Cardiology Experts in Residence: Focus on Managing Patients with Chronic Heart Failure - PowerPoint Presentation

Cardiology Experts in Residence: Focus on Managing Patients with Chronic Heart Failure Ileana L Piña, MD, MPH Professor, Department of Medicine Professor, Department of Epidemiology & Population Health Albert Einstein College of Medicine Associate Chief of Cardiology Montefiore Medical Center Bronx, New York

Learning Objectives Upon completion of this program, participants should be able to: Construct appropriate pharmacological regimens based upon an understanding of the pathophysiologic mechanisms of heart failure Individualize treatment to reduce the burden of secondary heart failure hospitalizations Initiate and titrate evidence-based guideline-directed medical treatment Integrate new heart failure medications into patient management Implement strategies to improve patient self-management Implement strategies to address institutional gaps in inpatient, transitional, and outpatient practice/care

Module 1: Pathophysiology Upon completion of this module, participants should be able to: Construct appropriate pharmacological regimens based upon an understanding of the pathophysiologic mechanisms of heart failure

¯ LV Function ­ Impedance Salt and Water Retention Progressive Heart Failure ¯ Cardiac Output Neurohormone Activation RAA System Catecholamines ANF Coronary heart disease Hypertension Cardiomyopathy Pathogenesis of CHF: Neurohormonal Hypothesis ANF, atrial natriuretic factor; RAA, renin-angiotensin-aldosterone system

Adapted from Dzau and Braunwald. Am Heart J . 1991;121(4 Part 1):1244-1263. Risk factors Hyperlipidemia Hypertension Diabetes Insulin resistance Atherosclerosis Left Ventricular Hypertrophy Coronary Artery Disease Myocardial ischemia Coronary thrombosis Myocardial infarction Loss of muscle Arrhythmia Sudden death Remodeling Ventricular dilation Heart failure Death A B C D From Risk Factors to Heart Failure: The Cardiovascular Continuum

What Should the Target Systolic Blood Pressure Be? 9361 persons with SBP ≥130 mm Hg + ↑ CV risk (but not diabetes) Randomized to Standard treatment to achieve SBP <140 mm Hg Intensive treatment to achieve SBP <120 mm Hg Treatment algorithm similar to ACCORD Trial stopped early at a median follow-up of 3.26 yearsAt 1 year, the mean SBP was136.2 mm Hg (standard)121.4 mm Hg (intensive) Outcome % per Year Hazard Ratio P Intensive Standard Primary*1.65 2.19 0.75 <0.001 MI0.65 0.78 0.83 0.19 ACS 0.270.27 1.000.99Stroke 0.410.470.89 0.50 HF 0.41 0.67 0.62 0.002 CV Death 0.25 0.43 0.57 0.005 All-cause Death 1.03 1.40 0.73 0.003 ACCORD, Action to Control Cardiovascular Risk in Diabetes trial; ACS, acute coronary syndrome; CV, cardiovascular; HF, heart failure; MI, myocardial infarction; SBP, systolic blood pressure Wright JT, et al for the Sprint Research Group. N Engl J Med . 2015;373(22):2103-2116. *Composite of MI, other ACS, stroke, HF, or CV death

Blood Pressure Goals In patients at increased risk, stage A heart failure, the optimal blood pressure in those with hypertension should be <130/80 mm Hg Patients with HF r EF and hypertension should be prescribed GDMT titrated to attain SBP <130 mm Hg Patients with HF p EF and persistent hypertension after management of volume overload should be prescribed GDMT titrated to attain SBP <130 mm Hg GDMT, guideline-directed medical therapy; HFpEF ,  heart failure with a preserved ejection fraction; HFrEF, HF with reduced ejection fraction; SBP, systolic blood pressureYancy CW, et al. Circulation. 2017; doi: 10.1161/CIR.0000000000000509.

Neurohormonal Activation in Heart Failure Cohn JN. Cardiology . 1997;88(suppl 2):2–6. Levels Plasma Norepinephrine (pg/mL) 600 500 400 300 200 100 0 NL HF Plasma Renin Activity (ng/mL/h) 15 12 9 6 3 0 NL HF Arginine Vasopressin (pg/mL) 12 6 4 2 0 NL HF Atrial Natriuretic Peptide (pg/mL) 300 250 200 150 100 50 0 NL HF 8 6 4 0 NL HF 2 Endothelin-1 (pg/mL)

Deleterious Effects of Norepinephrine and the Sympathetic Nervous System Increased left ventricular volumes and pressure Peripheral vasoconstriction Impaired sodium excretion by the kidneys Left ventricular hypertrophy Arrhythmias Increased automaticity of cardiac cells Increased triggered activity in the heart Increased risk of hypokalemia Apoptosis Stimulation of cellular growth and oxidative stress Steering Committee and Membership of the Advisory Council to Improved Outcomes Nationwide in Heart Failure. Am J Cardiol . 1999;83(Suppl 1):1A-38A.

