Chronic Heart Failure with Reduced Ef Guide to

Chronic Heart Failure with Reduced Ef Guide to Outpatient Success Kelly Axsom, MD Assistant Professor of Medicine Division of Heart Failure, Transplantation and Mechanical Circulatory Support March 1, 2018

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Outline Heart Failure Background Biomarkers Background for Neurohormonal Blockade Treatment Guideline/Pathway - Drug Class Review - Outpatient Visit Review Non-LVAD Technologies for Outpatient Management

Heart Failure is a Syndrome Symptoms – Dyspnea – Edema Supported by imaging, hemodynamics, labs “Preserved” LV Function “Reduced” LV Function Ischemic Non-ischemic – Inherited – Myocarditis • Infection • Inflammatory – – Valvular heart disease Post cardiotomy Idiopathic Infiltrative

Heart Failure Global Healthcare Impact Estimated 26 million worldwide – US 5. 7 million – 670, 000 new cases/year Leading cause for hospitalization in US and Europe – 1 million admissions/year – >25% monthly readmission rate 50% mortality within 5 years of diagnosis $32 billion annual cost • With aging population it is estimated that HF will cost $70 billion in 2030 80% due to hospitalizations Fonarow et al JACC 2007; 50: 768 -77.

NYHA Functional Class I II IV No limitation of physical activity. Slight limitation of physical activity. Comfortable at rest Symptoms with ordinary activity Marked limitation of physical activity. Comfortable at rest Symptoms at rest. Unable to carry on any physical activity without HF symptoms.

AHA/ACC Stages Incidence A B C D High Risk for Heart Failure Asymptomatic Heart Failure 5 -year Survival NYHA Class none NYHA I-IV NYHA IV ~5 mil pts/year Symptomatic Heart Failure 97% 96% 75% ~200, 000 pts/year End-Stage Heart Failure 20% ~65 mil pts/year ~10 mil pts/year h NYHA I Yancy CW, et al. Circulation. 2013; 128: e 240 -e 327.

Biomarkers

Troponin • Only found in cardiac myocytes • Commonly elevated in heart failure • Acute • Chronic

BNP HF diagnosis High Age, arrhythmia, pulmonary disease, stroke, high output ARNI (entresto) increases BNP (not NT-pro. BNP) Low Obesity, Tamponade, flash pulmonary edema, PRE-LV reasons for HF Trending NT-pro. BNP is NOT associated with improved 6 mo all cause mortality or HF readmission Stienen et al Circ. 2017 epub. De Vecchis et al J Clin Med 2016: 5: 99. ACC/AHA 2017 Heart Failure Guidelines

Future Biomarkers • Soluble ST 2 • Cardioprotective signaling in the myocardium • Interleukin (IL)‐ 1 receptor‐like family of proteins, is released in response to myocyte stretch; neutralizes IL-33 • Galectin-3 • -galactoside binding lectin and a mediator of tissue fibrosis and inflammation • Persistently elevated galectin-3 predicts new-onset HF • Useful in chronic HFp. EF to predict worsening • Hopeful for predictive of worsening in chronic HF • Future: test to screening for heart failure Circ HF. 2013; 6: 117 -1179 de Boer RA, et al. Annals of Med 2011; 43(1): 60 -8

Neurohormonal Activation in Heart Failure Myocardial injury to the heart (CAD, HTN, CMP, valvular disease) Initial fall in LV performance, wall stress Activation of RAS and SNS Remodeling and progressive worsening of LV function Fibrosis, apoptosis, hypertrophy, cellular/molecular alterations, myotoxicity Morbidity and mortality Arrhythmias Pump failure RAS, renin-angiotensin system; SNS, sympathetic nervous system. Peripheral vasoconstriction Sodium retention Hemodynamic alterations Heart failure symptoms Fatigue Activity altered Chest congestion Edema Shortness of breath

GM-HF PARADI 2014 2011 EMPH AS 2004 A-He. FT IS US V AL-He. FT 2001 COPE RNIC CIBIS-II 1999 RALES MERIT -HF ol HFS 1996 US Carvedil 1991 CONSEN SUS SO LVD V-He 1992 SOLVD FT 1986 V-He. FT 1 II Landmark Neurohormonal Trials V He. FT 1 – Hydralazine/Nitrates CONSENSUS – Enalapril SOLVD – Enalapril VEHFTII – Enalapril vs Hydral/Nitrates SOLVD – Enalapril asymptomatic US Carvedilol – Carvedilol RALES – spironolactone CIBUS – Bisoprolol MERIT HF – Metoprolol XL Copernicus – Carvedilol VAL-HEFT – Valsartan A-He. FT – Hydral/Nitrates AA EMPHASIS – Eplerenone Paradigm-HF - Entresto

