Transcript PowerPoint-presentatie - pace

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
21 MILLION adults worldwide are
living with heart failure
This number is expected to
rise.1,2
ECONOMIC BURDEN
In 2012, the overall worldwide
cost of heart failure was nearly
$108 BILLION.6
MORTALITY
50% of heart failure patients die
within 5 years from diagnosis.5
REHOSPITALISATION
Heart failure is the NUMBER 1
cause of hospitalisation for
patients aged >65 years.4
COMORBIDITIES: The vast
majority of HF patients has 3 or
more comorbidities 3
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*:
Related to time-course:
Related to progression:
Related to location:
HFrEF (reduced ejection fraction: EF<40%)
HFmEF (mildly impaired EF: EF 40-49%
HFpEF (preserved ejection fraction: EF ≥50%)*
New onset, transient, chronic
Acute, stable, worsening
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
•
•
•
•
Mitral
Aortic
Trisuspid
Pulmonary
MYOCARDIAL DISEASE
•
•
•
Coronary artery disease
Hypertension
Cardiomyopathy
ENDOCARDIAL DISEASE
• With/without hypereosinophilia
• Endocardial fibroelastosis
PERICARDIAL DISEASE
•
•
Constrictive pericarditis
Pericardial effusion
HIGH OUTPUT STATES
•
•
•
•
•
HEART
FAILURE
Anaemia
Sepsis
Thyrotoxicosis
Paget‘s disease
Arteriovenous fistula
Renal failure
Iatrogenic (e.g. postoperative fluid infusion
•
•
•
•
•
Tachyarrhythmia
Atrial
Ventricular
Bradyarrhythmia
Sinus node dysfunction
CONDUCTION
DISORDERS
VOLUME OVERLOAD
•
•
ARRHYTHMIA
•
CONGENITAL
HEART DISEASE
Atrioventricular block
McMurray et al. Eur Heart J 2012;33:1787–847
Pathophysiology of HF
Injury to myocytes
due to myocardial
infarction or other
cause
ELECTRICAL INSTABILITY
VENTRICULAR
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
functional abnormality
No signs or symptoms
Stage B
Developed structural heart disease strongly Class II
associated with development of HF, but
without signs or symptoms
Slight limitation of physical activity. Comfortable
at rest, but ordinary physical activity results in
HF symptoms
Stage C
Symptomatic HF associated with underlying Class III
structural heart disease
Marked limitation of physical activity.
Comfortable at rest, but less than ordinary
activity results in HF symptoms
Stage D
Advanced structural heart disease and
marked symptoms of HF at rest, despite
maximal medical therapy
Symptoms of HF present at rest. If any physical
activity is undertaken, discomfort is increased
Dickstein et al. Eur Heart J 2008;29:2388–442
Hunt et al. J Am Coll Cardiol 2009;53:e1–90
Class I
Class IV
No limitation of physical activity. Ordinary
physical activity does not cause undue fatigue,
palpitation or dyspnoea
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
physical
activity ↓
CVD risk factors
& biomarkers
genetic determinants
Myocardial Remodeling
Krum, Gilbert. Lancet 2003;362:147–58
McMurray et al. Eur Heart J 2012;33:1787–847
B
Diastolic Heart Failure
Systolic
Dysfunction
Systolic
Heart Failure
Disturbed
Microcirculation
CAD / Infarktion
Stage A
Diastolic
Dysfunction
C/D
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
Norepinephrine
306±64*
287±62*
MLHFQ
24.8±4.4
43.8±3.9
169±80
-
*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
40
30
20
10
0
5.5
Campbell J Am Coll Cardiol 2012
HFpEF
hypertension
5.3
diabetes
4.6
hypertension
50
hypertension
60
hypertension
Per 1000 patient years
70
hypertension, very elderly
80
stable angina & hypertension
HF HOSPITALIZATION
69
43
7.1
7.5
11
11.5
73
Outcomes of patients
with HFpEF as
compared with those
in trials of other
cardiovascular
disease, with similar
ages, sex and
comorbidities profiles
HFpEF is a major public health problem
Per 1000 patient years
50
40
30
20
11.4
15.7
0
Campbell J Am Coll Cardiol 2012
16.4
Hypertension
very elderly
HFpEF
76
47.2
25.6
10
hypertension
hypertension
hypertension
60
stable angina & hypertension
70
hypertension
80
diabetes
OVERALL MORTALITY
17.3
28.7
53
54
Outcomes of patients
with HFpEF as
compared with those
in trials of other
cardiovascular
disease, with similar
ages, sex and
comorbidities profiles
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
16
HFpEF (LVEF >40%)
HFrEF (LVEF ≤40%)
14
Percent distribution
12
10
8
6
4
2
0
0–<10 10 –<20 20 –<30 30 –<40 40 –<50 50 –<60 60 –<70 70 –<80 80 –<90
Better QoL
MLHF summary score range
1. Lewis et al. Eur J Heart Fail 2007;9:83–91
2. Kitzman et al. JAMA 2002;288:2144-50
>90
Worse QoL
• Distribution of the MLHF
questionnaire responses in patients
(n=2709) with HFpEF and HFrEF.
