HF TREATMENT PROGRESS

Transcription

1 Mortality Digoxin, Diuretics, Hydralazi ne HF TREATMENT PROGRESS SOLVD CONCENSUS -16 to -31 % + ACE-I CIBIS II COPERNICUS -35 % + b- blockers RALES -22 % COMPANION & CARE HF -36 % + Aldostero ne Inhibitors + CRT-ICD Ellenbogen KA, J Am Coll Cardiol 2005; 46:

2 The new Heart Failure Paradox Striking improvements in the prognosis of individual cardiac conditions (ACS, severe hypertension, valvular and congenital heart disease) but growing prevalence of heart failure. Braunwald E. JACC Heart Failure 2013: 1: 1-20

3 US: Discharges from HF hospitalization Braunwald E. JACC Heart Failure 2013: 1: 1-20

4 Laribi S, et al. Eur J Heart Fail 2012;14:234-9

5 IN-HF Outcome 1-year all-cause mortality Worsening HF: 27.7% De Novo HF: 19.2% Chronic HF: 5.9% Days from enrollment Tavazzi L, et al Circ Heart Fail. 2013;6:

6 Evidence-Based Heart Failure RCTs: All Pharmacologic Therapies have Focused on Neurohormonal Blockade HFrEF V-HeFT CONSENSUS SOLVD SAVE RALES CIBIS-2 MERIT-HF COPERNICUS Val-HeFT CHARM EPHESUS SHIFT EMPHASIS ACEis MRAs Beta-Blockers ARB IVABRADINE

7 Ivabradine Overview

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9 Recent Strategies in Heart Failure Therapy Inotropic Diuretic Substituting Hormonal Anti inflammatory Anti neurohormonal?

10 Recent Strategies in Heart Failure Therapy HR lowering CRT Mitra Clip Telemonitoring?

11 Primary composite endpoint Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY) Cumulative frequency (%) HR = 0.82 [95% CI ] p< NNT 1 year = 26-18% 10 Ivabradine Placebo Months

12 Primary composite endpoint according to HR achieved at day 28* Patients with primary composite endpoint (%) bpm 70-<75 bpm 60-<65 bpm 65-<70 bpm <60 bpm Day Months *Data exclude patients reaching primary composite endpoint in the first 28 days

13 LV End Diastolic Volume Index LVEDVI (ml/m 2 ) 100 DD-5.5; p = D -7.9 ml/m 2 D -1.8 ml/m Baseline M 8 Ivabradine (n=204) Baseline M 8 Placebo (n=199) Tardif JC et al. Eur Heart J 2011;32(20):

14 LV End Systolic Volume Index Primary endpoint LVESVI, ml/m 2 75 DD= -5.8; p = D ml/m 2 D ml/m Baseline M 8 Ivabradine (n=208) Baseline M 8 Placebo (n=203) Tardif JC et al. Eur Heart J 2011;32(20):

15 LV Ejection Fraction LVEF (%) ± 29.1 DD= 2.7; p = D = +2.4 % D = % Baseline M 8 Ivabradine (n=204) Baseline M 8 Placebo (n=199) Tardif JC et al. Eur Heart J 2011;32(20):

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21 Heart Rate reduction is a positive inotropic intervention in HF!!

22 Force- Frequency Relationship Human Papillary Muscle Strips NF NYHA IV Frequency (Hz) Böhm M, et al. Clin Invest. 1992;70:

23 Recent Strategies in Heart Failure Therapy Inotropic Diuretic Substituting Hormonal Anti inflammatory Anti neurohormonal?

24 Ivabradine Overview

25 (pg/ml) BNP Levels Class I Class II Class III Class IV

26 Nesiritide

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28 Neprilysin (neutral endopeptidase 24.11; NEP) is responsible for NP degradation Metabolism of ANP and other peptide hormones by NEP NEP is the major enzyme responsible for degrading the NPs (ANP, BNP, CNP) 1,3-5 ANP + NEP enzyme NEP catalyzes the degradation of other vasoactive peptides: vasodilating peptides substance P 6 NPR-C NPR-A Inactive fragments bradykinin 1 Clearance of ANP Guanylate cyclase GTP cgmp Diuresis Natriuresis Vasodilation Antiproliferative/ antihypertrophic 28

