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Gerasimos Filippatos, MD, FESC, FHFA
President HFA
Acute Heart Failure: Update 2015
Disclosures
• Principal Investigator or Committee member in trials sponsored by Novartis, Bayer, Cardiorentis, Vifor, European Union
Outcome in acute HF is still poor
Death, Rehospitalization or ER visit
DOSE CARRESS-HF
40% at
60 days
All-cause death or hospitalization 1892 pts with acute HF& 3226 pts with chronic
HF
Chronic HF: 17.2%
Acute HF: 35.1%
Days from enrollment
A. Maggioni, U Dahltrom, G, Filippatos et al EJHF2011
EURObservational Research Program:
The Heart Failure Pilot Survey
1-year all cause mortality:
acute HF – 16.8% chronic HF – 6.8%
Management of acute heart failure:
why so difficult ?
Clinical Factors: Underlying causes: multifactorial, precipitating factor often not identified
Clinical presentation: spectrum of various conditions, heterogeneous
pathophysiology
Cardiovascular and non-cardiovascular comorbidities
Pathophysiological targets: uncertain
End-points selection: not standardized
Courtesy of Piotr Ponikowski
• Terminology
(AHF, ADHF, HHF, WHF, WCHF,
AHFS….)
Filippatos G et al 2015
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
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
Recommendations for the treatment of acute
heart failure in HFA – ESC 2012 guidelines
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
Important developments
Better use of old drugs
New Drugs
Treatment of co-morbidities
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure
Decompensated chronic HF
• Consider higher dose of diuretics in
renal dysfunction or with chronic
diuretic use.
Diuretic Optimization Strategies
Evaluation in Acute Heart Failure (DOSE)
To evaluate the safety and efficacy of various initial strategies of furosemide
therapy in patients with ADHF
– Route of administration: • Q12 hours bolus
• Continuous infusion
– Dosing • Low intensification (1 x oral dose)
• High intensification (2.5 x oral dose)
Felker NEJM 2011
JACC 2012
Diuretic Strategies in Patients with Acute
Heart Failure. The DOSE Trial
Diuretics in Hospitalized Patients
If patients are already receiving loop diuretic therapy, the
initial intravenous dose should equal or exceed their
chronic oral daily dose and should be given as either
intermittent boluses or continuous infusion.
I IIa IIb III
Vasopressin Receptor Antagonists in Different Stages of Development
V1a V1b V2 V1a/V2
Relcovaptan
OPC-21268 SSR-149415
Lixivaptan
Mozavaptan*
Satavaptan
Tolvaptan
RWJ-351647
Conivaptan*
RWJ-676070
Filippatos G et al. Journal of Cardiac Failure 2008
If symptomatic hypotension is absent, intravenous
nitroglycerin, nitroprusside or nesiritide may be considered
an adjuvant to diuretic therapy for relief of dyspnea in
patients admitted with acutely decompensated HF.
I IIa IIb III
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
Members of the Natriuretic Peptide Family
S S
Ser
Pro
Lys
Met
Val Gln
Gly
Cys Gly Ser Phe
His Arg
Arg Leu
Val
Lys Cys
Gly
Leu Gly Ser
Gly Arg Lys
Met Asp
IIe
Ser
Ser
Ser
Arg
COOH-
NH2
BNP
CNP
S S
Gly
Leu
Ser
Lys Gly
Cys
Phe
Cys
Gly
Leu Gly Ser
Met
Ser
Gly
IIe
Arg
Asp Leu
Lys Leu Gly
COOH-
NH2
NH2
COOH-
Ser Leu
Arg
Arg
Ser
Ser Cys
Phe
Gly
Gly Arg
Cys
Gly
Arg Tyr
Asn
Phe Ser
Gly
Leu Ser
Gin
Ala
Gly
IIe
Arg
Asp Met
S S
ANP
Urodilatin
Thr
Ala Pro
Arg Ser
Leu Arg
Arg
Tyr
Arg
Phe Ser
Asn
Cys
Gly
Leu Gly Ser Gin
Ala
Gly
IIe
Arg
Asp
Met Arg Gly
Gly Phe
Cys
Ser Ser
S S
COOH-
NH2
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)
D
PC
WP
(m
mH
g)
† †
†
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
– 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 Outcome Marco 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 AHF RELAX-AHF
Teerlink et al, Lancet 2012
• 1161 AHF pts, • SBP >125 mmHg • Serelaxin, recombinant human relaxin 2,
• 48-hour iv or placebo • Early treatment
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 45 30 14
HR 1.02 ( 0.74, 1.41)
p=0.89
Placebo
Serelaxin
580 559 539 522 501 581 563 531 514 498
p value by log rank test
HR estimate by Cox model
2°Endpoint: CV Death or HF/RF
Re-hospitalization through Day 60
Days
RELAX-AHF:
Cardiovascular and All-Cause Death
Teerlink 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)
0.97 LVEF ≥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)
0.87 LVEF ≥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 rEF RELAX-AHF
Filippatos et al, ESC HFA 2013, Late Breaking Clinical Trials Eur Heart J 2014
2 weeks
Randomization
Placebo
Aliskiren 300 mg
Conventional therapy‡
Aliskiren
150 mg Acute HF LVEF<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)
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 Patients CV 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
Hasenfuss and Teerlink, EHJ 2011
Inotropic Therapies
ISTAROXIME
• Inotropic and lusitropic agent
• Calcium cycling modulator through the
inhibition of Na/K ATPase and
activation of SERCA ATPase.
• Improves systolic and diastolic
function without arrhythmias or ↑ in
MVO2. (1, 2)
.J Am Coll Cardiol 2008
AHJ 2009
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
Pooled Placebo
OM Cohort 1
OM Cohort 2
OM Cohort 3
Dys
pn
oea
Res
po
nse
Rat
e
(% R
esp
on
der
s)
0 5
10 15 20 25 30 35 40 45 50 55
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
Non-steroidal MRAs: more selective for cardiac/vascular than renal tissue?
ARTS
ARTS-HF Safety 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-DN Safety and efficacy study of BAY 94-8862 in patients with type 2 diabetes mellitus
and the clinical diagnosis of diabetic nephropathy
Primary aim Investigate 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
• CoChairs: B. Pitt & G Filippatos
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
37
Conclusions
The therapeutic approach to acute HF has not
changed much in the last few decades
• only one drug in the USA and one drug in Europe have
been approved in the last 15 years
There is a need to identify treatment strategies
and regimens that reduce mortality and the
incidence of HF rehospitalization in patients post-
acute HF1
38