9/10/ , American Heart Association 2

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2 Clyde W. Yancy, MD, MSc, MACC, FAHA, MACP Vice Dean, Diversity & Inclusion Magerstadt Professor of Medicine Professor of Medical Social Sciences Chief, Division of Cardiology Northwestern University, Feinberg School of Medicine Associate Director, Bluhm Cardiovascular Institute Gregg C. Fonarow, MD, FACC, FAHA The Eliot Corday Professor of Cardiovascular Medicine and Science Co-Chief of Clinical Cardiology UCLA Division of Cardiology Director, Ahmanson-UCLA Cardiomyopathy Center Co-Director, UCLA Preventative Cardiology Program 9/10/ , American Heart Association 2

3 2015 GWTG-HF Program Update GWTG-Heart failure was launched in 2005 and currently has 562 contracted hospitals Total patients entered=908,723 Total records entered=1,169,585 Total Awards: Participating-47 Bronze-28 Gold-63 Gold Plus-204 Silver-27 Silver Plus-35 Target HF-88 TJC AHA Advanced Certification in Heart Failure-54 sites to date 3

4 Number of records GWTG-HF: Data Submission Apr-14 Jul-14 Oct-14 Jan-15 Apr-15 Jul-15 July 2015

5 Compliance GWTG-HF: Achievement Measures 100.0% 90.0% 80.0% 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% LV Function Measurement ACEI or ARB at D/C for LVSD Evidence-Based Beta Blocker at D/C for LVSD Beta Blocker at Discharge Post Discharge Appointment for HF patients Discharge Instructions Composite Performance Measure* 100% Compliance Measure* Baseline 90.1% 81.2% 61.0% 87.3% 39.3% 69.7% 80.3% 62.1% Current 98.4% 95.3% 91.8% 97.8% 71.1% 95.9% 96.6% 93.2% Achievement Measure * Modified to include Beta Blocker at Discharge and Discharge Instructions rather than Evidence-Based Beta Blocker at D/C and Post Discharge Appointment Baseline = Admissions Jan2005 Dec2005 July 2015 Current = Overall

6 Compliance GWTG-HF: Quality Measures (1) 100.0% 90.0% 80.0% 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% Warfarin at d/c Aldosterone antagonist at d/c for LVSD Hydralazine/Isosorbide at d/c for AA ICD Counseling or ICD placed or prescribed at D/C Baseline 57.3% 19.9% 10.8% 31.3% Current 83.2% 34.4% 28.5% 45.3% Quality Measure Baseline = Admissions Jan2005 Dec2005 July 2015 Current = Overall

7 Compliance GWTG-HF: Quality Measures (2) 100.0% 90.0% 80.0% 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% Pnemococcal Vaccine Influenza Vaccine Follow-up visit within 7 days or less DVT Management CRT placed or prescribed at discharge Baseline 22.9% 17.7% 61.9% 25.4% 39.9% Current 66.2% 69.5% 77.9% 79.2% 51.3% Quality Measure Baseline = Admissions Jan2009 Dec2009 July 2015 Current = Overall

