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Heart Failure with Preserved EjectionFraction- What is new?
3rd Dubrovnik Cardiology Highlights
ESC Update Programme, Dubrovnik, 26.-29.9.2013
Prof. Burkert Pieske
Department of Cardiology
Medical University Graz
&
Ludwig-Boltzmann-Institute
Translational HF Research
www.kardiologie-graz.at www.heart.lbg.ac.at
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The Relationship Between Pressure and Volume
HFPEF, HFNEF, or Diastolic Heart Failure??
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HFpEF – News 2013
• News I: Pathophysiology
• News II: Diagnosis?
• News III: Therapy?
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„Heart failure“with
preserved EF
Ventricular Dysfunction• Impaired relaxation• Impaired filling• Systolic Dysfunction
Atrial dysfunction
Autonomic dysfunctionChronotropic incompetence
Elevated blood pressureInadequate BP response to exercisePulmonary hypertension
Vascular dysfunctionVascular stiffeningVentriculo-arterial coupling
Valvular diseaseDynamic mitral regurgitation
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„Heart failure“with
preserved EF
Lung DiseaseCOPD
Iron deficiencyand anemia
Renal dysfunctionVolume overload
Aging & Deconditioning
Obesity &Sarcopenia
Psychic DisordersDepression
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„Heart failure“with
preserved EF
Lung DiseaseCOPD
Iron deficiencyand anemia
Renal dysfunctionVolume overload
Aging & Deconditioning
Obesity &Sarcopenia
Psychic DisordersDepression
Ventricular Dysfunction• Impaired relaxation• Impaired filling• Systolic Dysfunction
Atrial dysfunction
Autonomic dysfunctionChronotropic incompetence
Elevated blood pressureInadequate BP response to exercisePulmonary hypertension
Vascular dysfunctionVascular stiffeningVentriculo-arterial coupling
Valvular diseaseDynamic mitral regurgitation
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HFpEF – News 2013
• News I: Pathophysiology
• News II: Diagnosis?
• News III: Therapy?
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EF
40-5
0 %
Mega-Trial Approach: HF + “preserved EF”
Fonarow G et al. JACC. 2007; 50:768-777.
EF
≥ 5
0 %
OPTIMIZE-HF Registry, N=41,267
EF
≤ 4
0 %
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I-Preserve Echo Substudy
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Structural LV Remodeling
Zile et al.; Circulation 2011; 124
Almost 50%: no structural LV Remodeling!
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HFA/ESC Recommendations
Paulus W et al., Eur Heart J 2007; 2539-2550
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HFA/ESC Recommendations: Diagnosis
1. Signs and/or Symptoms of Heart Failure
2. Preserved global systolic LV Function (EF>50%)
3. Indices of abnormal LV relaxation, filling, compliance
or stiffness
4. BNP or NTproBNP
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Diagnosis: Diastolic Heart Failure
HFA/ESC 2007
Paulus W et al.
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Diagnosis: Diastolic Heart Failure
HFA/ESC 2007
Paulus W et al.
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E/é and LVEDP
Little et al.; Circulation 2009; 120: 802-809
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Diagnosis: Diastolic Heart Failure
Change in Paradigms 2013:
• New Echo Techniques & Parameters
(e.g., strain, torsion)
• Echo Stress test („Diastolic Stress Test“)!
• New Biomarkers: Subgroups, Response
to Therapy (e.g., Galectin-3, ST2)
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HFpEF – News 2013
• News I: Pathophysiology
• News II: Diagnosis?
• News III: Therapy?
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Systolic Heart Failure: Therapy 2013
NYHA I NYHA II NYHA III NYHA IV
Beta-Blockers
Diuretics
ACE – Inhibitors
Digitalis
MR Antagonists
AT-1-Antagonists/Ivabradine
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Diastolic Heart Failure: Therapy 2013
NYHA I NYHA II NYHA III NYHA IV
?
Diuretics ?
?
?
?
?
