Updates on Heart Failure 2018

Transcription

1 Updates on Heart Failure 2018 John R. Teerlink, M.D. FACC, FAHA, FESC, FHFA, FHFSA, FRCP(UK) Professor of Clinical Medicine, University of California San Francisco Director of Heart Failure, San Francisco Veterans Affairs Medical Center San Francisco, CA, USA Presenter Disclosure Information: UCSF Advances in Internal Medicine 2018 Financial Disclosure J.R. Teerlink has received research grants and/or consulting fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Cytokinetics, Janssen, Medtronic, Novartis, Relypsa. Unlabeled/unapproved uses disclosure I will be discussing investigational therapies that are not approved by the FDA. Welcome to UCSF Home of Evidence-based Medicine! Heart Failure Evidence-base 2013 ACC/AHA Heart Failure Guideline (Yancy CW, et al. J Am Coll Cardiol 2013;62:e references) 2016 ACC/AHA Focused Update on New Pharmacological Therapy for Heart Failure (Yancy CW, et al. J Am Coll Cardiol 2016;68: references) 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure ( 205 references)

2 Updates on Heart Failure 2018 Updates on Heart Failure 2018 Goal to: Remind you of what you know you should be doing Discuss what you may not know that you should be doing Share what you may be doing in the future Definition, Nomenclature, Epidemiology Evaluation and Diagnosis Treatment of Stages of Heart Failure Co-morbidities Future directions Updates on Heart Failure 2018 Definition, Nomenclature, Epidemiology Heart Failure HF is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood. May result from disorders of the pericardium, myocardium, endocardium, heart valves, or great vessels or from certain metabolic abnormalities, but most patients with HF have symptoms due to impaired left ventricular (LV) myocardial function. No single diagnostic test for HF; a clinical diagnosis based on careful history and physical examination, supplemented by diagnostic studies. Heart failure (not Congestive Heart Failure)

3 Heart Failure: Here Comes Everybody Benjamin EJ, et al. Circulation 2018;137:e67 e492. Heart Failure with Reduced/Preserved Ejection Fraction (HFrEF and HFpEF) Yancy CW, et al. J Am Coll Cardiol 2013;62:e Lifetime risk of developing HF is 20% for Americans 40 years of age >1,000,000 new HF cases diagnosed annually Approximately 6.5 million persons in the US have clinically manifest HF Blacks have the highest risk for HF and a greater 5-year mortality rate than whites Absolute mortality rates for HF remain approximately 40-50% within 5 years of diagnosis Cost of heart failure in 2012: $71-$127 billion (Voigt J, et al. Clin Cardiol , 5, ) Stages of Heart Failure Yancy CW, et al. J Am Coll Cardiol 2013;62:e ACCF/AHA Stages Compared to NYHA Functional Class Yancy CW, et al. J Am Coll Cardiol 2013;62:e

4 Updates on Heart Failure 2018 Physical Exam in Heart Failure Definition, Nomenclature, Epidemiology Evaluation and Diagnosis First, strike for the jugular and let the rest go -Oliver Wendell Holmes, Jr. Symptoms Dyspnea (Exertional, PND, Orthopnea) Cough Fatigue Abd discomfort (bloating, anorexia) Sleep disturbances Diagnosis of Heart Failure Physical Exam Edema (Legs, Abd, Sacral) Rales, Effusion JVP, HJR/AJR Weight Cool extremities MR murmur S3 (S4) Blood/ pulse pressure Pulsus alternans Natriuretic peptide Biomarker-based Screening

5 St Vincent s Screening to Prevent Heart Failure (STOP-HF) Study 1374 participants with CV risk factors, 40 years and had a history of 1 of the following: Hypertension; Obesity; Hypercholesterolemia; Vascular disease; Diabetes mellitus; Arrhythmia requiring therapy; Moderate to severe Valvular disease. Randomized to: Usual care BNP Screening. If BNP 50, Echo and Collaborative Care Ledwidge M, et al. JAMA 2013;310: Indications for Use of Biomarkers in Heart Failure Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) 894 (1100 planned) pts with HFrEF: LVEF 40% h/o HF event within the prior 12 months, NT-proBNP >2000 pg/ml or BNP >400 pg/ml within prior 30 days. Randomized to: NT-proBNP guided strategy (n=446): HF therapy titrated with target NTproBNP <1000 pg/ml. Usual care (n=448): Intensive guideline-based care Primary endpoint: time-to-first HF hospitalization or cardiovascular mortality (stopped early for futility) Felker GM, et al. JAMA 2017;318: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) Felker GM, et al. JAMA 2017;318: Secondary Outcomes

