La Terapia Medica della Fase Cronica:

dati attuali e prospettive future

Michele Senni Cardiologia 1

Probability of death in Heart Failure: IN-HF Registry

19.2%

27.2%

5.9%

Cumulative one-year mortality rate

6% in 2008-9

9% in 1999

15% in 1995 Tavazzi L et al. Circ HF 2013

Senni M et al. J Card Fail 2005

↓Vasoconstrictor/

anti-natriuretic

/pro-mitotic

Mediators

↑ Vasodilator/

natriuretic/

anti-mitotic

Mediators

Natriuretic

peptides

ACEi and ARBs

Beta-blockers

Aldosterone

antagonists

Heart Failure: a state of “neurohumoral imbalance”

A “paradigm shift”: from “neurohumoral

inhibition” to “neurohumoral modulation”

LCZ696 – Mechanism of Action

4

Vasodilation

blood pressure

sympathetic tone

aldosterone levels

fibrosis

hypertrophy

Natriuresis/Diuresis

Inactive

fragments

BNP, ANP, CNP

NP system RAAS

pro-BNP

Pre-proBNP

Inert NT-pro BNP

X Neprilysin

(degrades)

Natriuretic Peptide System

AT1 receptor X

Vasoconstriction

blood pressure

sympathetic tone

aldosterone

fibrosis

hypertrophy

Angiotensinogen

(liver secretion)

Angiotensin I

Angiotensin II

Renin

Renin Angiotensin System

NH

N

N

N

N

O

OH

O

O H

O N H

O

O H

O

valsartan AHU377

↓

LBQ657

HF

LCZ696: sacubitril valsartan sodium A first in class angiotensin receptor – neprilysin inhibitor

Gu et al. J. Clin. Pharmacol. 2010;50:401-414 Feng et al. Tetrahedron Let. 2012;53:275-276

LCZ696 PLASMA

First pass esterase

AHU377 pro-drug

(t1/2 = 1.1h)

LBQ657 drug

(t1/2 = 11.1h)

Valsartan ARB

(t1/2 = 11.7h)

Plasma AHU377 VAL Valsartan

AUC equivalent 97 mg 103 mg 160 mg

LCZ696 200 mg oral Dose

LCZ696 is a salt complex that comprises

the two active moieties:2,3

–sacubitril (AHU377) – a pro-drug; further

metabolized to the neprilysin inhibitor

LBQ657, and

–valsartan – an AT1 receptor blocker

in a 1:1 molar ratio

PARADIGM-HF Study Design

2 weeks ~ 21 to 43 months (event-driven)

Randomization

(N = 8,399 patients)

Enalapril 10 mg bid

LCZ696 200 mg bid

LCZ696

200 mg bid

On top of standard heart failure therapy (excluding ACEIs and ARBs)

Primary endpoint: CV death or HF hospitalization

Testing tolerability to target doses of

enalapril and LCZ696*

LCZ696

100 mg bid

Enalapril

10 mg bid‡

1-2 weeks 2-4 weeks

Single-blind run-in period

Double-blind randomized treatment period

|

Primary

endpoint Cardiovascular

death

LCZ696 Enalapril

PARADIGM-HF: cause/mode of death

0.80 0.00004

835

693

311

184

711

558

250

147

0

100

200

300

400

500

600

700

800

900

0.80 0.008

0.79 0.034

0.84 < 0.001

Nu

mb

er

Enalapril

LCZ696

HR p =

All causes CV causes Worsening HF Sudden

0.80 0.00008

Paker M, Circ 2014

CV mortality in SOLVD-T, CHARM-Alternative and PARADIGM-HF

Hazard Ratio

for Mortality

Favours

Active Drug

Favours

Placebo

HR: 0.83 (0.73,0.95) p = 0.008

HR: 0.85 (0.71,1.02) p = 0.072

HR: 0.66 (0.56,0.79) p < 0.0001

0.5 1 2

SOLVD-T

CHARM-Alt.

PARADIGM-HF putative placebo

from SOLVD-T

from CHARM-Alt. HR: 0.68 (0.55,0.84)

p < 0.0001

McMurray J, EHJ 2014

Indirect comparison

# VASODILATORS : V-HeFT I, PROFILE, FIRST

# ACE INHIBITORS : CONSENSUS, V-HeFT II, SAVE, SOLVD TREAT/PREV, NETWORK, ATLAS

# AII R ANTAGONISTS: ELITE, RESOLVD, ELITE II, VAL-HeFT

# Ca ANTAGONISTS : PRAISE, V-HeFT III, MACH-1

# DIGITALIS : CAPTOPRIL-DIGOXIN MRG, CADS, RADIANCE, DIG

# INOTROPES : PROMISE, VEST, PRIME II

# AMIODARONE : GESICA, CHF-STAT

# BETA-BLOCKERS : XAMOTEROL, MDC, CIBIS I, CIBIS II, ANZ, US CARVEDILOL, MERIT, BEST COPERNICUS, CAPRICORN

# MISCELLANEOUS : WASH, RALES, MUSTIK, SHIFT, EPHESUS

RANDOMIZED CLINICAL TRIALS in HFrEF

(N=38) 1988-2014

Drugs reducing mortality

CONSENSUS enalapril 1987

RALES spironolactone 1999

CIBIS-2 bisoprolol 1999

PARADIGM LCZ696 2014

PARADIGM first trial proposing a substitution rather than

an “add-on” strategy in HFrEF patients.