8 ACEI/ARB at Discharge Use

9 ACC/AHA HF Guidelines 2013 Stages, Phenotypes and Treatment of HF At Risk for Heart Failure Heart Failure STAGE A At high risk for HF but without structural heart disease or symptoms of HF STAGE B Structural heart disease but without signs or symptoms of HF STAGE C Structural heart disease with prior or current symptoms of HF STAGE D Refractory HF e.g., Patients with: HTN Atherosclerotic disease DM Obesity Metabolic syndrome or Patients Using cardiotoxins With family history of cardiomyopathy Structural heart disease e.g., Patients with: Previous MI LV remodeling including LVH and low EF Asymptomatic valvular disease Development of symptoms of HF e.g., Patients with: Known structural heart disease and HF signs and symptoms Refractory symptoms of HF at rest, despite GDMT e.g., Patients with: Marked HF symptoms at rest Recurrent hospitalizations despite GDMT HFpEF HFrEF THERAPY Goals Heart healthy lifestyle Prevent vascular, coronary disease Prevent LV structural abnormalities Drugs ACEI or ARB in appropriate patients for vascular disease or DM Statins as appropriate THERAPY Goals Prevent HF symptoms Prevent further cardiac remodeling Drugs ACEI or ARB as appropriate Beta blockers as appropriate In selected patients ICD Revascularization or valvular surgery as appropriate THERAPY Goals Control symptoms Improve HRQOL Prevent hospitalization Prevent mortality Strategies Identification of comorbidities Treatment Diuresis to relieve symptoms of congestion Follow guideline driven indications for comorbidities, e.g., HTN, AF, CAD, DM Revascularization or valvular surgery as appropriate THERAPY Goals Control symptoms Patient education Prevent hospitalization Prevent mortality Drugs for routine use Diuretics for fluid retention ACEI or ARB Beta blockers Aldosterone antagonists Drugs for use in selected patients Hydralazine/isosorbide dinitrate ACEI and ARB Digoxin In selected patients CRT ICD Revascularization or valvular surgery as appropriate THERAPY Goals Control symptoms Improve HRQOL Reduce hospital readmissions Establish patient s endof-life goals Options Advanced care measures Heart transplant Chronic inotropes Temporary or permanent MCS Experimental surgery or drugs Palliative care and hospice ICD deactivation Yancy CW et al. J Am Coll Cardiol. 2013;62:

10 Treatment of Stages A to D Pharmacological Treatment for Stage C HFrEF

11 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:

12 Medical Therapy for Stage C HFrEF: Magnitude of Benefit Demonstrated in RCTs GDMT RR Reduction in Mortality NNT for Mortality Reduction (Standardized to 36 months) RR Reduction in HF Hospitalizations ACE inhibitor or ARB 17% 26 31% Beta blocker 34% 9 41% Aldosterone antagonist 30% 6 35% Hydralazine/nitrat e 43% 7 33% Yancy CW et al. J Am Coll Cardiol. 2013;62:

13 New Therapeutic Option for HFrEF

14 % Decrease in Mortality Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction 0% Angiotensin receptor blocker ACE inhibitor Mineralocorticoid Beta receptor blocker antagonist 10% 20% 30% 40% Drugs that inhibit the renin-angiotensin system have modest effects on survival Based on results of SOLVD-Treatment, CHARM-Alternative, COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

15 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

16 Mechanisms of Progression in Heart Failure Myocardial or vascular stress or injury Increased activity or response to maladaptive mechanisms Angiotensin receptor blocker Decreased activity or response to adaptive mechanisms Inhibition of neprilysin Evolution and progression of heart failure

17 Mechanism of Action: LCZ-696 Vardney O et al. JACC:Heart Failure. 2014;2:

18 LCZ696: Angiotensin Receptor Neprilysin Inhibition LCZ696 Angiotensin receptor blocker Inhibition of neprilysin

19 A Comparison of Angiotensin Receptor- Neprilysin Inhibition (ARNI) With ACE Inhibition in the Long-Term Treatment of Chronic Heart Failure With a Reduced Ejection Fraction Milton Packer, John J.V. McMurray, Akshay S. Desai, Jianjian Gong, Martin P. Lefkowitz, Adel R. Rizkala, Jean L. Rouleau, Victor C. Shi, Scott D. Solomon, Karl Swedberg and Michael R. Zile for the PARADIGM-HF Investigators and Committees

20 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) LCZ mg daily Enalapril 20 mg daily SPECIFICALLY DESIGNED TO REPLACE CURRENT USE OF ACE INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS AS THE CORNERSTONE OF THE TREATMENT OF HEART FAILURE

21 PARADIGM-HF: Entry Criteria NYHA class II-IV heart failure LV ejection fraction 40% 35% BNP 150 (or NT-proBNP 600), 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 10 mg daily for at least 4 weeks Guideline-recommended use of beta-blockers and mineralocorticoid receptor antagonists Systolic BP 95 mm Hg, egfr 30 ml/min/1.73 m 2 and serum K 5.4 meq/l at randomization

22 PARADIGM-HF: Study Design Randomization Single-blind run-in period Double-blind period Enalapril 10 mg BID 100 mg BID LCZ mg BID LCZ mg BID (1:1 randomization) Enalapril 10 mg BID 2 weeks 1-2 weeks 2-4 weeks

