Learning Objectives. Heart Failure (HF): Scope of the Problem. Temporal Trends in Age-Adjusted Survival After HF Diagnosis

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1 7:5 :5 am Update in Heart Failure SPEAKER Orly Vardeny, PharmD, MS Presenter Disclosure Information The following relationships exist related to this presentation: Orly Vardeny, PharmD, MS: Advisory Board for Novartis Pharmaceuticals Corporation. Contracted Research for Novartis Pharmaceuticals Corporation. Speaker s Bureau for Novartis Pharmaceuticals. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Learning Objectives 1. Review the pathophysiologic basis of HF therapy. Discuss the data supporting current HF management 3. Evaluate the newer approved HF therapies, including angiotensin receptor neprilysin inhibitor and heart rate reducing therapies Patients in US (millions) Heart Failure (HF): Scope of the Problem US prevalence*: 5. million US annual incidence: 7, Annual mortality:,75 5-1% depending on severity Cost: $39. billion 53% of cost due to hospitalization % HF increases with age 5 s s 7 s > AHA Statistical Update. Circulation. 1;11:e-e. Croft JB et al. J Am Geriatr Soc. 1997;5:7 75. Rich M. J Am Geriatric Soc. 1997;5:9 97. Hospital discharges for heart failure by sex in United States: 19 1 and Projected Temporal Trends in Age-Adjusted Survival After HF Diagnosis Go A S et al. Circulation. 13;17:e-e5 Heidenreich P, et al. Circ Heart Fail 13. Men Women Levy D, et al. N Engl J Med. ;37:

2 More malignant than cancer Projected Costs of Heart Failure Care Women Men % of costs related to hospitalization Heidenreich P, et al. Circ Heart Fail. 13. Heart Failure Definition Heart Failure Symptoms Pathophysiology: The inability to provide adequate cardiac output to the body at rest or with exertion, or to do so only in the setting of elevated cardiac filling pressures. -E. Braunwald modified by B. Borlaug and M. Redfield Clinically: A clinical syndrome characterized by breathlessness, fatigue and edema caused by an abnormality of the heart Dyspnea Orthopnea Number of pillows Cough GI Effects Nausea, early satiety Fatigue Reduced perfusion to skeletal muscles Peripheral edema CNS effects Confusion, hallucinations Extremity effects Cool extremities Urinary effects Polyuria, nocturia Heart Failure with Preserved Ejection Fraction (HFpEF) accounts for up to Half of Heart Failure OPTIMIZE-HF Registry, N=1,7 HFrEF HFpEF Fonarow G et al. JACC. 7; 5: % Similar Signs and Symptoms in Patients with HFpEF and HFrEF Edema PND Rest dyspnea HFrEF HFpEF S 3 Crackles JVP > cm Orthopnea Cardiomegaly CHARM Investigators

3 Chlorothiazide induced diuresis in a patient with CHF Treatment of Heart Failure Empiric and Evidence-Based Neurohormonal Activation in Heart Failure Pathophysiology Plasma Plasma Renin Norepinephrine Activity (pg/ml) (ng/ml/h) 1 Arginine Vasopressin (pg/ml) Atrial Natriuretic Peptide (pg/ml) 3 Endothelin-1 (pg/ml) Myocardial injury Left ventricular systolic dysfunction Levels NL HF NL HF NL HF NL HF NL HF Adapted from Cohn JN. Cardiology. 1997;(suppl ): Systemic vasoconstriction Renal sodium and water retention Perceived reduction in circulating volume and pressure Neurohumoral activation SNS RAAS ET, AVP etc ( Natriuretic peptides) Effect of ACE inhibition in patients with CHF HFSA 1 Practice Guideline ACE Inhibitors Mortality, % CONSENSUS* NYHA Class IV (n = 1) (n = 1) SOLVD Treatment NYHA Class II III (n = 1) (n = ) Generic Name Trade Name Initial Daily Dose Target Dose Mean Dose in Clinical Trials Captopril Capoten.5 mg tid 5 mg tid 1.7 mg/day Vasotec.5 mg bid 1 mg bid 1. mg/day Fosinopril Monopril 5-1 mg qd mg qd N/A Lisinopril Zestril, Prinivil.5-5 mg qd mg qd.5 mg/day, 33. mg/day* Quinapril Accupril 5 mg bid mg qd N/A *Risk reduction % (P =.3). Months Risk reduction 1% (P =.3). Swedberg K et al for the CONSENSUS Trial Study Group. Circulation. 199;: The SOLVD Investigators. N Engl J Med. 1991;35:93 3. Ramipril Altace mg qd 1 mg qd N/A Trandolapril Mavik 1 mg qd mg qd N/A *No mortality difference between high and low dose groups, but 1% lower risk of death or hospitalization in high dose group vs. low dose group.

