Καρδιακή Ανεπάρκεια Κ ΑΡΑΜΗΤΣΟΣ ΘΕΟΔΩΡΟΣ Ε Π Ι Κ Ο Υ Ρ Ο Σ Κ Α Θ Η Γ Η Τ Η Σ Κ Α Ρ Δ Ι Ο Λ Ο Γ Ι Α Σ Α Κ Α Ρ Δ Ι Ο Λ Ο Γ Ι Κ Η Κ Λ Ι Ν Ι Κ Η

Καρδιακή Ανεπάρκεια με ελαττωμένο κλάσμα εξώθησης Κ ΑΡΑΜΗΤΣΟΣ ΘΕΟΔΩΡΟΣ Ε Π Ι Κ Ο Υ Ρ Ο Σ Κ Α Θ Η Γ Η Τ Η Σ Κ Α Ρ Δ Ι Ο Λ Ο Γ Ι Α Σ Α Κ Α Ρ Δ Ι Ο Λ Ο Γ Ι Κ Η Κ Λ Ι Ν Ι Κ Η Ν Ο Σ Ο Κ Ο Μ Ε Ι Ο Α Χ Ε Π Α

Conflicts of Interest Honoraria and Consultancy fees (minor) - ASTRAZENECA - ELPEN - NOVARTIS - SERVIER

What is Heart Failure? HF is a clinical syndrome Symptoms (dyspnea, fatigue, ankle swelling) Signs (peripheral oedema, elevated jugular pressure, crackles) Before symptoms become apparent: Asymptomatic cardiac abnormalities Systolic or diastolic dysfunction

Discharges in thousands Healthcare Burden Epidemiology Improvements in survival following myocardial infarction, an aging population and increasing prevalence of risk factors such as diabetes and hypertension may all contribute to an increasing prevalence of HF 1 700 Men Women 600 500 400 300 200 100 0 1980 1985 1990 1995 2000 2005 2010 Hospital discharges for HF by sex (US: 1980 2010). Note: Hospital discharges include people discharged alive, dead and of unknown status 2 1. Hunt et al. J Am Coll Cardiol 2009;53:e1 90; 2. Go et al. Circulation 2013;127:e6 e245

Survival (%) Survival (%) Survival Rates Have Improved Over Time Epidemiology Temporal trends in 5-year mortality after the diagnosis of HF by gender show improvements in survival 100 Men 100 Women 1996 2000 80 80 1991 1995 1985 1990 60 60 1979 1984 40 40 20 20 0 0 1 2 3 4 5 6 7 8 9 10 0 0 1 2 3 4 5 6 7 8 9 10 Years Years... nevertheless, there remains a high rate of residual 5-year mortality Population-based cohort study analysing data from the Rochester Epidemiology Project, Minnesota, USA. 4,537 patients with a diagnosis of HF between 1979 and 2000 were included. Framingham criteria and clinical criteria were used to validate the diagnosis. Roger et al. JAMA 2004;292:344 50

Ασθενής 48 ετών με ΚΑ Πρόσθιο έμφραγμα 2014 με καθυστερημένη προσέλευση Echo EF 34% NYHA II ΑΠ 128/77mmHg, HR 67bpm Κρεατινίνη 1.0mg/dl, K + = 4.1mEq/L egfr 112 ccs/min

HF is a progressive condition with high morbidity and mortality With each acute event, myocardial injury may contribute to progressive LV dysfunction Increasing frequency of acute events with disease progression leads to high rates of hospitalization and increased risk of mortality Chronic decline Function & quality of life (QoL) Mortality Acute episodes Disease progression Adapted from Gheorghiade et al. 2005 Ahmed et al. Am Heart J 2006;151:444 50; Gheorghiade et al. Am J Cardiol 2005;96:11G 17G Gheorghiade & Pang. J Am Coll Cardiol 2009;53:557 73; Holland et al. J Card Fail 2010;16:150 6 Muntwyler et al. Eur Heart J 2002;23:1861 6

