OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Sacubitril-Valsartan – Entresto®

DRUG CLASS

Cardiovascular Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

View in own window

DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Sacubitril	149709-62-6	C24-H29-NO5
Valsartan	137862-53-4	C24-H29-N5-O3

ANNOTATED BIBLIOGRAPHY

References updated: 09 July 2024

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Expert review of hepatotoxicity of cardiovascular agents published in 1999 before the availability of sacubitril and valsartan).
• Halegoua-DeMarzio DH, Navarro VJ. Hepatotoxicity of cardiovascular and antidiabetic medications. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 522-6.

  (Review of hepatotoxicity of cardiovascular agents published before the availability of sacubitril, but mentions that cases of hepatotoxicity of candesartan, irbesartan, losartan, and valsartan, none of which were fatal and having in both latency to onset [1 week to 6 months] and clinical presentation [cholestatic and hepatocellular]).
• Hilal-Dandan R. Renin and angiotensin. In, Brunton LL, Halal R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 471-488.

  (Textbook of pharmacology and therapeutics).
• FDA. Integrated Review. Entresto. 2015. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2015/207620Orig1s000MedR.pdf

  (FDA review of the data submitted in support of the approval of sacubitril-valsartan for prevention of cardiovascular death and hospitalization in patients with heart failure mentions that ALT or AST elevations above 3 times ULN arose in 1.3% of those on sacubitril-valsartan vs 1.0% on enalapril which were above 5 times ULN in 0.5% vs 0.3%, and that one patient developed marked enzyme elevations with jaundice [ALT 730 U/L], but this occurred after the combination was stopped and during acute decompensation of heart failure).
• Reñé JM, Buenestado J, Sesé E, Miñana JM. Acute hepatitis induced by valsartan. Med Clin (Barc) 2001; 117: 637-8. [PubMed: 11714476]

  (54 year old woman developed jaundice 18 weeks after starting valsartan for hypertension [bilirubin 23.6 mg/dL, ALT 1664 U/L, Alk P 385 U/L], resolving within 2 months of stopping).
• Kiykim A, Altintas E, Sezgin O, Sezer K, Tiftik N, Akbay E, Seyrek E, et al. Valsartan-induced hepatotoxicity in a HBsAg-positive patient. Am J Gastroenterol 2003; 98: 507. [PubMed: 12591083]

  (52 year old woman with hypertension and HBsAg without chronic ALT elevations developed jaundice 4 weeks after starting valsartan [peak bilirubin 7.8 mg/dL, ALT 780 U/L, Alk P 1840 U/L], resolving within 3 months of stopping).
• McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, et al.; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004. [PubMed: 25176015]

  (Among 8442 patients with chronic heart failure and ejection fraction of 40% or less who were started on sacubitril-valsartan or enalapril twice daily and continued for a median of 27 months, cardiovascular deaths and hospitalizations for heart failure were less in those on the combination [21.8% vs 26.5%], and while symptomatic hypotension was more frequent with sacubitril-valsartan, cough and elevations in serum creatinine and potassium were more frequent with enalapril; no mention of ALT elevations, but no hepatic severe adverse events).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US multicenter prospective study between 2004 and 2013, none were attributed to sacubitril, but one case was attributed to valsartan).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, Chirino AR, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, none of which were attributed to sacubitril or valsartan).
• Havakuk O, Elkayam U. Angiotensin receptor-neprilysin inhibition. J Cardiovasc Pharmacol Ther. 2017;22:356-364. [PubMed: 28587583]

  (Review of the mechanism of action and history of development of neprilysin inhibitors and the importance of angiotensin II receptor blockage during their use with an in-depth review of the PARADIGM trial [McMurray 2014] of sacubitril-valsartan for heart failure with reduced cardiac ejection fraction; no mention of ALT elevations or hepatotoxicity).
• Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E; PIONEER-HF Investigators. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380:539-548. [PubMed: 30415601]

