1.   The Basic Science of Heart Failure: Dual-Action Molecules in Perspective

2. Adverse Neurohormonal Activation in HF Has Formed the Basis for Evidence-Based Pharmacologic Therapy

3. Renin-Angiotensin-Aldosterone System

4. RAAS Inhibition in CHF

5. Effect of ACE Inhibition in Patients With CHF: CONSENSUS Trial

6. Effect of ACE Inhibition in Patients With CHF: SOLVD Trial

7. ARBs: Another Way to Inhibit the RAS

8. ARBs: No Better Than ACE Inhibitors But Probably AS GOOD AS

9. ATMOSPHERE: Would Dual Blockade of the RAS With Evidence-Based Background Therapy Be Superior to Single-Agent RAS Inhibition?

10. ATMOSPHERE: Direct Renin Inhibition and ACE Inhibition Similar: DUAL Inhibition NO BETTER and Produced More Side Effects

11. Have we pushed inhibiting the RAAS as far as we could go?

12. NP System: Endogenous Compensatory Mechanisms in HF Counteract Some Deleterious Effects of RAAS Activation

13. Action and Clearance of NPs

14. Sacubitril/Valsartan: ARNI—Simultaneously Inhibits RAS and Augments Vasoactive Peptides

15. PARADIGM-HF: Study Design

16. PARADIGM-HF Primary Results: Significant Reduction in Primary Endpoints, CV Death, and All-Cause Mortality

17. PARADIGM-HF: Sacubitril/Valsartan (LCZ696) vs Enalapril on Primary Endpoint and on CV Death, by Subgroups

18. PARADIGM-HF: Early Benefit of Sacubitril/Valsartan

19. PARADIGM-HF: Sacubitril/Valsartan Effective Across a Spectrum of Risk: The MAGGIC Risk Score

20. The PARADIGM-HF Trial

21. Influence of Sacubitril/Valsartan on 30-Day Readmission After HF Hospitalization

22. Estimated Long-term Benefit of 1
Estimated Long-term Benefit of Years Using Actuarial Methods: Based on PARADIGM-HF

23. Potential Mortality Reduction With Optimal Implementation of ARNI Therapy in HF

24. Sacubitril/Valsartan Was Effective Across the Spectrum of EF: PARADIGM-HF Enrolled >2000 Patients With EF Between 35% and 40%

25. PARADIGM-HF: Baseline MRA (Aldosterone) Use

26. PARADIGM-HF: Comparison of Sacubitril/Valsartan vs Enalapril in Dose-Reduced Patients

27. NT-proBNP and BNP

28. PARADIGM-HF: Measurement of NT-proBNP and BNP

29. No Heterogeneity in Treatment Effect by NT-proBNP at Baseline

30. PARADIGM-HF: Influence of Sacubitril/Valsartan on NT-proBNP Reduction and Influence on Outcomes

31. ARNI Use in HF: Guideline Recommendations

32. PARAMOUNT: Designed in Parallel With PARADIGM-HF to Provide Pilot Data for Sacubitril/Valsartan in HFpEF

33. PARAMOUNT: Significant Reduction in NT-proBNP With Sacubitril/Valsartan at 12 Weeks

34. PARAMOUNT: Improvement in Left Atrial Size and NYHA Class With Sacubitril/Valsartan at 36 Weeks

35. PARAGON-HF: Trial Design

36. PARADISE-MI: Trial Design

37. Summary

38. Abbreviations

39. Abbreviations (cont)

40. Abbreviations (cont)