Presentation Objectives

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1 Managing Heart Failure What s old, What s new? Steve Kuehn, M.D. Director, Cardiac Catheterization Lab Cox South Hospital Presentation Objectives Be Familiar with the utilization of new pharmacotherapy in concert with the tried and true Know the benefits and drawbacks of various monitoring options, both invasive and noninvasive The Epidemic of Heart Failure Heart failure patients (mm) million patients with HF in US 1 55, new cases/year 6.6% 9.8% aged >65 years have HF 1. AHA. 24 Heart and Stroke Statistical Update. 2. Levy D, et al. N Engl J Med 22;347:

2 Projected increase in the US population 65 years of Age or Older Millions of persons >65 Yr Old Millions of persons Percent of population Percent of population > 65 Yr Old US Census Bureau Hospitalizations/1, Population Heart Failure: A Public Health Crisis Hospitalizations Have Tripled in last 25 Years 65+ years years Year NHLBI. Morbidity and Mortality: 2 Chartbook on Cardiovascular, Lung, and Blood Diseases. Geneva: World Health Organization; Classification of Recommendations and Levels of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/ efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated.

3 Stages, Phenotypes and Treatment of HF Asymptomatic Stages of Heart Failure A At high risk for HF but without structural heart disease or symptoms of HF (e.g., patients with HTN or CAD) NYHA Class B Structural heart disease but without symptoms of HF C Structural heart disease with prior or current symptoms of HF D Refractory/advanced HF requiring specialized interventions Class I Asymptomatic: No limitation of physical activity. Ordinary activity does not cause sxs. II Symptomatic with moderate exertion. Ordinary physical activity causes SOB, fatigue III Symptomatic with minimal exertion. Less than usual activity causes sxs IV Symptomatic at rest. Unable to carry on any activity without discomfort. Symptomatic ACC/AHA Guidelines 213 NYHA Class and Mortality Class I Asymptomatic: No limitation of physical activity. Ordinary activity does not cause sxs. II Symptomatic with moderate exertion. Ordinary physical activity causes SOB, fatigue III NYHA Class Symptomatic with minimal exertion. Less than usual activity causes sxs IV Symptomatic at rest. Unable to carry on any activity without discomfort. 1-Yr Mortality 5-1% 5-1% 1-25% 25-6% ACC/AHA Guidelines 213

4 I II III IV New York Heart Association Classification of Heart Failure Class Asymptomatic Mild Moderate Severe Patient Symptoms No limitation of physical activity No undue fatigue, palpitation or dyspnea Slight limitation of physical activity Comfortable at rest Less than ordinary activity results in fatigue, palpitation, or dyspnea Marked limitation of physical activity Comfortable at rest Less than ordinary activity results in fatigue, palpitation, or dyspnea Unable to carry out any physical activity without discomfort Symptoms of cardiac insufficiency at rest Physical activity causes increased discomfort Criteria Committee of the New York Heart Association, Stage C: Nonpharmacological Interventions I IIa IIb III Continuous positive airway pressure (CPAP) can be beneficial to increase LVEF and improve functional status in patients with HF and sleep apnea. I IIa IIb III Cardiac rehabilitation can be useful in clinically stable patients with HF to improve functional capacity, exercise duration, HRQOL, and mortality. Pathophysiology and Mechanisms in Heart Failure

5 Pathological Progression of CV Disease 1 Coronary artery disease Arrhythmia Underlying etiology in ~6% of CHF 1 Left ventricular injury Pathologic remodeling Low ejection fraction Death Hypertension Cardiomyopathy Valvular Disease Underlying etiology in ~4% of CHF 1 Neurohormonal stimulation Endothelial dysfunction Myocardial toxicity Vasoconstriction Renal sodium retention Symptoms: Dyspnea Fatigue Edema Pump failure Chronic heart failure 1 Adapted from Cohn JN. N Engl J Med. 1996;335: He J, Ogden LG, Bazzano LA, et al. Risk Factors for Congestive Heart Failure in US Men and women: NHANES I epidemiologic follow-up study. Arch Intern Med 21, 161: Pathophysiologic Progression of HF Normal Injury Adaptation Remodeling Architectural distortion Normal Compensatory hypertrophy Dilated and fibrotic Courtesy of A. Agocha, MD Neurohumoral Response: Renin-Angiotensin-Aldosterone (RAAS) Renin Angiotensin Converting Enzyme Angiotensinogen Angiotensin I Angiotensin II AT I receptor Vasoconstriction Vascular remodeling Aldosterone Cell Growth Oxidative Stress LV remodeling

