Updates in Heart Failure (HF) 2016: ACC / AHA and ESC

Updates in Heart Failure (HF) 2016: ACC / AHA and ESC Patrick McBride, MD, MPH Professor of Medicine & Family Medicine, UW School of Medicine and Public Health Special thanks to: Clyde W. Yancy, MD, MSc Professor of Medicine, Chief, Cardiology Northwestern University, Deputy Editor, JAMA Cardiology Patrick E. McBride, MD, MPH Professor of Medicine and Family Medicine Associate Director, Preventive Cardiology Interim, Associate Dean for Faculty Affairs Senior Research Director, Research Networks ICTR I have no conflicts of interest to disclose 1

Objectives: The diagnosis and treatment of HFrEF* New Epidemiology 2016 Prevention New Guidelines New Therapies New Phenotype *HFrEF = heart failure reduced ejection fraction From: A Contemporary Appraisal of the Heart Failure Epidemic in Olmsted County, Minnesota, 2000 to 2010 JAMA Intern Med. 2015;175(6):996-1004. doi:10.1001/jamainternmed.2015.0924 Figure Legend: Temporal Trends in Heart Failure Incidence Rates Overall and by Reduced or Preserved Ejection Fraction Among Women and Men in Olmsted County, Minnesota, 2000 to 2010Yearly rates (smoothed using 3-year moving average) per 100 000 persons have been standardized by the direct method to the age distribution of the US population in 2010. HFpEF indicates heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction. Copyright 2016 American Medical Association. All rights reserved. 2

A Contemporary Appraisal of the HF Epidemic Age and sex-specific incidence of heart failure has declined 315/100,000 to 219/100,000 Rate reduction of 37.5% Incidence decline was greater for HFrEF 45.1% vs. HFpEF-27.9% Risk for CV death was lower for HFpEFbut the same for non-cv death Hospitalizations have increased 34% Most hospitalizations, 63%, were due to non-cardiovascular causes Thus today s epidemic of heart failure is defined by a marked increase in hospitalizations, predominance of non-cv death rate, and persistence and predominance of HFpEF Roger VL et al. JAMAIntern Med. 2015; April 20. Stages, Phenotypes and Treatment of HF 3

The treatment of HFrEF; 2016- Update New Epidemiology Prevention New Guidelines New Therapies New Phenotype Prevalence and prognostic significance of HF Stages Survival (years) Ammar et al. Circulation 2007; 115:1563 4

Comparison of short-term vs lifetime cumulative risks of CHF for men and women at selected index ages ONE IN FIVE INDIVIDUALS WILL DEVELOP HF FRAMINGHAM Donald M. Lloyd-Jones et al Circulation 2002;106:3068 Lifetime risk for HF; indexed to blood pressure & sex 5

STAGE A HF: Hypertension as a Risk Factor for HF in African Americans Bibbins-Domingo et al. N Engl J Med. 360(12):1179-1190 Incidence of heart failure in young Americans Bibbins-Domingo et al. New England Journal of Medicine. 360(12):1179-1190 6

SPRINT Hypertension Trial Study Design: Randomized Single Blind Primary Outcome Measures: First occurrence of a myocardial infarction (MI), acute coronary syndrome (ACS), stroke, heart failure (HF), or CVD death [ Time Frame: 6 years ] Secondary Outcome Measures: All-cause mortality ; Development of end stage renal disease (ESRD), Dementia, Decline in cognitive function, Small vessel cerebral ischemic disease Estimated Enrollment: 9250 Increased CV risk as defined by SPRINT: clinical or subclinical cardiovascular disease other than stroke; chronic kidney disease, excluding polycystic kidney disease, with an estimated glomerular filtration rate (egfr) of 20 to less than 60 ml per minute per 1.73 m 2 of body-surface area, calculated with the use of the four-variable Modification of Diet in Renal Disease equation; a 10-year risk of cardiovascular disease of 15% or greater on the basis of the Framingham risk score; or an age of 75 years or older 7

Systolic Blood Pressure in the Two Treatment Groups over the Course of the Trial The SPRINT Research Group. N Engl J Med 2015;373:2103-2116 Primary Outcome and Death from Any Cause The SPRINT Research Group. N Engl J Med 2015;373:2103-2116 8

Primary and Secondary Outcomes and Renal Outcomes 38% RR TheSPRINT Research Group. N Engl J Med 2015;373:2103-2116 The diagnosis and treatment of HFrEF New Epidemiology Prevention New Guidelines New Therapies New Phenotype 9

