Pre-Activity Assessment/ Evaluation Form

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1 Pre-Activity Assessment/ Evaluation Form Pre-Activity Assessment Please take a moment to complete the pre-activity assessment prior to the start of the activity. Evaluation Form Please take a moment at the conclusion of the activity to complete the evaluation form in the back of the workbook. The on-site staff will collect the pre-activity assessment and evaluation forms at the conclusion of the activity. Friday, April 21, :00am-10:00am St. Anthony Hospital Medical Plaza Rapp Center 535 NW 9th Street Oklahoma City, OK 73102

2 Faculty Michael B. Bottorff, PharmD, FCCP, FNLA, CLS Professor and Chair Department of Pharmacy Practice Manchester College of Pharmacy Fort Wayne, IN Program Agenda 5 minutes Introduction and Overview: The challenge of reducing hospitalization and readmission in HF 10 minutes Epidemiology and health-system burden of HF in the US 10 minutes Pathophysiology and risk factors of HF 10 minutes Updating the treatment of HF 15 minutes New frontiers in workup, monitoring, and treatment of HF 10 minutes Conclusions and Q&A

3 CE Information Target Audience This educational activity is directed toward hospital and health-system pharmacists and pharmacy technicians that manage patients with HF. Provider This activity is provided by Medical Learning Institute, Inc. Commercial Support Acknowledgment This activity is supported by educational grants from Novartis Pharmaceuticals Corporation and Relypsa, Inc., a Vifor Pharma Company. Credit Designation Registered Pharmacy Designation The Medical Learning Institute, Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.10 CEU) of continuing pharmacy education credit. Universal Activity Number L01-P Universal Activity Number: L01-T

4 Learning Objectives Upon completion of this activity, the participant will be able to: Pharmacists Describe the high incidence and burden of HF including the risk of hospitalization and the need to meet quality metrics for the reduction of readmissions in HF Explain the complex pathophysiology and risk factors for HF Integrate new classes of pharmacologic agents for HF into the current effective treatment paradigm Plan for the use of biomarkers and novel electronic monitoring technologies to work-up, monitor treatment follow-up, and medication adjustment in HF Pharmacy Technicians Explain the burden of and challenges faced in reducing hospitalization and readmission in HF Describe the types, causes, and signs and symptoms of HF Identify new classes of pharmacologic agents for HF Recognize new frontiers in workup, monitoring and treatment in HF Disclosure Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any offlabel discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The associates of Medical Learning Institute Inc, the accredited provider for this activity do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CPE activity for any amount during the past 12 months. Name of Planner/Manager Title Reported Financial Relationship Shelley Chun, PharmD Peer Reviewer Has nothing to disclose.

5 Faculty Disclosures Michael B. Bottorff, PharmD, FCCP, FNLA, CLS, is on the Speakers' Bureau for Novartis, Pfizer/BMS Alliance, and Reliant/Sanofi Alliance. He does not intend to discuss any non-fda-approved or investigational use of any products/devices. Disclaimer The information provided at this CPE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this activity should be inferred.

6 Instructions for Credit There is no fee for this activity. To receive credit for this CPE activity, please take a few minutes to complete the pre-activity assessment and evaluation form and return it to the on-site coordinator. Your confirmation of reported participation will be ed to you within 4 weeks. You may also choose to complete this evaluation form off-site, return it by mail or fax to: Medical Learning Institute, Inc. 203 Main Street, Suite 249 Flemington, NJ (fax) For questions regarding the accreditation of this activity, please contact Medical Learning Institute, Inc. at or ndane@mlicme.org. For pharmacists and pharmacists technicians, Medical Learning Institute, Inc. will accept your completed evaluation form up to 30 days following participation and will report your participation in this educational activity to the NABP ONLY if you provide your NABP e-profile number and date of birth. Within 6 weeks of participation, you will receive a confirmation and can then view your participation record at the NABP. Heart Failure Treatment Options and Guidelines Michael B. Bottorff, PharmD, FCCP, FNLA, CLS Professor and Chair Department of Pharmacy Practice Manchester College of Pharmacy Fort Wayne, IN

