
and Group Practice for
Internal Medicine
Steiner Thor, Straubing
GERMANY

n parallel to the increasing complexity of medical and device therapy in


chronic heart failure, patients in need of treatment are growing older. Specifically in the case of deterioration of cardiac function and symptoms of heart
failure, evaluation of heart failure status may differ between subjective assessment of well-being and assessment based on objective parameters. Advances in telemonitoring may offer an opportunity to help rebalance the continuously growing health economic burden. Current concepts of telemonitoring
in heart failure include measurement of weight, vital signs, and concentrations
of B-type natriuretic peptide, as well as changes in intrathoracic impedance
and in pulmonary artery and left atrial pressures. The importance of remote
monitoring in patients with cardiac implantable electronic devices is already
positively addressed in current European guidelines. However, clear interpretation of studies on noninvasive telemonitoring has been hindered by nonstandardized definitions of end points and by the lack of end point definitions
specific enough to describe successful disease management through telemedical intervention. Although 2 meta-analyses have demonstrated an overall beneficial effect of telemedicine over usual care in patients with chronic
heart failure, 2 large randomized trials did not confirm former positive results.
Subsequently, todays international guidelines do not state a clear recommendation for telemedical support. Despite these limitations, telemonitoring
has the potential to improve heart failure care in various ways, most importantly by improving quality of life and by reducing cardiovascular morbidity
and mortality.
Medicographia. 2015;37:202-207 (see French abstract on page 207)

Address for correspondence:


Professor Dr. med. Christian Zugck,
Facharzt fr Innere Medizin,
Kardiologie, Angiologie und
Intensivmedizin, Geschftsfhrer
Internistische Gemeinschaftspraxis
Steiner Thor, Bahnhofstr. 1, 94315,
Straubing, Germany
Branch: FachArztZentrum Bogen,
Mussinanstrae 31, 94327 Bogen,
Germany
(e-mail:
zugck@internisten-steinerthor.de)
(Website:
www.internisten-steinerthor.de)
www.medicographia.com

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

enerally speaking, telecardiology is one of the most advanced fields in telemedicine. Looking back to Willem Einthovens first description of the successful transmission of a single-lead electrocardiogram (ECG) over a telegraph line in 1906, many decades would pass before the importance of telemonitoring
in heart disease would surface again. Today, over a century later, state-of-the-art
medical device technology for heart disease facilitates communication between
patients and caregivers. Specifically, in the case of chronic heart failure, telemonitoring can contribute to timely diagnostic and therapeutic measures. A number of
concurrent developments such as demographic change in industrialized countries
and revolutionary improvements in cardiovascular diagnostics, therapy, and medical device technologyspecifically in regard to hypertension and coronary heart
disease in recent yearscan be implicated in the clearly growing number of heart

Telemonitoring in heart failure management Zugck

U P DAT E

failure patients.1 Indeed, current data of the German population estimate there are more than 1.8 million inhabitants suffering from chronic heart failure. Put in other numbers, every
tenth inhabitant over 65 years of age is affected and approximately 200 000 to 300 000 cases are newly diagnosed every
year.2 Other population-based statistics such as those for
the United States reveal similarly increasing numbers.3,4 In
Germany alone, the cost of heart failure treatment is approximately 3 billion per year. Advances in telemonitoring of these
patients may provide an opportunity to help rebalance the
continuously growing health economic burden. The development of efficient and secure information/communication
technology and the growing use of Internet-based platforms
enable a broad spectrum of telemonitoring methods to surface. The present article reviews current concepts of telemonitoring in the field of heart failure, all carrying the potential to
improve medical caregiving in various ways and thus, ideally,
reducing morbidity and mortality in heart failure.

Perspectives for telemonitoring in heart failure


u Subjective assessment and objective surveillance
parameters
Specifically in the case of deterioration of cardiac function and
symptoms of heart failure, evaluation of heart failure status
may differ between subjective assessment of well-being and
assessment based on objective parameters. In daily practice,
relying on patients subjective perception of clinical symptoms
may therefore not be sufficiently reliable to detect cardiac decompensation at an early stage. For many of these patients,
recurrent in-hospital treatment may seem unavoidable. The
starting point of heart failure treatment strongly depends on
the patients venue of usual care. Clinical practices and ther-

SELECTED

ABBREVIATIONS AND ACRONYMS

CHAMPION

CardioMEMS Heart sensor Allows Monitoring


of Pressure to Improve Outcomes in NYHA
class III patients

CRT-D

cardiac resynchronization therapy defibrillator

ECG

electrocardiogram

ESC

European Society of Cardiology

HHH

Home or Hospital in Heart failure

HOME-HF

Evaluation of Patients With Heart Failure


Using Home Telemonitoring

HOMEOSTASIS Hemodynamically Guided Home Self-Therapy


in Severe Heart Failure Patients
LVEF

left ventricular ejection fraction

NYHA

New York Heart Association

Tele-HF

Telemonitoring to improve Heart Failure


outcomes

TEN-HMS

Trans-European Network Home-Care


Management System

TIM-HF

Telemedical Interventional Management in


Heart Failure

Telemonitoring in heart failure management Zugck

apeutic regimens may differ between medical specialties, individual physicians, and even sexes. In addition, the accessibility of dedicated heart failure clinics and patient education activities depends on regional circumstances.
Current concepts of telemonitoring in heart failure include
measurement of weight, vital signs, and concentrations of
B-type natriuretic peptide, as well as changes in intrathoracic
impedance and in pulmonary artery and left atrial pressures.
The relationship between these objective parameters and the
clinical situation, however, may be quite complex and prone
to interference due to cofactors. For example, in some patients, significant weight gain may not always correlate with
fluid retention or can occur slightly delayed to decompensation. Understandably, there are limits to any single parameter applied as a surrogate for imminent cardiac decompensation.
A classification of telemedicine in heart failure proposed by
Anker et al in 2011 describes 4 generations of noninvasive
telemonitoring strategies (Figure 1, page 204)5 and thus does
not touch upon the use of remote monitoring via cardiac implantable electronic devices.
u Appropriate end point definitions in telemonitoring
studies
Current studies on heart failure management with use of telemonitoring are discussed in detail further below. So far, clear
interpretation of these studies has been hindered by nonstandardized end point definitions and by the lack of those
specific enough to describe successful disease management
through telemedical intervention. Undoubtedly, frequent hospitalizations are a relevant health economic burden and inhospital care due to heart failure is an important marker of disease deterioration. However, counting hospital admissions in
order to measure clinical success of telemonitoring may not
accurately reflect the whole situation.

The primary choice of applicable end points and the appropriate interpretation of study results depend largely on the
design and duration of the individual study. Contemporary
time-to-event outcome analysis can therefore be misleading.
Indeed, an analysis of time to first hospitalization for heart failure or cardiovascular death would suggest that a patient who
had an early, short rehospitalization and perhaps no further
hospitalization afterwards would have a worse outcome than
a patient who died just some time later, which is clearly not
the case. Hence, novel methods of comparison carrying the
potential to reveal the true impact of hospitalization on the
clinical status of heart failure patients are warranted. It is conceivable that patients who receive telemonitoring or other
measures of intensified care may even be hospitalized more
often, though quite possibly in a less symptomatic stage and
ideally with a shorter length of stay than patients who are hospitalized acutely in a very critical situation.

MEDICOGRAPHIA, Vol 37, No. 2, 2015

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Figure 1. Proposal for classification of telemedicine in heart failure.


Abbreviations: ECG, electrocardiogram; GP, general practitioner; HF, heart failure; TMC, telemedical center.
Based on reference 5: Anker et al. Lancet. 2011;378(9792):731-739. Courtesy of Koehler F.

From another perspective, hospitalization is often accompanied by the chance to escalate medical therapy, optimize medical device therapy, offer novel patient education programs,
or discuss candidacy for cardiac transplantation. Surely, the
definition of success of adjunct telemonitoring in heart failure
is still in the concept stage and its decisive role will remain
open to discussion for some time yet.
Of note, days alive and out of hospital represents one of the
newer clinical end points used in statistical analysis of outcome in chronic diseases such as chronic heart failure. In comparison with contemporary time-to-event measures, the end
point days alive and out of hospital incorporates both the
number and the duration of multiple rehospitalizations. Further advantages are that it allows for greater emphasis on
mortality and may reveal significant variations in treatment.
The section below summarizes the current evidence in telemonitoring for improving adherence to treatment and for predicting and preventing disease progression in heart failure.