29 Neprilysin (neutral endopeptidase 24.11; NEP) is responsible for NP degradation Metabolism of ANP and other peptide hormones by NEP 1,2,8,9 ProEndothelin + + Endothelin (ET1) Inactive fragments NEP is the major enzyme responsible for degrading the NPs (ANP, BNP, CNP) 1,3-5 NPR-C Clearance of ANP GTP ANP + NPR-A Guanylate cyclase Inactive fragments cgmp NEP enzyme Ang II Substance P Bradykinin Adrenomedullin Diuresis Natriuresis Vasodilation Antiproliferative/ antihypertrophic + NEP catalyzes the degradation of other vasoactive peptides: vasodilating peptides substance P 6 bradykinin 1 vasoconstrictor peptides ET-1 7 Ang II 1 NEP converts big ET-1 to the active vasoconstrictor peptide ET Erdos, Skidgel. FASEB J 1989;3:145 51; 2. Levin et al. N Engl J Med 1998;339;321 8; 3. Stephenson et al. Biochem J 1987;243:183 7; 4. Lang et al. Clin Sci 1992;82:619 23; 5. Kenny et al. Biochem J 1993;291:83 8; 6. Skidgel et al. Peptides 1984;5: Abassi et al. Metabolism 1992;41:683 5; 8. Murphy et al. Br J Pharmacol 1994;113: Jiang et al. Hypertens Res 2004;27:109 17

30 Neprilysin inhibition enhances the effects of NPs Metabolism of ANP and other peptide hormones by NEP NPR-C Clearance of ANP GTP ProEndothelin ANP NPR-A Guanylate cyclase Inactive fragments cgmp Endothelin (ET1) NEP enzyme Inactive fragments Ang II Substance P Bradykinin Adrenomedullin Diuresis Natriuresis Vasodilation Antiproliferative/ antihypertrophic 1. Erdos, Skidgel. FASEB J 1989;3:145 51; 2. Levin et al. N Engl J Med 1998;339;321 8; 3. Murphy et al. Br J Pharmacol 1994;113:137 42; 4. Jiang et al. Hypertens Res 2004;27:109 17; 5. Ferro et al. Circulation 1998;97: ; 6. Martinez-Rumayor et al. Am J Cardiol 2008;101[suppl]:3A-8A; 7. Richards et al. J Hypertens 1993;11: Neprilysin (NEP) is the major enzyme responsible for degrading NPs 5 BNP, not NT-proBNP, is a NEP substrate 6 Inhibition of NEP enhances the effects of NPs 7 Studies suggest the potential effects of NEP inhibitors may be offset by an increase in Ang II levels 2,5,7

31 Neprilysin has many substrates that are metabolized with differing levels of affinity Metabolism of natriuretic and other vasoactive peptides* by NEP 1 9 Implications for NEP inhibition Relative affinity for NEP ANP and CNP Ang II Ang I NEP substrates can have opposing biological actions 10 Overall effect is dependent upon the net effect on NEP metabolism of individual substrates 10 Adrenomedullin Substance P Bradykinin Endothelin NEP Inactive fragments or metabolites Benefits in enhancing NP system may be offset by increased Ang II 11 Needs to be complemented by simultaneous RAAS suppression 2,11,12 BNP *Not an exhaustive list of all neprilysin substrates; the most relevant substrates for cardiovascular physiology are listed Ang=angiotensin; ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; CNP=C-type natriuretic peptide; NEP=neprilysin; NP=natriuretic peptide; RAAS=renin angiotensin aldosterone system 1. Erdos, Skidgel. FASEB J 1989;3:145 51; 2. Levin et al. N Engl J Med 1998;339;321 8; 3. Stephenson et al. Biochem J 1987;243:183 7; 4. Lang et al. Clin Sci 1992;82:619 23; 5. Kenny et al. Biochem J 1993;291:83 8; 6. Skidgel et al. Peptides 1984;5:769 76; 7. Abassi et al. Metabolism 1992;41:683 5; 8. Murphy et al. Br J Pharmacol 1994;113:137 42; 9. Jiang et al. Hypertens Res 2004;27:109 17; 10. Langenickel & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131 9; 11. Richards et al. J Hypertens 1993;11:407 16; 12. Ferro et al. Circulation 1998;97:

32 OMAPATRILAT

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34 Packer M et al, Circulation 2002;106:920.26

35 In OCTAVE ( hypertensive ) angioedema was more frequent with omapatrilat than enalapril (2.17% v 0.68%).

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37 LCZ696 First in Class Dual-acting Angiotensin Receptor Neprilysin Inhibitor LCZ696 is a crystalline complex comprised of 6 valsartan moieties, 6 sacubitril (AHU377) moieties, sodium cations, and water held together by network of hydrogen bonds Sacubitril Valsartan in LCZ696 is present in anionic form, and is thus more biovailable than in valsartan as a free acid. 200 mg of LCZ696 is equivalent to 160 mg of standard valsartan Valsartan

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39 BNP is formed by cleavage of precursor molecules 1 6 Pre-proBNP probnp (aa1-aa108) NP effects include 7,8 : Wall stress NT-proBNP (aa1-aa76) Cleavage DPP-IV BNP 1 32 (aa77-aa108) Meprin A vasodilation blood pressure sympathetic tone aldosterone levels natriuresis diuresis fibrosis hypertrophy NPs are degraded by NEP. 9 Therefore, NP effects can be enhanced by inhibiting NEP BNP 3 32 BNP Martinez-Rumayor et al. Am J Cardiol 2008;101[suppl]:3A 8A; 2. Daniels, Maisel. J Am Coll Cardiol 2007:50: ; 3. Melanson, Lewandrowski. Am J Clin Pathol 2005;124:S122 8; 4. Ichiki, Burnett. Circulation 2010;122:229 32; 5. De Palo et al. Clin Chem 2000;46:843 7; 6. Ruskoaho. Endocrine Rev 2003;24:341 56; 7. Levin et al. N Engl J Med 1998;339;321 8; 8. Nathisuwan, Talbert. Pharmacotherapy 2002;22:27 42; 9. Erdos, Skidgel. FASEB J 1989;3:145 51

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41 PARADIGM-HF tre first time For the first time after many years a new drug reduces mortality in HF For the first time an hormonal substituting drug appears clinically effective For the first time a trial does not add a new drug on top of the list but substitutes one of the standard molecules

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43 PARADIGM-HF: Baseline characteristics Baseline characteristic SOLVD-T N=2569 CHARM- Added N=2548 HEAAL a N=3834 RAFT N=17 98 SHIFT N=650 5 EMPHASIS -HF N=2737 PARADIGM -HF N=8442 Mean age, years Women, % NYHA class, % I II III IV Race, % White Black Asian Other Mean heart rate, bpm Mean blood pressure, mmhg Systolic Diastolic Mean LVEF, % Mean QRS duration, ms Mean BMI, kg/m Ischemic etiology, % a Median; McMurray et al. Eur J Heart Fail. 2014;16:

44 The PARADIGM patients on Enalapril 1-yr CV mortality 8% 1-yr CV death or hospitalization 15%

45 PARADIGM-HF: Patient disposition 10,513 patients entered enalapril run-in phase (median duration, 15 days; interquartile range [IQR], 14 21) 9419 entered LCZ696 run-in phase (median duration, 29 days; IQR, 26 35) 8442 underwent randomization 1102 discontinued study: 591 (5.6%) had adverse event 66 (0.6%) had abnormal laboratory or other test result 171 (1.6%) withdrew consent 138 (1.3%) had protocol deviation, administrative problem or were lost to follow-up 49 (0.5%) died 87 (0.8%) had other reasons 977 discontinued study: 547 (5.8%) had adverse event 58 (0.6%) had abnormal laboratory or other test result 100 (1.1%) withdrew consent 146 (1.6%) had protocol deviation, had administrative problem, or were lost to follow-up 47 (0.5%) died 79 (0.8%) had other reasons 43 were excluded: 6 did not undergo valid randomization 37 were from four sites prematurely closed because of major Good Clinical Practice violations 4187 were assigned to receive LCZ had known final vital status 11 had unknown final vital status 4212 were assigned to receive enalapril 4203 had known final vital status 9 had unknown final vital status McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

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52 Early Benefit of LCZ Months after Randomization Enalapril LCZ696

