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Heart Failure :Current Management and beyond
Gerasimos Filippatos, MD, FESC, FCCP
President Elect
Heart Failure Association ESC
• Acute Heart Failure
• Chronic Heart Failure
• Devices
• Acute Heart Failure
• Chronic Heart Failure
• Devices
• Definition
• Classification
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
HFREF, HFPEF – why to bother
?
• EF: prognostic importance & inclusion
criterion in most clinical trials (effective
therapies only for HF patients with
reduced EF or ‘systolic HF’ ie EF
≤35%)
• HF-PEF – patients with EF >50%
• those with EF 35–50% - ‘grey area’;
primarily mild systolic dysfunction ?
Flow chart is showing alternative
„echocardiography first‟ (blue) or
„natriuretic peptide first‟ (red)
approaches.
Diagnostic flow chart
for patients with
suspected heart failure
MR-proANP non-inferior
to BNP & NT-proBNP.
(BACH study)Maisel et al., JACC 2011
• Terminology
(AHF, ADHF, HHF, WHF, WCHF,
AHFS….)
Outcome in acute HF is still poor
Death, Rehospitalization or ER visit
DOSE CARRESS-HF
40% at
60 days
Figure 1. Clinical presentation of acute heart failure (AHF) patients in total and Greek cohorts
in the Acute Heart Failure Global Registry of Standard Treatment (ALARM-HF) and the in-
hospital patients arm of the European Society of Cardiology-Heart Failure (ESC-HF) pilot
survey.
Filippatos G et al. European Heart Journal: Acute
Cardiovascular Care 2014;2048872614527012Copyright © by European Society of Cardiology
Management of acute heart failure:
why so difficult ?
Clinical Factors: multifactorial, precipitating factor often not identified
Clinical presentation: spectrum of various conditions, heterogeneous
pathophysiology
Cardiovascular and non-cardiovascular comorbidities
Pathophysiological targets: uncertain
Widely accepted Admission Criteria not available
Discharge Criteria not available
End-points selection: not standardized
Hospitalization May Contribute to the Progression of Heart Failure
Gheorghiade M Am J Cardiol 2005, Gheorghiade M Eur J Heart Fail 2010Time
Ve
ntr
icu
lar
fun
ctio
n
With each event, hemodynamic alterations
(neurohormonal activation, subendocardial
ischemia), resulting in myocardial necrosis
contribute to progressive ventricular dysfunction.
Acute
event
Advanced HF
End-stage HF
Goals of Treatment in Acute Heart Failure
Immediate
(ED/ICU/CCU)
Intermediate (in-hospital)
Long-term and pre-
discharge
management
Phases in the
AHF management
• Treat symptoms
• Restore oxygenation
• Improve organ perfusion &
haemodynamics
• Limit cardiac/renal damage
• Prevent thrombo-embolism
• Minimize ICU length of
stay
• Stabilise patient and
optimise treatment strategy
• Initiate and up-titrate
disease-modifying
pharmacological therapy
• Consider device therapy in
appropriate patients
• Identify aetiology and
relevant co-morbidities
• Plan follow-up strategy
• Enrol in disease
management programme,
educate, initiate appropriate
lifestyle adjustments
• Plan to up-titrate/optimize
disease-modifying drugs
• Assess for appropriate
device therapy
• Prevent early readmission
• Improve symptoms, quality
of life and survival
ESC Guidelines for the Diagnosis and
Treatment
of Acute and Chronic Heart Failure 2012
1. Acute management
Oxygen
Diuretics
Opiates
Vasodilators
Nesiritide
Inotropes
Vasopressors
Acute Heart Failure – in hospital management
Pharmacological therapy
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
2. After stabilization
ACE inhibitor / ARB
Beta-blocker
Mineralocorticoid receptor
antagonist
Digoxin
Non-pharmacological therapy
1.Sodium and fluid intake
restriction
Ventilation
non-invasive
invasive
Mechanical circulatory
support
IABP
VAD
Ultrafiltration
Figure 3. Use of intravenous (iv) medications during hospitalisation in total and Greek
cohorts in the Acute Heart Failure Global Registry of Standard Treatment (ALARM-HF) and
the in-hospital patients arm of the European Society of Cardiology-Heart Failure (ESC-HF)
pilot survey.