4 Is an ARB better than an ACE inhibitor? Losartan Heart Failure Survival Study: ELITE II Primary Endpoint All-Cause Mortality Liver Angiotensinogen Renin DRI Probability of survival 1. Corticosteroids MR MRA Aldosterone K + ACTH Adrenal gland Kidney β blocker Chymase Angiotensin I Angiotensin II AT 1 R BK Breakdown products DRI, direct renin inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist; K + potassium ion; ACE, angiotensin converting enzyme; ACTH, adrenocorticotropic hormone (corticotropin); BK, bradykinin; AT 1R, angiotensin II type 1 receptor; MR, mineralcorticoid receptor ACE ACE inhibitor ARB.... Captopril, (n=7), 5 events Losartan, (n=7), events Losartan/captopril Hazard Ratio (95% CI): 1.13 (.95, 1.35) P= Days of follow-up Pitt et al Lancet. ; 355: -7. ARBs Class I: ARBs are recommended in patients with HFrEF with current or prior symptoms who are ACEI intolerant, unless contraindicated, to reduce morbidity and mortality Level of Evidence = A Class IIb: Addition of an ARB may be considered in persistently symptomatic patients with HFrEF who are already being treated with an ACEI and a β-blocker in whom an aldosterone antagonist is not indicated or tolerated Level of Evidence = A ARBs: Doses Generic Name Trade Name Initial Daily Dose Target Dose Mean Dose in Clinical Trials Candesartan Atacand mg QD 3 mg QD mg/day Losartan Cozaar mg QD NOT a class effect, target doses used in clinical trials. 5 mg QD 19 mg/day Valsartan Diovan mg BID 1 mg BID 5 mg/day Routine combined use of an ACEI, ARB, and aldosterone receptor antagonist is potentially harmful for patients with HFrEF. Level of Evidence = C Circulation 13;1:e-37. Beta-blockers are the most evidencebased therapy in heart failure MERIT-HF CIBIS- HFSA 1 Practice Guideline Beta Blockers Generic Name Trade Name Initial Daily Dose Target Dose Mean Dose in Clinical Trials Bisoprolol Zebeta 1.5 mg qd 1 mg qd. mg/day Carvedilol Coreg 3. mg bid 5 mg bid 37 mg/day Carvedilol Coreg CR 1 mg qd mg qd COPERNICUS SENIORS Metoprolol succinate CR/XL Toprol XL mg qd mg qd 9 mg/day Clinical Tidbits: ACEI first, to low doses β-blocker at LOW dose; titrate to target or maximum tolerated dose Go back to titrate ACEI to target dose

