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ARNI initiation during hospitalization in real-world HFrEF patients is safe
Literature - López-Azor JC, Vicent L, Valero-Masa MJ et al., - ESC Heart Fail. 2019. doi: 10.1002/ehf2.12527.

Introduction and methods

Compared to enalapril treatment, sacubitril/valsartan treatment for HF with reduced ejection fraction (HFrEF) more effectively reduces CV mortality and hospital admission when started in a stable phase in outpatients [1]. In addition, sacubitril/valsartan treatment has been shown to be safe when initiated during admission, predicting its extended use in inpatients [2, 3]. However, generalizability of these findings is limited because patients included in clinical trials often do not represent real-life patients.

The present study compares the clinical profile of a non-selected cohort of inpatients who initiated sacubitril/valsartan treatment during admission (n=100), with the clinical profile of patients included in the PIONEER-HF trial (n=440) (Comparison of Sacubitril-Valsartan versus Enalapril on Effect on N-terminal pro-B type natriuretic peptide in Patients Stabilized from an Acute Heart Failure Episode) [2]. Also, the safety and tolerance of sacubitril/valsartan treatment is compared between the inpatient cohort (n=100) and an outpatient cohort (n=427). A register with prospective follow-up was performed, enrolling patients from 17 Spanish hospitals with indication of initiated treatment based on HFrEF, Functional Class ≥ II, and systolic blood pressure ≥ 100 mmHg and with serum potassium ≤ 5.4 mmol/L. Follow-up outcome measures included functional class, left ventricular ejection fraction, treatment changes and titration, de-escalation or removal of sacubitril/valsartan, potential adverse effects attributed to sacubitril/valsartan (symptomatic hypotension, renal failure, hyperkalaemia, and angioedema), unexpected hospital admissions, and all-cause death.

Main results

  • Compared to patients in the PIONEER-HF trial, overall inpatients had a higher risk profile. They were older (inpatients, 71±12 vs. trial patients, 61±14 years; P<0.001), had more frequently Functional Class II (inpatients [41.0%] vs. trial patients [22.7%]; P <0.001) although less frequently Functional Class III (inpatients [45.0%] vs. trial patients [64.3%]; P <0.001), higher levels of N-terminal pro-B type natriuretic peptide (inpatients, 4044 [1630–8680] vs. trial patients, 2883 [1610–5403] ng/mL; P <0.001), and received angiotensin-converting enzyme inhibitors/angiotensin receptor blockers more frequently (inpatients [92.0%] vs. trial patients [47.3%]; P <0.001).
  • Compared to non-selected outpatients, inpatients had a higher risk profile. They were older (inpatients, 71±12 vs. outpatients, 68±12 years; P=0.02), had more frequent Functional Class III (inpatients [45.0%] vs. outpatients [27.0%]; P<0.001) and Functional Class IV (inpatients [13.0%] vs. outpatients [3.3%]; P <0.001), had higher levels of N-terminal pro-B type natriuretic peptide (inpatients, 4044 [1630–8680] vs. outpatients, 2013 (1002–4132) ng/mL; P <0.001), were receiving angiotensin-converting enzyme inhibitors/angiotensin receptor blockers target dose less frequently (inpatients [55.0%] vs. outpatients [78.5%]; P <0.001), and started sacubitril/valsartan with a low dose (50 mg/12h) more frequently (inpatients [80.0%] vs. outpatients [48.8%]; P <0.001).
  • In addition, the initiation of sacubitril/valsartan in outpatients was an independent predictor of high-dose use, 100 or 200 mg b.i.d. (OR 3.1; 95% CI, 1.7–5.6; P <0.001).
  • The follow-up time in the inpatient and outpatient cohorts, including all patients enrolled, was similar (inpatients, 7.0 ± 0.1 vs. outpatients, 7.2 ± 2.6 months; P=0.72). All-cause admissions during follow-up were more frequent in inpatients (inpatients [28.9%] vs. outpatients [11.4%]; P=0.001), with no relevant differences in all-cause mortality or CV death. There was no significant difference in sacubitril/valsartan withdrawal rate (inpatients [17.0%] vs. outpatients [11.5%]; P=0.13). The incidence of adverse effects was also similar: hypotension (inpatients [16.0%] vs. outpatients [16.7%]; P=0.88), worsening renal function (inpatients [7.0%] vs. outpatients [6.8%]; P=0.94), and hyperkalaemia (inpatients [1.0%] vs. outpatients [4.9%]; P=0.09).


Sacubitril/valsartan treatment initiation in hospitalized HFrEF patients in daily clinical practice is safe. Inpatients more frequently receive low starting doses of sacubitril/valsartan as compared to outpatients.


1. Mc Murray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371: 993–1004.

2. Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E. Angiotensinneprilysin inhibition in acute decompensated heart failure. N Engl J Med 2019; 380: 539–548.

3. Wachter R, Senni M, Belohlavek J, Butylin D, Noe A, Pascual-Figal D. TRANSITION study Investigators. Initiation of sacubitril/valsartan in hospitalized patients with heart failure with reduced ejection fraction after hemodynamic stabilization: primary results of the TRANSITION study. Eur Heart J 2018; 39: 1.

Find this article online at ESC Heart Failure

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