Emerging Challenges in Primary Care: Applying the Latest Advances and Evidence of Clinical Outcomes to Individualize Heart Failure Treatment

Transcription

1 Emerging Challenges in Primary Care: 2016 Applying the Latest Advances and Evidence of Clinical Outcomes to Individualize Heart Failure Treatment

2 Faculty Ola Akinboboye, MD, MPH, MBA, FACP, FACC, FASNC Associate Professor of Clinical Medicine, Cornell University Past President, Association of Black Cardiologists Medical Director, Queens Heart Institute, Rosedale, NY Jan Basile, MD Professor of Medicine, Seinsheimer Cardiovascular Health Program Division of General Internal Medicine, Medical University of South Carolina Ralph H Johnson VA Medical Center, Charleston, SC Phillip B. Duncan, MD Heart Care for You, PC, Chester, VA Brent M. Egan, MD Professor of Medicine, University of South Carolina School of Medicine Greenville Chief Science Officer, Care Coordination Institute President, International Society on Hypertension in Blacks, Greenville, SC Keith C. Ferdinand, MD, FACC, FAHA, FNLA, FASH Professor of Medicine, Tulane University School of Medicine Tulane Heart and Vascular Institute, New Orleans, LA 2

3 Faculty Icilma V. Fergus, MD, FACC Past President, Association of Black Cardiologists Director, Cardiovascular Disparities and Associate Professor of Medicine Mount Sinai School of Medicine, New York, NY Robert L. Gillespie, MD, FACC, FASE, FASNC Immediate Past Chairman of the Board, Association of Black Cardiologists Director of Nuclear Imaging, Sharp Rees-Stealy Medical Group, San Diego, CA Barbara Hutchinson, MD, PhD, FACC President, Association of Black Cardiologists President, Chesapeake Cardiac Care, Annapolis, MD Elizabeth Ofili, MD, MPH, FACC Professor of Medicine (Cardiology), Senior Associate Dean, Clinical Research Director, Clinical Research Center, Morehouse School of Medicine Founder and Chairman of the Board, AccuHealth Technologies, Inc., Atlanta, GA 3

4 Faculty Anekwe Onwuanyi, MD Professor of Medicine, Chief of Cardiology, Morehouse School of Medicine Medical Director, Heart Failure Program, Grady Health System Atlanta, GA Priscilla E. Pemu, MD, MSCR, FACP Professor of Medicine, Morehouse School of Medicine Atlanta, GA David N. Smith, MD Clinical Assistant Professor of Medicine, Yale University Associate Professor of Medicine, Wingate University Adjunct Professor at UNC Chapel Hill Externship Preceptor and Advisory Board Member for ECPI Charlotte, NC 4

5 Faculty Kevin L. Thomas, MD Associate Professor of Medicine, Duke University Medical Center Division of Clinical Cardiac Electrophysiology, Duke Clinical Research Institute, Durham, NC Mark A. Thompson, MD Invasive Non-Interventional Cardiologist, Cardiac & Vascular Interventional Group Dallas, TX Laurence O. Watkins, MD, MPH, FACC Former Director, Healthy Heart Center Port St. Lucie, FL Karol E. Watson, MD, PhD Professor of Medicine/Cardiology, Co-director, UCLA Program in Preventive Cardiology Director, UCLA Barbra Streisand Women s Heart Health Program Los Angeles, CA 5

6 Disclosures Ola Akinboboye, MD, MPH, MBA - As per the American Board of Internal Medicine, Dr. Akinboboye will not present content that will have any direct link with the Cardiovascular Board Exam. Jan Basile, MD serves on the grant/research support team for The National Heart, Lung, and Blood Institute (Sprint). Dr. Basile also serves as a consultant and the grant/research support for the National Heart, Lung, and Blood Institute (Sprint) and Eli-Lilly (Rewind). He is also on the speaker s bureau for Arbor, Amgen and Janssen. Phillip B. Duncan, MD serves on the advisory board for Arbor. Dr. Duncan is also on the speakers bureau for Novartis. Brent M. Egan, MD serves on the advisory committee for AstraZeneca and Valencia as well as a speaker for Medtronic. Dr. Egan serves on the Clinical Evaluation and Treatment team for Up-To-Date. Keith C. Ferdinand, MD, FACC serves as a consultant for Boehringer Ingelheim, Sanofi, Amgen and Eli Lilly. 5