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Clinical studies for noninvasive use of


telemedicine in heart failure
In 2005, the TEN-HMS study (Trans-European Network
Home-Care Management System) was the first larger study
that analyzed the role of telemonitoring in selected patients
with heart failure.6 TEN-HMS was a 3-arm, prospective randomized study in which patients included had a recent admission for heart failure, a left ventricular ejection fraction (LVEF)
under 40%, persisting symptoms of heart failure, the need for
diuretic therapy, and at least 1 predefined additional marker
of higher risk, such as an LVEF under 25% or treatment with
furosemide at a dosage of greater than or equal to 100 mg/day.
In total, 426 patients were assigned randomly to telemonitoring, nurse telephone support, or usual care in a 2:2:1 ratio.
Telemonitoring enabled data transfer (weight, blood pressure,
ECG) via a conventional telephone line to a central Web server and then via secure intranet connections to a workstation
based at each investigator site. Patients were asked to transfer data twice daily. Values greater than or less than prede-

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fined limits were signaled automatically to study nurses who


could provide advice to the patient directly or, in more severe cases, first inform the primary care physician.
In addition to usual care, patients in the group with nurse telephone support were able to contact the heart failurespecialist nurse by telephone at any time during office hours. Additionally, the nurse contacted the patients by telephone each
month in order to assess their symptoms and current medication and to provide advice. In comparison with usual care
alone, mortality and rehospitalization rates were lower in the
groups receiving either telemonitoring or nurse telephone support, with no significant differences between both these intervention groups. Of note, the duration of hospital stay and
therefore the time until outpatient care was sufficient was 6
days shorter in the group of patients receiving telemonitoring.
A number of other studies, such as HOME-HF (Evaluation of
Patients With Heart Failure Using Home Telemonitoring)7 and
HHH (Home or Hospital in Heart failure)8 have described similar benefits of telemonitoring in heart failure in regard to the
frequency and duration of hospitalizations and contacts with
emergency services due to recurrent decompensation.
Bringing together the available data, 2 meta-analyses demonstrated an overall beneficial effect of telemedical intervention over usual care in patients with chronic heart failure.5,9,10
A Cochrane Collaboration meta-analysis published in 2011
described the advantage of telemonitoring in heart failure in
respect to reducing overall mortality by 44% and hospitalizations by 21%.9 However, the variable methodological quality between studies and small study populations limited data
interpretation.
In contrast, 2 large, prospective randomized trials: Tele-HF
(Telemonitoring to improve Heart Failure outcomes)11 and
TIM-HF (Telemedical Interventional Management in Heart Failure)12 did not confirm former positive results.
Tele-HF randomized 1653 patients to either telemonitoring with
use of a commercially available system (Tel-Assurance, Pharos
Innovations, USA) or usual care. Telemonitoring operated on
the basis of toll-free calls to an interactive voice response system that questioned general health, heart failure symptoms,
and body weight daily and signs of depression once a month.
Clinicians reviewed patients answers on business days and
patients whose data indicated worsening of heart failure were
contacted. Individual contact with nurses or doctors by telephone was not provided. In Tele-HF, telemonitoring with use
of the automated Tel-Assurance did not improve outcomes.
The primary end point defined as all-cause hospital readmission or death within 180 days was achieved in a comparably
high number of patients (52.3% in the telemonitoring group
and 51.5% in the group receiving usual care; P=0.75). Furthermore, death rates did not differ between groups.11

Telemonitoring in heart failure management Zugck

The TIM-HF trial equally randomized 710 patients suffering


from heart failure in New York Heart Association (NYHA) functional class II or III and an ejection fraction less than or equal
to 35% to 2 groupsthe first receiving usual care and the
second receiving a portable device with which they could
transfer data on weight, blood pressure, and ECG via Bluetooth to a telemedical service center. In comparison with earlier concepts, the telemedical center provided physician-led
medical support 24 hours per day, 7 days per week for the
entire study period. Furthermore, the telemedical center contacted the patients local physician at least every 3 months
and an emergency system was integrated in accordance with
standard operating procedures. Follow-up duration was 12
months minimum; mean follow-up was 26 months. All-cause
mortality constituted the primary outcome. The main secondary outcome measure was cardiovascular death or hospitalization due to worsening of heart failure. Patients in both study
arms had optimized medical therapy (angiotensin-converting enzyme [ACE] inhibitors, 96.6% versus 94.1%; b-blockers, 92.% versus 93.0%; aldosterone antagonists, 65.3% versus 63.2% in the usual care group versus the telemonitoring
group, respectively). Compliance with daily data transfers was
high (>70%). In regard to the primary and secondary outcome measures, no significant effect of telemonitoring was
detected.12
To summarize the 2 aforementioned trials, in comparison with
usual care and medical therapy, both randomized studies were
unable to detect a significant reduction in all-cause mortality or rehospitalization in the group receiving telemedical intervention as an adjunct to usual care. However, the study
design and population of both trials require critical analysis.
In the Tele-HF trial, the concept of data transfer for weight and
symptoms to an automated speech recognition system was
hardly made use of by most study patients and in itself does
not represent todays perception of telemedical care. For the
case of the TIM-HF trial, body weight, blood pressure, and a
3-lead ECG were transmitted on a daily basis; however, requirement for study patient enrolment included fully optimized
and guidelines-adherent therapy before initiation of telemonitoring. The high percentage of patients with implantable cardioverter defibrillators (>40%) may be reflected in the low mortality rate (<8% per year) in this study as well. Unfortunately,
such pronouncedly optimized drug and device therapy in patients who additionally were cared for by a cardiologist every
3 months, as in the TIM-HF study, does not reflect real-world
medical care in heart failure. This preoptimized situation may,
however, explain why the TIM-HF study did not reveal an
additional benefit of telemonitoring and the very low occurrence of end points in the overall cohort. Subgroup analysis
showed a significant benefit of telemonitoring in certain cohorts, such as those patients who suffered decompensated
heart failure in the past. These promising results in subgroups
lead to the initiation of the TIM-HF II study (Telemedical Inter-

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ventional Management in Heart Failure II). This ongoing trial


is assessing 1500 patients with chronic heart failure (NYHA
class II or III), an LVEF less than or equal to 45% or greater
than 45%, a minimum of 1 diuretic in permanent medicinal
therapy, and a previous hospitalization due to decompensated heart failure within the last 12 months before randomization. All participants will continue to receive usual care from
their general practitioner and specialist and will undergo a
checkup every 3 months. Half of the patient cohort will be
randomly allocated to daily telemonitoring (weight, blood pressure, and heart rate). The primary end point of this study is
days lost due to unplanned cardiovascular hospitalization or
death.13

Implantable sensors
Novel concepts to measure physiological signs of disease
progression, such as increasing pulmonary artery pressures
measured directly with implantable monitors, may complement the current strategy of external, remote telemonitoring.
In the CHAMPION trial (CardioMEMS Heart Sensor Allows
Monitoring of Pressure to Improve Outcomes in NYHA class III
Patients), tailored therapy according to pulmonary artery pressures was associated with a 39% reduction in heart failure
hospitalizations.14 Furthermore, the HOMEOSTASIS study (Hemodynamically Guided Home Self-Therapy in Severe Heart
Failure Patients) described improved hemodynamics, symptoms, and outcomes in patients at high risk for recurrent decompensation who, in addition to usual care and under guidance from a heart failure team, self-adjusted their diuretic
therapy according to the measurements of an implanted left
atrial pressure sensor.15
Timely prognostication of upcoming decompensation may
also be provided by certain cardiac resynchronization therapy
defibrillator (CRT-D) devices, which also have the functionality
to monitor fluid index and patient activity. In the PARTNERS
HF study (Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With
Heart Failure), a combined algorithm was used to detect which
patients of the 694 included fulfilled predefined criteria for
higher risk. The criteria included long atrial fibrillation duration,
rapid ventricular rate during atrial fibrillation, high fluid index,
low patient activity, abnormal autonomics (increased heart
rate at night or low heart rate variability), and device therapy.
The algorithm required at least 2 abnormal parameters to be
considered positive. The results revealed that those patients
who had positive combined heart failure device diagnostics
had a 5.5-fold increased risk of heart failure hospitalization
with pulmonary signs or symptoms within the next month.
Thus, the study suggested that regarding subsequent events,
diagnostics driven by CRT-D device data may stratify heart
failure patients into high- and low-risk groups.16

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Guideline recommendations
Due to sufficient evidence available, the importance of remote
monitoring in patients with cardiac implantable electronic devices is already positively addressed in current European guidelines (European Society of Cardiology [ESC] class IIa, Level
A17). Of note, this current article focuses on the use of noninvasive telemonitoring techniques in heart failure. According
to the American College of Cardiology Foundation/American
Heart Association (ACCF/AHA) 2009 and 2013 heart failure
guidelines, postdischarge systems of care, such as telecommunication, should be used to support the transition to effective outpatient care. However, the American guidelines summarize current evidence for the individual components of heart
failure management such as home-based care,18,19 disease
management,20 and remote telemonitoring programs as mixed
and comment that the quality and cost-effectiveness of such
programs require further evaluation. Similarly, though acknowledging the data from a meta-analysis of randomized
controlled trials supporting the reduction in hospitalizations,
the ESC/ESC-Heart Failure Association (ESC-HFA) guidelines
do not state a clear recommendation for telemedical support.17
The European guidelines argue that only a few individual randomized controlled trials have shown this benefit, and thus
the evidence is not robust enough to support a guideline recommendation.

Conclusion
While the complexity of medical and device therapy in chronic heart failure is increasing, patients in need of treatment are
also growing older. Contemporary evaluation measures often
fail to early identify those critical heart failure patients at risk
for worsening of heart failure. Hospitalization is therefore common after heart failure diagnosis. The economic burden is not
limited to the cost of health care services and medications,
but includes lost productivity of patients and family caregivers
as well. These developments may lead to difficulties in the
optimal implementation of guideline specifications in daily practice. Individualized patient care seems, therefore, inevitable.
From these aspects, telemonitoring may be beneficial in both
the acute posthospitalization, or bridge-to-stability phase,
and in long-term care in order to establish close and longlasting control of clinical stability. Numerous nonstandardized
definitions including those that have defined the specific elements of telemonitoring and optimal patient cohorts in need
of support and those that have defined clinical success have
been the main limitations so far. This issue has subsequently
made the appropriate interpretation of data and the transfer
to guideline recommendations difficult. Despite these limitations, current data point toward the potential of telemonitoring
to improve heart failure care in various ways, most importantly by improving quality of life and by reducing cardiovascular
morbidity and mortality.