7 Heart Failure Objectives for the Pharmacist Know the general concepts about the epidemiology of heart failure Number of patients, high rate of hospitalizations, high mortality Explain the relationship between heart failure outcomes and neurohormonal imbalance Know how to initiate, titrate, monitor and adjust the following drugs Diuretics, ACEI/ARB, beta blockers, aldosterone receptor antagonists, ARNI, ISDN/hydralazine, digoxin, ivabradine Know the difference between drugs that improve symptoms/hospitalizations vs those that improve survival Examine a patient medication profile and recommend AHA Class I recommended therapy, discontinue Class III therapies Epidemiology of Heart Failure in the US Heart Failure Patients in US (Millions) * More deaths from heart failure than from all forms of cancer combined 550,000 new cases/year 1 in 9 deaths in 2009 listed heart failure as a contributing cause Estimated costs exceed $30 billion each year The Paradox : Increasing age of population Increase in risk factors Improved post MI survival *Rich M. J Am Geriatric Soc. 1997;45: American Heart Association Heart and Stroke Statistical Update. American Heart Association Heart and Stroke Statistical Update. Heidenreich PA et al. Circulation. 2011;123(8):

8 Pathologic Progression of CV Disease Coronary artery disease Sudden Death Hypertension Diabetes Myocardial injury Pathologic remodeling Low ejection fraction Death Cardiomyopathy Valvular disease Pump failure Neurohormonal stimulation Myocardial toxicity Symptoms: Dyspnea Fatigue Edema Chronic heart failure Adapted from Cohn JN. N Engl J Med. 1996;335: Overactivation of the RAAS and SNS is Detrimental in HFrEF and Underpins the Basis of Therapy Natriuretic peptide system 1 NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy HFrEF SYMPTOMS & PROGRESSION Sympathetic nervous system Epinephrine Norepinephrine 1, 1, 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility Renin angiotensin aldosterone system The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs 1 Benefits of blockers indicate that the SNS also plays a key role 1 ACEI: angiotensin-converting-enzyme inhibitor; Ang: angiotensin; ARB: angiotensin receptor blocker; AT 1 R: angiotensin II type 1 receptor; MRA: mineralocorticoid receptor antagonist; NPs: natriuretic peptides; NPRs: natriuretic peptide receptors; RAAS: renin-angiotensin-aldosterone system; SNS: sympathetic nervous system 1. McMurray et al. Eur Heart J 2012;33: ; Figure References: Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Kemp & Conte. Cardiovascular Pathology 2012;365 71; Schrier & Abraham. N Engl J Med 2009;341: Ang II AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis

9 Heart Failure: Neurohormonal Imbalance NE AT-II Endothelin Aldosterone Vasopressin ANP BNP NO Bradykinin Prostacyclin Vasoconstriction Tachycardia Fluid retention Vasodilation Suppress sympathetic NS Suppress RAAS Natriuresis/diuresis Rev Cardiovasc Med. 2001;2(suppl 2):S2-S6. Causes of Heart Failure Coronary artery disease (with or without MI) Hypertension Idiopathic dilated cardiomyopathy Valvular disease (aortic stenosis, mitral regurgitation) Post-partum cardiomyopathy Viral cardiomyopathy Anticancer drugs (adriamycin) Heavy metal toxicity

10 Clinical Presentation Left sided heart failure signs and symptoms DOE Orthopnea Tachypnea Right sided heart failure signs and symptoms Abdominal pain Nausea Constipation Non-specific signs and symptoms Fatigue Weakness Bibasilar rales Pulmonary edema S 3 gallop Peripheral edema JVD Hepatomegaly Tachycardia Cardiomegaly Two Types of Heart Failure Systolic dysfunction Low ejection fraction Below 40-45% Largest group of HF patients All beneficial drug outcome trials All guidelines Diastolic dysfunction Impaired relaxation Similar symptoms Slightly less common Few outcome studies

