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C hance
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ISSN 0243-3397
Medicographia
The vulnerable phase
of heart failure:
a window of opportunity
Pa s t e u r
2015
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Medicographia
123
Ser vier
publication
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
139
144
149
155
163
Medicographia
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
EDITORIAL
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
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
119
EDITORIAL
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.
120
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.
Hospitalization for heart failure: can we prevent it? Can we predict it? Komajda
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-
122
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.
123
DITORIAL
Conclusion
Mots cls : insuffisance cardiaque ; hospitalisation ; prvention ; prise en charge aprs la sortie de lhpital
124
THE
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)
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
125
THE
A
VULNERABLE
WINDOW
OF
PHASE
OF
HEART
FAILURE:
OPPORTUNITY
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.
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-
their lifetime
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
126
THE
VULNERABLE
A
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
ACE
angiotensin-converting enzyme
ARB
BNP
CONSENSUS
127
THE
A
VULNERABLE
WINDOW
OF
PHASE
OF
HEART
FAILURE:
OPPORTUNITY
Cons
Pros
Major clinical
outcomes
Total mortality
Cardiovascular
mortality
Self-evident.
Self-evident.
Sudden death
Self-evident.
Hospitalization and
rehospitalization
Stroke, myocardial
infarction
Self-evident
Renal failure
Other clinical
outcomes
Physician dependent.
Surrogates for
outcomes
Ventricular function,
eg, LVEF
Easy to measure.
Hemodynamic
improvement
Arrhythmias
Number of days in ICU
Physician dependent.
BNP
Heart rate
Related to prognosis.
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
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.
PHASE
OF
WINDOW
HEART
OF
FAILURE:
OPPORTUNITY
129
THE
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
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
IA
1,2
b-Blockers
Systolic HF
1999
Hypotension, bradycardia,
asthma, AV block.
IA
1,2
Aldosterone
blockers
Systolic HF
Improved survival.
Reduced rehospitalization.
Reduced sudden death.
1999
IA
1,2
2004
Benefit demonstrated in
ethnic subgroups (African
Americans).
2011
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
Not
approved
yet.
19
Devices
ICD
Systolic HF
1996
IA
1,2
CRT
Systolic HF and
LBBB
Improved survival.
Reduced rehospitalization.
2004
IA
1,2
Improved survival.
2004
1,2
1,2
LV assist devices
HeartMate
Refractory HF
Selected patients
Heart transplant
Refractory HF
Selected patients
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.
130
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.
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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
27
Nesiretide
Acute HF
Neutral.
30
Adenosine A1 blockers
Rolofylline
Acute HF
31
Inotropes
Dobutamine, Dopamine,
Milrinone, Epinephrine
Acute HF
49-51
Inotropes
Milrinone
Acute HF
Neutral.
52,53
Digoxin
HF, general
54
Diuretics
HF, general
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
45-48
24
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.
131
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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
Components
Poor understanding of
pathophysiology
Incomplete understanding
of the drug
Wrong selection of
patients
Heterogeneous populations.
Comorbidities. Nonresponders.
Errors/difficulties in design
of clinical trials
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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References
1. McMurray J, Adamopoulos S, Anker S, 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 Heart J. 2012;33:1787-1847.
2. Yancy C, Jessup M, Bozkurt V, et al. 2013 ACCF/AHA Guideline for the management of heart failure: executive summary. A report of the American College
of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:1495-1539.
3. Cowie MR, Anker S, Cleland J, et al. Improving care for patients with acute heart
failure: before, during and after hospitalization. London, United Kingdom: Oxford PharmaGenesis Ltd; 2013.
4. Jean Hall MJ, Levant S, DeFrances CJ. Hospitalization for congestive heart
failure in the United States, 2000-2010. NCHS Data Brief. No. 108. October
2012. http://www.cdc.gov/nchs/data/databriefs/db108.pdf.
5. Storrow A, Jenkins C, Self W, et al. The burden of acute heart failure on U.S.
emergency departments. JACC Heart Fail. 2014;2:269-277.
6. Heidenreich PA, Trogdon JG, Khavjou OA, et al; American Heart Association
Advocacy Coordinating Committee. Forecasting the future of cardiovascular
disease in the United States: A policy statement from the American Heart Association. Circulation. 2011;123:933-944.
