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Revision as of 16:49, 5 December 2015

Pharmaceutical compound
Sacubitril/valsartan
Valsartan/sacubitril
Combination of
ValsartanAngiotensin II receptor antagonist
SacubitrilNeprilysin inhibitor
Clinical data
Trade namesEntresto
AHFS/Drugs.comentresto
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
CompTox Dashboard (EPA)

Valsartan/sacubitril (brand name Entresto, previously known as LCZ696) is a combination drug for use in heart failure developed by Novartis. It consists of the angiotensin receptor blocker valsartan and the neprilysin inhibitor sacubitril, in a 1:1 mixture by molecule count. The combination is sometimes described as an "angiotensin receptor-neprilysin inhibitor" (ARNi). It was approved under the FDA's priority review process on July 7, 2015. As of September 2015, it is also on track to approval in Europe after receiving the backing of EU regulators.

Medical uses

Valsartan/sacubitril is used to treat heart failure in people with reduced left ventricular ejection fraction (LVEF). It is not known whether valsartan/sacubitril is useful for the treatment of heart failure patients with preserved LVEF.


The Pardigm-HF trial compared treatment with valsartan/sacubitril to treatment with enalapril. People with heart failure and reduced LVEF (10,513) were sequentially treated on a short term basis with enalapril and then with valsartan/sacubitril. Those that were able to tolerate both regimens (8442, 80%) were randomly assigned to long-term treatment with either enalapril or valsartan/sacubitril. Participants were mainly white (66%), male (78%), middle aged (median 63.8 +/- 11 years) with NYHA stage II (71.6%) or stage III (23.1%) heart failure.

The trial was stopped early after a prespecified interim analysis revealed a statistically significant reduction in the primary endpoint of cardivascular death or heart failure in the valsartan/sacubitril group relative to those treated with enalapril. Taken individually, the reductions in cardiovascular death and heart failure hospitalizations retained statistical significance. Relative to enalapril, valsartan-sacubitril provided reductions in

  • the composite endpoint of cardiovascular death or hospitalization for heart failure (incidence 21.8% vs 26.5%)
  • cardiovascular death (incidence 13.3% vs 16.5%)
  • first hospitalization for worsening heart failure (incidence 12.8% vs 15.6%), and
  • all cause mortality (incidence 17.0% vs 19.8%)

The favorable effect of valsartan/sacubitril was seen in all subgroups examined, including those based on age, sex, weight, race, NYHA class, presence or absence of reduced kidney function, diabetes, atrial fibrillation, hypertension, and prior hospitalization.

Limitations of the trial include limited representation of important subgroups, such as blacks and those with implantable pacemakers, and lack of data regarding those with NYHA heart failure stages other than II or III.

A 2015 review stated that switching 1000 patients from an ACE inhibitoror Angiotensin II receptor antagonist to valsartan/sacubitril for 2.7 years would prevent 31 deaths, 53 hospitalizations for heart failure, and 111 hospitalizations overall, and recommended "broad use" of valsartan/sacubitril. A second review stated that valsartan/sacubitril represents "an advancement in the chronic treatment of heart failure with reduced ejection fraction" but that widespread clinical success with the drug will require taking care to use it in appropriate patients, specifically those with characteristics similar to those in the clinical trial population. A third review called the reductions in mortality and hospitalization conferred by valsartan/sacubitril "striking", but noted that its effects in heart failure patients with hypertension, diabetes, Chronic kidney disease, and the elderly needed to be evaluated in additional clinical trials.

Adverse effects

Common adverse effects the main study were cough, hyperkalemia (high potassium levels in the blood, which can be caused by valsartan), renal dysfunction, and hypotension (low blood pressure, a common side effect of vasodilators and ECF volume reducers). 12% of the patients withdrew from the study during the run-in phase because of such events.

Valsartan-sacubitril is contraindicated in pregnancy because it contains valsartan, a known risk for birth defects.

Mechanism of action

Valsartan blocks the angiotensin II receptor type 1 (AT1). This receptor is found on both vascular smooth muscle cells, and on the zona glomerulosa cells of the adrenal gland which are responsible for aldosterone secretion. In the absence of AT1 blockade, angiotensin causes both direct vasoconstriction and adrenal aldosterone secretion, the aldosterone then acting on the distal tubular cells of the kidney to promote sodium reabsorption which expands extracellular fluid (ECF) volume. Blockade of (AT1) thus causes vasodilation and reduction of ECF volume.

Sacubitril is a prodrug that is activated to sacubitrilat (LBQ657) by de-ethylation via esterases. Sacubitrilat inhibits the enzyme neprilysin, a neutral endopeptidase that degrades vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Thus, sacubitril increases the levels of these peptides, causing vasodilation and reduction of ECF volume via sodium excretion.

Physical and chemical properties

LCZ696 is co-crystallized valsartan and sacubitril, in a one-to-one molar ratio. One LCZ696 complex consists of six valsartan anions, six sacubitril anions, 18 sodium cations, and 15 molecules of water, resulting in the molecular formula C288H330N36Na18O48·15H2O and a molecular mass of 5748.03 g/mol.

The substance is a white powder consisting of thin hexagonal plates. It is stable in solid form as well as in aqueous (watery) solution with a pH of 5 to 7, and has a melting point of about 138 °C (280 °F).