11 Chronic Congestive Heart Failure Evolution of Clinical Stages No symptoms Normal exercise Normal LV fxn NORMAL Asymptomatic LV Dysfunction No symptoms Normal exercise Abnormal LV fxn Compensated CHF Decompensated CHF No/minimal symptoms Exercise Abnormal LV fxn Symptoms Exercise Abnormal LV fxn Refractory CHF Symptoms not controlled with treatment Classification of HF: Comparison Between ACC/AHA HF Stage and NYHA Functional Class ACC/AHA HF Stage 1 NYHA Functional Class 2 A At high risk for heart failure but without structural heart disease or symptoms of heart failure (eg, patients with hypertension or coronary artery disease) B Structural heart disease but without symptoms of heart failure C Structural heart disease with prior or current symptoms of heart failure I II III Asymptomatic Symptomatic with moderate exertion Symptomatic with minimal exertion D Refractory heart failure requiring specialized interventions IV Symptomatic at rest 1 Hunt SA et al. J Am Coll Cardiol. 2001;38: New York Heart Association/Little Brown and Company, Adapted from: Farrell MH et al. JAMA. 2002;287:

12 Goals in the Management of Heart Failure Stabilize the patient (improve symptoms and quality-of-life) Stabilize the disease (slow progression) Reduce hospitalizations Reduce mortality (prolong life) Non-pharmacologic Therapy Physical activity Diet Na+ restriction Meals Fluid intake Surgical correction of underlying processes Smoking cessation Adequate support and counseling Severe disease measures

13 Heart Failure Medications Improve Symptoms Diuretics Digoxin Improve Survival Beta-blockers ACE-inhibitors Mineralocorticoid receptor antagonists (MRA) Angiotensin receptor blockers (ARB s) ARNI Patient with Heart Failure A 66 yo male presents to the pharmacy for a refill of his HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx MI 3 yrs ago), and diabetes Medications: HCTZ 12.5mg po QD Pioglitazone 45mg po QD Atenolol 50mg po QD Simvastatin 40mg po QD Diltiazem CR 240mg po QD ASA 81mg po QD

14 Diuretics in Heart Failure Thiazide diuretics possible for mild congestion Loop diuretics preferred for most patients Furosemide for the majority of patients Torsemide has better, more reliable absorption Less hospitalizations, lower cost of care (Clin Therapeutics 1999, ASCPT 2000) Metolazone reserved for apparent diuretic resistance Diuretic advantages Necessary for fluid control Synergistic effect with ACE-inhibitors Diuretic disadvantages Electrolyte disturbances (arrhythmogenic, dig toxicity) Potassium, magnesium depletion Hypovolemia, hypotension, renal dysfunction Worsening of the neurohormonal balance Loop Diuretics Thiazide-Like Diuretic Used in Combination with Loop

15 Pharmacological Therapy for Management of Stage C HFrEF Diuretics Recommendations COR LOE Diuretics are recommended in patients with HFrEF with fluid retention I C The target dose of diuretic in HFrEF is the dose that keeps patients at their dry weight; that is the weight where a patient is as symptom free as their heart failure will let them be. Many patients will monitor their daily weight and self-adjust their own loop diuretic therapy. Patient with Heart Failure A 66 yo male presents to the pharmacy for a refill of his HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx MI 3 yrs ago), and diabetes Medications: HCTZ 12.5mg po QD Pioglitazone 45mg po QD Atenolol 50mg po QD Simvastatin 40mg po QD Diltiazem CR 240mg po QD ASA 81mg po QD

16 Patient with Heart Failure A 66 yo male presents to the pharmacy for a refill of his HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx MI 3 yrs ago), and diabetes Medications: D/C HCTZ 12.5mg po QD, initiate furosemide 40mg po QD Pioglitazone 45mg po QD Atenolol 50mg po QD Simvastatin 40mg po QD Diltiazem CR 240mg po QD ASA 81mg po QD ACEI in HFrEF Improved Symptoms (QoL), hospitalizations, and survival Altered/delayed remodeling of LV post-mi Disadvantages Side effects (cough, angioedema, rash - captopril) Hypotension, reduce renal function, hyperkalemia

17 Drugs Commonly Used for HFrEF (Stage C HF) Pharmacological Therapy for Management of Stage C HFrEF Diuretics Recommendations COR LOE Diuretics are recommended in patients with HFrEF with fluid retention I C ACE Inhibitors Recommendations COR LOE ACE inhibitors are recommended for all patients with HFrEF I A ARBs Recommendations COR LOE ARBs are recommended in patients with HFrEF who are ACE inhibitor intolerant I A ARBs are reasonable as alternatives to ACE inhibitor as first line therapy in HFrEF IIa A The addition of an ARB may be considered in persistently symptomatic patients with HFrEF on GDMT IIb A Routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is potentially harmful III: Harm C