Stages, Phenotypes and Treatment of HF Yancy, C. Jessup M, Bozkurt B. et al. JACC 2013 Pharmacologic Treatment for Stage C HFrEF Yancy, C et al. JACC 2013 10

New Guidelines Have Emerged- 2016 RAASi in Heart Failure and Post-MI LV Dysfunction Post-MI Low EF Mild-Mod CHF Low EF CHF Severe HF CHF Preserved EF ACEi 1 AIRE SAVE SOLVD CONSENSUS PEP-CHF (perindopril) MRA EPHESUS 1 (eplerenone) EMPHASIS 1 (eplerenone) RALES 1 (spironolactone) TOPCAT 2 (spironolactone) ARB 1 OPTIMAAL VALIANT ELITE-II HEALL VAL-HeFT CHARM CHARM-Preserved I-PRESERVE ARNI 3 PARADIGM-HF (LCZ-696) RAASi=renin-angiotensin-aldosterone inhibitor; MI=myocardial infarction; EF: ejection fraction; CHF=chronic heart failure; ACEi=angiotensin-converting enzyme inhibitor; MRA=mineralocorticoid receptor antagonist; ARB=angiotensin II receptor blocker; ARNI=angiotensin receptor-neprilysin inhibitor. 1. Mentz RJ, et al. Int J Cardiol. 2013:167:1677-1687. 2. Pitt B, et al. N Engl J Med. 2014;370(15):1383-1392. 3. McMurray JJV, et al. N Engl J Med 2014;371:993-1004. 11

RAAS inhibition- 2016 ACE-I & ARB -2016 12

ARNI 2016 ARNI (Harm) 2016 13

Ivabradine 2016 ESC HF Guidelines 2016 14

ESC HFrEF Treatment Algorithm The treatment of HFrEF: 2016 - Update New Epidemiology Prevention New Guidelines New Therapies New Phenotype 15

Effects of Neprilysin Inhibition in Heart Failure Endogenous vasoactive peptides (natriuretic peptides, adrenomedullin, bradykinin, substance P, calcitonin gene-related peptide) Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Na+ retention Neprilysin Neprilysin inhibition Inactive metabolites McMurray JJV, et al. N Engl J Med. 2014;371:993-1004. PARADIGM-HF: Primary Endpoint of CV Death or Heart Failure Hospitalization Cumulative Probability Number at Risk Sac/Val Enalapril 1.0 0.6 0.5 0.4 0.3 0.2 0.1 Number needed to treat = 21 Enalapril 1117 events (26.5%) 0 0 180 360 540 720 900 1080 Days since Randomization 4187 4212 3922 3883 3663 3579 HR 0.80 (95% CI, 0.73 0.87), p<0.001 3018 2922 2257 2123 1544 1488 Sac/Val 914 events (21.8%) 896 853 1260 249 236 Sac/Val = Sacubitril/Valsartan. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004. 16

PARADIGM-HF: Effect of Sac/Val vs. Enalapril on the Primary Endpoint and Its Components 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) <0.001 Cardiovascular death 558 (13.3%) 693 (16.5%) 0.80 (0.71 0.89) <0.001 Hospitalization for heart failure 537 (12.8%) 658 (15.6%) 0.79 (0.71 0.89) <0.001 Sac/Val = Sacubitril/Valsartan. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004. Sac/Val vs. Enalapril on Primary Endpoint and on CV Death by Subgroups Subgroup All Patients Age <65 years 65 years Sex Male Female NYHA Class I or II III or IV Estimated GFR <60 ml/min/1.73 m 2 60 ml/min/1.73 m 2 Ejection fraction 35% >35% NT-proBNP Median >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 Sac/Val 4187 2111 2076 3308 879 3187 1002 1541 2646 3715 472 2079 2103 1218 2969 921 3266 1916 2271 1580 2607 No. Enalapril 4212 2168 2044 3259 953 3130 1076 1520 2692 3722 489 2116 2087 1241 2971 946 3266 1812 2400 1545 2667 Primary Endpoint Hazard Ratio (95% CI) p-value for Interaction 0.47 0.63 0.03 0.91 0.36 0.16 0.87 0.09 0.10 0.10 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 Death from Cardiovascular Causes Hazard Ratio p-value for (95% CI) Interaction 0.70 0.92 0.76 0.73 0.36 0.33 0.14 0.06 0.32 0.19 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 Sac/Val Better Enalapril Better McMurray JJV, et al. N Engl J Med. 2014;371:993-1004. Sac/Val Better Enalapril Better 17

