How Do You Mend a Broken Heart: The New Agents to Treat HF Paradigm Shift or Just the Same Old Drugs?

How Do You Mend a Broken Heart: The New Agents to Treat HF Paradigm Shift or Just the Same Old Drugs? Gregg C. Fonarow, MD FACC, FAHA, FHFSA Co-Chief UCLA Division of Cardiology Director, Ahmanson-UCLA Cardiomyopathy Center Los Angeles, CA

Disclosure Dr. Fonarow has consulted for Amgen, Janssen, Medtronic, and Novartis, and has received research grants from the National Institutes of Health (NIH) and Medtronic.

Scope of Heart Failure Population Group Prevalence Incidence Mortality Hospital Discharges Cost1 Total population 5,700,000 870,000 50% at 5 years 1,023,000 $30.7 billion Heart failure (HF) is a major public health problem resulting in substantial morbidity and mortality 6 12 million outpatient office visits Despite available effective treatments, a large number of eligible patients are not receiving optimal care Mozaffarian D, et al. Circulation. 2015;131:e29-e322. Jessup M. Circulation. 2014;129:2717-2722.

Neurohormonal Activation in Heart Failure Myocardial injury to the heart (CAD, HTN, CMP, valvular disease) Initial fall in LV performance, wall stress Activation of RAAS and SNS Remodeling and progressive worsening of LV function Morbidity and mortality Arrhythmias Pump failure Fibrosis, apoptosis, hypertrophy, cellular/ molecular alterations, myotoxicity RAAS = renin-angiotensin-aldosterone system; SNS = sympathetic nervous system; CMP = cardiomyopathy. Fonarow GC. Rev Cardiovasc Med. 2001;2:7-12. Peripheral vasoconstriction Hemodynamic alterations Heart failure symptoms Fatigue Activity altered Chest congestion Edema Shortness of breath

ACC/AHA HF Guidelines 2013: Management of HFrEF (Stage C) Life-Prolonging Medical Therapy ACE inhibitors or ARB (Class I, evidence A) in all patients without contraindications or intolerance. Evidence-based beta-blockers (Class I, evidence A) in all patients without contraindications or intolerance. This would include carvedilol (immediate or extended release), metoprolol succinate, or bisoprolol. Aldosterone antagonists (Class I, evidence A) in all patients with Class II IV HF without contraindications or intolerance when close monitoring can be ensured. Yancy CW, et al. J Am Coll Cardiol. 2013;62:1495-1539.

Pharmacologic Treatment for Stage C HFrEF HFrEF Stage C NYHA Class I IV Treatment: Class I, LOE A ACEI or ARB AND Beta-blocker For all volume overload, NYHA Class II IV patients For persistently symptomatic African Americans, NYHA Class III IV For NYHA Class II IV patients. Provided estimated creatinine >30 ml/min and K+ <5.0 meq/dl ADD ADD ADD Class I, LOE C Loop Diuretics Class I, LOE A Hydral- Nitrates Class I, LOE A Aldosterone Antagonist Yancy CW, et al. J Am Coll Cardiol. 2013;62:1495-1539.

New Tools for HFrEF

Counterregulatory Peptide Systems Activated in Heart Failure Patients Prostaglandin Bradykinin These peptides promote vasodilation, salt and water diuresis and have antiremodeling effects that modulate the adverse effects of the RAAS and SNS Adrenomedullin NPs (Natriuretic peptides) Since neprilysin breaks down these peptides, inhibitors of this enzyme should increase their levels and effects in heart failure ANP BNP CNP Urodilatin Dendroaspis ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; NP, natriuretic peptide; NPS, natriuretic peptide system. Mann DL et al. Braunwald s Heart Disease. 10th ed. Philadelphia, PA: Saunders; 2015.

