Innovation in Clinical

Care in Heart Failure

Teaching slides developed based on Heart Failure Summit
held on October 30-31, 2015, Barcelona, Spain
Guidance for the use of the slide curriculum
This educational activity is intended for an international audience of healthcare
professionals, including cardiologists, primary care physicians, and other healthcare
professionals involved in the management of patients with heart failure.

The goal of this activity is to review the current developments, as well as the unmet
needs and areas for improvement, in clinical care in heart failure.

Upon completion of this activity, participants will be able to:

• Recognize the burden of heart failure and understand its reasons
• Understand the difficulties in preventing, diagnosing and treating patients with
heart failure
• Understand the need to improve a multidisciplinary approach when dealing with
heart failure patients
• Describe the role of new generation therapies that interrupt the vicious
pathophysiology cycle leading to worsening of heart failure
Educational objectives
• Increase awareness for heart failure as a disease
• Learn about the latest scientific and clinical advances in heart failure
and adopt a guidelines adherence attitude
• Address unmet needs that deserve to be investigated in future
clinical research
• Discuss the roles of different stake holders, such as payers, patient
organizations, specialized nurses, primary care, cardiologists and
policy makers in heart failure care
• Establish a multidisciplinary approach for the management of heart
failure
• Provide practical guidance to different stakeholders involved in heart
failure management
Contents
• HEART FAILURE: Scope of the problem

• EPIDEMIOLOGY of HF

• DIAGNOSIS of HF

• MANAGEMENT of HF
• Guidelines
• Challenges
• Implementation of policy and guidelines
• Improving Heart Failure Management

• NOVEL INSIGHTS AND INNOVATIONS IN TARGETING THE NEUROHUMORAL SYSTEM

• SELF ASSESSMENT
HEART FAILURE:
Scope of the problem
The burden of heart failure
NUMBER of PATIENTS ECONOMIC BURDEN
21 MILLION adults worldwide are In 2012, the overall worldwide
living with heart failure cost of heart failure was nearly
This number is expected to rise.1,2 $108 BILLION.6

MORTALITY
50% of heart failure patients die
within 5 years from diagnosis.5

REHOSPITALISATION COMORBIDITIES: The vast

Heart failure is the NUMBER 1 majority of HF patients has 3 or
cause of hospitalisation for more comorbidities 3
patients aged >65 years.4

1. Mozaffarian D et al. Circulation. 2015;131(4):e29-e322.

2. Mosterd A et al. Heart. 2007;93(9):1137-1146.
3. http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Chronic-Conditions/Downloads/2012Chartbook.pdf
4. Cowie MR et al. Oxford PharmaGenesis; 2014. http://www.oxfordhealthpolicyforum.org/AHFreport. Accessed February 18, 2015.
5. Fauci AS et al. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008.
6.  Cook C et al. Int J Cardiol. 2014;171(3):368-376.
 Definition of Heart Failure
Heart failure can be defined as an abnormality of cardiac structure or function leading to
failure of the heart to deliver oxygen at a rate commensurate with the requirements of
the metabolizing tissues, despite normal filling pressures (or only at the expense of
increased filling pressures).1

TERMINOLOGY used to describe HF2

Related to EF*: HFrEF (reduced ejection fraction: EF<40%)

HFmEF (mildly impaired EF: EF 40-49%
HFpEF (preserved ejection fraction: EF ≥50%)*
Related to time-course: New onset, transient, chronic
Related to progression: Acute, stable, worsening
Related to location: Left heart, right heart, combined

* There is no consensus concerning the cut-off for preserved EF2

1. McMurray et al. Eur Heart J 2012;33:1787–847

2. Dickstein K et al. Eur Heart J 2008;29:2388–
442
Aetiology of HF
VALVULAR HEART DISEASE MYOCARDIAL DISEASE
• Coronary artery disease
• Mitral
• Hypertension
• Aortic
• Cardiomyopathy
• Trisuspid
• Pulmonary
ENDOCARDIAL DISEASE
PERICARDIAL DISEASE • With/without hypereosinophilia
• Constrictive pericarditis • Endocardial fibroelastosis
• Pericardial effusion
HEART
ARRHYTHMIA
HIGH OUTPUT STATES FAILURE • Tachyarrhythmia
• Anaemia • Atrial
• Sepsis • Ventricular
• Thyrotoxicosis • Bradyarrhythmia
• Paget‘s disease • Sinus node dysfunction
• Arteriovenous fistula CONDUCTION
DISORDERS
VOLUME OVERLOAD • Atrioventricular block
• Renal failure
• Iatrogenic (e.g. post-
CONGENITAL
operative fluid infusion HEART DISEASE McMurray et al. Eur Heart J 2012;33:1787–847
Pathophysiology of HF
Injury to myocytes
due to myocardial ELECTRICAL INSTABILITY
infarction or other VENTRICULAR
cause REMODELING
REDUCTION of EF

NEUROHUMORAL
IMBALANCE

An imbalance occurs in three key neurohumoral systems:

• The renin–angiotensin–aldosterone system
• The sympathetic nervous system
• The natriuretic peptide system

The systemic responses in the renin–angiotensin–aldosterone and sympathetic nervous systems cause further
myocardial injury, and have detrimental effects on the blood vessels, and various organs, thereby creating a
pathophysiological ‘vicious cycle’. The natriuretic peptide system has a protective function, which can
counterbalance these detrimental effects.

1. McMurray JJ. N Engl J Med 2010;362:228–238

2. Shah AM. Lancet 2011;378:704–712
Symptoms and signs of HF
The diagnosis of HF can be difficult, especially in the early stages

Symptoms Signs
Typical More specific
Breathlessness Elevated jugular venous pressure
Orthopnoea Hepatojugular reflux
Paroxysmal nocturnal dyspnoea Third heart sound (gallop rhythm)
Reduced exercise tolerance Laterally displaced apical impulse
Fatigue, tiredness, increased time
Cardiac murmur
to recover after exercise
Ankle swelling

McMurray et al. Eur Heart J 2012;33:1787–847

McMurray et al. Eur Heart J 2012;33:1787–847

Classification of Heart Failure
ACC/AHA stages of HF NYHA functional classification
(based on structure and damage to heart) (based on symptoms or physical activity)
Stage A At high risk for HF, but without structural or Class I No limitation of physical activity. Ordinary
functional abnormality physical activity does not cause undue fatigue,
No signs or symptoms palpitation or dyspnoea

Stage B Developed structural heart disease strongly Class II Slight limitation of physical activity. Comfortable
associated with development of HF, but at rest, but ordinary physical activity results in
without signs or symptoms HF symptoms

Stage C Symptomatic HF associated with underlying Class III Marked limitation of physical activity.
structural heart disease Comfortable at rest, but less than ordinary
activity results in HF symptoms

Stage D Advanced structural heart disease and Class IV Symptoms of HF present at rest. If any physical
marked symptoms of HF at rest, despite activity is undertaken, discomfort is increased
maximal medical therapy

Dickstein et al. Eur Heart J 2008;29:2388–442

Hunt et al. J Am Coll Cardiol 2009;53:e1–90
Natural history of HF
HF is a silently progressing disease
We begin to look at the disorder at the end of its natural history - that is too late!

The cardiovascular continuum

Vascular Remodeling

environmental
determinants

LVH
Diastolic
Diastolic Heart Failure
Dysfunction
physical CVD risk factors Disturbed
activity ↓ & biomarkers Microcirculation
Systolic Systolic
Dysfunction Heart Failure
CAD / Infarktion

genetic determinants

Myocardial Remodeling

Stage A B C/D

Krum, Gilbert. Lancet 2003;362:147–58

McMurray et al. Eur Heart J 2012;33:1787–847
The classic domains of HFrEF are
also present in HFpEF1
severely reduced exercise capacity, neuroendocrine activation, impaired quality
of life

Domains HFpEF HFrEF Controls

Peak VO2 14.2±0.5* 13.1±0.5* 19.9±0.7
Angiotensin 9.1±0.3* 8.7±0.3* 11.5±0.4
169±80
Norepinephrine 306±64* 287±62*

MLHFQ 24.8±4.4 43.8±3.9 -

*P<0.05 vs controls

HFpEF: HF despite absence of pump failure

Half of patients with HF have HFpEF2

1. Borlaug BA and Paulus WJ. Eur Heart J 2011;32: 670–679

2. Kitzman DW et al. JAMA 2002; ;288(17):2144-2150
 HFpEF is a major public health problem
HF Hospitalization
80 HFpEF

hypertension
hypertension

hypertension
stable angina & hypertension

hypertension

diabetes
hypertension, very elderly

70 Outcomes of patients
with HFpEF as
Per 1000 patient years

60
compared with those
50 in trials of other
40 cardiovascular
69 73
30 disease, with similar
43
ages, sex and
20
comorbidities profiles
10
7.1 7.5 11 11.5
4.6 5.3 5.5
0
N T -2 FE D E AT rv
e d
EF
O VE P LI R LU ve
TI Y B O LH s e e r -P
AC H AN C VA AL re es IG
AC I-P -P r D
M
AR
H
C

Campbell J Am Coll Cardiol 2012

 HFpEF is a major public health problem
Overall Mortality
HFpEF

Hypertension
diabetes

hypertension

hypertensio
hypertensio

hypertensio
80

very elderly
Outcomes of patients
70
with HFpEF as
60 compared with those

n
n

n
in trials of other
stable angina &

50
Per 1000 patient years

hypertension

cardiovascular
40 76 disease, with similar
30
53 54 ages, sex and
47.2
20 comorbidities profiles
25.6 28.7
10 15.7 16.4 17.3
11.4
0
D -2 N FE E AT T
rv
e d
EF
R P IO LI U E e rve
C
O B T AL LL
H YV s e -P
AN AC V H re es IG
AC A I-P
-P
r D
M
A R
H
C