6 Selected Potential Causes of Elevated Natriuretic Peptide Levels CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III HF Patients (CHAMPION) 550 pts with heart failure: 18 years old NYHA III for at least 3 months Any LVEF HF hospitalization within past 12 months, On optimal GDMT All patients implanted and take daily readings. Randomized to: Physician access (n=270) Usual care (n=280) Primary endpoint: rate of heart failurerelated hospitalizations at 6 months Abraham WT, et al. Lancet 2011;377: CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III HF Patients (CHAMPION) Cumulative HF-related Hospitalizations Abraham WT, et al. Lancet 2011;377: All-cause Death or HF-related Hospitalization Ambulatory Hemodynamic Monitoring Reduces Heart Failure Hospitalizations in Real-World Clinical Practice Desai AS, et al. J Am Coll Cardiol 2017;69: Retrospective cohort study, U.S. Medicare claims data from patients undergoing pulmonary artery pressure sensor implant (June 1, 2014-December 31, 2015) Pre-Implant 1114 pts with full 6-month pre-implant data 480 pts with full 12-month pre-implant data Post-Implant

7 Updates on Heart Failure 2018 Stage A Heart Failure: When you re a Hammer, Everything looks like a Nail! Definition, Nomenclature, Epidemiology Evaluation and Diagnosis Treatment of Stages of Heart Failure Stages of Heart Failure Risk Factor Modification in HF Weight loss Smoking cessation Hypertension therapies Diabetes management Lipid control Sleep apnea Exercise

8 Essential Topics in Patient Education Dickstein K, et al. Eur Heart J 2008;29: Stages of Heart Failure Stages of Heart Failure Treatment of Heart Failure with reduced Ejection Fraction (HFrEF) Stage C and D

9 Use of Diuretics in Heart Failure Patients Self-titration: need dry weight on patient s scale Daily weights (routine; daily log with symptoms, etc.) If weight increased by >3-5 lbs, take double diuretic If patient requires supplemental potassium, also double If worsening at any time or no improvement after 2-3 days, call Some patients can be maintained on thiazides (i.e. HCTZ) Many patients will require loop diuretics; furosemide has short duration of action, should be dosed b.i.d. (AM and mid-afternoon/ early evening) Many patients may not require diuretics when ACE inhibitor, beta blocker, mineralocorticoid receptor antagonist, etc. are optimized; reassess diuretic requirements after time on stable regimen Use of Diuretics in Heart Failure Patients-Redux Often increasing creatinine can be evidence of worsening heart failure, elevated CVP and need for more diuretics Furosemide s poor bioavailability is worse in the setting of abdominal edema/ congestion. Diuretic resistance may be treated with switch to bumetanide/ torsemide, metolazone, (or adding spironolactone). Sequential nephron blockade with loop diuretic and metolazone very effective for diuresis, but should be done VERY cautiously or by specialist Frequent monitoring of electrolytes is imperative; HYPOkalemia is as dangerous as HYPERkalemia (maintain K + 4.0). Importance of Afterload Reduction Use of ACE Inhibitors in Heart Failure Patients Indicated in potentially ALL pts with HF and EF 40% Some ACE Inhibitor is better than none Start low dose, up-titrate q2 wks or so; check labs within 1-2 weeks of dose adjustment, then about q4 months Asymptomatic low blood pressure: usually no change Symptomatic Hypotension: Re-evaluate other meds (nitrates, diuretics, etc.); may improve with time (reassure); Cough: Other causes, rechallenge, consider ARB Worsening renal function: Increase in creatinine up to 50% above baseline is acceptable; K<5.5 ARBs may be INFERIOR to ACEi in CHF/ Sacubitril/Valsartan BETTER than ACEi

