Angiotensin-Neprilysin Inhibition as the First-Line Therapy for HF over ACE inhibitors?

Trial Reference
Velazquez EJ, Morrow DA, DeVore AD, et al; PIONEER-HF Investigators. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380(6):539-548. doi:10.1056/ NEJMoa1812851
Expert Comment
Koji Hasegawa
Kyoto Medical Center, Japan


Angiotensin receptor/neprilysin inhibitor (ARNI) is a molecular complex of the angiotensin receptor blocker (ARB) valsartan and the neprilysin (NEP) inhibitor sacubitril. In the PIONEER-HF trial,1 patients hospitalised for acute heart failure or acute worsening of chronic heart failure due to heart failure with reduced ejection fraction (HFrEF) were randomised to two study arms: starting ARNI before discharge and starting angiotensin-converting enzyme (ACE) inhibitor enalapril. Changes in NT-proBNP at week 4 and 8 of medication were compared between the two arms. This trial revealed that NT-pro-BNP decrease in the ARNI arm was greater than that in the ACE inhibitor arm. Moreover, the sub-analysis revealed a significantly lower rate of readmission within 8 weeks for the ARNI arm. Considering these findings, Gaziano TA compared the cost-effectiveness of ARNI and enalapril initiated before discharge and found that ARNI was more cost-effective than the ACE inhibitor because of prevention of readmission with the former.2

Conclusions and Perspectives

Chronic heart failure patients have a diminished quality of life and significant impairments in their daily life. They also have a high incidence of sudden death due to frequently occurring fatal arrhythmias. In the US, one million patients with acute heart failure are admitted annually, with high rates of readmission (21%) and mortality. The progression of chronic heart failure is marked by repeated acute exacerbation. The disease places great physical and economic burden on heart failure patients and their caregivers. This increased burden is a social problem in various countries worldwide because of their ageing populations.

ACE inhibitors that inhibit neurohumoral factors, as well as ARBs, beta-blockers and mineralocorticoid receptor antagonists have been used as pharmacological therapies for HFrEF. In the PARADIGM-HF trial3 in NYHA class II-IV HFrEF patients with left ventricular ejection fraction ≤40%, ARNI reduced cardiovascular mortality and admission for heart failure more effectively than enalapril, an ACE inhibitor used as a first-line treatment for heart failure. Moreover, ARNI was reportedly more cost-effective than ACE inhibitors in a study conducted on older adults with chronic heart failure. The present study also demonstrated that administering ARNI early on before discharge to patients hospitalised for acute heart failure increased cost-effectiveness by preventing readmissions.2 Heart failure guidelines list ACE inhibitors, ARBs and ARNI as first-line therapies; however, the above findings might influence experts’ opinions toward selecting ARNI as the first-line therapy for heart failure over ACE inhibitors or ARBs.


  1. Velazquez EJ, Morrow DA, DeVore AD, et al; PIONEER-HF Investigators. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl Med. 2019;380(6):539-548. doi:10.1056/ NEJMoa1812851
  2. Gaziano TA, Fonarow GC, Velazquez EJ, et al; Cost-effectiveness of Sacubitril-Valsartan in Hospitalized Patients Who Have Heart Failure With Reduced Ejection Fraction. JAMA Cardiol. 2020 Nov 1;5(11):1236-1244. doi: 10.1001/jamacardio.2020.2822.
  3. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. doi:10.1056/NEJMoa1409077