Campbell J Am Coll Cardiol 2012

 HF has a detrimental effect on Quality of Life

Patients with HF commonly report psychological distress,

including:
• depression
• hostility and anxiety
• limitation in their activities of daily living
• disruption of work roles and social interaction with friends and
family
HF=heart failure;

• reduced sexual activity and satisfaction

Grady. Crit Care Nurs Clin North Am 1993;5:661–70 2010

 Health related QoL is similar for patients with
HFpEF and HFrEF
• Distribution of the MLHF
questionnaire responses in patients
(n=2709) with HFpEF and HFrEF.
Scores range from 0 to 105 with a
16
HFpEF (LVEF >40%)
low score reflecting a better health-
14 HFrEF (LVEF ≤40%) related QoL
• Distribution of MLHF QoL scores
12
reflects the wide range of health-
Percent distribution

10 related QoL among patients with

8
chronic HF1
• Patients with HFpEF and those with
6 HFrEF have a similar distribution of
4 MLHF QoL scores
• Patients with HFpEF may have
2
greatly reduced general and
0 symptom-specific QoL2
0–<10 10 –<20 20 –<30 30 –<40 40 –<50 50 –<60 60 –<70 70 –<80 80 –<90 >90

Better QoL MLHF summary score range Worse QoL

1. Lewis et al. Eur J Heart Fail 2007;9:83–91

2. Kitzman et al. JAMA 2002;288:2144-50
Comorbidities in HF
Comorbidities impact prognosis in patients with HF1,2

Why comorbidities are relevant in HF1:

• Comorbidities may affect the use of
Gout treatments for HF
Hyperlipidaemia • Drugs used to treat comorbidities may cause
COPD Iron deficiency worsening of HF
• Drugs used to treat HF and comorbidities
Comorbidities in may interact and reduce patient adherence
patients with HF Depression • Most comorbidities are associated with
Hypertension Sleep disturbance worse clinical status and are predictors of
Angina Cancer poor prognosis in HF

Diabetes mellitus
Renal Anaemia
dysfunction Cachexia
Obesity

1. McMurray et al. Eur Heart J 2012;33:1787–847

2. Ennezat et al. Nephrol Dial Transplant 2011;26:3908-13
HF imposes a significant burden
on the caregiver
 Caregiving tasks related to feelings of burden include personal
care, such as assisting with washing and bathing and mobility1
 Caregiving burden in partners of patients with HF is similar to that
in partners of patients with cancer1
 HF caregivers report being socially isolated, physically exhausted
and unprepared for the stress of the caregiver role, with sleep and
anxiety issues over current and future needs, and worry over
financial concerns2
 Older caregivers experience decreased psychological functioning,
increased risk of health problems and mortality3

1. Luttik et al. Eur J Heart Fail 2007;9:695–701

2. Saunders. West J Nurs Res 2008;30:943–59
3. Schulz & Beach. JAMA 1999;282:2215–19
Section
Summary

Heart failure: Scope of the problem

• Heart failure can be defined as ‘an abnormality of cardiac structure or function leading to failure of
the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing
tissues, despite normal filling pressures (or only at the expense of increased filling pressures)‘

• The global burden of HF is increasing in number and complexity, due to an aging patient population,
often with multiple comorbidities. Reducing readmissions can limit the burden for healthcare
systems.

• There are many causes of HF that result in ventricular remodeling, reduction of the left ventricular
ejection fraction, and neurohumoral imbalance.

• Many of the symptoms of HF are non-specific. HF severity can be classified based on structure and
damage to heart (ACC/AHA) or based on symptoms or physical activity (NYHA). HF is a silently
progressive condition.

• HFrEF and HFpEF may present similarly within the clinical syndrome of HF. Half of patients have
HFpEF. Outcomes in HFpEF patients are worse than in similar patient populations with other
cardiovascular disease

• HF has a large impact on quality of life, including physical activities and psychological distress.
Comorbidities impact prognosis in patients with HF.

• HF places a significant physical and emotional burden on the caregiver.

DIAGNOSIS of HEART FAILURE
Principles of diagnosis of HF
All diagnostic steps are equally important

 Consider: Medical history, signs, symptoms

 Confirm: Natriuretic peptides, Echocardiography
 Assess clinical phenotype: HFrEF vs. HFpEF
 Assess etiology: Angiography, cMRI, Biopsy
 Risk stratification
 Workup for targeted therapies

Presented by BM Pieske during HF SUMMIT 2015

The diagnosis of HF is a staged process

Risk assessment at • Clinical assessment/Comorbidities

A preclinical stage • Biomarkers (Cardiac +EOD)
• Echocardiography
• Stress test
Initial diagnostic workup
in symptomatic patients

• Stress echocardiography
Detailed workup in case • Invasive tests &
B of uncertainity hemodynamics
• Cardiac MRI
• Comorbidities
• Cardiac MRI +++
Underlying patho- •
C physiology & aetiology •
Biopsy
Scintigraphy
• SPECT, Molecular imaging(?)

Presented by BM Pieske during HF SUMMIT 2015

Diagnosing HF
The diagnosis of HFpEF is more difficult than the diagnosis of HFrEF

The diagnosis of HFrEF requires three conditions to be satisfied

1. Symptoms typical of HF
2. Signs typical of HF
3. Reduced LVEF

The diagnosis of HFpEF requires four conditions to be satisfied

1. Symptoms typical of HF
2. Signs typical of HF
3. Normal or only mildly reduced LVEF and LV not dilated
4. Relevant structural heart disease (LV hypertrophy/LA enlargement)
and/or diastolic dysfunction

McMurray et al. Eur Heart J 2012;33:1787–847

ESC HF diagnostic algorithm 2012
Acute onset Non-acute onset

ECG, Chest x-ray ECG, Possibly chest x-ray

Echocardiography BNP/NT-pro BNP* BNP/NT-pro BNP Echocardiography

ECG normal and ECG abnormal or ECG abnormal or ECG normal and
NT-proBNP < NT-proBNP > NT-proBNP > 125 NT-proBNP <
300pg/mL or 300pg/mLbb or pg/mLaa or 125pg/mL or
BNP < 100 pg/mL BNP > 100 pg/mL bb BNP > 35 pg/mL aa BNP < 35 pg/mL

HF unlikely cc
HF unlikely cc
Echocardiography

If heart failure is confirmed by echocardiography,

determine aetiology and start appropriate treatment.

*In the acute setting, MR-proANP may also be used (cut-off point 120 pmol/L, i.e. <120 pmol/L = heart failure unlikely).
a. Exclusion cut-off points for natriuretic peptides are chosen to minimize the false-negative rate while reducing unnecessary referrals for echocardiography.
b. Other causes of elevated natriuretic peptide levels in the acute setting are an acute coronary syndrome, atrial or ventricular arrhythmias, pulmonary embolism, and severe
chronic obstructive pulmonary disease with elevated right heart pressures, renal failure, and sepsis. Other causes of an elevated natriuretic level in the non-acute setting are:
old age (>75 years), atrial arrhythmias, left ventricular hypertrophy, chronic obstructive pulmonary disease, and chronic kidney disease.
c. Treatment may reduce natriuretic peptide concentration, and natriuretic peptide concentrations may not be markedly elevated in patients with HF-PEF.

McMurray et al. Eur Heart J 2012;33:1787–847

HFA/ESC diagnostic recommendations HFpEF
Symptoms or signs of HF

Normal or mildly reduced LV systolic function (LVEF >50% and LVEDVI <97 mL/m 2)

Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness

Invasive hemodynamic TD Biomarkers

measurements EIE′ >15 15 >EIE′ >8 NT-proBNP >220 pg/mL or
mPCW >12 mmHg BNP >200 pg/mL
or LVEDP >16 mmHg
or  >48 ms
or b >0.27
Biomarkers TD
Echo – blood flow Doppler
NT-proBNP EIA>50 yr <0.5 and DT>50 yr >280 ms EIE′ >8
>220 pg/mL or or Ard–Ad >30 ms
BNP >200 pg/mL or LAVI >40 mL/m2
or LVMI >122 g/m2(♀); >149 g/m2 (♂) or
atrial fibrillation

HFpEF
Paulus et al. Eur Heart J 2007;28:2539–50
Particular relevance of BNP
• diagnosis
• staging
• risk stratification
• monitor/titrate therapy
• admission/discharge decisions:
> rule out symptomatic LV dysfunction

A normal natriuretic peptide level in an untreated patient virtually

excludes significant cardiac disease
Consider different cut-off values in various clinical situations

Presented by K Dickstein during HF SUMMIT 2015

Section
Summary

Diagnosis of HF
• Adequate diagnosis of HF includes screening for cardiac dysfunction in
patients at risk, confirming the clinical suspicion with objective diagnostic
measures, and identifying the underlying phenotype and aetiology.

• The HF diagnosis should be considered at all levels of care, to guide

management decisions.

• The diagnosis of HFpEF is more difficult than the diagnosis of HFrEF because
it is largely one of exclusion.