10 ACE inhibitors/ ARBs for Heart Failure Use of Beta blockers in Heart Failure Patients Indicated in potentially ALL pts with HF and EF 40% Some beta blocker is better than none Some beta blocker probably better than more ACE inhibitor Start low dose, up-titrate q2 wks or so. Severe asthma is a contraindication (NOT COPD) Asymptomatic low blood pressure: usually no change Symptomatic Hypotension: Re-evaluate other meds (nitrates, diuretics, etc.); often improves with time (reassure); Worsening HF: Congestion, Increase diuretic; Fatigue, usually reassurance Low heart rate: if <55 bpm, halve dose Other beta blocker side effects minimal in HF patients Magnitude of Benefit of Therapies for Heart Failure Yancy CW, et al. J Am Coll Cardiol 2013;62:e Use of Mineralocorticoid Receptor Antagonists (MRAs) in HF Patients Indicated in potentially ALL NYHA II-IV pts with HF and EF 35% Start low dose, up-titrate after q4-8 wks or so; check labs within 1 and 4, 8 and 12 weeks of dose adjustment, at 6,9,12 months, and then q4 months Avoid potassium repletion and K-containing salt substitutes Hyperkalemia: If K>5.5 or Cr 2.5 mg/dl, halve dose and f/u; if K>6.0 or Cr >3.5 mg/dl, d/c dose and f/u. Consider rechallenge if reversible cause identified. Gynecomastia in males: change to eplerenone

11 MRAs, Beta-blockers and ISDN/Hydralazine for Heart Failure (HFrEF) An Approach to Management of Patient with Stage C Symptomatic HF-REF Control volume overload with diuretics Initiate ACE inhibitor therapy (2.5-5 mg lisinopril); substitute with ARB only if absolutely necessary Initiate Beta blocker therapy (prefer Carvedilol or 6.25 mg po bid) and up-titrate to max tolerated Initiate spironolactone (switch to eplerenone if needed) Maximize ACE inhibitor/ Switch to ARNI (discussed later) If after stable therapy and meets criteria, ICD/CRT If still symptomatic, consider ISDN/ Hydral Treatment of Heart Failure with reduced Ejection Fraction (HFrEF) Stage C and D Sacubitril/ Valsartan A First-in-Class Angiotensin Receptor Neprilysin Inhibitor (ARNI) Natriuretic Peptide System pro-bnp Heart Failure Renin Angiotensin System Angiotensinogen (liver secretion) Inactive fragments BNP Neprilysin X Vasodilation blood pressure sympathetic tone aldosterone levels fibrosis hypertrophy Natriuresis/Diuresis NT-pro BNP O HO HN O OH O Sacubitril (AHU377) LBQ657 LCZ696 O N N N N O OH NH Valsartan X Angiotensin I Angiotensin II AT 1 receptor Vasoconstriction blood pressure sympathetic tone aldosterone fibrosis hypertrophy

12 Enalapril 10 mg bid LCZ mg bid PARADIGM-HF: Study design McMurray JJV, et al. Eur J Heart Fail 2013;15: Double-blind treatment period CHF NYHA Class II-IV, LVEF < 35%, Elevated BNP/ NT-proBNP; on stable standard therapy LCZ mg bid Single-blind run-in period LCZ mg bid N = 8458 pts randomized PARADIGM-HF: Main Results McMurray JJV, et al. N Engl J Med 2014;371: hour washout period Testing tolerability to target doses of Enalapril and LCZ696 Enalapril 10 mg bid On top of standard heart failure therapy (excluding ACEIs and ARBs) 2 weeks 1-2 weeks 2-4 weeks ~ 17 to 52 months (event-driven) Primary outcome: CV death or HF hospitalization (event driven: 2,410 pts with primary events) PARADIGM-HF: Adverse Events McMurray JJV, et al. N Engl J Med 2014;371: PARADIGM-HF: Adverse Events McMurray JJV, et al. N Engl J Med 2014;371:

13 Physicians love ACE inhibitors/ ARBs PARADIGM-HF: Putative Placebo Analysis From Medical School on Decades of familiarity Improves clinical outcomes in multiple disease states Guidelines Quality metrics CV Death + HF Hosp HF Hosp McMurray JJV, et al. Eur Heart J 2015;36: CV Death All-Cause Death Secondary Studies from PARADIGM-HF Sacubitril/Valsartan better than Enalapril in Preventing worsening HF: HF hosp, ED, observation ward, and clinic visits with intensification of therapy for HF (Okumura N, et al. Circulation 2016;133: ) Decreasing recurrent HF hospitalizations (Packer M, et al. Circulation 2015;131:54-61.) Reducing 30-day Rehospitalizations (Desai A, et al. J Am Coll Cardiol 2016;68:241 8.) Improving Health-related quality of life (Lewis EF, et al. Circ Heart Fail 2017 Aug;10(8). pii: e ) Increasing Physical and Social Activity (Chandra A, et al. JAMA Cardiol 2018 Apr 4. doi: /jamacardio ) Secondary Studies from PARADIGM-HF Sacubitril/Valsartan better than Enalapril In all risk levels- MAGGIC, EMPHASIS (Simpson J, et al. J Am Coll Cardiol 2015; 66: ) With/without baseline diuretic, digoxin, MRA, ICD, Coronary revascularization, optimal beta blocker dose, etc. (Okumura N, et al. Circ Heart Fail 2016;9:e ) In all EF ranges <40% (Solomon SD, et al. Circ Heart Fail 2016;9:e ) Regardless of percentage of target dose achieved (Vardeny O, et al. Eur J Heart Fail 2016;18: )

