Heart Failure disease burden,

Management and treatments

Ahmed Tarbousha
Dammam November,2019
Introduction to Heart Failure:
History and Definition
 HF – abnormality of cardiac structure and/or
function
• Abnormality of cardiac structure or function leads to failure of the heart to adequately perfuse organ
systems11

•• Weakening or stiffening of the heart muscle over time leads to pump failure and insufficient delivery
of blood around the body22

Normal heart HF

Weakened heart
muscle

1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. Harrison’s ‘Principles of Internal

Medicine’, Seventeenth Edition p1442–55 Images from: Wilde and Behr. Nat Rev
HF, heart failure Cardiol 2013;10:571–83
 HF is a chronic condition interspersed with
acute episodes
• Increasing frequency of acute events with disease progression leads to high rates of hospitalization
and
and increased
increased risk
risk of
of mortality
mortality1–7
1–7

Compensated

Episode of acute
decompensation
Clinical status

Chronically
decompensated

Acutely
decompensated
Disease Progression Death

Adapted from Gheorghiade et al. 2005 2

1. Ahmed et al. Am Heart J 2006;151:444–50; 2. Gheorghiade et al. Am J Cardiol 2005;96:11G–17G 3.
Gheorghiade, Pang. J Am Coll Cardiol 2009;53:557–73; 4. Holland et al. J Card Fail 2010;16:150–6; 5. Muntwyler
HF, heart failure et al. Eur Heart J 2002;23:1861–6; 6. McCullough et al. J Am Coll Cardiol 2002;39:60–9; 7. McMurray JJ. et al. Eur
Heart J. 2012;33(14):1787–1847
 Chronic HF can be classified as HF with reduced,
mid-range or preserved ejection fraction
HF with preserved ejection HF with middle range ejection HF with reduced ejection
Characteristic fraction (HFpEF)1-5 fraction (HFmrEF)5 fraction (HFrEF)1-5
Dysfunction Diastolic Mild systolic with features of Systolic
diastolic
LVEF ≥50% 40-49% <40%
LV remodeling Concentric - Eccentric
-

• Normal end-diastolic • ↑ end-diastolic volume

volume • ↓ wall thickness
• ↑ wall thickness and mass • Low ratio of mass:volume
• High ratio of mass:volume

Prognostic improvement No - Yes, but morbidity and mortality

with current HF therapy remain high

HF, heart failure; HFpEF, heart failure with preserved ejection fraction;
1. Aurigemma. Circulation 2006;113;296–304; 2. Paulus et al. Eur Heart J 2007;28:2539–50 ; 3. Colucci (Ed.).
HFrEF, heart failure with reduced ejection fraction; LV, left ventricular; LVEF, Atlas of Heart Failure, 5th ed. Springer 2008; 4. McMurray et al. Eur Heart J 2012;33:1787–847; 5. Ponikowski et
left ventricular ejection fraction al. Eur J Heart Fail. 2016 doi: 10.1002/ejhf.592. [Epub ahead of print]
Epidemiology
 HF is common and the prevalence is growing

• 1 in 5 people aged 40 years and

over will develop HF in their
lifetime1

• It is the most rapidly growing

cardiovascular condition.2 This is
Projections of HF prevalence in the US primarily driven by deteriorating
(2010–2030)4
lifestyles and aging populations3
Prevalence of HF (%)

25%
• The prevalence of HF is predicted
to increase in developed countries
because of aging populations: in
the US it is estimated to increase
2010 2015 2020 2025 2030
Year by 25% between 2010–20304
1. Lloyd-Jones et al. Circulation 2002;106:3068–72; 2. McMurray & Stewart. Eur Heart J Suppl 2002;4(Suppl. D):D50–8;
3. Ponikowski et al. Heart failure: preventing disease and death worldwide. http://www.escardio.org/communities/HFA/Documents/WHFA-
whitepaper-15-May-14.pdf;
4. Heidenreich et al. Circulation 2011;123:933–44
 HF significantly increases mortality

