professor michel komajda université pierre & marie curie – hôpital pitié salpêtrière...
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Professor Michel KOMAJDAUniversité Pierre & Marie Curie – Hôpital Pitié Salpêtrière
Département de CardiologieParis (France)
Future perspectives in Heart Future perspectives in Heart failurefailure
Sarajevo, May 2010Sarajevo, May 2010
Have we been successful?Have we been successful?
Cumulative benefit of Cumulative benefit of poly-pharmacypoly-pharmacy in mild-moderate HFin mild-moderate HF
Diuretic/digoxin
ACE inhib.
Diuretic/digoxin
13.2
8.8 8.7
6.1
0
5
10
15
20
1 y
ea
r m
ort
alit
y (
%) 15.7
12.4
Diuretic/digoxin
ACE inhib.
Diuretic/digoxin
ACE inhib.Beta-blocker
Diuretic/digoxin
ACE inhib.Beta-blocker
Diuretic/digoxin
ACE inhib.Beta-blocker
ARB
CHARM-Added(Beta-blocker subgroup)
2003
CIBIS 21999
SOLVD-T1991
Are there failures?Are there failures?
ACUTE HEART FAILUREACUTE HEART FAILURE
Negative trialsNegative trials
TRIALTRIAL DrugDrug Duration Duration (Mo)(Mo) NN PEPPEP
ESSENTIALESSENTIALEnoximoneEnoximone
Low doseLow dose
NEGATIVENEGATIVE
66 1.8541.854 . AC death/CV hosp.. AC death/CV hosp.
. PGA. PGA
. 6 MWT. 6 MWT
SURVIVESURVIVELevosimendan vs Levosimendan vs DobutamineDobutamine
NEGATIVENEGATIVE66 1.3271.327 AC deathAC death
REVIVEREVIVE
Levosimendan vs Levosimendan vs pbopbo
Composite betterComposite better
Increase deathIncrease death
66 600600 CompositeComposite
EVERESTEVEREST TolvTolvaptanaptan 3.6003.600 . AC death. AC death
. AC death/CV hosp.. AC death/CV hosp.
. PGA. PGA
0.0
0.4
0.5
0.6
0.7
0.8
0.9
1.0
EVEREST: Primary EndpointEVEREST: Primary Endpoint
Peto-Peto Wilcoxon Test: P = .68
Pro
po
rtio
n a
liv
e
Months In Study
HR 0.98; 95% CI (.87–1.11)
Meets criteria for non-inferiority
CV Mortality or HF CV Mortality or HF HospitalizationHospitalization
Peto-Peto Wilcoxon Test: P = .55
Pro
po
rtio
n w
ith
ou
t e
ve
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 MortalityAll-Cause Mortality
Konstam MA. JAMA. 2007.
0 3 6 9 12 15 18 21 24
2072 1812 1446 1112 859 589 404 239 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
A Mebazaa et al. JAMA 2007; 297:1883-1891
Overall 180-d Mortality: 27%
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 30 60 90 120 150 180
Days Since Start of Study Drug Infusion
Pro
bab
ility
of
Su
rviv
ing
Levosimendan
Dobutamine
SURVIVESURVIVE
Adenosine Antagonists
Afferent arteriolar constrictio
n
Proximal tubular sodium
reabsorption
Furosemide
Increasd distal
tubular sodium
concentration
Adenosine
release
PROTECT
Placebo
Rolofylline 30 mg
Treatment phase Follow-up
Randomisation Rolofylline to placebo, 2:1
All cause mortalityCV/Renal hosp All cause
mortality
Kidney Function
Days 1 2 3 4 5 6 7 14 60 180
Screening• AHF & fluid
overload, need of iv loop diuretic
• CrCl, 20-80 ml/min
Primary EndpointPrimary Endpoint
Odds ratio (95% CI) vs Pbo: 0.92 (0.78, 1.09) P
erc
en
t of P
atie
nts 36.0
44.2
19.8
40.6
37.5
21.80
20
40
60
80
100
Placebo Ro 30 mg
Treatment Success Patient Unchanged Treatment Failure
p=0.348 for comparison of distribution using the van Elteren extension of Wilcoxon test
1.1. Patient heterogeneityPatient heterogeneity Substrate (ischaemic / non ischaemic, HT).Substrate (ischaemic / non ischaemic, HT).
Trigger ( ACS, arrhythmias, Hypertension Trigger ( ACS, arrhythmias, Hypertension crisis).crisis).
Pathophysiology ( systolic vs diastolic HF / Pathophysiology ( systolic vs diastolic HF / low vs high BP).low vs high BP).