6 Neurohormonal Blockade Across the CV Disease Continuum Angiotensin II (Renin-Angiotensin System [RAS]) Norepinephrine (Sympathetic Nervous System [SNS]) RAS Inhibition Beta-Blockade Disease Progression Treatment of Post-MI Patients with Asymptomatic LV Dysfunction (LVEF <4%) SAVE Study All-cause mortality 19% CV mortality 21% HF development 37% Recurrent MI 25% Mortality Rate Placebo Years Captopril 19% relative risk reduction p = Pfeffer et al. NEJM 1992;327: SOLVD: Studies Of Left Ventricular Dysfunction Cumulative all-cause mortality Mortality (%) Placebo Enalapril No. of Months after start of treatment patients alive Placebo Enalapril P =.36 The SOLVD Investigators. N Engl J Med 1991;325:

7 Effect of ACE Inhibitors on Mortality Reduction in Patients With LVD or Heart Failure Trial ACEI Controls RR (95% CI) Chronic CHF CONSENSUS I SOLVD (Treatment) SOLVD (Prevention) Post MI SAVE AIRE TRACE 39% 54%.56 (.34.91) 35% 4%.82 (.7.97) 15% 16%.92 ( ) 2% 25%.81 (.68.97) 17% 23%.73 (.6.89) SMILE 6.5% 8.3%.78 ( ) Average Mortality 35% 42% 21% 25%.78 (.67.91) Garg R et al. JAMA. 1995;273: Neurohumoral Interventions Across the Continuum Post-MI LV dysfunction Mild CHF Moderate CHF Severe CHF AIRE/SAVE/TRACE (ramipril/captopril/ trandolapril) SOLVD Treatment (enalapril) CONSENSUS (enalapril) Patients With Reduced Left Ventricular Ejection Fraction I IIa IIb III Angiotensin-converting enzyme (ACE) inhibitors are recommended for all patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated. NO CHANGE

8 ARBS in Patients Not Taking ACE Inhibitors: Val-HeFT & CHARM-Alternative 1 Val-HeFT 5 CHARM-Alternative Survival % Valsartan Placebo p = Months CV Death or HF Hosp % Placebo 4 3 Candesartan 2 1 HR.77, p = Months Maggioni AP et al. JACC 22;4: Granger CB et al. Lancet 23;362: Patients With Reduced Left Ventricular Ejection Fraction I IIa IIb III Angiotensin ll Receptor Blockers Angiotensin II receptor blockers are recommended inpatient with current or prior symptoms of HF and reduced LVEF who are ACE- inhibitor intolerant (see full text guidelines). NO CHANGE Trials with Aldosterone Blockade Primary Endpoint: All-Cause Mortality Placebo Aldosterone Hazard Log-rank Blockade Ratio P-Value EPHESUS 554/ / (.75,.96).8 RALES 386/ /822.7 <.1 (.6,.82)

9 RALES: Spironolactone Improves Survival Probability of Survival Spironolactone Placebo Study Design NYHA Class III-IV (N=1663) EF 35% Frequent monitoring of potassium 3% reduction in death 35% risk of hospitalization Months Pitt B, et al. N Engl J Med. 1999;341: (Permission for use requested) EPHESUS: Improved Survival and Decreased Hospitalization Event rate at 16 months (% n=478 n=554 n=885 n=993 Mortality Mortality or Hospitalization Eplerenone Placebo P value.8.2 Pitt B, et al. N Engl J Med 23;348: (Permission for use requested) Patients With Reduced Left Ventricular Ejection Fraction I IIa IIb III The Risks of Aldosterone Antagonists Addition of an aldosterone antagonist is recommended in selected patients with moderately severe to severe symptoms of HF and reduced LVEF who can be carefully monitored for preserved renal function and normal potassium concentration. Creatinine 2.5 mg/dl or less in men or 2. mg/dl or less in women and potassium should be less than 5. meq/l. Under circumstances where monitoring for hyperkalemia or renal dysfunction is not anticipated to be feasible, the risks may outweigh the benefits of aldosterone antagonists. NO CHANGE