Scores range from 0 to 105 with a
low score reflecting a better healthrelated QoL
• Distribution of MLHF QoL scores
reflects the wide range of healthrelated QoL among patients with
chronic HF1
• Patients with HFpEF and those with
HFrEF have a similar distribution of
MLHF QoL scores
• Patients with HFpEF may have
greatly reduced general and
symptom-specific QoL2
Comorbidities in HF
Comorbidities impact prognosis in patients with HF1,2
Why comorbidities are relevant in HF1:
COPD
Gout
Hyperlipidaemia
Iron deficiency
Comorbidities in
patients with HF
Hypertension
Angina
Renal
dysfunction
1. McMurray et al. Eur Heart J 2012;33:1787–847
2. Ennezat et al. Nephrol Dial Transplant 2011;26:3908-13
Depression
Sleep disturbance
Cancer
Diabetes mellitus
Anaemia
Cachexia
Obesity
• Comorbidities may affect the use of
treatments for HF
• Drugs used to treat comorbidities may
cause worsening of HF
• Drugs used to treat HF and comorbidities
may interact and reduce patient adherence
• Most comorbidities are associated with
worse clinical status and are predictors of
poor prognosis in HF
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
A
Risk assessment at
preclinical stage
Initial diagnostic workup
in symptomatic patients
•
•
•
•
Clinical assessment/Comorbidities
Biomarkers (Cardiac +EOD)
Echocardiography
Stress test
B
Detailed workup in case
of uncertainity
• Stress echocardiography
• Invasive tests &
hemodynamics
• Cardiac MRI
• Comorbidities
C
Underlying pathophysiology & aetiology
•
•
•
•
Presented by BM Pieske during HF SUMMIT 2015
Cardiac MRI +++
Biopsy
Scintigraphy
SPECT, Molecular imaging(?)
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, Possibly chest x-ray
ECG, Chest x-ray
Echocardiography
BNP/NT-pro BNP*
BNP/NT-pro BNP
Echocardiography
ECG normal and
NT-proBNP <
300pg/mL or
BNP < 100 pg/mL
ECG abnormal or
NT-proBNP >
300pg/mLb or
BNP > 100 pg/mL b
ECG abnormal or
NT-proBNP > 125
pg/mLa or
BNP > 35 pg/mL a
ECG normal and
NT-proBNP <
125pg/mL or
BNP < 35 pg/mL
HF unlikely c
HF unlikely c
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/m2)
Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness
Invasive hemodynamic
measurements
mPCW >12 mmHg
or LVEDP >16 mmHg
or  >48 ms
or b >0.27
TD
EIE′ >15
15 >EIE′ >8
Biomarkers
NT-proBNP
>220 pg/mL or
BNP >200 pg/mL
HFpEF
Paulus et al. Eur Heart J 2007;28:2539–50
Biomarkers
NT-proBNP >220 pg/mL or
BNP >200 pg/mL
Echo – blood flow Doppler
EIA>50 yr <0.5 and DT>50 yr >280 ms
or Ard–Ad >30 ms
or LAVI >40 mL/m2
or LVMI >122 g/m2(♀); >149 g/m2 (♂) or
atrial fibrillation
TD
EIE′ >8
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
Discharges in thousands
600
Female
500
400
300
200
100
0
79
80
85
*Hospital discharges include people discharged alive, dead and of unknown status
Lloyd-Jones et al. Circulation 2010;121:e46–e215
90
Years
95
00
05
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 obesity2
70
Patients with preserved
ejection fraction (%)
r=0.92, p<0.001
60
50
40
30
20
0
1986
1. Owan et al. N Engl J Med 2006;355:251–9
2. Blanche et al. Swiss Med Wkly 2010;140:66–72
1990
1994
1998
2002
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
Survival distribution function
Survival distribution function
1.00
0.75
0.50
0.25
0
HFpEF (LVEF >45%)
HFrEF (LVEF ≤45%)
0.75
0.50
0.25
0
0
200
400
600
Time (days)
800
Wikstrom et al. ESC 2011 Gothenburg, Sweden, 21–24 May 2011
1,000
0
200
400
600
Time (days)
Wikstrom et al. ESC 2011 Gothenburg,
800
1,000
Sweden, May
21–24, 2011
HFpEF & HFrEF: Similar hospital
readmission rates
p=0.09
Percentage of patients
18
16.1
16
13.5
14
12
HFpEF
10
8
6
HFrEF
p=0.66
4.5
4.9
4
2
0
30-day readmission
for HF*
