Acute Heart Failure: Update Gerasimos Filippatos, MD, FESC, FHFA President HFA

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1 Acute Heart Failure: Update 2015 Gerasimos Filippatos, MD, FESC, FHFA President HFA

2 Disclosures Principal Investigator or Committee member in trials sponsored by Novartis, Bayer, Cardiorentis, Vifor, European Union

3 Outcome in acute HF is still poor DOSE Death, Rehospitalization or ER visit CARRESS-HF 40% at 60 days

4 EURObservational Research Program: The Heart Failure Pilot Survey All-cause death or hospitalization 1892 pts with acute HF& 3226 pts with chronic HF 1-year all cause mortality: acute HF 16.8% chronic HF 6.8% Acute HF: 35.1% Chronic HF: 17.2% Days from enrollment A. Maggioni, U Dahltrom, G, Filippatos et al EJHF2011

5 Management of acute heart failure: why so difficult? Clinical Factors: Underlying causes: multifactorial, precipitating factor often not identified Clinical presentation: spectrum of various conditions, heterogeneous pathophysiology Cardiovascular and non-cardiovascular comorbidities Pathophysiological targets: uncertain End-points selection: not standardized Courtesy of Piotr Ponikowski

6 Terminology (AHF, ADHF, HHF, WHF, WCHF, AHFS.) Filippatos G et al 2015

7 Goals of Treatment in Acute Heart Failure Treat symptoms Restore oxygenation Improve organ perfusion & haemodynamics Limit cardiac/renal damage Prevent thrombo-embolism Minimize ICU length of stay Immediate (ED/ICU/CCU) Stabilise patient and optimise treatment strategy Initiate and up-titrate disease-modifying pharmacological therapy Consider device therapy in appropriate patients Identify aetiology and relevant co-morbidities Intermediate (in-hospital) Plan follow-up strategy Enrol in disease management programme, educate, initiate appropriate lifestyle adjustments Plan to up-titrate/optimize disease-modifying drugs Assess for appropriate device therapy Prevent early readmission Improve symptoms, quality of life and survival Phases in the AHF management Long-term and predischarge management ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012

8 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012

9 Recommendations for the treatment of acute heart failure in HFA ESC 2012 guidelines

10 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Fail Acute Heart Failure in hospital management Pharmacological therapy 1. Acute management Oxygen Diuretics Opiates Vasodilators Nesiritide Inotropes Vasopressors 2. After stabilization ACE inhibitor / ARB Beta-blocker Mineralocorticoid receptor antagonist Digoxin Non-pharmacological therapy 1.Sodium and fluid intake restriction Ventilation non-invasive invasive Mechanical circulatory support IABP VAD Ultrafiltration

11 Important developments Better use of old drugs New Drugs Treatment of co-morbidities

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13 Decompensated chronic HF Consider higher dose of diuretics in renal dysfunction or with chronic diuretic use. ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure

14 Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE) To evaluate the safety and efficacy of various initial strategies of furosemide therapy in patients with ADHF Route of administration: Q12 hours bolus Continuous infusion Dosing Low intensification (1 x oral dose) High intensification (2.5 x oral dose)

15 Diuretic Strategies in Patients with Acute Heart Failure. The DOSE Trial Felker NEJM 2011 JACC 2012

16 Diuretics in Hospitalized Patients I IIa IIb III If patients are already receiving loop diuretic therapy, the initial intravenous dose should equal or exceed their chronic oral daily dose and should be given as either intermittent boluses or continuous infusion.

17 Vasopressin Receptor Antagonists in Different Stages of Development V1a V1b V2 V1a/V2 Lixivaptan Relcovaptan OPC SSR Mozavaptan* Satavaptan Tolvaptan Conivaptan* RWJ RWJ Filippatos G et al. Journal of Cardiac Failure 2008

18 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 I IIa IIb III If symptomatic hypotension is absent, intravenous nitroglycerin, nitroprusside or nesiritide may be considered an adjuvant to diuretic therapy for relief of dyspnea in patients admitted with acutely decompensated HF.