7. Goyal A, Norton CR, Thomas TN, et al. Predictors of incident heart failure in a
large insured population: a one million person-year follow-up study. Circulation
Heart Fail. 2010;3:698-705.
8. Loehr LR, Rosamond WD, Poole C, et al. The potentially modifiable burden
of incident heart failure due to obesity: the atherosclerosis risk in communities
study. Am J Epidemiol. 2010;172:781-789.
9. Paradis G, Chiolero A. The cardiovascular and chronic diseases epidemic in
low- and middle-income countries: a global health challenge. J Am Coll Cardiol. 2011;57;1775-1777.
10. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE. How to diagnose diastolic heart failure: a consensus statement on
the diagnosis of heart failure with normal left ventricular ejection fraction by the
Heart Failure and Echocardiography Associations of the European Society of
Cardiology. Eur Heart J. 2007;28:2359-2550.
11. Zile MR, Gaasch WH, Anand IS, et al; I-Preserve Investigators. Mode of death
in patients with heart failure and a preserved ejection fraction. Results from
Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-Preserve)
Trial. Circulation. 2010;121:1393-1405.
12. Nieminen M, Brutsaert D, Dickstein K, et al; EuroHeart Survey Investigators.
Euroheart Failure Survey II EHFS II. A survey on hospitalised acute heart failure patients. Description of population. Eur Heart J. 2006;27:2725-2736.
13. Remme WJ, McMurray JJ, Hobbs FD, et al; SHAPE Study Group. Awareness
and perception of heart failure among European cardiologists, internists, geriatricians, and primary care physicians. Eur Heart J. 2008;29:1739-1752.
14. Fox K, Borer JS, Camm AJ, et al; Heart Rate Working Group. Resting heart rate
in cardiovascular disease. J Am Coll Cardiol. 2007;50:823-830.
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. Borer J, Bhm M, Ford I, et al. 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.
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: an observation
from the SHIFT study. Clin Res Cardiol. 2013;102:11-22.
18. Tardif JC, OMeara E, Komajda M, et al; SHIFT Investigators. Effects of selective heart rate reduction with ivabradine on left ventricular remodeling and function: results from the SHIFT echocardiography substudy. Eur Heart J. 2011;
32:2507-2515.
19. The Consensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med. 1987;316:1429-1435.
20. Lpez-Sendn J, Swedberg K, McMurray J, et al. Expert consensus document
133
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40. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent
atrial fibrillation. N Engl J Med. 2011;365:2268-2276.
41. Kowey PR, Crijns HJ, Aliot EM, et al. Efficacy and safety of celivarone, with
amiodarone as calibrator, in patients with an implantable cardioverter-defibrillator for prevention of implantable cardioverter-defibrillator interventions or death:
the ALPHEE study. Circulation. 2011;124:2649-2660.
42. Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive
heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med. 1995;333:77-82.
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
failure: preliminary results of the PROFILE study. Circulation.1993;88(suppl I):
I-301. Abstract.
44. Califf R, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International
Randomized Survival Trial (FIRST). Am Heart J. 1997;134:44-54.
45. Packer M, McMurray J, Massie BM, et al. Clinical effects of endothelin receptor
antagonism with bosentan in patients with severe chronic heart failure: results
of a pilot study. J Card Fail. 2005;11:12-20.
46. OConnor CM, Gattis WA, Adams KF, et al. Tezosentan in patients with acute heart
failure and acute coronary syndromes. J Am Coll Cardiol. 2003;41:1452-1457.
47. Packer M. Effects of the endothelin receptor antagonist bosentan on the morbidity and mortality in patients with chronic heart failure. Results of the ENABLE 1 and 2 trial program. Congress of the American College of Cardiology
2002; Late Breaking Clinical Trials: Special Topic #412.
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.
49. OConnor CM, Gattis WA, Uretsky BF, et al: Continuous intravenous dobutamine is associated with increased risk of death in patients with advanced heart
failure: insights from the Flolan International Randomized Survival Trial (FIRST).
Am Heart J. 1999;138:78-86.