5 The stunning success of ACE inhibitors and beta blockers in mild-moderate HF 1 year mortality (%) Diuretic/ digoxin SOLVD-T Diuretic/ digoxin 13. Diuretic/ digoxin CIBIS Diuretic/ digoxin Beta-blocker Corticosteroids MR MRA Is aldosterone (mineralocorticoid) antagonism beneficial in HF? Aldosterone Liver K + ACTH Adrenal gland Kidney β blocker Angiotensinogen Chymase Renin Angiotensin I Angiotensin II AT 1 R BK ARB DRI Breakdown products DRI, direct renin inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist; K + potassium ion; ACE, angiotensin converting enzyme; ACTH, adrenocorticotropic hormone (corticotropin); BK, bradykinin; AT 1R, angiotensin II type 1 receptor; MR, mineralcorticoid receptor ACE ACE inhibitor Trials comparing an aldosterone/mr antagonist to placebo (added to an ACE inhibitor) in systolic HF Probability of survival RALES 13 NYHA class III/IV patients 95% ACE I/1% β blocker Spironolactone.5 RRR (95% CI) 3 (1 )% P < Years from randomization Probability of survival EMPHASIS HF 737 NYHA class II patients 93% ACE I or ARB/7% β blocker Eplerenone.5 RRR (95% CI) (5 3)% P = Years from randomization Pitt B, et al. N Engl J Med. 1999;31: Zannad F, et al. N Engl J Med. 1;3:11 1. Aldosterone Receptor Antagonists (ARAs or MRAs): ACCF/AHA Guidelines Aldosterone receptor Aldosterone receptor antagonists are antagonists (or MRAs) are recommended to reduce recommended in patients morbidity and mortality after with NYHA class II IV and an acute MI in patients who who have LVEF of 35% or have LVEF of % or less less, unless who develop symptoms of contraindicated, to reduce HF or who have a history of morbidity and mortality. diabetes mellitus, unless contraindicated. Strength of Evidence = A Strength of Evidence = B Circulation 13;1:e-37. Aldosterone Antagonists: Doses MRAs: Contraindications Generic Name Trade Name Initial Daily Dose Target Dose Mean Dose in Clinical Trials Spironolactone Aldactone mg qd 5 mg qd mg/day Eplerenone Inspra 5 mg qd 5 mg qd. mg/day Not recommended when: creatinine is >.5 mg/dl (or creatinine clearance is < 3 ml/minute) or serum potassium is > 5. mmol/l Level of Evidence = A Circulation 13;1:e-37.

6 Hydralazine and Isosorbide Dinitrate Class I: The combination of hydralazine and isosorbide dinitrate is recommended to reduce morbidity and mortality for patients selfdescribed as African Americans with NYHA class III IV HFrEF receiving optimal therapy with ACEIs and β-blockers, unless contraindicated Level of Evidence = A Class IIa: A combination of hydralazine and isosorbide dinitrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACEI or ARB because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated Level of Evidence = B ICD Therapy in HF: MADIT-II and SCD-HeFT Circulation 13;1:e-37. Moss et al, New Engl J Med Bardy et al, New Engl J Med 5 Cumulative benefit of poly-pharmacy (and CRT) in severe HF Heart Failure with Preserved Ejection Fraction (HFpEF) accounts for up to Half of Heart Failure 35 RALES 1999 OPTIMIZE-HF Registry, N=1,7 1 year mortality (%) COPERNICUS CARE-HF HFrEF HFpEF 5 Aldo. antag. Aldo. antag. Aldo. antag Beta-blocker Aldo. antag Beta-blocker Aldo. antag Beta-blocker CRT Fonarow G et al. JACC. 7; 5: Outcomes Trials in HFpEF TOPCAT: 1 Outcome (CV Death, HF Hosp, or Resuscitated Cardiac Arrest) CHARM-Preserved PEP-CHF 351/173 (.%) 3/17 (1.%) I-PRESERVE TOPCAT Spironolactone HR =.9 (.77 1.) p=.13