1-year readmission
for HF*
*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
• In new-onset HF, rates of
readmission for HF and inhospital complications do
not differ substantially
between HFpEF and HFrEF1
• Readmission is as likely in
HFpEF as in HFrEF,
following hospital discharge,
with a re-hospitalization rate
of 29% within 60–90 days,2
and a median time to rehospitalization of 29 days3
Mean length of hospital stay increases
with each rehospitalization for HF
Length of hospital stay following hospitalization for HF
Mean length of stay (days)
8.5
8.0
7.5
All HF
HFrEF
HFpEF
Acute HF
Chronic HF
7.0
6.5
6.0
First
Second
Third
Fourth
Hospitalization
Fifth
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
278,307 patients in
the USA with ≥1
hospitalization with
a HF claim were
followed from first
HF hospitalization
for 24 months or
until disenrollment
or end of data
availability
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 1987–20011
 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
HFrEF (LVEF <50%)
HFpEF (LVEF ≥50%)
Survival
0.8
0.6
0.4
0.2
p=0.03
0
0
1
2
Year
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
3
4
5
HFpEF survival rates are not improving
Patients with HFpEF (LVEF ≥50%)
1.0
1.0
1987–1991
1992–1996
1997–2001
0.6
0.4
1987–1991
1992–1996
1997–2001
0.8
Survival
0.8
Survival
Patients with HFrEF (LVEF <50%)
0.6
0.4
0.2
0.2
p=0.005
p=0.36
0
0
0
1
2
3
Year
Owan et al. N Engl J Med 2006;355:251–9
4
5
0
1
2
3
Year
4
5
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
•
•
•
•
•
•
•
•
•
•
•
3. Prevention
Dickstein et al. Eur Heart J 2008;29:2388–442
McMurray et al. Eur Heart J 2012;33:1787–847
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
occurrence of myocardial damage
progression of myocardial damage
remodelling of the myocardium
reoccurrence of symptoms and fluid
accumulation
• hospitalization
ACC/AHA Guidelines recommend incremental
addition of treatments as HF progresses
Hunt et al. J Am Coll Cardiol 2009;53:e1–90
Drugs
 ACEIs or ARBs in
appropriate
patients
 β-blockers in appropriate
patients
Devices in selected patients
 Implantable defibrillators
Development of symptoms of HF
Drugs
 ACEIs or ARBs in
appropriate patients for
vascular disease or
diabetes
STAGE C
Structural heart disease
with prior or current
symptoms of HF
Therapy goals
 All measures under
Stage A
Structural heart disease
Therapy goals
 Treat hypertension
 Encourage smoking
cessation
 Treat lipid disorders
 Encourage regular exercise
 Discourage alcohol intake,
illicit drug use
 Control metabolic syndrome
STAGE B
Structural heart
disease, but without
signs or symptoms or
HF
Therapy goals
 All measures under Stages
A and B
 Dietary salt restriction
Drugs for routine use
 Diuretics for fluid retention
 ACEIs
 β-blockers
Drugs in selected patients
 Aldosterone antagonists
 ARBs
 Digitalis
 Hydralazine/nitrates
Devices in selected patients
 Biventricular pacing
 Implantable defibrillators
STAGE D
Refractory HF
requiring specialized
interventions
Refractory symptoms of HF at rest
STAGE A
At high risk for HF, but
without structural heart
disease or
symptoms of HF
Therapy goals
 Appropriate measures
under Stages A, B, C
 Decision re: appropriate
level of care
Options
 Compassionate end-oflife care/hospice
 Extraordinary measures
 Heart transplant
 Chronic inotropes
 Permanent mechanical
support
 Experimental surgery or
drugs
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
ADD an MR antagonist
McMurray et al. Eur Heart J 2012;33:1787–847
NO
No further specific treatment
Continue in disease-management
programme
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
SR and HR ≥ 70
beats/min ?
