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So I just came across that the Valsartan/sacubitril (Entresto) was given a strong class 1 recommendation by the American College of Cardiology for heart failure. I haven’t seen much of it in med-recs yet, so I just wanted to post a couple of high points that I think we need to know from the ER side. From what I’m reading this drug will start to replace ACE-Inhibitors in the treatment of Class II-IV heart failure. It’s also prescribed in slightly odd dosing in the combination (51 mg/49 mg or 26 mg/24 mg).
Sacubitril is a prodrug that converts to sacubitrilat. Sacubitrilat is responsible for the benefits of this drug as it inhibits the enzyme neprilysin and stops it from degrading atrial/brain natriuretic peptide.
Ultimately the main thing you need to know are the contraindications with other drugs. Basically there are 3: Lithium, ACE-Is, and Aliskiren. Lithium levels have the potential to increase with this drug, while the other 2 can lead to significant hypotension in combination with Valsartan/sacubitril.
Here’s the ACC release: http://www.acc.org/latest-in-cardiology/articles/2016/05/20/11/30/societies-release-focused-update-for-hf-management?wt.mc_id=fb
Would be appreciate if someone with a stronger background in pharmacy or cardiology than I can chime in.
Great summary Kennedy(!), to add a few points:
About Entresto: It is dosed in atypical combinations and is available in three strengths (24mg /26mg sacubitril/valsartan BID, 49mg/51mg BID up to 97mg/103mg BID). It is indicated in chronic HF patients (NYHA class II-IV) and reduced EF in place of ACEI or ARB. Patients must go through a 36 hour washout period of ACEI (d/t concerns for angioedema) or aliskiren (in patients with DM) before Entresto may be initiated. It is contraindicated in pregnancy (Black Box Warning). It is not technically CI with lithium; however, just know that it may increase the serum concentration of lithium (check lithium levels and be keen for s/s of lithium toxicity).
History: ACEI have been the cornerstone of HF treatment in patients with reduced EF as they have been proven to reduce mortality in HF. The Paradigm-HF trail was designed to replace current use of ACEI and ARB as the cornerstone of HF treatment. Sacubitril is a first-in-class neprilysin inhibitor. Neprilysin is abundant in the kidney and is a neutral endopeptidase that degrades several endogenous vasoactive peptides (natriuretic peptides, bradykinin, and adrenomedullin). Inhibition of neprilysin increases levels of these peptides and counters neurohormonal over activation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling. Sacubitril + valsartan = Entresto
Why not add sacubitril to an ACEI? The combination of sacubitril + ACEI caused unacceptably high rates angioedema.
The PARADIGM-HF (N Engl J Med 2014) was a double-blinded trial which studied patients with HF (class II-IV HF and EF <40%). It compared an ACEI and Neprilysin/ARB (enalapril 10mg BID with sacubitril/valsartan 40/160mg BID) used in addition to standard HF therapy (n=8442). Primary outcome was a composite of death from CV causes or hospitalization for HF. More patients in the sacubitril/valsartan group had higher frequency of symptomatic hypotension compared to enalapril. Enalapril was more likely to cause cough, hyperkalemia and renal impairment (scr elevations).
The trial was discontinued early because of the reduction found in the primary composite outcome (death from CV causes or first hospitalization for worsening HF, death from CV causes and first hospitalization for worsening HF) with sacubitril/valsartan (21.8%) verses enalapril (26.5%). In patients with HF and reduced EF, sacubitril/valsartan found to be more effective than enalapril in reducing the risk of CV death and HF hospitalization. Sacubitril/valsartan slowed the progression of HF.