19 Members of the Natriuretic Peptide Family NH 2 COOH- NH 2 Ser Leu Arg Gly Arg Arg Gly Met Ser Phe Asp Ser Cys Arg Cys Gly Asn Gly Ala Ser Leu Phe Gly Ser Gin Arg Tyr Gly Leu Ser Lys Phe Gly Cys COOH- S S S S Cys ANP CNP Gly Leu Lys Leu Asp Arg Gly Gly Ser Leu Met Gly Ser IIe IIe NH 2 NH 2 Ser Pro Lys BNP Met Val Gln Gly Gly Arg Lys Met Ser Phe Asp Gly Cys Arg COOH- S S Cys Lys Gly Val Arg Leu Arg His Leu Gly Ser Urodilatin IIe Ser Ser Ser Pro Arg Ser Ala Leu Arg Thr Gly Arg Arg Gly Met Ser Phe Asp Ser Cys Arg COOH- Ularitide/urodilatin S S IIe Cys Gly Asn Gly Ser Ala Phe Leu Gly Ser Gin Arg Tyr

20 Urodilatin Synthesized in distal tubular cells Binds downstream in IMC duct to NPR-A Increases Renal Plasma Flow (via cgmp) Increases GFR: Dilates Vas afferens Constricts Vas efferens Relaxes mesangials cells Decreases sodium reabsorption in PCT and CD via cgmp dependent phosphorylation of ENaC Inhibits renin, aldosterone, and vasopressin secretion NOT degraded by NEP inhibition mod. Forssmann Cardiovasc Res 2006

21 SIRIUS II: Ularitide Reduces PCWP D PCWP (mmhg) * * * * p<0.01 vs Placebo p<0.05 vs Placebo - 8 * * * * * - 10 * * * - 12 * Time (Hours) Placebo 7.5 ng /kg/min 15 ng /kg/min 30 ng /kg/min Mitrovic Eur Heart J 2006

22 TRUE-AHF TRial of Ularitide's Efficacy and safety in patients with Acute Heart Failure The first-ever acute heart failure (AHF) Phase III trial to be specifically designed to assess the effect of early treatment on cardiovascular mortality as a co-primary endpoint. Study aim efficacy and safety of ularitide on clinical status and mortality in AHF build on the growing body of evidence to treat AHF patients as early as possible

23 Relaxin: Mechanisms of Action Relaxin Receptor LGR7 Found in men and women Increased in pregnancy Vasodilation Upregulation of ETB receptor Preferential dilation of constricted vessels Anti-inflammatory Anti-apoptotic Anti-fibrotic Teichman, SL, et al. Heart Fail Rev 2009 Dschietzig, T, et al. Pharmacol Therap 2006

24 Published online 06.November, 2012 Effect of Serelaxin on Cardiac, Renal and Hepatic Biomarkers in the RELAX-AHF Development Program: Correlation with Outcome Marco Metra, MD; Gad Cotter, MD; Beth A. Davison, PhD; G. Michael Felker, MD, MHS; Gerasimos Filippatos, MD; Barry H. Greenberg, MD; Piotr Ponikowski, MD, PhD; Elaine Unemori, PhD; Adriaan A. Voors, MD, PhD; Kirkwood F. Adams, Jr., MD; Maria Dorobantu, MD; Liliana Grinfeld, MD; Guillaume Jondeau, MD; Alon Marmor, MD; Josep Masip, MD; Peter S. Pang, MD; Karl Werdan, MD; Margaret F. Prescott, PhD; Christopher Edwards; Samuel L. Teichman, MD; Angelo Trapani, PhD; Christopher A. Bush, PhD; Rajnish Saini, MD; Christoph Schumacher, PhD; Thomas Severin, MD; John R. Teerlink, MD; for the RELAXin in Acute Heart Failure (RELAX-AHF) Investigators J Am Coll Cardiol 2013

25 1161 AHF pts, SBP >125 mmhg Serelaxin, recombinant human relaxin 2, 48-hour iv or placebo Early treatment Relaxin in AHF RELAX-AHF Teerlink et al, Lancet 2012

26 2 Endpoint: CV Death or HF/RF Re-hospitalization through Day 60 K-M estimate for time to first CV Death or HF/RF re-hosp (%) Composite event components (%) 14 Serelaxin CV death: (% subjects) HF/RF re-hospitalization (% subjects) 12 HR 1.02 ( 0.74, 1.41) p=0.89 HR=0.7 p=0.23 HR=1.2 p= Placebo Days n=27 n=19 n=50 n=60 p value by log rank test HR estimate by Cox model