50. Gheorghiade M, Gattis W, Liviu K. OPTIME in CHF trial: rethinking the use of
inotropes in the management of worsening chronic heart failure resulting in
hospitalization. Eur J Heart Fail. 2003;5:9-12.
51. Unverzagt S, Wachsmuth L, Kirch K, et al. Inotropic agents and vasodilator
strategies for acute myocardial infarction complicated by cardiogenic shock or
low cardiac output syndrome. Cochrane Database Syst Rev. 2014;1:CD009669.
52. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milrinone for
acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA.
2002;287:1541-1547.
53. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality
in severe chronic heart failure. The PROMISE Study Research Group. N Engl
J Med. 1991;325:1468-1475.
54. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525-533.
55. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456-2467.
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.
60. Calvo G, McMurray J, Granger C, et al. Large streamlined trials in cardiovascular disease. Am Heart J. 2011;161:848-854.
LE
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.
134
THE
H
Dimitrios FARMAKIS, MD
FESC
Gerasimos FILIPPATOS,
MD, FESC
John PARISSIS, MD, FESC
John LEKAKIS, MD, FESC
Heart Failure Unit
Department of Cardiology
Attikon University Hospital
Athens, GREECE
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
The social and economic burden of hospitalization for heart failure Farmakis and others
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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
136
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
HF
HHF
heart failure
hospitalization for heart failure
The social and economic burden of hospitalization for heart failure Farmakis and others
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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.
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OPPORTUNITY
LA
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.
138
The social and economic burden of hospitalization for heart failure Farmakis and others
THE
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
139
THE
A
VULNERABLE
WINDOW
OF
PHASE
OF
HEART
FAILURE:
OPPORTUNITY
SELECTED
BNP
EF
ESC-HF pilot
EVEREST
HF
HFREF
IN-HF
MI
NT-proBNP
RELAX-AHF
SCD
140
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
THE
VULNERABLE
A
PHASE
OF
WINDOW
HEART
OF
FAILURE:
OPPORTUNITY
Heart failure
Neurohormonal activation
Inflammatory activation*
Fluid overload
Long-term changes
(days to weeks)
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
141
THE
A
VULNERABLE
WINDOW
OF
PHASE
OF
HEART
FAILURE:
OPPORTUNITY
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
1. Jhund PS, Macintyre K, Simpson CR, et al. Long-term trends in first hospitalization for heart failure and subsequent survival between 1986 and 2003:
a population study of 5.1 million people. Circulation. 2009;119:515-523.
2. Stewart S, Ekman I, Ekman T, Oden A, Rosengren A. Population impact of heart
failure and the most common forms of cancer: a study of 1 162 309 hospital
cases in Sweden (1988 to 2004). Circ Cardiovasc Qual Outcomes. 2010;3:573580.
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
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.
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
Pilot Survey (ESC-HF Pilot). Eur J Heart Fail. 2013;15:808-817.
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
and subsequent mortality in chronic heart failure: a propensity-matched study.
J Card Fail. 2008;14:211-218.
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.
15. Gorodeski EZ SR, Blackstone EH. Are all readmissions bad readmissions?
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
worsening heart failure and subsequent re-hospitalization and mortality in the
EVEREST trial. Eur Heart J. 2009;30:1666-1673.
19. Eapen ZJ, Reed SD, Li Y, et al. Do countries or hospitals with longer hospital
142
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
THE
VULNERABLE
A
PHASE
OF
WINDOW
HEART
OF
FAILURE:
OPPORTUNITY
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.
RSULTATS
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.
143
THE
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)
H
Alexandre MEBAZAA
MD, FESC, FHFA
University Paris Diderot
Hpital Lariboisire
Paris, FrAnCE
144
Definition and characteristics of the vulnerable phase in heart failure Yilmaz and Mebazaa
THE
VULNERABLE
A
PHASE
OF
WINDOW
HEART
OF
FAILURE:
OPPORTUNITY
Figure 1.
The vulnerable phase
of heart
failure.
Abbreviations:
AHF, acute
heart failure;
WHF, worsening heart
failure.
