Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure

Abstract

IMPORTANCE In PIONEER-HF, among stabilized patients with acute decompensated heart failure (ADHF), the in-hospital initiation of sacubitril/valsartan was well tolerated and led to improved outcomes compared with enalapril. However, there are limited data comparing the strategies of in-hospital vs postdischarge initiation of sacubitril/valsartan. OBJECTIVE To describe changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients recently hospitalized for ADHF and switching from taking enalapril to taking sacubitril/valsartan after discharge and compare clinical outcomes for patients randomized to receive in-hospital initiation of sacubitril/valsartan vs in-hospital initiation of enalapril who later switched to taking sacubitril/valsartan during an open-label extension phase. INTERVENTIONS Sacubitril/valsartan titrated to 97/103 mg twice daily. DESIGN, SETTING, AND PARTICIPANTS The PIONEER-HF trial was a multicenter, randomized, double-blind, active-controlled trial conducted at 129 US sites between May 2016 an May 2018 that compared the in-hospital initiation of sacubitril/valsartan vs enalapril (titrated to target dose, 10 mg twice daily) for 8 weeks among patients admitted for ADHF with reduced ejection fraction and hemodynamic stability. All patients were to continue in a 4-week, open-label study of sacubitril/valsartan; of 881 patients enrolled in PIONEER-HF, 832 (94%) continued in the open-label study. MAIN OUTCOMES AND MEASURES Changes in NT-proBNP levels from week 8 to 12 as well as the exploratory composite of heart failure rehospitalization or cardiovascular death from randomization through week 12. RESULTS Of 881 participants, 226 (27.7%) were women, 487 (58.5%) were white, 297 (35.7%) were black, 15 (1.8%) were Asian, and 73 (8.8%) were of Hispanic ethnicity; the mean (SD) age was 61 (14) years. For patients who continued to take sacubitril/valsartan, NT-proBNP levels declined −17.2% (95% CI, −3.2 to −29.1) from week 8 to 12. The NT-proBNP levels declined to a greater extent for those switching from taking enalapril to sacubitril/valsartan after the week 8 visit (−37.4%; 95% CI, −28.1 to −45.6; P < .001; comparing changes in 2 groups). Over the entire 12 weeks of follow-up, patients that began taking sacubitril/valsartan in the hospital had a lower hazard for the composite outcome compared with patients that initiated enalapril in the hospital and then had a delayed initiation of sacubitril/valsartan 8 weeks later (hazard ratio, 0.69; 95% CI 0.49-0.97). CONCLUSIONS AND RELEVANCE Switching patients' treatment from enalapril to sacubitril/valsartan at 8 weeks after randomization led to a further 37% reduction in NT-proBNP levels in patients with heart failure with reduced ejection fraction and a recent hospitalization for ADHF. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02554890.

Salivary Oxidative Stress Increases with the Progression of Chronic Heart Failure

“…Similarly, in human studies, the oxidative stress caused by chronic vascular disease (CVD) versus HFrEF cannot be differentiated. HF is more common in men [69][70][71]; however, the unequal gender distribution in our study may be due that women reach a similar HF risk as men only after the menopause [3]. In addition, we evaluated only the selected oxidative stress biomarkers, which is also a limitation of the study.…”

Long-Term Effects of Angiotensin Receptor–Neprilysin Inhibitors on Myocardial Function in Chronic Heart Failure Patients with Reduced Ejection Fraction

“…Importantly, the beneficial effects of these medical therapies were repeatedly associated with their potential to promote myocardial reverse remodeling manifested mainly by the reduction of left ventricular size and improvement of its function [ 18 ]. While paradigm-HF and pioneer-HF data clearly demonstrated superior clinical efficacy of ARNI therapy compared to ACEI in terms of reduced heart failure-associated hospital admissions, cardiovascular and all-cause mortality, until recently the association between these clinical effects and reverse remodeling of the failing myocardium remained unexplored [ 1 , 2 ]. Basing largely on the small patient cohorts and short-term follow-up recently published data support the association between ARNI and left ventricular reverse remodeling as these studies consistently showed an improvement in left ventricular ejection fraction (ΔLVEF +4–5%) and a decrease in left ventricular size (ΔLVEDD—6% or ΔLVEDV—8–10%) after three months of ARNI therapy [ 7 , 8 , 9 ].…”

“…The study demonstrated that in HFrEF patient treatment with ARNI, compared to angiotensin converting enzyme inhibitor (ACEI) enalapril, resulted in significant benefits considering heart failure hospitalizations and cardiovascular (CV) and all-cause mortality [ 1 ]. Subsequent transition and pioneer-HF trials further demonstrated comparable safety and superior efficacy of ARNI over ACEI also in HFrEF patients with more advanced stages of the disease, largely establishing ARNI as an evolving first-line treatment approach in this patient population [ 2 , 3 ]. However, despite these encouraging findings, the underlying mechanisms still remain incompletely understood.…”

Angiotensin receptor-neprilysin inhibitor for the treatment of heart failure: a review of recent evidence

“…DeVore et al [32] investigated this open-label extension treatment of sacubitril/valsartan and found similar levels of NT-proBNP between the enalapril and sacubitril/ valsartan groups after 4 weeks of ARNI treatment. However, the difference in the risk of cardiovascular death or rehospitalization for HF between the groups remained at 12 weeks following randomization (HR, 0.69; 95% CI, 0.49 to 0.97; p = 0.032) [32]. In another sub-study of the PIONEER-HF trial, soluble ST2 and high-sensitivity cardiac troponin T, which are considered surrogate markers of myocardial stress and injury, were significantly reduced in the sacubitril/valsartan group at the 1-and 4-week follow-up timepoints.…”

“…All participants in the PIONEER-HF trial completed 4 weeks of sacubitril/valsartan treatment following the 8-week study duration per protocol [31]. DeVore et al [32] investigated this open-label extension treatment of sacubitril/valsartan and found similar levels of NT-proBNP between the enalapril and sacubitril/ valsartan groups after 4 weeks of ARNI treatment. However, the difference in the risk of cardiovascular death or rehospitalization for HF between the groups remained at 12 weeks following randomization (HR, 0.69; 95% CI, 0.49 to 0.97; p = 0.032) [32].…”