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  • How Do You Mend a Broken Heart: The New Agents to Treat HF…

    Paradigm Shift or Just the Same Old Drugs?

    Gregg C. Fonarow, MD FACC, FAHA, FHFSA

    Co-Chief UCLA Division of Cardiology

    Director, Ahmanson-UCLA Cardiomyopathy Center

    Los Angeles, CA

  • Disclosure

    • Dr. Fonarow has consulted for Amgen, Janssen, Medtronic, and Novartis, and has received research grants from thehas received research grants from the National Institutes of Health (NIH) and Medtronic.

  • Scope of Heart Failure

    • Heart failure (HF) is a major public health problem

    Population Group

    Prevalence Incidence Mortality Hospital

    Discharges Cost1

    Total population

    5,700,000 870,000 50% at 5 years

    1,023,000 $30.7 billion

    • Heart failure (HF) is a major public health problem resulting in substantial morbidity and mortality

    • 6–12 million outpatient office visits

    • Despite available effective treatments, a large number of eligible patients are not receiving optimal care

    Mozaffarian D, et al. Circulation. 2015;131:e29-e322. Jessup M. Circulation. 2014;129:2717-2722.

  • Myocardial injury to the heart (CAD, HTN, CMP, valvular disease) Initial fall in LV performance,  wall stress

    Fibrosis, apoptosis,

    Activation of RAAS and SNS

    Neurohormonal Activation in Heart Failure

    Morbidity and mortality Arrhythmias Pump failure

    Peripheral vasoconstriction Hemodynamic alterations

    Remodeling and progressive worsening of LV function

    Fibrosis, apoptosis, hypertrophy,

    cellular/ molecular

    alterations, myotoxicity

    Heart failure symptoms Fatigue

    Activity altered Chest congestion

    Edema Shortness of breath

    RAAS = renin-angiotensin-aldosterone system; SNS = sympathetic nervous system; CMP = cardiomyopathy. Fonarow GC. Rev Cardiovasc Med. 2001;2:7-12.

  • ACC/AHA HF Guidelines 2013: Management of HFrEF (Stage C)

    Life-Prolonging Medical Therapy

    • ACE inhibitors or ARB (Class I, evidence A) in all patients without contraindications or intolerance.

    • Evidence-based beta-blockers (Class I, evidence A) in all• Evidence-based beta-blockers (Class I, evidence A) in all patients without contraindications or intolerance. This would include carvedilol (immediate or extended release), metoprolol succinate, or bisoprolol.

    • Aldosterone antagonists (Class I, evidence A) in all patients with Class II–IV HF without contraindications or intolerance when close monitoring can be ensured.

    Yancy CW, et al. J Am Coll Cardiol. 2013;62:1495-1539.

  • Pharmacologic Treatment for Stage C HFrEF HFrEF Stage C

    NYHA Class I–IV Treatment:

    Class I, LOE A ACEI or ARB AND

    Beta-blocker

    Yancy CW, et al. J Am Coll Cardiol. 2013;62:1495-1539.

    For persistently symptomatic African Americans, NYHA Class III–IV

    For NYHA Class II–IV patients. Provided estimated creatinine

    >30 mL/min and K+

  • New Tools for HFrEF

  • Counterregulatory Peptide Systems Activated in Heart Failure Patients

    Prostaglandin

    Bradykinin

    Adrenomedullin Since neprilysin breaks down these

    These peptides promote vasodilation, salt and water diuresis and have anti- remodeling effects that modulate the adverse effects of the RAAS and SNS

    Mann DL et al. Braunwald’s Heart Disease. 10th ed. Philadelphia, PA: Saunders; 2015.

    ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; NP, natriuretic peptide; NPS, natriuretic peptide system.

    Adrenomedullin

    ANP BNP CNP Urodilatin Dendroaspis

    NPs (Natriuretic peptides)

    Since neprilysin breaks down these peptides, inhibitors of this enzyme should increase their levels and effects in heart failure

  • Endogenous

    vasoactive peptides

    (natriuretic peptides, adrenomedullin,

    bradykinin, substance P,

    Neurohormonal

    activation

    Vascular tone

    Cardiac fibrosis,

    hypertrophy

    Effects of Neprilysin Inhibition in Heart Failure

    bradykinin, substance P,

    calcitonin gene-related peptide)

    Inactive metabolites

    hypertrophy

    Sodium retention

    Neprilysin Neprilysin inhibition

    McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

  • NEP < median

    NEP < median

    Neprilysin Levels in Blood Predict Outcomes in HF Patients

    NEP ≥ median

    NEP ≥ median

    Bayés-Genís A et al. JACC 65: 657-665, 2014

  • Sacubitril/Valsartan (LCZ696) Mechanism of Action

    Buggey et al. Journal of Cardiac Failure, Volume 21, Issue 9, 2015, 741–750

  • Prospective comparison of ARNI with ACEI to

    Determine Impact on Global Mortality and

    morbidity in Heart Failure trial (PARADIGM-HF)