Angiotensinogen Angiotensin I Angiotensin II Sodium and fluid retention Vasoconstriction Sympathetic activation Cell growth AT 1 -receptor Non-ACE pathways Tissue plasminogen activator Cathepsin G Chymase CAGE Renin ACE ACE pathways Bradykinin Inactive fragments ACE, angiotensin converting enzyme; CAGE, chymotrypsin-like angiotensin-generating enzyme Hollenberg NK, et al. Hypertension. 1998;32(3):387-392. Renin-Angiotensin-Aldosterone System and Cardiovascular Disease

Deleterious Effects of Angiotensin II Myocyte growth Vascular smooth muscle growth  Collagen Remodeling  PAI-1/ thrombosis Platelet aggregation Superoxide production  Vasopressin Activate SNS  Aldosterone  Endothelin Abnormal vasoconstriction Angiotensin II PAI-1, plasminogen activator inhibitor-1; SNS, sympathetic nervous system Burnier M, et al. Lancet. 2000;355:637-645.Brown NJ, et al. Adv Intern Med. 2000;45:419-429

Module 2: Current Management Upon completion of this module, participants should be able to: Individualize treatment to reduce the burden of secondary heart failure hospitalizations Initiate and titrate evidence-based guideline-directed medical treatment Implement strategies to improve patient self-management

Therapeutic Objectives: Clinical Improve functional capacity Improve survival Proactive clinical care Reduce heart failure-related hospitalizations Improve symptoms and health status

Therapeutic Objectives: Pathogenesis Protect/Preserve myocardium RAAS inhibitors  -blockers Improve hemodynamics Digoxin Diuretics Hydralazine/Nitrates Prevent ischemic events Revascularization Antiplatelet agents Statins Prevent sudden arrhythmic death -blockersImplantable cardioverter-defibrillator RAAS, renin-angiotensin-aldosterone system

Management of Heart Failure HF p EF , heart failure with preserved ejection fraction; HF r EF , heart failure with reduced ejection fraction Yancy CW, et al. Circulation . 2013;128:e240-e327. Assess etiology Plan treatment strategyHFp EFHFr EFTreatment directed at signs and symptoms, hemodynamics, etiology Guideline-directed medical therapy

Key treatment Diuretic If fluid retention Coronary revascularization If angina or demonstrable myocardial ischemia despite GDMT Bloo d pressure control - blocker, ACEI, ARB according to published guidelines Atrial fibrillation According to published guidelines Other Aldosterone antagonist (to decrease hospitalizations) If EF ≥45%, elevated BNP levels or HF admission within 1 year, eGFR >30 mL/min , Cr <2.5 mg/dL, K + <5.0 mEq/L Pharmacological Therapy of Stage C HF p EF ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; Cr, serum creatinine; EF, ejection fraction; eGFR , estimated glomerular filtration rate; GDMT, guideline-directed medical therapy; HF, heart failure; K + , serum potassium levelYancy CW, et al. Circulation. 2017; doi: 10.1161/CIR.0000000000000509.

a ARNI is associated with hypotension. ARNI is approved for symptomatic HF r EF and is intended to be substituted for ACEI and ARB therapy. b Combination of hydralazine/isosorbide dinitrate with ARNI has not been robustly tested. BP response should be carefully monitored. c Receiving optimal treatment with ACEI and BB. ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor- neprilysin inhibitor; BB,  -blocker; BP, blood pressure; C/I, contraindication; CrCl , creatinine clearance; GDMT, guideline-directed medical therapy; HFrEF, HF with reduced ejection fraction; HR, heart rate; NSR, normal sinus rhythmYancy CW, et al. Circulation. 2017; doi: 10.1161/CIR.0000000000000509. Continue GDMT with serial reassessment and optimized dosing/adherenceRecommendations for Pharmacological Therapy of Stage C HFr EF

Recommendations for Device Therapy of Stage C HF r EF* ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB,  -blocker; CRT-D, cardiac resynchronization therapy-device; GDMT, guideline-directed medical therapy; HFrEF , HF with reduced ejection fraction; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSR, normal sinus rhythm; QRS, QRS interval Yancy CW, et al. Circulation . 2017; doi: 10.1161/CIR.0000000000000509.Continue GDMT with serial reassessment and optimized dosing/adherence

Digoxin ACE Inhibitors - blockers Diuretics Vasodilators ¯ LV Function ­ Impedance Salt and Water Retention Progressive Heart Failure ¯ Cardiac Output Neurohormone Activation RAA System Catecholamines ANF Coronary heart disease Hypertension Cardiomyopathy Mechanisms of Action of Medications for Heart Failure

AT 1 R Liver Angiotensinogen Angiotensin I Angiotensin II Kidney Renin DRI Chymase ARB Bradykinin Breakdown products ACTH K + Aldosterone MR MRA Corticosteroids β -blocker Adrenal gland ACE ACE inhibitor Key Therapeutic Targets in Heart Failure ACE, angiotensin converting enzyme; ACTH, adrenocorticotropic hormone ( corticotropin ); ARB, angiotensin receptor blocker; AT1R, angiotensin II type 1 receptor; DRI, direct renin inhibitor; K+, potassium ion; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonistAtlas SA. J Manag Care Pharm . 2007;13(8 Suppl S-b):S9-S20.