• Measuring natriuretic peptide levels can help diagnosis. A normal natriuretic

peptide level in an untreated patient virtually excludes significant cardiac
disease, making an echocardiogram unnecessary.
EPIDEMIOLOGY of HEART FAILURE
HF is increasing in prevalence
Hospital discharges for HF by gender (USA: 1979-2006)*

700
Male
600
Female
Discharges in thousands

500
400
300
200
100
0

79 80 85 90 95 00 05
Years

*Hospital discharges include people discharged alive, dead and of unknown status

Lloyd-Jones et al. Circulation 2010;121:e46–e215

Increasing HFpEF prevalence trends
• Prevalence of HFpEF among patients with a discharge diagnosis of HF increased
from 38% to 54% from 1987–20011
• Increasing prevalence of HFpEF may be a consequence of growing recognition,
population aging and increases in hypertension and obesity 2

70
r=0.92, p<0.001
60
Patients with preserved
ejection fraction (%)

50

40

30

20
0
1986 1990 1994 1998 2002

1. Owan et al. N Engl J Med 2006;355:251–9

2. Blanche et al. Swiss Med Wkly 2010;140:66–72
HFpEF & HFrEF: Similar initial hospital
rates
In a retrospective study of 451 patients with HF in Sweden, time from diagnosis to
first post-diagnosis CV- or HF-related hospitalization was not significantly different
between HFpEF and HFrEF (p=0.49 and p=0.08, respectively)

Time to first CV hospitalization Time to first HF hospitalization

1.00 1.00

HFpEF (LVEF >45%)

HFrEF (LVEF ≤45%)
Survival distribution function

Survival distribution function

0.75 0.75

0.50 0.50

0.25 0.25

0 0
Wikstrom et al. ESC 2011 Gothenburg,
0 200 400 600 800 1,000 0 200 400 600 800 May1,000
Sweden, 21–24, 2011

Time (days) Time (days)

Wikstrom et al. ESC 2011 Gothenburg, Sweden, 21–24 May 2011
HFpEF & HFrEF: Similar hospital
readmission rates
18 p=0.09 • In new-onset HF, rates of
16.1
16 readmission for HF and in-
13.5
Percentage of patients

14 hospital complications do
12 not differ substantially
10 between HFpEF and HFrEF1
8 HFpE
F
6 p=0.66
4.5 4.9 • Readmission is as likely in
4 HFpEF as in HFrEF,
2 following hospital discharge,
0 with a re-hospitalization rate
30-day readmission 1-year readmission of 29% within 60–90 days,2
for HF* for HF*
and a median time to re-
hospitalization of 29 days3
*Readmission rates were calculated for the 2,339 patients who survived the
index admission: 1,493 with HFrEF and 846 with HFpEF

1. Bhatia et al. N Engl J Med 2006;355:260–9

2. Fonarow et al. J Am Coll Cardiol 2007;50:768–77
3. Lenzen et al. Eur Heart J 2004;25:1214–20
 Mean length of hospital stay increases
with each rehospitalization for HF
Length of hospital stay following hospitalization for HF
8.5
278,307 patients in
Mean length of stay (days)

8.0 the USA with ≥1

hospitalization with
7.5 a HF claim were
All HF followed from first
7.0 HFrEF HF hospitalization
HFpEF for 24 months or
6.5
Acute HF until disenrollment
Chronic HF or end of data
availability
6.0

First Second Third Fourth Fifth

Hospitalization
Korves et al. Presented at the American Heart Association Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke
2010 Scientific Sessions, Washington, D.C., May 19–21, 2010
HFpEF & HFrEF: Similarly high mortality
 Survival rate among patients with a discharge diagnosis of HF in the USA was slightly
higher among patients with HFpEF than those with HFrEF between 1987–2001 1
 Respective mortality rates were 29% and 32% at 1 year and 65% and 68% at 5 years
 HFpEF is associated with significant morbidity and mortality, despite having a slightly higher
survival rate compared with HFrEF2,3

1.0

0.8 HFrEF (LVEF <50%)

HFpEF (LVEF ≥50%)

0.6
Survival

0.4

0.2
p=0.03
0
0 1 2 Year 3 4 5

1. Owan et al. N Engl J Med 2006;355:251–9

2. Blanche et al. Swiss Med Wkly 2010;140:66–72
3. Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). Eur Heart J 2012;33:1750–7
 HFpEF survival rates are not improving

Patients with HFpEF (LVEF ≥50%) Patients with HFrEF (LVEF <50%)

1.0 1.0 1987–1991

1987–1991
1992–1996 1992–1996
0.8 0.8
1997–2001 1997–2001

0.6 0.6

Survival
Survival

0.4 0.4

0.2 0.2
p=0.36 p=0.005
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Year Year

Owan et al. N Engl J Med 2006;355:251–9

Section
Summary

Epidemiology of HF
• HF is increasing in prevalence. Changes in population demographics
account for these increases.

• HFpEF and HFrEF have similar initial hospitalisation rates and similar
rehospitalisation rates.

• Mean length of hospital stay increases with each rehospitalisation for HF

• HFpEF and HFrEF have similarly high mortality. While survival rates in
HFpEF have not changed in recent years, survival rates in HFrEF have
improved.
HF Guidelines
There are many treatment objectives for chronic HF

Objectives of treatment for chronic HF

1. Prognosis • reduce mortality
2. Morbidity • relieve symptoms and signs
• improve QoL
• eliminate edema and fluid retention
• increase exercise capacity
• reduce fatigue and breathlessness
• reduce the need for hospitalization
• provide end of life care

3. Prevention • occurrence of myocardial damage

• progression of myocardial damage
• remodelling of the myocardium
• reoccurrence of symptoms and fluid
accumulation
• hospitalization

Dickstein et al. Eur Heart J 2008;29:2388–442

McMurray et al. Eur Heart J 2012;33:1787–847
ACC/AHA Guidelines recommend incremental
addition of treatments as HF progresses

STAGE
STAGE A A STAGE
STAGE B B STAGE
STAGE C C STAGE
STAGE D D
At
At high
high risk
risk for
for HF,
HF, but
but Structural heart
Structural heart Structural
Structural heart
heart disease
disease Refractory
Refractory HF
HF
without
without structural
structural heart
heart disease,
disease, but
but without
without with
with prior
prior or
or current
current requiring
requiring specialized
specialized
disease
disease or
or signs
signs or
or symptoms
symptoms oror symptoms of
symptoms of HF
HF interventions
interventions
symptoms
symptoms of of HF
HF HF
HF
Therapy
Therapy goals goals Therapy
Therapy goals
goals Therapy
Therapy goals
goals Therapy
Therapy goalsgoals
 TreatTreat hypertension  All
All measures
measures under  All
All measures
measures under
under Stages
Stages A  Appropriate
hypertension under A Appropriate measures
measures
 Encourage
Encourage smoking Stage
Stage A and B under
smoking A and B under Stages
Stages A,
A, B,
B, C

Refractory symptoms of HF at rest

C

Development of symptoms of HF
cessation  Dietary
Dietary salt
salt restriction  Decision
cessation Drugs
Drugs
restriction re: appropriate
Decision re: appropriate
 Treat
Treat lipid
lipid disorders
disorders  ACEIs level
level of
of care
Structural heart disease

 Encourage
Encourage regular
regular exercise
exercise ACEIs or
or ARBs
ARBs in
in Drugs
Drugs for for routine
routine use
use care
appropriate
appropriate  Diuretics
Diuretics for
for fluid
fluid retention
retention
 Discourage
Discourage alcohol
alcohol intake,
intake, patients  ACEIs
Options
Options
illicit patients ACEIs  Compassionate
illicit drug
drug use
use  β-blockers
β-blockers in
in appropriate
appropriate  β-blockers
β-blockers Compassionate end-of-
end-of-
 Control
Control metabolic
metabolic syndrome life
syndrome patients
patients life care/hospice
care/hospice
Drugs
Drugs in in selected
selected patients  Extraordinary
Drugs Devices
patients Extraordinary measures
measures
Drugs Devices inin selected
selected patients
patients  Aldosterone
Aldosterone antagonists
 ACEIs
ACEIs or
or ARBs
ARBs in  Implantable
antagonists  Heart
Heart transplant
transplant
in
appropriate patients
patients for Implantable defibrillators
defibrillators  ARBs
ARBs  Chronic
Chronic inotropes
inotropes
appropriate for  Digitalis
vascular Digitalis
vascular disease
disease or
or  Hydralazine/nitrates
Hydralazine/nitrates
 Permanent
Permanent mechanical
mechanical
diabetes
diabetes support
support
Devices
Devices in in selected
selected patients
patients  Experimental
Experimental surgery
surgery or
or
 Biventricular
Biventricular pacing
pacing drugs
drugs
 Implantable
Implantable defibrillators
defibrillators

Hunt et al. J Am Coll Cardiol 2009;53:e1–90

HFpEF and HFrEF respond differently to
pharmacological treatment options

Treatment option HFpEF HFrEF

Diuretics YES YES
CCBs YES NO
Beta-blockers NO YES
ACEIs NO YES
ARBs NO YES
MR antagonists NO YES
Ivabradine NO YES
Digoxin NO YES
H-ISDN NO YES
ARNIs PARAGON-HF study YES

Raina A and Kanwar M. Curr Heart Fail Rep. 2014: 11(4):374-81

Tschöpe C and Lam CS. Herz 2012: 37(8):875-9
Treatment options for chronic HF
ESC Guidelines 2012
Chronic symptomatic systolic HF (NYHA II-IV) – Step 1
Diuretics to relieve symptoms/signs of congestion
+
ACE inhibitor (or ARB if not tolerated)

ADD a beta-blocker

Still NYHA class

II-IV?
YES NO

No further specific treatment

ADD an MR antagonist Continue in disease-management
programme

McMurray et al. Eur Heart J 2012;33:1787–847

Treatment options for chronic HF
ESC Guidelines 2012
Chronic symptomatic systolic HF (NYHA II-IV) – Step 2
Still NYHA class II-IV?

YES NO

LVEF ≤ 35% ?

