New combo therapy for chronic heart failure


Entresto® is a newly approved combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker (ARB) for patients who have chronic heart failure NYHA Class II-IV and reduced ejection fraction.

Entresto® is a newly approved combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker (ARB) for patients who have chronic heart failure NYHA Class II-IV and reduced ejection fraction.

Sacubitril exerts its effect by inhibiting the metabolism of natriuretic peptides, thereby subsequently augmenting excretion of sodium in the urine. Valsartan selectively blocks angiotension II receptors which reduces angiotensin-mediated aldosterone release and decreases vasoconstriction caused by dysregulation of the renin-angiotensin aldosterone system.1

The American College of Cardiology, the American Heart Association and the Heart Failure Society of America published a consensus statement of the newest pharmacological recommendations in the management of heart failure based on the latest literature.2

This update includes recommendations for the angiotensin receptorneprilysin inhibitor (ARNI) in NYHA class II-IV heart failure with reduced ejection fraction. When ARNI therapy is combined with a recommended beta-blocker and aldosterone antagonist, the risk of morbidity and mortality is reduced.

This is a class I-BR recommendation, a strong recommendation based on moderate quality of evidence from a randomized controlled trial. The PARADIGM- HF study was an RCT involving over 8,000 patients given either the ARNI or enalapril. The primary endpoint was a composite of cardiovascular-related deaths or first hospitalization.

There was a 20% decrease in CV-related deaths (HR: 0.80 [95% CI: 0.71–0.89; p<0.001]) and a 21% decrease in first hospitalizations for heart failure (HR: 0.79 [(95% CI: 0.71– 0.89; p<0.001]), although there was an increase in the incidence of hypotension in the ARNI group (14% vs. 9.2%; p<0.001).

Treatment-naïve patients, or those on a low dose ACE inhibitor or ARB therapy should be started on the sacubitril 24 mg/valsartan 26 mg strength, twice daily. The 49mg/51mg twice daily dose can be initiated in those switching from greater than 10 mg of enalapril or 160 mg or more of valsartan daily.


The target dose should be 97mg/103mg as long as the patient can tolerate therapy without substantial side effects. A 36-hour washout period is warranted when switching to sacubitril/ valsartan from an ACE inhibitor.

Of note, the valsartan component in Entresto® is more bioavailable than that of the single tablet formulations currently marketed; therefore, the valsartan dose differs from the traditional formulation in the Entresto® combination.

Use the lower strength formulation when starting therapy in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or moderate hepatic impairment (Child Pugh B). Doses may be doubled every 2 to 4 weeks as tolerated up to sacubitril 97 mg/valsartan 103 mg twice daily. Use is not recommended in severe hepatic impairment.

Side effects of sacubitril/valsartan may include: hypotension, increase in serum creatinine; anemia, cough, and hyperkalemia. Most of these can be attributed to the ARB in the combination.

Contraindications to starting Entresto® are concomitant ACE inhibitor use, prior angioedemia from an ACE inhibitor or ARB, and concomitant use of the antihypertensive agent aliskiren in diabetic patients. Notable drug interactions may occur with potassium sparing diuretics, lithium, and NSAIDs.

Germin Fahim, Pharm.D., BCPS is Clinical Assistant Professor at Ernest Mario School of Pharmacy at Rutgers University, and Clinical Pharmacist at Monmouth Medical Center in Long Branch, New Jersey.

Joseph E. Cruz, Pharm.D., BCPS is Clinical Assistant Professor at Rutgers University, and The State University of New Jersey Clinical Coordinator - Internal Medicine Englewood Hospital and Medical Center.


1. Entresto [product information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015

2. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Focused Update update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2016;68(13):1476-1488.

3. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993.

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