53 PARADIGM-HF: Absolute benefits Switching 1000 patients from an ACE inhibitor/arb to LCZ696 avoided: 47 primary endpoints 31 cardiovascular deaths 28 patients hospitalized for HF 37 patients hospitalized for any reason 53 admissions for HF 111 admissions for any reason over a median treatment period of 27 months Adapted from Packer M. et al., Circulation 2015

54 PARADIGM-HF a un anno dalla pubblicazione Nuovi risultati Timori Dati meccanicistici Riflessione sulla collocazione terapeutica

55 Alcuni timori PARADIGM-HF angioedema rischio competitivo fra mortalità e riospedalizzazione eccessiva preselezione nel run-in albuminuria e funzione renale Amyloid β Neoplasie mammarie e prostatiche

56 Event-free survival gain 1.3 yrs

57 Geometric Mean (nmol/l) Geometric Mean (pmol/l) Effect of LCZ696 vs Enalapril on Downstream Biomarkers cgmp Aldosterone Renin Period Enalapril Renin LCZ696 Renin Randomization Week Week 3 Week 4 Months 3 Week Week 3 Week 4 Months 3 Enalapril LCZ696

58 NT-proBNP pg/ml BNP pg/ml PARADIGM-HF: NT-proBNP and BNP NT-proBNP BNP Enalapril LCZ696 Months Adapted from Packer M. et al., Circulation 2015

59 Gori M et al, on behalf of the PARADIGM-HF Investigators ESC 2015

60 Gori M et al, on behalf of the PARADIGM-HF Investigators ESC 2015

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62 PARADIGM-HF: Study design Single-blind active run-in period Randomization n=8442 Double-blind Treatment period Enalapril LCZ mg BID LCZ mg BID LCZ mg BID 10 mg BID* Enalapril 10 mg BID 2 Weeks 1 2 Weeks 2 4 Weeks ~34 months (event-driven) On top of standard HFrEF therapy (excluding ACEIs and ARBs) *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. McMurray et al. Eur J Heart Fail. 2013;15: ; McMurray et al. Eur J Heart Fail. 2014;16:

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64 PARADIGM-HF may well represent a new threshold of hope for patients with HF Now, a novel drug, LCZ696, a dual inhibitor of angiotensin II receptor and neprilysin, may prove to be the first disruptive agent to the heart-failure treatment algorithm, which has remained essentially unchanged for a decade The beneficial results seen in PARADIGM-HF may apply to a wide spectrum of patients, even those who are currently receiving the best possible therapy Necessità di sorveglianza post marketing su effetti collaterali specifici Opportunità di trial dedicati allo scompenso cardiaco con FE preservata Jessup. N Engl J Med 2014; epub ahead of print: DOI: /NEJMe

65 Chronic Heart Failure Drug Therapy Diuretics, Ivabradine, Digitalis (ARB) ACE-I Nebivolol Carvedilol Bisoprolol Metoprolol Eplerenone Spirolonac.

66 Chronic Heart Failure Drug Therapy Diuretics, Ivabradine, Digitalis? LCZ 696 (ARNI) (ARB) ACE-I Nebivolol Carvedilol Bisoprolol Metoprolol Eplerenone Spirolonac.

67 Ivabradine Overview

68 PARADIGM PARAMETER PARAGON

69 The most stable PARADIGM patients 20 % of the most stable patients (no prior HF hospitalization) had a primary event 17 % died during the course of the trial In the most stable patients with a primary events, death occurred prior to a heart failure hospitalization in 51 % 60 % of these deaths were sudden cardiac deaths

70 FACTORS Associated with Noncompletion During the Run-in Period Prior to Randomization and the Efficacy of LCZ696 in the PARADIGM-HF Trial Desai A.S. et al., ESC 2015 Multivariable Predictors of Noncompletion Impact of LCZ696 vs. Enalapril on Clinical Outcomes, with IPW According to likelihood of randomization

71 Mortality HF TREATMENT PROGRESS Digoxin, Diuretics, Hydralaz ine SOLVD CONCENSUS -16 to -31 % CIBIS II COPERNICUS -35 % RALES -22 % + ACE-I + b- blockers + Aldostero ne Inhibitors COMPANION & CARE HF -36 % + CRT-ICD