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

HFr. EF – Mortality Reduction Fonarow et al. JAMA Cardiology. 2016; 1(6): 714 -717,

Ischemia CXR CMP, CBC, troponin, BNP, TFTs HIV, Ferritin, ANA Toxins ACEI/ARB/ARNI Beta-Blocker Aldosterone antagonist Hydral/Nitrate Ivabradine ICD BIVICD (LBBB >120 ms) Every Visit ECG Diuretics Neurohormonal Blockade TTE Neurohormonal Blockade Work-up Etiology Treatment Pathway Evaluate Volume status Increase Meds Educate patient - HF symptoms - Weights - Diet Consider Cardiac Rehab Healthcare Maintenance

Diuretics Loop Diuretic PO IV Notes Bumetanide 1 mg Oral bioavail 80 -90% Torsemide 20 mg N/A Oral bioavail 80 -100% Furosemide 40 mg 20 mg Oral bioavail ~50% Ethacrynic Acid 50 mg Oral bioavail 100% Thiazide/Thiazide-like Diuretic (Boosters) PO Freq Notes Chlorothiazide 250 mg q 12 h $$$; Avail IV, hypo. K hypo. Na Hydrochlorothiazide 25 mg q 12 h hypo. K hypo. Na Metolazone 2. 5 mg q 24 h hypo. K hypo. Na

ACEI/ARB Suppression of angiotensin II production Increases kinin-mediated prostaglandin production ↓ LV Function ↑ Impedance ↓ Cardiac Output Arterial vasodilation Decrease LV afterload Favorable cardiac remodeling ↑ Vasoconstriction ACC/AHA Class I Recommendation First Drug Class ↑ H 20, Na Retention Compensation ↑ Sympathetic ↑ RASS

ACEI/ARB Drug Starting Dose Target Dose 6. 25 mg 3 x daily 2. 5 mg twice daily 2. 5 -5 mg twice daily 1. 25 mg daily 50 mg 3 x daily 10 -20 mg twice daily 20 -40 mg daily 10 mg daily 4 -8 mg daily 25 -50 mg daily 40 mg twice daily 32 mg daily 150 mg daily 160 mg twice daily ACEI Captopril Enalapril Lisinopril Ramipril ARB Candesartan Losartan Valsartan

Angiotensin Receptor-Neprilysin Inhibitor Entresto (Valsartan Sacubitril)

PARADIGM-HF: CV Death or HF Hospitalization Kaplan-Meier Estimate of Cumulative Rates (%) 40 Enalapril 32 (n=4212) 914 24 LCZ 696 (n=4187) 16 8 0 0 180 360 540 720 900 1080 1260 Days After Randomization Patients at Risk LCZ 696 Enalapril 1117 4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 249 236

Starting Entresto • Because of risk of angioedema • NO ACEI for 36 h prior to dosing • Never concomitant ACEI/ARB and Entresto • Dosing: 24/26; 49/51; 97/103 – twice daily • When starting: • Decrease diuretic by half (unless overloaded) • Big impact on BP

Sympathetic Nervous System Activation Beta-Blockers Mediated through actions on α 1, β 1 and β 2 receptors Increases ventricular volumes Peripheral vasoconstriction Impairs sodium excretion by kidneys Induces cardiac hypertrophy Provokes arrhythmias Increases heart rate AHA/ACC Class I Recommendation Start with ACEI or as 2 nd drug

Beta-Blockers Drug Bisoprolol Starting Dose 1. 25 mg daily Target Dose 10 mg daily Carvedilol 3. 125 mg q 12 h 25 mg twice daily Metoprolol XL 12. 5 – 25 mg daily 200 mg daily 50 mg twice daily (>85 kg) 12. 5 mg q 6 -8 h Metoprolol Tartrate Only for titration NONE

Discharge on Beta-Blocker Reduces Mortality Japanese Registry OPTIMIZE-HF Registry Tsuchihashi-Makaya et al Circ J 2010: 74: 1364 -1371 Fonarow et al Am Heart J 2007: 153: 82 ew-82 e 11.

Beta-blockers and HF • Without BB at discharge • Mortality rate 8. 6% in 60 -90 days • Rehospitalization rate 29. 6% within 60 -90 days • No difference in outcomes with β-blocker with and those without COPD • β-blocker use in patients with COPD and HF • Decrease risk mortality • Decrease risk of COPD exacerbation O’Connor et al Am Heart J 2008: 156: 662 -73. ; Mentz et al Am J Cardiol. 2013: 111: 582 -7. ; Du et al PLo. S One. 2014: 9: e 113048.