10 Neurohormonal Blockade Across the CV Disease Continuum Post-MI LV dysfunction Mild CHF Moderate CHF Severe CHF AIRE/SAVE/TRACE (ramipril/captopril/ trandolapril) EPHESUS (eplerenone) SOLVD Treatment (enalapril)? CONSENSUS (enalapril) RALES (spironolactone) Neurohormonal Blockade Across the CV Disease Continuum Angiotensin II (Renin-Angiotensin System [RAS]) Norepinephrine (Sympathetic Nervous System [SNS]) RAS Inhibition β-blockade Disease Progression Deleterious Effects of Norepinephrine in CV Disease Injury to the heart (eg, MI, HTN, DM) Levels of norepinephrine Negative cardiac effects Negative vascular effects Negative renal effects β 1 β 2 α 1 α 1 β 1 α 1 Cardiac injury Hypertrophy Arrhythmias Vasoconstriction Activation of RAS Sodium retention Disease progression

11 Survival Benefits of Beta Blockers MERIT-HF 1 COPERNICUS 2 1. β -blocker 1. β -blocker Mortality.8 Placebo.8 Placebo.6 Risk 34% 1 2 P=.62 Metoprolol: n=199 Placebo: n=21.6 Risk 35 % P< Time (years) Carvedilol: n=1156 Placebo: n= MERIT-HF Study Group. Lancet 1999;353: (Permission for use requested) 2. Packer M, et al. N Engl J Med 21;344: (Permission for use requested) Effect of Beta-Blockade on Outcome in Patients With Heart Failure and Post-MI LVD Target HF Dosage Study Drug Severity (mg/day) Outcome US Carvedilol 1 carvedilol mild/ 6.25 to 25 48% disease progression moderate bid (P=.1) CIBIS-II 2 bisoprolol moderate/ 1 qd 34% mortality severe (P<.1) MERIT-HF 3 metoprolol mild/ 2 qd 34% mortality succinate moderate (P=.62) COPERNICUS 4 carvedilol severe 25 bid 35% mortality (P=.14) CAPRICORN 5 carvedilol Post-MI LVD 25 bid 23% mortality (P=.31) 1 Colucci WS et al. Circulation. 1996;94: CIBIS II Investigators and Committees. Lancet. 1999;353: MERIT-HF Study Group. Lancet. 1999;353: Packer M et al. N Engl J Med. 21;344: The CAPRICORN Investigators. Lancet. 21;357: Neurohormonal Interventions Across the Continuum Post-MI LV dysfunction Mild CHF Moderate CHF Severe CHF AIRE/SAVE/TRACE (ramipril/captopril/ trandolapril) CAPRICORN (carvedilol) SOLVD Treatment (enalapril) US Carvedilol Trials (carvedilol) MERIT-HF (metoprolol) CIBIS II (bisoprolol) CONSENSUS (enalapril) COPERNICUS (carvedilol)

12 Patients With Reduced Left Ventricular Ejection Fraction I IIa IIb III Use of 1 of the 3 beta blockers proven to reduce mortality (i.e., bisoprolol, carvedilol, and sustained release metoprolol succinate) is recommended for all stable patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated. Modified Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure Anne L. Taylor, M.D., Susan Ziesche, R.N., Clyde Yancy, M.D., Peter Carson, M.D., Ralph D'Agostino, Ph.D., Keith Ferdinand, M.D., Malcolm Taylor, M.D., Kirkwood Adams, M.D., Michael Sabolinski, M.D., Manuel Worcel, M.D., Jay N. Cohn, M.D. and the African-American Heart Failure Trial Investigators N Engl J Med Volume 351;2: November 11, 24

13 Kaplan-Meier Estimates of Overall Survival Taylor, A. et al. N Engl J Med 24;351: Conclusions The addition of a fixed dose of isosorbide dinitrate/hydralazine to standard therapy for african americans with heart failure 43% Reduction in mortality (P =.12) 39% Risk of 1 st Hospitalization (P<.1) Improvement in Minnesota Living with Heart Failure Questionnaire Patients With Reduced Left Ventricular Ejection Fraction Recommendations for Hydralazine and Nitrates I IIa IIb III The combination of hydralazine and nitrates is recommended to improve outcomes for patients selfdescribed as African-Americans, with moderate-severe symptoms on optimal therapy with ACE inhibitors, beta blockers, and diuretics. I IIa IIb III The addition of a combination of hydralazine and a nitrate is reasonable for patients with reduced LVEF who are already taking an ACE inhibitor and beta blocker for symptomatic HF and who have persistent symptoms. NO CHANGE New

