Prof. Marco Metra Cardiologia. Università di Brescia Conflitto: Novartis come co-chairman RELAX-AHF-2

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1 Terapia dello scompenso cardiaco cronico: novità in arrivo? Se ho visto più avanti degli altri è stato solo stando sulle spalle dei giganti Isaac Newton Prof. Marco Metra Cardiologia. Università di Brescia Conflitto: Novartis come co-chairman RELAX-AHF-2

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4 Neurohormonal activation in patients with heart failure and LV dysfunction: a substudy of SOLVD Francis et al. Circulation 1990;82:

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7 Neurohormonal activation in patients with heart failure and LV dysfunction: a substudy of SOLVD Francis et al. Circulation 1990;82:

8 Neprilysin a promiscous enzyme breaking down Natriuretic Peptides and Angiotensin II LCZ696 Natriuretic peptides BK, ADM, Subst.P, VIP, CGRP sacubitril Angiotensin II valsartan - - Neprilysin AT 1 receptor Vasodilation Diuresis natriuresis Inhibition of hypertrophy Degradation products Modified from McMurray JJV. Eur J Heart Fail Mar;17(3): Vasoconstriction Sodium-water retention Hypertrophy/ fibrosis

9 Molecular structure of LCZ696 Angiotensin receptor neprilysin inhibitor (ARNI) LCZ696 active ingredient AHU377 pro-drug PLASMA LBQ657 active NEPi Molecular complex of: A highly selective neprilysin inhibitor with low activity on ACE and Aminopeptidase P An ARB - valsartan Upon ingestion of LCZ696: plasma exposure of the NEPi pro-drug AHU 377, the active NEP inhibitor LBQ657 and valsartan O NaO HN O O Valsartan ARB N N N N O O O OH NH Esterase HN O HO O OH O

10 Dual Angiotensin Receptor and Neprilysin inhibition (ARNI) as an alternative to ACE inhibition in patients with chronic systolic HF. Design of the PARADIGM HF Trial McMurray et al. European Journal of Heart Failure; 15:

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12 Kaplan Meier Curves for Key Study Outcomes, According to Study Group McMurray JJV et al. N Engl J Med 2014;371:

13 Effect of LCZ696 compared with enalapril on mode of death in heart failure patients Sudden cardiac death Worsening HF death Akshay S. Desai et al. Eur Heart J 2015;36:

14 McMurray et al. Eur J Heart Fail 2015

15 Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril in chronic heart failure. Effects on clinical progression in surviving patients with HF Time to first HF hospitalization in the first 30 days after discharge Cumulative number of HF hospitalizations per 100 patients Packer et al. Circulation. published online November 17, 2014;

16 Prespecified Subgroup Analyses McMurray JJV et al. N Engl J Med 2014;371:

17 Adverse Events during Randomized Treatment. McMurray JJV et al. N Engl J Med 2014;371:

18 Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction Estimated Glomerular Filtration Rate Voors et al. European Journal of Heart Failure 2015; 17:510-7

19 A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure CV death or HF hospitalization CV death HF hospitalization All-cause death John McMurray et al. Eur Heart J 2015;36:

20 Clinical outcomes according to age. Pardeep S. Jhund et al. Eur Heart J 2015;36:

21 Treatment effect of sacubitril/valsartan by tertile of LV EF for all outcomes Scott D. Solomon et al. Circ Heart Fail. 2016;9:e002744

22 Effect of Angiotensin Receptor Neprilysin Inhibitor on Clinical Outcomes: The MAGGIC Risk Score Category Simpson et al. J Am Coll Cardiol. 2015;66(19):

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25 An increased risk of Alzheimer disease with neprilysin inhibition? Neprilysin inhibition might lead to accumulation of amyloid-beta peptides in the brain (Miners et al. J Neuropathol Exp Neurol 2011;70:944-59) Increases in amyloid beta peptides in cerebrospinal fluid but not in the brain tissue of monkeys (McMurray et al. NEJM 2014; 371:2336) Up to 20 enzymatic pathways involved in the beta amyloid peptides clearance in the brain (Baranello et al. Curr Alzheimer Res 2015; 12:32) No cognition, memory, and dementia-related adverse effects not increased in PARADIGM-HF

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29 Guidelines committees Regulatory authorities Payers Clinical community