Professor Michel KOMAJDA Université Pierre & Marie Curie – Hôpital Pitié Salpêtrière Département de Cardiologie Paris (France) Future perspectives in Heart.

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 !