14 The Impact of Neurohormonal Interventions on SCD in Heart Failure: Are We Making Any Progress? 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 3% 6 35% Hydralazine/nitrate 43% 7 33% Mortality Reduction with Pharmacotherapy Optimal pharmacologic therapy (OPT) is effective in reducing mortality 7% Reduction in mortality (%) 6% 5% 4% 3% 2% 1% 4% 3% 3% 21% % Beta-blockers Mean 1 ACE inhibitors Mean 2 Courtesy of A. Agocha, M.D. 1. Mean mortality reduction from major β-blocker trials 2. Mean mortality reduction from major ACE inhibitor trials Spironolactone RALES 3 3. N Engl J Med 1999;341: N Engl J Med 23;348: Eplerenone EPHESUS 4

15 SCD in Heart Failure 1, 2 Despite improvements in medical therapy, symptomatic HF still confers a 2-25% risk of premature death in the first 2.5 yrs after diagnosis. 1 Bardy G. The Sudden Cardiac Deatth-Heart Failure Trial (SCD-HeFT) in Woosley RL, Singh S, Arrhythmia Treatment and Therapy, Copyright 2 by Marcel Dekker, Inc., pp , 2 Sweeney MO PACE 21;24: Magnitude of SCA in the US Stroke 3 Lung Cancer 2 167, ,4 SCA claims more lives each year than these other diseases combined 45, Sudden Cardiac Arrest 4 Breast Cancer 2 AIDS 1 4,6 42,156 1 U.S. Census Bureau, Statistical Abstract of the United States: American Cancer Society, Inc., Surveillance Research, Cancer Facts and Figures Heart and Stroke Statistical Update, American Heart Association. 4 Circulation. 21;14: The #1 Cause of Death In people diagnosed with CHF, sudden cardiac arrest occurs at 6-9 times the rate of the general population 1 Age-adjusted annual rate/ No CHF CHF Overall Mortality Sudden Death Women Men Women Men CHF predicts increased sudden death and overall mortality. During a 39-year followup of subjects in the Framingham heart Study, the presence of CHF significantly increased sudden death and overall mortality in both men and women. 2 1 Kannel WB, Wilson PWF, D'Agostino RB, Cobb J. Sudden coronary death in women. Am Heart J Aug; 136:

16 Relationship of SCD and Left Ventricular Dysfunction Reduced left ventricular ejection fraction (LVEF) remains the single most important risk factor for overall mortality and sudden cardiac death 1 Increased risk is measurable at ejection fractions above 3%, but an ejection fraction 3% is the single most powerful independent predictor for SCD 2 1 Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J, 21;22: Myerburg RJ, In Braunwald E, Zipes DP, Libby P, Heart Disease, A textbook of Cardiovascular Medicine. 6 th ed. Philadelphia: W.B. Saunders, Co. 21: 895. LVEF and SCA Incidence % SCA Victims % 5.1% 2.8% 1.4% -3% 31-4% 41-5% >5% LVEF Gorgels PMA. European Heart Journal. 23;24: Severity of Heart Failure Modes of Death NYHA II 64% 12% 24% 33% 11% CHF Other Sudden Death n = 13 NYHA IV 56% CHF Other 59% Sudden Death n = 27 NYHA III 26% 15% CHF Other Sudden Death n = 13 The greatest opportunity for SCD prevention is in patients that have mild to moderate CHF. MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). LANCET. 1999;353:21-7.

17 Underlying Arrhythmias of Sudden Cardiac Arrest Torsades de Pointes 13% Bradycardia 17% VT 62% Primary VF 8% Bayés de Luna A. Am Heart J. 1989;117: Etiology of Sudden Cardiac Death Coronary Heart Disease An estimated 13 million people had CHD in the U.S. in Sudden death was the first manifestation of coronary heart disease in 5% of men and 63% of women. 1 CHD accounts for at least 8% of sudden cardiac deaths in Western cultures. 3 Etiology of Sudden Cardiac Death 2,3 5% Other* 15% Cardiomyopathy 1 American Heart Association. Heart Disease and Stroke Statistics 23 Update. Dallas, Tex.: American Heart Association; Adapted from Heikki et al. N Engl J Med, Vol. 345, No. 2, 21. 8% Coronary Heart Disease * ion-channel abnormalities, valvular or congenital heart disease, other causes 3 Myerberg RJ. Heart Disease, A Textbook of Cardiovascular Medicine. 6 th ed. P. 895.

