Systolic Dysfunction Clinical /Hemodynamic Guide for Management From Neprilysin Inhibitors to Ivabradine

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1 Systolic Dysfunction Clinical /Hemodynamic Guide for Management From Neprilysin Inhibitors to Ivabradine Donna Mancini MD Choudhrie Professor of Cardiology Columbia University

2 Speaker Disclosure Amgen Speakers bureau

3 Heart Failure Management Arnold JMO, Howlett JG, et al. Can J Cardiol 2007;23(1):21-45.

4 % Decrease in Mortality Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction 0% Angiotensin receptor blocker ACE inhibitor Beta blocker Mineralocorticoid receptor antagonist 10% 20% 30% 40% Drugs that inhibit the renin-angiotensin system have modest effects on survival Based on results of SOLVD-Treatment, CHARM-Alternative, COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

5 Are there recent changes in HF therapy?? Drugs 2003 Eplerenone approved for CHF 2005 Bidil approved for self identified black patients 2015 ivabradine (blocks SA node I f channels for reduction of HR CHF pts in NSR w HR>70 W LVEF <35% 2015 Entresto-ARNI (ARB + Neprilysin Inhibitor) Devices HMII (4/08 BTT;1/10DT),HW (6/13 BTT) mitral clip for degenerative MV (10/13) cardiomems (5/14),

6 Drugs Neprilysin Inhibitors Entresto Ivabradine Seralaxin Gene Therapy Serca2-Mydicar Devices LVADs Stem Cells mirnas-antagomirs There is hope for Heart Failure

7 PARADIGM Angiotensin Neprilysin Inhibition versus Enalapril in Heart Failure John J.V. McMurray, M.D., Milton Packer, M.D., Akshay S. Desai, M.D., M.P.H., Jianjian Gong, Ph.D., Martin P. Lefkowitz, M.D., Adel R. Rizkala, Pharm.D., Jean L. Rouleau, M.D., Victor C. Shi, M.D., Scott D. Solomon, M.D., Karl Swedberg, M.D., Ph.D., Michael R. Zile, M.D., for the PARADIGM-HF Investigators and Committees N Engl J Med Volume 371(11): September 11, 2014

8 von Lueder Circulation: Heart Failure. 6(3): , 2013 May. NEP interrupts Alternative AII generating Pathway

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10 Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter Maladaptive Mechanisms in Heart Failure Endogenous vasoactive peptides (natriuretic peptides, adrenomedullin, bradykinin, substance P, calcitonin gene-related peptide) Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention Neprilysin Neprilysin inhibition Inactive metabolites

11 OVERTURE in Class II-IV HF pts Enalopril 10 mg po BID vs Omapatrilat 40 mg daily Omapatrilat inhibited ACE, aminopeptidase P and neprilysin No difference in outcome Hypotension and angioedema (0.5%) more frequent with Omapatriat

12 OVERTURE Time to death or hospitalization in the omapatrilat and enalapril groups. Packer M et al. Circulation. 2002;106:

13 Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) LCZ mg sacubitril mg valsartan BID vs Enalopril 10 mg po BID Inclusion criteria: Class II-IV CHF LVEF <40% BNP >150 or >100 if CHF hospitalization the prior year Exclusion critera: BP < 100 systolic GFR < 30 K>5.2 h/o angioedema Primary endpoint CV mortality and CHF hospitalizations 8442 patients randomized 1:1 to LCZ696 vs enalopril

14 PARADIGM-HF: Study Design Single-blind run-in period Double-blind period LCZ mg BID Enalapril LCZ696 (1:1 randomization) 10 mg BID 100 mg BID 200 mg BID Enalapril 10 mg BID 2 weeks 1-2 weeks 2-4 weeks

15 PARADIGM-HF: Baseline Characteristics LCZ696 (n=4187) Enalapril (n=4212) Age (years) 63.8 ± ± 11.3 Women (%) 21.0% 22.6% Ischemic cardiomyopathy (%) 59.9% 60.1% LV ejection fraction (%) 29.6 ± ± 6.3 NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9% Systolic blood pressure (mm Hg) 122 ± ± 15 Heart rate (beats/min) 72 ± ± 12 N-terminal pro-bnp (pg/ml) 1631 ( ) 1594 ( ) B-type natriuretic peptide (pg/ml) 255 ( ) 251 ( ) History of diabetes 35% 35% Digitalis 29.3% 31.2% Beta-adrenergic blockers 93.1% 92.9% Mineralocorticoid antagonists 54.2% 57.0% ICD and/or CRT 16.5% 16.3%

16 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk LCZ696 Enalapril Days After Randomization HR = 0.80 ( ) P = Number needed to treat =

17 Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: Cardiovascular Death HR = 0.80 ( ) P = Number need to treat = 32 Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk Days After Randomization LCZ696 Enalapril

18 PARADIGM-HF: Effect of LCZ696 vs Enalapril on Primary Endpoint and Its Components LCZ696 (n=4187) Enalapril (n=4212) Hazard Ratio (95% CI) P Value Primary endpoint 914 (21.8%) 1117 (26.5%) 0.80 ( ) Cardiovascular death 558 (13.3%) 693 (16.5%) 0.80 ( ) Hospitalization for heart failure 537 (12.8%) 658 (15.6%) 0.79 ( ) Subgroup AnalysesLCZ696 superior in all subgroups