7 Disclosures Icilma V. Fergus, MD, FACC has no relationships to disclose. Robert L. Gillespie, MD, FACC, FASE, FASNC serves as an investor for Relypsa. Barbara Hutchinson, MD, PhD, FACC has no relationships to disclose. Elizabeth Ofili, MD, MPH, FACC serves on the grant/research support team for the National Institute of Health. Dr. Ofili also serves as a consultant/advisory board member for Bristol-Myers Squibb, Novartis, Arbor, Merck & Co., Janssen Research and Development. Anekwe Onwuanyi, MD serves as a speaker for Novartis. 6

8 Disclosures Priscilla E. Pemu, MD, MSCR, FACP serves as an Employee for Morehouse School of Medicine, Piedmont Medical Care Corporation. David N. Smith, MD serves as a speaker for Arbor and CardioDx. Kevin L. Thomas, MD serves as a Consultant for BMS and Pfizer. Mark A. Thompson, MD serves as a speaker/training member for Novartis. Laurence O. Watkins, MD, MPH, FACC is involved in the patient care at Healthy Heart Center, Inc. Karol E. Watson, MD, PhD serves as a consultant for Amgen, GSK, Merck and Quest. 6

9 Educational Objectives Know the risk factors for heart failure and the role of biomarkers in diagnosis and treatment Recognize the importance of heart rate in cardiovascular risk of heart failure Utilize the most recent clinical evidence to inform decisions for the management of heart failure Identify approaches to facilitate early recognition and optimization of heart failure management 9

10 PRE-TEST QUESTIONS 8

11 Pre-test ARS Question 1 Which of the following was the most prevalent modifiable risk factor for heart failure among predominantly African American patients admitted with a primary diagnosis of heart failure? 1. Hypertension 2. Hyperglycemia 3. Current smoking 4. Hypercholesterolemia 11

12 Pre-test ARS Question 2 In the SHIFT trial, the use of ivabradine was associated with reductions in cardiovascular mortality or heart failure hospitalization compared to placebo in all patients, EXCEPT those treated with maximum tolerated dose beta blockers. 1. True 2. False 12

13 Pre-test ARS Question 3 A 69-year-old white woman presents with a history of NYHA class III/ stage C heart failure with left ventricular ejection fraction 30%, CAD, hypertension, and dyslipidemia. She reports shortness of breath when climbing stairs, but no other symptoms. BP 109/71 mmhg, HR 64 bpm, potassium 4.5 meq/l, and egfr 33 ml/min/1.73m 2. Meds: furosemide 40 mg bid, metoprolol succinate 200 mg qd, lisinopril 20 mg qd, eplerenone 50 mg qd, and atorvastatin 80 mg qd. Which of the following might be appropriate at this time? 1. Patient is stable; maintain current regimen 2. Discontinue metoprolol and initiate ivabradine 3. Discontinue eplerenone based on serum potassium levels 4. Discontinue lisinopril and initiate sacubitril/valsartan after 36 hours 13

14 Pre-test ARS Question 4 How often do you consider changes to medical therapy for patients with heart failure and a heart rate 70 bpm? 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 14

15 Pre-test ARS Question 5 A 61-year-old African American man, NYHA class II/stage C heart failure and left ventricular ejection fraction 30%, obesity (BMI 32.4 kg/m 2 ), hypertension, and dyslipidemia presents for a checkup. He reports shortness of breath when he walks more than 100 feet, but no other symptoms. BP today is 120/78 mmhg, HR 66 bpm, egfr 41 ml/min/ 1.73m 2, and potassium 4.7 meq/l. Meds: metoprolol SR 100 mg qd, furosemide 40 mg bid, valsartan 160 mg bid, atorvastatin 80 mg qd, eplerenone 50 mg qd, aspirin 81 mg qd After reviewing the brief scenario above, please rate each of the statements as consistent with or not consistent with best clinical practice for management of heart failure: Initiate isosorbide dinitrate/hydralazine. 1. Yes, it is consistent 2. No, it is not consistent 15