18 Patient with Heart Failure A 66 yo male presents to the pharmacy for a refill of his HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx MI 3 yrs ago), and diabetes Medications: Furosemide 40mg po qd Pioglitazone 45mg po QD Atenolol 50mg po QD Simvastatin 40mg po QD Diltiazem CR 240mg po QD ASA 81mg po QD Start Lisinopril 5mg po QD Risk of hyperkalemia and need for monitoring K and SCr at week 1, 4, and 8 when starting therapy Are all Beta Blockers Equally Beneficial In Heart Failure?

19 Recent Trials of Beta Blockers in Heart Failure 35 Beta-blocker Placebo * % Mortality * * * 5 0 CIBIS-II MERIT-HF CAPRICORN COPERNICUS BEST * P<0.05 Bisoprolol Metoprolol Carvedilol Carvedilol Bucindolol Beta-Blocker Therapy Monitoring Hypotension Temporarily reduce vasodilator therapy If hypotension persists, decrease blocker dose Beta Blocker Therapy Fluid Retention Slow down the rate of dose titration Temporarily increase diuretic dose Bradycardia Reduce blocker dose to highest tolerable dose If bradycardia persists, discontinue blocker

20 Pharmacological Therapy for Management of Stage C HFrEF and Drugs Commonly Used for HFrEF (Stage C HF) Beta Blockers Recommendations COR LOE Use of 1 of the 3 beta blockers proven to reduce mortality is recommended for all stable patients I A Beta Blockers Drug Initial Daily Dose (s) Maximum Dose(s) Mean Doses Achieved in Clinical Trails Bisoprolol 1.25 mg once 10 mg once 8.6 mg/d (118) Carvedilol mg twice 50 mg twice 37 mg/d (446) Carvedilol CR 10 mg once 80 mg once Metoprolol succinate extended release (metoprolol CR/XL) 12.5 to 25 mg once 200 mg once 159 mg/d (447) Patient with Heart Failure A 66 yo male presents to the pharmacy for a refill of his HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx MI 3 yrs ago), and diabetes Medications: Furosemide 40mg po qd Pioglitazone 45mg po QD Atenolol 50mg po QD (d/c and initiate carvedilol 12.5mg bid) Simvastatin 40mg po QD Diltiazem CR 240mg po QD ASA 81mg po QD Lisinopril 5mg po QD

21 Role of Aldosterone Receptor Antagonists in Heart Failure Anti-Aldosterone Agents Spironolactone O Eplerenone O O O SCOCH 3 COOCH 3 Binding to mineralocorticoid receptors Partial affinity for glucocorticoid receptors Inhibition of P450 enzymes in endocrine organs Induction of P450 enzymes in the liver Complex metabolism Greater specificity for mineralocorticoid receptors Fewer progestational and anti-androgenic actions No effect on P450 hydroxylases in endocrine organs Minimal increase in liver P450 enzymes

22 Aldosterone Antagonists Pharmacological Therapy for Management of Stage C HFrEF and Drugs Commonly Used for HFrEF (Stage C HF) Recommendations COR LOE Aldosterone receptor antagonists are recommended in patients with NYHA class II-IV HF who have LVEF < 35% Aldosterone receptor antagonists are recommended in patients following an acute MI who have LVEF <40% with symptoms of HF or DM Inappropriate use of aldosterone receptor antagonists may be harmful I I III: Harm A B B Aldosterone Antagonists Drug Initial Daily Dose (s) Maximum Dose(s) Mean Doses Achieved in Clinical Trails Spironolactone 12.5 to 25 mg once 25 mg once or twice 26 mg/d (424) Eplerenone 25 mg once 50 mg once 42.6 mg/d (445) Patient with Heart Failure A 66 yo male presents to the pharmacy for a refill of his HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx MI 3 yrs ago), and diabetes Medications: Furosemide 40mg po qd Pioglitazone 45mg po QD Carvedilol 12.5mg po bid Simvastatin 40mg po QD Diltiazem CR 240mg po QD ASA 81mg po QD Lisinopril 5mg po QD Initiate spironolactone 25mg po QD