Effects of Neprilysin Inhibition in Heart Failure Endogenous vasoactive peptides (natriuretic peptides, adrenomedullin, bradykinin, substance P, calcitonin gene-related peptide) Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention Neprilysin Neprilysin inhibition Inactive metabolites McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

Neprilysin Levels in Blood Predict Outcomes in HF Patients NEP < median NEP < median NEP median NEP median Bayés-Genís A et al. JACC 65: 657-665, 2014

Sacubitril/Valsartan (LCZ696) Mechanism of Action Buggey et al. Journal of Cardiac Failure, Volume 21, Issue 9, 2015, 741 750

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) Sacubitril/Valsartan 97/103 mg twice daily Enalapril 10 mg twice 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 Trial: Design Entry Criteria: NYHA Class II-IV HF, LVEF 40% amended to 35% BNP 150 pg/ml (or NT-proBNP 600 pg/ml) or 1/3 lower if hospitalized for HF within 12 mos On a stable dose of ACEI or ARB equivalent to 10 mg of enalapril daily for 4 weeks Unless contraindicated, on stable dose of beta-blocker for 4 weeks SBP 95 mm Hg, egfr 30 ml/min/1.73 m2 and serum K 5.4 mmol/l at randomization Single-blind run-in period Enalapril 10 mg BID (n=10,513) Sac/Val 49/51 mg to 97/103 mg BID (n=9,419) HF Patients (n=8,442) R Study stopped early after median follow-up of 27 mos Enalapril 10 mg BID (n=4,212) Sac/Val 97/103 mg BID (n=4,187) 2 Weeks 4 6 Weeks 34-month follow-up Primary endpoint: Death from CV causes or hospitalization for HF Sac/Val = Sacubitril/Valsartan. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

PARADIGM-HF: Baseline Characteristics Sac/Val (n=4187) Enalapril (n=4212) Age (years) 63.8 ± 11.5 63.8 ± 11.3 Women (%) 21.0% 22.6% Ischemic cardiomyopathy (%) 59.9% 60.1% LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3 NYHA functional Class II/ III (%) 71.6%/ 23.1% 69.4%/ 24.9% Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15 Heart rate (beats/min) 72 ± 12 73 ± 12 N-terminal pro-bnp (pg/ml) 1631 (885 3154) 1594 (886 3305) B-type natriuretic peptide (pg/ml) 255 (155 474) 251 (153 465) History of diabetes 34.7% 34.6% Digitalis 29.3% 31.2% Beta-adrenergic blockers 93.1% 92.9% Mineralocorticoid antagonists 54.2% 57.0% ICD and/or CRT 21.9% 21.4% McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

PARADIGM-HF: Primary Endpoint of CV Death or Heart Failure Hospitalization Cumulativ ve Probability 1.0 0.6 0.5 0.4 0.3 0.2 0.1 Number needed to treat = 21 HR 0.80 (95% CI, 0.73 0.87), p<0.001 Enalapril 1117 events (26.5%) Sac/Val 914 events (21.8%) 0 Number at Risk 0 180 360 540 720 900 1080 Days since Randomization Sac/Val 4187 3922 3663 3018 2257 1544 896 Enalapril 4212 3883 3579 2922 2123 1488 853 1260 249 236 Sac/Val = Sacubitril/Valsartan. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

PARADIGM-HF: CV Death Cumulativ ve Probability 1.0 0.6 0.5 0.4 Number at Risk Sac/Val Enalapril 0.3 0.2 0.1 Sac/Val = Sacubitril/Valsartan. 0 McMurray JJV, et al. N Engl J Med. 2014;371:993-1004. Number needed to treat = 31 HR 0.80 (95% CI, 0.71 0.89), p<0.001 Enalapril 693 events (16.5%) 0 180 360 540 720 900 1080 4187 4212 4056 4051 Days since Randomization 3891 3860 3282 3231 2478 2410 1716 1726 Sac/Val 558 events (13.3%) 1005 994 1260 280 279

PARADIGM-HF: Effect of Sac/Val vs. Enalapril on the Primary Endpoint and Its Components Sac/Val (n=4187) Enalapril (n=4212) Hazard Ratio (95% CI) p- Value Primary endpoint 914 (21.8%) 1117 (26.5%) 0.80 (0.73 0.87) <0.001 Cardiovascular death 558 (13.3%) 693 (16.5%) 0.80 (0.71 0.89) <0.001 Hospitalization for heart failure 537 (12.8%) 658 (15.6%) 0.79 (0.71 0.89) <0.001 Sac/Val = Sacubitril/Valsartan. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

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

Cumulativ ve Probability 1.0 0.6 0.5 0.4 0.3 0.2 0.1 PARADIGM-HF: All-Cause Mortality Number needed to treat = 36 HR 0.84 (95% CI, 0.76 0.93), p<0.001 Enalapril 835 events (19.8%) Sac/Val 711 events (17.0%) 0 Number at Risk 0 180 360 540 720 900 1080 Days since Randomization Sac/Val 4187 4056 3891 3282 2478 1716 1005 Enalapril 4212 4051 3860 3231 2410 1726 994 1260 280 279 Sac/Val = Sacubitril/Valsartan. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