• 1-year death rates for patients hospitalized

with HF vary between 17–45%1

• In-hospital death rates range from 2–17% for

patients with HF1

• Approximately half of patients with HF die

within 5 years of diagnosis2–4
1. Ponikowski et al. Heart failure: preventing disease and death worldwide.
http://www.escardio.org/communities/HFA/Documents/WHFA-whitepaper-15-May-14.pdf;
2. Go et al. Circulation 2014;129:e28-e292; 3. Yancy et al. Circulation 2013;128:e240–327;
4. Levy et al. N Engl J Med 2002;347:1397–402
 HF is associated with high rates of
hospitalizations
• HF is the most common cause of hospitalization in patients >65 years of age in
developed countries1,2

• Length of stay for HF hospitalization ranges between 5–10 days3

• In addition to increasing the risk of death, hospitalization for HF is associated with

an increased risk for worsening HF leading to readmissions 4–6

• In the US, 30-day readmission rates are around 20–25%2

• In Europe, readmission rates range from 24% at 12 weeks to 44% at 1 year post-
discharge2
1. Korves et al. J Med Econ 2012;15:925–37;
2. Cowie et al. Improving care for patients with acute heart failure. Oxford Health Policy Forum 2014:
http://www.oxfordhealthpolicyforum.org/html-version/improving-care-for-patients-with-acute-heart-failure;
3. Ponikowski et al. Heart failure: preventing disease and death worldwide.
http://www.escardio.org/communities/HFA/Documents/WHFA-whitepaper-15-May-14.pdf;
4. Du et al. Circ J 2014;78:542–52; 5. Teerlink et al. Lancet 2013;381:29–39;
6. Costanzo et al. Am Heart J 2008;155:341–9
HF Disease Burden in Saudi Arabia
 HF Disease Burden in Saudi Arabia
Background

• There is no local epidemiological data for HF in Saudi Arabia. However,

Medical Experts are expecting at least 450’000 HF patients in the kingdom 1
• HF is associated with high mortality rate in Saudi, local data is showing
24.3% all cause mortality at 3 years 2
• HF patients (with ACS) in Saudi are more likely to have more cardiac risk
factors, and less likely to be treated with optimum medical treatment on
admission 3
• Major challenges in HF management are :
– Non-compliance to HF therapy is 21% 2
– Non-compliance to HF diet is 25.2% 2
– 1 year re-admission rate is 37% 4
– Days of CCU and/or ICU stay, median = 5 days 4

1. Extrapolation of US prevalence data with age adjustment

2. HEARTS Registry
3. Albackr et al. Congestive heart failure in Saudi patients 2013
4. Elasfar et al. Clinical characteristics, management, and outcomes of patients with high risk chronic heart failure referred to a Heart Failure Clinic in Saudi Arabia
Disease Overview and Pathophysiology
 The pathophysiology of HFrEF
Damage
Damage to
to cardiac
cardiac myocytes
myocytes andand extracellular
extracellular matrix
matrix leads
leads to
to changes
changes in
in
the
the size,
size, shape
shape and
and function
function of
of the
the
heart
heart and
and cardiac
cardiac wall
wall stress
stress

Systemic
Systemic neurohormonal
neurohormonal overactivation
overactivation

Vasoconstriction,
Vasoconstriction, fibrosis,
fibrosis, apoptosis,
apoptosis, hypertrophy,
hypertrophy,
cellular and molecular alterations, myotoxicity
cellular and molecular alterations, myotoxicity

Maladaptive
Maladaptive remodeling
remodeling and
and
Hemodynamic
Hemodynamic alterations,
alterations, progressive
progressive worsening
worsening
salt
salt and
and water
water retention
retention of
of LV
LV function
function

HF
HF symptoms:
symptoms: Morbidity
Morbidity and
and mortality:
mortality:
dyspnea,
dyspnea, edema,
edema, fatigue
fatigue arrhythmias,
arrhythmias, pump
pump failure
failure

HF, heart failure; HFrEF, heart failure with reduced 1. McMurray. N Engl J Med 2010;362:228–38; 2. Francis et al. Ann Intern Med
1984;101:370–7; 3. Krum and Abraham. Lancet 2009;373:941–55.
ejection fraction; LV, left ventricular
Cardiac structural abnormalities occur as a result
of injury and remodeling in patients with HF1,2
Spherical ventricular
Cardiac injury Infarct zone dilation
(e.g. MI) thinning and elongation