14 2016 ACC/AHA/HFSA Guideline Update: Sacubitril/ Valsartan Yancy CW, et al. J Am Coll Cardiol 2016;68: Treatment of Heart Failure with reduced Ejection Fraction (HFrEF) Stage C and D Ivabradine: Mechanism of Action Psotka M, Teerlink JR. Circulation 2016;133: Hyperpolarization-activated cyclic nucleotidegated (HCN) channels in sino-atrial node Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT) Event-driven, multinational, randomized, double-blind, placebocontrolled, parallel-group trial NYHA II-III, LVEF 35%, NSR>70 bpm, HF Hospitalization within 12 months 6558 total 3268 Ivabradine ( mg bid) 3290 Placebo Median f/u 22±9 (IQR 18 28) months Swedberg K, et al. Lancet 2010; 376: CV Death or HF Hospitalization

15 Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT) Swedberg K, et al. Lancet 2010; 376: Adverse Events in SHIFT Swedberg K, et al. Lancet 2010; 376: CV Death HF Hospitalization Adverse Events in SHIFT Swedberg K, et al. Lancet 2010; 376: Secondary Studies from SHIFT Compared to placebo, Ivabradine Prevented recurrent Heart Failure hospitalizations (Borer JS, et al. Eur Heart J 2012;33, ) Improved health-related quality of life (Ekman I, et al. Eur Heart J 2011;32: ) Effective and safe in patients with Diabetes mellitus (Komajda M, et al. Eur J Heart Fail 2015;17: )

16 Ivabradine Approvals Approved in the US in April 15, Indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction 35%, who are in sinus rhythm with resting heart rate 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. Teerlink JR. Lancet 2010; 376: Relative Contraindications to Beta-blockers in Heart Failure Heart rate <60 bpm Symptomatic hypotension Signs of peripheral hypoperfusion PR interval >0.24 sec Second- or third-degree atrioventricular block (without electronic pacemaker) History of asthma or reactive airways (NOT COPD) Peripheral artery disease with resting limb ischemia 2016 ACC/AHA/HFSA Guideline Update: Ivabradine Yancy CW, et al. J Am Coll Cardiol 2016;68:

17 Digoxin-Associated Mortality in Patients with Atrial Fibrillation or Heart Failure: A Meta-Analysis Vamos M, et al. Eur Heart J 2015; doi: /eurheartj/ehv143. Treatment of Heart Failure with reduced Ejection Fraction (HFrEF) Stage C and D Atrial fibrillation 9 studies of only AF 3 studies of AF + HF Total 235,047 AFib pts Heart Failure 7 studies of only HF 3 studies of AF + HF Total 91,379 HF pts Recommendations for Stage C Heart Failure with preserved Ejection Fraction (HFpEF) Recommendations for Stage C Heart Failure with preserved Ejection Fraction (HFpEF)

18 Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Pitt B, et al. N Engl J Med 2014;370: Randomized, double-blind, placebo-controlled, multicenter trial Target 3515 pts with 1 sign and 1 symptom of HF, LVEF 45%, SBP <140 mm Hg (or 160 mm Hg if 3 BP meds), serum K <5.0 mmol/l; either HF hosp 12 months or BNP 100 pg/ml or NTproBNP 360 pg/ml 3445 pts randomized to Placebo or Spironolactone mg qd Potassium monitored baseline, wks 1 & 4, then q4 mo Hyperkalemia: Spiro 18.7% vs. 9.1% Placebo Hypokalemia: Spirono 16.2% vs. 22.9% Placebo Worsening renal function: Spiro 10.2% vs. 7.0% Placebo; p < TOPCAT: Regional Outcomes Pfeffer MA, et al. Circulation 2015;131: fold greater composite event rate in 1767 enrolled from the United States, Canada, Brazil, Argentina (Americas) compared to the 1678 patients randomized from Russia/Georgia Significant differences in patient characteristics and outcomes Recommendations for Stage C Heart Failure with preserved Ejection Fraction (HFpEF) PDE5i in HFpEF: RELAX (Redfield MM, et al. JAMA 2013;309: ) Nitrates in HFpEF: NEAT-HFpEF (Redfield MM, et al. N Engl J Med 2015;373: ) Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF (INDIE-HFpEF ) Reddy YNV, et al. Circ Heart Fail 2017;10:e Multicenter, randomized, double-blind, placebo-controlled, crossover study 105 Ambulatory patients with HF, 40 yo; LVEF 50%; NYHA II-IV (dyspnea); Evidence of heart failure, with one or more of following criteria within 12 months: Prior HF hosp with CXR demonstrating pulmonary congestion LVEDP at rest 18 mmhg or PCWP at rest 15 mmhg or with exercise 25 mmhg NT-proBNP>400 pg/ml or BNP >200 pg/ml Doppler echo evidence of diastolic dysfunction. Peak VO 2 75% predicted with peak respiratory exchange ratio 1.0 on CPET 1 endpoint: peak VO 2 on CPET after 4 weeks treatment