PARADIGM-HF: Adverse Events Prospectively identified adverse events Sac/Val (n=4187) Enalapril (n=4212) p- Value Symptomatic hypotension 14.0% 9.2% <0.001 Serum potassium > 6.0 mmol/l 4.3% 5.6% 0.007 Serum creatinine 2.5 mg/dl 3.3% 4.5% 0.007 Cough 11.3% 14.3% <0.001 Discontinuation for adverse event 10.7% 12.3% 0.03 Discontinuation for hypotension 0.9% 0.7% 0.38 Discontinuation for hyperkalemia 0.3% 0.4% 0.56 Discontinuation for renal impairment 0.7% 1.4% 0.002 Angioedema (adjudicated) Medications, no hospitalization 6 (0.1%) 4 (0.1%) 0.52 Hospitalized; no airway compromise 3 (0.1%) 1 (<0.1%) 0.31 Airway compromise 0 0 McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

PARADIGM-HF: Summary of Findings In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril: Sac/Val was more effective than enalapril in Reducing the risk of CV death and HF hospitalization by incremental 20% 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 Sac/Val 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 McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

Angiotensin Neprilysin Inhibition with Sac/Val Doubles Effect on CV Death of Current Inhibitors of the RAS 0 Angiotensin Receptor Blocker 1 ACE Inhibitor 2 Angiotensin Neprilysin Inhibition 3 ity (%) 10 15% 18% Decrease in Mortali 20 30 20% 40 1. Granger CB, et al. Lancet. 2003;362:772-776. 2. The SOLVD Investigators. N Engl J Med. 1991;325:293-302. 3. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

New FDA-Approved Sacubitril/Valsartan Sacubitril/Valsartan Brand name Indication Dosage Renal/hepatic impairment Switching from an ACE inhibitor Contraindications Side effects Entresto The fixed-dose combination of the neprilysin inhibitor sacubitril and the ARB valsartan is indicated to reduce the risk of CV death and HF hospitalization in patients with HF with reduced ejection fraction. Start with 49/51 mg twice daily. Double the dose after 2 4 weeks as tolerated to maintenance dose of 97/103 mg twice daily. For patients not currently taking an ACEI or ARB, or for those with severe renal impairment (egfr <30 ml/min/1.73 m 2 ) or moderate hepatic impairment, start with 24/26 mg twice daily. Stop ACE inhibitor for 36 hours before starting treatment. History of angioedema related to previous ACE inhibitor or ARB, concomitant use of ACE inhibitors, concomitant use of aliskiren in patients with diabetes. WARNING pregnancy, hyperkalemia. Hypotension, hyperkalemia, cough, dizziness, renal failure, and angioedema (0.5% Sac/Val vs. 0.2% Enalapril). http://www.pdr.net/full-prescribing-information/entresto?druglabelid=3756. Accessed October 20, 2015.

Practical Points on Use of Sacubitril/Valsartan Starting dose is 24/26 mg twice daily, unless patient is currently tolerating full dose ACEI or ARB in which case start 49/51 mg twice daily Target dose is 97/103 mg twice daily After 2-4 weeks uptitrate to next dose with ultimate goal to achieve target dose Monitor SBP, renal function and K as you would with ACEI or ARB use Space out dosing from other vasoactive medications if needed Adjust diuretics doses based on volume status

Influence of Sacubitril/Valsartan on Readmission Rates After HF Hospitalization: PARADIGM-HF 30 Day All Cause Readmission Odds Ratio: 0.74; 95% CI 0.56-0.97 30 Day HF Readmission Odds Ratio: 0.62; 95% CI 0.45-0.87 2,383 investigator-reported HF hospitalizations, of which 1,076 (45.2%) occurred in subjects assigned to sacubitril/valsartan and 1,307 (54.8%) occurred in subjects assigned to enalapril. Desai, A.S. et al. J Am Coll Cardiol. 2016;68(3):241 8.