18 Conditions Predisposing to Ventricular Arrhythmia in Heart Failure Patients Electrophysiological abnormalities Cellular hypertrophy & interstitial fibrosis can result in prolongation of the action potential Increases propensity for early after depolarizations (Torsades de Pointes) Neurohormonal Activation Persistent adrenergic stimulation of the failing heart is maladaptive & arrhythmogenic Singh S.J Cardiovas Electrophysiol 1997;8:89-97 Conditions Predisposing to Ventricular Arrhythmia in Heart Failure Patients Electrolyte abnormalities Predisposition to hypokalemia is caused by diuretic therapy, activation of the renin-angiotensinaldosterone system, and sympathetic activation The effects of hypokalemia on ventricular arrhythmias are amplified in the setting of structural heart disease Sweeney MO. PACE 21;24: Underlying Arrhythmias of Sudden Cardiac Arrest Torsades de Pointes 13% Bradycardia 17% VT 62% Primary VF 8% Bayés de Luna A. Am Heart J. 1989;117:

19 Implantable Cardioverter Defibrillator(ICD) ICD Survival Benefit: Secondary Prevention Studies % Mortality Reduction Overall Death Arrhythmic Death AVID at 3 Years CASH at 3 Years CIDS at 2 Years The AVID Investigators. N Engl J Med. 1997;337: Kuck K. Circ.2;12: Connolly S. Circ. 2;11: Urgency of Sudden Cardiac Arrest 1 Resuscitation Success vs. Time 9 Chance of success reduced 7-1% every minute % Success Adapted from text: Cummins RO, Annals of Emergency Medicine. 18: Time (minutes)

20 The Epidemic of Heart Failure Heart failure patients (mm) million patients with HF in US 1 55, new cases/year 6.6% 9.8% aged >65 years have HF 1. AHA. 24 Heart and Stroke Statistical Update. 2. Levy D, et al. N Engl J Med 22;347: Despite medical advances, Heart Failure hospitalization is a worsening epidemic Significant Reduction in Coronary Deaths 1 Significant Increase in HF Hospitalizations 2 Deaths/1, Population Number of HF Hospitalizations With HF as Primary or Secondary Diagnosis, by 5-Year Time Period 2,, 15,, 1,, 5,, - THE PROBLEM: Unless focused, dramatic measures are taken, the clinical and financial burden to society is only going to escalate. 1. Graph adapted from NIH, Accessed Graph adapted from Fang J, et al. JACC, Cardiomems: another mode to help patients and reduce rehospitalization Prevents Acute Decompensation Clinical trial and early commercial use demonstrates that PA-pressure guided therapy: Lowers Hospitalization and Readmission Rates Effectively Lowers PA Pressures Improves Quality of Life Abraham WT, Lancet, 211 6

21 Goal of heart failure management: slow disease progression by preventing decompensation Each Event Accelerates Downward Spiral of Myocardial Function With each subsequent HF-related admission, the patient leaves the hospital with a further decrease in cardiac function. THE GOAL: Maintain fluid volume to avoid acute decompensation and hospitalization, using proven drug and device therapies. Graph adapted from: Gheorghiade MD, et al. Am J. Cardiol Current HF Management: how well do current tools KEEP PATIENTS STABLE and out of the hospital? 6% Post-hoc analysis of 463 acute decompensated HF patients from 4% DOSE-HF and congestion 3 congestion 3 moderate to severe CARRESS-HF absent or mild 1. Adams KF, et al. Am Heart J Krum H and Abraham WT. Lancet Lala A, et al. JCF % of HF hospitalizations due to symptoms of pulmonary 9% of HF Hospitalizations congestion 1,2 due to symptoms of pulmonary congestiont DISCHARGE AT 6-DAY FOLLOW- UP 41% of previously decongested patients had severe or partial re-congestion 3 TODAY S TOOLS ARE INADEQUATE at relieving congestion (inpatient) and preventing recongestion and readmission (outpatient) even at well-established HF management programs and with the best HF-trained specialists. 6 2 Current HF Management: Can we reliably use weight change as an indicator of rising pressure? Lbs Body Weight and RV Diastolic Pressure 1 (COMPASS Trial Control Group) HOSPITALIZATION mmhg Weight Gain Sensitivity Specificity 2 kg weight gain over hrs2 9% 97% 2% weight gain over hrs2 17% 94% 3 lbs in 1 day or 5 lbs in 3 days % Body Weight (lbs) RV Diastolic Pressure (mmhg) 1. Data based on Zile MR, et al. Circulation, 28. Presented at FDA Advisory Panel, October 9, Lewin J. et al. Eur J HF Abraham WT. et al. Cong Heart Failure NO CORRELATION Daily weights do not correlate with filling pressures. 6 3