  (Among 881 patients hospitalized for acute heart failure started on sacubitril-valsartan or enalapril twice daily for 8 weeks, serum levels of NT-proBNP decreased by 47% with the combination vs only 25% with enalapril, while the frequency and types of treatment emergent adverse events were similar in both groups; no mention of ALT levels or hepatotoxicity).
• Drugs for chronic heart failure. Med Lett Drugs Ther. 2019;61(1569):49-54. [PubMed: 31169796]

  (Concise review of the mechanism of action, clinical efficacy, safety, and costs of medications approved for use in the US for treatment of heart failure, mentions that the combination of a neprilysin inhibitor and angiotensin receptor inhibitor is the preferred first line therapy for chronic heart failure and includes discussion of sacubitril-valsartan adverse events, but does not mention hepatotoxicity or ALT elevations).
• Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, et al.; PARAGON-HF Investigators and Committees. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381:1609-1620. [PubMed: 31475794]

  (Among 4822 patients with heart failure and preserved cardiac ejection fraction [45% or greater] but elevations in natriuretic peptide levels who were treated with sacubitril-valsartan or valsartan with a median follow up of 35 months, the primary outcome of cardiovascular death or hospitalizations for heart failure occurred less often with combination therapy but the differences were not statistically significant; combination therapy was associated with higher rates of hypotension and angioedema but lower rates of serum creatinine and potassium elevations; hepatic adverse events arose in similar proportions of both groups [6.3% vs 7.5%], but there were no severe hepatic adverse events).
• Achuthanandan S, Dhaliwal A, Patti R. Drug-induced liver injury from sacubitril-valsartan versus a single dose of acarbose. Cureus. 2022;14:e27005. [PMC free article: PMC9386752] [PubMed: 35989811]

  (76 year old woman with heart failure developed fatigue and liver test abnormalities one month after starting sacubitril-valsartan and one day after taking a single dose of acarbose for diabetes [bilirubin 1.2 mg/dL, ALT 1652 U/L, Alk P 55 U/L, INR 2.8], with rapid improvement on stopping both drugs and normal liver tests 3 weeks later).
• Zhang T, Cai JL, Yu J. Sacubitril/valsartan-induced liver injury: A case report and literature review. Medicine (Baltimore). 2023;102:e34732. [PMC free article: PMC10419355] [PubMed: 37565914]

  (90 year old Chinese woman with heart failure and HBsAg without HBV DNA developed mild elevations in ALT within a week of starting sacubitril-valsartan, which worsened on continuation to a peak one month later [bilirubin 1.4 mg/dL, ALT 640 U/L, Alk P not provided], falling once sacubitril-valsartan was stopped and with normal values 6 weeks later).
• Lerman TT, Greenberg N, Fishman B, Goldman A, Talmor-Barkan Y, Bauer M, Goldberg I, et al. The real-world safety of sacubitril/valsartan among older adults (≥75): A pharmacovigilance study from the FDA data. Int J Cardiol. 2024;397:131613. [PubMed: 38030039]

  (Review of the FDA’s Adverse Event Reporting System [FAERS] for sacubitril-valsartan and angiotensin II receptor blockers [ARBs] from 2004 to 2022 identified 18,435 reports, 5802 in elderly subjects [75 years or above] and, compared to ARBs, sacubitril-valsartan had higher rates of hypotension and hyperkalemia but similar rates of angioedema; no mention of ALT elevations or hepatotoxicity).
• Morrow DA, Velazquez EJ, Desai AS, DeVore AD, Lepage S, Park JG, Sharma K, et al. Sacubitril/valsartan in patients hospitalized with decompensated heart failure. J Am Coll Cardiol. 2024;83:1123-1132. [PubMed: 38508844]

  (Pooled analysis of controlled trials of sacubitril-valsartan versus an angiotensin receptor blocker [ARB] alone in 1347 patients with heart failure and the full spectrum of left ventricular ejection fraction [both ≤ 40% and >40%], found that cardiovascular deaths and hospitalizations were reduced by 30% regardless of ejection fraction and the combination had higher rates of hypotension and hyperkalemia but numerically lower rates to death, angioedema, and worsening of renal function; no mention of ALT elevations or hepatotoxicity).