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References
1. Cleland JG, Swedberg K, Follath F, et al; Study Group on Diagnosis of the
Working Group on Heart Failure of the European Society of Cardiology. The
EuroHeart Failure survey programmea survey on the quality of care among
patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J. 2003;24(5):442-463.
2. Statistisches Bundesamt Deutschland. Gesundheitswesen, Anzahl der Gestorbenen nach Kapiteln der ICD-10. 2004. http://www.destatis.de/basis/d/gesu/
gesutab19.htm.
3. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics
2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117(4):e25-e146.
4. Cubbon RM, Gale CP, Kearney LC, et al. Changing characteristics and mode
of death associated with chronic heart failure caused by left ventricular systolic
dysfunction: a study across therapeutic eras. Circ Heart Fail. 2011;4(4):396403.
5. Anker SD, Koehler F, Abraham WT. Telemedicine and remote management of
patients with heart failure. Lancet. 2011;378(9792):731-739.
6. Cleland JG, Louis AA, Rigby AS, Janssens U, Balk AH. Noninvasive home
telemonitoring for patients with heart failure at high risk of recurrent admission
and death: the Trans-European Network-Home-Care Management System
(TEN-HMS) study. J Am Coll Cardiol. 2005;45(10):1654-1664.
7. Dar O, Riley J, Chapman C, et al. A randomized trial of home telemonitoring
in a typical elderly heart failure population in North West London: results of the
Home-HF study. Eur J Heart Fail. 2009;11(3):319-325.
8. Mortara A, Pinna GD, Johnson P, et al. Home telemonitoring in heart failure
patients: the HHH study (Home or Hospital in Heart Failure). Eur J Heart Fail.
2009;11(3):312-318.
9. Inglis SC, Clark RA, McAlister FA, Stewart S, Cleland JG. Which components
of heart failure programmes are effective? A systematic review and meta-analysis of the outcomes of structured telephone support or telemonitoring as the primary component of chronic heart failure management in 8323 patients: Abridged
Cochrane Review. Eur J Heart Fail. 2011;13(9):1028-1040.
10. Klersy C, De Silvestri A, Gabutti G, Regoli F, Auricchio A. A meta-analysis of remote monitoring of heart failure patients. J Am Coll Cardiol. 2009;54(18):
1683-1694.
11. Chaudhry SI, Mattera JA, Curtis JP, et al. Telemonitoring in patients with heart
failure. N Engl J Med. 2010;363(24):2301-2309.

12. Koehler F, Winkler S, Schieber M, et al. Impact of remote telemedical management on mortality and hospitalizations in ambulatory patients with chronic heart failure: the telemedical interventional monitoring in heart failure study.
Circulation. 2011;123(17):1873-1880.
13. Charite University, Berlin, Germany; German Federal Ministry of Education and
Research University of Leipzig. Telemedical Intervention Management in Heart
Failure II (TIM-HF II). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National
Library of Medicine (US). Updated June 17, 2014. Available from: http://clini
caltrials.gov/show/NCT01878630. NLM Identifier: NCT01878630.
14. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery hemodynamic monitoring in chronic heart failure: a randomised controlled trial.
Lancet. 2011;377(9766):658-666.
15. Ritzema J, Troughton R, Melton I, et al. Physician-directed patient self-management of left atrial pressure in advanced chronic heart failure. Circulation.
2010;121(9):1086-1095.
16. Whellan DJ, Ousdigian KT, Al-Khatib SM, et al. Combined heart failure device
diagnostics identify patients at higher risk of subsequent heart failure hospitalizations: results from PARTNERS HF (Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart
Failure) study. J Am Coll Cardiol. 2010;55(17):1803-1810.
17. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for
the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the
European Society of Cardiology. Developed in collaboration with the Heart
Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14(8):803-869.
18. Stewart S, Marley JE, Horowitz JD. Effects of a multidisciplinary, home-based
intervention on unplanned readmissions and survival among patients with chronic congestive heart failure: a randomised controlled study. Lancet. 1999;354
(9184):1077-1083.
19. Stewart S, Pearson S, Horowitz JD. Effects of a home-based intervention among
patients with congestive heart failure discharged from acute hospital care.
Arch Intern Med. 1998;158(10):1067-1072.
20. Faxon DP, Schwamm LH, Pasternak RC, et al. Improving quality of care through
disease management: principles and recommendations from the American
Heart Association's Expert Panel on Disease Management. Circulation. 2004;
109(21):2651-2654.

Keywords: chronic heart failure; device therapy; therapy optimization

LA

TLSURVEILLANCE DANS LA PRISE EN CHARGE DE L INSUFFISANCE CARDIAQUE


QUE FAUT- IL POUR LADAPTER LA PRATIQUE QUOTIDIENNE ?

Paralllement la complexit croissante des traitements mdicaux et instrumentaux de linsuffisance cardiaque, les
patients qui en ont besoin vieillissent. Lvaluation de linsuffisance cardiaque peut varier entre une estimation subjective du bien-tre et celle de paramtres objectifs, surtout en cas de dtrioration de la fonction cardiaque et des
symptmes dinsuffisance cardiaque. Les progrs de la tlsurveillance peuvent aider rquilibrer le poids conomique sans cesse croissant de la sant. La mesure du poids, les signes vitaux et les concentrations de peptide
natriurtique de type B, ainsi que les modifications de limpdance intrathoracique et des pressions artrielle pulmonaire et auriculaire gauche sont les concepts actuels de la tlsurveillance dans linsuffisance cardiaque. Les recommandations europennes actuelles prennent dj en charge de faon positive limportance du contrle distance des patients porteurs de dispositifs lectroniques implantables cardiaques. Cependant, le manque de dfinition assez spcifique des critres pour dcrire une prise en charge russie de la maladie grce une intervention
tlmdicale et leur non-standardisation ont empch une interprtation claire des tudes de tlsurveillance non
invasive. Deux mtaanalyses ont dmontr un effet global bnfique de la tlmdecine pour les soins courants des
patients insuffisants cardiaques chroniques, mais deux grandes tudes randomises nont pas confirm de rsultats
positifs. Les recommandations internationales daujourdhui nont pas prsent par la suite de directives claires pour
lassistance tlmdicale. Malgr ces limites, la tlsurveillance permet damliorer de diffrentes faons les soins
de linsuffisance cardiaque, surtout en amliorant la qualit de vie et en diminuant la morbidit et la mortalit cardiovasculaires.

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OF FRANCE
hroughout the history of
the Mediterranean region
of France, two cities have
shone with particularly intense
light: Marseille, an offshoot of Greco-Roman culture, and Montpellier, founded in the Middle Ages.
Mediterranean cultural heritage
past and present is now showcased in todays vibrant Marseille
in the Museum of European and
Mediterranean Civilizations (MuCEM), and Montpellier, the seat of
the oldest medical faculty in Europe, remains to this day a torchbearer of French medical science
and clinical excellence.

MuCEM,
the pride of Marseille
M . R a i v e , Fra n c e
Page 210

The Medical Faculty of


Montpellier: one thousand
years of medicine
C . R g n i e r, Fra n c e
Page 221

Museum of European
Civilization and
the Mediterranean
(MuCEM):
Lattice, Bridge to Fort
Saint-Jeana jewel
set against the blue
Mediterranean sky
and waters.
Edmund Sumner/
VIEW:Corbis.

A TOUCH
uCEM seems to hover
between sea and sky. A
square and sober block,
enveloped by a veil of openwork
concrete evocative of Islamic
mashrabiyas, MuCEMs main building (15 000 m2 ) has become a waterfront extension of the city on the
pier from where, until decolonization, travelers from around the
world came and went: jazz arrived
here from the United States in the
1920s, and a decade later artists
and writers fled Nazism in the other direction.

OF

FRANCE

MuCEM,
the pride of Marseille

b y M . R a i v e , Fra n c e
ike a majestic black vessel poised between land and sea, the Muse des
civilisations de lEurope et de la Mditerrane (MuCEM) stands at the entrance to the port of Marseille. A perfect square girded by concrete latticework redolent of Islamic mashrabiyas, MuCEM was inaugurated in June
2013, one of the few provincial museums opened in France in recent times.
Designed by Rudy Ricciotti, a 62-year-old Algerian-born French architect,
MuCEM draws visitors from around the world. From Marseille too, because
this cultural institution is also a place where locals can stroll along walkways
between the historic quarter of the upper part of town and the waterfront,
taking ownership as it were of their Mediterranean port and city, founded in
600 BC by Greeks from Phocaea (Anatolia in present-day Turkey). Through its
focus on society, MuCEM has from its inauguration curated high-level and
thought-provoking exhibitions from sundry collections of popular art (250 000
objects and hundreds of thousands of documents) inherited from the former
Muse National des Arts et Traditions Populaires in Paris: great artworks and
archaeological treasures, contemporary art alongside 19th-century agricultural tools, traditional costumes from all over Europe, a fine collection of merrygo-rounds, and their wooden horses. Through a multidisciplinary dialogue
between cultures and continents, MuCEM challenges us, questions us, and
shows us how art is part of life.

L
Mathilde RAIVE, journalist

Medicographia. 2015;37:210-220 (see French abstract on page 220)

arely has a contemporary building helped a townspeople take ownership of


their city like the Muse des civilisations de lEurope et de la Mditerrane
(MuCEM) in Marseille. Inaugurated in June 2013, architect Rudy Ricciottis creation at the entrance to the port was the centerpiece of the celebrations that year
when Marseille was designated European Capital of Culture. Wrapped in concrete
latticework, this remarkable building, with breathtaking views across the azure of
the Mediterranean, is reason enough for a stroll along its 115-meter footbridge
over its encircling moats and beyond. MuCEM rose to its challenge from the outset: to attract lovers of art and architecture from around the world, but also to appeal to those for whom cultural institutions are an alien world.