22 Current HF Management: How reliable are clinical examinations in assessing RISING pressure? N = 366 Variable JVP Edema Pulse Press S3 Dyspnea Rales Estimate of RAP Cardiac Index PCWP Sensitivit y (%) 48 1 Specificit y (%) PPV (%) 6 55 NPV (%) RESULTS Data from clinical evaluations has poor sensitivity and predictive value in determining hemodynamic profile. Clinical examination has LIMITED RELIABILITY in assessing filling pressures. Table adapted from Capomolla S, et al. Eur J Heart Failure, The CLINICAL burden : heart failure is A GROWING GLOBAL CONCERN FOR PATIENTS, PROVIDERS AND HEALTH CARE SYSTEMS UNITED STATES PREVALENCE INCIDENCE MORTALITY 1. AHA 216 Statistics at a Glance, Krumholz HM, et al. Circ Cardiovas Qual Outcomes Heidenreich PA et al. Circ Heart Failure % prevalence Projected to increase to > 8M people 18 years of age with HF by , people 45 years of age are newly diagnosed each year with HF. For AHA/ACC stage C/D patients diagnosed with HF: 5.7M HF patients 5% readmitted within 6 months. 5% will die within 5 years. HIGH INCIDENCE, HIGH PREVALENCE AND POOR PROGNOSIS despite advances in the treatment of heart failure over the past few decades. 6 5 The ECONOMIC burden: heart failure is a significant and growing contributor to overall HEALTH system costs UNITED STATES HOSPITALIZATIONS & READMISSIONS > 1,1, > 3,, hospitalizations for hospitalizations include HF as a contributor. 2 ~5 days average length of hospital stay 3 HF 1 ~25% all-cause readmission within 3 days; ~5% within 6 months. 5,6 COSTS Total medical costs for HF are projected to increase to $7B by 23, a 2x increase from 213.* 5% of the costs are attributed to hospitalizatio n. 4 Despite advances in medical therapies to treat heart failure, the hospitalization rate has not changed significantly from 2. As a result, heart failure continues to be a MAJOR DRIVER OF OVERALL HEALTH CARE COSTS. *Study projections assumes HF prevalence remains constant and continuation of current hospitalization practices 1. CDC NCHS National Hospital Discharge Survey, Yancy CW, et al. Circulation, Blekcer et al. JACC, Krumholz HM, et al. Circ Cardiovas Qual Outcomes Yancy et al. JACC, Wexler DJ, et al. Am Heart J,

23 Current HF Management: How can we get ahead of symptoms associated with acute decompensation? Graph adapted from Adamson PB, et al. Curr Heart Fail Reports, Cardiomems HF System: Delivers insight into the early onset of worsening HF to more proactively manage HF patients and improve outcomes Pulmonary Artery Pressure Sensor Target location for PA pressure sensor Patient Electronics System Merlin.net PCN Abraham WT, Lancet, CHAMPION TRIAL design: RANDOMIZED (Part 1) AND OPEN ACCESS (part 2) TRIAL HYPOTHESIS: In addition to basing treatment on signs and symptoms, adjusting medications based on PA pressures will reduce HF-related hospitalizations. Previously hospitalized patients (past 12 months) with NYHA class III HF for at least 3 months, regardless of LVEF All took daily readings. CardioMEMS PA Sensor Implanted n = 55 Treatment Group n = 27 RANDOMIZATION Control Group n = 28 CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association (NYHA) Class III Heart Failure Patients (CHAMPION) Trail Study Exit n = 93 Transition to Former Treatment Group n = 177 Study Exit n = 11 Transition to Former Control Group n = 17 PART 1: RANDOMIZED ACCESS 1 PART 2: OPEN ACCESS 2 1. Abraham W, et al. Lancet, Abraham W, et al. Lancet,