ACCF
ACE
AHA
AHF
HF
HFREF
MRA
Definition and characteristics of the vulnerable phase in heart failure Yilmaz and Mebazaa
145
THE
A
VULNERABLE
WINDOW
OF
PHASE
OF
HEART
FAILURE:
OPPORTUNITY
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
146
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
WINDOW
HEART
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
References
1. 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(4):619-626.
2. Maggioni AP, Dahlstrom 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.
3. Kansagara D, Englander H, Salanitro A, et al. risk prediction models for hospital readmission: a systematic review. JAMA. 2011;306(15):1688-1698.
4. Desai AS. The three-phase terrain of heart failure readmissions. Circ Heart
Fail. 2012;5(4):398-400.
5. Teerlink Jr, Cotter G, Davison BA, et al; rELAXin in Acute Heart Failure (rELAXAHF) Investigators. Serelaxin, recombinant human relaxin-2, for treatment of
acute heart failure (rELAX-AHF): a randomised, placebo-controlled trial. Lancet. 2013;381(9860):29-39.
6. Butler J, Braunwald E, Gheorghiade M. recognizing worsening chronic heart
failure as an entity and an end point in clinical trials. JAMA. 2014;312(8):789790.
7. Cotter G, Metra M, Davison BA, et al; VErITAS Investigators. Worsening heart
failure, a critical event during hospital admission for acute heart failure: results
from the VErITAS study. Eur J Heart Fail. 2014;16(12):1362-1371.
8. Adams KF Jr, Fonarow GC, Emerman CL, et al; ADHErE Scientific Advisory
Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary
observations from the first 100,000 cases in the Acute Decompensated Heart
Failure national registry (ADHErE). Am Heart J. 2005;149(2):209-216.
9. Felker GM, Lee KL, Bull DA, et al; nHLBI Heart Failure Clinical research network. Diuretic strategies in patients with acute decompensated heart failure.
N Engl J Med. 2011;364(9):797-805.
10. 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(10):742-749.
11. 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.
12. nieminen MS, Brutsaert D, Dickstein K, et al; EuroHeart Survey Investigators,
Heart Failure Association European Society of Cardiology. EuroHeart Failure
Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J. 2006;27(22):2725-2736.
13. 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.
14. Cleland JG, McDonagh T, rigby AS, et al; national Heart Failure Audit Team for
England and Wales. The national heart failure audit for England and Wales
2008-2009. Heart. 2011;97(11):876-886.
15. Bohm M, Link A, Cai D, et al. Beneficial association of b-blocker therapy on
recovery from severe acute heart failure treatment: data from the Survival of
Patients With Acute Heart Failure in need of Intravenous Inotropic Support trial.
Crit Care Med. 2011;39(5):940-944.
16. Jondeau G, neuder Y, Eicher JC, et al; Investigators BC. B-COnVInCED: Betablocker COntinuation Vs. Interruption in patients with Congestive heart failure
hospitalizED for a decompensation episode. Eur Heart J. 2009;30(18):21862192.
17. Swedberg K, Komajda M, Bohm M, et al; SHIFT Investigators. Ivabradine and
outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled
study. Lancet. 2010;376(9744):875-885.
18. Cavusoglu Y, Mert U, nadir A, Mutlu F, Morrad B, Ulus T. Ivabradine treatment
prevents dobutamine-induced increase in heart rate in patients with acute
decompensated heart failure. J Cardiovasc Med (Hagerstown). 2014 Jun 11.
Epub ahead of print.
19. Seferovic PM, Stoerk S, Filippatos G, et al; Committee of national Heart Failure
Societies or Working Groups of the Heart Failure Association of the European
Society of Cardiology. Organization of heart failure management in European
Society of Cardiology member countries: survey of the Heart Failure Association of the European Society of Cardiology in collaboration with the Heart Failure national Societies/Working Groups. Eur J Heart Fail. 2013;15(9):947-959.
20. ranasinghe I, Wang Y, Dharmarajan K, Hsieh AF, Bernheim SM, Krumholz HM.
readmissions after hospitalization for heart failure, acute myocardial infarction,
or pneumonia among young and middle-aged adults: a retrospective observational cohort study. PLoS Med. 2014;11(9):e1001737.