19 Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF (INDIE-HFpEF ) Borlaug BA, et al. ACC.18 Late-breaking Clinical Trial. Treatment of Heart Failure with reduced Ejection Fraction (HFrEF) Stage C and D Yancy CW, et al. J Am Coll Cardiol 2017; Primary Endpoint Secondary Endpoints Placebo Nitrite Treatment Effect Advanced Therapies: Mechanical Cardiac Support Kirlin JK, et al. INTERMACS Quarterly Report; accessed 23.April, Palliative Care in Heart Failure (PAL-HF Study) Rogers JG, et al. J Am Coll Cardiol 2017;70: Heartmate 3

20 Updates on Heart Failure 2018 Definition, Nomenclature, Epidemiology Evaluation and Diagnosis Treatment of Stages of Heart Failure Co-morbidities Management of Co-morbidities in Patients with Stage C HFrEF Yancy CW, et al. J Am Coll Cardiol 2013;62:e Co-Morbidities: Hypertension Surgical/ Percutaneous/ Transcatheter Interventions in Heart Failure Yancy CW, et al. J Am Coll Cardiol 2013;62:e

21 Multicenter, randomized, open-label, blinded-endpoint assessment trial 1212 patients (July 2002-May 2007): and an ejection fraction of 35% or lower. Coronary artery disease amenable to CABG LVEF 35% Randomized 1:1 to: CABG (n=610) Medical Therapy (n=602) *Also Surgical Ventricular Reconstruction Arm Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) Velazquez EJ, et al. N Engl J Med 2016;374: All-cause Mortality Co-Morbidities: Anemia RED-HF: Darbepoetin alfa, 2278 pts (Swedberg K, et al. N Engl J Med 2013;368: ) All cause death or HF Hosp Co-Morbidities: Iron Deficiency FAIR-HF (459 pts): Anker SD, et al. N Engl J Med 2009;361: CONFIRM-HF (304 pts): Ponikowski P, et al. Eur Heart J 2015;361: endpoint 7020 patients Randomized to Placebo vs. Empagliflozin (10 or 25 mg) Patients were: Type 2 Diabetics Adults ( 18 years of age) BMI 45 egfr 30 ml per minute per 1.73 m2 (MDRD) Established cardiovascular disease Received no glucose-lowering agents for at least 12 weeks before randomization HgbA1c % or had received stable glucose-lowering therapy for at least 12 weeks before randomization and HgbA1c %. Co-Mobidities: Diabetes Mellitus EMPA-REG Outcome Trial Zinman B, et al. N Engl J Med 2015;373: CV Death, nonfatal MI, or nonfatal stroke

22 EMPA-REG Outcome Trial: Heart Failure-related Outcomes Fitchett D, et al. Eur Heart J 2016;37: Co-Morbidities: Hyperkalemia Sarwar CMS, et al. J Am Coll Cardiol 2016;68: Hyperkalemia (K> 5.0 mmol/l): 1-10% in hospitalized patients Patients with CKD, HF, DM 2-3 times higher risk ACEi, ARB, ARNI, MRA can all cause/ exacerbate Sodium polystyrene sulfonate (Kayexalate): Binds Na+, K+, Ca2+, Mg2+ (esp. Ca2+) Works mostly in colon Potential severe GI side effects (colonic necrosis) Co-morbidity: Hyperkalemia Sarwar CMS, et al. J Am Coll Cardiol 2016;68: Co-Morbidities: Sleep-Disordered Breathing Patiromer ZS9