References

  1. "New ATC". WHO Collaborating Centre for Drug Statistics Methodology. World Health Organization. 2015-04-29. Retrieved 8 July 2015.
  2. ^ Gu, J; Noe, A; Chandra, P; Al-Fayoumi, S; Ligueros-Saylan, M; Sarangapani, R; Maahs, S; Ksander, G; Rigel, D. F.; Jeng, A. Y.; Lin, T. H.; Zheng, W; Dole, W. P. (2010). "Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi)". The Journal of Clinical Pharmacology. 50 (4): 401–14. doi:10.1177/0091270009343932. PMID 19934029.
  3. Ruilope, Luis Miguel; Dukat, Andrej; Böhm, Michael; Lacourcière, Yves; Gong, Jianjian; Lefkowitz, Martin P (2010). "Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: A randomised, double-blind, placebo-controlled, active comparator study". The Lancet. 375 (9722): 1255. doi:10.1016/S0140-6736(09)61966-8.
  4. ^ "FDA approves new drug to treat heart failure". Food and Drug Administration. 7 July 2015.
  5. "Novartis' new heart drug on track for approval in Europe". Reuters. 25 September 2015.
  6. King JB, Bress AP, Reese AD, Munger MA (2015). "Neprilysin Inhibition in Heart Failure with Reduced Ejection Fraction: A Clinical Review". Pharmacotherapy. 35 (9): 823–37. doi:10.1002/phar.1629. PMID 26406774.
  7. King JB, Bress AP, Reese AD, Munger MA (2015). "Neprilysin Inhibition in Heart Failure with Reduced Ejection Fraction: A Clinical Review". Pharmacotherapy. 35 (9): 823–37. doi:10.1002/phar.1629. PMID 26406774.
  8. ^ McMurray, John J.V.; Packer, Milton; Desai, Akshay S.; Gong, Jianjian; Lefkowitz, Martin P.; Rizkala, Adel R.; Rouleau, Jean L.; Shi, Victor C.; Solomon, Scott D.; Swedberg, Karl; Zile, Michael R. (August 30, 2014). "Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure". N Eng J Med. 371: 140830040023009. doi:10.1056/NEJMoa1409077. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  9. King JB, Bress AP, Reese AD, Munger MA (2015). "Neprilysin Inhibition in Heart Failure with Reduced Ejection Fraction: A Clinical Review". Pharmacotherapy. 35 (9): 823–37. doi:10.1002/phar.1629. PMID 26406774.
  10. ^ "Entresto prescribing information" (PDF). Novartis. July 2015.
  11. King JB, Bress AP, Reese AD, Munger MA (2015). "Neprilysin Inhibition in Heart Failure with Reduced Ejection Fraction: A Clinical Review". Pharmacotherapy. 35 (9): 823–37. doi:10.1002/phar.1629. PMID 26406774.
  12. King JB, Bress AP, Reese AD, Munger MA (2015). "Neprilysin Inhibition in Heart Failure with Reduced Ejection Fraction: A Clinical Review". Pharmacotherapy. 35 (9): 823–37. doi:10.1002/phar.1629. PMID 26406774.
  13. Lillyblad MP (2015). "Dual Angiotensin Receptor and Neprilysin Inhibition with Sacubitril/Valsartan in Chronic Systolic Heart Failure: Understanding the New PARADIGM". Ann Pharmacother. 49 (11): 1237–51. doi:10.1177/1060028015593093. PMID 26175499.
  14. Bavishi C, Messerli FH, Kadosh B, Ruilope LM, Kario K (2015). "Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials". Eur. Heart J. 36 (30): 1967–73. doi:10.1093/eurheartj/ehv142. PMID 25898846.
  15. Mutschler, Ernst; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 579. ISBN 3-8047-1763-2.
  16. Zouein, Fouad A.; De Castro Brás, Lisandra E.; Da Costa, Danielle V.; Lindsey, Merry L.; Kurdi, Mazen; Booz, George W. (2013). "Heart Failure with Preserved Ejection Fraction". Journal of Cardiovascular Pharmacology. 62 (1): 13–21. doi:10.1097/FJC.0b013e31829a4e61. PMC 3724214. PMID 23714774.
  17. Solomon, SD. "HFpEF in the Future: New Diagnostic Techniques and Treatments in the Pipeline". Boston. p. 48. Retrieved 2012-01-26.
  18. Schubert-Zsilavecz, M; Wurglics, M. "Neue Arzneimittel 2010/2011" (Document) (in German). {{cite document}}: Cite document requires |publisher= (help)CS1 maint: postscript (link)
  19. Monge, M.; Lorthioir, A.; Bobrie, G.; Azizi, M. (2013). "New drug therapies interfering with the renin-angiotensin-aldosterone system for resistant hypertension". Journal of the Renin-Angiotensin-Aldosterone System. 14 (4): 285. doi:10.1177/1470320313513408. PMID 24222656.
  20. ^ Lili Feng, L; et al. (2012). "LCZ696: a dual-acting sodium supramolecular complex". Tetrahedron Letters. 53: 275–276. doi:10.1016/j.tetlet.2011.11.029. {{cite journal}}: Explicit use of et al. in: |author2= (help); Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
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