21. Hernandez AF, Greiner MA, Fonarow GC, et al. relationship between early
physician follow-up and 30-day readmission among Medicare beneficiaries
hospitalized for heart failure. JAMA. 2010;303(17):1716-1722.
22. 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(14):1433-1441.
23. Gheorghiade M, Follath F, Ponikowski P, et al; European Society of Cardiology,
European Society of Intensive Care Medicine. 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(5):423-433.
24. Wu Jr, Frazier SK, rayens MK, Lennie TA, Chung ML, Moser DK. Medication
adherence, social support, and event-free survival in patients with heart failure.
Health Psychol. 2013;32(6):637-646.
Definition and characteristics of the vulnerable phase in heart failure Yilmaz and Mebazaa
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DFINITION
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.
148
Definition and characteristics of the vulnerable phase in heart failure Yilmaz and Mebazaa
THE
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.
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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
ACE
angiotensin-converting enzyme
AHF
COPD
ESC
heart failure
ID
iron deficiency
SHIFT
WRF
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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.
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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.
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
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
152
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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
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.
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.
153
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OPTIMISATION
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.
154
THE
Postdischarge assessment
and management of
patients with heart failure
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
155
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COACH
ESC
MAHLER
NICE
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
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
157
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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.
158
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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
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-
159
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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
References
1. National Institute for Cardiovascular Outcomes Research, Institute of Cardiovascular Science, University College London. National Heart Failure Audit 2012/3.
http://www.hqip.org.uk/assets/NCAPOP-Library/NCAPOP-2013-14/UCLHF-2013-Report-2013-ONLINE-v2.pdf. Published November 2013. Accessed
September 21, 2014.
2. Cleland JG, Swedberg K, Follath F, et al. The EuroHeart Failure survey programme a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J. 2003;24:442463.
3. Kociol RD, Hammill BG, Fonarow GC, et al. Generalizability and longitudinal
outcomes of a national heart failure clinical registry: comparison of Acute Decompensated Heart Failure National Registry (ADHERE) and non-ADHERE
Medicare beneficiaries. Am Heart J. 2010;160:885-892.
4. Dharmarajan K, Hseih 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.
5. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients
in the Medicare fee-for-service program. N Engl J Med. 2009;360:1418-1428.
6. McDonald K, Conlon C, Ledwidge M. Disease management programs for heart
160
failure: not just for the sick heart failure population. Eur J Heart Fail. 2007;9:
113-117.
7. 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 Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;
62:e147-e239.
8. 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: 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(14):1787-1847.
9. Acute heart failure: diagnosing and managing acute heart failure in adults. National Institute for Health and Care Excellence, London, UK; Published October
2014. http//:www.nice.org.uk. Accessed September 21, 2014.
10. McAlister FA, Stewart S, Ferrua S, et al. Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials. J Am Coll Cardiol. 2004;44:810-819.
11. Koelling TM, Johnson ML, Cody RJ, et al. Discharge education improves clinical
THE
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35. Institute of Medicine. Crossing the Quality Chasm: a new health system for the
21st Century. Washington, DC: National Academies Press; 2001.
36. Hughes JC, Bamford C, May C. Types of centredness in health care: themes
and concepts. Med Health Care Philos. 2008;11:455-463.
37. Bergeson SC, Dean JC. A systems approach to patient-centered care. JAMA.
2006;296:2848-2851.
38. Illingworth R. What does patient-centred mean in relation to the consultation?
Clin Teach. 2010;7:116-120.
39. Lorig KR, Sobel DS, Stewart AL, et al. Evidence suggesting that a chronic disease self-management program can improve health status while reducing hospitalization: a randomized trial. Med Care. 1999;37:5-14
40. Department of Health. The Expert Patient: a new approach to chronic disease
management for the 21st Century. London, UK: United Kingdom Department
of Health; August 2001.
41. Ekman I, Wolf A, Olsson LE, et al. Effects of person-centred care in patients with
chronic heart failure: the PCC-HF study. Eur Heart J. 2012;33:1112-1119.
42. Marti CN, Georgiopoulou W, Giamouzis G, et al. Patient-reported selective adherence to heart failure self-care recommendations: a prospective cohort study:
the Atlanta Cardiomyopathy Consortium. Congest Heart Fail. 2013;19:16-24.