Increased Interstitial
collagen
Ventricle

Fibrous scar
Myocyte hypertrophy

Adapted from Konstam et al. 2011

1. Konstam et al. JACC Cardiovasc Imaging 2011;4:98–108; 2. Zile MR et al.
HF, heart failure; MI, myocardial infarction Circulation. 2011;124:2491–501
 Signs and symptoms: clinical manifestations of
reduced cardiac output and hemodynamic
alterations Tiredness
Shortness of breath

Pumping action of Coughing

the heart grows

• Symptoms weaker Fluid retention

– Breathlessness/dyspnea
– Orthopnea Pleural effusion

– Paroxysmal nocturnal dyspnea

– Reduced exercise tolerance
– Fatigue
– Ankle swelling

• Signs Swelling of feet,

ankles, abdomen
– Elevated jugular venous pressure and lower back area

– Hepato-jugular reflux
– Third heart sound
– Cardiac murmur
Pulmonary edema
McMurray et al. Eur Heart J 2012;33:1787–847.
Neurohormonal Systems in Heart Failure
Decline in systolic function leads to activation
of three major neurohormonal systems
Sympathetic
nervous system
Epinephrine α1, β1, β2
Norepinephrine receptors
Vasoconstriction
RAAS activity
Natriuretic peptide Vasopressin
system HF SYMPTOMS &
PROGRESSION
Heart rate
Contractility
NPRs NPs

Vasodilation
Blood pressure Renin-angiotensin-
Sympathetic tone
Natriuresis/diuresis
aldosterone system
Vasopressin Ang II AT1R
Aldosterone
Fibrosis Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis

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

Ang=angiotensin; AT1R=angiotensin II type 1 receptor; Pharmacotherapy 2002;22:27–42 . Kemp & Conte. Cardiovascular Pathology
HF=heart failure; NPs=natriuretic peptides; NPRs=natriuretic peptide 2012;365–71 . Schrier & Abraham. N Engl J Med 1999;341:577–85
receptors; RAAS=renin-angiotensin-aldosterone system
 The natriuretic peptide system: NPs are formed
by cleavage of precursor molecules1−6
proBNP
Pre-proBNP
• Wall stress as a result of volume (aa1-aa108)
expansion or pressure overload induces
the synthesis of
precursors of NPs22
• Heart acts as an endocrine organ Cleavage
releasing NPs in response to mechanical
stretch countering some effects of the
RAAS22
• NP system consists mainly of BNP1–32
NT-proBNP
three peptides1,6
1,6
(aa1-aa76) (aa77-aa108)
–
– ANP:
ANP: Produced
Produced primarily
primarily in
in atrial
atrial
myocardium
myocardium DPP-4 Meprin A?
–
– BNP:
BNP: Produced
Produced primarily
primarily in
in the
the
ventricular myocardium
ventricular myocardium
–
– CNP:
CNP: Predominates
Predominates inin brain,
brain, kidney,
kidney,
vascular
vascular endothelial cells and plasma
endothelial cells and plasma

BNP3–32 BNP7–32

ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; CNP=C-
type natriuretic peptide; DPP-4=dipeptidyl peptidase-4; NT-proBNP=N-
terminal pro-BNP; NP=natriuretic peptide;;RAAS= renin-angiotensin-
aldosterone system
1. Volpe et al., Clin Science, 2016: 130:57-77 2. Daniels and Maisel. J Am Coll
Cardiol 2007;50:2357–68;. 3. Melanson and Lewandrowski. Am J Clin Pathol
2005;124:S122–8; 4. Ichiki and Burnett. Circulation 2010;122:229–32; 5. Ruskoaho.
Endocrine Rev 2003;24:341–56; 6. Levin et al. N Engl J Med 1998;339;321–8.
Effects of the natriuretic peptide system: NPs mediate a wide range of physiological
effects via NP receptors