YES NO

SR and HR ≥ 70
beats/min ? NO
No further specific treatment
YES Continue in disease-management
programme
ADD ivabradine

Still NYHA class II-IV

and LVEF ≤ 35% ?

McMurray et al. Eur Heart J 2012;33:1787–847

Treatment options for chronic HF
ESC Guidelines 2012
Chronic symptomatic systolic HF (NYHA II-IV) – Step 3
Still NYHA class II-IV and LVEF
≤35% ?

YES NO

QRS duration ≥120 ms?

YES NO

Consider CRT-P/CRT-D Consider ICD

No further specific treatment
NO Continue in disease-management
Stil NYHA class II-IV? programme

YES Consider digoxin and/or H-ISDN

If end stage, consider LVAD and/or
transplantation

McMurray et al. Eur Heart J 2012;33:1787–847

Adding therapies is adding life
24 month mortality

NUMBER of THERAPIES ODDS RATIO

(vs 0 or 1 therapy) (95% confidence interval)

2 therapies 0.63 (0.47-0.85) p=0.0026

3 therapies 0.38 (0.29-0.51) p<0.0001
4 therapies 0.30 (0.23-0.41) p<0.0001
5, 6, or 7 therapies 0.31 (0.23-0.42) p<0.0001
0 0.5 1 1.5 2

This study examined the individual and incremental clinical effectiveness of guideline-recommended therapies for patients with HF and
reduced LVEF. 
ORs for 24-month mortality associated with the number of guideline-recommended therapies received at baseline.
Analysis includes all patients from the case-control population (N=4128). The number (%) of patients receiving each number of therapies at
baseline was as follows: 0 or 1, 238 (5.8%); 2, 712 (17.3%); 3, 1327 (32.2%); 4, 1123 (27.2%); and 5, 6, or 7, 728 (17.6%).

Fonarow GC et al. J Am Heart Assoc 2012;1:16-26

Adding therapies is adding life
Beta- Beta- Beta- Beta- Beta-blocker + Beta-blocker +
blocker blocker + blocker + blocker + ACEI/ARB + ACEI/ARB + ICD
Change in Odds of 24-Month Mortality (%)

ACEI/ARB ACEI/AR ACEI/ARB ICD + HF + HF education

B + ICD + ICD + HF education + +
education anticoagulation anticoagulation
for AF for AF + CRT
0%
-10%
-20%
-30%
-40%
-39%
-50%
-60%
-70% -63%
-80% -76%
-81% -83% -81%
-90%
(-28% to -49%) (-54% to -71%) (-68% to -81%) (-75% to -86%) (-77% to -88%) (-72% to -87%)
P<0.0001 P<0.0001 P<0.0001 P=0.0038 P=0.1388 P=0.1208

Fonarow GC et al. J Am Heart Assoc 2012;1:16-26

Treatment options for HFpEF
Improving signs & symptoms

To control sodium and water retention

Diuretics To relieve breathlessness and oedema

To improve exercise capacity

CCBs To control ventricular rate in AF
To treat hypertension and myocardial ischaemia

Management
Adequate treatment of hypertension
of underlying Adequate treatment of myocardial ischaemia
disease

McMurray et al. Eur Heart J 2012;33:1787–847

HEART FAILURE SUMMIT 2016, BARCELONA

Treatment options for HFpEF
Improving prognosis
‘No treatment has yet been shown, convincingly, to reduce morbidity and
mortality in patients with HFpEF.’ (ESC Guidelines 2012)
#
STUDY Study drug Endpoint Outcome Publication
Patients
Yusuf S et al
CHARM- CV death or HF
Candesartan 3023 Lancet 2003
Preserved hospitalization
Primary
Cleland JG et al
Death or HF end-point
PEP-CHF Perindopril 850 Eur Heart J 2006
hospitalization not met

Death or HF Massie BN et al NEJM

I-Preserve Irbesartan 4128 hospitalization 2008

McMurray et al. Eur Heart J 2012;33:1787–847

Yusuf S et al. Lancet 2003;362:777
Cleland JG et al. Eur Heart J 2006;27:2338
Massie BM et al. NEJM 2008;359:2456
Holistic management of HF
ESC Guidelines 2012
Management programmes for patients with HFrEF & HFpEF
Characteristics
• Should employ a multidisciplinary approach
• Should target high-risk symptomatic patients
• Should include competent and professionally educated staff

Components
• Optimized medical and device management
• Adequate patient education, with special emphasis on adherence and self-care
• Patient involvement in symptom monitoring and flexible diuretic use
• Follow-up after discharge
• Increased access to healthcare
• Facilitated access to care during episodes of decompensation
• Assessment of (and appropriate intervention in response to) an unexplained increase in
weight, nutritional status, functional status, quality of life, and laboratory findings
• Access to advanced treatment options
• Provision of psychosocial support to patients and family and/or caregivers McMurray et al. Eur Heart J 2012;33:1787–847

McMurray et al. Eur Heart J 2012;33:1787–847

ESC recommendations
for exercise prescription and multidisciplinary management
RECOMMENDATIONS
It is recommended that regular
aerobic exercise is encouraged
in patients with heart failure to
improve functional capacity and
symptoms
It is recommended that patients
with heart failure are enrolled in a
multidisciplinary care
management programme to
reduce the risk of heart failure
hospitalization
McMurray et al. Eur Heart J 2012;33:1787–847
CLASS LEVEL • Services, such as cardiac rehabilitation
and palliative care, must be integrated
I A into the overall provision for patients
with HF
• Multidisciplinary management
programmes are vital, designed to
improve outcomes through structured
I A follow-up with patient education,
optimization of medical treatment,
psychosocial support, and improved
access to care.
Personalised medicine in HF
Personalisation for patients with HF will surely improve in
the future, but also today one does not fit all
Personalisation by traditional biomarkers:
• Echo
• ECG
• Blood Pressure
• Laboratory examinations (renal function, electrolytes, hemoglobin, glycemia)

Other more recent biomarkers

How can we improve the personalisation of treatment in the future
• Genetics
• Pharmacogenomics
• Gene therapy

Presented by A. Maggioni during HF SUMMIT 2015

Section
Summary

Summary: HF Guidelines
• ACE-inhibitors, beta-blockers and mineralocorticoid receptor antagonists
form the cornerstone of HF therapy, given their mortality benefit. Incremental
addition of treatments is recommended as HF progresses: Adding therapies
is adding life.

• HFrEF and HFpEF differently respond to treatment. Treatment in HFpEF is

aimed to improve signs and symptoms, as no treatment has yet been shown
to improve prognosis in HFpEF.

• HF care is already somewhat personalised, since management is guided by

traditional biomarkers (echo, ECG, blood pressure, laboratory examinations).
In the future, genetics, pharmacogenomics and gene therapy may yield more
targeted treatment strategies.

• The ESC guidelines also recommend regular aerobic exercise and enrolment
in care-management programmes.
MANAGEMENT of HEART FAILURE
Challenges
Adherence to guidelines

Euro Heart Survey on Heart Failure

Diuretics • The most commonly prescribed class of agent

• Used in 61% of patients and almost 80% of those with HFrEF

ACE • Reached 50-60% of the target recommended dose
inhibitors • Captopril was prescribed at much lower doses

Beta- • Less widely used (overall 37%, in patients with HFrEF 49%)
• Daily dosage far below the target dose used in randomized
blockers trials

Komajda M et. Eur Heart J 2003;24:464–474

 Adherence to guidelines
Predictor of outcome in chronic heart failure: the MAHLER survey

6 month hospitalisation rate (%)

20.6
P = 0.0003 P = 0.0003
15.9
14.7

11.2
9.7
6.7

Good Moderate Low Good Moderate Low

Adherence Adherence

CHF HOSPITALISATION CV HOSPITALISATION

Komajda. Eur. Heart J 2005 Aug;26(16):1653-9.

Hyperkalemia impacts ACEI treatment
Results from BIOSTAT

30
• Prospective, observational,

Subjects at target dose (%)

multicenter study in Europe 25

• N = 2,517 20 <3.6 mmol/L

3.6 - 5.0
15
• New-onset or worsening heart mmol/L
failure, with or without >5.0 mmol/L
10
hospitalisation
• Not previously treated with 5
ACEi/ARBs or receiving P=0.026
≤50% of target dose at time 0
Baseline 3 months 9 months
of inclusion
Time

Presented by P. van der Meer during HF SUMMIT 2015

Improving symptoms, EC, and QoL in HF
Relevant co-morbidities in CHF that require medical attention

- CAD / ischemia & Hypertension & Atrial Fibrillation

Targeting some of
the comorbidities - Diabetes mellitus & Metabolic syndrome
will improve - Sleep apnoea Consider individual
symptoms - Depression / other neurological disease
preferences regarding
improving prognosis vs.
- Renal dysfunction and kidney injury symptoms
- Anemia and iron deficiency
- COPD
- Liver & bowel dysfunction
- Cachexia & muscle wasting

Presented by S. Anker during HF SUMMIT 2015

Managing AF in patients with HF
AF and HF beget each other

Heart
failure
30-41%

33-56%
Atrial
fibrillation

Presented by D. Kotecha during HF SUMMIT 2015

Management of AF in HF
1. AF in HF patients usually signifies a deteriorated clinical picture associated
with worse outcomes, regardless of LVEF
2. HFrEF patients in AF may not respond to usual therapies in the same way
but a pragmatic approach is important
3. Currently catheter ablation of AF is indicated for symptoms only
4. Rate control using beta-blockers or digoxin has no effect on mortality (we
need more data comparing quality of life and LVEF)
5. Anticoagulation to prevent thromboembolism is indicated in most patients

AF is an umbrella term and individual characteristics will ultimately determine the

effectiveness of therapy and prognosis

Presented by D. Kotecha during HF SUMMIT 2015

Treatment options for AF in HFrEF/HFpEF
Ventricular rate-control in persistent/permanent atrial fibrillation
HFrEF HFpEF
Beta-blocker Rate-limiting CCB (or b-blocker)
 yes yes 
Ventricular rate controlled Ventricular rate controlled
no no
Add digoxin Add digoxin
 

Maintenance
yes yes
Ventricular rate controlled? Ventricular rate controlled?
no no

therapy
Substitute amlodarone for digoxin Substitute b-blocker (or rate-
 limiting CCB) for digoxin
yes yes 
Ventricular rate controlled?
Ventricular rate controlled?

no no
Seek specialist advice, including Seek specialist advice, including
consideration of AV node ablation consideration of AV node ablation

McMurray et al. Eur Heart J 2012;33:1787–847

Section
Summary

Challenges in HF management
• Although prescription of ACE inhibitors and beta-blockers is increasing, they still remain
underused. Adherence of physicians to treatment guidelines is a strong predictor of fewer CV
hospitalizations in actual practice.