Αίτια Καρδιακής Ανεπάρκειας Ισχαιμική μυοκαρδιοπάθεια (πχ μετά από έμφραγμα μυοκαρδίου) Γενετικές ανωμαλίες (DCM, HCM, ARVC etc) Διηθητικά νοσήματα (αμυλοείδωση, σαρκοείδωση) Αυτοάνοση / Φλεγμονώδης προσβολή (μυοκαρδίτιδα) Τοξικοί παράγοντες (αλκοόλ, φάρμακα) Μεταβολικά νοσήματα (θυρεοειδοπάθεια, ΣΔ, φαιοχρωμοκύτωμα) Υπέρταση Βαλβιδοπάθειες

Κατευθυντήριες 2016 ESC HF Guidelines Οδηγίες and ESC ACC/AHA/HFSA Focused για Καρδιακή Updates Ανεπάρκεια Ponikowski P et al., ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 21 May 2016 Yancy CW et al., ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure, JACC. 21 May 2016 ACC, American College of Cardiology; AHA, American Heart Association; ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blocker, ARNI, angiotensin receptor neprilysin inhibitor; CV, cardiovascular; ESC, European Society of Cardiology; HF, heart failure; HFSA, Heart Failure Society of America; HFrEF, HF with reduced ejection fraction; NYHA, New York Heart Association Ponikowski et al. Eur Heart J. 21 May 2016. doi:10.1093/eurheartj/ehw128 Yancy et al. J Am Coll Cardiol. Published 21 May 2016. doi:10.1016/j.jacc.2016.05.011;

Ponikowski et al. Eur Heart J. 21 May 2016. doi:10.1093/eurheartj/ehw128

Types of Heart Failure Ponikowski et al. Eur Heart J. 21 May 2016. doi:10.1093/eurheartj/ehw128

Βελτίωση της κλινικής τους κατάστασης Βελτίωση της λειτουργικής τους ικανότητας Βελτίωση της ποιότητας ζωής τους Πρόληψη των επαναλαμβανόμενων νοσηλειών Μείωση του κινδύνου θανάτου

Νέος θεραπευτικός αλγόριθμος Τα διουρητικά συστήνονται σε όλα τα βήματα αμεα & β-blockers Μετά MRAs ARNI Ivabradine CRT Ponikowski et al. Eur Heart J. 21 May 2016. doi:10.1093/eurheartj/ehw128

Overactivation of the RAAS and SNS is detrimental in HFrEF and underpins the basis of therapy SNS β-blockers Natriuretic peptide system NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy HFrEF SYMPTOMS & PROGRESSION Epinephrine Norepinephrine RAAS Ang II α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis RAAS inhibitors (ACEI, ARB, MRA) The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs 1 Benefits of β-blockers indicate that the SNS also plays a key role 1 1. McMurray et al. Eur Heart J 2012;33:1787 847 Figure references: Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Kemp & Conte. Cardiovascular Pathology 2012;365 371; Schrier & Abraham. N Engl J Med 1999;341:577 85

Natriuretic peptides are cleared by NPR-C and neprilysin NP signaling and effects NP degradation and clearance RAAS over-activation in HF NPR-A ANP BNP CNP NPR-B ANP BNP CNP NPR-C ANP BNP CNP Neprilysin Inactive cleavage products Ang II AT 1 receptor GTP cgmp GTP Endocytosis Inactivation of NPs Receptor recycling Signaling cascades Vasodilation Cardiac fibrosis/hypertrophy Natriuresis/diuresis Vasoconstriction Cardiac fibrosis/hypertrophy Sodium/water retention Levin et al. N Engl J Med 1998;339;321 8; Gardner et al. Hypertension 2007;49:419 26 ANP=atrial natriuretic peptide; Ang=angiotensin; AT 1 =angiotensin II type 1; BNP=B-type natriuretic peptide; cgmp=cyclic guanosine monophosphate; CNP=C-type natriuretic peptide; GTP=guanosine triphosphate; HF=heart failure; NP=natriuretic peptide; NPR=natriuretic peptide receptor; RAAS=renin-angiotensin-aldosterone system Molkentin. J Clin Invest 2003;111:1275 77; Nishikimi et al. Cardiovasc Res 2006;69:318 28 Guo et al. Cell Res 2001;11:165 80; Von Lueder et al. Circ Heart Fail 2013;6:594 605 Yin et al. Int J Biochem Cell 2003;35:780 3; Mehta and Griendling. Am J Physiol Cell Physiol 2007;292:C82 97; Mangiafico et al. Eur Heart J 2013;34:886 93; Potter. FEBS J 2011;278:1808 17