Cardiomyocytes1 Endothelial cells1

ANP and BNP

CNP
NPR-A NPR-B NPR-C

GTP GTP Receptor

cGMP cGMP
Internalization recycling


 Vasodilation1,2
1,2


 Antihypertrophy1,21,2 
 Vasodilation1,21,2 Degradation

 Antiproliferation22 
 Antihypertrophy1,2 1,2 of NPs77

 Vascular regeneration33 
 Antiproliferation22

 Myocardial relaxation4,5 4,5 
 Vascular regeneration11

 1,2
Diuresis, natriuresis1,2 
 Venodilation11 Natriuretic peptide

 Antiapoptosis66 
 Antifibrosis11 degradation and clearance

 Anti-aldosterone1,2
1,2


 Renin secretion inhibition77

 Reduced sympathetic tone88

 Lipolysis77
1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Gardner et al. Hypertension
2007;49:419–26; 3. Yamahara et al., PNAS, 2003, 100:3404-09. 4. Yamamoto et al. ,AJP,
ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; CNP=C-type natriuretic 1997, 273: H2406-14. 5. Clarkson et al., Clin Science 1995: 88: 159-64. 6. Kasama et al., Eur.
peptide; cGMP=cyclic guanosine monophosphate; GTP=guanosine triphosphate; Heart. J. 2008: 29:1485-94. 7.Volpe et al., Clin Science, 2016: 130:57-77. 8. Levin et al. N
NPR=neprilysin receptor Engl J Med 1998;339;321–8.
 Effects of the natriuretic peptide system: cardiovascular and
renal effects of NP system counteract the action of RAAS
Inactive
NP ANP ANP/CNP/
fragments
ANP/BNP/CNP BNP CNP BNP Ang II

Neprilysi NPR- NPR- NPR- AT1

n A B C receptor
GTP GTP
Receptor
Signalling
recycling
cascades
Internalization
cGMP
Gene expression; ↑ protein
synthesis; ↑ cell proliferation
Inactive peptides

Vasodilation Vasoconstriction
 Cardiac fibrosis/hypertrophy  Cardiac fibrosis/hypertrophy
 Natriuresis/diuresis  Sodium/water retention

ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide;

CNP=C-type natriuretic peptide; Ang=angiotensin; AT1=angiotensin
type 1; NP=natriuretic peptide; NPR=neprilysin receptor
Levin et al. N Engl J Med 1998;339;321–8; Gardner et al. Hypertension
2007;49:419–26; Von Lueder et al. Circ Heart Fail 2013;6:594–605;
 Natriuretic peptides are cleared via NPR-C and
degraded by the protease, neprilysin
Cardiomyocytes1 Endothelial cells1 ANP
BNP
ANP and BNP CNP Inactive
cleavage
CNP
products
NPR-A NPR-B NPR-C
NE
P
Neprilysin

Receptor
GTP GTP recycling
cGMP cGMP
Endocytosis

 Vasodilation
Vasodilation
1,2
1,2
 Vasodilation 1,2
 Vasodilation1,2

 Antihypertrophy1,2 1,2

 Antihypertrophy 1,2
Antihypertrophy1,2

 Antiproliferation22 
 Antiproliferation22 Inactivation of

 Vascular regeneration33 
 Vascular regeneration
Vascular regeneration11 NPs77

 Myocardial relaxation4,5 4,5 
 Venodilation
Venodilation1
1


 Diuresis,
Diuresis, natriuresis 1,2
natriuresis1,2 
 Antifibrosis11

 Antiapoptosis66
Antiapoptosis Natriuretic peptide

 Anti-aldosterone
Anti-aldosterone1,2
1,2
degradation and clearance

 Renin secretion
Renin secretion inhibition
inhibition77

 Reduced
Reduced sympathetic
sympathetic tone
8
tone8

 Lipolysis77

Natriuretic
ANP=atrial natriuretic peptide; BNP=B-type peptide signaling
natriuretic peptide; and effects
CNP=C-type 1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Gardner et al. Hypertension 2007;49:419–
natriuretic peptide; cGMP=cyclic guanosine monophosphate; GTP=guanosine 26; 3. Yamahara et al., PNAS, 2003, 100:3404-09. 4. Yamamoto et al. ,AJP, 1997, 273: H2406-
triphosphate; NPR=neprilysin receptor 14. 5. Clarkson et al., Clin Science 1995: 88: 159-64. 6. Kasama et al., Eur. Heart. J. 2008:
29:1485-94. 7.Volpe et al., Clin Science, 2016: 130:57-77. 8. Levin et al. N Engl J Med
1998;339;321–8;.
HFrEF: Treatment Landscape
Objectives of treatment in chronic HF

