ARNI reduces outcomes irrespective of HF history or ACEi/ARB use in HFrEF after ADHF
Angiotensin Receptor-Neprilysin Inhibition Based on History of Heart Failure and Use of Renin-Angiotensin System Antagonists
Introduction and methods
Based on the results of the PARADIGM-HF trial, several societies recommend that an ACE inhibitor or ARB should be replaced by sacubitril/valsartan in stable HFrEF patients, with a class I recommendation [1-3]. Patients in PARADGIM-HF were ambulatory patients with chronic HFrEF, and patients with de novo HF or patients who were naïve or previously on a low dose of ACEi or ARB were excluded. The PIONEER-HF trial investigated the safety and the potential role of sacubitril/valsartan vs. enalapril in stabilized HFrEF patients after acute decompensated HF (ADHF) [4-6]. Results of the PIONEER-HF trial demonstrated that in-hospital initiation of sacubitril/valsartan vs. enalapril was safe, well tolerated, reduced NT-proBNP and lowered CV death or rehospitalization for HF.
This subanalysis of the PIONEER-HF trial examined the efficacy and safety of sacubitril/valsartan in subgroups of patients with de novo HF compared to those with worsening chronic HF; and in patients who had received an ACE inhibitor or ARB during admission compared to those who were not treated with an ACEi or ARB.
The PIONEER-HF trial was a prospective, multicenter, double-blind, randomized clinical trial in HFrEF patients stabilized following admission for ADHF. Patients with EF ≤40% and NT-proBNP ≥1600 pg/mL or BNP ≥400 pg/mL were eligible to participate, between 24 h and 10 days from initial presentation while still in the hospital. Patients were randomized in 1:1 ratio to in-hospital initiation of sacubitril/valsartan or enalapril for 8 weeks. Primary endpoint of the trial was time-averaged proportional change in NT-proBNP from baseline to week 4 and 8. This subanalysis included all 881 patients (879 patients for the subanalysis of prior HF status): 303 patients (34%) had de novo HF and 576 chronic HF (66%); 422 patients (48%) were treated with ACEi/ARB and 459 (52%) were not treated with ACEi/ARB. Of the 576 chronic HF patients, 358 were receiving an ACEi or ARB and 218 were not receiving an ACEi or ARB.
- Patients who received sacubitril/valsartan had a significantly greater decrease in NT-proBNP compared to those who received enalapril, evident at week 1 till week 8 in patients with de novo HF and worsening chronic HF (Pinteraction=non-significant).
- In patients with worsening chronic HF, there was no difference in treatment effect by sacubitril/valsartan in those who had received an ACEi/ARB compared to those who had not received an ACEi or ARB (Pinteraction=non-significant). Similar findings were observed when all patients were included (de novo HF and worsening HF).
- Patients assigned to sacubitril/valsartan had a significantly lower incidence of the composite of CV death or rehospitalization for HF in patients with de novo HF and with worsening chronic HF (Pinteraction=non-significant).
- In patients with worsening HF, sacubitril/valsartan significantly lowered the composite of CV death or rehospitalization for HF compared to enalapril in those on ACEi/ARB, but not in those who did not receive ACEi/ARB. Outcomes were numerically lower though with sacubitril/valsartan vs. enalapril irrespective of ACEi/ARB treatment status. Findings were directionally similar when both patients groups (de novo and worsening chronic HF) were included.
- Incidence of adverse events, including worsening renal function, hyperkalemia, symptomatic hypotension, angioedema were similar with sacubitril/valsartan vs. enalapril in all 4 subgroups (Pinteraction=non-significant).
In patients admitted for ADHF, treatment effect on NT-proBNP and clinical outcomes of sacubitril/valsartan vs. enalapril was similar in subgroups of de novo HF patients and those with worsening chronic HF; and in those who received ACEi/ARB and those who did not receive ACEi/ARB. In addition, in these subgroups of patients sacubitril/valsartan was safe and well tolerated.