Aldosterone Antagonist Drug Starting Dose Target Dose Aldosterone Antagonist -Class I NYHA Class II-IV Ef <35%, AMI/LVEf <40% w HF or DM Eplerenone 25 mg daily 50 mg daily Spironolactone 12. 5 -25 mg daily 25 -50 mg daily

Afterload Reduction Drug Starting Dose Target Dose Vasodilators -Class I NYHA Class III-IV HFr. EF AA on ACEI and BB -Class IIa HFr. EF Class II-IV cannot receive ACEI/ARB/ARNI Hydralazine 25 mg 3 x daily 75 mg 3 x daily Isosorbide 20 mg 3 x daily 40 mg 3 x daily dinitrate Fixed combo 20 mg/37. 5 mg 3 x 2 tabs 3 x daily Imdur not studied in HF

Funny Channel (If) Inhibitor • Reduce HF hospitalizations • NNT 26 over 12 mo to prevent combined HF admit or death • No impact on Mortality • Must be in sinus • On maximally tolerated BB

Ivabradine Drug Ivabradine Starting Dose 2. 5 -5 mg q 12 h Target Dose Titrate to HR 50 -60 bpm Max 7. 5 mg twice daily Class IIa HFr. EF on maximally tolerated NH titrate to HR <70 bpm

Medication Titration Every visit increase neurohormonal blockade to target doses Lisinopril 20 mg/Losartan 150 mg daily/Entresto 49/51 mg or higher Coreg 25 mg BID/Metoprolol XL 200 mg Spironolactone 25 -50 mg Hydralazine 75 mg/Isosorbide 40 mg TID Increase doses in between visits Diuretics to maintain euvolemia *Entresto often need less diuretic

Education What is Heart Failure Understanding/Reviewing symptoms Medication Reconciliation Help live longer and better Cost and barriers to getting or taking meds Give new medication list Low sodium diet/fluid restriction Daily weight checks What to do who to call if weights change 2 lbs in a day or 5 lbs in a week Call or if inc then double diuretic

Heart Failure Decompensation Chronic heart failure 5 million in the US 10 million in Europe Normal heart Heart Viability Initial myocardial injury Death First ADHF episode: Pulmonary edema ER admission Later ADHF episodes: Rescue therapy ICU admission Initial phase Last year Gheorghiade M. Am J Cardiol. 2005; 96(suppl 6 A): 1 -4 G.

Consider Advanced Heart Failure High Risk Features - - 2 or more ED visits/Hospitalizations for Heart Failure in 6 months - - - Intolerance to HF Medications - Recent need for IV inotropes - Persistent symptoms - Exercise limitation, profound fatigue, dyspnea at rest or w/ ADLs - Hypotension (BP <100/60) - Renal Insufficiency (Cr >1. 7, BUN >45) Challenging arrhythmias or ICD shocks Age <50 Complex congenital or valve disease

Newer Non-LVAD HF Devices

Cardio. MEMS – Abbott NYHA Class III (HFr. Ef or HFp. Ef) At least 3 HFRH in 12 months Comorbidities COPD, CKD, Obesity Engaged patients CUMC Experience - 9 patients on monitoring - 12 m prior to implant 38 HFRH - 55 monitored months 1 HFRH

Metolazone Hydralazine Admitted every year with combo – URI HF Prednisone ↑Imdur 86 F ICM Ef 15%, severe COPD, multiple prior cancers, CKD Double Lasix RSV Positive

Re. DS – Sensible Medical • Radar sensors – technology used to see through walls • Vest that measures fluid • Uses • • • ER POC In-patient Units SAR Transitions of care • Community health workers

Heart. Logic. TM – Boston Scientific

NYP Outpatient HF Cards

Ischemia CXR CMP, CBC, troponin, BNP, TFTs HIV, Ferritin, ANA Toxins ACEI/ARB/ARNI Beta-Blocker Aldosterone antagonist Hydral/Nitrate Ivabradine ICD BIVICD (LBBB >120 ms) Every Visit ECG Diuretics Neurohormonal Blockade TTE Neurohormonal Blockade Work-up Etiology Treatment Pathway Evaluate Volume status Increase Meds Educate patient - HF symptoms - Weights - Diet Consider Cardiac Rehab Healthcare Maintenance

Thank you Email: kma 2161@cumc. columbia. edu New Outpatients: 212 -305 -9268 Cell: 302 -981 -1278