Transcript Slide 1

Future perspectives in Heart
failure
Sarajevo, May 2010
Professor Michel KOMAJDA
Université Pierre & Marie Curie – Hôpital Pitié Salpêtrière
Département de Cardiologie
Paris (France)
 Have we been successful?
Cumulative benefit of poly-pharmacy in
mild-moderate HF
1 year mortality (%)
20
SOLVD-T
1991
CIBIS 2
1999
15.7
15
12.4
CHARM-Added
(Beta-blocker subgroup)
2003
13.2
10
8.8
8.7
6.1
5
0
Diuretic/
digoxin
Diuretic/
digoxin
ACE inhib.
Diuretic/
digoxin
ACE inhib.
Diuretic/
Diuretic/
Diuretic/
digoxin
digoxin
digoxin
ACE inhib.
ACE inhib.
ACE inhib.
Beta-blocker Beta-blocker Beta-blocker
ARB
 Are there failures?
ACUTE HEART FAILURE
Negative trials
TRIAL
ESSENTIAL
Drug
Enoximone
Low dose
NEGATIVE
Duration
(Mo)
N
PEP
6
1.854
. AC death/CV hosp.
. PGA
. 6 MWT
SURVIVE
Levosimendan vs
Dobutamine
NEGATIVE
6
1.327
AC death
REVIVE
Levosimendan vs
pbo
Composite better
Increase death
6
600
EVEREST
Tolvaptan
3.600
Composite
. AC death
. AC death/CV hosp.
. PGA
EVEREST: Primary Endpoint
CV Mortality or HF Hospitalization
All-Cause Mortality
HR 0.98; 95% CI (.87–1.11)
Meets criteria for non-inferiority
1.0
Proportion without event
0.9
Proportion alive
HR 1.04; 95%CI (.95–1.14)
1.0
0.8
0.7
0.6
0.5
0.4
Peto-Peto Wilcoxon Test: P = .68
0.0
0.9
0.8
0.7
0.6
0.5
0.4
Peto-Peto Wilcoxon Test: P = .55
0.0
2072 1812 1446 1112 859 589 404 239
97 TLV
2072 1562 1146 834 607 396 271 149
58 TLV
2061 1781 1440 1109 840 580 400 233
95 PLC
2061 1532 1137 819 597 385 255 143
55 PLC
0
3
6
9
12
15
18
21
24
0
Months In Study
3
6
9
12
15
18
21
Months In Study
Tolvaptan
Placebo
Konstam MA. JAMA. 2007.
24
Probability of Surviving
SURVIVE
1.0
Levosimendan
0.9
Dobutamine
0.8
0.7
Overall 180-d
Mortality: 27%
0.6
0.5
0.4
0
30
60
90
120
150
180
Days Since Start of Study Drug Infusion
A Mebazaa et al. JAMA 2007; 297:1883-1891
Adenosine Antagonists
Afferent
arteriolar
constriction
Adenosine
release
Proximal
tubular
sodium
reabsorption
Furosemide
Increasd distal
tubular sodium
concentration
PROTECT
Treatment phase
Screening
• AHF & fluid
overload, need of
iv loop diuretic
• CrCl, 20-80
ml/min
Days
Follow-up
Rolofylline
30 mg
All cause mortality
CV/Renal hosp All cause
mortality
Placebo
1
2
Randomisation
Rolofylline to
placebo, 2:1
3
4
5
6
Kidney Function
7
14
60
180
Primary Endpoint
Odds ratio (95% CI) vs Pbo: 0.92 (0.78, 1.09)
Percent of Patients
100
80
36.0
40.6
44.2
37.5
19.8
21.8
Placebo
Ro 30 mg
60
40
20
0
Treatment Success
Patient Unchanged
Treatment Failure
p=0.348 for comparison of distribution using the van Elteren extension of Wilcoxon test
1. Patient heterogeneity

Substrate (ischaemic / non ischaemic, HT).

Trigger ( ACS, arrhythmias, Hypertension
crisis).