27 RELAX-AHF: Cardiovascular and All-Cause Death Teerlink Lancet 2012

28 Relaxin in AHF: pef vs ref RELAX-AHF Placebo, K-M% Serelaxin, K-M% HR (95%CI) p value for interaction CV death or hospitalization for heart/renal failure through Day 60 (secondary endpoint) Overall population (0.74, 1.41) LVEF <50% (0.75, 1.61) LVEF 50% (0.57, 2.06) 0.97 CV death through Day 180 (efficacy endpoint) Overall population (0.41, 0.96) LVEF <50% (0.39, 1.07) LVEF 50% (0.23, 1.50) 0.87 All-cause mortality through Day 180 (safety endpoint) Overall population (0.43, 0.93) LVEF <50% (0.39, 1.00) LVEF 50% (0.32, 1.50) Hazard ratio (vs placebo) Filippatos et al, ESC HFA 2013, Late Breaking Clinical Trials Eur Heart J 2014

29 design overview Primary outcome: CV death or HF hospitalization Randomization at 6 months (381 events) Acute HF LVEF<40% BNP >400pg/mL SBP 110mmHg ~1,800 patients Aliskiren 150 mg Aliskiren 300 mg Placebo Conventional therapy In-hospital 2 weeks ~15 months (event-driven)* entry and Except concomitant use of an ACEI and ARB initiation * Follow-up at Week 2, Month 1, 2 and 3, with on-going assessments every 3 months thereafter

30 Kaplan-Meier estimate of cumulative event rate (%) Primary Endpoint in non-dm Patients CV Death or HF Re-hospitalization Within 6 Months Aliskiren (102/489 patients with events; 20.9%) Placebo (114/464 patients with events; 24.6%) HR: 0.80 (95% CI: ) p = Time in study (days) Number of subjects Aliskiren Placebo Aliskiren n (%) Placebo n (%) HR (95% CI) p-value (two-sided) CV death 42 (8.6) 49 (10.6) 0.73 ( ) 0.14 HF re-hospitalization 74 (15.1) 86 (18.5) 0.77 ( ) 0.10

31 Inotropic Therapies Hasenfuss and Teerlink, EHJ 2011

32 ISTAROXIME Inotropic and lusitropic agent Calcium cycling modulator through the inhibition of Na/K ATPase and activation of SERCA ATPase. Improves systolic and diastolic function without arrhythmias or in MVO 2. (1, 2).J Am Coll Cardiol 2008 AHJ 2009

33 Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator Mechanochemical Cycle of Myosin Omecamtiv mecarbil increases the entry rate of myosin into the tightly-bound, force-producing state with actin More hands pulling on the rope Increases duration of systole Increases stroke volume No increase in myocyte calcium Force production No change in dp/dt max Malik FI, et al. Science 2011; 331: No increase in MVO 2 Teerlink JR, et al. Lancet 2011; 378: ; Cleland JGF, et al. Lancet 2011; 378:

34 Dyspnoea Response Rate (% Responders) Efficacy 41% A Phase 2 Study of Intravenous Omecamtiv Mecarbil, A Novel Cardiac Myosin Activator, In Patients With AHF Pooled Placebo Primary Efficacy Endpoint: Dyspnoea Response (Likert Scale) 42% OM Cohort 1 47% OM Cohort 2 OM did not meet the 1 endpoint of dyspnoea relief Safety Overall SAE profile and tolerability similar to placebo p-value = % OM Cohort 3 Increase in troponin; no clear relationship to OM concentration Teerlink J, et al

35 Non-steroidal MRAs: more selective for cardiac/vascular than renal tissue?

36 ARTS ARTS-HF Safety and efficacy study of BAY in patients with WCHF and left ventricular systolic dysfunction and either type 2 diabetes mellitus with or without CKD or moderate CKD alone ARTS-DN Safety and efficacy study of BAY in patients with type 2 diabetes mellitus and the clinical diagnosis of diabetic nephropathy Primary aim Investigate efficacy [percentage of patients with a relative decrease in NT-proBNP of more than 30% from baseline to visit 8 (day 90±2)] and safety of BAY Secondary aims Analyse the composite endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentations for WCHF until visit 8 (day 90±2) Monitor changes in health-related quality of life as assessed by the KCCQ and EQ-5D-3L Primary aim Investigate change in UACR after treatment with BAY once daily over 90 days versus placebo Secondary aims Investigate the safety and tolerability by assessing effects of different doses of BAY on serum potassium and renal function Analyse changes in health-related quality of life as assessed by the KDQOL-SF and EQ-5D-3L CoChairs: B. Pitt & G Filippatos

37 Conclusions The therapeutic approach to acute HF has not changed much in the last few decades only one drug in the USA and one drug in Europe have been approved in the last 15 years There is a need to identify treatment strategies and regimens that reduce mortality and the incidence of HF rehospitalization in patients postacute HF 1 37

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