1. Improve the clinical status of patients with HF

2. Improve functional capacity and quality of life

3. Prevent hospital admission and reduce mortality

Ponikowski et al., Eur Heart J, 2016; 37:2129-200

McMurray et al. Eur Heart J 2012;33:1787–847
 Evolution of HF therapy

MRAs*
(spironolactone)

ARNi
Sacubitril/valsartan¥

*Recommended for AHF after stabalisation †Recommended for treatment of hypertension in patients with symptomatic HF (NYHA class II-IV) ≠Tolvaptan may be used to treat patients with resistant
hyponatremia ‡ ESC-HF guidelines recommend ivabradine for use in patients with a heart rate ≥70 bpm. May also be considered in patients with a contraindication to β-blockers. ¥recommended as a
replacement for an ACEI to further reduce the risk of HF hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACEI, a beta-blocker and
an MRAb.

ACEI=angiotensin converting enzyme inhibitor; ARB=angiotensin receptor blocker; AHF=acute heart failure;
CHF=chronic heart failure; ESC=European Society of Cardiology; ISDN=isosorbide dinitrate;
MRA=mineralocorticoid receptor antagonist; VRA=vasopressin receptor 2 antogonist
 Success and failure of Heart Failure studies
Overview of Clinical Trials in HF (1985-2015)

COPERNICUS
Val-HeFT SENIORS
V-HeFTRef PARADIGM-HF
COMET AF-CHF
CONSENSUSRef USCP CHARM HF-ACTION
RALES A-HeFT HEAAL SHIFT
CIBIS II COMPANION
SOLVDRef MERIT-HF EMPHASIS-HF
ATLAS
DIG

1985-1989 1990-1994 1995-1999 2000-2004 2005-2009 2010-2014 2015

ELITE WARCEF
CAST PROMISE PRIME PRAISE-II CORONA RED-HF
CAST- II SWORD MACH ECHOS
VEST BEST ACCLAIM
DIAMOND-CHF OVERTURE GISSI-HF
MOXCON ANDROMEDA
RENEWAL

Positive Clinical Trial

Negative Clinical Trial

Ponikowski et al., Eur Heart J, 2016; 37:2129-200

Landmark trials in patients with HFrEF
CHARM-Alternative3 (2003)
SOLVD-T (1991) 1 2,028 patients SHIFT5 (2010) PARADIGM-HF7 (2014)
2,569 patients Candesartan (ARB) vs 6,558 patients 8,442 patients
Sacubitril/valsartan (ARNI) vs
Ecnalapril (ACEI) vs placebo: placebo: Isvabradine (If inhibitor) vs enalapril:
• 16%  all-cause mortality • 23%  CV mortality or HF placebo: • 20%  CV mortality or HF
hospitalization • 18%  CV death or HF hospitalization
hospitalization
CIBIS-II8 (1999)
2,647 patients
Bisoprolol (BB) vs placebo:
• 34%  all-cause mortality

1990s 2000s 2010s

CHARM-Added4 (2003) EMPHASIS-HF6 (2011)

MERIT-HF (1999) 2
2,548 patients 2,737 patients
3991 patients Candesartan (ARB) vs Eplerenone (MRA) vs
Metorprolol vs placebo: placebo: 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. MERIT-HF study group, Lancet,

ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker;
ARNI=angiotensin receptor neprilysin inhibitor; BB=beta blocker; CV=cardiovascular;
HF=heart failure; HFrEF=heart failure with reduced ejection fraction;
MRA=mineralocorticoid receptor antagonist. See notes for definitions of study names
1999, 353:2001-7 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 8 CIBIS-II Investigators.
Lancet 1999;353:9–13
 Substitution of an ACEI with ARNI resulted in further
reduction in mortality in patients with HFrEF
-Blockers* MRAs* ARNIs†
ACEIs* ARBs*
+ ACEI/ARB vs. + ACEI/ARB + -blockers vs. ARNI + -blockers + MRA vs.
vs Placebo vs Placebo
ACEI/ARB alone ACEI/ARB + -blockers ACEI/ARB + -blockers + MRA
Reduction in relative risk of
all-cause mortality

16% 17% 16%

(2.8% ARR;
(4.5% ARR;
(3.0% ARR; median follow up
mean follow up
of 41.4 months)
median follow up
of 33.7 months)
24% of 27 months)
(7.6% ARR; mean
SOLVD1,2 PARADIGM
CHARM- 34% follow up of 21
months) -HF6
Alternative3 (3.8% ARR;
EMPHASIS-
mean follow up
of 1 year) HF1,5
MERIT-HF4

*On top of standard therapy at the time of study, except in CHARM-Alternative where patients were intolerant to ACEI:
On top of standard therapy and as a replacement for ACE!s (enalapril)
†

Patient populations varied between trials and as such relative risk reductions cannot be directly compared

ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin receptor blocker;

HF=heart failure; ARR=absolute risk reduction; HFrEF=heart failure with reduced 1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. SOLVD Investigators. N
ejection fraction; LVEF=left ventricular ejection fraction; MRA=mineralocorticoid Engl J Med 1991;325:293–302; 3. Granger et al. Lancet 2003;362:772–66; 4.
receptor antagonist MERIT-HF study group. Lancet 1999;353: 2001-7 5. Pitt et al. N Engl J Med
1999;341:709-17; 6. McMurray et al.,N. Eng. J Med. 2014, 371:993-1004
 PARADIGM-HF Study
Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality
and morbidity in Heart Failure

A multicenter, randomized, double-blind, parallel-group, active-

controlled study to evaluate the efficacy and safety of LCZ696
compared with enalapril on morbidity and mortality in patients
with chronic HF and reduced ejection fraction
 PARADIGM-HF: study design
Randomization
(N=8,436 patients with chronic HF
[NYHA Class II–IV with LVEF ≤40%*]
and elevated NTpro-BNP or BNP) Double-blind randomized treatment period

Single-blind run-in period

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

Enalapril 10 mg BID§

Testing tolerability to target doses of On top of standard HF therapy

enalapril and LCZ696 (excluding ACEIs and ARBs)

2 weeks 1–2 weeks 2–4 weeks ~34 months (event-driven)

*The ejection fraction entry criteria was lowered to ≤35% in a protocol
amendment,; **Enalapril 5 mg BID (10 mg TDD) for 1–2 weeks followed by Primary outcome: CV death or HF hospitalization
enalapril 10 mg BID (20 mg TDD) as an optional starting run-in dose for (event driven: 2,410 patients with primary events)
those patients who are treated with ARBs or with a low dose of ACEI; †200
mg TDD; ‡400 mg TDD; §20 mg TDD

McMurray et al. Eur J Heart Fail 2013 [Epub ahead of print]

 LCZ696 actively inhibits neprilysin and the AT1 receptor, thus
enabling alternative degradation pathways for bradykinin1
 Bradykinin
Bradykinin is
is aa substrate
substrate of
of neprilysin
neprilysin and
and other
other vasopeptidases
vasopeptidases (ACE,
(ACE, APP,
APP, DPP-4)
DPP-4) –– its
its elevation
elevation has
has
been
been associated
associated with
with cough
cough and
and angioedema
angioedema 2,3
2,3

 Omapatrilat
Omapatrilat inhibits
inhibits three
three enzymes
enzymes (ACE,
(ACE, APP,
APP, NEP)
NEP) involved
involved in
in the
the breakdown
breakdown of
of bradykinin,
bradykinin, which
which is
is
likely to be responsible for the development of angioedema
likely to be responsible for the development of angioedema 2
2