16 Pre-test ARS Question 6 61 y/o AA male, NYHA Class II/stage C, SOB walking 100 feet EF 30% VS: 120/78, HR 66 Labs: egfr 41, K 4.7 meq/l Meds: metoprolol SR 100 mg qd, furosemide 40 mg bid, valsartan 160 mg bid, atorvastatin 80 mg qd, eplerenone 50 mg qd, ASA 81 mg qd. After reviewing the brief scenario above, please rate each of the statements as consistent with or not consistent with best clinical practice for management of heart failure: Consider switching from valsartan to lisinopril/ hydrochlorothiazide. 1. Yes, it is consistent 2. No, it is not consistent 16

17 Pre-test ARS Question 7 61 y/o AA male, NYHA Class II/stage C, SOB walking 100 feet EF 30% VS: 120/78, HR 66 Labs: egfr 41, K 4.7 meq/l Meds: metoprolol SR 100 mg qd, furosemide 40 mg bid, valsartan 160 mg bid, atorvastatin 80 mg qd, eplerenone 50 mg qd, ASA 81 mg qd. After reviewing the brief scenario above, please rate each of the statements as consistent with or not consistent with best clinical practice for management of heart failure: Discontinue eplerenone based on serum potassium levels. 1. Yes, it is consistent 2. No, it is not consistent 17

18 Pre-test ARS Question 8 61 y/o AA male, NYHA Class II/stage C, SOB walking 100 feet EF 30% VS: 120/78, HR 66 Labs: egfr 41, K 4.7 meq/l Meds: metoprolol SR 100 mg qd, furosemide 40 mg bid, valsartan 160 mg bid, atorvastatin 80 mg qd, eplerenone 50 mg qd, ASA 81 mg qd. After reviewing the brief scenario above, please rate each of the statements as consistent with or not consistent with best clinical practice for management of heart failure: Initiate ivabradine. 1. Yes, it is consistent 2. No, it is not consistent 18

19 Pre-test ARS Question 9 61 y/o AA male, NYHA Class II/stage C, SOB walking 100 feet EF 30% VS: 120/78, HR 66 Labs: egfr 41, K 4.7 meq/l Meds: metoprolol SR 100 mg qd, furosemide 40 mg bid, valsartan 160 mg bid, atorvastatin 80 mg qd, eplerenone 50 mg qd, ASA 81 mg qd. After reviewing the brief scenario above, please rate each of the statements as consistent with or not consistent with best clinical practice for management of heart failure: Switch patient from valsartan to sacubitril/valsartan. 1. Yes, it is consistent 2. No, it is not consistent 19

20 Pre-test ARS Question 10 Please rate your confidence in your ability to manage patients with heart failure in accordance with current guidelines and evidence: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 20

21 Definition of Heart Failure Heart failure (HF) is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood The cardinal manifestations of HF are dyspnea and fatigue, which may limit exercise tolerance and fluid retention, which may lead to pulmonary congestion and peripheral edema HF pathology may affect heart size, wall thickness and ejection fraction Normal heart Hypertrophied heart: HF with preserved EF (HFpEF) Dilated heart: Heart failure, reduced EF (HFrEF) 1. Hunt SA et al. Circulation. 2005;112:e154-e Jessup M et al. N Engl J Med. 2003;348:

22 Heart Failure: Causal Mechanisms Smoking Dyslipidemia Diabetes Obesity OSA MI Systolic Dysfunction Hypertension HF LVH Diastolic Dysfunction Normal LV Structure and Function LV Remodeling Subclinical LV Dysfunction Overt Heart Failure ACC/AHA Stage A Stage B Stage C Modified from: Vasan RS and Levy D. Arch Int Med.1996;153:

23 Heart Failure: Autopsy and Echocardiogram HFpEF Normal LV HFpEF LVH Diastolic Dysfunction HFrEF Dilated LV Aurigemma GP et al. Circulation. 2006;113: Aurigemma GP et al. Circulation. 2006;113:

24 Heart Failure is Associated with Neurohormonal Excess and Nitric Oxide Insufficiency Neurohormones (RAAS/SNS) Endothelial Nitric Oxide Neurohormonal Antagonists Beta Blockers (Class I-IV) Renin-Angiotensin Antagonists -ACE Inhibitors (Class I-IV) -ARBs (Class I-IV) Mineralocorticoid Receptor Antag (Class II-IV) Nitric Oxide Enhancment (NOE) Fixed-dose combination ISDN/HYD Omapatrilat ( Dual ACE and NEP inh) Angiotensin-Neprilysin Antagonist 24

25 Risk factors for Heart Failure Diseases that damage the heart increase the risk for heart failure and include: -Coronary heart disease and MI -Hypertension -Diabetes Unhealthy behaviors can also increase the risk for heart failure and include: -Smoking tobacco -Eating foods high in fat, cholesterol, and sodium(salt) -Not getting enough physical activity(inactive or sedentary). -Being obese 25

26 ACC/AHA 2013 Heart Failure Guideline Recognition and Treatment of Elevated Blood Pressure Hypertension may be the single most important modifiable risk factor for heart failure in the US Hypertensive men and women have substantially greater risk for developing heart failure than normotensive men and women Yancy CW et al. J Am Coll Cardiol. 2013;62:e147-e

27 Cardiovascular Risk Factors & Co-morbidities in Heart Failure Patients HTN 98% LVH 61% Uncontrolled HTN CAD 52% 59% Age ± 64 yrs N= % AAs DM 42% ETOH Abuse Ofili EO et al. Am J Cardiol. 1999;83: % Uncontrolled hypertension and LVH associated with increased hospitalization 27

28 Natriuretic Peptides: Diagnosis 13

29 AHA/ACC Heart Failure Stage Stage A: High risk of developing HF but w/o sxs or structural changes Hypertension, Diabetes, Alcohol Abuse, Family history of cardiomyopathy Stage B: Evidence of structural changes in the heart, but w/o signs or sxs Stage C: Prior or Current symptoms of HF Stage D: Refractory Symptoms despite medical care 2013 ACCF/AHA Guideline for the Management of Heart Failure. Circulation. 2013;128:e240-e319 Yancy CW et al., J Am Coll Cardiol 2013 Oct 15; 62:e147 29

30 New York Heart Association Classification- Functional Status Class I No limitation of physical activity. Ordinary physical activity does not cause undue breathlessness, fatigue, or palpitations. Class II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in undue breathlessness, fatigue, or palpitations. Class III Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in undue breathlessness, fatigue, or palpitations. Class IV Unable to carry on any physical activity without discomfort. Symptoms at rest can be present. If any physical activity is undertaken, discomfort is increased. 30

31 Treatment Options for Heart Failure Drug Class Mechanism of Action Common Adverse Effects Angiotensin converting enzyme inhibitors (ACEIs) Angiotensin receptor blockers (ARBs) Aldosterone antagonists Block excess activation of the renin-angiotensin system Block excess activation of the renin-angiotensin system Block excess aldosterone; potassium-sparing diuretic Cough, lightheadedness Lightheadedness Increased urination, hyperkalemia,gynecomastia Adrenergic blockers; beta blockers (BBs) Diuretics Isosorbide Dinitrate and Hydralazine (FDC I/H) Block effect of excess norepinephrine release Reverse excessive water retention Produces vasodilation by increasing nitric oxide Fatigue, lightheadedness Hypovolemia, hypokalemia Headache, lightheadedness Digoxin Increases cardiac contractility Dysrhythmia 31

32 New Treatment Options for Heart Failure Drug Class Mechanism of Action Common Adverse Effects Angiotensin receptor blocker, neprilysin inhibitor (ARNI) Ivabridine Block AT1 receptor activation, breakdown of bradykinin, BNP, Ang II Block cardiac lf (funny channel) Hypotension, renal insufficiency, angioedema Reduced heart rate via effects on SA node 32

33 Heart Failure: Key Issues in 2016 How and when to incorporate new agents into the management of HF How to optimize HF therapy in racial/ethnic minority groups to improve outcomes and reduce disparities 33

34 ARS Question Which of the following is the best option for a patient with heart failure Stage IIIC on guideline-directed medical therapy who may be intolerant of optimal beta blocker doses, has CAD and a resting heart rate 80 bpm? 1. Digoxin 2. Ivabradine 3. Sacubitril/valsartan 4. Calcium channel blocker 34