23 A-Heft Trial: Primary Endpoint All individual components of the primary composite endpoint were significantly improved with ISDN-hydralazine therapy, namely death, first hospitalization for heart failure, and change in the quality-of-life score (a larger negative score indicates a better quality of life). Presented at AHA Pharmacological Therapy for Management of Stage C HFrEF and Drugs Commonly Used for HFrEF (Stage C HF) Hydralazine and Isosorbide Dinitrate Recommendations COR LOE The combination of hydralazine and isosorbide dinitrate is recommended for African Americans, with NYHA class III-IV HFrEF on GDMT I A A combination of hydralazine and isosorbide dinitrate can be useful in patients with HFrEF who cannot given ACE inhibitors or ARBs IIa B Hydralazine & Isosorobide Dinitrate Drug Initial Daily Dose (s) Maximum Dose(s) Mean Doses Achieved in Clinical Trails Fixed dose combination (423) 37.5 mg hydralazine/ 20 mg isosorbide Dinitrate 3 times daily 75 mg hydralazine/ 40 mg isosorbide Dinitrate 3 times daily ~175 mg hydralazine/ 90 mg isosorbide Dinitrate daily Hydralazine and Isosorbide Dinitrate (448) Hydralazine: 25 to 50 mg, 3 or 4 times daily and isosorbide Dinitrate: 20 to 30 mg 3 or 4 times daily Hydralazine: 300mg daily in divided doses and isosorbide Dinitrate 120 mg daily in divided doses

24 Medical Therapy for Stage C HFrEF: Magnitude of Benefit Demonstrated in RCTs GDMT RR Reduction in Mortality NNT for Mortality Reduction (Standardized to 36 mo) RR Reduction in HF Hospitalizations ACE inhibitor or ARB 17% 26 31% Beta blocker 34% 9 41% Aldosterone antagonist 30% 6 35% Hydralazine/nitrate 43% 7 33% Digoxin in HFrEF: Mortality % 20 Placebo n=3403 p = DIGOXIN n=3397 DIG Months 48 N Engl J Med 1997;336:525

25 Association of Serum Digoxin Concentration and Outcomes Mortality (% at Mean of 37 months) 6.3% (p<0.05) 2.6% 11.8% (p<0.05) _ One Month SDC (ng/ml) Rathore et al, JAMA 2003:289:871. Digoxin Clinical Uses AF with rapid ventricular response CHF refractory to other drugs Should be combined with other drugs

26 Pharmacologic Therapy for Management of Stage C HFrEF (Continued) Digoxin Recommendations COR LOE Digoxin can be beneficial in patients with HFrEF IIa B Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides that Counter Maladaptive Mechanisms in Heart Failure Endogenous vasoactive peptides (natriuretic peptides, adrenomedullin, bradykinin, substance P, calcitonin gene-related peptide) Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention Neprilysin Neprilysin inhibition Inactive metabolites

27 LCZ696 Mechanism of Action PARADIGM-HF: Study Design Randomization Single-blind run-in period Double-blind period LCZ mg BID Enalapril LCZ696 (1:1 randomization) 10 mg BID 100 mg BID 200 mg BID Enalapril 10 mg BID 2 weeks 1-2 weeks 2-4 weeks

28 PARADIGM HF Trial Efficacy Results Primary Endpoint Death from Any Cause Death from CV Causes: 13.3% vs 16.5%; HR 0.8 ( ), p<0.001 First Hospitalization for HF: 12.8% vs 15.6%, HR 0.79 ( ), p<0.001 Change in quality of life: vs HR 1.64 ( ); p= PARADIGM-HF: Effect of LCZ696 vs Enalapril on Secondary Endpoints LCZ696 (n=4187) Enalapril (n=4212) Treatment effect P Value KCCQ clinical summary score at 8 months 2.99 ± ± (0.63, 2.65) New onset atrial fibrillation 84/2670 (3.2%) 83/2638 (3.2%) Hazard ratio 0.97 (0.72,1.31) 0.84 Protocol-defined decline in renal function 94/4187 (2.3%) 108/4212 (2.6%) Hazard ratio 0.86 (0.65, 1.13) 0.28