Drugs that Reduce Mortality in HF rEF Reduction in Mortality (%) Angiotensin Receptor Blocker 1 Angiotensin Converting Enzyme Inhibitor 2 - Blocker 3,4 Mineralocorticoid Receptor Antagonist 5,6 Summary of Data from CHARM-LowEF, 1 CIBIS II, 3 EMPHASIS-HF,5 MERIT-HF, 4 RALES,6 and SOLVD-Treatment2HFrEF, HF with reduced ejection fraction 1. Young JB, et al. Circulation. 2004;110(17):2618-2626; 2. SOLVD Investigators. N Engl J Med. 1991;325(5):293-302; 3. CIBIS II Investigators. Lancet 1999;353(9146):9-13; 4. MERIT-HF Study Group. Lancet 1999;353(9169):2001-2007; 5. Zannad F, et al. N Engl J Med 2011; 364(1):11-21; 6. Pitt B, et al. N Engl J Med. 1999;341(10):709-717.

Cumulative Benefit of Poly-Pharmacy and Cardiac Resynchronization Therapy in Severe Heart Failure ACEI ACEI + AA + BB 27 . 3 21 12 . 8 12 . 6 9 . 7 35 ACEI + AA ACEI + AA ACEI + AA + BB ACEI + AA + BB + CRT 19 . 7 5 10 15 20 25 30 0 1-year m ortality (%) RALES 1999 1 COPERNICUS 2001 CARE-HF 2005 AA, aldosterone antagonist; ACEI, angiotensin converting enzyme inhibitor; BB,  -blocker; CRT, cardiac resynchronization therapy 1. Zannad F, et al. N Engl J Med 2011; 364(1):11-21;

Device Therapy in HFr EF Implantable cardioverter-defibrillator (ICD) Mortality benefit in Ischemic heart disease 1 Idiopathic and ischemic heart disease 2 Consider in patients who are stable, survival >1 year, low ejection fraction despite guideline-directed medical therapy Cardiac resynchronization therapyAdditional mortality benefit when combined with ICD therapy3,4 HFrEF, HF with reduced ejection fractionMoss AJ, et al. N Engl J Med . 2002;346(12):877-883. Bardy GH, et al. N Engl J Med. 2005;352(3):225-237.Moss AJ, et al. N Engl J Med. 2009;361;1329-1338. Tang AS, et al. N Engl J Med. 2010;363(25):2385-2395.

Association Between Hypertension, Obesity, Diabetes and Heart Failure HF, heart failure Ahmad FS, et al. JACC Heart Fail . 2016;4;911-919. Prevention of hypertension, obesity, and diabetes by ages 45 and 55 years may substantially prolong HF-free survival and ↓HF-related morbidity.

Module 3: New Medications Upon completion of this module, participants should be able to: Integrate new heart failure medications into patient management

Ivabradine: Pure Heart Rate Reduction I f (funny channel) inhibition reduces the diastolic depolarization slope, and thereby lowers heart rate Thollon C, et al . Br J Pharmacol . 1994 ; 112(1) : 37-42 . RR Pure heart rate reduction 0 mV -40 mV -70 mV closed open closed Ivabradine ∆RR, change in the R-R interval ∆ 

SHIFT: Patients and Follow-up Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81. *Based on heart rate and tolerability BID, twice daily Study duration: Median: 22.9 months Maximum: 41.7 months 6558 randomized 3268 to ivabradine 5 mg BID; then 7.5 mg/2.5 mg BID* 3290 to matching placebo 3264 analyzed 1 lost to follow-up 3241 analyzed 2 lost to follow-up 7411 screened Excluded: 27 Excluded: 26

∆KCCQ Overall Summary Score ∆KCCQ Clinical Summary Score P <0.001 P =0.018 Ekman I, et al. Eur Heart J. 2011;32(19):2395-2404. *Prespecified analysis using Kansas City Cardiomyopathy Questionnaire (KCCQ) SHIFT: Improved Quality of Life with Ivabradine*

