FDA Expands Label for Sacubitril/Valsartan (Entresto) to Include Some HFpEF Patients

In a historic move, the US Food and Drug Administration (FDA) has expanded the indication of sacubitril/valsartan (Entresto) to include reducing the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure—making sacubitril/valsartan the first and only therapy approved to treat heart failure patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF), according to a statement from Novartis.

The approval comes just two months after a 12-to-1 vote by the FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) in favor of a new indication for sacubitril/valsartan based on the results of the PARAGON-HF, PARAMOUNT, and PARADIGM-HF trials.

“This approval is a significant advancement, providing a treatment to many patients who were not eligible for treatment before because their ejection fraction was above the region we normally considered reduced. Until now, treatment for these patients was largely empiric,” said Scott Solomon, MD, Professor of Medicine at Harvard Medical School and Brigham and Women's Hospital, and PARAGON-HF Executive Committee Co-Chair, in the aforementioned statement. “We can now offer a treatment to a wider range of patients who have an LVEF below normal.”

With previous approvals for the treatment of patients with HFrEF dating back to 2014, the label expansion means sacubitril/valsartan has the potential to be included in treatment algorithms for approximately 5 million patients. According to the aforementioned statement from Novartis, the label expansion was based on efficacy and safety evidence from within the PARAGON-HF trial.

A phase 3 trial enrolling 4822 patients with an ejection fraction of 45% or greater, PARAGON-HF compared sacubitril/valsartan (97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (160 mg twice daily). Despite not meeting its primary endpoint, results of the trial indicate the angiotensin receptor-neprilysin inhibitor (ARNI) fell just short of proving statistical significance for reducing heart failure hospitalizations and death in HFpEF patients with a P-value of .06.

“We are proud of our goal to reimagine medicine. This commitment has enabled us to bring Entresto to millions more heart failure patients in the US, many of whom did not have an approved treatment option until now,” said Marie-France Tschudin, President, Novartis Pharmaceuticals. “This achievement would not have been possible without tremendous dedication from investigators, patients in our clinical trials, and the advocacy community, to whom we are extremely grateful.”

For further insight into the use of sacubitril/valsartan for treating patients with HFpEF, check out this video from PARALLAX lead investigator Burkert Pieske, MD, professor of medicine and director of cardiology at Charite University Medicine, from ESC 2020.