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Redfield M, Circ Heart Fail 2012;5;653-659
Large Trials in HFPEF – no clear benefit
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Emerging Therapies
1. Pharmacological management
Ivabradine
PDE-5 Inhibition
Guanylate cyclase stimulation
Neprilysin Inhibition
MR antagonists
2. Interventions and Devices
Renal Denervation
Interatrial Shunting, Vagus/Baroreceptor stimulation..
3. Physical acitvity and Exercise
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Reil et al, Eur Heart J, 2012:1-11
Ivabradine – If channel inhibition
Genetic mouse model of HFPEF (db/db)
Invasive hemodynamics with Ivabradine
Ivabradine improved diastolic function
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Study CL2-16257-101
Effects of ivabradine versus placebo on cardiac
function, exercise capacity, and neuroendocrine
activation, in patients with Chronic Heart Failure and
Preserved left ventricular Ejection Fraction
An 8-month, randomised double-blind, placebo controlled,
international, multicentre study
Phase II
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Ivabradine phase II study in HFPEF
Primary objective
Ivabradine vs placebo on diastolic function, exercise capacity and
neuroendocrine activation over an 8-month treatment period in patients with
chronic HF-PEF
Primary endpoint
Co-primary endpoint based on echocardiography (E/e’),
neuroendocrine activation (NT-proBNP) and six-minute walk test evaluated at
8 months
Secondary objectives
-To evaluate the effects of ivabradine compared to placebo on cardiac
function and structural parameters, quality of life (KCCQ) , NYHA
classification and other biomarkers
-To evaluate the safety and tolerance profile of ivabradine compared to
placebo
Start: May 2013 !
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Increasing cyclic GMP in HFPEF ?
Redfield M, Circulation. 2012;5;653-659
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Myocardial dysfunction impaired relaxation, diastolic
stiffening, energy wastage
Endothelial dysfunction disturbed endothelium-dependent
vasotone regulation
Insufficient soluble Guanylate Cyclase (sGC): an unmet mechanism in HFPEF
ß-BlockersMRA
ACE-I / ARB
PDE5 Inhibition?
Desai A S, American Heart Journal, December 2011
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Redfield M, JAMA, 2013;309(12)
RELAX
216 patients
Randomized, double
blind, placebo-controlled
Sildenafil 3x20mg
(12w), 3x60mg 12w)
EF>50%
Elevated NTproBNP
PEP: peak VO2
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Redfield M, JAMA, 2013;309(12)
RELAX
Outcomes after 24 weeks:
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Myocardial dysfunction impaired relaxation, diastolic
stiffening, energy wastage
Endothelial dysfunction disturbed endothelium-dependent
vasotone regulation
Insufficient soluble Guanylate Cyclase (sGC): an unmet mechanism in HFPEF
ß-BlockersMRA
ACE-I / ARB sGC stimulators
Desai A S, American Heart Journal, December 2011
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55
60
65
70
75
80
Placebo (N=56)
0.5 mg (N=22)
1.0 mg (N=28)
2.0 mg (N=54)
Heart
rate
(b
pm
)
Heart rate
1,8
2
2,2
2,4
2,6
2,8
Placebo (N=56)
0.5 mg (N=22)
1.0 mg (N=27)
2.0 mg (N=54)
Card
iac i
nd
ex (
L·m
in–1·m
–2)
Cardiac index
Changes from baseline in cardiac index, heart rate, and MAP at 16 weeks
Riociguat Riociguat
31
Adjusted placebo-corrected difference:
+0.36 L·min–1·m–2 (95% CI: 0.18 to
0.54)
P=0.0001
Adjusted placebo-corrected difference:
–0.4 bpm (95% CI: –4.0 to 3.2)
P=0.83
0 0 0
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SOCRATES Study Program: parallel phase IIb studieswith once daily oral sGC stimulator (coming Fall 2013)
SOCRATES-REDUCED SOCRATES-PRESERVED