PARADIGM-HF: Adverse Events Prospectively identified adverse events Sac/Val (n=4187) Enalapril (n=4212) p- Value Symptomatic hypotension 14.0% 9.2% <0.001 Serum potassium > 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% <0.001 Discontinuation for adverse event 10.7% 12.3% 0.03 Discontinuation for hypotension 0.9% 0.7% 0.38 Discontinuation for hyperkalemia 0.3% 0.4% 0.56 Discontinuation for renal impairment 0.7% 1.4% 0.002 Angioedema (adjudicated) Medications, no hospitalization 6 (0.1%) 4 (0.1%) 0.52 Hospitalized; no airway compromise 3 (0.1%) 1 (<0.1%) 0.31 Airway compromise 0 0 McMurray JJV, et al. N Engl J Med. 2014;371:993-1004. Brand name Indication Dosage Renal/hepatic impairment Switching from an ACE inhibitor Contraindications Side effects New FDA-Approved Sacubitril / Valsartan Sacubitril/Valsartan Entresto The fixed-dose combination of the neprilysin inhibitor sacubitril and the ARB valsartan is indicated to reduce the risk of CV death and HF hospitalization in patients with HF with reduced ejection fraction. Start with 49/51 mg twice daily. Double the dose after 2 4 weeks as tolerated to maintenance dose of 97/103 mg twice daily. For patients not currently taking an ACEI or ARB, or for those with severe renal impairment (egfr <30 ml/min/1.73 m 2 ) or moderate hepatic impairment, start with 24/26 mg twice daily. Stop ACE inhibitor for 36 hours before starting treatment. History of angioedema related to previous ACE inhibitor or ARB, concomitant use of ACE inhibitors, concomitant use of aliskiren in patients with diabetes. WARNING pregnancy, hyperkalemia. Hypotension, hyperkalemia, cough, dizziness, renal failure, and angioedema (0.5% Sac/Val vs. 0.2% Enalapril). http://www.pdr.net/full-prescribing-information/entresto?druglabelid=3756. Accessed October 20, 2015. 18

Practical Points on Use of Sacubitril / Valsartan Starting dose is 24 / 26 mg twice daily, unless patient is currently tolerating full dose ACEI or ARB in which case start 49 / 51 mg twice daily Target dose is 97 / 103 mg twice daily After 2-4 weeks up-titrate to next dose with ultimate goal to achieve target dose Monitor SBP, renal function and K as you would with ACEI or ARB use Space out dosing from other vasoactive medications if needed Adjust diuretics doses based on volume status Ivabradine Acts by inhibiting the If channel, present in the cardiac SA node Reduces elevated HR SA node Evaluated as treatment of HFrEF who have a resting HR of at least 70 beats per minute, in sinus rhythm, and who are also taking the highest tolerable dose of a beta blocker DiFrancesco D. Curr Med Res Opin. 2005;21:1115-1122. 19

SHIFT Study: Primary Endpoint of CV Death or Hospitalization for Worsening HF Patients with Primary Endpoint (%) 40 30 20 10 0 Ivabradine (n=3241) Placebo (n=3264) Placebo 937 events (29%) Ivabradine 793 events (24%) HR 0.82 (95% CI, 0.75 0.90) p<0.0001 ARR = 5%, NNT = 20 0 6 12 18 24 30 Months 18% Swedberg K, et al. Lancet. 2010;376:875-885. SHIFT Study: Effect of Ivabradine on Outcomes Endpoint Ivabradine (n=3241) Placebo (n=3264) HR p-value Primary endpoint 24% 29% 0.82 <0.0001 All-cause mortality 16% 17% 0.90 0.092 Death from HF 3% 5% 0.74 0.014 All-cause hospitalization 38% 42% 0.89 0.003 Any CV hospitalization 30% 34% 0.85 0.0002 CV death, hospitalization for worsening HF, or hospitalization for non-fatal MI 25% 30% 0.82 <0.0001 Swedberg K, et al. Lancet. 2010;376:875-885. 20

