Speaker s bureau - European Society of Cardiology · 2017-07-12 · Speaker’s bureau: Servier, Bayer, Roche Boehringer Ingelheim ... MDC 1993 CIBIS 1994 US-HF 1996 ANZ 1997 CIBIS-II

Speaker’s bureau: Servier, Bayer, Roche

Boehringer Ingelheim

Research grant: Servier, Boehringer Ingelheim, Novartis, Roche

Advisory Board: Servier, Bayer, Roche Boehringer Ingelheim

Disclosures

Heart failure with

reduced ejection

fraction in 2015

Roberto Ferrari

Introduction

• ESC 2012 guidelines

(GL)

• New findings since 2012

• Still existing challenges,

limitations and barriers

2012 GL: Confirmation

• Diuretics

• A -blocker and an ACE inhibitor

as soon as possible for:

- Better action on remodelling

- More sudden death reduction

• New - caution for blockers in AF

MDC 1993

CIBIS 1994

US-HF 1996

ANZ 1997

CIBIS-II 1999

MERIT-HF 1999

COPERNICUS 2001

CAPRICORN 2001

BEST 2001

CHRISTMAS * 2003

SENIORS 2005

Efficacy of beta-blockers in heart failure patients with atrial fibrillation: An individual patient data meta-analysis

Randomised controlled trials

Reporting mortality as a major trial endpoint

Planned >6m follow-up

>300 patients (accounts for >95% of eligible RCT participants)

Pooling of individual data from 18,254 heart failure patients randomised to beta-blockers or placebo, according to a published extraction and analysis plan.†

* Excluded from sinus rhythm versus AF analysis due to study exclusion criteria Kotecha D et al, Lancet 2014 on line

Unadjusted Kaplan-Meier survival (includes all reported deaths). Hazard ratios (HR) derived from the adjusted one-stage Cox model.

Efficacy of beta-blockers for preventing death

All-cause mortality: Sinus rhythm All-cause mortality: Atrial fibrillation

Kotecha D et al, Lancet 2014 on line

Changes from 2008 GL

Drugs

• An expanded indication for

mineralocorticoid receptor

antagonists (MRAs).

• A new indication for the sinus

node inhibitor Ivabradine.

EMPHASIS

CV Death /HF hospitalisations

Placebo )

Eplerenone

0

10

20

30

40

50

0 1 2 3

Years

HR [95% CI] = 0.63 [ P < 0.0001

N Eng J Med 364;1 January 2011

Eplerenone in mild HF (NYHA II – III) on top of

contemporary treatment

Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY)

0 6 12 18 24 30

Months

40

30

20

10

0

Primary composite endpoint

- 18%

Cumulative frequency (%)

Ivabradine

Placebo

HR = 0.82 [95% CI 0.75-0.90]

p<0.0001

Age <65 years ≥65 years

Sex Male Female

Beta-blockers No Yes

Aetiology of heart failure Non-ischaemic Ischaemic

NYHA class NYHA class II NYHA class III or IV

Diabetes No Yes

Hypertension No Yes

Baseline heart rate <77 bpm ≥77 bpm

Test for interaction

p=0.029

1.5 1.0 0.5 Hazard ratio

Favours ivabradine Favours placebo

Pre-specified subgroups

New: ShIft substudies support Ivabradine in

•In elderly patients

•In patients with COPD

•In patients receiving MRAS

•In patients with renal

dysfunction

•In patients with HF and

diabetes

New: ShIft substudies support Ivabradine in

Devices and procedures

•Expanded indication for

resynchronisation (CRT)

•New role of coronary

revascularisation

•Recognition of the growing

use of assist devices (VADs).

Changes from 2008 GL

CRT indications in 2012

• NYHA class III, ambulatory IV: LBBB QRS ≥120ms, LVEF ≤35% (rec IA)

non-LBBB QRS ≥150ms, LVEF ≤35% (rec IIa A)

• NYHA class II LBBB QRS ≥ 130ms, LVEF ≤30% (rec IA)

non-LBBB ≥ 150ms, LVEF ≤30% (rec IIa A)

New: CRT team to guide

implantation based on • Longitudinal echo

speckle tracking

• Nuclear magnetic

resonance

• A team of electrophysiologists,

clinicians and imaging experts

improves the response

Delaied segments

Necrosis

New data since 2012

•The paradigm trial

•The (disappointing?) role of

stem cell supplementation

•The (important) role of

remote monitoring

Beta blocker

Mineralocorticoid receptor

antagonist

Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction

ACE inhibitor

Angiotensin receptor blocker

Drugs that inhibit the renin-angiotensin system have modest effects on

survival

Based on results of SOLVD-Treatment, CHARM-Alternative,

COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

10%

20%

30%

40%

0%

% D

ec

rea

se

in

Mo

rta

lity

LCZ696


Inhibition of neprilysin

Angiotensin Receptor Neprilysin Inhibition

One Enzyme — Neprilysin — Degrades Many Endogenous Vasoactive Peptides

Endogenous

vasoactive peptides

(natriuretic peptides, adrenomedullin,

bradykinin, substance P,

calcitonin gene-related peptide)

Inactive metabolites

Neprilysin

Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter

Maladaptive Mechanisms in Heart Failure

Endogenous

vasoactive peptides

(natriuretic peptides, adrenomedullin,

bradykinin, substance P,

calcitonin gene-related peptide)

Inactive metabolites

Neurohormonal activation

Vascular tone

Cardiac fibrosis, hypertrophy

Sodium retention

Neprilysin Neprilysin

inhibition

Study Design

R

LCZ696 200 mg BID

Enalapril 10 mg BID

8399 patients randomized for ITT analysis

Enalapril

10 mg BID

LCZ696

100 mg BID

200 mg BID

2 weeks 1-2 weeks 2-4 weeks

Single-blind run-in period Double-blind period

M. Packer and JJV McMurray

PARADIGM-HF

Primary endpoint was cardiovascular death or hospitalization for heart failure, but the sample size of the trial was determined by effect on cardiovascular mortality