23 PARADIGM-HF: Secondary Endpoints All-cause mortality Change from baseline in the clinical summary score of the Kansas City Cardiomyopathy Questionnaire at 8 months Time to new onset of atrial fibrillation Time to first occurrence of a protocol-defined decline in renal function

24 PARADIGM-HF: Patient Disposition 10,521 patients screened at 1043 centers in 47 countries Did not fulfill criteria for randomization (n=2079) Randomized erroneously or at sites closed due to GCP violations (n=43) 8399 patients randomized for ITT analysis LCZ696 (n=4187) At last visit 375 mg daily 11 lost to follow-up median 27 months of follow-up Enalapril (n=4212) At last visit 18.9 mg daily 9 lost to follow-up

25 PARADIGM-HF: Baseline Characteristics LCZ696 Enalapril (n=4187) (n=4212) Age (years) 63.8 ± ± 11.3 Women (%) 21.0% 22.6% Ischemic cardiomyopathy (%) 59.9% 60.1% LV ejection fraction (%) 29.6 ± ± 6.3 NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9% Systolic blood pressure (mm Hg) 122 ± ± 15 Heart rate (beats/min) 72 ± ± 12 N-terminal pro-bnp (pg/ml) 1631 ( ) 1594 ( ) B-type natriuretic peptide (pg/ml) 255 ( ) 251 ( ) History of diabetes 35% 35% Digitalis 29.3% 31.2% Beta-adrenergic blockers 93.1% 92.9% Mineralocorticoid antagonists 54.2% 57.0% ICD and/or CRT 16.5% 16.3%

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27 Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Enalapril (n=4212) Patients at Risk LCZ696 Enalapril Days After Randomization LCZ696 (n=4187) HR = 0.80 ( ) P = Number needed to treat =

28 Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: Cardiovascular Death HR = 0.80 ( ) P = Number need to treat = 32 Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk Days After Randomization LCZ696 Enalapril

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%) 0.80 ( ) Cardiovascular death 558 (13.3%) 693 (16.5%) 0.80 ( ) Hospitalization for heart failure 537 (12.8%) 658 (15.6%) 0.79 ( )

30 LCZ696 vs Enalapril on Primary Endpoint and on Cardiovascular Death, by Subgroups Primary endpoint Cardiovascular death

31 Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: All-Cause Mortality HR = 0.84 ( ) P< Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk Days After Randomization LCZ696 Enalapril

32 PARADIGM-HF: Effect of LCZ696 vs Enalapril on Secondary Endpoints LCZ696 Enalapril Treatment P (n=4187) (n=4212) effect 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

33 PARADIGM-HF: Adverse Events Prospectively identified adverse events LCZ696 (n=4187) Enalapril (n=4212) P Value 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

34 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

35 % Decrease in Mortality 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 10% 15% 18% 20% 30% 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

36 The Newest Data: TITRATION Trial ESC HF, May 2015, LBCTs; Senni et al for the PARADIGM HF investigators TITRATION was a randomized, double blind study that assessed the safety and tolerability of initiating and up-titrating LCZ696 from 50mg BID to a target dose of 200mg BID in a 3-week (condensed) versus 6-week (conservative) regimen in patients with HFrEF (ejection fraction 35%). Primary endpoints were the proportion of patients experiencing prespecified adverse events: symptomatic hypotension, hyperkalaemia, renal dysfunction, angioedema 540 patients enrolled; 498 randomized (92%); 86% completed the study Condensed arm- 78% success Conservative arm 84% success Study participants included inpatients and ACE-I naïve patients

37 Sacubitril/Valsartan for HFrEF The fixed-dose combination of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan is indicated to reduce the risk of cardiovascular death and heart failure hospitalization in patients with heart failure with reduced ejection fraction. Recommended starting dosage is 49/51 mg twice daily. The dose should be doubled after 2-4 weeks as tolerated to reach the target maintenance dosage 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 m2) or moderate hepatic impairment, the starting dosage of is 24/26 mg twice daily. ACE inhibitor treatment should be stopped for 36 hours before starting treatment. Contraindications: hyperkalemia, pregnancy, symptomatic hypotension or shock, concurrent use with ACEI. Side effects: Hypotension and hyperkalemia. Angioedema occurred in 0.5% of patients compared to 0.2% with ACEI.

