Drug Class: Angiotensin-receptor neprilysin inhibitor
Mechanism of Action:
Sacubitril (neprilysin inhibitor)
neprilysin is a neutral endopeptidase that degrades vasoactive & natriuretic peptides, bradykinin & adrenomedullin.
the active metabolite of sacubitril increases the levels of these peptides, which decreases vasoconstriction, sodium retention & maladaptive remodeling
Valsartan (Ang II receptor blocker)
inhibits the effects of Ang II & the release of aldosterone
Indications:
Treatment of Heart Failure (HF) with reduced Ejection Fraction (HFrEF)
Approval is based upon the results of the PARADIGM-HF trial (the largest clinical trial ever conducted in heart failure)
In September 2016 the ACC, AHA & HFSA gave this drug their strongest level of evidence-based recommendation:
For chronic HFrEF patients to reduce morbidity and mortality, Sacubitril/Valsartan (Entresto ®) is a guideline-recommended standard therapy as an alternative to angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB), together with a beta blocker and an aldosterone antagonist.
To further reduce morbidity and mortality, the guideline specifically advises doctors to switch chronic HFrEF patients with mild to moderate symptoms (NYHA Class II-III) who are otherwise tolerating an ACE or ARB to Sacubitril/Valsartan (Entresto ®) .
In patients with class II-IV HF & reduced EF (Med Lett Drugs Ther, 2015), compared to valsartan therapy, the drug combination produced a significantly greater:
reduction of first hospitalization rates for worsening of HF.
reduced incidence of death from CV causes.
slowed the progression of HF.
Contraindications:
Pregnancy (ARBs can reduce fetal renal function & cause neonatal morbidity/death)
Pharmacokinetics:
taken orally, twice daily
Side Effects:
Hypotension (14%)
Hyperkalemia
Renal impairment/failure
Inhibiting the RAAS system can result in a decrease in renal function
5% renal failure in the PARADIGM-HF trial
16% of both patients on either sacubitril+valsartan or enalapril alone had an increase in serum creatinine of > 50% in the PARADIGM-HF trail
Cough (11.3%)
Angioedema (0.5%)
Drug interactions:
ACE inhibitors: Concurrent use with Entresto increases the risk of serious angioedema, which occurs more often in black patients.
K-sparing diuretics or K-supplements: can result in hyperkalemia (esp in patients with renal impairment, diabetes or hypoaldosteronism)
NSAIDs: worsening of renal failure
Li: lithium toxicity has occurred when taken with an ARB.
References:
Colucci WS, Pfeffer, MA (2015): Use of angiotensin II receptor blocker and neprilysin inhibitor in heart failure with reduced ejection fraction. In: In: UpToDate, Basow, DS (Ed), Waltham, MA. Cited 9/11/15
The Medical Letter on Drugs and Therapeutics (2015): Sacubitril/Valsartan (Entresto) for Heart Failure. 57 (1474):107-109.