19 PARADIGM-HF: Adverse Events McMurray JJV et al. N Engl J Med 2014;371: LCZ696 (n=4187) Enalapril (n=4212) P Value Prospectively identified adverse events Symptomatic hypotension < Serum potassium > 6.0 mmol/l Serum creatinine 2.5 mg/dl Cough < Discontinuation for adverse event Discontinuation for hypotension NS Discontinuation for hyperkalemia NS Discontinuation for renal impairment Angioedema (adjudicated) Medications, no hospitalization 16 9 NS Hospitalized; no airway compromise 3 1 NS Airway compromise

20 PARADIGM-HF: Summary of Findings In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril: LCZ696 was more effective than enalapril in... Reducing the risk of CV death and HF hospitalization Reducing the risk of CV death by incremental 20% Reducing the risk of HF hospitalization by incremental 21% Reducing all-cause mortality by incremental 16% Incrementally improving symptoms and physical limitations LCZ696 was better tolerated than enalapril... Less likely to cause cough, hyperkalemia or renal impairment Less likely to be discontinued due to an adverse event More hypotension, but no increase in discontinuations Not more likely to cause serious angioedema

21 Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin-Angiotensin System % Decrease in Mortality 0% Angiotensin receptor blocker ACE inhibitor Angiotensin neprilysin inhibition 10% 15% 18% 20% 30% 20% 40% Effect of ARB vs placebo derived from CHARM-Alternative trial Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

22 Criticisms of study Dose of enalopril may not have been optimal; lower than used in clinical practice; valsartan at maximal dose Run in period of the study Hypotension w ARNI Neprilysin also breaks down beta amyloid which builds up in Alzheimer s; long term effect of this drug is unknown 20% reduction in events is really decrease from 26 to 22 % absolute reduction in endpoints

23 When to Transition from ARB/ACE to ARNI???? Symptomatic on ACE/ARB Asymptomatic but volume overloaded on ACE/ARB with edema, JVD, rales- Consider switching to ARNI rather than increasing diuretic

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26 Corlanor (Ivabradine ) Corlanor is indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic CHF w LVEF < 35% In sinus rhythm with resting HR >70 bpm on maximally tolerated doses of beta blockers or have a contraindication to beta blockers

27 Contraindications to Corlanor Atrial Fibrillation Acute Decompensated HF BP<90/50 SSS, SA block, or CHB unless PM is present Resting HR<60 Severe hepatic impairment Pacemaker dependence

28 Systolic Heart Failure Treatment with the I f Inhibitor Trial (SHIFT) Mortality Morbidity Driven Trial of 6,505 patients w CHF Patients received Corlanor or placebo in addition to Standard of Care medications Dose started at 5 mg BID and titrated up or down to 7.5 mg BID or 2.5 mg BID depending on HR Median F/U 23 months

29 SHIFT Inclusion/Exclusion Criteria Inclusion Sinus Rhythm Stable CHF x 4 wks NYHA Class II-IV LVEF < 35% HR>70 CHF Hospitalization in the preceding year Exclusion MI w/in past 2 mo or scheduled revascularization V Paced> 40% of day Permanent Afib/flutter Severe or Uncontrolled HT

30 Baseline Characteristics Ivabradine group (n=3241) Placebo group (n=3264) Age (years) 60.7 (11.2) 60.1 (11.5) Sex (male) 2462 (76%) 2508 (77%) Heart rate (bpm) 79.7 (9.5) 80.1 (9.8) SBP (mmhg) (16.1) (15.9) LVEF (%) 29 0% (5 1) 29 0% (5 2) NYHA class Class II 1585 (49%) 1584 (49%) Class III 1605 (50%) 1618 (50%) Class IV 50 (2%) 61 (2%)

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32 Benefit derived from decrease in hospitalizations not mortality Swedberg, Lancet 2010; Vol 376; p 875

33 When to Add Ivabradine? At maximum dose of B Blocker but still with a HR >70 bpm In NSR Not totally paced BP >90 systolic

34 Epidemic of Heart Failure in the US 5.2 million cases 650,000 incidence cases/yr 1 million hospital admissions annually Rehospitalization rate of 25% within 1 month; 50% within 6 months 50% of patients diagnosed with heart failure will die in 5 years 300,000 deaths/yr Cost >$40 billion/yr

35 Timeline of Congestion

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37 Trends over days Pressures /sec

38 Champion Trial 550 patients w sensor implants All patients take daily readings Primary Endpoint Rate of HF hospitalizations 270 patients in treatment armhemodynamically guided therapy 280 control arm standard therapy Abraham W,Lancet 2011;377:

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40 Champion 37% reduction in HF hospitalizations over 15 months (p < ) In patients with HFpEF, 60% reduction in HF hospitalization over 15 months (p<0.0004) In patients with HFrEF, similar reductions in HF hospitalization in patients with and without a CRT device

41 There is hope for Heart Failure Drugs Neprilysin Inhibitors Entresto Ivabradine??miRNAs-antagomirs?? Seralaxin Physiologic Monitors Percutaneous Valve repairs LVADs????Stem Cells

42 Telemedicine is here!!! Cellulitis diagnosed in New York on transplant Patient in New Delhi 1/10/16