First in Class ARNI, Valsartan/Sacubitril as a New Treatment of Chronic HFrEF

Sang Hong Baek MD, PhD, FACC, ESC
Professor of Medicine (Cardiology), Seoul St. Mary’s Hospital, The Catholic University of Korea



The first approved ARNI (angiotensin receptor-nephrilysin inhibitor), valsartan/sacubitril, is a combination drug for use in chronic symptomatic heart failure reduced ejection fraction (HFrEF) NYHA class II or IV who tolerate an ACE inhibitor or ARB. In ARNI, an ARB is combined with an neprilysin inhibitor, an enzyme that degrades natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides, in a 1:1 mixture by molecule count.

The >8000-person PARADIGM-HF randomized clinical trial showed that patients with chronic HF treated with ARNI had a 20% decrease in CV death or HF hospitalizations vs those treated with the ACE inhibitor enalapril, as well as a significant reduction in all-cause mortality.

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved this drug for a broad indication: that is, for patients with symptomatic chronic HF and reduced EF (NYHA class II–IV and left ventricular EF ≤40 %) to fill an unmet medical need.

The ACC, AHA, and HFSA issued a Class I, Level B-R recommendation and the ESC issued a Class I, Level B recommendation for valsartan/sacubitril, as an alternative to ACE inhibitors to reduce morbidity and mortality in patients with chronic HFrEF who remain symptomatic despite optimal treatment with an ACE inhibitor, an evidence-based beta-blocker and a mineralocorticoid receptor antagonist. Replacement by an ARNI is recommended to further reduce morbidity and mortality. However, we need more data to generalize this drug in daily clinical practice. At present, the first line therapy for HF in guidelines is the use of ACE inhibitors. Whether ANRI will improve survival in asymptomatic patients with chronic HF should be investigated.

In safety concerns, combined treatment with an ACEI (or ARB) and sacubitril/valsartan is contraindicated. The use of ARNI is associated with the risk of hypotension and renal insufficiency and may lead to angioedema, as well.


ARNI is an option for those patients who continue having HF symptoms despite optimal medical treatment. More evidence is required to generally use ARNI in daily clinical practice.



  1. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med. 2014; 371:993-1004.
  2. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2017 Aug 8;70(6):776-803.
  3. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016 Jul 14;37(27):2129-2200.