FDA Advisory Panel Recommends Expanded Use of HF Drug

December 18, 2020
Grace Halsey

An FDA panel voted to recommend the expanded use of sacubitril/valsartan for patients with heart failure with preserved ejection fraction.

An FDA panel voted early this week to recommend expanding the use of sacubitril/valsartan (Entresto; Novartis) to patients with heart failure with preserved ejection fraction (HFpEF), according to a press release from the company. The Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted 12 to 1 that the data presented by the company support its recommendation.

Currently there are no therapies approved for patients with HFpEF to prevent HF hospitalization, emergency department or urgent care visits. The fixed combination of a neprilysin inhibitor (sacubitril) and an angiotensin receptor blocker (valsartan) was approved in 2015 by the FDA for patients with NYHA class II through IV heart failure, to reduce risk of cardiovascular (CV) death and hospitalization. The treatment subsequently was granted a label expansion to include patients with HF with reduced ejection fraction (HFrEF) and those aged ≥1 year with symptomatic HF with systemic left ventricular systolic dysfunction.

The CRDAC recommendation was based on combined safety and efficacy analyses from 3 studies of sacubitril/valsartan in HF patients: a pre-specified subgroup analysis of the PARAGON-HF phase 3 study in patients with HFpEF, the PARAMOUNT phase II trial, also in patients with HFpEF, and from the phase III PARADIGM-HF trial in patients with HFrEF.

The PARAGON-HF trial missed its primary endpoint of reducing total hospitalization and CV death in patients with HFpEF, but the data did suggest benefit in some patients within HFpEF population. Although FDA approval in such a case is unusual, the CDRAC notes in its briefing document that it is not unprecedented.

Findings from PARAGON-HF suggested benefit in patients with ejection fraction toward the lower end of the range studied, or closer to the range for patients with HFrEF, according to the CDRAC meeting notes.

In PARAGON-HF, a total of 4822 patients were randomly assigned to sacubitril/valsartan or valsartan. Patients in the study were required to have signs and symptoms of HF, a left ventricular ejection fraction (LEVF) of 45% or greater, evidence of natriuretic peptide elevation, and structural heart disease. The median follow-up was 34 months.

The rate ratio for the primary end point was 0.87 (95% confidence interval [CI] 0.75-1.01; p=0.059), which was just short of statistical significance and driven by a decline in HF hospitalization with no effect on CV death or all-cause mortality. However, the results indicated greater benefit in patients with ejection fraction below the median of 57%, with a 22% reduction (rate ratio 0.78; 95% CI 0.64-0.95) and in women, with a 28% reduction (rate ratio 0.73; 95% CI 0.59-0.90) in the primary end point.

“The prevalence of HF with LVEF ≥45% is increasing in the US, with increasing life expectancy, and epidemics of metabolic syndrome and [diabetes mellitus],” the CDRAC briefing document states. “The overall benefit-risk considerations may support approval of sacubitril/valsartan to treat patients with HF with LVEF ≥45%.”

“Managing HFpEF has historically been a clinical and scientific challenge due to the heterogeneity of the condition,” 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 Novartis press release. “Today’s vote represents much needed progress in this area of unmet need and is a positive step toward bringing a potential therapy to millions of patients suffering from this type of heart failure.”

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