Indication HF with reduced EF (HFrEF) HF with preserved EF (HFpEF)
LVEF <45% ≥45%
Medical need
High event rates after hospitalization for HF despitestandard treatment
No specific standard therapy approved
Evidence Well tolerated cardiac index increase at 16 weeks Riociguat added to standard therapy in systolic HF and sec. PH (LEPHT)
• cGMP deficiency: causal role in HFPEF
• Myocardial and vascular targets
Design Parallel conduct of two dose finding ph IIb studies, each with 5 parallel arms (2 low doses and 2 with uptitration to higher doses) in patients stabilized after hospitalization for worsening chronic HF
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Solomon S D, Lancet 2012;380:1387-95
Neprilysin Inhibition – The PARAMOUNT Trial
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LCZ696 – A First-in-Class Angiotensin
Receptor Neprilysin Inhibitor
34
Vasodilation
blood pressure
sympathetic tone
aldosterone levels
fibrosis
hypertrophy
Natriuresis/Diuresis
Inactive
fragments
BNP
pro-BNP
NT-pro BNP
XNeprilysin
Natriuretic Peptide System
AT1 receptorX
Vasoconstriction
blood pressure
sympathetic tone
aldosterone
fibrosis
hypertrophy
Angiotensinogen
(liver secretion)
Angiotensin I
Angiotensin II
Renin Angiotensin System
NH
N
N
N
N
O
OH
O
OH
ONH
O
OH
O
ValsartanAHU377
↓LBQ657
Heart Failure
LCZ696
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PARAMOUNT: Study Design
Primaryobjective
NT pro-BNP reduction from baseline at 12 weeks
Secondaryobjectives
Echocardiographic measures of diastolic function, left atrial size, LV size and function, PASP
HF symptoms, Clinical composite assessment and Quality of life (KCCQ)
Safety and tolerability
LCZ696100 mg BID
LCZ696 50 mg BID
Valsartan40 mg BID
1 week 10 weeks2 weeks
Placebo run-in
Discontinue ACEI or ARB therapy one day prior to randomization
LCZ696 200 mg BID
Valsartan80 mg BID Valsartan 160 mg BID
1 week
Prior ACEi/ARB use discontinued
6 month extension
Baseline randomization visit and visit at end of 12 weeks of core study
Week
Visit
-2
1
0
2
21
3 4
12
7
4 8
65 8 9 10 11
18 24 30 36
Clinicaltrials.gov NCT00887588
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Weeks Post Randomization
LCZ696
Valsartan
0 5 10200
300
400
500
600
700
800
900
1000
NT
pro
BN
P(p
g/m
l)
LCZ696/Valsartan:
0.77 (0.64, 0.92)
P = 0.005
p = 0.063
12
Primary Endpoint: NT-proBNP at 12 Weeks
783 (670,914)
862 (733,1012) 835 (710, 981)
605 (512, 714)
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Changes in Key Echocardiographic Measures
Left Atrial Volume
12 Weeks 36 Weeks
-6
-5
-4
-3
-2
-1
0
1
2
Cha
ng
e in
Le
ft A
tria
l V
olu
me
(m
l)
Valsartan
LCZ696
12 Weeks 36 Weeks
-2.0
-1.8
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Cha
ng
e in
E/E
'
E/E’
P = 0.18 P = 0.003
P = 0.71 P = 0.42
12 weeks 36 weeks0.0
0.5
1.0
1.5
2.0
Cha
ng
e in
La
tera
l M
itra
l A
nn
ula
r
Rela
xa
tio
n V
elo
city (
E') (
cm
/s)
P = 0.56
P = 0.40
Lateral E’
12 weeks 36 weeks
-0.20
-0.15
-0.10
-0.05
0.00
Cha
ng
e in
LA
Wid
th (cm
)
P = 0.07 P = 0.03
Left Atrial Width
No Significant Changes in LV volumes, Ejection Fraction, or LV mass at 12 or 36 weeks
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3. Board Meeting LBI.HF,
21.03.2013
38
MR Receptor Antagonism – Aldo-DHF
Edelmann F,.. Pieske B. JAMA 2013; February 27, 2013-Vol 309, No.8
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Placebo (n= 210)
Spironolactone 25 mg daily (n= 210)
Week/
Month
Qualifying
Screen
Initial
Screen
Visit
< - 1w - 1w + 1w0 1w 3mo 6mo + 4w9mo 12mo (18mo)
2 31 4 5 76 8 (9)(8) 9 (10)
Treatment Period
Primary Endpoint
Equally ranked co-primary endpoints: Change in diastolic function (E/é) and maximal exercise capacity (peak VO2) after 12 months for spironolactone compared to placebo.