43. Jaarsma T, Stromberg A, Ben Gal T, et al. Comparison of self-care behaviours
of heart failure patients in 15 countries worldwide. Patient Educ Couns. 2013;
92:114-120.
44. Butler J, Arbogast PG, Daugherty J, et al. Outpatient utilization of angiotensinconverting enzyme inhibitors among heart failure patients after hospital discharge. J Am Coll Cardiol. 2004;43:2036-2043.
45. Jones CD, Holmes GM, Dewalt DA, et al. Is adherence to weight monitoring or
weight-based diuretic self-adjustment associated with fewer heart failure-related emergency department visits or hospitalizations? J Cardiac Fail. 2012;18:
576-584.
46. Moser DK, Doering LV, Chung ML. Vulnerabilities of patients recovering from
an exacerbation of chronic heart failure. Am Heart J. 2005;150:984.
47. Wu JR, Moser DK, Chung ML, Lennie TA. Predictors of medication adherence
using a multi-dimensional adherence model in patients with heart failure. J Card
Fail. 2008;14:603-614.
48. Sayers SL, Riegel B, Pawlowski S, Coyne JC, Samaha FF. Social support and
self-care of patients with heart failure. Ann Behav Med. 2008;35:70-79.
49. Gallagher R, Luttik ML, Jaarsma T. Social support and self-care in heart failure.
J Cardiovasc Nurs. 2011;26:439-445.
50. Rosland AM, Heisler M, Choi HJ, Silveira MJ, Piette JD. Family influences on selfmanagement among functionally independent adults with diabetes or heart failure: do family members hinder as much as they help? Chronic Illn. 2010;6:
22-33.
51. Agren S, Evangelista L, Stromberg A. Do partners of patients with chronic heart
failure experience caregiver burden? Eur J Cardiovasc Nurs. 2010;9:254-262.
52. Pressler SJ, Gradus-Pizlo I, Chubinski SD, et al. Family caregiver outcomes in
heart failure. Am J Crit Care. 2009;18:149-159.
53. Hwang B, Fleischmann KE, Howie-Esquivel J, Stotts NA, Dracup K. Caregiving for patients with heart failure: impact on patients families. Am J Crit Care.
2011;20:431-441.
54. Metra M, Gheorghiade M, Bonow RO, Dei Cas L. Post-discharge assessment
after a heart failure hospitalization: the next step forward. Circulation. 2010;122:
1782-1785.
55. Inglis SC, Clark RA, McLaister FA, et al. Structured telephone support or telemonitoring programmes for patients with chronic heart failure. Cochrane Database Syst Rev. 2010;8:CD007228.
56. Pandor A, Gomersall T, Stevens JW, et al. Remote monitoring after recent
hospital discharge in patients with heart failure: a systematic review and network meta-analysis. Heart. 2013;99:1717-1726.
57. Chaudhry SI, Mattera JA, Curtis JP, et al. Telemonitoring in patients with heart
failure. N Engl J Med. 2010;363;2301-2309.
58. Koehler F, Winkler S, Scheiber 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;123:1873-1880.
59. Hindricks G, Taborsky M, Glikson M, et al. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled
trial. Lancet. 2014;384:583-590.
60. Cowie MR. Telemonitoring implants for patients with heart failure. Lancet. 2014;
384:560-562.
61. Morgan JM, Dimitrov B, Gill J, et al. Rationale and study design of the REM-HF
study: remote management of heart failure using implanted devices and formalized follow-up procedures. Eur J Heart Fail. 2014;16:1039-1045.
62. Cowie MR, Chronaki K, Vardas P. E-health innovation: time for engagement
161
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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.
162
THE
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)
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
163
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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
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
OR
odds ratio
RR
relative risk
164
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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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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
166
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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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
167
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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
References
1. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93(9):
1137-1146.
2. Heidenreich PA, Trogdon JG, Khavjou OA, et al; American Heart Association
Advocacy Coordinating Committee; Stroke Council; Council on Cardiovascular
Radiology and Intervention; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Council on Arteriosclerosis; Thrombosis and Vascular
Biology; Council on Cardiopulmonary; Critical Care; Perioperative and Resuscitation; Council on Cardiovascular Nursing; Council on the Kidney in Cardiovascular Disease; Council on Cardiovascular Surgery and Anesthesia, and Interdisciplinary Council on Quality of Care and Outcomes Research. Forecasting
the future of cardiovascular disease in the United States: a policy statement from
the American heart association. Circulation. 2011;123(8):933-944.