ESC GUIDELINES

ESC Guidelines for the diagnosis and treatment

of acute and chronic heart failure 2012

The Task Force for the Diagnosis and Treatment of Acute and

Chronic Heart Failure 2012 of the European Society of Cardiology.

Developed in collaborat ion with the Heart Failure Associat ion (HFA)

of the ESC

Authors/Task Force Members: John J. V. McMurray (Chairperson) (UK)*,

Stamat is Adamopoulos (Greece), Stefan D. Anker (Germany), Angelo Aur icchio

(Switzer land), Michael Bohm (Germany), Kenneth Dickstein (Norway),

Volkmar Falk (Switzer land), Gerasimos Filippatos (Greece), Candida Fonseca

(Portugal), Miguel Angel Gomez Sanchez (Spain), Tiny Jaarsma (Sweden),

Lars Køber (Denmark), Gregory Y. H. Lip (UK), Aldo Piet ro Maggioni (Italy),

Alexander Parkhomenko (Ukraine), Burker t M. Pieske (Austr ia), Bogdan A. Popescu

(Romania), Per K. Rønnevik (Norway), Frans H. Rut ten (The Nether lands),

Juerg Schwit ter (Switzer land), Petar Seferovic (Serbia), Janina Stepinska (Poland),

Pedro T. Tr indade (Switzer land), Adr iaan A. Voors (The Nether lands), Faiez Zannad

(France), Andreas Zeiher (Germany).

ESC Commit tee for Pract ice Guidel ines (CPG): Jeroen J. Bax (CPG Chairperson) (The Nether lands),

Helmut Baumgartner (Ger many), Claudio Ceconi (Italy), Veronica Dean (France), Chr ist i Deaton (UK),

Robert Fagard (Belgium), Chr ist ian Funck-Brentano (France), David Hasdai (Israel), Arno Hoes (The Nether lands),

Paulus Kirchhof (Germany/UK), Juhani Knuut i (Finland), Philippe Kolh (Belgium), Theresa McDonagh (UK),

Cyr il Moulin (France), Bogdan A. Popescu (Romania), Zeljko Reiner (Croat ia), Udo Sechtem (Germany),

Per Anton Sirnes (Norway), Michal Tendera (Poland), Adam Torbicki (Poland), Alec Vahanian (France),

Stephan W indecker (Switzer land).

Document Reviewers: Theresa McDonagh (CPG Co-Review Coordinat or) (UK), Udo Sechtem (CPG Co-Review

Coordinator) (Germany), Luis Almenar Bonet (Spain), Panayiot is Avraamides (Cyprus), Hisham A. Ben Lamin

(Libya), Michele Br ignole (Italy), Antonio Coca (Spain), Peter Cowburn (UK), Henry Dargie (UK), Perry Elliot t

(UK), Frank Arnold Flachskampf (Sweden), Guido Francesco Guida (Italy), Suzanna Hardman (UK), Bernard Iung

* Correspondingauthor. Chairperson: Professor John J.V. McMurray, University of Glasgow G12 8QQ, UK. Tel: + 44 141 330 3479, Fax: + 44 141 330 6955, Email: john.mcmurray@

glasgow.ac.uk

Other ESC entities having participated in the development of this document:

Associations: European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Association of Echocardiography (EAE), European Heart Rhythm Association

(EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI)

Working Groups: Acute Cardiac Care, Cardiovascular Pharmacology and Drug Therapy, Cardiovascular Surgery, Grown-up Congenital Heart Disease, Hypertension and the Heart,

Myocardial and Pericardial Diseases, Pulmonary Circulation and Right Ventricular Function, Thrombosis, Valvular Heart Disease

Councils: Cardiovascular Imaging, Cardiovascular Nursing and Allied Professions, Cardiology Practice, Cardiovascular Primary Care

The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the

ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of awritten request to Oxford

University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC.

Disclaimer . The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written. Health

professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelinesdo not, however, override the individual responsibility of health

professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient’s

guardian or carer. It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

& The European Society of Cardiology 2012. All rights reserved. For permissions please email: journals.permissions@oxfordjournals.org

European Heart Journal

doi:10.1093/eurheartj/ehs104

Risultati: End point primario

Fox K. Et al for the SIGNIFY Investigators NEJM 2014

Analisi sottogruppi

+18% nei pazienti con angina CCS II-IV

(morte CV, IM non fatale)

Considerazione sui risultati: Ipotesi Curva J

FC

Even

ti

Finestra

terapeutica

Dosaggio RCP

No CYP3A4