23 Catheter Ablation versus Standard Conventional Therapy in Patients with LV Dysfunction and Atrial Fibrillation (CASTLE-AF) Marrouche NF, et al. N Engl J Med 2018;378: patients: Paroxysmal/ persistent A Fib Absence of response to, unacceptable side effects from, or unwillingness to take antiarrhythmic drugs NYHA II-IV chronic heart failure LVEF 35% Randomized to: Catheter ablation Medical therapy Updates on Heart Failure 2018 Definition, Nomenclature, Epidemiology Evaluation and Diagnosis Treatment of Stages of Heart Failure Co-morbidities Future directions Antithrombotic Therapy in Heart Failure with Normal Sinus Rhythm All Cause Mortality Hopper I, et al. Eur J Heart Fail 2013;15: Cardiovascular Outcome Modification, Measurement AND Evaluation of Rivaroxaban in patients with HF Zannad F, et al. Eur J Heart Fail 2015;17: All Stroke

24 Vericiguat: Soluble Guanylate Cyclase (sgc) Stimulator Armstrong PW, et al. J Am Coll Cardiol HF 2018;6: VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) Armstrong PW, et al. J Am Coll Cardiol HF 2018;6: Target enrollment 4872 Vericiguat 2.5 mg uptitrated to 10 mg qd vs. Placebo Primary Outcome Measure: Time to Cardiovascular (CV) Death or Heart Failure Hospitalization Inclusion Criteria: History of chronic HF (NYHA Class II-IV) on standard therapy before qualifying HF decompensation Previous HF hospitalization within 6 months prior to randomization or intravenous (IV) diuretic treatment for HF (without hospitalization) within 3 months. BNP levels: NSR- 300 pg/ml; A Fib- 500 pg/ml and NT-proBNP levels: NSR pg/ml; A Fib pg/ml within 30 days prior to randomization LVEF<45% assessed within 12 months prior to randomization by any method Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator Mechanochemical Cycle of Myosin OM increases the entry rate of myosin into the tightly-bound, force-producing state with actin More hands pulling on the rope Increases duration of systole Placebo, n= 149; All PK-Titration, n= 146 Overall Effects of Omecamtiv Mecarbil Teerlink JR, et al. Lancet 2016; 388: Force production Malik FI, et al. Science 2011; 331: Shen YT, et al. Circ Heart Fail 2010;3: Planelles-Herrero VJ, et al. Nat Commun 2017;8:190. Increases stroke volume No increase in myocyte calcium No change in dp/dt max No increase in MVO 2 LS, Least square; LVEDD, LVESD: Left ventricular end-diastolic (systolic) dimension; LVFS, left ventricular fractional shortening; SE, standard error; SET, systolic ejection time

25 GALACTIC-HF Chronic HF pts on standard of care therapy, LVEF 35%, NYHA II-IV, HF hospitalization within 12 months, elevated natriuretic peptides 1 endpoint: CV death & HF Hospitalization ~8,000 patient, event-driven trial, powered for CV death NCT clinicaltrials.gov; accessed 10.March, Potential Mechanisms of Improvement in Heart Failure by SGLT2 Inhibition Butler J, et al. Eur J Heart Fail 2017; doi: /ejhf.933. On-going SGLT2 Inhibitor Trials in Heart Failure Butler J, et al. Eur J Heart Fail 2017; doi: /ejhf.933. PARAGON: Study design Solomon SD, et al. JACC Heart Fail 2017;5: yo LVEF 45% LAE or LVH Symptomatic HF (NYHA II-IV) Diuretics for HF 30d AND either: 1) Elevated BNP/ NT-proBNP; or 2) HF Hosp within 9 mo

26 Updates on Heart Failure 2018 Improving Adherence: Focus On The Patient Definition, Nomenclature, Epidemiology Evaluation and Diagnosis Treatment of Stages of Heart Failure Co-morbidities Future directions Care Coordination/Integration Medication and Disease Education Consider Cost and Access Shared Decision Making Domain Management Approach to Heart Failure in the Geriatric Patient Gorodeski EZ, et al. J Am Coll Cardiol 2018;71: More than 50% of HF hospitalizations occur in adults 75 years New proposed model of care for the geriatric HF patient Thank you! San Francisco Veterans Affairs Medical Center