• Hyperkalemia may limit the use of guideline recommended therapy. Compounds are in
development to reduce potassium levels.

• Targeting certain comorbidities in chronic HF may improve symptoms, but the balance
between improving symptoms vs. improving prognosis needs to be discussed with the
individual patient.

• Preventing loss of fat and skeletal muscle is important, and also preventing anaemia and iron
deficiency can improve symptoms and quality of life.

• Atrial fibrillation and heart failure show strong interdependence and affect each others
outcome, thus management of AF is important in patients with HF.
MANAGEMENT of HEART FAILURE
Implementation of policy and guidelines
Key areas of development in HF
Effective innovations include:

Implementation of Guidelines: evidenced based medicine

Care delivery: HF management programmes, role of HF nurse, role of ER
physicians and GPs
Education: nurses, primary care, HF speciality, patients
Prevention: primary, secondary prevention
Surveys/Registries: ESC EORP
Networking: ESC, Associations, National Societies
Cyberspace: online education

Presented by K Dickstein during HF SUMMIT 2015

How to benefit optimally from available
interventions
Evidence-based policy recommendations
• have the potential to drive improvements with the power to save lives,
• aim to make prevention and management of HF a global health
priority,

Improving HF care
• involve policy-makers, healthcare professionals, professional associations,
organizations that fund healthcare, industry, the public, caregivers and
patients themselves
HF prevention: Policy recommendations
Oxford Health Policy Forum – policy iniative

Promote heart failure prevention

Improve heart failure awareness among

healthcare professionals
Ensure equity of care
for all patients with heart failure

Support and empower patients and their

caregivers

Promote heart failure research

Presented by J. Riley during HF SUMMIT 2015

http://www.oxfordhealthpolicyforum.org/reports/heart-failure/heart-failure, accessed 14.12.2015
Acute HF: Policy recommendations
Oxford Health Policy Forum – policy iniative

Appoint experts to lead heart failure care

Promote acute heart failure prevention
across the disciplines

Develop and implement better measures of

Optimise care transitions
care quality

Improve end-of-life care Improve patient education and support

Provide equity of care

Stimulate research into new therapies
for all patients with heart failure

Presented by J. Riley during HF SUMMIT 2015

http://www.oxfordhealthpolicyforum.org/reports/heart-failure/heart-failure, accessed 14.12.2015
 Establishing an integrated hospital-
primary care HF programme

Diagnose the problem Inventarisation of unmet needs Create an answer

Chronic Heart Failure System Designed for Acute Conditons Chronic Care Model

Presented by J. Comin-Colet during HF SUMMIT 2015

Integrated hospital-PC HF programme
Challenges

In order for an integrated hospital-primary care HF programme to be

successful, various types of barriers need to be overcome:
SYSTEMIC BARRIERS - related to awareness among the public and policy makers

INSTITUTIONAL BARRIERS - related to facilitation of truly integrated healthcare

pathways

PROFESSIONAL BARRIERS - to stimulate teamwork and shared leadership.

Presented by J. Comin-Colet during HF SUMMIT 2015

Systemic barriers
1. Increase the awareness of heart failure as a problem for patients and for the
sustainability of public healthcare systems

2. Increase the awareness among healthcare services managers and healthcare

professionals that multidisciplinary team management and integrated care are
the best approaches for HF patients

3. From a societal perspective, place the importance of heart failure at the same
level of other important chronic conditions such as cancer

Presented by J. Comin-Colet during HF SUMMIT 2015

Institutional barriers
1. Promote the creation of truly integrated healthcare pathways and clinical
processes for HF patients (local settings) with professional teams working at
various levels of care

2. Healthcare pathways for the management of HF (functional teams) with

organizational autonomy and executive capacity (support form managers and
healthcare authorities)

3. Promote the access of professionals involved in the care of HF patients to

quality indicators and to participate in the process of creation of
multidisciplinary teams

Presented by J. Comin-Colet during HF SUMMIT 2015

Professional barriers
1. Increase TEAMWORK culture among healthcare professionals

2. Allow shared leadership

3. Training, training, training (at all levels of care)

4. Health and social integration (in multidisciplinary teams but also in

early stages of training and education)

Presented by J. Comin-Colet during HF SUMMIT 2015

Section
Summary

Implementation of policy and guidelines

• A broad range of important innovations to manage HF is already available.
Guideline-recommended evidence-based medicine, multidisciplinary HF
management programmes, prevention programmes can be really effective, provided
that they are adequately applied in clinical practice.

• The Oxford Health Policy evidence-based policy recommendations have the

potential to drive improvements with the power to save lives, with the aim to make
prevention and management of HF a global health priority.

• Multidisciplinary care pathways are important to ensure continuity and equal access
of care. The local situation and patient preferences should be considered when
organising care.

• Several barriers (systemic, institutional and professional) may be faced when setting
up an integrated hospital-primary care HF programme.
MANAGEMENT of HEART FAILURE
Improving Heart Failure Management
Perspectives from stake holders
Current challenges in HF
Stake holders exchanged different perspectives and shared views on how Heart
Failure management can be improved:

Patient Cardiologist

Primary Care Physician Heart Failure Nurse

A patient’s perspective
Current challenges in HF
Direct from the Patient Community: What would people like to see?
• Access to care and therapies needs to be equal
• Better initial engagement of patients in self management
• Better understanding of HF from non-cardiologists
• Better continuity of care
• Are the pathways followed? Patients look at pathways as well
• Speed up access to help and self learning.
• How you are dealt with in ER – Don’t you believe me? I have HF!

Presented by N Hartshorne Evans during HF SUMMIT 2015

Cardiologist’s perspective
TOPIC RECOMMENDATION
Adherence to guidelines
Improving HF management •
•
Fight medical inertia
Create a national quality control programme

Treatment optimisation • Prevent the decompensation of the patient

• Create a nationwide system (prognostic markers)
• Improve early detection of HF degradation and need for LVAD

Education • Integrate patient self-management education into basic HF management

Prevention • Improve prevention of HF

Multidisciplinary approach • Create acute HF teams in each regional hospital to streamline the acute HF management
• Create a real cooperation process between nurses and doctors

Optimisation of care transition • Limit time from admission to treatment at the emergency department by improving and
speeding up the intra-hospital pathways
• Try to reduce in-hospital stay
• Bridge the time between hospital discharge and primary care physician follow-up

Telemedicine • Integrate telemedicine into healthcare process

Presented by P. Jourdain during HF SUMMIT 2015

Primary care physician’s perspective
TOPIC RECOMMENDATION
Adherence to guidelinesImproving HF management • Implement use of evidence-based medications better

Treatment optimisation • Better identify higher risk HF patients using natriuretic peptides

Education • Improve understanding of HF burden for primary care

• Improve understanding of HF impact on patients
• Improve understanding of HF impact on health system costs

Prevention • Get evidence on whether screening strategies work

Early diagnosis • Provide open access to natriuretic peptide assays – for early diagnosis
• Provide open access to echocardiography – for early diagnosis
• Consider specialist referral after diagnostic triage – for early diagnosis

New treatment options • Develop more treatment options

Presented by R. Hobbs during HF SUMMIT 2015

HF nurse’s perspective
TOPIC
Adherence to guidelines
Improving HF management RECOMMENDATION
• Adherence to the guidelines with regard to fluid and salt restriction
• More practical knowledge regarding advice on exercise

Treatment optimisation • More time for the patient

• Use of telemonitoring to optimise care

Education • Development of a clear European HF nurse educational programme and profile, including
training on the main comorbidities and challenging subjects such as motivational
interviewing and end-of-life conversations

Multidisciplinary approach • Better integration of HF nurse specialism across primary and secondary care
• Nurses as consultants in primary care as well as in palliative care teams
• Bridge between the hospital, GP’s and HF outpatient clinic nurses
• More clarity on the roles and responsibilities in the team and recognition of capabilities

Practical tools for the patient • Medication reminder systems

• HF medication up-titration tools

Research • Collect evidence for optimal non pharmacological heart failure care
• Examine patient motivation methods

Presented by T. Jaarsma during HF SUMMIT 2015

Different disciplines have several
common needs CARDIOLOGIST

Improving HF management Optimisation

of care transition
Telemedicine

Prevention Multidisciplinary
approach
Adherence to
guidelines

Treatment
Early optimisation
diagnosis Practical
Education
tools for the
New treatment patient
options

Research HF NURSE
PC PHYSICIAN

Views expressed by care professionals during HF SUMMIT 2015

Section
Summary

Improving HF Management
The HF patient community generally feels well looked after, with specific appreciation of HF nurses. Patients do
feel that continuity of care could be improved as well as awareness among non-cardiologists, including the
understanding of the mental impact of the syndrome

