fit in? Felipe Martinez Professor of Medicine. Cordoba National - - PowerPoint PPT Presentation
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
Felipe Martinez
Professor of Medicine. Cordoba National University.
Inmediate Past President. Intl. Soc of CV Pharmacotherapy
Digital XVIII Cent. I I -- B Diuretics ??? I -- B ACEI 1987 I – A BB 1990 I – A MRA 1999 I -- A ARB 2003 I – B
20-30 % OUTCOMES
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 prescribed with HCTZ, BB, ACEI 6 months ago. His GP uptitrated BB and added Spiro 4 weeks ago Apyrexial tachypnoeic and 109 bpm, BP 106/68. Crackles and rales in both lung fields. There was sacral
EKG: sinus tachycardia. XR: cardiomegalia and severe congestion ECHO: dilated heart, EF 21%
Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter Maladaptive Mechanisms in Heart Failure Endogenous vasoactive peptides
(natriuretic peptides, adrenomedullin, bradykinin, substance P,etc)
Inactive metabolites
Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention
Neprilysin Neprilysin inhibition
Vasorelaxation Blood pressure Sympathetic tone Aldosterone levels Fibrosis Hypertrophy Natriuresis/diuresis Inactive fragments
Natriuretic and other vasoactive peptides*
AT1 Receptor
Vasoconstriction Blood pressure Sympathetic tone Aldosterone Fibrosis Hypertrophy Angiotensinogen (liver secretion) Ang I Ang II
RAAS
–
LCZ696
Sacubitril (AHU377; pro-drug) Inhibiting Enhancing LBQ657 (NEP inhibitor)
OH O HN O HO OValsartan
N NH N N N O OH OLCZ696 simultaneously inhibits NEP and blocks the AT1 receptor
1 6 3 2 4 2 4 8
Enalapril
(n=4212)
360 720 1080 180 540 900 1260
Days After Randomization
4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 249 236 LCZ696 Enalapril Patients at Risk
1117
Kaplan-Meier Estimate of Cumulative Rates (%)
914
LCZ696
(n=4187)
HR = 0.80 (0.73-0.87) P = 0.0000002 Number needed to treat = 21
PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (PEP)
FEWER HOSPITALIZ. FOR H.F WITH LCZ696
P< 0.001
Packer M, MacMurray J, Martinez F et al; Circulation 2014.r
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.
Geographical variations in the PARADIGM-HF trial
Soren Christensen, Felipe Martinez, John McMurray et al. Eur Heart. Journal .June 2016
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.
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
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
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 prescribed with HCTZ, BB, ACEI 6 months ago. His GP uptitrated BB and added Spiro 4 weeks
ago
Apyrexial tachypnoeic and 109 bpm, BP 106/68. Crackles and rales in both lung fields. There was sacral
EKG: sinus tachicardia. XR: cardiomegalia and severe congestion.ECHO: dilated heart, EF 21%
Selective Inhibition of «F» channel produces pure reduction of HR
Similar reduction of HR compared with atenolol
Anti-ischemic effect of ivabradine compared with amiodarone
Ivabradine decrease morbimortality compared with placebo on top of UT
PARAGON-HF: study design
Target patient population: 4,300 patients with symptomatic HF (NYHA Class II–IV) and LVEF 45% up to 2 weeks ~240 weeks
Valsartan 160 mg BID LCZ696 200 mg BID
LCZ696 100 mg BID
On top of optimal background medications for co-morbidities (excluding ACEIs and ARBs) Primary outcome: CV death and total (first and recurrent) HF hospitalizations (anticipated ~1,721 primary events)
Valsartan 80 mg BID* Screening
3–8 weeks Active run-in period Double-blind treatment period Randomization 1:1
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