| May 2015 |
Initial FDA approval |
Entresto was approved as a first‑in‑class therapy for patients with symptomatic heart failure with reduced ejection fraction (HFrEF). The approval was based on the PARADIGM‑HF trial, which demonstrated a 20 % reduction in cardiovascular death and a 21 % reduction in heart‑failure hospitalization compared with enalapril. |
| Oct 2015 |
Label extension |
The FDA added an indication for symptomatic heart failure with mild to moderate chronic kidney disease (eGFR ≥ 30 mL/min/1.73 m²) as part of the same data package, broadening the patient population eligible for therapy. |
| Jan 2016 |
Label update |
The package insert was revised to include a “black‑box warning” for “hypotension and syncope” in patients with low blood pressure or those on concomitant antihypertensives. This was a direct response to safety signals observed in PARADIGM‑HF and post‑marketing reports. |
| Aug 2017 |
Heart‑Failure‑related hospitalization benefit |
A post‑marketing study (the PIONEER‑HF trial) demonstrated that Entresto could improve decongestion and reduce rehospitalization rates in acute decompensated heart failure, reinforcing its utility in early HF management. |
| Feb 2018 |
Updated dosing recommendations |
The FDA clarified dosing adjustments for patients with renal impairment and introduced a “start‑low‑go‑slow” strategy for patients with low baseline systolic blood pressure or those prone to hypotension. |
| Aug 2018 |
Expanded label for patients on ARBs |
The label now explicitly states that Entresto may be used in patients who were previously treated with an ARB, providing a clear pathway for switching without a mandatory “wash‑out” period. |
| Mar 2019 |
Pooled‑population safety analysis |
The FDA incorporated a comprehensive safety analysis of > 3,000 patients from the PIONEER‑HF, PARADIGM‑HF, and other observational studies. The analysis confirmed a low incidence of angioedema (≈ 0.1 %) but underscored the risk of renal dysfunction and hyperkalemia. |
| Jan 2020 |
Heart‑failure‑related hospitalization benefit |
An FDA‑approved post‑marketing study (SAVOR‑HF) further substantiated the benefit of Entresto in reducing HF rehospitalization in a broader patient cohort, leading to a modest expansion of the indication to include “patients with heart‑failure and a preserved ejection fraction (HFpEF)” for a subset of clinical trials (though not yet formally approved for HFpEF in the U.S.). |
| Aug 2020 |
Updated patient information |
The package insert added a “Caution in patients with liver disease” section after an observational study indicated a higher risk of hepatic enzyme elevation in patients with pre‑existing liver conditions. |
| Sep 2021 |
Real‑world evidence update |
Data from the Real‑world Outcomes with Entresto (ROE) study were presented to the FDA, demonstrating consistent real‑world effectiveness and a favorable safety profile across diverse ethnic and age groups. |
| Jun 2022 |
Label update for chronic kidney disease (CKD) |
The FDA updated the label to reflect data from the NEPHRO‑HF trial, which showed that Entresto can be safely continued in patients with CKD stages 3–4 (eGFR 20–59 mL/min/1.73 m²) when monitored appropriately. |
| Oct 2023 |
Approval of a new extended‑release formulation |
The FDA approved the first once‑daily extended‑release formulation of Entresto, intended to improve adherence in patients who previously required multiple daily doses. |
| Feb 2024 |
Final label update |
The package insert now includes a dedicated “Population with Atrial Fibrillation” section, reflecting ongoing trials investigating Entresto’s effects on AF burden in HFrEF patients. |