Aldosterone Antagonist. Hyd/ISDN*

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1 Μedical management of heart failure: Update 2014 Dr John T Parissis Attikon University Hospital Athens, Greece Disclosures: Received honoraria as consultant or research grants by Orion- Pharma, Servier, Pfizer

2 Evidence-Based Treatment for Heart Failure with Reduced LVEF Reduce Mortality Control Volume ACEI or ARB β-blocker ivabradine Aldosterone Antagonist Sodium Restriction* Diuretics* ICD* CRT ± an ICD* Hyd/ISDN* Treat Residual Symptoms Digoxin* *For select indicated patients. Enhance Adherence Education Disease Management Performance Improvement Systems Treat Comorbidities Aspirin* Warfarin* Statin* 18

3 ESC 2012

4 Adherence to HF guidelines predicts HF hospitalizations 1.0 Hospitalization free survival High (100%) Moderate (50-67%) Low (0-33%) Log rank test p = days Komajda M et al. Eur Heart J 2005.

5 Heart Failure Guidelines and Clinical Practice (Please mind the gap)

6 Overall, only 25% of patients are discharged from hospital receiving ACE/ARB + BB + diuretic oral combination therapy, suggesting poor compliance with guidelines (ALARM REGISTRY) Oral heart failure medications on discharge All patients receiving BB + ACE and/or ARB + DIUR Mexico 5% 16% 16% 20% 20% 25% 19% 31% 38% 60% Brazil Australia Turkey Greece UK Spain Italy Germany 0% 10% 20% 30% 40% 50% 60% 70% France Sample =All discharged/surviving AHF patients, 4491 Follath F, Yilmaz B, Parissis J, et al. Intensive Care Med 2011 Sept;38(1):

7 Maggioni A P et al. Eur J Heart Fail 2010;12:

8 Impact of Discharge Use of Beta Blocker on Early Clinical Outcomes in Heart Failure Probability Survival day Survival P<0.01 P= Beta-Blocker No Beta-Blocker Patients at Risk Days After Hospital Discharge Beta-blocker 1,946 1,855 1, No Beta-blocker *Only subset of patients with 60- to 90-day follow-up are included. Patients with beta-blocker contraindications are excluded. Fonarow et al. J Am Coll Cardiol. 2008;52:

9 ESC HF LONG TERM REGISTRY

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11 Patient education and support reduces HF hospitalization rates and cost Krumholz et al. J Am Coll Cardiol 2002;39:83 9

12 A Maisel JACC 2013

13 Primary Results of the HABIT Trial (Heart Failure Assessment With BNP in the Home) Maisel et al. J Am Coll Cardiol 2013;61:

14 ESC guidelines 2012

15 Conventional Treatments of Acute Heart Failure Diuretics Vasodilators Inotropes Reduce fluid volume Decrease preload and/or afterload Augment contractility Fonarow GC. Rev Cardiovasc Med. 2001;2(suppl 2):S7 S12.

16 Impact of high vs low dose of diuretics on short term mortality of AHF patients using propensity matched scores Whole cohort of ALARM Patients with EF<40% A. Mebazaa and J. Parissis on behalf of ALARM investigators EJHF 2012

17 Role of Congestion and Its Interaction With Renal Function in Advanced HF Metra M et al. Circ Heart Fail 2012

18 Short-term Survival by Treatment Among Patients Hospitalized with Acute Heart Failure: The Global ALARM-HF Registry Using Propensity Scoring Methods 0.4 tal mortality In-hospit Inotropes Whole cohort Diuretics Vasodilators Days Mebazaa A, Parissis J, Porcher R, et al. Intensive Care Med 2011 Feb;37(2):

19 Available inotropic agents Dobutamine: cl IIa, Level evidence C PDEIs: cl III, Level evidence B Dopamine: cl IIb, Level evidence C Levosimendan: cl IIb,Level evidence C for patients on beta-blocker ESC Guidelines 2012.

20 Classical therapies are insufficient to protect peripheral organs ESC HF pilot, ALARM-HF, ADHERE, SURVIVE demonstrated: Worsening of renal function (30-45%) Hepatic dysfunction (20-30%) Ongoing myocardial injury (Tn release) (30%) Hyponatremia, CNS abnormalities ( 12-20%)

21 Investigational pharmacotherapies for the management of ADHF INOTROPES - Myocin activators - SERCA enhancers and Na/K-ATPase inhibitors - Ryanodine receptor stabilizers METABOLIC MODULATORS - CPT-1 inhibitors DIURETICS - Adenosine antagonists - Vasopressin antagonists - Natriuretic peptides (ularitide) VASODILATORS - Relaxin DeComa et al. JACC 2006;48:2397

22 The challenge of cardiac myocin activation - Target the force generating enzyme cardiac myosin ATPase, accelerating its activity. - Increase fractional shortening of cardiac myocytes without altering intracellular calcium levels in experimental models. - An IV formulation of CK is currently in phase I clinical development. Malic et al. AHA Scientific Sessions 2005 Dallas TX

23 HFSA 2006

24 Circ Heart Fail 2010;3:

25 Istaroxime: a Na/K-ATPase inhibitor with positive lusitropic properties Adamson et al. J Cardiovasc Pharmacol 2003;42:169 Sabbah et al. Am J Cardiol 2007;99:41A