Filippatos G et al. European Heart Journal: Acute
Cardiovascular Care 2014;2048872614527012
Copyright © by European Society of Cardiology
Figure 2. Use of life-prolonging medications on admission and at discharge in total and Greek
cohorts in the Acute Heart Failure Global Registry of Standard Treatment (ALARM-HF) and
the in-hospital patients arm of the European Society of Cardiology-Heart Failure (ESC-HF)
pilot survey.
Filippatos G et al. European Heart Journal: Acute
Cardiovascular Care 2014;2048872614527012
Copyright © by European Society of Cardiology
Recommendations for the treatment of acute heart
failure in HFA – ESC 2012 guidelines
Important developments
Better Use of old Drugs
New Drugs
New Concepts ie replacing rather than adding drugs
Treatment of co-morbidities
M. Felker NEJM 2011
JACC 2012
Diuretic Strategies in Patients with Acute
Heart Failure. The DOSE Trial
Sites of Expression and Physiologic Actions of the Vasopressin Receptor Subtypes
Vasopressin Receptor
SubtypeSite of Expression Physiologic Actions
V1a (V1-vascular)
Liver, vascular smooth
muscle, platelets, adrenal
cortex, kidney, spleen,
adipocytes, reproductive
organs, brain
Vasoconstriction, human
platelet aggregation,
mitogenesis in vascular
smooth muscle cells
V1b (V3-pituitary)
Corticotropin cells, possibly
kidney, pancreas, adrenal
medulla
Release of ACTH and β-
endorphin
V2-renal Renal collecting ducts Antidiuresis
ACTH = adrenocorticotrophic hormone (corticotropin).
Russell SD, DeWald T. Am J Cardiovasc Drugs. 2003;3:13-20.
Lee CR, et al. Am Heart J. 2003;146:9-18.
0.0
0.4
0.5
0.6
0.7
0.8
0.9
1.0
EVEREST: Primary Endpoint Analysis
Peto-Peto Wilcoxon Test: P = .68
Pro
po
rtio
n a
live
Months In Study
HR 0.98; 95% CI (.87–1.11)
Meets criteria for non-inferiority
CV Mortality or HF Hospitalization
Peto-Peto Wilcoxon Test: P = .55
Pro
po
rtio
n w
ith
ou
t eve
nt
0 3 6 9 12 15 18 21 24
2072 1562 1146 834 607 396 271 149 58
2061 1532 1137 819 597 385 255 143 55
HR 1.04; 95%CI (.95–1.14)
Months In Study
Tolvaptan Placebo
All-Cause Mortality
Konstam MA. JAMA. 2007.
0 3 6 9 12 15 18 21 24
2072 1812 1446 1112859 589 404 239 97
2061 1781 1440 1109 840 580 400 233 95
0.0
0.4
0.5
0.6
0.7
0.8
0.9
1.0
TLV
PLC
TLV
PLC
Vasopressin Receptor Antagonists in Different Stages of Development
V1a V1b V2 V1a/V2
Relcovaptan
OPC-21268SSR-149415
Lixivaptan
Mozavaptan*
Satavaptan
Tolvaptan
RWJ-351647
Conivaptan*
RWJ-676070
Filippatos G et al. Journal of Cardiac Failure 2008
Members of the Natriuretic Peptide Family
SS
Ser
Pro
Lys
Met
ValGln
Gly
CysGlySer Phe
HisArg
ArgLeu
Val
LysCys
Gly
LeuGly Ser