7 TOPCAT: Heart Failure Hospitalizations Exploratory (post-hoc): vs. Spiro by region Total HF Hosp Spiro : 39 : 75 P<.1* 5/173 (1.%) US, Canada, Argentina, Brazil HR=. (.9-.9) : /1 (31.%) /17 (1.%) Spironolactone HR =.3 (.9.99) p=. Interaction p=.1 Russia, Rep Georgia HR=1.1 ( ) : 71/ (.%) *poisson regression 1 Update No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HF-PEF. Diuretics are used to control sodium and water retention and relieve breathlessness and oedema as in HF-REF. Adequate treatment of hypertension and myocardial ischaemia is also considered to be important, as is control of the ventricular rate in patients with AF Sinus node inhibition with Ivabradine MOA: Blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel in the sinoatrial node, responsible for the I f current Delays diastolic depolarization Does not affect other ion channels Does not alter myocardial contractility and intra-cardiac conduction SHIFT Study Design N=55 Patients > 1 years old NSR & HR 7 bpm NYHA FC II-IV and stable on meds for wks LVEF 35% On target or maximally tolerated doses of BB Hospitalization for worsening HF in 1 mo Ivabradine 5mg BID x weeks, then 7.5mg BID N=3 BID N=39 Median f/u duration.9 months SHIFT Study Results Number of Events Outcome Ivabradine HR (95% CI) ARR CV Death or HF (.75,.9).% Hospitalization CV Death (., 1.3) 1.1% HF Hospitalization (.,.3).7% The treatment effect reflected only a reduction in the risk of hospitalization for worsening HF; there was no benefit observed for the mortality component of the primary endpoint 1 day run-in Swedberg K. Lancet. 1;37(97):75-5. Swedberg K. Lancet. 1;37(97):75-5.

8 HN O HO O OH O O N N N N O OH NH Adverse Drug Reactions with Rates 1% on Ivabradine versus Adverse Reaction Ivabradine N=3 N=37 Bradycardia 1%.% Hypertension.9% 7.% Atrial Fibrillation.3%.% Phosphenes (visual brightness)*.%.5% *inhibition of the retinal current I h, responsible for curtailing retinal responses to bright light stimuli. Most pronounced under triggering circumstances (rapid changes in brightness) Ivabradine Considerations Indication: To reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF LVEF 35% In sinus rhythm with resting heart rate 7 beats/minute Either on maximally tolerated doses of β-blockers or have a contraindication to β-blocker use Doses: Starting dose 5 mg twice daily, up to 7.5mg twice daily Swedberg K. Lancet. 1;37(97):75-5. A first-in-class Angiotensin Receptor Neprilysin Inhibitor Simultaneously Inhibits NEP and the RAS PARADIGM-HF: Study Design Vasoactive Peptide System pro-bnp Heart Failure Renin Angiotensin System Angiotensinogen (liver secretion) Randomization (N = patients) Single-blind run-in period Double-blind randomized treatment period mg bid ANP BNP CNP Adrenomedullin Bradykinin Substance P (angiotensin II) Neprilysin Inactive fragments Vasodilation blood pressure sympathetic tone aldosterone levels fibrosis hypertrophy Natriuresis/Diuresis NT-pro BNP Sacubitril (AHU377) LBQ57 X is a novel crystalline complex consisting of the molecular moieties of valsartan and sacubitril in an equimolar ratio Valsartan X Angiotensin I Angiotensin II AT 1 receptor Vasoconstriction blood pressure sympathetic tone aldosterone fibrosis hypertrophy 1 mg bid 1 mg bid Testing tolerability to target doses of enalapril and mg bid 1 mg bid On top of standard heart failure therapy (excluding ACEIs and ARBs) weeks 1- weeks - weeks ~ 1 to 3 months (event-driven) 5 mg bid for 1- weeks followed by enalapril 1 mg bid as an optional starting run-in dose for those pts who are treated with ARBs or with low dose of ACEI Primary outcome: CV death or heart failure hospitalization (event driven:,1 patients with primary events) PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) 3 1 Patients at Risk 17 1 (n=1) (n=17) HR =. (.73-.7) P =. Number needed to treat = Days After Randomization McMurray et al. NEJM Cardiovascular Death Kaplan-Meier Estimate of Cumulative Rates (%) 3 1 HR =. (.71-.9) P =. Number need to treat = 3 McMurray et al. NEJM 1 (n=1) (n=17) Days After Randomization Patients at Risk

