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Sacubitril/Valsartan (LCZ696) in Heart Failure.

Abstract It has been known since the 1990s that long-term morbidity and mortality is improved in patients with heart failure with reduced ejection fraction (HFrEF) by treatments that target the renin-angiotensin-aldosterone system (RAAS). It has also long been thought that enhancement of the activity of natriuretic peptides (NPs) could potentially benefit patients with HFrEF, but multiple attempts to realize this benefit had failed over the years - until 2014, when a large, phase III, randomized, controlled clinical trial (PARADIGM-HF) was completed comparing sacubitril/valsartan with enalapril, a well-established treatment for HFrEF. Sacubitril/valsartan (formerly known as LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that simultaneously suppresses RAAS activation through blockade of angiotensin II type 1 receptors and enhances vasoactive peptides including NPs through inhibition of neprilysin, the enzyme responsible for their degradation. In PARADIGM-HF, patients with HFrEF treated with sacubitril/valsartan had 20% less risk for cardiovascular death or hospitalization for heart failure (the primary endpoint), 20% less risk for cardiovascular death, 21% less risk for first hospitalization for heart failure, and 16% less risk for death from any cause, compared with enalapril (all pā€‰<ā€‰0.001). Concerning tolerability, the sacubitril/valsartan group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough, compared with the enalapril group. The use of sacubitril/valsartan has been endorsed by the latest heart failure treatment guidelines in Europe and the USA. This chapter reviews the discoveries, scientific reasoning, and clinical evidence that led to the development of sacubitril/valsartan, the first novel therapy in a new drug class to improve survival in HFrEF in the last 15 years.
PMID
Related Publications

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Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial.

Dual Angiotensin Receptor and Neprilysin Inhibition with Sacubitril/Valsartan in Chronic Systolic Heart Failure: Understanding the New PARADIGM.

Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.

Authors

Mayor MeshTerms
Keywords

HFrEF

Natriuretic peptides

Neprilysin

PARADIGM-HF

Sacubitril/valsartan

Journal Title handbook of experimental pharmacology
Publication Year Start




PMID- 28004291
OWN - NLM
STAT- Publisher
DA  - 20161222
LR  - 20161223
IS  - 0171-2004 (Print)
IS  - 0171-2004 (Linking)
DP  - 2016 Dec 22
TI  - Sacubitril/Valsartan (LCZ696) in Heart Failure.
LID - 10.1007/164_2016_77 [doi]
AB  - It has been known since the 1990s that long-term morbidity and mortality is
      improved in patients with heart failure with reduced ejection fraction (HFrEF) by
      treatments that target the renin-angiotensin-aldosterone system (RAAS). It has
      also long been thought that enhancement of the activity of natriuretic peptides
      (NPs) could potentially benefit patients with HFrEF, but multiple attempts to
      realize this benefit had failed over the years - until 2014, when a large, phase 
      III, randomized, controlled clinical trial (PARADIGM-HF) was completed comparing 
      sacubitril/valsartan with enalapril, a well-established treatment for HFrEF.
      Sacubitril/valsartan (formerly known as LCZ696) is a first-in-class angiotensin
      receptor neprilysin inhibitor (ARNI) that simultaneously suppresses RAAS
      activation through blockade of angiotensin II type 1 receptors and enhances
      vasoactive peptides including NPs through inhibition of neprilysin, the enzyme
      responsible for their degradation. In PARADIGM-HF, patients with HFrEF treated
      with sacubitril/valsartan had 20% less risk for cardiovascular death or
      hospitalization for heart failure (the primary endpoint), 20% less risk for
      cardiovascular death, 21% less risk for first hospitalization for heart failure, 
      and 16% less risk for death from any cause, compared with enalapril (all p &lt;
      0.001). Concerning tolerability, the sacubitril/valsartan group had higher
      proportions of patients with hypotension and nonserious angioedema but lower
      proportions with renal impairment, hyperkalemia, and cough, compared with the
      enalapril group. The use of sacubitril/valsartan has been endorsed by the latest 
      heart failure treatment guidelines in Europe and the USA. This chapter reviews
      the discoveries, scientific reasoning, and clinical evidence that led to the
      development of sacubitril/valsartan, the first novel therapy in a new drug class 
      to improve survival in HFrEF in the last 15 years.
FAU - Khder, Yasser
AU  - Khder Y
AD  - Novartis Institutes for Biomedical Research, Postfach, 4002, Basel, Switzerland. 
      [email protected]
FAU - Shi, Victor
AU  - Shi V
AD  - Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ,
      07936-1080, USA.
FAU - McMurray, John J V
AU  - McMurray JJ
AD  - British Heart Foundation Cardiovascular Research Centre, Institute of
      Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
FAU - Lefkowitz, Martin P
AU  - Lefkowitz MP
AD  - Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ,
      07936-1080, USA.
LA  - eng
PT  - Journal Article
DEP - 20161222
PL  - Germany
TA  - Handb Exp Pharmacol
JT  - Handbook of experimental pharmacology
JID - 7902231
OTO - NOTNLM
OT  - HFrEF
OT  - Natriuretic peptides
OT  - Neprilysin
OT  - PARADIGM-HF
OT  - Sacubitril/valsartan
EDAT- 2016/12/23 06:00
MHDA- 2016/12/23 06:00
CRDT- 2016/12/23 06:00
AID - 10.1007/164_2016_77 [doi]
PST - aheadofprint
SO  - Handb Exp Pharmacol. 2016 Dec 22. doi: 10.1007/164_2016_77.

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