NO
NO
YES
ADD ivabradine
Still NYHA class II-IV
and LVEF ≤ 35% ?
McMurray et al. Eur Heart J 2012;33:1787–847
No further specific treatment
Continue in disease-management
programme
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
Stil NYHA class II-IV?
YES
McMurray et al. Eur Heart J 2012;33:1787–847
NO
Consider digoxin and/or H-ISDN
If end stage, consider LVAD and/or
transplantation
No further specific treatment
Continue in disease-management
programme
Adding therapies is adding life
24 month mortality
NUMBER of THERAPIES
(vs 0 or 1 therapy)
ODDS RATIO
(95% confidence interval)
2 therapies
3 therapies
4 therapies
5, 6, or 7 therapies
0.63 (0.47-0.85)
0.38 (0.29-0.51)
0.30 (0.23-0.41)
0.31 (0.23-0.42)
0
0.5
1
1.5
p=0.0026
p<0.0001
p<0.0001
p<0.0001
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
Change in Odds of 24-Month Mortality (%)
Adding therapies is adding life
Betablocker
Betablocker +
ACEI/ARB
Betablocker +
ACEI/AR
B + ICD
Betablocker +
ACEI/ARB
+ ICD + HF
education
Beta-blocker + Beta-blocker +
ACEI/ARB +
ACEI/ARB + ICD
ICD + HF
+ HF education
education +
+
anticoagulation anticoagulation
for AF
for AF + CRT
0%
-10%
-20%
-30%
-40%
-50%
-39%
-60%
-63%
-70%
-80%
-76%
-90%
-81%
-83%
-81%
(-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
Diuretics
CCBs
To control sodium and water retention
To relieve breathlessness and oedema
To improve exercise capacity
To control ventricular rate in AF
To treat hypertension and myocardial ischaemia
Management
of underlying
disease
McMurray et al. Eur Heart J 2012;33:1787–847
HEART FAILURE SUMMIT 2016, BARCELONA
Adequate treatment of hypertension
Adequate treatment of myocardial ischaemia
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
CHARMPreserved
PEP-CHF
I-Preserve
Study drug
Candesartan
Perindopril
Irbesartan
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
#
Endpoint
Patients
3023
850
4128
Outcome
Yusuf S et al
Lancet 2003
CV death or HF
hospitalization
Death or HF
hospitalization
Death or HF
hospitalization
Publication
Primary
end-point
not met
Cleland JG et al
Eur Heart J 2006
Massie BN et al NEJM
2008
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
CLASS
LEVEL
It is recommended that regular
aerobic exercise is encouraged in
patients with heart failure to
improve functional capacity and
symptoms
I
A
It is recommended that patients
with heart failure are enrolled in a
multidisciplinary care
management programme to
reduce the risk of heart failure
hospitalization
I
McMurray et al. Eur Heart J 2012;33:1787–847
A
• Services, such as cardiac
rehabilitation and palliative care, must
be integrated into the overall provision
for patients with HF
• Multidisciplinary management
programmes are vital, designed to
improve outcomes through structured
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
ACE
inhibitors
•
•
•
Betablockers
Komajda M et. Eur Heart J 2003;24:464–474
Used in 61% of patients and almost 80% of those with HFrEF
Reached 50-60% of the target recommended dose
Captopril was prescribed at much lower doses
• Less widely used (overall 37%, in patients with HFrEF 49%)
• Daily dosage far below the target dose used in randomized
trials
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
Adherence
Low
CHF HOSPITALISATION
Komajda. Eur. Heart J 2005 Aug;26(16):1653-9.