38 Update to GWTG-HF PMT

39 GWTG-HF PMT Updated Admission Medications Fields

40 Updated Discharge Medication Fields

41 Updated Measure Description ACEI/ARBs at Discharge: Percent of heart failure patients with left ventricular systolic dysfunction (LVSD) and without both angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) contraindications who are prescribed an ACEI, ARB, or ARNi at hospital discharge. For purposes of this measure, LVSD is defined as chart documentation of a left ventricular ejection fraction (LVEF) less than 40% or a narrative description of left ventricular function (LVF) consistent with moderate or severe systolic dysfunction. Numerator Heart failure patients who are prescribed an ACEI, ARB, or ARNi at hospital discharge ACEI prescribed at discharge: Yes OR ARB prescribed at discharge: Yes OR ARNi prescribed at discharge: Yes

42 GWTG-HF Program GWTG-HF Offers the Most Comprehensive Measure Set Available Achievement Measures Quality Measures Reporting Measures 9/10/2015 ACEI/ARBs at Discharge Aldosterone Antagonist at Blood Pressure Control at Evidence-Based Specific Discharge Discharge Beta Blockers Anticoagulation for Atrial Beta Blocker at Discharge Measure LV Function Fibrillation and Atrial Flutter Beta Blocker Medication at Post-Discharge Hydralazine Nitrate at Discharge Appointment for Heart Discharge Lipid-Lowering Medications Failure Patients DVT Prophylaxis at Discharge CRT-D or CRT-P Placed or Omega-3 Fatty Acid Prescribed at Discharge Supplement Use at ICD Counseling Provided Discharge or Prescribed or Placed at Diabetes Treatment Discharge Diabetes Teaching Influenza Vaccination Smoking Cessation During Flu Season Discharge Instructions Pneumococcal Vaccination ICD Placed or Prescribed at Follow-Up Visit Scheduled Discharge Within 7 Days or Less Advanced Care Plan QRS Duration Documented Heart Failure Disease Management Program Referral Follow-Up Visit or Contact Within 48 Hours of Discharge Scheduled 2010, American Heart Association 42

43 GWTG-HF Program Most Comprehensive Measure Set Available Reporting Measures (Continued) Descriptive Measures Mortality & Readmission Measures Follow Up Visit or Contact Within 72 Hours of Discharge Scheduled 60 Minutes of Heart Failure Education Referral to AHA Heart Failure Interactive Workbook Referral to HF Disease Management, 60 Minutes Patient Education, Or HF Interactive Workbook Heart Failure Activity Level Heart Failure Diet Heart Failure Follow-Up Heart Failure Weight Heart Failure Symptoms Worsen Length of Stay Care Transition Record Transmitted Advance Directive Executed Discharge Disposition Age Diagnosis Gender Race HF Composite Measure HF Defect-Free Measure JC/CMS HF Defect Free Measure Target: HF Defect Free Measure In-Hospital Mortality Risk Adjusted Mortality Ratio Readmission Frequency & Rate 30, 60 & 90 Day Readmissions & Rate Not equivalent to the CMS 30-Day Risk-Standardized Readmission Measure. It is not risk-adjusted, does not represent all cause readmission, and does not capture readmissions from other hospitals. 9/10/ , American Heart Association 43

44 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 Therapy 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 Updated from Fonarow GC, et al. Am Heart J 2011;161:

45 Cumulative Impact of Clinical Trial Evidence Based Heart Failure Therapies Relative-risk 2 yr Mortality None % ACEI or ARB 23% 27% Beta Blocker 35% 18% Aldosterone Ant 30% 13% CRT-D (EF<35, QRS>120) 36% 8.3% ARNI 16% 6.9% Cumulative risk reduction if all evidence-based therapies are used: 80% Absolute risk reduction: 28.1%, NNT = 3.6 Updated from Fonarow GC, et al. Am Heart J 2011;161: and Lancet 2008;372:

46 The Approach to Heart Failure The economic burden of HF continues to grow and HF is one of the single most expensive and deadly health care problems Medical therapies and nonpharmacologic measures for HF that can impact patients' need for re-hospitalization, costs of care, and survival are underutilized in conventional practice settings Every efforts should be made to implement evidence-based HF therapies when indicated and optimize care of HF

47 Questions? 9/10/ , American Heart Association 47