26 Changes in hemodynamic and other measures in the HORIZON-HF trial, three dosages of IV istaroxime vs placebo Parameter 0.5, n=29 µg/kg/min 1.0, n=30 1.5, n=30 Placebo, n=31 PCWP a (mm Hg) -3.2 b -3.3 c -4.7 d 0.0 Systolic BP (mm Hg) b d +1.3 MAP (mm Hg) c +0.9 LVEDV (ml) b +3.9 QTc (ms) e e e -2.4 a. Primary end point b. p<0.05 c. p<0.01 d. p<0.001 e. p= PCWP=pulmonary capillary wedge pressure MAP=mean arterial pressure LVEDV=left ventricular end-diastolic volume; QTc=corrected QT interval Gheorghiade M et al. J Am Coll Cardiol 2008; 51:

27 Treatment of SR Ca 2+ leak in HF with ryanodine receptor stabilizers Masafumi Yano et al.circulation. 2003;107:

28 CURRENT VASOPRESSIN ANTAGONISTS G. Filippatos and J. Parissis, J Card Fail 2008;14:

29 Vasopressin Antagonist for Heart Failure: ACTIV in CHF Trial Percent (%) 60-Day All-cause Mortality Placebo Tolvaptan P< P < N = (20%) (22%) (37%) (46%) (51%) (68%) Overall Hyponatremia (Na+ <136 meq/l) BUN (> 29 mg/dl) Congestion* Gheorghiade M. JAMA. 2004;291: * Edema, Dyspnea, and JVD at baseline

30 Kaplan-Meier analysis of all-cause mortality in the EVEREST trial 1 Proportio on Surviving 0,8 0,6 0,4 Log-Rank Test: P=.76 Tolvaptan Placebo 0, Months in Study Konstam et al. JAMA 2007;297:

31 Effects of adenosine antagonists on GFR and diuresis in ADHF Gottlieb et al. Circulation 2002;105:1348

32 Primary Endpoint (PROTECT) Odds ratio (95% CI) vs Pbo: 0.92 (0.78, 1.09) 100 Percent of Patients Placebo Ro 30 mg Treatment Success Patient Unchanged Treatment Failure p=0.348 for comparison of distribution using the van Elteren extension of Wilcoxon test

33 Time to Death or CV or Renal Rehospitalization - Day Cumulative Risk Hazard Ratio (95% CI) = 0.98 (0.83, 1.17) P-value = Placebo Rolofylline 30 mg Study Day Death: Placebo 9.5% vs rolofylline 8.9% Re-hospitalization: Placebo 25.6% vs rolofylline 25.7%

34 New natriuretic peptides: ularitide In 1988, Urodilatin, a renally synthesized isoform of ANP was isolated from human urine. Both experimental and early clinical trials demonstrated therapeutic effects of urodilatin (diuresis, natriuresis, vasodilation, reduction of PCWP) to a greater extent than ANP. In SIRIUS I (n=24 pts) and II (n=221pts) ularitide caused a greater improvement of CI and reduction of SVR and NT-proBNP than placebo persisting at 24 hours (neutral effect on 30-day mortality and renal function). Ularitide at 30 ng/kg/min caused SBP reduction/ hypotension in 16% of pts. (SBP< 80 mm Hg in 10.9% of pts) Mitrovic et al. Am Heart J 2005;150:1239 Mitrovic et al. Eur Heart J 2006; 27:2823

35 Beneficial effects of ularitide on clinical status of decompensated HF patients: SIRIUS II The Ularitide Global Evaluation in Acute Decompensated Heart Failure (URGENT), a phase 3, randomized, double-blind, placebo-controlled study of ularitide in the treatment of patients with AHFS is expected to begin soon. Mitrovic, V. et al. Eur Heart J : ; doi: /eurheartj/ehl337

36 Relaxin Mechanisms of Action Relaxin Vasodilation NO, cgmp effectors Induction of NOS II/III Upregulation of endothelial endothelin type B receptor, which mediates vasodilation Preferential dilation of constricted vessels Relaxin-upregulated ET B receptors act as vasodilating ET-1 sink Anti-inflammatory Down-modulation of inflammatory cytokines linked to outcome in HF (TNF-α, TGF-β) Other: Anti-ischemic, Anti-apoptotic, Antifibrotic Teichman, SL, et al. Heart Fail Rev 2009; Dschietzig, T, et al. Pharmacol Therap 2006

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38 RELAX-AHF Effect of serelaxin on AHF symptoms Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects Inclusion criteria (1161pts) dyspnoea congestion on Rx Increased BNP/NT-proBNP GFR: 30-75ml/min Systolic BP>125 mm Hg. 48-h i.v. serelaxin or placebo (30 μg/kg per day) within 16 h from presentation Teerlink et al. Lancet 2013;381:29-39

39 RELAX-AHF Effect of serelaxin on 180d mortality Teerlink et al. Lancet 2013;381:29-39

40 Effect of Serelaxin on Cardiac, Renal, and Hepatic Biomarkers in RELAX-AHF J Am Coll Cardiol 2013;61: )

41 Serelaxin in AHF patients with preserved LVEF: RELAX-AHF sub-analysis Filippatos et al Eur Heart J 2013 November 12

42 Etiology of Anemia in Patients With Advanced Heart Failure 37 advanced CHF pts; NYHA IV; mean LVEF: 22%. Nanas J,, Anastasiou-Nana M. J Am Coll Cardiol 2006;48:2485 9

43 Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency (Anker S, Colet C, Filippatos G, et al. NEJM 2009)

44 CONCLUSION Patient education and further implementation of treatment guidelines are essential approaches to improve outcomes in HF. There are still no Class I effective therapies in AHF in comparison to CHF. Investigational drugs targeting to novel pathophysiologic concepts are promising treatment approaches and ongoing trials will define their clinical efficacy and safety.