HFrEF , HF with reduced ejection fraction; LVESVI, left ventricular end systolic volume index Tardif JC, et al. Eur Heart J . 2011; 32:2507-2515. 0 50 75 70 65 60 55 D - 7.0 mL/m 2 D - 0.9 mL/m 2 = -5.8; P =0.0002 Baseline Month 8 Ivabradine (n=208) Baseline Month 8 Placebo (n=203) LVESVI, mL/m 2 Heart Rate Reduction and Cardiac Function in HF r EF

Effect of Ivabradine on Heart Rate by Categories of Baseline  -Blocker Doses and Baseline Heart Rate Swedberg K, et al. J Am Coll Cardiol . 2012;59(22):1938-1945. Note: ~25% of patients reached recommended target dose of  -blockers; ~50% achieved ≥50% of target dose

Clinical Implications of Heart Rate Reduction with Ivabradine In patients with chronic HF and in sinus rhythm with heart rate ≥70 bpm and already receiving recommended therapies, isolated HR reduction substantially improves outcomes in addition to those achievable with beta blockade, including Reduction in CV death or HF hospitalizations Improvement in LV function Reduction in total hospitalizations during prolonged interval Improvement in health-related quality of life These benefits reduce the total burden of HF Reduction in hospitalizations also can be expected to substantially reduce health care costs CV, cardiovascular; HF, heart failure; LV, left ventricular

Effect of Heart Rate Variation on Cardiovascular Outcomes* Placebo Ivabradine Coefficient of HR Variation (HR-CV) Mean HR HFrEF , HF with reduced ejection fraction; HR, heart rate Bohm M, et al. J Am Heart Assoc . 2016;5:e002160.*Composite of cardiovascular death or heart failure hospitalization PlaceboIvabradineClear association between higher mean heart rate and increased risk of composite endpoint and in both placebo and ivabradine groups Lowest HR-CV tertile had highest risk of composite endpoint with placebo, indicating low visit-to-visit variation of HR might signal increased risk of cardiovascular outcomes in HF rEF. Note that ivabradine increases visit-to-visit variation of HR, which may explain the decreased risk of cardiovascular outcomes.Years YearsYears Years

SHIFT: Adverse Events with Ivabradine Adverse events with rates ≥1.0% higher on ivabradine than placebo occurring in >1% on ivabradine Ivabradine (n=3260) Placebo (n=3278) Bradycardia 10% 2.2% Hypertension, blood pressure increased 8.9% 7.8% Atrial fibrillation 8.3% 6.6% Phosphenes, visual brightness 2.8% 0.5% Ivabradine [package insert]. Thousand Oaks, CA: Amgen Inc.; April 2015.

Ivabradine Initiation Prior to Discharge: PRIME-HF Primary objective Test if a treatment strategy of initiating ivabradine prior to discharge for a hospitalization for acute HF will be associated with a greater proportion of patients using ivabradine at 180 days compared with usual care Secondary objectives Assess change in heart rate from baseline to 180 days Assess median heart rate at 180 days Assess change in symptoms and quality of life from baseline to 180 days Assess safety and tolerability of ivabradine from baseline to 180 days Patients Age ≥18 y, hospitalized for acute HF, receiving optimized GDMT for HF rEFEstimated study completion date: July 2018 GDMT, guideline-directed medical therapy; HF, heart failure; HFrEF, HF with reduced ejection fractionClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02827500. Accessed May 16, 2017.

Ivabradine: Tips for Use Indication: to reduce the risk of hospitalization for worsening heart failure Appropriate patients Stable, symptomatic chronic heart failure and Left ventricular ejection fraction ≤35% and Sinus rhythm with resting heart rate ≥70 bpm and Taking maximally tolerated dose of  -blocker unless -blockers are contraindicated Ivabradine [package insert]. Thousand Oaks, CA: Amgen Inc.; April 2015.

Ivabradine : Tips for Use (cont ) Inappropriate patients Acute decompensated heart failure Blood pressure <90/50 mm Hg Sick sinus syndrome, sinoatrial block, 3 rd degree AV block, unless functioning demand pacemaker Heart rate (resting) <60 bpmSevere hepatic impairmentIn combination with strong CYP3A4 inhibitorsPacemaker dependent AV, atrioventricular; CYP3A4, cytochrome P450 3A4 Ivabradine [package insert]. Thousand Oaks, CA: Amgen Inc.; April 2015.

Ivabradine : Tips for Use (cont ) Dosing Begin a 5 mg twice daily* Titrate to maximum of 7.5 mg twice daily based on heart rate Females should use effective contraception Pregnant females should not use ivabradine Monitor for atrial fibrillation Monitor heart rate decreases, symptoms of bradycardia Not recommended in presence of 2nd degree AV block unless a functioning pacemaker is in placeAV, atrioventricular block *2.5 mg twice daily in patients with conduction defects or in whom bradycardia could lead to hemodynamic compromiseCorlanor [package insert]. Thousand Oaks, CA: Amgen Inc.; April 2015.