3. McMurray J, Hart W, Rhodes G. An evaluation of the cost of heart failure to the
National Health Service in the UK. Br J Med Econ. 1993;6:99-110.
4. Berry C, Murdoch DR, McMurray JJ. Economics of chronic heart failure. Eur J
Heart Fail. 2001;3(3):283-291.
5. Cowie MR, Fox KF, Wood DA, et al. Hospitalization of patients with heart failure:
a population-based study. Eur Heart J. 2002;23(11):877-885.
6. 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(5):407-413.
7. Kocher RP, Adashi EY. Hospital readmissions and the Affordable Care Act: paying for coordinated quality care. JAMA. 2011;306(16):1794-1795.
8. Blecker S, Agarwal SK, Chang PP, et al. Quality of care for heart failure patients
hospitalized for any cause. J Am Coll Cardiol. 2014;63(2):123-130.
9. Grimshaw JM, Russell IT. Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations. Lancet. 1993;342(8883):1317-1322.
10. Poelzl G, Altenberger J, Pacher R, et al. Dose matters! Optimisation of guideline
adherence is associated with lower mortality in stable patients with chronic heart
failure. Int J Cardiol. 2014;175(1):83-89.
168
11. 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(4):200-206.
12. Krumholz HM, Baker DW, Ashton CM, et al. Evaluating quality of care for patients with heart failure. Circulation. 2000;101(12):e122-e140.
13. Fonarow GC, Abraham WT, Albert NM, et al. Influence of a performance-improvement initiative on quality of care for patients hospitalized with heart failure: results of the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF). Arch Intern Med. 2007;
167(14):1493-1502.
14. Smaha LA; American Heart Association. The American Heart Association Get
With The Guidelines program. Am Heart J. 2004;148(5 suppl):S46-S48.
15. Ezekowitz JA, Van Walraven C, McAlister FA, Armstrong PW, Kaul P. Impact of
specialist follow-up in outpatients with congestive heart failure. Can Med Assoc J. 2005;172(2):189-194.
16. McDonagh TA, Blue L, Clark AL, et al. European Society of Cardiology Heart
Failure Association standards for delivering heart failure care. Eur J Heart Fail.
2011;13(3):235-241.
17. Hernandez AF, Greiner MA, Fonarow GC, et al. Relationship between early
physician follow-up and 30-day readmission among Medicare beneficiaries
hospitalized for heart failure. JAMA. 2010;303(17):1716-1722.
18. McAlister FA, Youngson E, Bakal JA, Kaul P, Ezekowitz J, van Walraven C.
Impact of physician continuity on death or urgent readmission after discharge
among patients with heart failure. CMAJ. 2013;185(14):E681-E689.
19. Lee DS, Schull MJ, Alter DA, et al. Early deaths in heart failure patients discharged from the emergency department: a population-based analysis. Circ
Heart Fail. 2010;109.
20. Sidhu RS, Youngson E, McAlister FA. Physician continuity improves outcomes
for heart failure patients treated and released from the emergency department.
JACC Heart Fail. 2014;2(4):368-376.
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21. Lee DS, Stukel TA, Austin PC, et al. Improved outcomes with early collaborative care of ambulatory heart failure patients discharged from the emergency
department. Circulation. 2010;122(18):1806-1814.
22. Jaarsma T, Strmberg A. Heart failure clinics are still useful (more than ever?).
Can J Cardiol. 2014;30(3):272-275.
23. Capomolla S, Febo O, Ceresa M, et al. Cost/utility ratio in chronic heart failure:
comparison between heart failure management program delivered by day-hospital and usual care. J Am Coll Cardiol. 2002;40(7):1259-1266.
24. 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.
25. Feltner C, Jones CD, Cen CW, et al. Transitional care interventions to prevent
readmissions for persons with heart failure: a systematic review and meta-analysis. Ann Intern Med. 2014;160(11):774-784.