Good
Moderate
Adherence
Low
CV HOSPITALISATION
Hyperkalemia impacts ACEI treatment
Results from BIOSTAT
•
•
•
•
Prospective, observational,
multicenter study in Europe
N = 2,517
New-onset or worsening
heart failure, with or without
hospitalisation
Not previously treated with
ACEi/ARBs or receiving
≤50% of target dose at time
of inclusion
Subjects at target dose (%)
30
25
<3.6 mmol/L
20
3.6 - 5.0
mmol/L
>5.0 mmol/L
15
10
5
P=0.026
0
Baseline 3 months9 months
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
Targeting some
of the
comorbidities
will improve
symptoms
- CAD / ischemia & Hypertension & Atrial Fibrillation
- Diabetes mellitus & Metabolic syndrome
- Sleep apnoea
- Depression / other neurological disease
- Renal dysfunction and kidney injury
- Anemia and iron deficiency
- COPD
- Liver & bowel dysfunction
- Cachexia & muscle wasting
Presented by S. Anker during HF SUMMIT 2015
Consider individual
preferences regarding
improving prognosis
vs. symptoms
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
HFpEF
HFrEF
Beta-blocker

Ventricular rate controlled
yes
Rate-limiting CCB (or b-blocker)

Ventricular rate controlled
no
yes
no
Add digoxin

Ventricular rate controlled?
no
yes
Substitute b-blocker (or ratelimiting CCB) for digoxin

Ventricular rate
controlled?
yes
Substitute amlodarone for
digoxin

Ventricular rate controlled?
no
Seek specialist advice, including
consideration of AV node
ablation
yes
Maintenance
therapy
no
Add digoxin

Ventricular rate controlled?
McMurray et al. Eur Heart J 2012;33:1787–847
yes
no
Seek specialist advice, including
consideration of AV node
ablation
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
Promote acute heart failure prevention
Appoint experts to lead heart failure care
across the disciplines
Optimise care transitions
Develop and implement better measures of
care quality
Improve end-of-life care
Improve patient education and support
Provide equity of care
for all patients with heart failure
Stimulate research into new therapies
Presented by J. Riley during HF SUMMIT 2015
http://www.oxfordhealthpolicyforum.org/reports/heart-failure/heart-failure, accessed 14.12.2015
Establishing an integrated hospitalprimary care HF programme
Diagnose the problem
Chronic Heart Failure
Inventarisation of unmet needs
System Designed for Acute Conditons
Presented by J. Comin-Colet during HF SUMMIT 2015
Create an answer
Chronic Care Model
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
Improving HF management
Adherence to guidelines
•
•
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
Improving HF management
Adherence to guidelines
•
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
•
•
•
New treatment options
•
Presented by R. Hobbs during HF SUMMIT 2015
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
Develop more treatment options
HF nurse’s perspective
TOPIC
Improving HF management
RECOMMENDATION
Adherence to guidelines
•
•
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
•
•
Research
•
•
Presented by T. Jaarsma during HF SUMMIT 2015
Medication reminder systems
HF medication up-titration tools
Collect evidence for optimal non pharmacological heart failure care
Examine patient motivation methods
Different disciplines have several
common needs
CARDIOLOGIST
Improving HF management
Optimisation
of care transition
Telemedicine
Multidisciplinary
approach
Prevention
Adherence
to guidelines
Early
diagnosis
New treatment
options
PC PHYSICIAN
Views expressed by care professionals during HF SUMMIT 2015
Treatment
optimisation
Education
Practical
tools for
the patient
Research
HF NURSE
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 noncardiologists, 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
β-blockers
SNS
Epinephrine
Norepinephrine
Natriuretic peptide
system
NPRs
NPs
Vasodilation
Blood pressure
Sympathetic tone
Natriuresis/diuresis
Vasopressin
Aldosterone
Fibrosis
Hypertrophy
HFrEF
SYMPTOMS &
PROGRESSION
α1, β1, β2
receptors
Vasoconstriction
RAAS activity
Vasopressin
Heart rate
Contractility
RAAS inhibitors
(ACEI, ARB, MRA)
RAAS
Ang II
AT1R
Vasoconstriction
Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
 The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs 1
 Benefits of β-blockers indicate that the SNS also plays a key role1
1. McMurray for
et al. Eurabbreviation
Heart J 2012;33:1787–847
See notes
Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan
& Talbert. Pharmacotherapy 2002;22:27–42 Kemp & Conte.