Efficacy of Sacubitril/Valsartan vs. Enalapril at Lower than Target Doses in HFrEF In the two treatment arms, participants with a dose reduction (43% of those randomized to enalapril and 42% of those randomized to sacubitril/valsartan) had similar baseline characteristics and similar baseline predictors of the need for dose reduction. However, the treatment benefit of sacubitril/valsartan over enalapril following a dose reduction was similar (HR 0.80, 95% CI 0.70 0.93, P <0.001) to that observed in patients who had not experienced any dose reduction (HR 0.79, 95% CI 0.71 0.88, P <0.001) European Journal of Heart Failure (2016) doi:10.1002/ejhf.580

2016 ACC/AHA/HFSA Heart Failure Guideline Update Pharmacological Treatment for Stage C HFrEF ARNI = angiotensin receptor blocker and neprilysin inhibitor; COR = class of recommendation; LOE = level of evidence. Reference: Yancy et al. Circulation. 2016;134:[ePub ahead of print].

Resting Heart Rate and CV Outcomes in Patients with HF Retrospective analysis of 7,599 symptomatic HF* patients from the CHARM studies, who were followed for a median of 38 months to determine the relationship between resting heart rate at baseline and all-cause mortality, and fatal and nonfatal CV outcomes. Tertile 1: Median heart rate 60 bpm Tertile 2: Median heart rate 72 bpm Tertile 3: Median heart rate 85 bpm 0.4 All-Cause Mortality p<0.001 0.4 CV Death or WHFH p<0.001 Probabili ity 0.3 0.2 0.1 0.3 0.2 0.1 0 0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Months Months Heart rate is an important predictor of mortality and CV outcomes in patients with HF WHFH = worsening heart failure hospitalization; *symptomatic HF defined as NYHA functional Class II to IV. Adapted from: Castagno D, et al. J Am Coll Cardiol. 2012;59:1785-1795.

Change in Heart Rate and Mortality Observed in Heart Failure Trials Relationship between changes in heart rate and mortality in studies of chronic heart failure Change in Mortality (%) 60 PROFILE 40 XAMOTEROL 20 PROMISE VHeFT (Prazosin) 0 VHeFT (HDZ/ISDN) CIBIS 20 BHAT SOLVD ANZ 40 NOR TIMOLOL 60 MOCHA CONSENSUS US CARVEDILOL 80 20 GESICA 15 10 5 0 5 10 Change in Heart Rate (bpm 1) HF trials with both beta-blocker and non-beta-blocker treatment demonstrate a relationship between a change in heart rate and the risk of mortality in HF Adapted from: Kjekshus J, et al. Eur Heart J. 1999;1(suppl H):H64-H69.

Beta-Blocker Dose and Heart Rate Reduction in Patients with Chronic Heart Failure Meta-analysis of 17 randomized trials in subjects with HF to examine whether the beta-blocker dose or the magnitude of heart rate reduction could account for differences in treatment effects among HF beta-blocker trials, 1966 2008. Potential Modifier # Trials # Subjects Ratio of Relative Risks (95% CI) p-value Heart rate reduction 17 17,831 0.82 (0.71 0.94) per 5 bpm 0.006 Beta-blocker dose 17 17,660 1.02 (0.93 1.10) per increment 0.69 Baseline heart rate 19 17,981 1.07 (0.88 1.32) per 5 bpm 0.47 Results of univariable meta-regressions evaluating the effect of individual covariates on the potential mortality benefits of beta-blockers in HF McAlister FA, et al. Ann Intern Med. 2009;150:784-794.

Regulating Heart Rate: Voltage-Gated Ion Current The activation of voltage-dependent channels helps drive sinus node automaticity during diastole Major Currents Involved in Sinus Node Automaticity I f (funny current) Specific to sinus node automaticity - Hyperpolarizationactivated current - Carried by Na + /K + in the SA node - Phase 4 depolarization generated - Automaticity of the pacemaker cells initiated I ca,t (T-type Ca 2+ currents) Specific to sinus node automaticity - May contribute to the inward current to the later phase 4 depolarization in pacemaker cells - May contribute to the action potential propagation in AV nodal cells I ca,l (L-type Ca 2+ currents) Specific to sinus node automaticity - Responsible for phase 0 depolarization and propagation in SA and AV nodal tissue - Main trigger of Ca 2+ release from sarcoplasmic reticulum (Ca 2+ - induced Ca 2+ release) SA = sinoatrial. Adapted from: Rubart M, et al. In: Libby P, et al., eds. Braunwald s Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed. Philadelphia, PA: Saunders Elsevier. 2008:Chap 31.