29 PARADIGM-HF: Adverse Events LCZ696 (n=4187) Enalapril (n=4212) P Value Prospectively identified adverse events Symptomatic hypotension < Serum potassium > 6.0 mmol/l Serum creatinine 2.5 mg/dl Cough < Discontinuation for adverse event Discontinuation for hypotension NS Discontinuation for hyperkalemia NS Discontinuation for renal impairment Angioedema (adjudicated) Medications, no hospitalization 16 9 NS Hospitalized; no airway compromise 3 1 NS Airway compromise PARADIGM-HF: Summary of Findings In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril: LCZ696 was more effective than enalapril in... Reducing the risk of CV death and HF hospitalization Reducing the risk of CV death by incremental 20% Reducing the risk of HF hospitalization by incremental 21% Reducing all-cause mortality by incremental 16% Incrementally improving symptoms and physical limitations LCZ696 was better tolerated than enalapril... Less likely to cause cough, hyperkalemia or renal impairment Less likely to be discontinued due to an adverse event More hypotension, but no increase in discontinuations Not more likely to cause serious angioedema

30 Current treatment Current dose Recommended treatment ACEi ARB Not on ACEi or ARB Patients receiving a total daily dose of >10mg of enalapril or therapeutically equivalent doses of another ACEi, for example 2 : Lisinopril >10mg Ramipril >5mg Patients receiving a total daily dose of < 10mg of enalapril or therapeutically equivalent doses of another ACEi, for example 2 : Lisinopril < 10mg Ramipril < 5 mg Stop ACEi 36 hours before starting sacubitril/ valsartan Stop ACEi 36 hours before starting sacubitril/ valsartan Start sacubitril/valsartan at the recommended dose of 49/51 mg twice daily Start sacubitril/ valsartan at the recommended dose of 24/26mg twice daily Double the dose after 2 to 4 weeks to 49/51 mg twice daily, as tolerated by the patient Double the dose of sacubitril/valsartan after 2 to 4 weeks, as tolerated by the patient, to reach the Target maintenance dose of 97/103 mg twice daily ACEi ARB Not on ACEi or ARB Patients receiving a total daily dose of >160mg of valsartan or therapeutically equivalent doses of another ARB, for example 2 : Losartan >50mg Olmesartan >10mg Patients receiving a total daily dose of < 160mg of valsartan or therapeutically equivalent doses of another ARB, for example 2 : Losartan <50mg Olmesartan <10mg Start sacubitril/valsartan at the recommended dose of 49/51 mg twice daily Start sacubitril/ valsartan at the recommended dose of 24/26mg twice daily Double the dose after 2 to 4 weeks to 49/51 mg twice daily, as tolerated by the patient Double the dose of sacubitril/ valsartan after 2 to 4 weeks, as tolerated by the patient, to reach the Target maintenance dose of 97/103 mg twice daily ACEi ARB Not on ACEi or ARB Not currently taking ACEis or ARBs Start sacubitril/ valsartan at the recommended dose of 24/26mg twice daily Double the dose after 2 to 4 weeks to 49/51 mg twice daily, as tolerated by the patient Double the dose of sacubitril/valsarta n after 2 to 4 weeks, as tolerated by the patient, to reach the Target maintenance dose of 97/103 mg twice daily Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin-Angiotensin System 0% Angiotensin receptor blocker ACE inhibitor Angiotensin neprilysin inhibition % Decrease in Mortality 10% 20% 30% 15% 18% 20% 40% Effect of ARB vs placebo derived from CHARM-Alternative trial Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

31 Optimal Implementation of ARNI in Heart Failure Inevitable delay for implemention into practice of newly established therapies Estimated 84% of U.S. patients with HFrEF as candidates for ARNI therapy Optimal implementation would: Prevent 28,484 deaths per year 12 month NNT 80 Fonarow GC et al. JAMA 2016 Cost-effectiveness Analysis of Sacubitril/Valsartan vs Enalapril in Patients with Heart Failure and Reduced Ejection Fraction Tornado DiagramUnivariate sensitivity analyses evaluating the effect of each variable s uncertainty on an overall cost-effectiveness ratio. The central black line represents the base-case analysis. None of the analyses lead to an incremental cost-effectiveness ratio greater than $ per quality-adjusted life-year (QALY). HR indicates hazard ratio. JAMA Cardiol. Published online June 22, doi: /jamacardio Copyright 2016 American Medical Association. All rights reserved. Date of download: 7/14/2016

