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Apr 23, 2023 •421 likes •681 views

Where new HF drugs fit in? Felipe Martinez Professor of Medicine. Cordoba National University. Director. Damic Institute-Rusculleda Foundation. Governor. Argentina Chapter of ACC. Inmediate Past President. Intl. Soc of CV Pharmacotherapy WE

  1. Where new HF drugs fit in? Felipe Martinez Professor of Medicine. Cordoba National University. Director. Damic Institute-Rusculleda Foundation. Governor. Argentina Chapter of ACC. Inmediate Past President. Intl. Soc of CV Pharmacotherapy

  2. WE STILL USE OLD DRUGS IN HF ?

  3. DRUG START GDL 2016 Digital XVIII Cent. I I -- B Diuretics ??? I -- B ACEI 1987 I – A 20-30 % BB 1990 I – A OUTCOMES MRA 1999 I -- A ARB 2003 I – B

  4. A 68-year-male patient was admitted from home with progressive increase in breathlessness, orthopnoea and ankle oedema over the previous 6 weeks He has been Apyrexial prescribed with tachypnoeic HCTZ, BB, ACEI and 109 bpm, BP 6 months ago. 106/68. His GP Crackles and uptitrated BB rales in both and added lung fields. Spiro 4 weeks There was sacral ago oedema. EKG: sinus tachycardia. XR: cardiomegalia and severe congestion ECHO: dilated heart, EF 21%

  6. WHICH ARE THE NEW DRUGS THAT COULD BE USED IN THIS PATIENT?

  8. ANGIOTENSINE RECEPTOR NEPRILISINE INHIBITOR

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

  10. LCZ696 simultaneously inhibits NEP and blocks the AT 1 receptor LCZ696 Natriuretic and other RAAS vasoactive peptides* Angiotensinogen – (liver secretion) Sacubitril (AHU377; pro-drug) Ang I LBQ657 Inactive Ang II Valsartan fragments (NEP inhibitor) AT 1 Receptor Enhancing Inhibiting O O Vasorelaxation N OH Vasoconstriction  Blood pressure  Blood pressure O HN  Sympathetic tone OH N O  Sympathetic tone N NH HO N  Aldosterone levels O  Aldosterone  Fibrosis  Fibrosis  Hypertrophy  Hypertrophy  Natriuresis/diuresis

  11. PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (PEP) 4 0 Enalapril 1117 Cumulative Rates 3 (n=4212) Kaplan-Meier 914 2 Estimate of 2 LCZ696 (%) 4 (n=4187) 1 6 HR = 0.80 (0.73-0.87) 8 P = 0.0000002 Number needed to treat 0 = 21 0 180 360 540 720 900 1080 1260 Days After Randomization Patients at Risk LCZ696 4187 3922 3663 3018 2257 1544 896 249 Enalapril 4212 3883 3579 2922 2123 1488 853 236

  12. P< FEWER 0.001 HOSPITALIZ. FOR H.F WITH LCZ696 Packer M, MacMurray J, Martinez F et al; Circulation 2014.r

  13. Comparing LCZ696 With Enalapril According to Baseline Risk Using the MAGGIC and EMPHASIS-HF Risk Scores: An Analysis of Mortality and Morbidity in PARADIGM-HF Joanne Simpson, MBChB; Pardeep S. Jhund, MBChB, PhD; Felipe Martinez MD; et al. J Am Coll Cardiol. 2015;66(19):2059-2071 .

  14. Geographical variations in the PARADIGM-HF trial Soren Christensen, Felipe Martinez, John McMurray et al. Eur Heart. Journal .June 2016

  15. Clinical Importance of the Findings of the PARADIGM-HF Trial For the last 25 years, the magnitude of the effect of ACE inhibitors on cardiovascular mortality has created an ethical mandate for their use in all patients with chronic heart failure who could tolerate treatment with these drugs. The finding that LCZ696 has an 20% greater effect on cardiovascular mortality than ACE inhibitors strongly supports the conclusion that LCZ696 should replace current use of ACE inhibitors and angiotensin receptor blockers in the management of chronic heart failure.

  16. Efficacy of Sacubitril/Valsartan Relative to a Prior Decompensation The PARADIGM-HF Trial Scott D. Solomon, MDa; Brian Claggett, PhDa; Milton Packer, MDb; Akshay Desai, MDa; Michael R. Zile, MDc; Karl Swedberg, MDd; Jean Rouleau, MDe; Victor Shi, MDf; Martin Lefkowitz, MDf; John J.V. McMurray, MDg JCHF. Oct.10, 2016;4(10):816-822.

  17. Efecto del Tto. con Sacubitril/Valsartan 1) Los pacientes considerados más estables por no haber tenido hospitalización por I.C., se beneficiaron con el tto de S-V tanto o aun más como los considerados menos estables y con descompensaciones recientes. 2) Estos hallazgos no permiten recomendar que deba esperarse la descompensación de pts con I.C. para cambiar de terapia con IECA/BRA para S-V

  18. A 68-year-male patient was admitted from home with progressive increase in breathlessness, orthopnoea and ankle oedema over the previous 6 weeks He has been Apyrexial prescribed with tachypnoeic HCTZ, BB, ACEI and 109 bpm, BP 6 months ago. 106/68. His GP Crackles and uptitrated BB rales in both and added lung fields. Spiro 4 weeks There was sacral ago oedema. EKG: sinus tachicardia. XR: cardiomegalia and severe congestion.ECHO: dilated heart, EF 21%

  19. Selective Inhibition of «F» channel produces pure reduction of HR Anti-ischemic effect of Similar reduction of HR ivabradine compared with compared with atenolol amiodarone

  20. Ivabradine decrease morbimortality compared with placebo on top of UT

  22. ?

  23. PARAGON-HF: study design Target patient population:  4,300 patients with symptomatic HF (NYHA Class II – IV) and LVEF  45% Randomization 1:1 Double-blind treatment period Active run-in period LCZ696 200 mg BID Valsartan LCZ696 Screening 80 mg BID* 100 mg BID Valsartan 160 mg BID On top of optimal background medications for co-morbidities (excluding ACEIs and ARBs) up to 2 weeks 3 – 8 weeks ~240 weeks Primary outcome: CV death and total (first and recurrent) HF hospitalizations (anticipated ~1,721 primary events )

  24. CONCLUSIONS 1) Effective old drugs are still being used in HF. 2) New drugs having proved an additional supperiority in lowering morbimortality are being consolidated. 3) Among them, ARNI in most of pts with HFrEF and Ivabradine in the group with HR >70 bpm, are highly recommended

  25. MANY THANKS MUCHAS GRACIAS

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