2.2. Lack of standard comparator.Lack of standard comparator.
3.3. Dose, Time points, Endpoints.Dose, Time points, Endpoints.
Heart failure with Heart failure with
Preserved Ejection Preserved Ejection
FractionFraction
CHARM-PreservedDeath or HF hospitalization
PEP-CHFDeath or HF hospitalization
Yusuf et al. Lancet 2003 Cleland et al. Eur Heart J 2006
RAAS blockade in HF-PEF: two key RAAS blockade in HF-PEF: two key trialstrials
HR 0.92; 95% CI (0.80-1.05);p=0.221
PlaceboCandesartan
0
10
20
30
40
0 12 24 36 48
Cumulative incidence (%)
Month
HR 0.92; 95% CI (0.70-1.21);p=0.545
PlaceboPerindopril
0
10
20
30
40
0 12 24 36
Cumulative incidence (%)
Month48
I-PRESERVE: Primary EndpointI-PRESERVE: Primary EndpointDeath or protocol specified CV hospitalizationDeath or protocol specified CV hospitalization
Months from Randomization
Cu
mu
lati
ve I
nci
den
ce o
f P
rim
ary
Eve
nts
(%
)
40 -
0 -
10 -
20 -
30 -
0 6 12 18 24 36 4230 48 6054
2067 1929 1812 1730 1640 1513 12911569 1088 4978162061 1921 1808 1715 1618 1466 12461539 1051 446776
No. at Risk
IrbesartanPlacebo
HR (95% CI) = 0.95 (0.86-1.05)Log-rank p=0.35
Placebo
Irbesartan
Treatment Of Preserved Cardiac function heart failure with an
Aldosterone anTagonist
New drugsNew drugs
New drug trialsNew drug trials Renin inhibitors (ATMOSPHERE: aliskiren Renin inhibitors (ATMOSPHERE: aliskiren
vs 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
Aliskiren 300mg/enalapril 20 mg Daily (n=2,200)
~48 weeks (event driven)4-8 weeks
Enalapril
Randomization
Double-blind
Primary outcome: CV death or heart failure hospitalization(event driven: 2162 patients)
Enalapril +Aliskiren
Open-label run-in
Aliskiren 300 mg once daily (n=2,200)
Enalapril 10 mg twice daily (n=2,200)
CK-1827452: BackgroundCK-1827452: Background
PreclinicalPreclinical Selective activator of cardiac myosinSelective activator of cardiac myosin Prolongs duration of systole byProlongs duration of systole by
• Increasing entry rate of myosin into force-Increasing entry rate of myosin into force-producing stateproducing state
• Therefore overall number of active cross-Therefore overall number of active cross-bridges increasesbridges increases
Increases stroke volumeIncreases stroke volume No change in dP/dtNo change in dP/dtmaxmax
No increase in MVONo increase in MVO22
Istaroxime A New Calcium Cycling
Modulator
ch
myofil
T-tu
bul
e
ATPPLBSR
RyR
I Ca
sarcolemma
Ca2+
Ca2+
Ca2+
Ca2+
ATP
2K
3Na
Na-HX
Na-CaX
H
2Na
3Na Na
H
Na
Ca2+
Ca2+
Ca2+
HCa
Infusion period Post-infusion
HORIZON-HF PCWP
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.
HORIZON-HF ConclusionsHORIZON-HF Conclusions
Relaxin Mechanisms of ActionRelaxin Mechanisms of Action
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
Relaxin Receptor LGR7
CD-NP: A Rationally DesignedCD-NP: A Rationally Designed Natriuretic Peptide Natriuretic Peptide
CNP
SS SS
GG LL SSKK
GGCCFF
GGLLKKLL
DD RR II GGSS
MMSSGG
LLGG
CC
NPR-B agonistVasodilation
CD-NP
G LS
CG
L
G
S
MS
GIRD
L
K
L
G
KG
CF
SS SS
DR
LS
P
PR
PN
AP
ST
SA
- - -+
DNP
SS SS
EEVVKK
YYDD PP
CCFF
GGHHKK
IIDD
RR II NNHH
VVSSNN
LLGG
CC PPSSLL
RRDD
PPRR
PPNN
SSPP
AASS
TTSS
NPR-A agonistRenal function
=
HR predicts outcome HR predicts outcome (placebo group)(placebo group)
Fox K, et al. Lancet. 2008;372:817-821.
SHIFT design paperSHIFT design paper
Composite primary endpoint•Cardiovascular death•Hospitalisation for worsening heart failure
Study designStudy design
www.controlled-trials.com
IvabradineIvabradine5mg bid5mg bid
Matching placebo, bid
Run-in7 to 30 days
D014D014 D028D028ASSEASSE Every 4 monthsEvery 4 monthsD000D000 M004M004
Ivabradine 2.5, 5 or 7.5mg bid according toHR and tolerability
IvabradineIvabradine5mg bid5mg bid
Matching placebo, bid
Run-in7 to 30 days
D014D014 D028D028ASSEASSE Every 4 monthsEvery 4 monthsD000D000 M004M004
Ivabradine 2.5, 5 or 7.5mg bid according toHR and tolerability
6500 pts randomised Results ESC 2010
NYHA II-IV . EF<35% .HF hosp in prior 12 months .HR >70 bpm
ARNi
Angiotensin 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 weeksPrior ACEi/ARB use discontinued
Single-blind periodDouble-blind period
N = 7980 (1:1 randomization)
New trials in acute HFNew trials in acute HF
ASCEND-HF design
completed in 2010# 7000 pts enrolled
2 weeks
Randomization
Placebo
Aliskiren 300 mg
Conventional therapy‡
Aliskiren 150 mg
Acute HFLVEF<40%
BNP >400pg/mLSBP≥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)
THANK YOU !THANK YOU !
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