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Sacubitril/valsartan

Combination of
Valsartan	Angiotensin II receptor antagonist
Sacubitril	Neprilysin inhibitor
Clinical data
Routes of administration	Oral
ATC code	none
Legal status
Legal status	Investigational
Identifiers
PubChem CID	24755604
CompTox Dashboard (EPA)	DTXSID50239500

Valsartan/sacubitril (codenamed LCZ696) is an investigational combination drug consisting of two antihypertensives (blood pressure lowering drugs), valsartan and sacubitril, in a 1:1 mixture. As of 2014 it is being developed by Novartis. The combination is often described as a dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) although the two effects are achieved by two different molecules.

Medical uses

Valsartan/sacubitril is not currently used as a medicine; it is in clinical trials as a treatment for hypertension and heart failure.

Mechanism of action

Valsartan blocks the angiotensin II receptor type 1 (AT₁) and thereby causes vasodilatation and increases excretion of sodium and water via the kidneys (by reducing aldosterone production). The latter mechanism leads to a reduction in blood volume.

Sacubitril is a prodrug that is activated to LBQ657 by de-ethylation via esterases. LBQ657 inhibits the enzyme neprilysin, which is responsible for the degradation of atrial and brain natriuretic peptide, two blood pressure lowering peptides that work mainly by reducing blood volume.

Physical and chemical properties

LCZ696 is synthesized by co-crystallisation of valsartan and sacubitril, in a one-to-one ratio; it is not simply a formulation of the two drugs together.

Research

Hypertension

A randomized, double-blinded clinical study published in 2010 found that LCZ696 decreased blood pressure more than placebo, or either of valsartan and sacubitril given alone, in people with stage 1–2 hypertension.

Heart failure

On 30 August 2014, the PARADIGM-HF investigators and committees reported in the New England Journal of Medicine (NEJM) that LCZ696 significantly reduced the risks of overall death, death from heart failure, and hospitalization for heart failure, compared to enalapril, in a Phase III trial. 8,442 people with with moderate to severe heart failure and an ejection fraction of 40% or less were enrolled in the trial, which randomized and double-blinded. The primary endpoint of the trial was the number of patients in each arm who experienced death from cardiovascular disease or hospitalization. At the time the study was stopped, 21.8% of those in the LCZ696 arm and 26.5% of those in the enalapril arm had died of cardiovascular causes or been hospitalized (hazard ratio 0.80); 17.0% of those receiving LCZ696 and 19.8% of those receiving enalapril had died (hazard ratio 0.84); and 13.3% of those receiving LCZ696 and 16.5% of those receiving enalapril had died of cardiovascular causes.

Expert commentary on publication of the PARADIGM-HF clinical trial varied widely, with some declaring a "new paradigm" in the treatment of heart failure, and others arguing that flaws in the trial design and lack of availability of patient level data for independent analysis make interpretation of the results impossible.

References

1. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19934029, please use {{cite journal}} with |pmid=19934029 instead.
2. Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/S0140-6736(09)61966-8, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/S0140-6736(09)61966-8 instead.
3. ^ Monge M et al. New drug therapies interfering with the renin-angiotensin-aldosterone system for resistant hypertension. J Renin Angiotensin Aldosterone Syst. 2013 Dec;14(4):285-9. doi: 10.1177/1470320313513408. Epub 2013 Nov 12. PMID 24222656
4. Zouein FA1 et al. Heart failure with preserved ejection fraction: emerging drug strategies. J Cardiovasc Pharmacol. 2013 Jul;62(1):13-21. doi: 10.1097/FJC.0b013e31829a4e61. PMID 23714774 PMC 3724214
5. Clinical trial number NCT01035255 for "This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure (PARADIGM-HF)" at ClinicalTrials.gov
6. Mutschler, Ernst; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 579. ISBN 3-8047-1763-2.
7. Solomon, SD. "HFpEF in the Future: New Diagnostic Techniques and Treatments in the Pipeline". Boston. p. 48. Retrieved 2012-01-26.
8. Schubert-Zsilavecz, M; Wurglics, M. "Neue Arzneimittel 2010/2011" (Document) (in German)Template:Inconsistent citations {{cite document}}: Cite document requires |publisher= (help)CS1 maint: postscript (link)
9. "Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure". N Eng J Med. 371. August 30, 2014. doi:10.1056/NEJMoa1409077. {{cite journal}}: Unknown parameter |authors= ignored (help)
10. "PARADIGM-HF: New Drug Class Outclasses ACE-I in Chronic HF".
11. "PARADIGM-HF Establishes a New Paradigm for Heart Failure Treatment - Forbes".
12. New Novartis Drug Effective in Treating Heart Failure, By Andrew Pollack, New York Times, AUG. 30, 2014
13. Richard Lehman’s journal review—8 September 2014. NEJM 4 Sep 2014. Vol 371. The BMJ, 8 September 2014.

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