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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

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  1. 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

  2. Disclosures for Presenter Within past 3 years (related to any aspect of heart failure): Consultant to: AMAG, Amgen, BioControl, CardioKinetix, CardioMEMS, Cardiorentis, Daiichi, Janssen, Novartis, Sanofi

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

  4. One Enzyme — Neprilysin — Degrades Many Endogenous Vasoactive Peptides Endogenous vasoactive peptides (natriuretic peptides, adrenomedullin, bradykinin, substance P, calcitonin gene-related peptide) Neprilysin Inactive metabolites

  5. Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter Maladaptive Mechanisms in Heart Failure Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention Endogenous vasoactive peptides (natriuretic peptides, adrenomedullin, bradykinin, substance P, calcitonin gene-related peptide) Neprilysin inhibition Neprilysin Inactive metabolites

  6. Mechanisms of Progression in Heart Failure Myocardial or vascular stress or injury Increased activity or response to maladaptive mechanisms Decreased activity or response to adaptive mechanisms Evolution and progression of heart failure

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

  8. LCZ696: Angiotensin Receptor Neprilysin Inhibition LCZ696 Angiotensin receptor blocker Inhibition of neprilysin

  9. 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) specifically designed to replace current use of ACE inhibitors and angiotensin receptor blockers as the cornerstone of the treatment of heart failure LCZ696 400 mg daily Enalapril 20 mg daily

  10. 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 m2 and serum K ≤ 5.4 mEq/L at randomization

  11. PARADIGM-HF: Study Design Randomization Single-blind run-in period Double-blind period LCZ696 LCZ696 200 mg BID Enalapril 10 mg BID (1:1 randomization) 100 mg BID 200 mg BID Enalapril 10 mg BID 2 weeks 1-2 weeks 2-4 weeks

  12. 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=8000 yielded 80% power)

  13. 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

  14. PARADIGM-HF: Study Organization Data Monitoring Committee H. Dargie (UK), chair R. Foley (US) G. Francis (US) M Komajda (FR) S. Pocock (UK) Executive Committee J. McMurray (UK), co-chair M. Packer (US), co-chair J. Rouleau (CA) S. Solomon (US) K. Swedberg (SW) M. Zile (US) • Endpoint and Angioedema • Adjudication • S. Solomon (US) • Desai (US) • A. Kaplan (US) • N. Brown (US) • B. Zuraw (US) National Leaders Novartis Operations Investigative Sites

  15. 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 Enalapril(n=4212) At last visit 18.9 mg daily 9 lost to follow-up median 27 months of follow-up

  16. PARADIGM-HF: Baseline Characteristics

  17. (all comparisons are versus enalapril 20 mg daily, not versus placebo)

  18. PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) 40 Enalapril (n=4212) 1117 32 24 Kaplan-Meier Estimate of Cumulative Rates (%) 16 8 0 0 180 360 540 720 900 1080 1260 Days After Randomization Patients at Risk LCZ696 Enalapril 4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 249 236

  19. PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) 40 Enalapril (n=4212) 1117 32 914 24 LCZ696 (n=4187) Kaplan-Meier Estimate of Cumulative Rates (%) 16 8 0 0 180 360 540 720 900 1080 1260 Days After Randomization Patients at Risk LCZ696 Enalapril 4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 249 236

  20. PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) 40 Enalapril (n=4212) 1117 32 914 24 LCZ696 (n=4187) Kaplan-Meier Estimate of Cumulative Rates (%) 16 HR = 0.80 (0.73-0.87) P = 0.0000002 Number needed to treat = 21 8 0 0 180 360 540 720 900 1080 1260 Days After Randomization Patients at Risk LCZ696 Enalapril 4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 249 236

  21. PARADIGM-HF: Cardiovascular Death 32 Enalapril (n=4212) 24 693 Kaplan-Meier Estimate of Cumulative Rates (%) 16 8 0 0 180 360 540 720 900 1080 1260 Days After Randomization Patients at Risk LCZ696 Enalapril 4187 4212 4056 4051 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279

  22. PARADIGM-HF: Cardiovascular Death 32 Enalapril (n=4212) 24 693 558 Kaplan-Meier Estimate of Cumulative Rates (%) 16 LCZ696 (n=4187) 8 0 0 180 360 540 720 900 1080 1260 Days After Randomization Patients at Risk LCZ696 Enalapril 4187 4212 4056 4051 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279

  23. PARADIGM-HF: Cardiovascular Death 32 Enalapril (n=4212) HR = 0.80 (0.71-0.89) P = 0.00004 Number need to treat = 32 24 693 558 Kaplan-Meier Estimate of Cumulative Rates (%) 16 LCZ696 (n=4187) 8 0 0 180 360 540 720 900 1080 1260 Days After Randomization Patients at Risk LCZ696 Enalapril 4187 4212 4056 4051 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279

  24. PARADIGM-HF: Effect of LCZ696 vs Enalapril on Primary Endpoint and Its Components

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

  26. PARADIGM-HF: All-Cause Mortality 32 Enalapril (n=4212) HR = 0.84 (0.76-0.93) P<0.0001 835 24 711 Kaplan-Meier Estimate of Cumulative Rates (%) 16 LCZ696 (n=4187) 8 0 0 180 360 540 720 900 1080 1260 Days After Randomization Patients at Risk LCZ696 Enalapril 4187 4212 4056 4051 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279

  27. PARADIGM-HF: Effect of LCZ696 vs Enalapril on Secondary Endpoints

  28. PARADIGM-HF: Adverse Events

  29. PARADIGM-HF: Adverse Events

  30. PARADIGM-HF: Adverse Events

  31. 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

  32. Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin-Angiotensin System Angiotensin receptor blocker Angiotensin neprilysin inhibition ACE inhibitor 0% 15% 18% 10% 20% % Decrease in Mortality 20% 30% 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 40%

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