GlyArg Lys
MetAsp
IIe
Ser
Ser
Ser
Arg
COOH-
NH2
BNP
CNP
SS
Gly
Leu
Ser
LysGly
Cys
Phe
Cys
Gly
LeuGly Ser
Met
Ser
Gly
IIe
Arg
AspLeu
LysLeuGly
COOH-
NH2
NH2
COOH-
SerLeu
Arg
Arg
Ser
SerCys
Phe
Gly
Gly Arg
Cys
Gly
ArgTyr
Asn
PheSer
Gly
LeuSer
Gin
Ala
Gly
IIe
Arg
AspMet
SS
ANP
Urodilatin
Thr
AlaPro
Arg Ser
LeuArg
Arg
Tyr
Arg
PheSer
Asn
Cys
Gly
LeuGly Ser Gin
Ala
Gly
IIe
Arg
Asp
MetArgGly
GlyPhe
Cys
SerSer
SS
COOH-
NH2
Ularitide/urodilatin
Ularitide/urodilatin
mod. Forssmann Cardiovasc Res 2006
Urodilatin
• Synthesized in distal tubular cells
• Binds downstream in IMC duct to NPR-A
• Increases Renal Plasma Flow (via cGMP)
• Increases GFR:
• Dilates Vas afferens
• Constricts Vas efferens
• Relaxes mesangials cells
• Decreases sodium reabsorption in PCT and CD
via cGMP dependent phosphorylation of ENaC
• Inhibits renin, aldosterone, and vasopressin secretion
• NOT degraded by NEP inhibition
SIRIUS II: Ularitide Reduces PCWP
Placebo 7.5 ng /kg/min 15 ng /kg/min 30 ng /kg/min
* p<0.01 vs Placebo
*
*
*
*
*
**
**
*
*
*
†
† p<0.05 vs Placebo
- 12
- 10
- 8
- 6
- 4
- 2
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (Hours)Time (Hours)
DP
CW
P (
mm
Hg)
††
†
Mitrovic Eur Heart J 2006
TRUE-AHF
TRial of Ularitide's Efficacy and safety in patients
with Acute Heart Failure
Study aim
• efficacy and safety of ularitide on clinical status and mortality in AHF
• build on the growing body of evidence to treat AHF patients as early as
possible
The first-ever acute heart failure (AHF) Phase III trial to be specifically designed to assess the effect of early
treatment on cardiovascular mortality as a co-primary endpoint.
Relaxin: Mechanisms of Action
• Found in men and women
• Increased in pregnancy
• Vasodilation
– NO, cGMP effectors
– Induction of NOS II/III
– Upregulation of ETB receptor
• Preferential dilation of constricted vessels
• Anti-inflammatory
• Anti-apoptotic
• Anti-fibrotic
Relaxin Receptor
LGR7
Teichman, SL, et al. Heart Fail Rev 2009
Dschietzig, T, et al. Pharmacol Therap 2006
Published online 06.November, 2012
Effect of Serelaxin on Cardiac, Renal and Hepatic
Biomarkers in the RELAX-AHF Development Program:
Correlation with OutcomeMarco Metra, MD; Gad Cotter, MD; Beth A. Davison, PhD; G. Michael Felker, MD, MHS; Gerasimos Filippatos, MD;
Barry H. Greenberg, MD; Piotr Ponikowski, MD, PhD; Elaine Unemori, PhD; Adriaan A. Voors, MD, PhD; Kirkwood F.
Adams, Jr., MD; Maria Dorobantu, MD; Liliana Grinfeld, MD; Guillaume Jondeau, MD; Alon Marmor, MD; Josep
Masip, MD; Peter S. Pang, MD; Karl Werdan, MD; Margaret F. Prescott, PhD; Christopher Edwards; Samuel L.