Based on the experience of a cardiologist, a primary care physician and an HF nurse, HF care could be improved
by:

• Optimising care pathways, from earlier initiation of therapy already in the emergency room, to facilitating the
transition from hospital to patient home. Open access to natriuretic peptide assays and ECG can improve
diagnosis in primary care and referral pathways

• Improving education about the syndrome and awareness of disease impact at all levels: among patients,
primary care physicians, nurses and specialists

• True cooperation between nurses and doctors, with a clear division of roles and responsibilities

• Better implementation of evidence-based guideline recommendations

• Educating patients on self-management, taking into account individual preferences and capabilities
Novel insights and innovations in
targeting the neurohumoral system
 An imbalance occurs in three key neurohumoral systems

SNS β-blockers

Epinephrine α1, β1, β2

Norepinephrine receptors

Vasoconstriction
RAAS activity
Natriuretic peptide Vasopressin
Heart rate
system HFrEF
Contractility
SYMPTOMS &
PROGRESSION
NPRs NPs

Vasodilation
Blood pressure RAAS inhibitors
Sympathetic tone RAAS (ACEI, ARB, MRA)
Natriuresis/diuresis
Vasopressin Ang II AT1R
Aldosterone
Fibrosis Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis

 The
The crucial
crucial importance
importance of
of the
the RAAS
RAAS is is supported
supported by
by the
the beneficial
beneficial effects
effects of
of ACEIs,
ACEIs, ARBs
ARBs and
and MRAs
1
MRAs1
 Benefits
Benefits of
of β-blockers
β-blockers indicate
indicate that
that the
the SNS
SNS also
also plays
plays aa key
key role
1
role1

See notes for abbreviation

1. McMurray et al. Eur Heart J 2012;33:1787–847
Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan

definitions
& Talbert. Pharmacotherapy 2002;22:27–42 Kemp & Conte.
Cardiovascular Pathology 2012;365–71
Schrier & Abraham. N Engl J Med 1999;341:577–85
Landmark trials in patients with HFrEF
SOLVD-T1 (1991) CHARM-Alternative 3 (2003) SHIFT5 (2010) PARADIGM-HF7 (2014)
2,569 patients 2,028 patients 6,558 patients 8,442 patients
Key benefits of enalapril (ACEI) vs Key benefits of candesartan Key benefits of ivabradine (If Key benefits of LCZ696
placebo: (ARB) vs placebo: inhibitor) vs placebo: (ARNI) vs enalapril:
• 16%  all-cause mortality • 23%  CV mortality or HF • 18%  CV death or HF • 20%  CV mortality or HF
hospitalization hospitalization hospitalization

1990s 2000s 2010s

CIBIS-II2 (1999) CHARM-Added4 (2003) EMPHASIS-HF6 (2011)

2,647 patients 2,548 patients 2,737 patients
Key benefits of bisoprolol (BB) vs Key benefits of candesartan Key benefits of eplerenone
placebo: (ARB) vs placebo: (MRA) vs placebo:
• 34%  all-cause mortality • 15%  CV mortality or HF • 37%  CV mortality or HF
hospitalization hospitalization

1. SOLVD Investigators. N Engl J Med 1991;325:293–302

2. CIBIS-II Investigators. Lancet 1999;353:9–13; 3. Granger et
al. Lancet 2003;362:772−6
4. McMurray et al. Lancet 2003;362:767–771; 5. Swedberg et
al. Lancet 2010;376:875–85
6. Zannad et al. N Engl J Med 2011;364:11–21; 7. McMurray Percentages are relative risk reductions vs comparator
et al. N Engl J Med 2014;371:993–1004
Mortality in HFrEF remains high despite the introduction
of therapies that improve survival
 Survival rates in chronic HF have improved with the introduction of new therapies 11

ACEI* β-blocker* MRA* ARB*

Reduction in relative risk of
mortality vs placebo

16% 17%
(4.5% ARR; mean (3.0% ARR; median
follow up of 41.4 follow up of 33.7
months) months)
SOLVD1,2
30% CHARM-
Alternative5
34% (11.0% ARR; mean
follow up of 24
(5.5% ARR; mean months)
follow up
of 1.3 years) RALES4
CIBIS-II 3

 However,
However, significant
significant mortality
mortality remains
remains –
– ~50%
~50% of
of patients
patients die
die within
within 5
5 years
years of
of diagnosis
6–8
diagnosis 6–8

*On top of standard therapy at the time of study (except in CHARM-Alternative where background ACEI therapy was excluded). Patient populations varied between trials and as such relative risk
reductions cannot be directly compared. SOLVD (Studies of Left Ventricular Dysfunction), CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) and RALES (Randomized Aldactone Evaluation Study)
enrolled chronic HF patients with LVEF≤35%. CHARM-Alternative (Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity) enrolled chronic HF patients with LVEF≤40%

1. McMurray et al. Eur Heart J 2012;33:1787–847;

2. SOLVD Investigators. N Engl J Med
1991;325:293–302; 3. CIBIS-II Investigators. Lancet 1999;353:9–13;
4. Pitt et al. N Engl J Med 1999;341:709-17; 5. Granger et al. Lancet
2003;362:772–66. 6. Go et al. Circulation 2014;129:e28-e292; 7.
Yancy et al. Circulation 2013;128:e240–327; 8. Levy et al. N Engl J
Med 2002;347:1397–402
Evolution of pharmacologic approaches in
HF:
LCZ696 as a new alternative to an ACEI or ARBs in patients with HFrEF1

SNS β-blockers

Epinephrine α1, β1, β2

Norepinephrine receptors
Neprilysin Vasoconstriction
inhibitors RAAS activity
Vasopressin
NP system HF SYMPTOMS & Heart rate
Contractility
PROGRESSION
NPRs NPs
Ne

Vasodilation
p
ril

Blood pressure
ys

RAAS inhibitors
in

Sympathetic tone RAAS (ACEI, ARB, MRA)

Natriuresis/diuresis
Vasopressin Ang II AT1R
Aldosterone INACTIVE
Fibrosis FRAGMENTS Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
LCZ696 Aldosterone
Hypertrophy
Fibrosis

 LCZ696:
LCZ696: enhancement
enhancement of
of natriuretic
natriuretic and
and other
other vasoactive
vasoactive peptides,
peptides, with
with simultaneous
simultaneous RAAS
RAAS suppression
suppression

1. McMurray et al. Eur J Heart Fail 2013;15:1062–73

Figure references: Levin et al. N Engl J Med 1998;339:321–8 Nathisuwan &
Talbert. Pharmacotherapy 2002;22:27–42
Kemp & Conte. Cardiovascular Pathology 2012;365–71
Schrier & Abraham. N Engl J Med 2009;341:577–85
LCZ696 simultaneously inhibits neprilysin (via LBQ657) and
blocks AT1 receptors (via valsartan)

LCZ696
ANP,
ANP, BNP,
BNP, CNP,
CNP, other
other
vasoactive peptides*
RAAS
RAAS
vasoactive peptides*
Angiotensinogen
Ne
pri (liver secretion)
Sacubitril
ly
si n
(AHU377; pro-drug)
Ang I

Inactive LBQ657 Ang II

fragments Valsartan
(NEP inhibitor)

O O
AT1 receptor
Enhancing N OH

Vasorelaxation
Vasorelaxation HN
O
Inhibiting
OH N
 Blood
 Blood pressure
pressure O
HO
N
N
NH
Vasoconstriction
Vasoconstriction

 Sympathetic tone
Sympathetic tone
O  Blood
 Blood pressure
pressure

 Aldosterone
Aldosterone levels
levels 
 Sympathetic tone
Sympathetic tone

 Fibrosis
Fibrosis 
 Aldosterone
Aldosterone
 Hypertrophy
 Hypertrophy 
 Fibrosis
Fibrosis

 Natriuresis/diuresis
Natriuresis/diuresis  Hypertrophy
 Hypertrophy

Levin et al. N Engl J Med 1998;339:321–8

Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42
Schrier & Abraham. N Engl J Med 2009;341:577–85
Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
Feng et al. Tetrahedron Letters 2012;53:275–6
PARADIGM-HF: Study design
For more details on the PARADIGM-HF study, refer to the dedicated slide kit

Randomization
n=8442 Double-blind
Treatment period

Single-blind active
run-in period
LCZ696 200 mg BID§

LCZ696
Enalapril LCZ696
200 mg BID§
10 mg BID* 100 mg BID‡

Enalapril 10 mg BID#

2 Weeks 1–2 Weeks 2–4 Weeks Median of 27 months’ follow-up

On top of standard HFrEF therapy (excluding ACEIs and ARBs)

.