The Data Monitoring Committee was allowed to stop the trial only for a compelling effect on cardiovascular mortality (in addition to the primary endpoint)


4187 4212

3922 3883

3663 3579

3018 2922

2257 2123

1544 1488

896 853

249 236

LCZ696 Enalapril

Patients at Risk

PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)

0

16

32

40

24

8

Enalapril (n=4212)

360 720 1080 0 180 540 900 1260 Days After Randomization

1117

Kap

lan

-Mei

er E

stim

ate

of

Cu

mu

lati

ve R

ates

(%

) 914

LCZ696 (n=4187)

HR = 0.80 (0.73-0.87) P = 0.0000002

Number needed to treat = 21

JJV McMurray et al NEJM 2014 online

HR = 0.80 (0.71-0.89) P = 0.00004

Number need to treat = 32

Kap

lan

-Me

ier

Esti

mat

e o

f

Cu

mu

lati

ve R

ate

s (%

)

Days After Randomization

4187 4212

4056 4051

3891 3860

3282 3231

2478 2410

1716 1726

1005 994

280 279

LCZ696 Enalapril

Patients at Risk

360 720 1080 0 180 540 900 1260 0

16

32

24

8

693

558

PARADIGM-HF: Cardiovascular Death

Enalapril (n=4212)

LCZ696 (n=4187)


4187 4212

4056 4051

3891 3860

3282 3231

2478 2410

1716 1726

1005 994

280 279

LCZ696 Enalapril

HR = 0.84 (0.76-0.93) P<0.0001

Kap

lan

-Mei

er E

stim

ate

of

Cu

mu

lati

ve R

ates

(%

)

Days After Randomization Patients at Risk

360 720 1080 0 180 540 900 1260 0

16

32

24

8

835

711

PARADIGM-HF: All-Cause Mortality

Enalapril (n=4212)

LCZ696 (n=4187)


PARADIGM-HF: Summary of safety findings

In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril the LCZ696 was:

Less likely to cause cough, hyperkalemia or renal impairment

Less likely to be discontinued due to an adverse event

More hypotension, but no increase in discontinuations

Not more likely to cause serious angioedema


10%

20%

30%

40%

ACE inhibitor


0%

% D

ecr

eas

e in

Mo

rtal

ity 18%

20%

Effect of ARB vs placebo derived from CHARM-Alternative trial Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial

Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

Angiotensin neprilysin inhibition

15%

LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin-Angiotensin System

New data since 2012





remote monitoring

•High expectancy in HF

•More than 650 post infarct

patients studied with EF in

the 35-60% range

Stem cell supplementation

• Short term safety proved, efficacy limited or transient

• Majority of patients did not have HF, needing little less other than current state of heart care

Stem cell supplementation

Evolution of stem cell studies

2001 First injection

2004 First randomised trial

2006 2 well conducted trial with

contrasting results

2010 Many other studies with small

or no improvement

2012 New momentum

Beltra

mi et. a

l. ,

Cell

114,

763

-776,

2003

SCIPIO (Bolli et al Lancet 2011)

•At CABG right atrial appendage

harvested and endogenous CSC

isolated and expanded

•CSC intra-coronary administered at a

mean of 113 days after surgery with

patients in stable condition

•Number of cells and site of

administration proportional to

size of infarct

Echocardiographic analysis of

CSC-treated patients and controls

A - LVEF at 4 months after baseline

B – EF at 4 months and 12 months after baseline

Bolli R et al Lancet 2011;378:1847-57

CADUCEUS Trial:

cardiospheres preperation

The Lancet , March 2012

CADUCEUS Trial: results

Scar

Viable


But no improvement in cardiac function


Problems

•Which cells?

•Endogenous or resident may

already be damaged

•How many cells? At least 1 billion!

•Where and how?

New data since 2012





remote monitoring

General problems to solve

• Non reproducibility of the trials’ context:

(Ex: issues in disease definitions and

patient clinical profiles)

• Drug target dose (optimal dose) vs target

effect (optimal therapy)

• >60% stent (FDA) and >50% ICD/CRT

devices are implanted of label

Target dose vs target

effect Target dose:

• defined in (dated) trials

• different background treatment

• by selected investigators

• other doses not tested

Target effect:

• evaluated by a marker of individual efficacy and safety

General problems to solve:

GL are not perfect

• Trials, and consequently the Guidelines,

are single disease-oriented

• Over the age of 65 comorbidity is normal

• Lack of prognostic profiles

• Full text is a “guide”

• Pocket format, posters are “prescriptive”

More problems: Barriers

from physicians

• Uniformed

• Unconvinced

• Forgotten

• Influenced by marketing

• Unwilling to accept “compulsory

recommendations”

• Unconvinced of benefit

• Inadequately informed

• Fear of adverse reactions

• Costs

• Other treatment priorities


from patients

• 40-80% of information is immediately

forgotten. Half of the information

recalled is incorrect!

• Both phisicians and patients elaborate

personal mindlines


from patients

• Prevention of HF

• Comorbidities

• Correct use of drugs and devices

• Value of remote monitoring

• HF SA battle to conduct together

It follows that…..there are

still several unmet needs

END

Documents

Speaker s bureau - European Society of Cardiology · 2017-07-12 · Speaker’s bureau: Servier, Bayer, Roche Boehringer Ingelheim ... MDC 1993 CIBIS 1994 US-HF 1996 ANZ 1997 CIBIS-II