Teichman, MD; Angelo Trapani, PhD; Christopher A. Bush, PhD; Rajnish Saini, MD; Christoph Schumacher, PhD;
Thomas Severin, MD; John R. Teerlink, MD; for the RELAXin in Acute Heart Failure (RELAX-AHF) Investigators
J Am Coll Cardiol 2013
Relaxin in AHFRELAX-AHF
Teerlink et al, Lancet 2012
•1161 AHF pts, •SBP >125 mmHg•Serelaxin, recombinant human relaxin 2,
• 48-hour iv or placebo
0
14
12
2
4
6
8
10
60
Composite event components (%)K-M estimate for time to first
CV Death or HF/RF re-hosp (%)
CV death:
(% subjects)
HR=0.7
p=0.23
HF/RF re-hospitalization
(% subjects)
HR=1.2
p=0.32
n=27 n=19 n=50 n=60
0 453014
HR 1.02 ( 0.74, 1.41)
p=0.89
Placebo
Serelaxin
580 559 539 522 501581 563 531 514 498
p value by log rank test
HR estimate by Cox model
2°Endpoint: CV Death or HF/RF
Re-hospitalization through Day 60
Days
Relaxin in AHFRELAX-AHF
Teerlink et al, Lancet 2012
Placebo,
K-M%
Serelaxin,
K-M%
HR (95%CI) p value for
interaction
CV death or hospitalization for heart/renal failure
through Day 60 (secondary endpoint)
Overall population1 13.0 13.2 1.02 (0.74, 1.41)
LVEF <50% 12.6 13.7 1.10 (0.75, 1.61)
0.97LVEF ≥50% 12.8 13.9 1.08 (0.57, 2.06)
CV death through Day 180 (efficacy endpoint)
Overall population1 9.6 6.1 0.63 (0.41, 0.96)
LVEF <50% 9.4 6.1 0.64 (0.39, 1.07)
0.87LVEF ≥50% 8.5 5.1 0.59 (0.23, 1.50)
All-cause mortality through Day 180 (safety endpoint)
Overall population1 11.3 7.3 0.63 (0.43, 0.93)
LVEF <50% 11.1 7.1 0.63 (0.39, 1.00)0.82
LVEF ≥50% 11.3 8.1 0.70 (0.32, 1.50)
Hazard ratio (vs placebo)
0 1 10
Relaxin in AHF: pEF vs rEFRELAX-AHF
Filippatos et al, ESC HFA 2013, Late Breaking Clinical Trials
Prognostic value of a >20% hs-cTnT increase
from baseline and effects of serelaxin
27,2
16,5
0
5
10
15
20
25
30
Placebo Serelaxin
Percent of patients with hs-cTnT increase
p = 0.0001
Organ Damage Hypothesis
Aliskiren
Aliskiren blocks RAAS proximally, preventing the compensatory rise in plasma renin activity in the setting of ACE-I or ARB therapy
There is a close relationship between plasma renin activity (PRA) and cardiovascular events in CHF.
Val-HeFT
Latini et al. Eur Heart J 2004
2 weeks
Randomization
Placebo
Aliskiren 300 mg
Conventional therapy‡
Aliskiren
150 mgAcute HFLVEF<40%
BNP >400pg/mL
SBP≥110mmHg
~1,800 patients
‡Except concomitant use of an ACEI and ARB*Follow-up at Week 2, Month 1, 2 and 3, with on-going
assessments every 3 months thereafter
~15 months (event-driven)*In-hospital
entry and
initiation
design overview
Primary outcome: CV death or HF hospitalization
at 6 months (381 events)
Aliskiren in AHFASTRONAUT
1639 AHF pts, LVEF <40%, BNP>400 pg/mL, fluid overload
Gheorghiade et al, JAMA 2013
Cardiovascular Death or Heart Failure Hospitalization
HR: 0.80 (95% CI: 0.61-1.04)
p = 0.11
10
5
0
25
20
15
Ka
pla
n-M
eie
r e
stim
ate
of
cu
mu
lative
eve
nt ra
te (
%)
Aliskiren (102/489 patients with events; 20.9%)
Placebo (114/464 patients with events; 24.6%)
0 30 60 90 190
Number of subjects
Aliskiren 489 466 444 427 383
Placebo 464 440 410 393 343
Time in study (days)
Primary Endpoint in non-DM PatientsCV Death or HF Re-hospitalization Within 6 Months
Aliskiren n (%)
Placebo n (%)
HR (95% CI)
p-value(two-sided)
CV death 42 (8.6) 49 (10.6) 0.73 (0.48-1.12) 0.14
HF re-hospitalization 74 (15.1) 86 (18.5) 0.77 (0.56-1.05) 0.10
30
Current inotropes
Hassenfuss & Teerlink. Eur Heart J 2011
Novel inotropes with clinical evidence
• Istaroxime
• Myosin activators
• SERCA2a gene transfer
Istaroxime
• inhibition of the Na-K ATPase– cytoplasmic calcium accumulation
– positive inotropic response
• stimulation of SERCA2– rapid clearance of cytoplasmic calcium to sarcoplasmic reticulum
– lucitropic response
– prevention of arrhythiogenesis
Omecamtiv Mecarbil (OM) is a Novel
Selective Cardiac Myosin Activator
Malik FI, et al. Science 2011; 331:1439-43.