definitions
Cardiovascular Pathology 2012;365–71
Schrier & Abraham. N Engl J Med 1999;341:577–85
Landmark trials in patients with HFrEF
SOLVD-T1 (1991)
2,569 patients
Key benefits of enalapril (ACEI)
vs placebo:
• 16%  all-cause mortality
CHARM-Alternative3
(2003)
2,028 patients
Key benefits of
candesartan (ARB) vs
placebo:
• 23%  CV mortality or HF
hospitalization
1990s
CIBIS-II2 (1999)
2,647 patients
Key benefits of bisoprolol
(BB) vs placebo:
• 34%  all-cause mortality
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
et al. N Engl J Med 2014;371:993–1004
SHIFT5 (2010)
6,558 patients
Key benefits of ivabradine
(If inhibitor) vs placebo:
• 18%  CV death or HF
hospitalization
2000s
CHARM-Added4 (2003)
2,548 patients
Key benefits of
candesartan (ARB) vs
placebo:
• 15%  CV mortality or HF
hospitalization
PARADIGM-HF7 (2014)
8,442 patients
Key benefits of LCZ696
(ARNI) vs enalapril:
• 20%  CV mortality or
HF hospitalization
2010s
EMPHASIS-HF6 (2011)
2,737 patients
Key benefits of
eplerenone (MRA) vs
placebo:
• 37%  CV mortality or HF
hospitalization
Percentages are relative risk reductions vs comparator
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 therapies1
Reduction in relative risk of
mortality vs placebo
ACEI*
β-blocker*
MRA*
ARB*
16%
17%
(4.5% ARR;
mean follow up of
41.4 months)
SOLVD1,2
(3.0% ARR; median
follow up of 33.7
months)
30%
34%
(5.5% ARR; mean
follow up
of 1.3 years)
CIBIS-II3
(11.0% ARR;
mean follow up of
24 months)
RALES4
CHARMAlternative5
 However, significant mortality remains – ~50% of patients die within 5 years of diagnosis6–8
*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:e28e292; 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
β-blockers
SNS
Epinephrine
Norepinephrine
Neprilysin
inhibitors
NP system
NPRs
HF SYMPTOMS &
PROGRESSION
NPs
Vasodilation
Blood pressure
Sympathetic tone
Natriuresis/diuresi
s
Vasopressin
Aldosterone
Fibrosis
Hypertrophy
Vasoconstrictio
n
RAAS activity
Vasopressin
Heart rate
Contractility
RAAS inhibitors
(ACEI, ARB, MRA)
RAAS
Ang II
INACTIVE
FRAGMENTS
LCZ696
α1, β1, β2
receptors
AT1R
Vasoconstriction
Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
 LCZ696: enhancement of natriuretic and other vasoactive peptides, with simultaneous RAAS 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, BNP, CNP, other
vasoactive peptides*
RAAS
Angiotensinogen
(liver secretion)
Sacubitril
(AHU377; pro-drug)
Inactive
fragments
LBQ657
(NEP inhibitor)
Ang I
Valsartan
O
O
Enhancing
Vasorelaxation
 Blood pressure
 Sympathetic tone
 Aldosterone levels
 Fibrosis
 Hypertrophy
 Natriuresis/diuresis
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
N
OH
N
OH
N
HO
N
O
AT1 receptor
Inhibiting
O
HN
O
Ang II
NH
Vasoconstriction
 Blood pressure
 Sympathetic tone
 Aldosterone
 Fibrosis
 Hypertrophy
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§
Enalapril
10 mg BID*
LCZ696
100 mg BID‡
LCZ696
200 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 evaluate the effect of LCZ696 200 mg BID compared with enalapril 10 mg BID, in
addition to conventional HFrEF treatment, in delaying time to first occurrence of either
CV death or HF hospitalization1
Rationale for endpoint selection
 Primary outcome of CV death or HF hospitalization was chosen as the one that
best reflects the major mortality and morbidity burden of HFrEF1,2
• ~80% of deaths in recent trials in patients with HFrEF are CV related 35
• HF is associated with a high risk of hospitalization,6 representing the leading cause of
hospitalization in patients aged ≥65 years69
 The most commonly used primary endpoint in recent HF trials:
CHARM-Added, SHIFT and EMPHASIS-HF1
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 patients entered enalapril run-in phase