Ivabradine Specific inhibitor of the If current in SA node This so-called funny current controls the rate of spontaneous activity of SA node myocytes Reduces the slope for diastolic depolarization Prolongs diastolic duration slows heart rate No action on other cardiac channels Does not modify cardiac contractility DiFrancesco D. Pharmacol Res. 2006;53(5):399-406. Savelieva I, Camm AJ. Drug Saf. 2008;31(2):95-107.

Objective of the SHIFT Study To evaluate whether the If inhibitor ivabradine improves cardiovascular outcomes in patients with: 1. Moderate to severe chronic HF 2. Left ventricular EF 35% 3. Heart rate 70 bpm, and 4. Recommended therapy Swedberg K, et al. Lancet. 2010;376:875-885.

SHIFT Study: Design Inclusion Criteria: 18 years; symptomatic HF NYHA Class II to IV; ischemic/non-ischemic etiology LV systolic dysfunction (EF 35%); heart rate 70 bpm; sinus rhythm Documented hospital admission for worsening HF 12 months Ivabradine 5 mg bid, titrate to 7.5 mg bid on D14, adjust dose to 7.5/5/2.5 mg bid according HR and tolerability n=3241 7,411 Screened HF Patients (n=6,558) D0 D 14 Median follow-up 22.9 months R n=3264 D0 D 14 Placebo bid Primary endpoint: CV death or hospitalization for worsening HF Swedberg K, et al. Lancet. 2010;376:875-885.

SHIFT Study: Baseline Characteristics Ivabradine (n=3241) Placebo (n=3264) 79.7 80.1 29.0% 29.0% 49% / 50% 49% / 50% Mean SBP, mm Hg 122.0 121.4 egfr, ml/min/1.73 m2 74.6 74.8 Beta-blocker (%) 89% 90% 79% / 14% 78% / 14% Diuretics (%) 84% 83% Aldosterone antagonist (%) 61% 59% Digitalis (%) 22% 22% CRT / ICD (%) 1% / 3% 1% / 4% Mean heart rate (bpm) Mean LVEF (%) NYHA Class II / III (%) ACE inhibitor/arb (%) Swedberg K, et al. Lancet. 2010;376:875-885.

Background Beta-Blocker Treatment 100 89 Ivabradine 90 90 Placebo 80 Patients (%) 70 56 60 56 50 40 26 30 26 20 10 0 BB at Randomization Swedberg K, et al. Lancet. 2010;376:875-885. At Least 50% Target Daily Dose Target Daily Dose

SHIFT Study: Primary Endpoint of CV Death or Hospitalization for Worsening HF 40 Ivabradine (n=3241) Patients with Primary Endpoint (%) Placebo (n=3264) Placebo 937 events (29%) 30 18% Ivabradine 793 events (24%) 20 10 HR 0.82 (95% CI, 0.75 0.90) p<0.0001 ARR = 5%, NNT = 20 0 0 6 12 18 Months Swedberg K, et al. Lancet. 2010;376:875-885. 24 30

SHIFT Study: Mean Heart Rate Mean ivabradine dose was 6.4 mg bid at 1 month and 6.5 mg bid at 1 year 90 Ivabradine Heart Rate (bpm) Placebo 80 80 75 75 70 67 64 60 HR reduction: Ivabradine HR 10.9 bpm at day 28, 9.1 bpm at 1 year, and 8.1 at study end vs. placebo. 50 0 2 weeks 1 4 8 12 16 Months Swedberg K, et al. Lancet. 2010;376:875-885. 20 24 28 32

SHIFT Study: Cardiovascular Death 30 Ivabradine Patients with Event (%) Placebo 20 Placebo 491 events (15%) Ivabradine 449 events (14%) 10 HR 0.91, p=0.128 0 0 6 12 18 Months Swedberg K, et al. Lancet. 2010;376:875-885. 24 30

Patients with First Hospitalization for Worsening HF (%) SHIFT Study: Hospitalization for Worsening HF 30 Ivabradine Placebo 672 events (21%) Placebo 26% 20 Ivabradine 514 events (16%) 10 HR 0.74 (95% CI, 0.66-0.83) p<0.0001 NNT = 20 0 0 6 12 18 Months Swedberg K, et al. Lancet. 2010;376:875-885. 24 30

SHIFT Study: Effect of Ivabradine on Outcomes Ivabradine (n=3241) Placebo (n=3264) HR p-value Primary endpoint 24% 29% 0.82 <0.0001 All-cause mortality 16% 17% 0.90 0.092 Death from HF 3% 5% 0.74 0.014 All-cause hospitalization 38% 42% 0.89 0.003 Any CV hospitalization 30% 34% 0.85 0.0002 CV death, hospitalization for worsening HF, or hospitalization for non-fatal MI 25% 30% 0.82 <0.0001 Endpoint Swedberg K, et al. Lancet. 2010;376:875-885.