Mechanochemical Cycle of Myosin
Force production
Omecamtiv mecarbil increases the entry rate of myosin into the
tightly-bound, force-producing state with actin
“More hands pulling on the rope”
Increases duration of systole
Increases stroke volume
No increase in myocyte calcium
No change in dP/dtmax
No increase in MVO2
Teerlink JR, et al. Lancet 2011; 378: 667–75; Cleland JGF, et al. Lancet 2011; 378: 676–83.
p-value = 0.331
PooledPlacebo
OMCohort 1
OMCohort 2
OMCohort 3
Dys
pn
oea
Res
po
nse
Rat
e (%
Res
po
nd
ers)
05
10152025303540455055
42%47%
51%
41%
A Phase 2 Study of Intravenous Omecamtiv Mecarbil, A Novel Cardiac Myosin Activator, In Patients With AHF
Primary Efficacy Endpoint:Dyspnoea Response (Likert Scale)
Teerlink J, et al
• Efficacy
– OM did not meet the 1° endpoint of dyspnoea relief
• Safety
– Overall SAE profile and tolerability similar to placebo
– Increase in troponin; no clear relationship to OM concentration
• Acute Heart Failure
• Chronic Heart Failure
• Devices
Cardiovasc Res 2000;46:225
Are ambulatory patients with heart failure treated in
accordance with ESC guidelines ?Rate of use
92.7%
YES
4439 pts
7.3%
NO
353 pts
67.0%
YES
3209 pts 33.0%
NO
1583 pts
ACE-I
(4710 pts)1380 (29.3)
ARBs
(1500 pts)362 (24.1)
B-blockers
(6468 pts)1130 (17.5)
Rate of patients at target dosage of recommended pharmacological treatments
MRAs
(4226 pts)1290 (30.5)
EORP Maggioni A, et al EJHF 2013
Non-steroidal MRAs: more selective for cardiac/vascular than renal tissue?
ARTS
ARTS-HFSafety and efficacy study of
BAY 94-8862 in patients with WCHF and left ventricular systolic dysfunction and either type 2 diabetes mellitus with or without CKD or moderate CKD alone
ARTS-DNSafety and efficacy study of BAY 94-8862 in patients with type 2 diabetes mellitus
and the clinical diagnosis of diabetic nephropathy
ARTS-DN and ARTS-HF: Phase 2b Studies of Fenerenone
Pis: B. Pitt, G. Filippatos (HF) G. Bakris, L. Ruilipe (DN)
Primary aimInvestigate efficacy [percentage of patients with a
relative decrease in NT-proBNP of more than 30% from baseline to visit 8 (day 90±2)] and safety of BAY 94-
8862
Secondary aims•Analyse the composite endpoint of death from any cause, cardiovascular hospitalizations, or emergency
presentations for WCHF until visit 8 (day 90±2)
• Monitor changes in health-related quality of life as assessed by the KCCQ and EQ-5D-3L
Primary aim Investigate change in UACR after treatment with BAY 94-8862 once daily over 90 days versus placebo
Secondary aims•Investigate the safety and tolerability by assessing effects of different doses of BAY 94-8862 on serum potassium and renal function
•Analyse changes in health-related quality of life as assessed by the KDQOL-SF and EQ-5D-3L
ARTS, MinerAlocorticoid Receptor Tolerability Study; BNP, B-type natriuretic peptide; CKD, chronic kidney disease; EQ-5D-3L, EuroQoL five dimension three level; KCCQ, Kansas City Cardiomyopathy Questionnaire; KDQOL-SF, kidney disease quality of life short form ; NT-proBNP,
amino-terminal pro-B-type natriuretic peptide; UACR, urinary albumin:creatinine ratio; WCHF, worsening congestive heart failure
ARNiAngiotensin Receptor
Neprilysin inhibitor
A new approach?