Pathophysiology ( systolic vs diastolic HF / low
vs high BP).
2. Lack of standard comparator.
3. Dose, Time points, Endpoints.
Heart failure with Preserved
Ejection Fraction
RAAS blockade in HF-PEF: two key trials
CHARM-Preserved
Death or HF hospitalization
PEP-CHF
Death or HF hospitalization
Cumulative incidence (%)
40
Placebo
Cumulative incidence (%)
40
Placebo
Candesartan
Perindopril
30
30
20
20
10
10
HR 0.92; 95% CI (0.80-1.05);
p=0.221
0
HR 0.92; 95% CI (0.70-1.21);
p=0.545
0
0
12
24
Month
36
Yusuf et al. Lancet 2003
48
0
12
24
Month
36
Cleland et al. Eur Heart J 2006
48
I-PRESERVE: Primary Endpoint
Death or protocol specified CV hospitalization
Cumulative Incidence of
Primary Events (%)
40 -
Placebo
30 -
Irbesartan
20 -
10 -
HR (95% CI) = 0.95 (0.86-1.05)
Log-rank p=0.35
00
6
12
18
24
30
36
42
48
Months from Randomization
No. at Risk
Irbesartan 2067 1929 1812 1730 1640 1569 1513 1291 1088
2061 1921 1808 1715 1618 1539 1466 1246 1051
Placebo
54
60
816
776
497
446
Treatment Of Preserved Cardiac
function heart failure with an
Aldosterone anTagonist
New drugs
New drug trials
 Renin inhibitors (ATMOSPHERE: aliskiren vs
enalapril vs combination)?
 Safe Inotropes (Istaroxime/Cardiac Myosin
activator)?
 New vasodilators /GMPc modulators.
 Chimeric Natriuretic peptides.
 Sinus node inhibition (SHIFT: ivabradine vs
placebo.
 NEP inhibitors(+ ARB).
ATMOSPHERE: design overview
Primary outcome: CV death or heart failure hospitalization
(event driven: 2162 patients)
Randomization
Enalapril 10 mg twice daily (n=2,200)
Open-label run-in
Enalapril
Enalapril
+Aliskiren
Aliskiren 300 mg once daily (n=2,200)
Aliskiren 300mg/enalapril
20 mg Daily (n=2,200)
Double-blind
4-8 weeks
~48 weeks (event driven)
CK-1827452: Background
 Preclinical
 Selective activator of cardiac myosin
 Prolongs duration of systole by
• Increasing entry rate of myosin into forceproducing state
• Therefore overall number of active crossbridges increases
 Increases stroke volume
 No change in dP/dtmax
 No increase in MVO2
Istaroxime
A New Calcium Cycling Modulator
HORIZON-HF PCWP
1
0
-1
mmHg
-2
-3
Placebo
Istar 0.5, p = 0.003
Istar 1.0, p = 0.014
Istar 1.5, p < 0.001
-4
-5
Infusion period
-6
0
2
Post-infusion
4
time (hours)
6
8
HORIZON-HF Conclusions
 Istaroxime given over a short period in patients
admitted with HF and LVEF ≤ 35% receiving
standard therapy:
 decreased PCWP and LVEDV
 increased CI
 Improved some indices of diastolic function.*
 No changes in neurohormones, renal function, or
troponin release.
 In contrast to other inotropic agents available,
these changes were associated with:
 Increase in SBP.
 Reduction in HR.
Relaxin Mechanisms of Action
Relaxin Receptor LGR7
 Vasodilation
 NO, cGMP effectors
 Induction of NOS II/III
 Upregulation of endothelial
endothelin type B receptor,
which mediates vasodilation
 Preferential dilation of
constricted vessels
 Relaxin-upregulated ETB
receptors act as vasodilating
ET-1 sink
 Anti-inflammatory
 Down-modulation of
inflammatory cytokines linked
to outcome in HF (TNF-, TGF-)
 Other: Anti-ischemic, Anti-apoptotic,
Anti-fibrotic
CD-NP: A Rationally Designed
Natriuretic Peptide
CNP
DNP
NPR-B agonist
Vasodilation
CD-NP
NPR-A agonist
Renal function
D
R I N
H
D
V
I
S
K
N
H
L
G
F
G
C SSCP
DP
S
Y
L
K
R
D
V
P
E
R
P
N
S
P
A
S
T
I G
S
DR
GL
S
L
M
K
S
L
G
G
L
G
F
C S S C
G
K
+
S
R I G
L
K
M
S
L
=
S
G
L
G
G
F
C
C
G - S S- P
S
K
L
S
L
R
G
D
P
R
P
N
A
P
S
T
S
A
-
HR predicts outcome
(placebo group)
Fox K, et al. Lancet. 2008;372:817-821.
SHIFT design paper
Study design
NYHA II-IV . EF<35% .HF hosp in prior 12 months .HR >70 bpm
Ivabradine
5mg bid
Run-in
7 to 30
days
ASSE
Ivabradine 2.5, 5 or 7.5mg bid according to
HR and tolerability
Matching placebo, bid
D000
D014
D028
6500 pts randomised
Composite primary endpoint
• Cardiovascular death
• Hospitalisation for worsening heart failure
www.controlled-trials.com
M004
Every 4 months
Results ESC 2010
A new approach?
ARNi
Angiotensin Receptor
Neprilysin inhibitor
LCZ 696
Molecular complex of:

An ARB - valsartan

A NEP inhibitor – AHU 377
PARADIGM-HF
A 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
Double-blind period
Single-blind period
LCZ696 200 mg BID (n~4000)
LCZ 200 mg bid
LCZ 100 mg bid
N = 7980 (1:1 randomization)
Enalapril 10 mg BID (n~4000)
Enalapril 5-10 mg bid
1-2 weeks
1-2 weeks
2 weeks
Prior ACEi/ARB use discontinued
Primary
objectives
Outcomes driven (estimated mean f/u = 30-32 months)
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.
New trials in acute HF
ASCEND-HF design
completed in 2010
# 7000 pts enrolled
Design overview
Primary outcome: CV death or HF hospitalization at 6 months (381 events)
Randomization
Acute HF
LVEF<40%
BNP >400pg/mL
SBP≥110mmHg
~1,800 patients
Aliskiren
150 mg
Aliskiren 300 mg
Placebo
Conventional therapy‡
In-hospital entry
and initiation
‡
2 weeks
Except concomitant use of an ACEI and ARB
~15 months (event-driven)*
* Follow-up at Week 2, Month 1, 2 and 3, with on-going assessments every 3 months thereafter
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