24 PURPOSE Evaluate the safety and efficacy of the CardioMEMS HF System in reducing HF related hospitalizations in NYHA class III heart failure patients. Treatment group managed to target PA pressures: CHAMPION TRIAL design: part 1: Prospective, multi-center, randomized, controlled, single-blind clinical trial Treatment Group n = 27 Traditional HF management guided by PA pressure information Study exits < 6 mos.: 26 (9.6%) Total 15 (5.6%) Death 11 (4.%) Other CardioMEMS PA Sensor Implanted n = 55 Control Group n = 28 Traditional HF management Primary Endpoint: Rate of HF hospitalization Study exits < 6 mos.: 26 (9.3%) Total 2 (7.1%) Death 6 (2.2%) Other Systolic mmhg Diastolic 8 2 mmhg Mean 1 25 mmhg Abraham W, et al. Lancet, 211. Secondary Endpoints: Change in PA pressure at 6 months No. of pts admitted to hospital for HF Days alive outside of hospital QOL (MLHFQ) 7 PURPOSE Given the Part 1 and Part 2 CHAMPION trial success, evaluate the impact of opening access to PA pressure information in the former control group. PART 1: RANDOMIZED ACCESS PART 2: OPEN ACCESS Abraham W, et al. Lancet, 216. CHAMPION TRIAL design: PART 2: Confirming Effectiveness and Sustained Benefit of PA Pressure Monitoring Treatment Group n = 27 Traditional HF management guided by PA pressure information Study exit n = 93 Transition to Former Treatment Group n = 177 Traditional HF management guided by PA pressure information Study exit: (17.5%) Death 27 (15.2%) Other CardioMEMS HF Sensor Implanted n = 55 NEW ACCESS to PA pressure information. Control Group n = 28 Traditional HF management Study exit n = 11 Transition to Former Control Group n = 17 Traditional HF management guided by PA pressure information Study exit: (12.3%) Death 22 (12.9%) Other 7 1 PART 1: RANDOMIZED ACCESS CHAMPION Trial results: PRIMARY ENDPOINT PART 2: OPEN ACCESS Cumulative Hazard Rate % Relative Risk Reduction in HF Hospitalizations in Treatment Group vs. Control Group p=.17 Control Treatment Patients managed with PA pressure data had SIGNIFICANT RELATIVE RISK REDUCTION as compared to the control group. Days From Implant # at Risk Control Treatment Abraham WT, et al. Lancet,

25 PART 1: RANDOMIZED ACCESS Primary Safety Endpoints Secondary Endpoints CHAMPION Trial results: Primary Safety Endpoints and Secondary Endpoints PART 2: OPEN ACCESS Device-related or system-related complications Treatment (n = 27) Control (n = 28) 3 (1%) 3 (1%) Total 8 (1%)* Pressure-sensor failures Change from baseline in PA mean pressure (mean AUC [mm Hg x days]) Number and proportion of patients hospitalized for HF (%) Days alive and out of hospital for HF (mean ±SD) Quality of life (Minnesota Living with Heart Failure Questionnaire, mean ± SD) P- value <.1 < (2%) 8 (29%) ± ± ± 26 51±25.2 Abraham WT, et al. Lancet, 211. ALL ENDPOINTS MET. Both primary safety endpoints and all secondary endpoints were met at 6 months. 7 3 CHAMPION Trial results: PA PRESSURE MEAN CHANGE FROM BASELINE PA Mean PA Mean Preasure Preasure AUC AUC (mmhg-days) (mmhg-days) By targeting PA pressure ranges and titrating medications, the overall mean PA pressure is reduced over time. Treatment ( mmhg-days) Treatment Control ( (33.1 mmhg-days) Control (33.1 mmhg-days) P = p = Days from Implant Abraham WT, et al. Lancet, 211. Monitoring PA pressure with the CardioMEMS HF System allows management of the pressure spikes that lead directly to exacerbation, as well as the long-term trends. 7 4 Intervention CHAMPION Trial results: Number Needed to Treat to Prevent One HF-related hospitalization Beta-blocker 1 Trial COPERNICU S Mean Duration of Randomized Follow-Up Annualized Reduction in HF Hospitalization Rates NNT/Year to Prevent 1 HF Hospitalizati on 1 months 33% 7 Aldosterone antagonist 2 RALES 24 months 36% 7 CRT 3 CARE-HF 29 months 52% 7 Beta-blocker 4 MERIT-HF 12 months 29% 15 ACE inhibitor 5 SOLVD 41 months 3% 15 Aldosterone antagonist 6 EMPHASIS- HF 21 months 38% 16 Digoxin 7 DIG 37 months 24% 17 Angiotensin receptor Val-HeFT 23 months 23% 18 blocker 8 Angiotensin CHARM 4 months 27% 19 receptor blocker 9 PA pressure CHAMPION 18 months 33% < 2 monitoring 1 7 5