26. Anker SD, Koehler F, Abraham WT. Telemedicine and remote management of
patients with heart failure. Lancet. 2011;378(9792):731-739.
27. 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.
PHASE
OF
WINDOW
HEART
OF
FAILURE:
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28. Riegel B, Moser DK, Anker SD, et al. State of the science promoting self-care
in persons with heart failure: a scientific statement from the American Heart
Association. Circulation. 2009;120(12):1141-1163.
29. McAlister FA, Stewart S, Ferrua S, McMurray JJ. Multidisciplinary strategies
for the management of heart failure patients at high risk for admission: a systematic review of randomized trials. J Am Coll Cardiol. 2004;44(4):810-819.
30. Blue L, Lang E, McMurray JJ, et al. Randomised controlled trial of specialist
nurse intervention in heart failure. BMJ. 2001;323(7315):715-718.
31. Jovicic A, Holroyd-Leduc JM, Straus SE. Effects of self-management intervention on health outcomes of patients with heart failure: a systematic review
of randomized controlled trials. BMC Cardiovasc Disord. 2006;6(1):43.
32. Weingarten SR, Henning JM, Badamgarav E, et al. Interventions used in disease
management programmes for patients with chronic illness: which ones work?
Meta-analysis of published reports. BMJ. 2002;325(7370):925.
33. Ahmed A. Quality and outcomes of heart failure care in older adults: role of multidisciplinary disease-management programs. J Am Geriatr Soc. 2002;50(9):
1590-1593.
34. Faxon DP, Schwamm LH, Pasternak RC, et al. Improving quality of care through
disease management: principles and recommendations from the American
Heart Associations Expert Panel on Disease Management. Circulation. 2004;
109(21):2651-2654.
IMPACT
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.
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
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 .
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
172
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.
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)
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.
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)
174
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.
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.
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
176
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.
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.
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.
177
CONTROVERSIAL
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)
178
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.
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)
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)
References
180
CONTROVERSIAL
QUESTION
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.
181
CONTROVERSIAL
QUESTION
182
CONTROVERSIAL
QUESTION
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.
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.
183
CONTROVERSIAL
QUESTION
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
184
PROCORALAN
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)
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
185
PROCORALAN
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
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
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.
187
PROCORALAN
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.
188
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
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.
189
PROCORALAN
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
190
PROCORALAN
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
191
PROCORALAN
PROCORALAN :
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.
192
INTERVIEW
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
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
193
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).
194
INTERVIEW
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.
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
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-
195
INTERVIEW
LDUCATION
THRAPEUTIQUE
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.
196
FOCUS
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
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
197
FOCUS
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
renin-angiotensin-aldosterone system
SHIFT
SOLVD
198
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.
FOCUS
Figure 2. Drug treatment at hospital discharge in patients with chronic heart failure.
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.
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
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.
199
FOCUS
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
200
FOCUS
LA
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.
201
U P DAT E
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
202
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
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.
SELECTED
CHAMPION
CRT-D
ECG
electrocardiogram
ESC
HHH
HOME-HF
NYHA
Tele-HF
TEN-HMS
TIM-HF
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.
203
U P DAT E
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.
204
U P DAT E
205
U P DAT E
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
206
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.
U P DAT E
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.
LA
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.
207
A TOUCH
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
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.
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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.
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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
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
211
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214
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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.
215
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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.
216
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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.
217
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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.
218
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Real or virtual? Sun shining through the signature concrete latticework of MuCEM on a terrace. Guillaume Horcajuelo/epa/Corbis.
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,
219
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LE MUCEM,
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.
220
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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
OF
FRANCE
b y C . R g n i e r, Fra n c e
H
Christian RGNIER, MD
Pierre and Marie Curie University
(UPMC Paris 6)
International Society for the
History of Medicine (ISHM)
Paris, FRANCE
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
222
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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
223
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224
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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.
225
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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.
226
AT
A TOUCH
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FRANCE
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.
227
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OF
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.
230
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-
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
231
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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 :
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.
232
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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
Medicographia
The vulnerable phase
of heart failure:
a window of opportunity
Pa s t e u r
2015
www.servier.com
www.medicographia.com