Bradykinin breakdown

Omapatrilat inhibits Active Inactive

ACE, APP and NEP2 bradykinin bradykinin

ACE APP NEP DPP-4

LCZ696 inhibits Active Inactive

only NEP1,4,5 bradykinin bradykinin

 In
In PARADIGM-HF,
PARADIGM-HF, aa higher
higher proportion
proportion of
of patients
patients in
in the
the LCZ696
LCZ696 group
group than
than in
in the
the enalapril
enalapril group
group had
had
non-serious
non-serious angioedema,
angioedema, but
but LCZ696
LCZ696 was
was not
not associated
associated with
with an
an increase
increase in
in serious
serious angioedema
6
angioedema 6
 There
There was
was aa lower
lower incidence
incidence of
of cough
cough in
in the
the LCZ696
LCZ696 group
group compared
compared with
with enalapril
6
enalapril 6

The information presented in this slide is from publically available data and not head-to–head clinical trials. ACE=angiotensin-converting enzyme; 1. McMurray et al. Eur J Heart Fail 2014;16:817–25
APP=aminopeptidase P; AT1= angiotensin II type 1; DPP-4=dipeptidyl peptidase; NEP=neprilysin; NYHA=New York Heart Association; PARADIGM- 2. Fryer et al. Br J Pharmacol 2008;153:947–55
45 HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure
3. Semple. J Hypertens Suppl 1995;13:S17–21;
4. Gu et al. J Clin Pharmacol 2010;50:401–14
5. McMurray et al. Eur J Heart Fail 2013;15:1062–73
6. McMurray et al. N Engl J Med 2014;371:993–1004
 PARADIGM-HF: key efficacy endpoints
• Primary endpoint measure:
– time to first occurrence of either CV mortality or HF hospitalization
• Secondary endpoint measures:
– change in HF symptoms and physical limitations measured by the
clinical summary score of the Kansas City Cardiomyopathy
Questionnaire (KCCQ)
– all-cause mortality
– new-onset atrial fibrillation
– renal progression assessed by first occurrence of 50% decline in
eGFR,
>30mL/min/1.73m2 decline in eGFR relative to baseline and to a
value of <60 mL/min/1.73m2,
or reaching end-stage renal disease
EQ-5D=EuroQol
McMurray et al. Eur J Heart Fail 2013 [Epub ahead of print]
 PARADIGM-HF: key inclusion and exclusion criteria
Key inclusion criteria: Key exclusion criteria:
 Males and females aged ≥18 years  History of angioedema
 Chronic HF NYHA class II–IV with  eGFR <30 mL/min/1.73m2 at screening, end of
LVEF ≤40%* and enalapril run-in or randomization, or a >35%
• BNP ≥150 pg/mL (NT-proBNP decrease in eGFR between screening and end
≥600 pg/mL) OR of enalapril run-in or between screening and
randomization
• BNP ≥100 pg/mL (NT-proBNP
≥400 pg/mL) and a hospitalization for HF  Serum potassium >5.2 mmol/L at screening OR
within the last 12 months >5.4 mmol/L at the end of the enalapril run-in
or end of the LCZ696 run-in
 Stable on an ACEI or an ARB (dosage
equivalent to enalapril ≥10 mg/day) for at  Requirement for treatment with both ACEI and
least 4 weeks ARBs
 Treatment with a stable dosage of a  Symptomatic hypotension, SBP
β-blocker for at least 4 weeks, unless <100 mmHg at screening, OR
otherwise contraindicated or not tolerated SBP <95 mmHg at end of enalapril run-in or at
randomization
 Optimized dosing of background HF
medications and use of aldosterone  Current acute decompensated HF
antagonists, where indicated  History of severe pulmonary disease

*The ejection fraction entry criteria was lowered to ≤35% in a protocol amendment
McMurray et al. Eur J Heart Fail 2013 [Epub ahead of print]
 Components of primary endpoint:

Death from CV causes

1.0

Enalapril
0.6
LCZ696
Cumulative probability

Hazard ratio = 0.80 (95% CI: 0.71–0.89)