SHIFT Study: Effect of Ivabradine in Prespecified Subgroups Test for Interaction Age <65 years 65 years p=0.099 Sex Male Female p=0.260 Beta-blockers No Yes p=0.103 Aetiology of heart failure Non-ischaemic Ischaemic p=0.059 NYHA Class NYHA Class II NYHA Class III or IV p=0.793 Diabetes No Yes p=0.861 Hypertension No Yes p=0.779 Baseline heart rate <77 bpm 77 bpm p=0.029 0.5 1.0 Hazard Ratio Favors Ivabradine Favors Placebo Swedberg K, et al. Lancet. 2010;376:875-885. 1.5

SHIFT Study: Effect of Ivabradine in Patients at 50% BB Target Dose (n=3181) Ivabradine Placebo Hazard Ratio p-value 0.90 ns 1.00 ns 0.81 p=0.021 Primary composite endpoint 330 362 (11.9 PY) (13.3 PY) Cardiovascular death 176 175 (5.9 PY) (5.9 PY) 213 260 (7.7 PY) (9.6 PY) Hospitalization for worsening HF 0.5 1.0 Hazard Ratio Favors Favors Ivabradine Placebo Swedberg K, et al. J Am Coll Cardiol. 2012;59(22):1938-1945. 1.5

SHIFT Study: Effect on Recurrence of Hospitalizations for Worsening HF Ivabradine (n=3241) Placebo (n=3264) Hazard Ratio p-value 514 672 0.75 p<0.001 (16%) (21%) Second hospitalization 189 283 0.66 p<0.001 (6%) (9%) Third hospitalization 90 128 0.71 p=0.012 (3%) (4%) First hospitalization 0.4 0.6 0.8 1.0 1.2 Hazard Ratio Favors Favors Ivabradine Placebo Broer JS, et al. Eur Heart J. 2012;33(22):2813-2820.

SHIFT Study: Incidence of Selected Adverse Events Endpoint Ivabradine (n=3241) Placebo (n=3264) p-value All serious adverse events 45% (1450) 48% (1553) 0.025 All adverse events 75% (2439) 74% (2423) 0.303 Heart failure 25% (804) 29% (937) 0.0005 Symptomatic bradycardia 5% (150) 1% (32) <0.0001 Asymptomatic bradycardia 6% (184) 1% (48) <0.0001 Atrial fibrillation 9% (306) 8% (251) 0.012 Phosphenes 3% (89) 1% (17) <0.0001 Blurred vision 1% (17) <1% (7) 0.042 Phosphenes are luminous phenomena; bradycardia is defined here as resting heart rate was lower than 50 bpm or the patient had signs or symptoms related to bradycardia. Swedberg K, et al. Lancet. 2010;376:875-885.

Summary of SHIFT Study HFrEF + elevated HR is associated with poor outcomes Primary composite endpoint with placebo = 18%/yr Ivabradine reduced CV death or hospitalization for worsening heart failure by 18% ARR = 5%; NNT = 20 This beneficial effect was driven mainly by a favorable effect on HF death/admission (RRR 26%) Treatment with ivabradine was safe and well tolerated

Effect of Ivabradine on Outcomes according to HR Achieved at 28 Days 75 bpm 40 Patients with Primary Composite Endpoint (%) 70 to <75 bpm 65 to <70 bpm 30 60 to <65 bpm <60 bpm 20 10 0 0 D 28 6 12 Time (months) Böhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22. 18 24

Effect of Ivabradine on Outcomes according to Magnitude of HR Reduction 0 bpm 40 Patients with Primary Composite Endpoint (%) 10 to <0 bpm > 10 bpm 30 20 10 0 0 D 28 6 12 Time (months) Böhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22. 18 24