Sacubitril/Valsartan– Simultaneous Inhibition of Neprilysin and Renin Angiotensin System AT 1 receptor Angiotensinogen (liver secretion) Angiotensin I Angiotensin II Valsartan Renin Angiotensin System Vasoactive Peptide System Vasodilation  blood pressure  sympathetic tone aldosterone level fibrosis hypertrophy Natriuresis /diuresis Inactive fragments X Neprilysin Vasoconstriction  blood pressure  sympathetic tone  aldosterone level fibrosis hypertrophy X Heart Failure pro-BNP NT-pro BNP ANP BNP CNP Adrenomedullin Bradykinin Substance P (angiotensin II) Sacubitril (AHU377) ↓ LBQ657

PARADIGM-HF: Sacubitril/Valsartan vs Enalapril Primary endpoint: CV death or heart failure hospitalization (event driven: 2,410 patients with primary events) ACEIs, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; CV, cardiovascular; S/V, sacubitril /valsartan ‡ Enalapril 5 mg bid for 1-2 weeks followed by enalapril 10 mg bid as an optional starting run-in dose for patients who are treated with ARBs or with low-dose ACEIMcMurray JJV, et al. Eur J Heart Fail. 2013;15:1062-1073. 2 weeks ~ 21 to 43 months (event-driven) Randomization (N = 8442 patients) Enalapril 10 mg bid Sacubitril/Valsartan 200 mg bid S/V 200 mg bid On top of standard heart failure therapy (excluding ACEIs and ARBs)Testing tolerability to target doses of enalapril and sacubitril/valsartanS/V 100 mg bid Enalapril 10 mg bid ‡ 1-2 weeks 2-4 weeks Single-blind run-in periodDouble-blind randomized treatment period1:1 randomization

1. SOLVD Investigators. N Engl J Med . 1991;325:293-302. 2. McMurray JJV, et al. N Engl J Med . 2014;371(11):993-1004. *Not head-to-head comparisons. In SOLVD, 7% of placebo patients and 8.3% of enalapril patients were taking a  -blocker. In PARADIGM-HF, 93.1% of sacubitril/valsartan patients and 92.9% of enalapril patients were taking a -blocker. 16% relative reduction 16% relative reduction 12 Sacubitril/Valsartan Augments the Survival Benefit of ACE Inhibition*

PARADIGM-HF: Clinical Outcomes by Age CV, cardiovascular; HF, heart failure Jhund PS, et al. Eur Heart J . 2015;36:2576-2584. Sacubitril/Valsartan was more beneficial than enalapril across the spectrum of age

PARADIGM-HF: Heart Failure Symptoms and Physical Limitations KCCQ, Kansas City Cardiomyopathy Questionnaire Lewis EF, et al. J Card Fail . 2016;22(8Suppl):S24. Abstract 064. Sacubitril /Valsartan improved the symptoms and physical limitations of heart failure more than enalapril; P =0.001

Age 55 years Age 65 years P =0.07 P <0.001 P <0.001 P =0.01 CV, cardiovascular; HF, heart failure Claggett B, et al. N Engl J Med . 2015;373(23):2289-2290. Long-Term Benefit of Sacubitril /Valsartan

PARADIGM-HF: Adverse Events Sacubitril/Valsartan (n=4187) Enalapril (n=4212) P value Prospectively identified adverse events Symptomatic hypotension 14.0% 9.2% <0.001 Serum potassium >6 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 0.02 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) Catecholamines /glucocorticoids, no hospitalization 0.1% 0.1% 0.52 Hospitalized, no airway compromise 0.1% <0.1% 0.31 Airway compromise 0% 0% — McMurray JJV, et al. N Engl J Med . 2014;371(11):993-1004

Sacubitril /Valsartan: Tips for Use Indication: to reduce the risk of cardiovascular death and hospitalization for heart failure Appropriate patients Chronic heart failure (NYHA II-IV) and reduced ejection fraction Usually in conjunction with other heart failure therapies, in place of ACE inhibitor or ARB Inappropriate patients History of angioedema related to ACE inhibitor or ARB Concomitant use with ACE inhibitor Concomitant use with aliskiren in patients with diabetes ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; NYHA, New York Heart Association Sacubitril/valsartan [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.

Sacubitril/Valsartan: Tips for Use – Dosing Initiating sacubitril/valsartan If on ACE inhibitor Recommended initial dose is 49/51 mg bid If on low dose or not taking ACE inhibitor or ARB Recommended initial dose is 24/26 mg bid BUT allow a 36-hour washout period between last dose of ACE inhibitor and first dose of sacubitril/valsartan Double the dose every 2 to 4 weeks to target maintenance dose of 97/103 mg bid Consider reducing dose of diuretic, especially if blood pressure is borderline ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker Sacubitril/valsartan [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.