9 vs on Primary Endpoint and on Cardiovascular Death, by Subgroups Primary endpoint McMurray et al. NEJM 1 Cardiovascular death PARADIGM-HF: All-Cause Mortality Kaplan-Meier Estimate of Cumulative Rates (%) 3 1 HR =. (.7-.93) P<.1 McMurray et al. NEJM 1 (n=1) (n=17) Days After Randomization Patients at Risk PARADIGM-HF: Adverse Events (n=17) Prospectively identified adverse events McMurray et al. NEJM 1 (n=1) P Value Symptomatic hypotension 5 3 <.1 Serum potassium >. mmol/l Serum creatinine >.5 mg/dl Cough 7 1 <.1 Discontinuation for adverse event Discontinuation for hypotension 3 9 NS Discontinuation for hyperkalemia 11 NS Discontinuation for renal impairment Angioedema (adjudicated) Medications, no hospitalization 1 9 NS Hospitalized; no airway compromise 3 1 NS Airway compromise ---- Early Benefit of Months after Randomization Packer et al. Circulation 1 Number PARADIGM-HF: Mode of Death HR p= All causes CV causes Sudden Worsening HF < Desai et al. Eur Heart J (%) PARADIGM-HF: Hospitalization for heart failure Proportion of patients HR.79 (.71,.9) p < Patients hospitalized Packer et al. Circulation 1 Number of admissions* RR.77 (.7,.9) p =. Hospitalizations *Includes repeat episodes

10 Is LCZ Effective Across the Spectrum of Heart Failure Components of MAGGIC Score: Age SBP BMI Creatinine NYHA Sex Smoking DM COPD Simpson et al. JACC PARADIGM-HF: Effect of according to age category rate per 1 patient years rate per 1 patient years 1 CV death or HF hospitalization < Age (years) 1 1 HF hospitalization 1 1 < Age (years) rate per 1 patient years rate per 1 patient years 1 CV death 1 1 enalapril 1 < Age (years) 1 1 All cause death 1 1 < Age (years) Jhund PS et al. Eur Heart J Mechanism: NT-proBNP and BNP Sacubitril/Valsartan Considerations NT-proBNP NT-proBNP BNP NT-proBNP remains an accurate measure of 1 severity of HF in the setting of treatment with but BNP will not be reliable! Pre Run-in Baseline Months BNP McMurray et al. NEJM 1 Indication: To reduce the risk of cardiovascular death and hospitalization for HF in patients with chronic heart failure (NYHA class II IV) and reduced ejection fraction Used in place of ACEI or ARB Doses: / mg, 9/51 mg, 97/13 mg Starting dose 9/51 mg twice daily for patients previously on ACEI or ARB, / mg for low dose ACEI/ARB (</= 1mg enalapril daily) or ACEI/ARB naive MUST have 3 hours washout between ACEI dose and sacubitril/valsartan initiation PARAMOUNT: Significant Reduction in NT-proBNP with at 1 Weeks NTproBNP (pg/ml) Solomon et al. Lancet 1 (733,11) 35 (71, 91) 73 (7,91) p = Weeks Post Randomization Valsartan /Valsartan:.77 (.,.9) P =.5 5 (51, 71) Solomon et al. Lancet 1 ESC Hotline 1 PARAGON-HF: Prospective comparison of ARni with Arb Global Outcomes in heart failure with preserved ejection fraction A randomized, double blind, trial to evaluate the long-term efficacy and safety profile of the angiotensin receptor neprilysin inhibitor (ARNI),, compared with valsartan, in patients with heart failure with preserved ejection fraction (HFpEF)

11 Summary Heart failure remains extremely morbid and deadly Current treatment of HFrEF is both empiric (diuretics, lifestyle) and evidenced-based (ACEi, ARBs, Beta-Blockers, MRAs) Devices used for specific subsets (ICD for reduced EF, CRT for reduced EF and wide QRS/LBBB, LVAD for end-stage or bridge to transplant) New Therapies are likely to be approved for use soon based on results of recent clinical trials In HFpEF, current treatment remains empiric, with some evidence that RAAS blockade can be useful in some patients Clinical trials in HFpEF are ongoing with novel agents