SHIFT Echo Substudy: Change in LVESVI from Baseline to 8 mos (Primary Endpoint) 5.8, p=0.0002 Left Ventricular End End-Systolic Volume Index (ml/m2) 75 70 7.0 ± 16.3 0.9 ± 17.1 65 60 55 65.2 ± 29.1 58.2 ± 28.3 63.6 ± 30.1 62.8 ± 28.7 Baseline 8 Months Baseline 8 Months 50 0 Ivabradine (n=208) LVESVI = left ventricular end-systolic volume index. Tardif JC, et al. Eur Heart J. 2011;32(20):2507-2515. Placebo (n=203)

SHIFT Echo Substudy: Change in LVEF from Baseline to 8 mos (Secondary Endpoint) Left Ventricular Ejection Fraction (%) +2.7, p=0.0003 40 2.4 ± 7.7 0.1 ± 8.0 35 30 25 20 15 32.3 ± 9.1 34.7 ± 10.2 31.6 ± 9.3 31.5 ± 10.0 Baseline 8 Months Baseline 8 Months 10 5 0 Ivabradine (n=204) LVESVI = left ventricular end-systolic volume index. Tardif JC, et al. Eur Heart J. 2011;32(20):2507-2515. Placebo (n=199)

Pooled Analysis of BEAUTIFUL and SHIFT Reduced EF, Heart Rate 75 bpm (N=7632) Fox K. Eur Heart J. 2013

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

Practical Points on Use of Ivabradine Starting dose is 5 mg twice daily Target HR is 50-60 bpm After 2 weeks: If HR >60 bpm: Increase dose to 7.5 mg twice daily (Max dose) If HR 50-60 bpm: Maintain initial dose If HR <50 bpm or symptomatic bradycardia: Lower dose to 2.5 mg twice daily If HR <50 bpm or symptomatic bradycardia and dose is 2.5 mg twice daily: Discontinue

2016 ACC/AHA/HFSA Heart Failure Guideline Update Pharmacological Treatment for Stage C HFrEF COR = class of recommendation; LOE = level of evidence. Reference: Yancy et al. Circulation. 2016;134:[ePub ahead of print].

Evidence-Based HFrEF Therapies Guideline Relative Risk Number Needed NNT for Mortality Relative Risk Recommended Reduction in to Treat for (standardized to Reduction in HF Mortality Mortality 36 months) Hospitalizations ACEI/ARB 17% 22 over 42 months 26 31% ARNI 16% 36 over 27 months 27 21% Beta-blocker 34% 28 over 12 months 9 41% Aldosterone Antagonist 30% 9 over 24 months 6 35% Hydralazine/Nitrate 43% 25 over 10 months 7 33% CRT 36% 12 over 24 months 8 52% ICD 23% 14 over 60 months 23 NA NA NA NA 26% Therapy Ivabradine Updated from Fonarow GC, et al. Am Heart J 2011;161:1024-1030.

Potential Impact of Optimal Implementation of Evidence-Based HFrEF Therapies on Mortality Guideline Recommended HF Patient Current HF Potential Lives Potential Lives Therapy Population Population Saved per Year Saved per Year Eligible for Eligible and Treatment, n* Untreated, n (%) ACEI/ARB 2,459,644 501,767 (20.4) 6516 (3336-11,260) Beta-blocker 2,512,560 361,809 (14.4) 12,922 (6616-22,329) Aldosterone Antagonist 603,014 385,326 (63.9) 21,407 (10,960-36,991) Hydralazine/Nitrate 150,754 139,749 (92.7) 6655 (3407-11,500) CRT 326,151 199,604 (61.2) 8317 (4258-14,372) ICD 1,725,732 852,512 (49.4) 12,179 (6236-21,045) Total - - 67,996 (34,813-117,497) 2,287,296 2,287,296 (100) 28,484 (18,230-41,017) ARNI (replacing ACEI/ARB) (Sensitivity Range*) Updated from Fonarow GC, et al. Am Heart J 2011;161:1024-1030. and JAMA Cardiology 2016

Advances in the Treatment of HF Increased attention to prevention ACEI / beta-blocker / aldosterone antagonist combination previously established as the cornerstone of therapy ARNI further reduces morbidity and mortality Evidence that beta-blockers effects are not homogeneous Ivabradine further reduces HF hospitalization risk Integration of CRT and ICD device therapy into the standard therapeutic regimen Recognition that special populations of HF patients may benefit from or require different approaches New strategies to improve utilization of evidence-based therapies