Frances newest museum


E-mail for correspondence:
mraive@gmail.com
www.medicographia.com

MuCEM, the pride of Marseille Raive

What is the measure of MuCEMs success? We need look no further than visitor
numbers. In the first year after its opening, it welcomed some 950 000 visitors to its
collections and exhibition rooms. Outside, over 2.8 million promenaders flocked to the

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MuCEM, the Pride of Marseille.


Edmund Sumner/VIEW:Corbis.

A TOUCH

OF

FRANCE

inclined gangways that run around the museum and on to


the metal footbridge that spans the waves and joins MuCEM
to the Mediterranean garden of the Fort Saint-Jean high above
the port. Numbers that outstripped expectations three-fold.
MuCEM, the latest museum in France and the only one inaugurated in the provinces for many years, is already riding
high among the worlds most visited museums.

it is true that half of these are from the Provence-Alpes-Cte


dAzur region, but the remaining 15% are from overseas: Germany (20%), Belgium (12%), Italy (11%), Switzerland (10%),
and the United States (6%). Visitors even come to Marseille
with the express purpose of discovering this architectural feat.
As a great museum focused on societal issues, MuCEM houses collections transferred from the erstwhile Muse national
des Arts et Traditions Populaires in Paris, created in 1937.
Ethnography was MuCEMs founding discipline, but its vocation has greater scope. Standing on the north shore of the
Mediterranean, it serves as a cultural city open to the human
sciences and to art in all its guises, by bringing together what
is known as world culture, in a crosscutting dialogue between the arts, cultures, and continents, between Europe,
the Americas, Africa, and the Orient. By
promoting exchanges between the two
shores of the Mediterranean, MuCEM
fulfills its calling, suggestive of the Tower
of Babel or of a casbah (North African
fortress) to be climbed so as to gaze
across to other horizons.

Overlooking the Mediterranean, the waterfront site blends


with brio into its setting, refining it the while, such that once
again it is becoming the cynosure of the Department of the
Bouches-du-Rhne. To the point that for the title of the symbol of Marseille it rivals the Catholic basilica Notre-Dame-dela-Garde, which for centuries has kept
watch majestically over the city from
its outcrop 150 meters above the port.
Like a Good Mother, as it is known,
the church has, since the Middles Ages,
watched over Marseilles sailors and
fishermen. Expanded in the mid-19th
century, Notre-Dame-de-la-Garde today stands on the site of the original
small medieval chapel. The Neo-Byzantine and Romanesque styles of the
How is it possible to remain untouched
church, with its square bell tower surby the sensuous delights of this buildmounted by a belfry topped by a stating open to the high seas at the enue of the Madonna and Child over 11
trance to the Old Port? By the melding
meters high, its copper gilded with gold
of sight and touch, of odors from the
leaf gleaming in the sunlight, contrast
sea, the taste of iodine on whistling
sharply with the harmonious and matwinds from afar. Even before it was comte blacks and grays of the MuCEM.
pleted, Rudy Ricciotti noted that with
As if this crossroads of anthropology,
its aerial walkways, MuCEM conjures
history, archaeology, art history, and
Rudy Ricciotti,
up the ascension of a ziggurat, a Mesocontemporary art did not wish to cast
the architect of MuCEM (2013). IBO/SIPA.
potamian terraced temple. Its mema shadow over the blue waters of the
Mediterranean. MuCEM seems to hover between sea and branes of dark concrete openwork evoke ties with a distant
sky. A square and sober block, enveloped by a veil of open- Orientalism. The south and west frontages, the sun-drenched
work concrete evocative of Islamic mashrabiyas, MuCEMs roof open to the public, are wrapped in a black concrete
main building (15 000 m2) has become a waterfront exten- mashrabiya, while the seawater circulates in the moats under
sion of the city on the pier from where, until decolonization, the gangways, the smell of iodine intensified by the mistral.
travelers from around the world came and went: jazz arrived
here from the United States in the 1920s, and a decade later
A visionary proud of his Mediterranean roots
artists and writers fled Nazism in the other direction.
Born in Algeria in 1952 to parents of Italian origin, raised in
Provence, Rudy Ricciotti graduated from the cole Nationale
MuCEM and its rich historical setting are so stately that they Suprieure d'Architecture de Marseille and is today resident
seem to have become the quintessential setting for a Sunday in Bandol (Provence-Alpes-Cte dAzur region). Winner of the
stroll for many of Marseilles folk, drawn as they have been 2006 Grand Prix national de l'architecture (Grand National
since its opening by affection for this contemporary vessel, Prize of Architecture), Ricciotti is a visionary proud of his
where they see, as its designer Rudy Ricciotti puts it, the Mediterranean roots. He loves materials rooted in the earth
know-how of those who built it, the work of the stonemasons,
and in the lives of men and women. Son of a stonemason, he
engineers, site foremen, and journeymen.
knows that construction is a task for men and women who
dream of defying the gods and eternity. Fascinated by the
Though MuCEM speaks to the heart of the people of Mar- secrets transmitted by site foremen or by skilled artisans, his
seille, as Ricciotti proudly relates, its attraction extends be- enthusiasm for concrete knows no bounds. It is, he feels, a
yond the city limits. Some 85% of the visitors are French, and royalty-free material easy to make from sand and cement

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Gateway to the Mediterranean: MuCEM and Fort Saint-Jean, in the old harbor of Marseille, linked by a pedestrian bridge. In the
background, Sainte-Marie-Majeure Cathedral. Tim White/SOPA RF/4Corners Images/SOPA/Corbis.

Main entrance to MuCEM, at dusk. Marc Dozier/Corbis

MuCEM, the pride of Marseille Raive

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Wooden painted Sicilian handcart, 19th century, from Palermo. Karim ADDA/Demotix/Corbis.

Display of traditional beekeeping items, early 20th century. MuCEM. Dist. RMN-Grand Palais/image MuCEM.

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

MuCEM, the pride of Marseille Raive

A TOUCH

Wooden horse from a merry-go-round, sculpted and


painted in Gustave Bayols (1859-1931) workshop in Avignon.

OF

FRANCE

Sixty-twokey orchestrophone, dated around 1880, by the


Limonaire Frres company, street organ and fairground organ builders.

RMN-Grand Palais/MuCEM/Herv Jzequel.

anywhere on the planet. Ricciotti loves the idea of working


with concrete, which is neither a scarce earth nor a speculative product. He also lauds its complexity: Concrete is a
Mephistophelian asset, but we can make a pact with it. No
one owns concrete. Nor am I a concreting architect. I dont
work concrete; it works me. Ricciotti is a respected professional, but draws barbs from some who see in his creations,
with their organic curves, the work of a mannerist, an architect out of step with the minimalism in vogue in contemporary architecture. In his own fashion, Ricciotti counters
by decrying the sensory autism and minimalist Salafism of some of his more illustrious peers. He has no time for minimalism
and argues for the demuseumification of
museums.

MuCEM. Dist. RMN-Grand Palais/image MuCEM.

arsenal. After three centuries of military duty, the Fort SaintJean was severely damaged in 1944 by an accidental explosion when used by the German occupiers as an ordnance
depot. A listed building since 1964, under the guardianship
of the Ministry of Culture, the Fort Saint-Jean from 1970 to
2005 housed the Department for Underwater and Undersea
Archaeological Research.

The footbridge between the roof terrace of


MuCEM and the garden of the restored Fort
Saint-Jean links the revamped Boulevard
du Littoral to the Panier district, the historical site of the Greek colony Massalia founded in 600 BC. A former military complex with
12th-century foundations and the square
mid15th-century Tower of Ren I, King of
Provence, the Fort Saint-Jean was constructed in the 17th century on the site of
the commandery of Saint John of Jerusalem
by order of Louis XIV, to strengthen the citys
Field work in the French Alps, before the
advent of mechanization.
MuCEM. Dist. RMN-Grand Palais/image MuCEM.

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Blue II, by Joan Mir, part of The Black and the Blue temporary exhibition at MuCEM in June 2013. The painting is part of a set of
three (Triptych Blue I, II, III) now at the Georges Pompidou Museum in Paris. The Triptych was completed in March 1961 in Palma de
Mallorca. Claude Paris/AP/SIPA.

Fully restored to current building code standards, the Fort


Saint-Jean is now open to the public for the first time, having
always served as a military site, except during the French
Revolution, when it was used as a prison for Philippe Egalit
(name taken by Louis Philippe II, Duke of Orlans) and two
of his sons, together with twenty or so Jacobins (members of
the revolutionary Jacobin Club). Henceforth, visitors can explore the Tower of Ren I, the Salle du Corps de Garde (guardhouse room), the Officers Gallery, and the Saint-Jean Chapel,
and discover there some of the collections inherited from
the Muse National des Arts et Traditions Populaires or deposited by the National Museum of Natural History in Paris.
Within the Fort Saint-Jean, the visitor enters a world of fairgrounds and leisure activities, through a giant model of a
circus with its sawdust-strewn ring, menagerie, and gallery,
funfair attractions, fairground amusements and costumes,
and everyday objects evoking the ages of life.

the contemporary world of MuCEM are now entwined by


this bridge suspended above the moats. The two sites, ancient and modern, linked by the two interwoven inclines,
seem indivisible, like past and future.
Access to MuCEM along the Fort Saint-Jean footbridge,
which links it to the upper slopes of town, leads to the museum roof terrace fitted out as a solarium, with a gourmet
restaurant run by Grald Passdat, a master of the herbs
and vegetables of Marseille and of the fish and seafood of the
Mediterranean. This terra firma overhang of a terrace juts into
the sea in the shape of a perfect square 72 meters by 72.
Within it, separated by winding stairs and open-air walkways,
stands a smaller square, this one 52 meters by 52, holding the
heart of the museum: the exhibition area and conference
rooms.

