Neprilysin Inhibitors, HFrEF and 2016 heart failure. Guidelines

Recently i.e. year 2016 both American and European guidelines have recommended combination of Neprilysin inhibitor with ARB i.e. LCZ696 (Sacubitril/valsartan) for treatment of heart failure with reduced ejection fraction(HFrEF)1,2. Landmark trial PARADIGM-HF was prematurely terminated due to significant decrease in primary composite endpoint  i.e. cardio- vascular death or Heart Failure  hospitalization in LCZ696 group compared to enalapril group by 20% (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.73 to 0.87; p value  0.0000004),  in individuals with heart failure with ejection fraction less the 40%. Hypotension was more frequently associated with LCZ696, elevations in serum creatinine and potassium and cough was less noted in LCZ696 as compared to enalapril 3.

American Guidelines.

2016 ACC/AHA/HFSA guidelines recommends, angiotensin receptor Neprilysin inhibitor (ARNI) as class one with level of evidence B randomized. It states so as below2.
1.ARNI in conjunction with evidence-based beta blockers, and aldosterone antagonists in selected patients is recommended for patients with chronic HFrEF to reduce morbidity and mortality.
2.In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality.
Following Class III recommendation (not advised) for ARNI
1.ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor4,5.
2.ARNI should not be administered to patients with a history of angioedema4.

European Guidelines.

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure1. See Figure 1, flow chart for drug treatment for HFrEF (less than 40% EF)
Figure 1 Flow chart for HFrEF as ESC 2016 heart failure Guidelines1
LCZ696 is recommended as a replacement for an Angiotensin converting enzyme inhibitors to further reduce the risk of Heart Failure hospitalization and death in ambulatory patients with HFrEF, who remain symptomatic despite optimal treatment with an Angiotensin converting enzyme inhibitors, a beta-blocker and mineralocorticoid antagonist this is class one B recommendation.
In another trial, heart failure with preserved ejection fraction decrease in NT-proBNP was seen when LCZ696 was compared with valsartan6.

Alzheimer’s disease. 

From animals studies, Neprilysin inhibitors have been considered to be associated with Alzheimer’s disease.  But, short term studies of LCZ696 for 14 days showed, no increase is in aggregable Aβ isoforms (1-42 and 1-40) in CSF. There was increase in Aβ isoforms1-38, clinical relevance of soluble is not known7. Long term studies are needed to prove safety from Alzheimer ’s disease.


1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Filippatos G, McMurray JJ V, Aboyans V, Achenbach S, Agewall S, Al-Attar N, et al., editors. Eur Heart J [Internet]. 2016; Available from:
2. Jessup M, Bozkurt B, Butler J, Casey DE, Masoudi FA, Colvin MM, et al. 2016 ACC / AHA / HFSA Focused 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 o. 2016;(April).
3. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med [Internet]. 2014;371(11):140830040023009. Available from:
4. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004 Feb;17(2):103–11.
5. Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau J-L, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002 Aug;106(8):920–6.
6. Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC Hear Fail. 2014;2(6):663–70.
7. Langenickel TH, Tsubouchi C, Ayalasomayajula S, Pal P, Valentin M-A, Hinder M, et al. The effect of LCZ696 (sacubitril/valsartan) on amyloid-beta concentrations in cerebrospinal fluid in healthy subjects. Br J Clin Pharmacol. 2016 May;81(5):878–90.

Author: Dr Umesh Bilagi

MBBS, MD, DM (cardiology). I am Interventional cardiologist. Blogging is my passion. Associate professor of cardiology KIMS Hubli. Director and consultant at Tatwadarsha Hospital Hubli. Owner of Jeevan Jyoti Hospital Hubli. Mobile +91 9343403620.

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