(median duration, 15 days; interquartile range [IQR], 14–21)
1,102 discontinued study:
591 (5.6%) had adverse event
66 (0.6%) had abnormal laboratory or other test result
171 (1.6%) withdrew consent
138 (1.3%) had protocol deviation, administrative
problem or were lost to follow-up
49 (0.5%) died
87 (0.8%) had other reasons
9,419 entered LCZ696 run-in phase
(median duration, 29 days; IQR, 26–35)
977 discontinued study:
547 (5.8%) had adverse event
58 (0.6%) had abnormal laboratory or other test result
100 (1.1%) withdrew consent
146 (1.6%) had protocol deviation, had administrative
problem, or were lost to follow-up
47 (0.5%) died
79 (0.8%) had other reasons
8,442 underwent randomization
43 were excluded:
6 did not undergo valid randomization
37 were from four sites prematurely closed because
of major Good Clinical Practice violations
4,187 were assigned to receive LCZ696
4,176 had known final vital status
11 had unknown final vital status
McMurray et al. N Engl J Med 2014;371:993–1004
4,212 were assigned to receive enalapril
4,203 had known final vital status
9 had unknown final vital status
PARADIGM-HF: Summary of baseline
characteristics
LCZ696
(n=4,187)
Enalapril
(n=4,212)
Age, years
Women, n (%)
Ischemic cardiomyopathy, n (%)
LV ejection fraction, %
63.8 ± 11.5
879 (21.0)
2,506 (59.9)
29.6 ± 6.1
63.8 ± 11.3
953 (22.6)
2,530 (60.1)
29.4 ± 6.3
NYHA functional class, n (%)
II
III
2,998 (71.6)
969 (23.1)
2,921 (69.3)
1,049 (24.9)
122 ± 15
72 ± 12
1,631 (885–3,154)
255 (155–474)
1,451 (34.7)
121 ± 15
73 ± 12
1,594 (886–3,305)
251 (153–465)
1,456 (34.6)
3,363 (80.3)
1,223 (29.2)
3,899 (93.1)
2,271 (54.2)
623 (14.9)
292 (7.0)
3,375 (80.1)
1,316 (31.2)
3,912 (92.9)
2,400 (57.0)
620 (14.7)
282 (6.7)
Characteristic*
SBP, mmHg
Heart rate, beats/min
NT-proBNP, pg/mL (IQR)
BNP, pg/mL (IQR)
History of diabetes, n (%)
Treatments at randomization, n (%)
Diuretics
Digitalis
β-blockers
Mineralocorticoid antagonists
ICD
CRT
*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
Cumulative probability
0.6
LCZ696
Hazard ratio = 0.80 (95% CI: 0.73–0.87)
p<0.001
0.4
0.2
0
0
No at risk
LCZ696
Enalapril
180
360
540
720
900
1,080
Days since randomization
4,187
4,212
3,922
3,883
McMurray et al. N Engl J Med 2014;371:993–1004
3,663
3,579
3,018
2,922
2,257
2,123
1,544
1,488
896
853
249
236
1,260
Primary outcome
Outcome, n %
LCZ696
(n=4,187)
Enalapril
(n=4,212)
Hazard ratio*
(95% CI)
p value‡
Primary composite outcome
Death from CV causes or first
hospitalization for worsening of HF
914 (21.8)
1,117 (26.5) 0.80 (0.73–0.87)
<0.001
Death from CV causes
558 (13.3)
693 (16.5)
0.80 (0.71–0.89)
<0.001
First hospitalization for worsening
of HF
537 (12.8)
658 (15.6)
0.79 (0.71–0.89)
<0.001
 The difference in favor of LCZ696 was seen early in the trial and at each interim
analysis
 Over the duration of the trial, the numbers of patients who would need to have been
treated (NNT) to prevent:
• one primary event was 21 patients, and
• one death from CV causes was 32 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
(n=4,187)
Enalapril
(n=4,212)
p value
588 (14.0)
112 (2.7)
388 (9.2)
59 (1.4)
<0.001
<0.001
139 (3.3)
63 (1.5)
188 (4.5)
83 (2.0)
0.007
0.10
674 (16.1)
181 (4.3)
474 (11.3)
727 (17.3)
236 (5.6)
601 (14.3)
0.15
0.007
<0.001
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
Airway compromise
3 (0.1)
0
1 (<0.1)
0
0.31
---
Event, n (%)
Hypotension
Symptomatic
Symptomatic with SBP <90 mmHg
Elevated serum creatinine
≥2.5 mg/dL
≥3.0 mg/dL
Elevated serum potassium
>5.5 mmol/L
>6.0 mmol/L
Cough
Angioedema (adjudicated by a blinded expert committee)
No treatment or use of antihistamines only
• Fewer patients in the LCZ696 group than in the enalapril group stopped their