32 Ivabradine: Mechanism of Action Primary Objective To evaluate whether the I f inhibitor ivabradine improves cardiovascular outcomes in patients with: 1. Moderate to severe chronic heart failure 2. Left ventricular ejection fraction 35% 3. Heart rate 70 bpm in sinus rhythm 4. Best recommended therapy Swedberg K, et al. Eur J Heart Fail. 2010;12:

33 Study Design Screening 7 to 30 days Ivabradine 5 mg bid Matching placebo, bid Ivabradine 7.5/5/2.5 mg bid according to HR and tolerability D0 D14 D28 M4 Every 4 months 3.5 years Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81 Effect of Ivabradine on Outcomes Endpoints Hazard ratio 95% CI p value Primary composite endpoint (CV death or hospital admission for worsening HF) 0.82 [0.75;0.90] p< All-cause mortality 0.90 [0.80;1.02] p=0.092 Death from heart failure 0.74 [0.58;0.94] p=0.014 All-cause hospital admission 0.89 [0.82;0.96] p=0.003 Any CV hospital admission 0.85 [0.78;0.92] p= CV death/hospital admission for HF or non-fatal MI 0.82 [0.74;0.89] p< Swedberg K, et al. Lancet. 2010;376(9744):

34 AHA HF Update 2016 Recommendations for Renin-Angiotensin System Inhibition with ACE Inhibitor or ARB or ARNI Recommendations COR LOE The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (Level of Evidence: A) (9-14), OR ARBs (Level of Evidence: A) (15-18), OR ARNI (Level of Evidence: B-R) (19) in conjunction with evidence based beta blockers (20-22), and aldosterone antagonists in selected patients (23, 24), is recommended for patients with chronic HFrEF to reduce morbidity and mortality. I ACE: A ARB: A ARNI: B-R In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality (19). ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor (31, 32) ARNI should not be administered to patients with a history of angioedema. I III: Harm III: Harm ARNI: B-R B-R C-EO Recommendations for Ivadradine Recommendation Symptomatic (NYHA class II, III) stable chronic HFrEF (LVEF < 35%) who are receiving GDEM, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with heart rate of 70 bpm or greater at rest (37-40) COR IIa LOE B-R Patient with Heart Failure A 66 yo male presents to the pharmacy for a refill of his HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx MI 3 yrs ago), and diabetes Medications: Furosemide 40mg qd Pioglitazone 45mg po QD Carvedilol 12.5mg bid Simvastatin 40mg po QD Diltiazem CR 240mg po QD ASA 81mg po QD D/C Lisinopril 5mg po QD, wait 36 hr, initiate sacubitril/valsartan 50mg po BID Spironolactone 25mg po QD

35 July 2016 Patient with Heart Failure A 66 yo male presents to the pharmacy for a refill of his HCTZ. He complains of increasing weight gain (10 lbs over 2 weeks), bilateral ankle swelling, increased shortness of breath when walking up stairs He has a past medical history of hypertension, CAD (Hx MI 3 yrs ago), and diabetes Medications: Furosemide 40mg qd D/C Pioglitazone 45mg po QD Carvedilol 12.5mg bid Simvastatin 40mg po QD D/C Diltiazem CR 240mg po QD ASA 81mg po QD D/C Lisinopril 5mg po QD, wait 36 hr, initiate sacubitril/valsartan 50mg po BID Spironolactone 25mg po QD

36 What drug improves survival in heart failure with preserved systolic function (HFpEF)? Clinical Trials Showing Improvement in Morbidity/Mortality in HFpEF

37 Treatment of HFpEF Recommendations COR LOE Systolic and diastolic blood pressure should be controlled according to published clinical practice guidelines I B Diuretics should be used for relief of symptoms due to volume overload I C Coronary revascularization for patients with CAD in whom angina or demonstrable myocardial ischemia is present IIa C despite GDMT Management of AF according to published clinical practice guidelines for HFpEF to improve symptomatic HF IIa C Use of beta-blocking agents, ACE inhibitors, and ARBs for hypertension in HFpEF IIa C ARBs might be considered to decrease hospitalizations in HFpEF IIb B Nutritional supplementation is not recommended in HFpEF III: No Benefit C