LCZ696 simultaneously inhibits NEP (via LBQ657) and blocks AT 1 receptors (via valsartan) LCZ696 ANP, BNP, CNP, other vasoactive peptides* RAAS Sacubitril (AHU377; pro-drug) Angiotensinogen (liver secretion) Ang I Inactive fragments LBQ657 (NEP inhibitor) Valsartan Ang II Enhancing Vasorelaxation Blood pressure Sympathetic tone Aldosterone levels Fibrosis Hypertrophy Natriuresis/diuresis HN O HO O OH O O N O OH N N N NH Vasoconstriction AT 1 Receptor Inhibiting Blood pressure Sympathetic tone Aldosterone Fibrosis Hypertrophy *Neprilysin substrates listed in order of relative affinity for NEP: ANP, CNP, Ang II, Ang I, adrenomedullin, substance P, bradykinin, endothelin-1, BNP Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Schrier & Abraham N Engl J Med 1999;341:577 85; Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131 9; Feng et al. Tetrahedron Letters 2012;53:275 6

PARADIGM-HF: study design Randomization (N=8,442 patients with chronic HF [NYHA Class II IV with LVEF 40%*] and elevated NT-proBNP or BNP) Double-blind randomized treatment period Single-blind run-in period LCZ696 200 mg BID Enalapril 10 mg BID** LCZ696 100 mg BID LCZ696 200 mg BID Enalapril 10 mg BID Testing tolerability to target doses of enalapril and LCZ696 On top of standard HF therapy (excluding ACEIs and ARBs) 2 weeks 1 2 weeks 2 4 weeks ~34 months (event-driven) Primary outcome: CV death or HF hospitalization (event driven: 2,410 patients with primary events) *The ejection fraction entry criteria was lowered from 40% to 35% in a protocol amendment on Dec 15,2010; **Enalapril 5 mg BID (10 mg TDD) for 1 2 weeks followed by enalapril 10 mg BID (20 mg TDD) as an optional starting run-in dose for those patients who are treated with ARBs or with a low dose of ACEI; 200 mg TDD; 400 mg TDD; 20 mg TDD. LVEF=left ventricular ejection fraction. There were 2 short washout periods during the run-in periods to minimize the potential risk of angioedema due to overlapping ACE inhibition and NEP inhibition at Visit 3 and Visit 5: (i) enalapril was stopped a day prior to starting LCZ696 at Visit 3 and (ii) LCZ696 was stopped a day prior to starting randomized study drug at Visit 5. McMurray et al. Eur J Heart Fail 2013;15:1062 73

Effect on CV death and HF hospitalisation McMurray et al. N Engl J Med 2014;371:993 1004

Diabetes and Heart Failure In the Framingham study, the relative risk of heart failure in patients with T2DM (age 45 74 years) was 2x for men and 6x in women Independent risk factors for the development of heart failure in T2DM: High HbA1c, increased BMI, advancing age, associated CAD, retinopathy, nephropathy, duration of T2DM.

Diabetes in Heart Failure Checklist Treat heart failure in patients with diabetes the SAME as you would a patient without diabetes METFORMIN recommended if egfr >30 ml/min If egfr <60 ml/min, use RAAS blockade carefully Do NOT use thiazolidinediones guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

Conclusions The incidence of HFREF is increased in patients with diabetes Individuals with diabetes and heart failure should receive the same heart failure therapies as those without diabetes o B-blockers o ACEi or ARNIs o MRAs METFORMIN recommended if egfr >30 ml/min Do NOT use thiazolidinediones