1) The document discusses the use of sacubitril/valsartan (ARNI), a first-in-class angiotensin receptor neprilysin inhibitor, for the treatment of heart failure. 2) It provides evidence from clinical trials that sacubitril/valsartan reduces cardiovascular death and heart failure hospitalizations compared to enalapril in patients with HFrEF. 3) A recent large trial found that sacubitril/valsartan reduced worsening heart failure events in patients with HFpEF, leading to an expanded FDA approval of the drug.

1. Diastology
Unlocking new possibilities in HF
management

2. ARNI - Right choice in Heart Failure
DR DINAKAR THATIMATLA
CONSULTANT AND INTERVENTIONAL CARDIOLOGIST
RENEE HOSPITAL

3. The Problem of HF Management in 2022

4. Despite guideline recommendations, HF therapy is not currently optimised
Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry.
J Am Coll Cardiol. 2018 Jul 24;72(4):351-366

6. HF-related events prevented by the treatment with sacubitril/valsartan
Front Cardiovasc Med. 2021 Nov 11;8:754499

7. Mechanisms involved in reducing the sudden death rate demonstrated by
sacubitril/valsartan
Front Cardiovasc Med. 2021 Nov 11;8:754499

8. Mechanisms of sacubitril/valsartan enhancement of ventricular remodeling
Front Cardiovasc Med. 2021 Nov 11;8:754499

9. Hemodynamic effects of neprilysin/RAAS inhibition
Front Cardiovasc Med. 2021 Nov 11;8:754499

10. Sacubitril/Valsartan – A first in class Angiotensin Receptor Neprilysin
Inhibitor – Simultaneously Inhibits NEP and the RAS

11. Effect of the treatment with sacubitril/valsartan on HF biomarkers
Front Cardiovasc Med. 2021 Nov 11;8:754499

12. Neprilysin/RAAS inhibition provides several renal benefits both in terms of functional
adaptations and structural remodeling
Front Cardiovasc Med. 2021 Nov 11;8:754499

13. Role of neprilysin inhibition in glucose homeostasis
Front Cardiovasc Med. 2021 Nov 11;8:754499

14. Effect of sacubitril/valsartan relative to enalapril on different components of quality of life
Front Cardiovasc Med. 2021 Nov 11;8:754499

15. PARAGON-HF: Study Design

16. PARAGON-HF: Primary and Secondary Outcomes

17. PARAGON-HF: HF Hospitalisations and CV death
Sacubitril–valsartan did not result in a significantly lower rate of total
hospitalizations for heart failure and death from cardiovascular causes among
patients with heart failure and an ejection fraction of 45% or higher.

18. PARAGON-HF: Greater benefit with LVEF below Normal
Greater benefit with ‘mid range’ LVEF consistent with prior trials

19. FDA Advisory Committee and Approval of Expanded Indication for
Sacubitril / Valsartan
• A positive decision was made by the FDA Cardiovascular and Renal Drugs Advisory Committee (CRDAC)
with 12 to 1 votes for recommendation of use of sacubitril/valsartan in treatment of patients with HFpEF.
This decision was based on data demonstrating benefit of sacubrtril/valsartan in reducing worsening HF
(total HF hospitalizations and urgent HF visits) in patients in the PARAGON-HF trial.
• Dec 15, 2020: FDA committee voted 12-1 to approve an expanded indication for sacubitril/ valsartan
based on PARAGON-HF
• Feb 16, 2021: US FDA approved expanded indication
• Sacubitril/valsartan is approved in 115 countries worldwide for the treatment of HFrEF. It has been shown
to reduce the rate of CV death and HF hospitalization, reduce the rate of all-cause mortality and improve
aspects of health-related quality of life compared to enalapril.
• Indicated to reduce the risk of CV death and hospitalisation for HF in CHF. Benefits are most clearly
evident in patients with LVEF below normal.
• LVEF is a variable measure, so use clinical judgement in deciding whom to treat

20. PARAGON-HF: Higher event rate and greater benefit with recent
hospitalisation
Greater benefit for patients in a more ‘congested’ state

21. Sacubitril/Valsartan Reduced CV Death, Hospitalisation for HF and all
Cause Mortality in HFrEF
McMurray et al, PARADIGM Invest NEJM 2014
Sacubitril/Valsartan was superior to enalapril in reducing the risks of death and of
hospitalization for heart failure.

22. Sacubitril/Valsartan Reduced CV Death, Hospitalisation for HF and all
Cause Mortality in HFrEF
Solomon Lancet 2012
Improvement in NT Pro BNP Improvement in Left Atrial Size

23. Clinical trials of sacubitril–valsartan in HFpEF, AMI, and acute and chronic HFrEF
populations
J Cardiovasc Pharmacol. 2021 Sep 1;78(3):331-33
• PARAGON-HF - HFpEF patients,
sacubitril–valsartan showed a trend
toward reduction in the hospitalizations
for HF, both first and recurrent ones.
• PARADISE-MI-in high-risk AMI,
sacubitril–valsartan led to a reduction of
10% in cardiovascular death,
hospitalization for HF, or outpatient HF.
• PARADIGM-HF trial, sacubitril–valsartan
was more effective than enalapril in
reducing both cardiovascular mortality
and first HF hospitalizations in patients
with HFrEF.
• PIONEER-HF, sacubitril–valsartan led to
a 44% reduction of rehospitalization for
HF versus enalapril in acute patients
with HFrEF.

24. Management of patients with HFrEF – Therapeutic Algorithm
ESC-HF June 29-July 1, 2021

25. Treatment after- The glorious Four
Management of HF patients with MR or TR - new guidelines and new
transcatheter options

26. Pharmacological treatments in patients with (NYHA class II-IV) heart failure with
mildly reduced ejection fraction

27. Thanks