35 Elevated Resting Heart Rate is a Risk Factor in Heart Failure Böhm M, et al; SHIFT Investigators. Lancet. 2010;376(9744):

36 Beta blockers Targeting Heart Rate in HF Block beta 1 receptors in sino-atrial node and myocardium to reduce heart rate and contractility New agent: Ivabradine Inhibit I f or funny channel of the sinus node pacemaker to reduce heart rate, without affecting BP or other ionic currents. Pure heart rate-reducing agent 36

37 SHIFT: Systolic Heart failure treatment with the If inhibitor ivabradine Trial Europe Germany Portugal Belgium Greece Spain Denmark Ireland Sweden Finland Italy Turkey France The Netherlands UK Participating Countries Bulgaria Czech Republic Estonia Hungary Latvia Lithuania Norway Poland Romania Russia Slovakia Slovenia Ukraine North America Canada South America Argentina Brazil Chili Asia China Hong Kong India South Korea Malaysia Australia 6505 patients, 37 countries, 677 centers 37

38 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 and 4. On Guideline-Directed Medical Therapy 38

39 Inclusion Criteria 18 years Class II to IV NYHA heart failure Ischemic/non-ischemic etiology LV systolic dysfunction (EF 35%) Heart rate 70 bpm Sinus rhythm Documented hospital admission for worsening heart failure 12 months Swedberg K, et al. Eur J Heart Fail. 2010;12: Swedberg K, et al. Lancet. 2010;376(9744):

40 Primary composite endpoint (CV Mortality or HF Hospitalization) Cumulative frequency (%) Ivabradine n=793 (14.5%PY) Ivabradine Placebo Placebo n=937 (17.7%PY) HR = 0.82 [95% CI ] p< % Months Swedberg K, et al. Lancet. 2010;376(9744):

41 Hospitalization for heart failure Cumulative frequency (%) 30 Ivabradine Placebo Ivabradine n=514 (9.4%PY) Placebo n=672 (12.7%PY) HR = 0.74 [95% CI ] p< % Months Swedberg K, et al. Lancet. 2010;376(9744):

42 Mean heart rate reduction Mean ivabradine dose: 6.4 mg bid at 1 month Heart rate (bpm) 90 Ivabradine Placebo 6.5 mg bid at 1 year weeks Months 42 Swedberg K, et al. Lancet. 2010;376(9744):

43 Effect of Ivabradine on Outcomes According to Magnitude of Heart Rate Reduction Patients with primary composite end point (%) bpm -10 to <0 bpm > -10 bpm Day Time (months) Böhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):

44 SHIFT Conclusions Heart failure with systolic dysfunction and elevated heart rate is associated with poor outcomes (primary composite endpoint in the placebo group is 18%/year) Ivabradine reduced primary endpoint (CV mortality or heart failure hospitalization) by 18% (p<0.0001). The absolute risk reduction was 4.2% This beneficial effect was mainly driven by a favorable effect on hospitalization for heart failure (RRR 26%) Overall, treatment with ivabradine was safe and well tolerated 44 Swedberg K, et al. Lancet. 2010;376(9744):

45 Ivabradine Approved for Systolic Heart Failure FDA approved in 2015 for patients with: stable chronic HF and EF < 35% normal sinus rhythm resting HR 70 bpm, and taking beta blockers at guideline-recommended or highest tolerable dose AHA/ACC Guidelines: Recommend ivabradine in patients with: HFrEF (EF 35%) in sinus rhythm HR 70 bpm, and beta-blocker intolerance, or elevated heart rate on maximally tolerated beta-blocker doses Level IIA/B-R recommendation 45

46 ARS Question According to guidelines, which of the following agents should be considered for African American patients with stage III/C CHF and reduced ejection fraction who are symptomatic? 1. Digoxin 2. Sacubitril/valsartan 3. Aldosterone antagonist 4. Isosorbide dinitrate/hydralazine 46

47 Any degree of uncertainty a physician may have relative to the condition of a patient can contribute to disparities in treatment. Smedley B. et al, IOM March 2002 McMurray J. et al NEJM 2014;371(11):