27 Heart Failure Society of America Ms. HCE (Here Comes Everybody): Question #1 Intake sheet reports: 68 yo woman with h/o diabetes mellitus (oral agents), hypertension, COPD, and obesity According to the ACC/AHA 2013/2017 Heart Failure Guidelines, does Ms. HCE have heart failure? A. Yes B. No C. Maybe; Need more information Ms. HCE (Here Comes Everybody) Question #1: Discussion 68 yo woman with h/o diabetes mellitus (oral agents), hypertension, COPD, and obesity Does Ms. HCE have heart failure? A. Yes B. No C. Maybe; Need more information Ms. HCE (Here Comes Everybody) Intake sheet reports: 68 yo woman with h/o diabetes mellitus, hypertension, COPD, and obesity ECG: LAE, LVH, possible inferior MI

28 Ms. HCE (Here Comes Everybody) 68 yo woman with h/o DM, HTM, COPD, and obesity ECG: LAE, LVH, possible inferior MI Reports early satiety, abdominal discomfort, mildly increasing abdominal girth, 5 kg weight gain HR 90 bpm, BP 134/76, RR 14, O2 sat 98% Lungs: clear to A&P CV: JVP~10 cm, -A(H)JR; S1,S2 +S4, no S3, Abd: mild RUQ tenderness, abd distension;?ascites Extrem: No peripheral edema Ms. HCE (Here Comes Everybody) 68 yo woman with h/o diabetes mellitus, hypertension, COPD, and obesity ECG: LAE, LVH, possible inferior MI Reports early satiety, abdominal discomfort, mildly increasing abdominal girth, 5 kg weight gain HR 90 bpm, BP 134/76, RR 14, O2 sat 98% Lungs: clear to A&P CV: JVP~10 cm, -A(H)JR; S1,S2 +S4, no S3, Abd: mild RUQ tenderness, abd distension;?ascites Extrem: No peripheral edema Labs: Na 135, K 3.9, BUN 30, Cr 1.6; BNP 825 pg/ml Echo: moderate LAE, mild LVH, mild LVE, EF 30%, global hypokinesis Ms. HCE : Question #2 68 yo woman with h/o diabetes mellitus, hypertension, COPD, obesity ECG: LAE, LVH, possible inferior MI Reports early satiety, abd discomfort, mildly increasing abd girth, 5 kg weight gain HR 90 bpm, BP 134/76, RR 14, O2 sat 98%; Lungs: clear to A&P CV: JVP~10 cm, -A(H)JR; S1,S2 +S4, no S3, Murmur; Abd: mild RUQ tenderness, abd distension,?ascites; Extrem: No peripheral edema Labs: Na 135, K 3.9, BUN 30, Cr 1.6; BNP 825 pg/ml Echo: moderate LAE, mild LVH, mild LVE, EF 30%, global hypokinesis The optimal initial therapy for this patient is: A. Furosemide 20 mg po qd B. Lisinopril 10 mg po qd C. Furosemide 20 mg po bid and Lisinopril 2.5 mg po qd D. Metoprolol tartrate 25 mg po bid Ms. HCE : Question #2 68 yo woman with h/o diabetes mellitus, hypertension, COPD, obesity ECG: LAE, LVH, possible inferior MI Reports early satiety, abd discomfort, mildly increasing abd girth, 5 kg weight gain HR 90 bpm, BP 134/76, RR 14, O2 sat 98%; Lungs: clear to A&P CV: JVP~10 cm, -A(H)JR; S1,S2 +S4, no S3, Murmur; Abd: mild RUQ tenderness, abd distension,?ascites; Extrem: No peripheral edema Labs: Na 135, K 3.9, BUN 30, Cr 1.6; BNP 825 pg/ml Echo: moderate LAE, mild LVH, mild LVE, EF 30%, global hypokinesis The optimal initial therapy for this patient is: A. Furosemide 20 mg po qd B. Lisinopril 10 mg po qd C. Furosemide 20 mg po bid and Lisinopril 2.5 mg po qd D. Metoprolol tartrate 25 mg po bid