26 The New Players Neprilysin breaks down important peptides that counter the negative consequences of the heart failure milieu Cardiac Failure Review, 216;2(1):4 6 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 Aim of the PARADIGM-HF Trial Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) LCZ696 4 mg daily Enalapril 2 mg daily SPECIFICALLY DESIGNED TO REPLACE CURRENT USE OF ACE INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS AS THE CORNERSTONE OF THE TREATMENT OF HEART FAILURE PARADIGM-HF: Entry Criteria NYHA class II-IV heart failure LV ejection fraction 4% BNP 15 (or NT-proBNP 6), but one-third lower if hospitalized for heart failure within 12 months Any use of ACE inhibitor or ARB, but able to tolerate stable dose equivalent to at least enalapril 1 mg daily at least 4 weeks for Guideline-recommended use of beta-blockers and mineralocorticoid receptor antagonists Systolic BP 95 mm Hg, egfr 3 ml/min/1.73 m 2 and serum K 5.4 meq/l at randomization PARADIGM-HF Was Designed to Show Incremental Effect on Cardiovascular Death Primary endpoint was cardiovascular death or hospitalization for heart failure, but PARADIGM-HF was designed as a cardiovascular mortality trial The sample size of the trial was determined by effect on cardiovascular mortality, not the primary endpoint The Data Monitoring Committee was allowed to stop the trial only for a compelling effect on cardiovascular mortality (in addition to the primary endpoint) Difference in cardiovascular mortality of 15% between LCZ696 and enalapril was prospectively identified as being clinically important (n=8 yielded 8% power)

28 (all comparisons are versus enalapril 2 mg daily, not versus placebo) PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk LCZ696 Enalapril Days After Randomization PARADIGM-HF: Cardiovascular Death 32 Kaplan-Meier Estimate of Cumulative Rates (%) HR =.8 ( ) P =.4 Number need to treat = 32 Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk LCZ696 Enalapril Days After Randomization

29 PARADIGM-HF: Effect of LCZ696 vs Enalapril on Primary Endpoint and Its Components LCZ696 (n=4187) Enalapril (n=4212) Hazard Ratio (95% CI) P Value Primary endpoint 914 (21.8%) 1117 (26.5%).8 ( ).2 Cardiovascular death 558 (13.3%) 693 (16.5%).8 ( ).4 Hospitalization for heart failure 537 (12.8%) 658 (15.6%).79 ( ).4 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 ± ± (.63, 2.65).1 New onset atrial fibrillation 84/267 (3.2%) 83/2638 (3.2%) Hazard ratio.97 (.72,1.31).84 Protocol-defined decline in renal function 94/4187 (2.3%) 18/4212 (2.6%) Hazard ratio.86 (.65, 1.13).28 Dosing

30 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 2% 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 Ivabradine (Corlanor) Ivabradine is indicated to reduce the risk of hospitalization for worsening HF (systolic) For patients with stable, symptomatic chronic HF with EF 35% or less Sinus rhythms with HR >/= 7 receiving maximally tolerated doses of beta blockers or have a contraindication to betablocker use. Ivabradine (Corlanor) Acts directly on sinus node, Na-K current No affect on blood pressure or cardiac conduction. No inotropic effect 5mg 7.5 mg BID

31 Ivabradine (Corlanor) Adverse events included bradycardia (1% for ivabradine versus 2.2% for placebo), hypertension (8.9% versus 7.8%), atrial fibrillation (8.3% versus 6.6%), and phosphenes (2.8% versus.5%) Ivabradine (Corlanor)