McMurray et al. Eur J Heart Fail 2013;15:1062–73

McMurray et al. Eur J Heart Fail 2014;16:817–25
McMurray et al. N Engl J Med 2014;371:993–1004
PARADIGM-HF: Primary objective
 To
To evaluate
evaluate the
the effect
effect of
of LCZ696
LCZ696 200
200 mg
mg BID
BID compared
compared with
with enalapril
enalapril 10
10 mg
mg BID,
BID, in
in addition
addition to
to
conventional
conventional HFrEF
HFrEF treatment,
treatment, in
in delaying
delaying time
time to
to first
first occurrence
occurrence of
of either
either CV
CV death
death or
or HF
HF
hospitalization
hospitalization
1
1

Rationale
Rationale for
for endpoint
endpoint selection
selection
 Primary
Primary outcome
outcome of
of CV
CV death
death or
or HF
HF hospitalization
hospitalization was
was chosen
chosen as
as the
the one
one that
that
best
best reflects
reflects the
the major
major mortality
mortality and
and morbidity
morbidity burden
burden of
of HFrEF
1,2
HFrEF 1,2
•• ~80%
~80% of
of deaths
deaths in
in recent
recent trials
trials in
in patients
patients with
with HFrEF
HFrEF are
are CV
CV related
35
related 35
•• HF
HF is
is associated
associated with
with aa high
high risk
risk of
of hospitalization,
hospitalization, 6 representing
6
representing the
the leading
leading cause
cause of
of hospitalization
hospitalization in
in
patients aged ≥65 years
patients aged ≥65 years
69
69

 The
The most
most commonly
commonly used
used primary
primary endpoint
endpoint in
in recent
recent HF
HF trials:
trials:
CHARM-Added,
CHARM-Added, SHIFT
SHIFT and
and EMPHASIS-HF
EMPHASIS-HF1
1

1. McMurray et al. Eur J Heart Fail 2013;15:1062–73; 2. Dunlay et al. Circ Cardiovasc
Qual Outcomes 2011;4:68–75; 3. McMurray et al. Lancet 2003;362:767–77; 4. Swedberg
et al. Lancet 2010;376:875–88; 5. Zannad et al. N Engl J Med 2011;364:11–2; 6. Cowie et
al. Oxford Health policy Forum 2014; 7.Hunt et al. J Am Coll Cardiol 2009;53:e1–90;
8.Yancy et al. Circulation 2013;128:e240–327;
9. Rodriguez-Artalejo et al. Rev Esp Cardiol 2004;57:163–70
PARADIGM-HF: Patient disposition
10,513
10,513 patients
patients entered
entered enalapril
enalapril run-in
run-in phase
phase
(median 1,102
1,102 discontinued
discontinued study:
(median duration,
duration, 15
15 days;
days; interquartile
interquartile range
range [IQR],
[IQR], 14–21)
14–21) study:
591
591 (5.6%)
(5.6%) had
had adverse
adverse event
event
66
66 (0.6%)
(0.6%) had
had abnormal
abnormal laboratory
laboratory or
or other
other test
test
result
result
171
171 (1.6%)
(1.6%) withdrew
withdrew consent
consent
138
138 (1.3%)
(1.3%) had
had protocol
protocol deviation,
deviation, administrative
administrative
problem
problem or
or were
were lost
lost to
to follow-up
follow-up
49
49 (0.5%) died
(0.5%) died
87
87 (0.8%) had
(0.8%) had other
other reasons
reasons

9,419
9,419 entered
entered LCZ696
LCZ696 run-in
run-in phase
phase
(median
(median duration,
duration, 29
29 days;
days; IQR,
IQR, 26–35)
26–35) 977 discontinued
977 discontinued study:
study:
547
547 (5.8%) had
(5.8%) had adverse
adverse event
event
58
58 (0.6%)
(0.6%) had
had abnormal
abnormal laboratory
laboratory or
or other
other test
test
result
result
100
100 (1.1%)
(1.1%) withdrew
withdrew consent
consent
146
146 (1.6%) had
(1.6%) had protocol
protocol deviation,
deviation, had
had
administrative
administrative
problem,
problem, or
or were
were lost
lost to
to follow-up
follow-up
47
47 (0.5%)
(0.5%) died
died
79
79 (0.8%) had
(0.8%) had other
other reasons
reasons
8,442
8,442 underwent
underwent randomization
randomization
43
43 were
were excluded:
excluded:
66 did
did not
not undergo
undergo valid
valid randomization
randomization
37
37 were from
were from four
four sites
sites prematurely
prematurely closed
closed
because
because
of
of major
major Good
Good Clinical
Clinical Practice
Practice violations
violations

4,187
4,187 were
were assigned
assigned to
to receive
receive LCZ696
LCZ696 4,212
4,212 were
were assigned
assigned to
to receive
receive enalapril
enalapril
4,176
4,176 had known final vital
had known final vital status
status 4,203
4,203 had known final vital
had known final vital status
status
11
11 had
had unknown
unknown final
final vital
vital status
status 9
9 had
had unknown
unknown final
final vital
vital status
status

McMurray et al. N Engl J Med 2014;371:993–1004

 PARADIGM-HF: Summary of baseline
characteristics
LCZ696 Enalapril
Characteristic* (n=4,187) (n=4,212)
Age, years 63.8 ± 11.5 63.8 ± 11.3
Women, n (%) 879 (21.0) 953 (22.6)
Ischemic cardiomyopathy, n (%) 2,506 (59.9) 2,530 (60.1)
LV ejection fraction, % 29.6 ± 6.1 29.4 ± 6.3
NYHA functional class, n (%)
II 2,998 (71.6) 2,921 (69.3)
III 969 (23.1) 1,049 (24.9)
SBP, mmHg 122 ± 15 121 ± 15
Heart rate, beats/min 72 ± 12 73 ± 12
NT-proBNP, pg/mL (IQR) 1,631 (885–3,154) 1,594 (886–3,305)
BNP, pg/mL (IQR) 255 (155–474) 251 (153–465)
History of diabetes, n (%) 1,451 (34.7) 1,456 (34.6)
Treatments at randomization, n (%)
Diuretics 3,363 (80.3) 3,375 (80.1)
Digitalis 1,223 (29.2) 1,316 (31.2)
β-blockers 3,899 (93.1) 3,912 (92.9)
Mineralocorticoid antagonists 2,271 (54.2) 2,400 (57.0)
ICD 623 (14.9) 620 (14.7)
CRT 292 (7.0) 282 (6.7)
*Mean ± standard deviation, unless stated.

McMurray et al. N Engl J Med 2014;371:993–1004

Primary endpoint: Death from CV
causes or first hospitalization for HF
1.0

Enalapril
0.6 LCZ696
Cumulative probability

Hazard
Hazard ratio
ratio =
= 0.80
0.80 (95%
(95% CI:
CI: 0.73–0.87)
0.73–0.87)
0.4 p<0.001
p<0.001

0.2

0
0 180 360 540 720 900 1,080 1,260

No at risk Days since randomization

LCZ696 4,187 3,922 3,663 3,018 2,257 1,544 896 249
Enalapril 4,212 3,883 3,579 2,922 2,123 1,488 853 236

McMurray et al. N Engl J Med 2014;371:993–1004

Primary outcome

LCZ696 Enalapril Hazard ratio*

Outcome, n % (n=4,187) (n=4,212) (95% CI) p value‡
Primary composite outcome
Death from CV causes or first 914 (21.8) 1,117 (26.5) 0.80 (0.73–0.87) <0.001
hospitalization for worsening of HF

Death from CV causes 558 (13.3) 693 (16.5) 0.80 (0.71–0.89) <0.001
First hospitalization for worsening 537 (12.8) 658 (15.6) 0.79 (0.71–0.89) <0.001
of HF

 The
The difference
difference in
in favor
favor of
of LCZ696
LCZ696 was was seen
seen early
early in
in the
the trial
trial and
and at
at each
each interim
interim analysis
analysis
 Over
Over the
the duration
duration of
of the
the trial,
trial, the
the numbers
numbers of
of patients
patients who
who would
would need
need to
to have
have been
been treated
treated
(NNT)
(NNT) to to prevent:
prevent:
•• one
one primary
primary event
event was
was 21
21 patients,
patients, and
and
•• one
one death
death from
from CV
CV causes
causes was
was 32
32 patients
patients

*Calculated with the use of stratified cox proportional-hazard models; ‡Two-sided p-values calculated by means of a stratified log-rank test without adjustment for
multiple comparisons.

McMurray et al. N Engl J Med 2014;371:993–1004

Prospectively defined safety events
LCZ696 Enalapril
Event, n (%) (n=4,187) (n=4,212) p value
Hypotension
Symptomatic 588 (14.0) 388 (9.2) <0.001
Symptomatic with SBP <90 mmHg 112 (2.7) 59 (1.4) <0.001
Elevated serum creatinine
≥2.5 mg/dL 139 (3.3) 188 (4.5) 0.007
≥3.0 mg/dL 63 (1.5) 83 (2.0) 0.10
Elevated serum potassium
>5.5 mmol/L 674 (16.1) 727 (17.3) 0.15
>6.0 mmol/L 181 (4.3) 236 (5.6) 0.007
Cough 474 (11.3) 601 (14.3) <0.001
Angioedema (adjudicated by a blinded expert committee)
No treatment or use of antihistamines only 10 (0.2) 5 (0.1) 0.19

Catecholamines or glucocorticoids without hospitalization 6 (0.1) 4 (0.1) 0.52

Hospitalized without airway compromise 3 (0.1) 1 (<0.1) 0.31

Airway compromise 0 0 ---
• Fewer
Fewer patients
patients in
in the
the LCZ696
LCZ696 group
group than
than in
in the
the enalapril
enalapril group
group stopped
stopped their
their study
study
medication
medication because
because of
of an
an AE
AE (10.7
(10.7 vs
vs 12.3%,
12.3%, p=0.03)
p=0.03)

McMurray et al. N Engl J Med 2014;371:993–1004

PARADIGM-HF results - efficacy

• ‘…angiotensin receptor–neprilysin inhibition with LCZ696 was superior to

ACE inhibition alone in reducing the risks of death and of hospitalization for
HF’
• ‘The magnitude of the beneficial effect of LCZ696, as compared with
enalapril, on CV mortality was at least as large as that of long-term
treatment with enalapril, as compared with placebo.’
• ‘This robust finding provides strong evidence that combined inhibition of the
angiotensin receptor and neprilysin is superior to inhibition of the RAS
alone in patients with chronic HF.’
• ‘…results are applicable to a broad spectrum of patients with HF, including
those who are currently taking an ACE inhibitor or ARB or who are likely to
be able to take such an agent without having unacceptable side effects.’