Observe for signs/symptoms of angioedema and hypotension Breastfeeding or drug should be discontinued Not recommended in severe hepatic impairment Monitor renal function and potassium in susceptible patients Sacubitril /valsartan [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015. Sacubitril/Valsartan: Tips for Use ( cont )

Hyperkalemia Will Remain an Issue With Sacubitril/Valsartan: PARADIGM-HF PARADIGM-HF selected a population at low risk for hyperkalemia prior to randomization Excluded patients with eGFR <30 mL/min/1.73 m 2 Excluded patients with serum potassium >5.2 mmol/L at screening (or >5.4 mmol/L at randomization) Run-in phase on ACEI excluded 6% of patients due to AE, then run-in phase on sacubitril/valsartan excluded another 6% of patients due to AE Hyperkalemia rates remained high in all patients despite carefully selected population ACEI, angiotensin-converting enzyme inhibitor; AE, adverse event; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure. McMurray J, et al. N Engl J Med. 2014;371(11):993-1004. Adverse Event Sacubitril/ValsartanACEi P value K+ >5.5 mmol/L16.1% 17.3%.15 K+ >6.0 mmol/L4.3%5.6% .007

Patiromer in Chronic Heart Failure 105 patients with HF and history of hyperkalemia resulting in d/c RAASi therapy and/or -blocker or CKD (eGFR <60 mL/min) Randomized to 4 weeks of Patiromer 30 g/d* or Placebo Spironolactone 25 mg/d initiated on day 1; increased to 50 mg/d on day 15 (if K + ≤5.1 mEq/L) *Investigational dose Patiromer CKD, chronic kidney disease; HF, heart failure; RAASi, renin-angiotensin-aldosterone system inhibitorPitt B, et al for the PEARL-HF Investigators. Eur Heart J. 2011;32:820-828.

Module 4: Unmet Needs Upon completion of this module, participants should be able to: Individualize treatment to reduce the burden of secondary heart failure hospitalizations Initiate and titrate evidence-based guideline-directed medical treatment

Increasing Hospitalization Rates Due to Heart Failure © Fang J, et al. J Am Coll Cardiol . 2008;52:428-434. Age-Adjusted Hospitalization Rates for Heart Failure* *Among patients with heart failure as the first-listed (1 st ) or additional (2 nd ) diagnosis

30-Day Readmission for Heart Failure is Common HF, heart failure; MI, myocardial infarction Dharmarajan K, et al. JAMA . 2013;309(4):355-363. 2007-2009 Medicare fee-for-service claims data for 30-day readmissions after 1,330,157 HF hospitalizations 548,834 MI hospitalizations 1,168,624 pneumonia hospitalizations

Patients With Heart Failure Often Are Not Seen in the First 30 Days After a Hospitalization Jencks SF, et al. N Engl J Med . 2009;360:1418-1428. 52% Patients With Heart Failure Rehospitalized With No Interim Physician Visit

Causes of Hospital Readmission for Congestive Heart Failure 17% Other 19% Failure to Seek Care 16% Inappropriate Prescription Medication Prescription Medication Nonadherence 24% Diet Nonadherence 24% Ashton CM, et al. Ann Intern Med. 1995;122(6):415-421. Over 2/3 of heart failure readmissions are preventable Post discharge monitoring

Lack of Persistence with Prescribed Medications in Heart Failure ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker Gislason GH, et al. Circulation . 2007;116(7):737-744. 107,092 patients discharged after first HF hospitalization in Denmark At 5 years 83% on statins 79% on ACEI/ARB 65% on -Blocker 56% on spironolactoneNonpersistence with -blockers, ACE/ARB, statins associated with higher rates of mortalityProportion of Patients (%) Years From First Dispensing

Bohm M, et al. Eur Heart J . 2016;18;672-683. Medication Adherence and Outcomes: SHIFT Trial (CV death and HF hospitalization) N=6491

Unmet Needs and Evidence Gaps Heart failure is common, with rising prevalence, and is associated with major morbidity/mortality Evidence gaps Impact of treatment beyond mortality to include health-related quality of life Insight into management of the elderly, women, underrepresented minorities Insight into management of persons with comorbidities Roles of ivabradine and sacubitril/valsartan in therapy Strategies to improve patient adherence Yancy CW, et al. Circulation . 2013;128:e240-e327.

Unmet Needs and Evidence Gaps ( cont) Evidence gaps 1 (cont) Benefit of sodium restriction Recognition and treatment of cardiorenal syndrome Convincing method to use biomarkers to optimize medical therapy Effective management of HF pEF beyond blood pressure control, including spironolactone in appropriate patients2 Identification of best processes of care, particularly in the transition from hospital to homePreventing the burden of heart failure through better risk modification, sophisticated screening, and treatment to reduce disease progression HF p EF , heart failure with preserved ejection fraction1. Yancy CW, et al. Circulation . 2013;128:e240-e327.2. Yancy CW, et al. Circulation. 2017;doi: 10.1161/CIR.0000000000000509.