LCZ 696
Molecular complex of:
• An ARB - valsartan
• A NEP inhibitor – AHU 377
PARADIGM-HFA multicenter, randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared to enalapril on morbidity and mortality in patients with chronic heart failure and
reduced ejection fraction
Primary objectives
Evaluate if LCZ696 is superior in delaying time to first occurrence of either CV mortality or HF hospitalization in CHF pts (NYHA Class II – IV) with reduced ejection fraction
Secondary objectives
All cause mortality
Renal progression (eGFR change)
Clinical summary score (assessed by KCCQ)
Patient population
• 7980 patients with CHF NYHA class II – IV and reduced ejection fraction (LVEF < 40%)
• BNP>150 pg/ml (NTproBNP > 600 pg/ml) or BNP > 100 pg/ml (NTproBNP > 400 pg/ml) and hospitalization within the last 12 months
LCZ696 200 mg BID (n~4000)
Enalapril 10 mg BID (n~4000)
Outcomes driven (estimated mean f/u = 30-32 months)1-2 weeks
Enalapril 5-10 mg bid
LCZ 100 mg bid
LCZ 200 mg bid
1-2 weeks 2 weeks
Prior ACEi/ARB use discontinued
Single-blind periodDouble-blind period
N = 7980 (1:1 randomization)
PARAMOUNT – LCZ696 for HFPEF (LVEF ≥45%, NT-proBNP >400pg/mL, NYHA 2-4, eGFR ≥30 mL/min, on diuretic)
LCZ696 = Angiotensin Receptor Neprilysin Inhibitor
Valsartan
N=152Age 71NYHA II: 78%NT-BNP: 870 pg/mLACEi/ARB: 53/41%BB/ARA: 80/23%
LCZ696
N=149Age 71NYHA II: 81%NT-BNP: 794 pg/mLACEi/ARB: 56/38%BB/ARA: 79/19%
Solomon et al.Lancet 2012
From: Braunwald’s Heart Disease. 9th ed. Philadelphia, Elsevier, 2011
20%
40%
60%
GFR<6021%
SOLVD-P
NYHA I-II
(n=3673)1
SOLVD-T
NYHA II-III
(n=2161)1
VALIANT
(post AMI, CHF / LVD)
(n=14,527)2
34%
62%
Clinical trials
(patients with severe RD excluded)
GFR<6036% GFR
60−75GFR
45−60
GFR<45
GFR>90
GFR60−90
GFR30−59
GFR<30
ADHERE
(acute, decompensated HF)
(n=118,465)3
“Real life” AHF
Renal Dysfunction in HF
Dries DL et al. J Am Coll Cardiol 2000Anavekar NS et al. N Engl J Med 2004
Heywood JT et al. J Card Fail 2007
% o
f p
atie
nts
with
ren
al d
ysfu
nctio
n
WRF in AHF
Filippatos, et al, Eur Heart J 2014 (in press)
Novel biomarkers of kidney injury
Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency
• In patients with heart failure and iron deficiency, intravenous iron therapy improved functional capacity and the quality of life
• The benefit was similar in patients with anemiaand those without anemia
• Iron therapy may have a role in treating heart failure when iron deficiency is also present
Anker SD, Collet C, Filippatos G et al. N Engl J Med 2009;361:2436-2448
Iron deficiency in CHF
Jankowska et al, Eur Heart J 2010
Find the “sweet spot” of euvolemia before discharge
NP level
Creatinine
Courtesy of Alan Maisel
Integrated systems biology approach to determine characteristics of responders and non-responders to evidence based CHF therapy
BIOSTAT-CHF (A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure)
EU Project
• Acute Heart Failure
• Chronic Heart Failure
• Devices
DEVICES: Where We Are Going… Cardiac Contractility Modulation Ventricular restraint Mitral valve dynamic annuloplasty Mitral Clip Breathing pattern modulation Systolic to diastolic energy transfer Mini-pumps ventricular assist devices Percutaneous ventriculart assist devices Ventricular partitioning device Less invasive ventricular enhancement Devices for sleep disorders Implantable Monitoring Devices External Monitoring Devices Telemonitoring Devices
1 registration, 2 congresses, 1 place!
Join us in Athens 17-20 May 2014Early registration 31 March 2014