Gallery of the Mediterranean


Before reaching the footbridge to the pier, a garden of migrations planted with white oaks, holm oaks, orange trees, myrtle, herbs, and spices has been created to illustrate, in fifteen
botanical landscapes, the melding of Mediterranean cultures.
The history of Marseille illustrated by the Fort Saint-Jean and

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MuCEMs permanent exhibition, the 1600 m2 Gallery of the


Mediterranean, uses everyday objects together with artworks
to illustrate practices and beliefs representative of civilizations
from the Neolithic era onwards. Four themes are covered.
First, there is the birth of agriculture some 10 000 years ago

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Real or virtual? Sun shining through the signature concrete latticework of MuCEM on a terrace. Guillaume Horcajuelo/epa/Corbis.

and the emergence in early societies of belief in divinities who


governed the success or failure of crops. The second theme
is the rise of monotheistic beliefs, illustrated by the example
of Jerusalem, which became a holy site for the three main
religions of the eastern Mediterranean: Judaism, Christianity,
and Islam. The third theme relates to citizens and responsibility in Mediterranean and European societies, the notion of
citizenship, from Athenian democracy to present-day human
rights. The fourth and last theme is an invitation to venture
beyond the known world, to undertake a voyage illustrated by
instruments used in maritime exploration, nautical charts, luxurious and exotic treasures that tell the story of mans exploration of the Mediterranean and points east.

Temporary exhibitions
This fascination with the Mediterranean was pursued further
in MuCEMs inaugural exhibition: The Black and the Blue, A
Mediterranean Dream. The black of Francisco Goya, the blue
of Joan Mir. An exhibition that displayed, as the MuCEM
website put it: The Enlightenment and its shadows, like two
sides of one world, a response to the very idea of civilization,
created in the 18th century. In his Disasters of War, a set of
eighty etchings and aquatints, Goya revealed, in the words of
Andr Malraux, what, in man, aspires to destroy him. Mirs
world, in contrast, was the sundrenched island of Majorca,

MuCEM, the pride of Marseille Raive

where blue was the color of his dreams. Mediterranean blue,


a symbol, an icon of mans desire to seek within himself his
own origins. The exhibition invited visitors to travel through
time from the world of Goya (1746-1828) to the here and now,
to recount, to dream, while never forgetting historys dark side,
for, as Walter Benjamin remarked, there is no document of
civilization which is not at the same time a document of barbarism.
Currently, one of MuCEMs temporary exhibitions is Such a
Sweet Moment by the French photographer Raymond Depardon and his use of color from the 1950s until now. Always
present, color took on a certain dominance in Depardons work
from the 2000s: he moved away from reportage in a quest for
truth and happiness through rediscovery of the light and colors of South America, Africa, and the United States, and a
new Mediterranean element entered his work. In the words
of French philosopher Clment Rosset, Depardon is now
seeking the sweetness of reality.
Another temporary exhibition, History Zero by Greek artist
Stefanos Tsivopoulos, is an installation originally commissioned
for the 55th International Art Exhibition, la Biennale di Venezia,
in 2013. History Zero casts an eye over how we value money and its role in human relationships. Against the backdrop

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of the 7th year of recession in Greece, Tsivopoulos believes


that the Greek economic crisis has to do with [] the way
we perceive or approach value, and how this perception has
been contested by different cultures, communities, and societies. He illustrates his ideas with archival material on currencies and exchangesfrom barter, shell money and trade
beads, and the gift economy to the emergence of money,
banking, microfinance, mobile money, and bitcoinsand a
film that tells the intertwined stories of three people in Athens.
Wandering the streets, an African immigrant searches for scrap
metal to sell. An artist seeks inspiration in the cityscape by

LE MUCEM,

randomly recording street scenes with his iPad. Alone in a


museum-like house, an elderly art collector afflicted by dementia spends her time folding euro banknotes into origami
flowers. These acquire new value when the young immigrant
happens across them in a bin, while his treasurethe trolley laden with scrap metalserves to inspire the artist.
Through its permanent and temporary exhibitions, MuCEM
spurs us to reflect, to be moved, to admire, and to question.
Is this not the purpose of a museum seeking its place in todays world?

FIERT DE

MARSEILLE

Cest un carr parfait ceint dun voile de bton, un vaisseau noir majestueux pos entre terre et mer lentre du port
de Marseille. Inaugur en juin 2013, le Muse des Civilisations de lEurope et de la Mditerrane (MuCEM) est lun
des seuls muses de province cre en France ces dernires annes. Une prouesse architecturale signe de larchitecte franais dorigine algrienne, Rudy Ricciotti, 62 ans. Un btiment tonnant que lont vient admirer du monde
entier pour la puret de sa forme et sa rsille de bton ouvrag qui rappelle les moucharabiehs arabes. Un difice plbiscit par les Marseillais parce quil leur offre plus quune institution culturelle pluridisciplinaire, un vritable lieu de
promenade qui leur permet de se rapproprier leur ville grce de nouvelles circulations entre le quartier historique
du haut de la ville, fonde en 600 avant JC par des Grecs venus de Phoce (rgion de lAnatolie en Turquie actuelle)
et le port. Si la vocation du MuCEM est dtre un muse de socit, sil doit composer avec des collections htroclites dart populaire (250 000 objets et centaines de milliers de documents) hrites de lancien Muse des Arts et
Traditions Populaires Paris, sa grande russite est dtre parvenu ds son inauguration prsenter des expositions
de trs bon niveau qui nous font rflchir. Les chefs duvres dart plastique, les trsors archologiques et dart
contemporain ctoient les outils agricoles du 19e sicle, des vtements traditionnels venus de toute lEurope, une impressionnante collection de chevaux de bois ou de sifflets. Au MuCEM, lart fait partie de la vie et nous interroge.

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he 16th century saw the
building in Montpellier of the
first anatomy amphitheater
in France and the creation of chairs
of anatomy and of surgery. From
then onwards, the reputation of
the Montpellier anatomists and
surgeons steadily grew and new
anatomical descriptions abounded: the caro quadrata sylvii (muscle) and os sylvii (lenticular process
of incus) of Jacobus Sylvius, (Gaspard) Bauhins (ileocecal) valve,
the reservoir of (Jean) Pecquet or
receptaculum chyli

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The Medical Faculty of


Montpellier: one thousand
years of medicine

b y C . R g n i e r, Fra n c e

All rights reserved

H
Christian RGNIER, MD
Pierre and Marie Curie University
(UPMC Paris 6)
International Society for the
History of Medicine (ISHM)
Paris, FRANCE

ard by the shores of the Mediterranean stands the oldest medical


faculty in Europe. Founded in 1220, the university at Montpellier in the
south of France was a crucible of learning for Jewish, Arab, and Latinspeaking physicians. It enjoyed the protection and indulgence of the counts
of Toulouse, the kings of Aragon, Popes, and then the kings of France. As famous in the Middle Ages as the medical schools of Salerno, Padua, Bologna,
or Paris, the Medical Faculty of Montpellier to this day enjoys an autonomy
that enables it to admit students from throughout Europe. In the 1500s, when
Montpelliers economic prosperity declined, the town councilors understood
that, if it was to keep its regional influence, Montpellier had to continue as
a university town with the best teachers. Despite the religious conflicts that
ravaged the town in the 17th century, the intellectual appeal of the Montpellier Faculty of Medicine lasted until the Revolution in 1789. Nearly half of all
doctors practicing in France at the time had qualified in Montpellier. During
the 18th century, the Montpellier school defended the medical-philosophical
doctrine of vitalism, which sought to overturn ideas about human physiology, hitherto explained in terms of the laws of mechanics and chemistry
alone. Paul-Joseph Barthez, a physician from Montpellier whose reputation
had spread throughout Europe and who authored articles on medicine and
surgery for the Encyclopedia of Diderot and dAlembert, was a fervent advocate of vitalism, which was debated throughout Europe until the 20th century.
A victim of Parisian centralism, the Montpellier Faculty of Medicine fell on hard
times in the first half of the 19th century, but from 1860, with the development
of viticulture, and then again in the 1960s as French settlers were repatriated
after Algerian independence, the faculty expanded, a blossoming that has continued to the present day.
Medicographia. 2015;37:221-232 (see French abstract on page 232)

tanding on two low hills, the site of todays Montpellier was, in the 2nd century bC, crossed by the Via Domitia, the first Roman road to link Gaul, Italy, and
Spain, along which salt from the Mediterranean was transported to Northern
Europe. Montpellier itself, however, was not founded until 985, when Count bernard II de Melgueil granted William I of Montpellier ten hectares of arable land known
variously as Mons Pessulus, lock hill (for its strategic position), Mons Pastellorum,
hill of pastels (for the quality of the pigments used in dyeing cloth), or Mons Pistillarius, hill of grocers (because of its flourishing commerce), all of which may explain the etymology of the towns name.1,2

S
Address for correspondence:
Docteur Christian Rgnier,
9 rue bachaumont, 75002, Paris
(e-mail:
dr.christian.regnier@wanadoo.fr)
www.medicographia.com

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The land was crossed by one of the paths along the Way of
Saint James, and the village, developed around the William
family chteau, served as a stopping place for pilgrims to Santiago de Compostela. Merchants, tradesmen, and Arab and
Jewish grocers-cum-physicians came to Montpellier, and by

the early 1200s the towns population of five thousand was


comparable to that of Nmes or Narbonne. Deftly playing the
game of political alliances, the William dynasty brought prosperity to Montpellier. Famed for its textile manufacturing, cosmopolitan Montpellier expanded to include two active ports
(Juvnal and Lattes) and turned its hand to maritime trade
with the great Mediterranean ports.1,2
Writing of Montpellier in 1165, Rabbi benjamin of Tudela noted
that: This is a place well situated for commerce. It is about
a parasang [6 kilometers] from the sea, and men come for
business there from all quarters, from Edom, Ishmael, the land
of Algarve, Lombardy, the dominion of Rome the Great, from
all the land of Egypt, Palestine, Greece, France, Asia, and England. People of all nations are found there doing business
through the medium of the Genoese and Pisans. In the city
there are scholars of great eminence.3

Montpellier, crucible of Jewish, Islamic, and


Christian medicine

The Montpellier Faculty of Medicine and Saint-Pierre Cathedral.