48 Adapted From: Atlas of Heart Failure: Cardiac Function and Dysfunction edited by Wilson Colucci, Eugene Braunwald; 3 rd Ed ISBN Ch 6: Neurohormonal, Renal and Vascular Adjustments in Heart Failure (p 116: Natriuretic Peptides) 48

49 Schematic Showing the Mechanism of Action of LCZ696 (Sacubitril/Valsartan) 49 Vardeny et al. Neprilysin Inhibition in Heart Failure; J A C C : H E A R T F A I L U R E V O L. 2, N O. 6, :

50 Pathophysiology of HF: Rationale for ARNI 50

51 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) Enalapril (n=4212) LCZ696 (n=4187) HR = 0.80 ( ) P = Patients at Risk LCZ696 Enalapril Days After Randomization Packer M., et al. For PARADIGM Investigators

52 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 Packer M., et al. For PARADIGM Investigators 52

53 PARADIGM-HF: Patient Demographics In the PARADIGM-HF trial, the incidence of angioedema was 0.1% in both the enalapril and sacubitril/valsartan run-in periods. In the double-blind period, the incidence of angioedema was higher in patients treated with sacubitril/ valsartan than enalapril (0.5% and 0.2%, respectively). The incidence of angioedema in Black patients was 2.4% with sacubitril/ valsartan and 0.5% with enalapril 53

54 PARADIGM-HF: Adverse Events The most common side effects were hypotension, hyperkalemia, and renal impairment. Angioedema was also reported with black patients and patients with a prior history of angioedema having a higher risk. 54

55 Sacubitril/valsartan Approved and Recommended FDA Approved to reduce the risk of cardiovascular death and hospitalization in chronic heart failure patients (NYHA Class II- IV) and reduced EF 2016 ACC/AHA Guidelines: Recommend sacubitril/valsartan for patients with: NYHA class II or III HF and reduced EF who tolerate an ACE inhibitor or ARB Replacement of ACE/ARB with ARNI recommended to further reduce morbidity/mortality Close surveillance of serum potassium and creatinine (LOE I-BR) Yancy, CW, et al Heart Failure Focused Update on Pharmacologic Therapy 55

56 Case # 1 58-year-old AA woman History of non-ischemic cardiomyopathy and hypertension frequent shortness of breath during normal daily activities 1 pillow orthopnea hospitalized 6 months ago for HF Dilated LV; EF 38%; mild mitral regurgitation; no history CAD Medications: valsartan 160 mg qd; carvedilol 25 mg bid; furosemide 40 mg bid. Allergic to enalapril. BP 125/80 mmhg, pulse 68 bpm, weight 255 Ibs No JVD; lungs clear; cardiac regular rate and rhythm; grade 2/6 systolic murmur; abdomen soft non tender; extremities 1+ bilateral edema 56

57 ARS Question What would you add to this patient s medication regimen to reduce risk for CV events and improve survival? 1. Digoxin 2. Ivabradine 3. Sacubitril/valsartan 4. Isosorbide dinitrate/hydralazine 57

58 Case #1 (cont d) Clinical Pearl #1 Patient has NYHA Class III HF, moderately symptomatic Patient was recently hospitalized due to HF During this follow up visit: evaluate for ongoing/new symptoms optimize evidence-based therapy to improve symptoms, reduce hospitalization and increase survival 58

59 2013 ACC/AHA Guideline: HYD and ISDN I IIa IIb III I IIa IIb III The combination of HYD and ISDN is recommended for African Americans with NYHA class III IV HFrEF on GDMT IA A combination of HYD and ISDN can be useful with HFrEF who cannot be given ACE-Is or ARBs IIa B GDMT-Guideline Directed Management Therapy Yancy CW et al. J Am Coll Cardiol. 2013:62:e147-e

60 Oxidative Stress Nitroso-Redox Imbalance in Heart Failure Isosorbide dinitrate Stimulation Nitric oxide synthase Citrulline Oxidase Hydralazine Inhibition L-Arginine NO O 2 O 2 O 2 Physiologic pathway Pathologic pathway Formation of cyclic guanosine monophosphate Peroxynitrite (ONOO ) DNA damage S-nitrosylation: post-translational modification of effector molecules Inhibition Cell damage Oxidized proteins 60 Hare JM. N Engl J Med. 2004;351:

61 Trial Heart Failure Trials: Rx Total Non- African Americans (%) African Americans African Americans (%) V-HeFT I + II1 ISDN/HYD, Enalapril SOLVD 2 Enalapril US Carvedilol 3 Carvedilol COPERNICUS 4 Carvedilol BEST 5 Bucindolol MERIT-HF 6 Metoprolol EPHESUS 7 Eplerenone Val-HeFT 8 Valsartan VALIANT9 Valsartan, Valsartan/Captopril CHARM 10 Candesartan A-HeFT 11 ISDN/HYD TOTAL 44,488 40,525 3, Carson P et al. J Card Fail. 1999;5: ; 2. Hall WD. Ethn Dis. 1999;9: ; 3. Yancy CW et al. N Engl J Med. 2001;344: ; 4. Packer M et al. N Engl J Med. 2001;344: ; 5. BEST Investigators. N Engl J Med. 2001;344: ; 6. MERIT-HF study group. Lancet. 1999;353: ; 7. Pitt B et al. N Engl J Med. 2003;348: ; 8. Cohn JN. N Engl J Med. 2001;345: ; 9. Pfeffer MA et al. N Engl J 61 Med. 2003;349: ; 10. Yusuf S et al. Lancet. 2003;362: Taylor AL et al. AHEFT- N Engl J Med. 2004;351:

62 62

63 African American Heart Failure Trial (A-HeFT) Objective Demonstrate the safety and efficacy of ISDN/HYD compared with placebo in African American patients with moderate to severe HF concurrently receiving standard HF treatment Inclusion Criteria Patients self-identified as African American NYHA class III or IV HF (> 3 months) LVEF < 35% (or < 45% with dilated LV by echo) Standard therapy for HF, including ACEI/ARB + BB (> 3 months) 63

64 A-HeFT Characteristics (Inclusion Criteria) Standard Therapy Medications (All Patients) Diuretics: 94% ACE inhibitors: 78% ARBs: 28% Beta-blockers: 87% Digoxin: 62% Spironolactone: 39% Taylor AL et al. N Engl J Med. 2004;351:

65 A-HeFT: All-Cause Mortality Primary Efficacy Endpoint Composite score: All-Cause Mortality; First HF Hospitalization; Change in QoL at 6 months relative to baseline 100 Fixed Dose Isosorbide/Hydralazine Survival (%) Placebo N=1050 Hazard ratio= % Decrease P= Days Since Baseline Visit Date Fixed-dose I/H Placebo Taylor AL et al. N Engl J Med. 2004;351:

66 Case #1 (cont d) Clinical Pearl #2 Patient has persistent symptoms despite optimal neurohormonal blockade with valsartan and carvedilol FDC I/H (Fixed Dose Combination Isosorbide Dinitrate and Hydralazine should be added to treatment regimen FDC I/H is the evidence-based guideline treatment that is recommended at this time for this patient with NYHA Class III HFrEF It is important to consider how the addition of FDC I/H to current treatment (valsartan and carvedilol) will affect the blood pressure in this patient 66

67 AHEFT: FDC I/H Did Not Significantly Reduce SBP when Baseline SBP was less than 112 mmhg Anand I S et al. Journal of the American College of Cardiology, Volume 49, Issue 1, 2007,

68 Conclusions Identifying and treating risk factors for heart failure is a continuous and ongoing process across the stages of HF (from stage A-C) Monitor at risk patients with diagnostic studies where appropriate, in order to detect cardiac remodeling and progression from stage A to B and C. Use biomarkers like BNP to support the diagnosis of decompensated HF 68

69 Conclusions (cont d) Heart failure with reduced ejection fraction (HFrEF) and elevated heart rate >70 bpm despite maximally tolerated beta blocker therapy, is associated with poor outcomes. These patients may benefit from the If inhibitor, Ivabradine. Sacubitril/valsartan may be appropriate for patients with HF and reduced ejection fraction; small sample size of African Americans in PARADIGM may limit use in this population. Recognize the impact of health disparities, and apply the best clinical trial evidence to support the treatment of HF in African Americans and other ethnic minorities. 69