0.4 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 4,056 3,891 3,282 2,478 1,716 1,005 280
Enalapril 4,212 4,051 3,860 3,231 2,410 1,726 994 279

51 CI=confidence interval; CV=cardiovascular; McMurray et al. N Engl J Med 2014;371:993 –1004

 Components of primary endpoint:

First hospitalization for HF

1.0

Enalapril
0.6 LCZ696
Cumulative probability

Hazard ratio = 0.79 (95% CI: 0.71–0.89)

p<0.001
0.4

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

52 CI=confidence interval; HF=heart failure McMurray et al. N Engl J Med 2014;371:993 –1004
 PARADIGM-HF
MENU

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 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.
53 CI=confidence interval; CV=cardiovascular; HF=heart failure; NNT=number needed to treat McMurray et al. N Engl J Med 2014;371:993–1004
 PARADIGM-HF
MENU

Death from any cause

1.0

Enalapril
0.6 LCZ696
Cumulative probability

Hazard ratio = 0.84 (95% CI: 0.76–0.93)

p<0.001
0.4

0.2

0
0 180 360 540 720 900 1,080 1,260
No at risk Days since randomization
LCZ696 4,187 4,056 3,891 3,282 2,478 1,716 1,005 280
Enalapril 4,212 4,051 3,860 3,231 2,410 1,726 994 279

54 CI=confidence interval McMurray et al. N Engl J Med 2014;371:993–1004

 PARADIGM-HF
MENU

Summary of results – efficacy

• Primary outcome
– 20% reduction in CV death or HF hospitalization with LCZ696 compared with
enalapril
– 20% reduction in CV mortality
– 21% reduction in HF hospitalization

• Secondary outcomes
– 16% reduction in all-cause mortality with LCZ696 vs enalapril
– LCZ696 superior to enalapril in reducing symptoms and physical limitations of
HF (indicated by KCCQ score)
– No significant difference in incidence of new onset atrial fibrillation between
treatment groups
– No significant difference in protocol-defined decline in renal function between
treatment groups

CV=cardiovascular; HF=heart failure;

55 KCCQ=Kansas City Cardiomyopathy Questionnaire McMurray et al. N Engl J Med 2014;371:993–1004
 PARADIGM-HF
MENU

Summary of results – safety

• 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

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

HFrEF: Treatment Guidelines
 Therapeutic algorithm for a patient with symptomatic HFrEF

Class I recommendation

Class IIa recommendation

a
Symptomatic ¼ NYHA Class II-IV. bHFrEF ¼ LVEF ,40%. cIf ACE inhibitor not tolerated/contra-indicated, use ARB. dIf MR antagonist not tolerated/contra-indicated, use ARB. eWith a hospital admission for HF within the last 6 months or with elevated natriuretic
peptides (BNP . 250 pg/ml or NTproBNP . 500 pg/ml in men and 750 pg/ml in women). fWith an elevated plasma natriuretic peptide level (BNP ≥ 150 pg/mL or plasma NT-proBNP ≥ 600 pg/mL, or if HF hospitalization within recent 12 months plasma BNP ≥ 100
pg/mL or plasma NT-proBNP ≥ 400 pg/mL). gIn
ACEI=angiotensin-converting doses equivalent
enzyme to enalapril 10 mg b.i.d. hWith
inhibitor; ARB=angiotensin-receptor a hospital
blocker; admissionfor HF within the previous year. iCRT is recommended if QRS ≥ 130 msec and LBBB (in sinus rhythm). jCRT should/may be considered if QRS ≥ 130
CRT=cardiac
msec with non-LBBB (in a sinus rhythm)
resynchronisation or HR-heart
therapy; for patients in AF
rate; provided a strategy
H-ISDN=hydrazine and to ensure bi-ventricular
isosorbide capture in place (individualized decision).
dinitrate; HFrEF=heart
failure with reduced ejection fraction; LVAD=left ventricular assist device; LVEF=left ventricular ejection
fraction; NYHA=New York Heart Association; VF/VT=ventricular fibrillation/ventricular tachycardia

Ponikowski et al., Eur Heart J, 2016; 37:2129-200

Treatment of HFrEF Stage C