Christophe Boisvieux/Corbis

A section of the Via Domitia at the Ambrussum (Villetelle), in the


close vicinity of Montpellier.
De Agostini Picture Library/C. Pratt/Bridgeman Images.

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The unofficial teaching of medicine began in Montpellier at the


start of the 12th century. Epistolary exchanges between travelers passing through praise the highly skillful and renowned
physicians who practiced there. by the late 1100s, Montpellier was already home to a small community of physicians
who received students from southern Europe.4 William VIII,
Lord of Montpellier, asserted the towns medical tradition by
authorizing all teachers to lecture on medicine, regardless of
their background or religious denomination. The town was a
melting pot of three sources of medical knowledge: Christian
through the Schola Medica Salernitana, Arabic by virtue of
Hispano-Mauresque medicine, and the Jewish medical tradition. This also ended incessant squabbling between physicians seeking to monopolize medical practice and the dissemination of learning. From its inception, the Medical Faculty
of Montpellier adopted a motto that affirmed its Hippocratic
liberalism: Olim Cous nunc Monspeliensis Hippocrates, In
times past, Hippocrates was from Cos; now he is from Montpellier.2,5-7
In 1220, the Universitas medicorum of Montpellier was granted its first statutes, establishing a monopoly in the teaching
and practice of medicine. Holders of the title Master Teacher
of the Montpellier Faculty were accorded the right to practice medicine hic et ubique terrarumhere and anywhere on
Earth. A distinction was drawn between Master Teachers who
transmitted the medical tradition of Salerno, in Latin, and those
who taught, in Arabic, the medical learning of the Arab world.
Teaching consisted in reading, commenting upon, and debatingsometimes quite freelyclassic Greek and Arabic medical texts. The students (laymen and monks) had a free choice
of teacher and, when they felt ready, asked to sit the exams
for a license to practice medicine. The first statutes did not
specify the length of studies, nor how diplomas were to be
awarded, but additional statutes 20 years later regulated stud-

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Map of
Montpellier
(Monspessulanus) published in 1572
by Braun and
Hogenberg in
Civitatis Orbis
Terrarum I.
Historic Cities
The Hebrew
University of
Jerusalem & The
Jewish National
& University
Library.

ies and their length, the examination procedures, and the graduation ceremony, measures that changed little over the centuries and remained in force until the French Revolution.4,5,7,8
between the 11th and 13th centuries, eight hospitals were
built outside the town of Montpellier by the William dynasty
(which came to an end in 1204, for want of a male heir). Each
hospital had a few dozen beds and was visited by the towns
physicians, surgeons, and apothecaries. The most famous
of these hospitals was founded by the monk physician Gui
de Montpellier and served Pope Innocent III as a model for
the whole of Italy.2,6,9
Gilles de Corbeil, physician to King Philip II of France (reigned
1180-1223), asserted that Montpellier was the only medical
school in his kingdom. Competition came from the School of
Salerno (Southern Italy), which at the time was the main medical teaching center of Christendom.4,10

Papal protection and burgeoning influence


For commerce, as for the arts and sciences, Montpelliers influence was at its greatest under the Kings of Aragon and under the watchful care of the 14th-century Avignon Papacy.
The University of Montpellier was created in 1289 by a papal
bull (charter) issued by Pope Nicholas IV, as the faculties of law
and medicine and the school of arts were merged. Whereas
several schools were authorized to dispense medical knowledge, only the faculty had the right to grade the students. After three years of studies, a diploma was awarded following

Eye surgery, from Book of Surgery by Rogier de Salerne (vellum,


14th century). Muse Atger, Facult de Mdecine, Montpellier,
France/Bridgeman Images.

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In spite of this direct supervision by the Supreme Pontiffs, the


faculty enjoyed a certain autonomy. This spirit of independence
was perpetuated over the centuries as Montpellier successively welcomed Jewish and Arab emigrants expelled from Spain,
survivors of the Albigensian Crusade against the Cathars, and
Calvinists.
because of this, teaching in Montpellier was freer and less
dogmatic than in Paris, where the university was dependent
on the court of the French kings. The university was close to
the papal court, a forum for the discussions of intellectuals
from throughout Christian Europe, and Montpellier physicians
treated Popes and cardinals. Teachers and students alike
fostered ties with the intellectual world of the Mediterranean
basin,4-6,10 and during the 13th century Montpelliers influence
was comparable to that of the great Italian centers of learning
at Padua and bologna. Over this period, the towns population quadrupled to 40 000, second in France only to Paris.4,5

Town and gown: economic decline and rising


prestige

Surgical instruments from a treatise by Abul Qasim Kalaf bin


al-Abbas al Zahrawi (Albucasis), 14th century.
Muse Atger, Facult de Mdecine, Montpellier, France/Bridgeman Images.

an open and public debate on the writings of Hippocrates and


Galen. All the teachers took part in the debate, which was
held in the Saint-Firmin Church or at the basilica of NotreDame-des-Tables. The teachers were canons and the chancellor of the faculty was always appointed by the bishop. The
students directly paid the teachers, who came to their homes
to teach them, and indeed until the 14th century the Medical Faculty had no building intended for this purpose.4-6,8,11
The teachers could perform dissections in their homes. Contrary to a widely held view, the Church did not forbid anatomical dissections. Legal proceedings were, however, brought
in cases of desecration of graves and body-snatching. Pope
boniface VIII forbade, upon pain of excommunication, the
dismembering of cadavers and their boiling to strip flesh from
the bones, in an attempt to counter the widespread practice
of reducing bodies to expedite their transport or to dispose of
mortal remains in more than one tomb.5,6,8,11

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The incorporation of Montpellier into France in 1350 did not


alter the status of the town, which was administered by six
noblemen from different guilds who were elected on the first
day of March every year. Good administrators, skilled diplomats, these so-called consuls brought prosperity by providing the town with a powerful commercial fleet, by concluding
alliances with the great ports of Italy and Spain, by obtaining
from Pope Urban V the right to trade with infidels, and by
supplying the courts of Europe with rare and much soughtafter oriental produce. A student at Montpellier, resident in
Avignon, Pope Urban V used funds from the Holy See to build
the monastery of Saints-benot-et-Germain (which became
the Faculty of Medicine in the 18th century). The College of
Twelve Physicians was founded to accommodate and provide sustenance to poor students. The Kings of France regularly gave donations to the Medical Faculty of Montpellier,
enabling it to balance the books1,2,5,6 and train more physicians (128 in the 14th century).4
In 1450, the Royal College of Medicine was set up in new
premises near Saint Matthews Church and, for the first time,
the Medical Faculty was housed within its own four walls.
Louis XII, in 1498, enacted new rules for the organization of the
Medical Faculty of Montpellier, Paris being the only faculty in
the kingdom to teach medicine regularly and to award recognized diplomas. Four physician-teachers were appointed by
the king and paid from the privy purse. They were held accountable for their teaching by the students, who formed a
brotherhood that watched over its interests and was represented by a procurator who played an important role in running the faculty, both in terms of the budget and the remuneration of the teachers. In the early 16th century, the Medical
Faculty decided it needed a treasurer, a beadle housed at the
Royal College of Medicine, and a secretary charged with rec-

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Dissection lesson at the Faculty of Medicine in Montpellier. From La Grande Chirurgie by Guy (or Gui) de Chauliac, 1363 (vellum).
Muse Atger, Facult de Mdecine, Montpellier, France/Bridgeman Images.

Layout of the Montpellier Botanical Garden, the oldest in France, created by Pierre Richier de Belleval in 1593.
Musum National dHistoire Naturelle. Dist. RMN-Grand Palais/image du MNHN, Bibliothque Centrale.

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FAMOUS 13TH- TO 18TH-CENTURY DOCTORS


THE M ONTPELLIER FACULTY OF M EDICINE
Arnaldo de Villanova (1238-1311) was physician to the
Popes and to the Kings of Aragon. His eclectic legacy includes learnings from the Jewish, Arab, Greek, and Christian traditions. Considered as one of the most eminent
physicians of his century, he was also an astrologist and
alchemist.
Henri de Mondeville (1260-1320) taught surgery in Montpellier and pioneered detailed anatomical studies. Surgeon to Philip IV of France, at his death he left unfinished
his master work Chirurgie, the first French treaty on surgery,
which until then had been reserved for barbers.
Guy de Chauliac (1298-1368) was surgeon to the Popes
in Avignon, traveled widely, and wrote Chirurgie Magna,
which remained a classic of surgery for three centuries.
Franois Rabelais (1483-1553). Ordained as a priest in
1520, Rabelais received his doctorate in medicine in 1537,
having started his career as a writer around 1530. He never stopped practicing medicine. In his five-volume work
Gargantua and Pantagruel (1532), Rabelais mocked the
Montpellier Faculty and its professors, among them his
own teacher Guillaume Rondelet.