New FDA-Approved Ivabradine Ivabradine Brand name Indication Dosage Contraindications Corlanor To reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with LVEF 35% who are in sinus rhythm with resting HR 70 bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. Start with 5 mg twice daily. After 2 weeks of treatment, adjust dose based on HR. Max is 7.5 mg twice daily. In patients with conduction defects or in whom bradycardia could lead to hemodynamic compromise, start with 2.5 mg twice daily. Acute decompensated HF; BP <90/50 mmhg; sick sinus syndrome or third-degree AV block, unless a functioning demand pacemaker is present; resting HR < 60 bpm prior to treatment; severe hepatic impairment; pacemaker dependence. WARNING fetal toxicity. Side effects Occurring in 1% of patients are bradycardia, hypertension, atrial fibrillation, and luminous phenomena (phosphenes). http://www.pdr.net/full-prescribing-information/corlanor?druglabelid=3713. Accessed October 20, 2015. Practical Use of Ivabradine Starting dose is 5 mg twice daily Target HR is 50-60 bpm After 2 weeks: If HR >60 bpm: Increase dose to 7.5 mg twice daily (Max dose) If HR 50-60 bpm: Maintain initial dose If HR <50 bpm or symptomatic bradycardia: Lower dose to 2.5 mg twice daily If HR <50 bpm or symptomatic bradycardia and dose is 2.5 mg twice daily: Discontinue 21

Pharmacologic Treatment for Stage C HFrEF Strategies: Disease Management Remote PA monitoring Process Improvement Patient Education Frailty Assessment Palliative Care Genetic Counseling? Valsartan/Sacubutril? Ivabradine From: Potential Mortality Reduction With Optimal Implementation of Angiotensin Receptor Neprilysin Inhibitor Therapy in Heart Failure JAMA Cardiol. Published online June 22, 2016. doi:10.1001/jamacardio.2016.1724 Table Title: Demonstrated Benefits of Evidence-Based Therapies for Patients With Heart Failure and Reduced Ejection Fraction Date of download: 7/11/2016 Copyright 2016 American Medical Association. All rights reserved. 22

The treatment of HFrEF: 2016 - Update New Epidemiology Prevention New Guidelines New Therapies New Classification A new classification? ESC HF GUIDELINES 2016 23

Definition of Heart Failure- ACC/AHA 2013 Classification I. Heart Failure with Reduced Ejection Fraction (HFrEF) Ejection Fraction Description 40% Also referred to as systolic HF. Randomized clinical trials have mainly enrolled patients with HFrEF and it is only in these patients that efficacious therapies have been demonstrated to date. II. Heart Failure with Preserved Ejection Fraction (HFpEF) 50% Also referred to as diastolic HF. Several different criteria have been used to further define HFpEF. The diagnosis of HFpEF is challenging because it is largely one of excluding other potential noncardiac causes of symptoms suggestive of HF. To date, efficacious therapies have not been identified. a. HFpEF, Borderline 41% to 49% These patients fall into a borderline or intermediate group. Their characteristics, treatment patterns, and outcomes appear similar to those of patient with HFpEF. b. HFpEF, Improved >40% It has been recognized that a subset of patients with HFpEF previously had HFrEF. These patients with improvement or recovery in EF may be clinically distinct from those with persistently preserved or reduced EF. Further research is needed to better characterize these patients. Yancy C et al, JACC 2013 Taking the failure out of HF -2016 ***We can prevent the progression of HF Greater use of PREVENTION, DIAGNOSIS, imaging, prognosis & treatment ; early introduction of RAAS inhibitors Quality Improvement Still with untapped effectiveness MAXIMIZE THERAPY! Device therapy (ICD/CRT) as indicated New drug therapies- ARNI (Sacubitril / Valsartan); Ivabradine Personalized Therapy driven by Pharmacogenomics -Future? Stem cells Gene Transfer; Growth Factors, Gene Editing 24

Thank You! From: Characteristics and Outcomes of Adult Outpatients With Heart Failure and Improved or Recovered Ejection Fraction JAMA Cardiol. Published online July 06, 2016. doi:10.1001/jamacardio.2016.1325 Figure Legend: Kaplan-Meier Curves, Adjusted for Age and Sex, Across the 3 Heart Failure GroupsThe stratified log-rank χ 2 2 was 15.0 (P <.001) for difference in mortality between groups. HFpEF indicates heart failure with preserved ejection fraction; HFrecEF, heart failure with recovered ejection fraction; and HFrEF, heart failure with reduced ejection fraction. Date of download: 7/11/2016 Copyright 2016 American Medical Association. All rights reserved. 25