29 Ms. HCE : Question #3 One week later, Ms. HCE presents to clinic with: Improvement in early satiety and abdominal bloating; 5 kg weight loss BP 128/76, HR 84, RR 14; JVP ~6 cm; abdomen soft, non-tender Labs: Na 136, K 3.8, BUN 24, Cr 1.8 An optimal next step would be to: A. Add Carvedilol mg po bid B. Repeat echocardiogram to re-assess EF C. Serially uptitrate Lisinopril to goal of 40 mg po qd with symptom, blood pressure, and lab monitoring D. Add Spironolactone 25 mg po qd Ms. HCE : Question #3 Discussion One week later, Ms. HCE presents to clinic with: Improvement in early satiety and abdominal bloating; 5 kg weight loss BP 128/76, HR 84, RR 14; JVP ~6 cm; abdomen soft, non-tender Labs: Na 136, K 3.8, BUN 24, Cr 1.8 An optimal next step would be to: A. Add Carvedilol mg po bid B. Repeat echocardiogram to re-assess EF C. Serially uptitrate Lisinopril to goal of 40 mg po qd with symptom, blood pressure, and lab monitoring D. Add Spironolactone 25 mg po qd Ms. HCE : Question #4 One year later, Ms. HCE presents to clinic with: Bendopnea; Early satiety and abdominal bloating; 5 kg wt gain; no cough, fever Current meds: Furosemide 40 >80 mg bid; Carvedilol 25 mg bid; Lisinopril 10 mg qd; Spironolactone 25 mg qd BP 128/76, HR 68, RR 18; JVP ~14 cm; abdomen distended, RUQ tenderness; o/w no change Labs: Na 134, K 4.2, BUN 48, Cr 2.8 (from 1.5) An optimal diagnostic step would be to: A. Order BNP (or NT-proBNP) B. Repeat echocardiogram C. Obtain Chest X-ray D. None of the above Question #4: Discussion An optimal diagnostic step would be to: A. Order BNP (or NT-proBNP) B. Repeat echocardiogram C. Obtain Chest X-ray D. None of the above

30 Ms. HCE : Question #5 One year later, Ms. HCE presents to clinic with: Bendopnea; Early satiety and abdominal bloating; 8 kg wt gain; no cough, fever Current meds: Furosemide 40 >80 mg bid; Carvedilol 25 mg bid; Lisinopril 10 mg qd; Spironolactone 25 mg qd BP 128/76, HR 68, RR 18; JVP ~14 cm; abdomen distended, RUQ tenderness; o/w no change Labs: Na 134, K 4.2, BUN 48, Cr 2.8 (from 1.5) An optimal therapeutic diuretic step would be to: A. Increase Furosemide to 160 mg bid B. Increase Spironolactone to 50 mg qd C. Hold all diuretics D. Discontinue Furosemide and start Bumetanide/ Torsemide E. Add Metolazone 5 mg qd Question #5: Discussion One year later, Ms. HCE presents to clinic with: Bendopnea; Early satiety and abdominal bloating; 8 kg wt gain Current meds: Furosemide 40 >80 mg bid; Carvedilol 25 mg bid; Lisinopril 10 mg qd; Spironolactone 25 mg qd BP 128/76, HR 68, RR 18; JVP ~14 cm; abdomen distended, RUQ tenderness; o/w no change Labs: Na 134, K 4.2, BUN 48, Cr 2.8 (from 1.5) An optimal therapeutic diuretic step would be to: A. Increase Furosemide to 160 mg bid B. Increase Spironolactone to 50 mg qd C. Hold all diuretics D. Discontinue Furosemide and start Bumetanide/ Torsemide E. Add Metolazone 5 mg qd Ms. HCE : Question #6 One year later, Ms. HCE presents to clinic with: Bendopnea; Early satiety and abdominal bloating; 8 kg wt gain Current meds: Furosemide 40 >80 mg bid; Carvedilol 25 mg bid; Lisinopril 10 mg qd; Spironolactone 25 mg qd BP 128/76, HR 68, RR 18; JVP ~14 cm; abdomen distended, RUQ tenderness; o/w no change Labs: Na 134, K 4.2, BUN 48, Cr 2.8 (from 1.5) Optimal management of concomitant medications includes: A. Discontinue Carvedilol B. Discontinue Lisinopril C. Discontinue Spironolactone D. Discontinue Carvedilol and Lisinopril E. None of the above Question #6: Discussion One year later, Ms. HCE presents to clinic with: Bendopnea; Early satiety and abdominal bloating; 8 kg wt gain Current meds: Furosemide 40 >80 mg bid; Carvedilol 25 mg bid; Lisinopril 10 mg qd; Spironolactone 25 mg qd BP 128/76, HR 68, RR 18; JVP ~14 cm; abdomen distended, RUQ tenderness; o/w no change Labs: Na 134, K 4.2, BUN 48, Cr 2.8 (from 1.5) Optimal management of concomitant medications includes: A. Discontinue Carvedilol B. Discontinue Lisinopril C. Discontinue Spironolactone D. Discontinue Carvedilol and Lisinopril E. None of the above