study medication because of an AE (10.7 vs 12.3%, 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
HFpEF1,2
•
•
•
•
•
•
Multiple, randomized controlled,
double-blinded, clinical trials
Therapeutic strategies based on
outcomes
General consensus on treatment
among the HF community
Randomized controlled trials have
been supported by observational
data
Evidence-based medicine
1. McMurray et al. Eur Heart J 2012;33:1787–847
2. Blanche et al. Swiss Med Wkly 2010;140:66–72
•
•
•
•
Mostly mechanistic studies and
small, non-definitive trials
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
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 HFpEF6 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 HFpEF6*
CCB‡§
(verapamil,
diltiazem)
Pre-1980
1985
1990
Digoxin‡
Loop diuretics (e.g.
furosemide, bumetanide)
1995
2000
Beta-blocker‡
(bisoprolol)
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
2005
2010
2015
There are several ongoing studies of
therapies in development for HFpEF
NCT01354613
Dobutamine
Amlodipine
NCT00839228
Perhexiline
PARAGON-HF
LCZ696
2009
Phase II
Phase III
2010
2011
NCT01516346
Isosorbide Dinitrate/
Isosorbide Dinitrate
+ Hydralazine
Phase IV
2012
D-HART2
Anakinra
ROPA-DOP
Furosemide
Dopamine
NCT01726049
Sildenafil
2014
2013
ULTIMATEHFpEF*
Udenafil
SOCRATESPRESERVED
Vericiguat
(BAY1021189)
2015
NCT02262078
Sodium Nitrite
Inhalation Solution
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=%22H
eart+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
Screening
Valsartan
80 mg BID*
LCZ696
100 mg BID
Valsartan 160 mg BID
On top of optimal background medications for comorbidities (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
 Current symptomatic HF
(NYHA class IIIV)
6 months prior to study entry that may have
reduced LVEF (unless LVEF confirmed as
45%)
 Requirement for treatment with two or more
 Structural heart disease
of 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
HF hospitalization*
within 9 months
prior to study entry
OR
Elevated NTproBNP
(>300 pg/mL for
patients with SR or
>900 pg/mL for
patients with 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)
b)
c)
d)
Is significantly higher in patients with HFrEF compared to HFpEF
Is significantly higher in patients with HFpEF compared to HFrEF
Has decreased significantly during the last 10 years
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:
a) 100 pg/mL
b) 120 pg/mL
c) 300 pg/mL
3. The following treatment options reduce mortality in patients with HFpEF
a)
b)
c)
d)
Diuretics
Heart rate limiting calcium-channel blockers
Beta-blockers
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)
b)
c)
d)
a strong predictor of lower mortality
a strong predictor of fewer CV hospitalisations
a strong predictor of improved quality of life
All of the above
Questions 6-8
6. HF management can be improved by:
a)
b)
c)
d)
Improving education and awareness among patients and health care professionals
Optimising care pathways and cooperation between nurses and doctors
Better implementation of evidence-based guideline recommendations
All of the above
7. In the PARADIGM-HF study the following was not observed:
a) LCZ696 was superior to ACE inhibition alone in reducing the risk of death and hospitalisation for
HF
b) More patients stopped their study medication because of adverse events in the LCZ696 group than
in the enalapril group
c) The Kaplan Meyer curves for the primary endpoint diverged early in the study
d) 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
a) The effect of LCZ696 in reducing CV death or HF hospitalisation in patients with HFrEF
b) The effect of LCZ696 in reducing CV death or HF hospitalisation in patients with HFpEF
c) 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