Michel de
Nostredame,
aka Nostradamus (15031566, French
physician,
pharmacist,
astrologer, and
writer. Painting
by his son,
Csar de
Nostredame
(1614).
De Agostini
Picture Library/
G. Costa/Bridgeman Images.

Nostradamus (1503-1566) entered the Montpellier Faculty of Medicine, but was expelled soon after on the discovery that he had worked as an apothecary (a manual trade
banned by the universitys statutes). He therefore never
qualified as a doctor, but nonetheless practiced medicine
and pharmacy all his life. Astronomer to Queen Catherine
de Medici, the publication of his Prophties (1555) brought
him fame across Europe.

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AT

Guillaume Rondelet (1507-1566) was a professor at the


Montpellier Faculty of Medicine and the teacher of Rabelais,
who used him as a model for his character Rondibilis in
the third volume of Gargantua and Pantagruel. He organized the first courses in botany in France and was the
Chancellor of the University.
Thophraste Renaudot (1586-1653) was awarded his doctorate in medicine in 1606, and much later (1631) founded
La Gazette de France, one of the countrys first newspapers. In Paris, he organized a bureau dadresses where job
offers and applicants were brought together in an attempt
to remedy poverty and homelessness. He also set up a
dispensary where the indigent could seek free medical consultations.
Raymond Vieussens (1641-1715) was physician to Louis
XIV and to his first cousin the Duchess of Montpensier. He
was a member of the French Academy of Sciences and
of the Royal Society of London. He gave his name to numerous anatomical structures and was one of the pioneers
of the study of heart valve diseases.
Franois Gigot de la Peyronie (1678-1747), first-surgeon
to Louis XV, was instrumental in the separation of the guild
of surgeons from the guild of barbers. He initiated the modern teaching of surgery, founded the French Royal Academy of Surgery, and wrote its statutes. He described a
disorder involving induration of the corpora cavernosa of
the penis, which is now known as Peyronies disease.
Jean Astruc (1684-1766), professor of medicine at Montpellier, was consulting physician to Louis XV. A member of
the Academy of Medicine, erudite, polyglot, he invented
bibliographic research and wrote the first major treatise on
syphilis and venereal diseases.
Franois Boissier de Sauvages (1706-1767) was a botanist
and for 18 years conservator of Montpelliers botanical
garden. He drew up a renowned nosology that for many
years was authoritative.
Paul Joseph Barthez (1734-1806), a leading contributor
to the Encyclopedia of Diderot and dAlembert, was honorary professor at the Montpellier faculty, senior member
of the Council of State, consultant physician to the king,
physician to Napoleon bonaparte, and member of several European learned societies. He originated the famous
vitalist doctrine of the Montpellier School.

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ording diplomas and organizing examinations. Even though the


royal power ceaselessly increased its influence over the Medical Faculty, the bishop of Montpellier retained, until the Revolution, the right to inspect the administration of the faculty.4,6
The Montpellier consuls continually promoted the development of the university and of the Medical Faculty to sustain
the towns intellectual appeal. The departure of the Popes from
Avignon (in 1419) triggered a decline in Montpelliers prosperity, exacerbated by increased commerce in the Rhne Valley
and the silting up of the ports of Lattes and Aigues-Mortes,
the towns main outlets to the sea. This benefited Marseille,
which was attached to the French crown in 1481, and which
had become an active, rival port. During the 15th century, Montpelliers population dropped to 15 000.1,2

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their chancellor and the main disciplines (surgery, pharmacy,


botany, and anatomy) were defined. Thereafter, teachers were
recruited following a competitive exam at which candidates
competed before a board of examiners in answering randomly chosen questions on medicine.
The 16th century saw the building in Montpellier of the first
anatomy amphitheater in France and the creation of chairs
of anatomy and of surgery. From then onwards, the reputation of the Montpellier anatomists and surgeons steadily
grew and new anatomical descriptions abounded: the caro
quadrata sylvii (muscle) and os sylvii (lenticular process of
incus) of Jacobus Sylvius, (Gaspard) bauhins (ileocecal)
valve, the reservoir of (Jean) Pecquet or receptaculum chyli,
and Raymond Vieussens, who gave his name to a centrum
(centrum semiovale), a brain ventricle (cavity of septum pellucidum), foramina (openings of smallest cardiac veins), a valve
(superior medullary velum), an isthmus (limbus of fossa ovalis),
an ansa (subclavian loop), ganglia (celiac ganglia), and veins
(innominate cardiac veins).2,4,5
In 1593, Henri IV encouraged the creation of Frances oldest
botanical garden, the Jardin des Plantes de Montpellier, by
Pierre Richer de belleval, holder of the newly created Chair of
botany at Montpellier. The gardens are still one of the finest
examples of Montpelliers cultural heritage.5,6,1
The teaching of Arab medical authors dwindled from the 15th
century and by 1646 had disappeared altogether. Likewise,
the teaching of Greek medicine was progressively removed
from the program of studies during the 17th century. In 1715,
the number of teachers increased from four to eight, and thereafter bore the title professor and occupied chairs. New disciplines emerged, such as chemistry, the chair of which was
created in 1673.4,6

The doctrine of vitalism in Montpellier

Franois Gigot de Lapeyronie, also spelled la Peyronie (16781747), first-surgeon to King Louis XV. Painting by Hyacinthe Rigaud
(1659-1743), at the Paris Museum of History of Medicine.
Bridgeman Images.

The Reformation reached Montpellier in the 16th century and


swayed its intellectuals, wealthy merchants, and artisans, but
violent clashes between Protestants and Catholics during the
French Wars of Religion drove the town to ruin. Yet the Medical Faculty of Montpellier, famed as it was for its prestigious
professoriat, was still able to attract students from all over Europe. In the mid-1500s, teachers were given the right to elect

Having rid itself of ancient theories, 18th-century medicine


incorporated chemistry and physics in an attempt to explain
the phenomena of life. This was a time characterized by
lively debates and heated controversies between medical
movements, schools of thought, and the defenders of medical and philosophical doctrines. This intense intellectual activity heralded medicines entry into the modern era, with
the emergence of new subjects like biology, physiology,
anatomical pathology, and histology.
In France, the doctrine of vitalism was born in Montpellier,
enunciated by Thophile de bordeu and Paul-Joseph barthez,
professors famed throughout 18th-century Europe. This doctrine asserted that the phenomena of life were not subject
solely to the laws of physics and chemistry, but also to a vital force. Collaborator at the Journal des Savants, barthez
was the author of over 2000 articles on medicine and surgery for the Encyclopedia of Diderot and dAlembert. barthez

The Medical Faculty of Montpellier: one thousand years of medicine Rgnier

MEDICOGRAPHIA, Vol 37, No. 2, 2015

227

Museum of Anatomy (Conservatoire dAnatomie)


of the Faculty of Medicine of Montpellier, and its
emblematic digging corch created in 1858 by
Alphonse Lami (1822-1867).
Pascal Parrot.

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FRANCE

Entrance to the old building of the Montpellier Faculty of Medicine, flanked by the statues of Franois Gigot de Lapeyronie (left) and
Paul-Joseph Barthez (right). FRILET/SIPA.

held that man comprised three elements: organized matter


or body, the soul, and the vital (or life) force. He believed that
medicine and the study of life should shed the century-old
straitjacket imposed by the mechanistic theory of Descartes.
With the development of the microscope and observations
of living tissue, anatomists were certain that the phenomena
of life could no longer be explained just by the laws of mechanics. barthez wondered whether the vital principle had
an independent existence or instead infused life into the human body.6,13-16
In a talk at the Medical Faculty of Montpellier in 1792, the
chemist Jean Antoine Chaptal characterized the vitalist spirit by the view that he who studies bodily functions alone will
never be a physician, because while he thinks he knows man,
in fact all he knows is the outer shell, the carcass. Such an approach, Chaptal argued, would overlook the fine connections
between man and his surroundings, reciprocal action and reaction with other bodies, the great system of movement that
fashions from all living things the organs of a larger whole.15,16
The vitalist theory of the Montpellier school created a stir
throughout Europe. Fiercely contested in Paris, it was seen
as far removed from the anatomical and clinical studies that

230

MEDICOGRAPHIA, Vol 37, No. 2, 2015

Parisian physicians deemed essential to pathophysiological


understanding. The physicians of the Medical Faculty of Paris
had their own organicist school of thought, based on the
anatomical and clinical method.
In the late 18th century, Xavier bichat applied the vitalist principle to his definition of life as an ensemble of functions that
oppose death. This vitalist theory was combatted by Jeanbaptiste de Lamarck, the originator of the theory of transformism, or the transmutation of species, and in the 19th century by Claude bernard, who deemed it incompatible with
the principles of experimental medicine: Vitalism runs counter to the scientific spirit () At the heart of vitalist doctrines
there is an irreparable error, which is to lend real existence ()
to something immaterial, something which in reality is just a
notion of the spirit. The vitalist theory debate between physicians raged on unabated for years.6,13-16

Revolutionary upheaval
The French Revolution passed almost unnoticed in Montpellier, which was spared bloody riots and mass executions. The
consuls who administered the town gave way to an elected
town council directed by a mayor. The enlightened bour-