McMurray et al. N Engl J Med 2014;371:993–1004

PARADIGM-HF Safety results
• The superiority of LCZ696 over enalapril was not accompanied by important
safety concerns
• Fewer patients stopped their study medication because of an adverse event in
the LCZ696 group than in the enalapril group
• There was no increase in the rate of discontinuation due to possible
hypotension-related adverse effects, despite a higher rate of symptomatic
hypotension in the LCZ696 group
• Fewer patients in the LCZ696 group developed renal impairment,
hyperkalemia or cough than in the enalapril group
• The LCZ696 group had a higher proportion of patients with non-serious
angioedema, but LCZ696 was not associated with an increase in serious
angioedema

McMurray et al. N Engl J Med 2014;371:993–1004

Patients with HFpEF may require novel
approaches to treatment

HFrEF1
•Multiple, randomized controlled, double-blinded, clinical trials
•Therapeutic strategies based on outcomes
HFpEF1,2
• Mostly mechanistic studies and small,
•General consensus on treatment among the HF community
•Randomized controlled trials have been supported by observational data non-definitive trials
•Evidence-based medicine
• Therapeutic strategies based on
symptoms and co-morbidities
• Limited consensus on treatment
among the HF community
• Disconnect between randomized
controlled trials and observational data
• Anecdote-based medicine

1. McMurray et al. Eur Heart J 2012;33:1787–847

2. Blanche et al. Swiss Med Wkly 2010;140:66–72
There is a need for therapeutic advances
in patients with HFpEF
 While recent advances in the management of HFrEF have resulted in a significant
extension of life expectancy,1–5 this is not reflected in HFpEF6
 No proven therapies exist for the treatment of HFpEF 6 and little progress has been made
towards identifying a suitable treatment in the last 30 years
There are few approved treatments recommended for the management of signs and symptoms of HFpEF 6*

CCB‡§
(verapamil,
diltiazem)

Pre-1980 1985 1990 1995 2000 2005 2010 2015

Digoxin‡
Beta-blocker‡
(bisoprolol)
Loop diuretics (e.g.
furosemide, bumetanide)

1. Dickstein et al. Eur Heart J 2008;29:2388–442; 2. SOLVD Investigators. N Engl J Med

1991;325:293–302; 3. Granger et al. Lancet 2003;362:772–6; 4. Pitt et al. N Engl J Med
2003;348:1309–21; 5. Zannad et al. N Engl J Med 2011;364:11–21; 6. McMurray et al.
Eur Heart J 2012;33:1787–847
There are several ongoing studies of therapies in
development for HFpEF
NCT01354613 PARAGON-HF
Dobutamine LCZ696
NCT00839228 Amlodipine
Perhexiline
D-HART2
NCT01726049 ROPA-DOP Anakinra
Sildenafil Furosemide
Dopamine

2009 2010 2011 2012 2013 2014 2015

NCT01516346
Isosorbide Dinitrate/
Phase II Isosorbide Dinitrate SOCRATES-
ULTIMATE- NCT02262078
+ Hydralazine PRESERVED
Phase III HFpEF* Sodium Nitrite
Vericiguat
Udenafil Inhalation Solution
Phase IV (BAY1021189)

NCT02053246
Nebivolol

Recruiting studies organized according to start date of trial. *The ULTIMATE-HFpEF trial has since terminated .

Information obtained from: http://clinicaltrials.gov/ct2/results?

term=HFpEF&recr=Open&cond=%22Heart+Failure%22&pg=1 Last accessed
Nov 27 2014
PARAGON-HF: Study design
Target patient population: 4,300 patients with symptomatic HF (NYHA Class II–IV) and LVEF 45%

Randomization 1:1
Double-blind treatment period

Active run-in period

LCZ696 200 mg BID

Valsartan LCZ696
Screening
80 mg BID* 100 mg BID

Valsartan 160 mg BID

On top of optimal background medications for co-

morbidities (excluding ACEIs and ARBs)

up to 2 weeks 3–8 weeks ~240 weeks

Primary outcome: CV death and total (first and recurrent)

HF hospitalizations (anticipated ~1,721 primary events)

*Valsartan 40 mg BID (up to 2 weeks) followed by

valsartan 80 mg BID as an optional starting run-in dose
for those patients being treated with less than the
minimum dose of ACEI or ARB at Visit 1;

Solomon et al. Poster presentation at ESC-HF Congress, 25 May 2013; Novartis data on file:
GMA&HEOR_LCZ696B_PARAGON-HF study_D2301_001_2.0
PARAGON-HF: Key objectives
Primary objective:
 To compare the effect of LCZ696 with valsartan in reducing the rate of the
composite endpoint of CV mortality or total (first and recurrent) HF
hospitalizations
Secondary objectives:
 To compare the effect of LCZ696 with valsartan in:
• reducing the rate of the composite endpoint of CV mortality, total HF
hospitalizations, total non-fatal strokes and total non-fatal MIs*
• improving NYHA functional classification at 8 months
• delaying time to new onset AF
• delaying time to all-cause mortality

*Total defined as first and all recurrent events

Solomon et al. Poster presentation at ESC-HF Congress, 25 May 2013

PARAGON-HF: Key inclusion and exclusion
criteria
Key inclusion criteria: Key exclusion criteria:
 Age 55 years; LVEF 45%  History of LVEF <45%
 Symptoms of HF requiring treatment with  MI, CABG or any event within the
diuretic(s) for 30 days prior to study entry 6 months prior to study entry that may have
 Current symptomatic HF reduced LVEF (unless LVEF confirmed as 45%)
(NYHA class IIIV)  Requirement for treatment with two or more of
 Structural heart disease the following: ACEI, ARB or renin inhibitor
(LAE and/or LVH)  SBP <110 mmHg OR SBP
180 mmHg at study entry*
AND either  Serum potassium >5.2 mmol/L at study entry
 eGFR <30 mL/min/1.73m2 at study entry

Elevated
Elevated NT-proBNP
NT-proBNP
HF
HF hospitalization*
hospitalization*
within
within 99 months
months OR (>300
(>300 pg/mL
pg/mL for
for
prior
prior to
to study
study entry
entry patients
patients with SR
with SR or
or
>900 pg/mL for
>900 pg/mL for
patients
patients with
with AF)
AF)

*If SBP >150 mmHg and <180 mmHg, the patient should be receiving ≥3 antihypertensive drugs

Solomon et al. Poster presentation at ESC-HF Congress, 25 May 2013

Section
Summary
Novel strategies targeting the
neurohumoral system
• Overactivation of the RAAS and SNS is detrimental in HFrEF and underpins the basis
of therapy.

• Mortality in HFrEF remains high despite the introduction of new therapies that
improve survival.

• The ARNI (RAAS and neprilysin inhibitor) LCZ696 simultaneously inhibits neprilysin
and blocks AT1 receptors. In addition to the three cornerstone therapies of heart failure,
replacing ACE inhibition by an ARNI has now been shown to further improve
morbidity and mortality in HFrEF.

• No proven therapies exist for improving prognosis in HFpEF. There is a need for
therapeutic advances
in patients with HFpEF.

• The ongoing PARAGON-HF study evaluates the effect of LCZ696 in reducing the rate
of the composite endpoint of CV death or total (first and recurrent) HF hospitalizations
in patients with HFpEF.
SELF assessment
Questions 1-3
1. Mortality in patients with heart failure
a) Is significantly higher in patients with HFrEF compared to HFpEF
b) Is significantly higher in patients with HFpEF compared to HFrEF
c) Has decreased significantly during the last 10 years
d) Is similar between patients with HFrEF and patients with HFpEF

2. The threshold concentration for BNP that excludes HF for patients presenting
with acute symptoms is:
e) 100 pg/mL
f) 120 pg/mL
g) 300 pg/mL

3. The following treatment options reduce mortality in patients with HFpEF

h) Diuretics
i) Heart rate limiting calcium-channel blockers
j) Beta-blockers
k) None of the above
Questions 4-5
4. The ESC guidelines recommend an incremental addition of treatment as HF
progresses. According to Fonarow GC et al., patients who received a greater
number of treatments at baseline were more likely
a) to be alive at 24 months
b) to be rehospitalised at 24 months
c) to be rehospitalised at 12 months
d) None of the above

5. Komajda et al showed that adherence of physicians to treatment guidelines

is:
a) a strong predictor of lower mortality
b) a strong predictor of fewer CV hospitalisations
c) a strong predictor of improved quality of life
d) All of the above
Questions 6-8
6. HF management can be improved by:
a) Improving education and awareness among patients and health care professionals
b) Optimising care pathways and cooperation between nurses and doctors
c) Better implementation of evidence-based guideline recommendations
d) All of the above

7. In the PARADIGM-HF study the following was not observed:

e) LCZ696 was superior to ACE inhibition alone in reducing the risk of death and hospitalisation for HF
f) More patients stopped their study medication because of adverse events in the LCZ696 group than in the
enalapril group
g) The Kaplan Meyer curves for the primary endpoint diverged early in the study
h) The LCZ696 group had a higher proportion of patients with non-serious angioedema, but LCZ696 was not
associated with an increase in serious angioedema

8. The PARAGON-HF study is evaluating

i) The effect of LCZ696 in reducing CV death or HF hospitalisation in patients with HFrEF
j) The effect of LCZ696 in reducing CV death or HF hospitalisation in patients with HFpEF
k) The effect of LCZ696 in reducing CV death or HF hospitalisation in patients with HFpEF and HFrEF
Answers
1d
2a
3d
4a
5b
6d
7b
8b