Use of Spironolactone Consider spironolactone to decrease hospitalizations in patients with HF p EF and Ejection fraction ≥45% Elevated BNP levels or heart failure admission within 1 year Estimated glomerular filtration rate >30 mL/min Serum creatinine <2.5 mg/dL Serum potassium <5.0 mEq/L BNP, b-type natriuretic peptide HF p EF , Heart failure with preserved ejection fraction  Yancy CW, et al. Circulation. 2017;doi: 10.1161/CIR.0000000000000509.

Practice Gaps Less than one-third of eligible patients hospitalized for heart failure in hospitals participating in the Get With the Guidelines program received aldosterone antagonist therapy 1 Guideline-directed medical therapy in the outpatient setting ranges from 35% to 86% 2 ~25% of patients with heart failure are rehospitalized within 30 days 3 Patients Hospitalized for Secondary Heart Failure 4 Albert NM, et al. JAMA . 2009;302:1658-1665. Fonarow GC, et al. Circulation. 2010;122:585-596. Krumholz HM, et al. Circ Cardiovasc Qual Outcomes. 2009;2:407-413. Blecker S, et al. J Am Coll Cardiol. 2013;61:1259-1267.

Module 5: Best Practices Upon completion of this module, participants should be able to: Individualize treatment to reduce the burden of secondary heart failure hospitalizations Implement strategies to improve patient self-management Implement strategies to address institutional gaps in inpatient, transitional, and outpatient practice/care

<50% of patients with heart failure report weighing themselves daily Many patients do not recognize symptoms of worsening disease Patient engagement is important Symptom monitoring and treatment adherence Self-Care Maintenance Self-Care Management Self-Care Confidence Symptom Recognition Treatment Evaluation Treatment Implementation Symptom Evaluation Self-Care of Heart Failure ModelRiegel B, et al. Circulation. 2009;120(12):1141-1163.

Keys to Promoting Self-Management Focus on skill development, not just knowledge Reading labels, self-monitoring strategies, emergency plans Provide specific, individualized instructions Utilize “teach back” Consider use of motivational techniques for behavioral change Partner with caregivers and primary physicians Provide systems of care Collaborate with social work, nutrition, psychiatry, palliative care providers Riegel B, et al. Circulation. 2009;120(12):1141-1163.

Identify and Address Barriers to Successful Self-Care Depression/anxiety Comorbid medical illness Complicates adherence to medication and dietary guidance Confounds symptom interpretation Poor health literacy Sleep disturbance Cognitive dysfunction Riegel B, et al. Circulation. 2009;120(12):1141-1163.

Educate Patients Prior to Hospital Discharge Koelling TM, et al. Circulation . 2005;111(2):179-185. Key Components: Lifestyle Diet, activity level Medications Schedule, adherence, titration Follow-up appointments When, with whom? Self-evaluation Weight monitoring, warning signs Rescue plan What to do, who to call? Written discharge instructions Control Education 60 0 120 180Days1.00.9 0.80.7 0.60.5 0.4 0.3Cumulative Event-free Survival P=0.012

Impact of a Pre-Discharge Heart Failure Checklist ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker Basoor A, et al. Congest Heart Fail . 2013;19(4):200-206.

Key Elements of a Written Action Plan Define warning signs that should provoke action Teach patients to recognize warning signs Emphasize importance of early treatment Explain what to do when warning signs occur Who to contact? Medication changes? Clinic vs. ED? McAlister FA, et al. J Am Coll Cardiol 2004;44(4): 810-819.

Provide a Structure for Heart Failure Disease Management After Discharge Evaluate patient needs Individualize plan Identify and resolve patient difficulties, including psychosocial Assess response to GDMT, titrate medications If further GDMT titration is needed, see in 2-3 weeks Reinforce self-management, adherence Reinforce self-management, adherence

Additional Strategies Fluid restriction (1.5-2.0 L/day) only for those with refractory symptoms and hyponatremia Moderation of alcohol intake Abstinence recommended for those with alcoholic cardiomyopathy Counsel regarding smoking cessation Influenza/pneumonia vaccination Counsel regarding avoidance of NSAIDs, herbal medications Cardiac rehabilitation/exercise prescription

Resources for Patient Education American College of Cardiology https://www.acc.org/tools-and-practice-support/clinical-toolkits/heart-failure-practice-solutions?w_nav=MN https://www.cardiosmart.org/Heart-Conditions/Heart-Failure?_ga=2.44016737.576635605.1494958855-891045848.1450728772 American Heart Association Living with Heart Failure http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/About-Heart-Failure_UCM_002044_Article.jsp#.WRs_8rCGNPa Rise Above Heart Failure https://www.heart.org/HEARTORG/Conditions/HeartFailure/Heart-Failure_UCM_002019_SubHomePage.jspHeart Failure Society of America http://www.hfsa.org/patient/learn/