The Medical Faculty of Montpellier: one thousand years of medicine Rgnier

A TOUCH

geoisie infiltrated the administrative machinery and took control. Somewhat predisposed to moderate revolutionary ideas,
the bourgeoisie lived through the Revolution without mishap.
The populations of the town and the surrounding countryside, however, suffered greatly from food shortages, military
requisitions, and, above all, a cholera epidemic, which killed
one-tenth of them (2500 people).1,2,17
The National Convention in 1793 promulgated the dissolution of antiquated universities and the closure of medieval
schools. Already closed were the corporations, the academies,
and the learned societies, charged with having sequestered
learning. In Montpellier, far from the prying eyes of the political powers in Paris, the Medical Faculty unobtrusively continued throughout the Revolution to accept and train students
and to award diplomas.
A decree the following year ordered the reopening of the
School of Health in Montpellier (and also those of Paris and
Strasbourg) and stipulated the number of students admitted
to each: 300 in Paris, 150 in Montpellier, and 100 in Strasbourg. Typical of the Paris-centric mentality of the elected
members of the National Convention, the law arbitrarily reduced student numbers in Montpellier and imposed Paris as the leading Medical Faculty in
France. The Paris School also benefited from
institutions such as the Collge de France and
the Museum of Natural History, which facilitated research. This harmonization of teaching and
courses at the three medical schools ended the
Montpellier Faculty of Medicines centuries-old
tradition of independence.14,17

OF

FRANCE

cunabula (books printed before 1501), 100 000 volumes printed before 1800, and all the theses of the medical faculties
of Montpellier and Paris since the 17th century. Known to all
medical students in France, this catalog of riches was the fruit
of Gabriel Prunelles vigorous policy of acquisition of works
and of library collections throughout Europe.14,17
In the early 1800s, the Medical Schools once more became
Faculties of Medicine, the doctorate was restored, and the
wearing of professorial gowns was rehabilitated, in a move towards the organization of an imperial university, which reintroduced competitive exams for the recruitment of professors.

Epilogue
In the mid19th-century, the town of Montpellier suffered demographic, economic, and even academic decline. The Faculty of Medicine lost its shine and was training only 700 students
a year. but the towns fortunes turned once more. The spectacular growth of the railroad network expedited the transportation of large volumes of wine and Languedoc and Montpellier developed winegrowing, leading to a flourishing wine
trade.1 The number of medical students rose to 1500 by the
early 1900s and to nearly 3000 on the eve of World War 2.4

Montpelliers physicians nonetheless remained


influential in France and elsewhere in Europe.
An early 19th-century survey by the Ministry of
the Interior indicated that of 2398 physicians
practicing in France, 1101 had trained in Montpellier, 226 in Toulouse, 195 in Caen, and 72 in
Paris. It should be borne in mind, however, that
many physicians, having started their studies
in Paris, completed them in Montpellier, where
the enrolment fees were lower.4,14,17
In 1795, the Montpellier Medical School moved
Anatomical wax head by Felice Fontana (1730-185), at the Museum of Anatomy
into its current premises, the Saint benot mon- of the Faculty of Medicine of Montpellier. Pascal Parrot.
astery adjoining the Saint-Pierre Cathedral. JeanAntoine Chaptal had the anatomy lecture hall built and saw boosted by the return of French settlers repatriated after Alto the transfer from Paris of a collection of wax anatomical gerian independence in 1962, Montpellier, as the capital of
models by the 18th-century Tuscan artist Felice Fontana, for
Languedoc, regained its regional influence in politics, culture,
display in the newly created museum of anatomy.
economics, and learning. Most of the universitys faculties
were rebuilt or refurbished and the number of students rose
Chaptal appointed Gabriel Prunelle inspector of libraries and
to 50 000 by 1990.4 by mid-2014 the University of Montof book depositories and charged him with the creation of pellier I, the heir to the School of Medicine founded in 1220,
the Medical Facultys library, which currently holds 300 in- counted over 22 000 medical students.

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MEDICOGRAPHIA, Vol 37, No. 2, 2015

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References
1. Cholvy G, ed. Histoire de Montpellier. Toulouse, France: Privat; 1984.
2. Thomas E. Montpellier: Guide l'tranger Dans Cette Ville et Dans ses Environs (ed.1857). Montpellier, France: Hachette bNF; 1857.
3. Adler MN. The Itinerary of Benjamin of Tudela: Critical Text, Translation and Commentary. New York, NY; Philip Feldheim; 1907.
4. bonnet H. La Facult de Mdecine de Montpellier, Huit Sicles dHistoire et
dclat. Montpellier, France: Sauramps Mdical; 1992.
5. Astruc J. Mmoires Pour Servir lHistoire de la Facult de Mdecine de Montpellier. Paris, France: P.G. Cavelier; 1767.
6. Dulieu L, ed. La Mdecine Montpellier du XIIe au XXe Sicle, Paris, France:
Hervas, 1986.
7. Mandin A, Jeanneau T. La donation des premiers statuts de la Facult de Mdecine de Montpellier. In: Grmek MD, ed. Histoire de lcole Mdicale de Montpellier. Colloque du 110e Congrs National des Socits Savantes (1985). Paris,
France: CTHS; 1985.
8. Jacquard D. La scolastique mdicale. In: Grmek MD, ed. Histoire de la Pense
Mdicale en Occident, Tome 1, Antiquit et Moyen ge. Paris, France: Seuil;
1995.
9. Dumas R. Les Hpitaux de Montpellier Mille Ans dHistoire. Montpellier, France:
Sauramps Mdical; 2012.
10. Mac Vaugh M. Montpellier et la renomme thrapeutique de ses mdecins au

LA FACULT

DE MDECINE DE

dbut du XIVe sicle. In: Grmek M D, ed. Histoire de lcole Mdicale de Montpellier. Colloque du 110e Congrs National des Socits Savantes (1985). Paris,
France: CTHS; 1985.
11. Castan P. Naissance Mdivale de la Dissection Anatomique. Montpellier, France:
Saurans; 1985.
12. Rossi M, Lhoir J. Le Jardin des Plantes de Montpellier : De la Mdecine la
Botanique. Montpellier, France: ditions Qu; 2013.
13. Rey R. Lme, le corps et le vivant. In: Grmek MD, ed. Histoire de la Pense Mdicale en Occident, Tome 2, De la Renaissance aux Lumires. Paris, France:
Seuil; 1995.
14. Raynaud D. La controverse entre organicisme et vitalisme: tude de sociologie
des sciences. Rev Fr Sociol. 1998;39:721-750.
15. Lavabre-bertrand T. Lvolution du Vitalisme Montpellier de Barthez Lordat,
Mmoire de DEA de Philosophie et dHistoire des Sciences, Paris 1, 1986.
16. Long b. Le vitalisme de Paul Joseph barthez. In: Grmek MD, ed. Histoire de
lcole Mdicale de Montpellier. Colloque du 110e Congrs National des Socits Savantes (1985). Paris, France: CTHS; 1985.
17. Goupil A. Le chimiste Jean Antoine Chaptal et lcole mdicale de Montpellier.
In: Grmek MD, ed. Histoire de lcole Mdicale de Montpellier. Colloque du
110e Congrs National des Socits Savantes (1985). Paris, France: CTHS,
1985.

MONTPELLIER :

MILLE ANS DE MDECINE

Tourne vers les rives de la Mditerrane, la ville de Montpellier conserve la plus ancienne facult de mdecine
dEurope encore en exercice. Fonde en 1220, luniversit fut le creuset des savoirs des mdecins juifs, arabes et
latins. Luniversit bnficia de la protection et de lindulgence des comtes de Toulouse, des rois dAragon, des
papes puis des rois de France. Aussi clbre au Moyen ge que les coles de mdecine de Salerne, Padoue, Bologne ou Paris, la facult de mdecine de Montpellier conserva toujours une autonomie qui lui permit daccueillir
des tudiants venus de toute lEurope. Au XVe sicle, lorsque la prosprit conomique de la ville dclina, les diles
municipaux comprirent que pour conserver son influence rgionale, Montpellier devait demeurer une ville universitaire servie par les meilleurs professeurs. En dpit des conflits religieux qui ravagrent la ville au XVIIe sicle, le pouvoir dattraction de la facult de mdecine perdura jusqu la Rvolution en 1789. Prs de la moiti des mdecins
exerant en France avaient obtenu leur diplme Montpellier. Au cours du XVIIIe sicle, lcole de mdecine de Montpellier dfendit une doctrine mdico-philosophique, le vitalisme , qui bousculait les ides sur la physiologie humaine explique jusqualors par les seules lois de la mcanique et de la chimie. Paul-Joseph Barthez, mdecin montpellirain de rputation europenne, auteur darticles de mdecine et de chirurgie dans la grande Encyclopdie, fut
lardent dfenseur de cette doctrine qui fut dbattue dans toute lEurope jusquau XXe sicle. Victime du centralisme parisien, la facult de mdecine de Montpellier connut un relatif dclin au XIXe sicle. En 1860, avec le dveloppement de la viticulture, puis dans les annes soixante, avec le retour des rapatris dAlgrie, la facult connut
un nouvel essor qui se prolonge jusqu aujourdhui.

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Medicographia
The vulnerable phase of heart failure: a window of opportunity

C hance
favors only
the prepared mind

ISSN 0243-3397

Vol 37, No. 2, 2015

Medicographia
The vulnerable phase
of heart failure:
a window of opportunity

Pa s t e u r

Vol 37, No. 2


Pages 117-234

2015

www.servier.com

15 MP 0123 X Printed in France

Servier - 50, rue Carnot - 92284 SureSneS Cedex (FranCe)

Quarterly Thematic Journal


of Clinical and Therapeutic Research
A Servier Publication

www.medicographia.com