La Terapia Medica della Fase Cronica: dati attuali e prospettive future. Michele Senni Cardiologia 1

Transcription

1 La Terapia Medica della Fase Cronica: dati attuali e prospettive future Michele Senni Cardiologia 1

2 Probability of death in Heart Failure: IN-HF Registry Cumulative one-year mortality rate 27.2% 19.2% 6% in % 9% in % in 1995 Tavazzi L et al. Circ HF 2013 Senni M et al. J Card Fail 2005

3 Heart Failure: a state of neurohumoral imbalance Vasodilator/ natriuretic/ anti-mitotic Mediators ACEi and ARBs Beta-blockers Aldosterone antagonists Natriuretic peptides A paradigm shift : from neurohumoral Vasoconstrictor/ anti-natriuretic /pro-mitotic Mediators inhibition to neurohumoral modulation

4 LCZ696 Mechanism of Action Natriuretic Peptide System Renin Angiotensin System pro-bnp Pre-proBNP HF Angiotensinogen (liver secretion) RAAS NP system Renin BNP, ANP, CNP Angiotensin I Inert NT-pro BNP Angiotensin II Inactive fragments Neprilysin (degrades) Vasodilation blood pressure sympathetic tone aldosterone levels fibrosis hypertrophy Natriuresis/Diuresis X H N O H O O AHU377 LBQ657 O H O O N O OH N N NH N valsartan X AT 1 receptor Vasoconstriction blood pressure sympathetic tone aldosterone fibrosis hypertrophy 4

5 LCZ696: sacubitril valsartan sodium A first in class angiotensin receptor neprilysin inhibitor LCZ696 PLASMA AHU377 pro-drug (t1/2 = 1.1h) LBQ657 drug (t1/2 = 11.1h) First pass esterase LCZ mg oral Dose Valsartan ARB (t1/2 = 11.7h) 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 AT 1 receptor blocker in a 1:1 molar ratio Plasma AHU377 VAL Valsartan AUC equivalent 97 mg 103 mg 160 mg Gu et al. J. Clin. Pharmacol. 2010;50: Feng et al. Tetrahedron Let. 2012;53:

6 PARADIGM-HF Study Design Primary endpoint: CV death or HF hospitalization Randomization (N = 8,399 patients) Single-blind run-in period Double-blind randomized treatment period LCZ mg bid Enalapril 10 mg bid LCZ mg bid LCZ mg bid Testing tolerability to target doses of enalapril and LCZ696* Enalapril 10 mg bid On top of standard heart failure therapy (excluding ACEIs and ARBs) 2 weeks 1-2 weeks 2-4 weeks ~ 21 to 43 months (event-driven)

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12 Primary endpoint Cardiovascular death

13 LCZ696 Enalapril

14 Number PARADIGM-HF: cause/mode of death Paker M, Circ 2014 All causes CV causes Sudden Worsening HF Enalapril LCZ HR p = 0.84 <

15 CV mortality in SOLVD-T, CHARM- Alternative and PARADIGM-HF McMurray J, EHJ 2014 Indirect comparison Hazard Ratio for Mortality SOLVD-T HR: 0.83 (0.73,0.95) p = CHARM-Alt. PARADIGM-HF putative placebo from SOLVD-T from CHARM-Alt. HR: 0.85 (0.71,1.02) p = HR: 0.66 (0.56,0.79) p < HR: 0.68 (0.55,0.84) p < Favours Active Drug Favours Placebo

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17 RANDOMIZED CLINICAL TRIALS in HFrEF (N=38) # VASODILATORS : V-HeFT I, PROFILE, FIRST Drugs reducing mortality # ACE INHIBITORS : CONSENSUS, V-HeFT II, SAVE, SOLVD TREAT/PREV, NETWORK, ATLAS CONSENSUS enalapril 1987 # AII R ANTAGONISTS: ELITE, RESOLVD, ELITE II, VAL-HeFT # Ca ANTAGONISTS : PRAISE, V-HeFT III, MACH-1 RALES spironolactone 1999 # DIGITALIS : CAPTOPRIL-DIGOXIN MRG, CADS, CIBIS-2 bisoprolol RADIANCE, DIG 1999 PARADIGM LCZ # INOTROPES : PROMISE, VEST, PRIME II # AMIODARONE : GESICA, CHF-STAT # BETA-BLOCKERS : XAMOTEROL, MDC, CIBIS I, CIBIS II, PARADIGM first trial proposing a substitution rather than ANZ, US CARVEDILOL, MERIT, BEST an add-on strategy in HFrEF COPERNICUS, patients. CAPRICORN # MISCELLANEOUS : WASH, RALES, MUSTIK, SHIFT, EPHESUS

18 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 collabor ation with the Heart Failure Association (HFA) of the ESC Authors/Task Force Members: John J. V. McMurray (Chairperson) (UK)*, Stamatis Adamopoulos (Greece), Stefan D. Anker (Germany), Angelo Auricchio (Switzerland), Michael Böhm (Germany), Kenneth Dickstein (Norway), Volkmar Falk (Switzerland), Gerasimos Filippatos (Greece), Cândida Fonseca (Portugal), Miguel Angel Gomez Sanchez (Spain), Tiny Jaarsma (Sweden), Lars Køber (Denmark), Gregory Y. H. Lip (UK), Aldo Pietro Maggioni (Italy), Alexander Parkhomenko (Ukraine), Burkert M. Pieske (Austria), Bogdan A. Popescu (Romania), Per K. Rønnevik (Norway), Frans H. Rutten (The Netherlands), Juerg Schwitter (Switzerland), Petar Sefer ovic (Serbia), Janina Stepinska (Poland), Pedro T. Trindade (Switzerland), Adriaan A.Voors(The Netherlands), Faiez Zannad (France), Andreas Zeiher (Germany). ESC Committee for Practice Guidelines (CPG): Jeroen J. Bax (CPG Chairperson) (The Netherlands), Helmut Baumgartner (Ger many), Claudio Ceconi (Italy), Veronica Dean (France), Christi Deaton (UK), Robert Fagard (Belgium), Christian Funck-Br entano (France), David Hasdai (Israel), Arno Hoes (The Netherlands), Paulus Kirchhof (Ger many/uk), Juhani Knuuti (Finland), Philippe Kolh (Belgium), Theresa McDonagh (UK), Cyril Moulin (France), Bogdan A. Popescu (Romania), Željko Reiner (Croatia), Udo Sechtem (Ger many), Per Anton Sirnes (Norway), Michal Tendera (Poland), Adam Torbicki (Poland), Alec Vahanian (France), Stephan W indecker (Switzerland). Document Reviewers: Theresa McDonagh (CPG Co-Review Coordinat or) (UK), Udo Sechtem (CPG Co-Review Coordinator) (Ger many), Luis Almenar Bonet (Spain), Panayiot is Avraamides (Cyprus), Hisham A. Ben Lamin (Libya), Michele Brignole (Italy), Antonio Coca (Spain), Peter Cowburn (UK), Henry Dargie (UK), Perry Elliott (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: , Fax: , 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

19 Risultati: End point primario (morte CV, IM non fatale) Analisi sottogruppi +18% nei pazienti con angina CCS II-IV Fox K. Et al for the SIGNIFY Investigators NEJM 2014

20 Eventi Considerazione sui risultati: Ipotesi Curva J Dosaggio RCP No CYP3A4 Finestra terapeutica FC