Secondary endpoints: Changes in other echocardiographic measures of cardiac function and structure; Changes in other measures of exercise capacity; Neuroendocrine activation; HF symptoms; Quality of life; Safety and tolerability of study medication.
Multicenter, randomised, placebo-controlled double-blind, two-armed parallel-group study
Aldo-DHF Study Design
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Ch
ange
in E
/e‘
1
0
-1
Baseline 6 months 12 months
p < 0.001 p < 0.001
Placebo
Spironolactone
Time since randomisation
Spironolactone: 12.73.6 to 12.1±3.7 Placebo: 12.84.4 to 13.6±4.3
(P<0.001 for difference between groups)
Primary endpoint - E/é
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Ch
ange
in p
eak
VO
2
Baseline 6 months 12 months
0.5
0
-0.5
p = 0.57 p = 0.81
Placebo
Spironolactone
1
Primary endpoint - peak VO2
Time since randomisation
Spironolactone: 16.33.6 to 16.8±4.6mL/min/kg Placebo: 16.43.5 to 16.9±4.4mL/min/kg
(P=0.67 for difference between groups)
Edelmann F,.. Pieske B. JAMA 2013; February 27, 2013-Vol 309, No.8
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Blood Pressure (BP)
Results for functional and structural reverse remodelling remained significant after adjusting for blood pressure effects
Change in systolic BP Change in diastolic BP
Ch
ange
in
blo
od
pre
ssu
re f
rom
bas
elin
e (
mm
Hg)
Placebo Spironolactone
0
-10
2
-2
-4
-6
-8
0
-2
-4
Placebo Spironolactone
3 months
6 months
12 months
**
*
** *
* p < 0.05 vs. Placebo
2
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TOPCAT: Trial Design
• AGE 50 YRS
• EF 45% WITHIN 6 MONTHS
• HEART FAILURE SYMPTOMS AND SIGNS
• CONTROLLED SYSTOLIC BP (< 140 mm Hg)*
• SERUM K+ 5.0 MMOL/L
PLUS ONE OF THE FOLLOWING:
• HF HOSPITALIZATION WITHIN 12 MONTHS
• BNP 100 PG/ML
• N-TERMINAL PRO-BNP 360 PG/ML
RANDOMIZE
SPIRONOLACTONE
15 MG
PLACEBO
15 MG
DOSE TITRATION (TARGET 30 MG)
* Optional Titration to 45 mg at 4 mos
COMPOSITE PRIMARY ENDPOINT
CV death, Aborted cardiac arrest, Hospitalization for
management of HF
Week 4
Week 0
~ 3.25 yrs
N=3500
Desai A S, American Heart Journal, 2011
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Emerging Therapies
1. Pharmacological management
Ivabradine
PDE-5 Inhibition
Guanylate cyclase stimulation
Neprilysin Inhibition
MR antagonists
2. Interventions and Devices
Renal Denervation
Interatrial Shunting
3. Physical acitvity and Exercise
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Results: Exercise Capacity
Primary Endpoint:
peak VO2
Maximum Workload
Edelmann F & Pieske B, JACC 2011;
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Diastolic Function & LA remodeling
Change in E/é Ratio Change in LA Volume Index
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Summary I
1. 50% of HF patients have HFPEF
1. Pathophysiology/Etiology is complex and multifactorial, comorbidities can contribute
2. Diagnosis?: EF>50% + objective evidence of diastolicdysfunction. Biomarkers? Stress test?
1. General management: Loop diuretics, risk factor control
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Summary II
1. No established targeted therapy for HFPEF
2. New pharmacological approaches under investigation:
Ivabradine (Phase II: Start 2013)
Soluble Guanlyte cyclase stimulation (Phase II: Start
2013 )
Neprilysin inhibition (Phase III: Start 2013)
MR Antagonists (Phase III: Ongoing)
3. New devices and interventions
4. Physical acivity and exercise training (Phase II: Ongoing)
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