Faculty Experience

Questions from Participants

Module 6: Case Studies Upon completion of this module, participants should be able to: Construct appropriate pharmacological regimens based upon an understanding of the pathophysiologic mechanisms of heart failure Individualize treatment to reduce the burden of secondary heart failure hospitalizations Initiate and titrate evidence-based guideline-directed medical treatment Integrate new heart failure medications into patient management Implement strategies to improve patient self-management Implement strategies to address institutional gaps in inpatient, transitional, and outpatient practice/care

The Case of the Busy Grandmother 69-year-old woman with a 3-year history of HF r EF being seen for a follow up visit Physical examination Mildly short of breath on exertion BP 136/88 mmHg; P 68 bpm Lungs: clear JVP 15 cm H 2OExtremities cool, 2+ edema BP, blood pressure; HFrEF, HF with reduced ejection fraction; JVP, jugular venous pressure

The Case of the Busy Grandmother (cont) Past medical history Type 2 diabetes mellitus Hypertension Echocardiogram: LVEF 30% Electrolytes- normal SCr 1.8 mg/dL HbA1c 7.6% NT-proBNP 2250 pg/mL HbA1c, hemoglobin A1c; LVEF, left ventricular ejection fraction; SCr, serum creatinine; NT-proBNP, N-terminal pro b-type natriuretic peptide 

The Case of the Busy Grandmother (cont) The patient reports that her overall level of functioning isn’t as good as it was a few months ago Upon questioning, she admits that she has not followed the treatment plan because she takes care of her young grandchildren while her daughter works Current treatment plan Brisk walking 30 minutes daily Hydrochlorothiazide 25 mg qAM Enalapril 10 mg bid Carvedilol 25 mg bid Metformin 1 g bid Sitagliptin 100 mg qAM

The Case of the Busy Grandmother (cont) What is(are) your primary objective(s) for this visit? What other assessments would you make? How would you help this patient better self-manage her heart failure? What changes, if any, would you make to her treatment plan?

The Case of the Depressed Salesman 60-year-old African-American man hospitalized with acute myocardial infarction 3 weeks ago; diagnosed with HF r EF Being seen for a follow-up visit History Long-standing hypertension Smokes 1 pack of cigarettes a day; frequent alcohol use Mother had a history of type 2 diabetes; father had a history of hypertension, chronic kidney disease HFrEF , HF with reduced ejection fraction

The Case of the Depressed Salesman ( cont ) Physical examination Mildly obese (body mass index 32.4 kg/m 2 ) Mildly short of breath while sitting Heart: BP 142/92 mmHg; P 76 bpm; 2/6 systolic ejection murmurLungs: mild wheezing Skin: cool, 2+ pedal edemaPast medical historyMI 3 weeks agoLong-standing hypertensionEchocardiogram: LVEF 25% Electrolytes- normal; K+ 4.8 mEq/LEstimated glomerular filtration rate 42 mL/min/1.73 m2BP, blood pressure; LVEF, left ventricular ejection fraction

The Case of the Depressed Salesman ( cont ) The patient reports that he has not been able to return to work; he feels tired and has difficulty walking up 1 flight of stairs Current treatment plan Cardiac rehabilitation Hydrochlorothiazide 25 mg qAM Furosemide 40 mg qAM Candesartan 8mg qAM Metoprolol XL 200 mg qAMIsosorbide dinitrate 40 mg tid

The Case of the Depressed Salesman ( cont ) What is your primary objective for this visit? What changes would you make to his treatment plan?

The Case of the Retiring General General Vasquez is a 58-year-old Hispanic man admitted for the third time in 4 months due to worsening symptoms of heart failure History Diagnosed with HF r EF 6 years ago Retired prematurely 2 weeks ago due to limited physical activity due to heart failure Physical examination BP 126/76 mmHg, P 62 bpm Normal S1, widely split S2, soft S3 gallop Echocardiogram: LVEF 28%; global hypokinesisJVP 14 cm H2OLungs clear; 3+ pedal edemaAbdomen soft, nontender BP, blood pressure; HFrEF, HF with reduced ejection fraction; LVEF, left ventricular ejection fraction; JVP, jugular venous pressure

The Case of the Retiring General (cont) Social history 75 pack-year history of smoking; quit 4 years ago Frequent alcohol use Lives with his wife Current treatment plan Hydrochlorothiazide 25 mg qAM Furosemide 120 mg bid Losartan 100 mg qAM Carvedilol 25 mg bidSpironolactone 25 mg qAM

The Case of the Retiring General (cont) Should General Vasquez undergo further evaluation? What other assessments would you make? What changes would you make to his treatment plan? What steps should be taken to help the patient better self-manage?