    Aim of the PARADIGM-HF Trial

    Sacubitril/Valsartan

    97/103 mg twice daily

    Enalapril 10 mg twice daily

    SPECIFICALLY DESIGNED TO REPLACE CURRENT USE

    OF ACE INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS AS THE CORNERSTONE OF THE

    TREATMENT OF HEART FAILURE

  • PARADIGM-HF Trial: Design Entry Criteria:

    • NYHA Class II-IV HF, LVEF ≤40% → amended to ≤35%

    • BNP ≥150 pg/mL (or NT-proBNP ≥ 600 pg/mL) or 1/3 lower if hospitalized for HF within 12 mos

    • On a stable dose of ACEI or ARB equivalent to ≥10 mg of enalapril daily for ≥4 weeks

    • Unless contraindicated, on stable dose of beta-blocker for ≥4 weeks

    • SBP ≥95 mm Hg, eGFR ≥30 mL/min/1.73 m2 and serum K ≤5.4 mmol/L at randomization

    Single-blind run-in period

    Enalapril 10 mg BID

    Study stopped early after median follow-up of 27 mos

    Sac/Val = Sacubitril/Valsartan.

    McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

    34-month follow-up

    HF Patients (n=8,442)

    R

    Enalapril 10 mg BID (n=4,212)

    Sac/Val 97/103 mg BID (n=4,187)

    Enalapril 10 mg BID (n=10,513)

    Sac/Val 49/51 mg to

    97/103 mg BID (n=9,419)

    2 Weeks 4–6 Weeks

    Primary endpoint: Death from CV causes or hospitalization for HF

  • Sac/Val (n=4187)

    Enalapril (n=4212)

    Age (years) 63.8 ± 11.5 63.8 ± 11.3

    Women (%) 21.0% 22.6%

    Ischemic cardiomyopathy (%) 59.9% 60.1%

    LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3

    NYHA functional Class II / III (%) 71.6%/ 23.1% 69.4%/24.9%

    Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15

    PARADIGM-HF: Baseline Characteristics

    Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15

    Heart rate (beats/min) 72 ± 12 73 ± 12

    N-terminal pro-BNP (pg/mL) 1631 (885–3154) 1594 (886–3305)

    B-type natriuretic peptide (pg/mL) 255 (155–474) 251 (153–465)

    History of diabetes 34.7% 34.6%

    Digitalis 29.3% 31.2%

    Beta-adrenergic blockers 93.1% 92.9%

    Mineralocorticoid antagonists 54.2% 57.0%

    ICD and/or CRT 21.9% 21.4%

    McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

  • Number needed to treat = 21

    PARADIGM-HF: Primary Endpoint of CV Death or Heart Failure Hospitalization

    0.4

    0.6

    1.0

    Enalapril 1117 events (26.5%)

    C u

    m u

    la ti

    v e

    P ro

    b a b

    il it

    y

    0.5

    HR 0.80 (95% CI, 0.73–0.87), p

  • Number needed to treat = 31

    0.4

    0.6

    1.0

    HR 0.80 (95% CI, 0.71–0.89), p

  • Sac/Val (n=4187)

    Enalapril (n=4212)

    Hazard Ratio (95% CI)

    p- Value

    Primary endpoint

    914 (21.8%)

    1117 (26.5%)

    0.80 (0.73–0.87)

  • Sac/Val vs. Enalapril on Primary Endpoint and on CV Death by Subgroups

    All Patients Age

    Median

    Hypertension No Yes

    Prior use of ACE inhibitor No Yes

    Prior use of aldosterone antagonist No Yes

    Prior hospitalization for heart failure No Yes

    1.70.3

    Sac/Val Better

    1.51.31.10.90.70.5

    Enalapril Better

    1.70.3

    Sac/Val Better

    1.51.31.10.90.70.5

    Enalapril Better

    2692

    3722 489

    2116 2087

    1241 2971

    946 3266

    1812 2400

    1545 2667

    2646

    3715 472

    2079 2103

    1218 2969

    921 3266

    1916 2271

    1580 2607

    0.91

    0.36

    0.16

    0.87

    0.09

    0.10

    0.10

    0.73

    0.36

    0.33

    0.14

    0.06

    0.32

    0.19

  • 0.4

    0.6

    1.0

    Enalapril

    C u

    m u

    la ti

    v e

    P ro

    b a b

    il it

    y

    0.5

    PARADIGM-HF: All-Cause Mortality

    HR 0.84 (95% CI, 0.76–0.93), p

  • Sac/Val (n=4187)

    Enalapril (n=4212)

    p- Value

    Prospectively identified adverse events

    Symptomatic hypotension 14.0% 9.2% 6.0 mmol/L 4.3% 5.6% 0.007

    Serum creatinine ≥ 2.5 mg/dL 3.3% 4.5% 0.007

    Cough 11.3% 14.3%

  • PARADIGM-HF: Summary of Findings In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril:

    Sac/Val was more effective than enalapril in …

    • Reducing the risk of CV death and HF hospitalization by increme