The extension of the Entresto label makes an additional 1.8 million IC patients eligible


Extended labeling for sacubitril / valsartan (Entresto, Novartis) to include adults with chronic heart failure (HF) with a lower than normal left ventricular ejection fraction (LVEF) could increase the treatment eligible population to 1.8 million and potentially prevent or delay up to 180,000 events of worsening of IC, according to a new analysis.

“If the barriers to pre-implementation of sacubitril / valsartan are quickly overcome, a population-level impact on worsening HF events in this high-risk population is certainly possible with a margin of safety. / efficacy favorable for most individuals, ”write Scott D. Solomon, MD, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and colleagues.

“However, the challenges based on access, cost and therapeutic inertia should not be underestimated,” they warn.

Their analysis was published online on September 15 in JAMA Cardiology. The data were presented this year at the meeting of the Association for Heart Failure of the European Society of Cardiology, the authors note.

Anticipated Impact of the expanded label

The United States Food and Drug Administration (FDA) approved sacubitril / valsartan in 2015 for the treatment of heart failure patients with a reduced ejection fraction of 40% or less based on the PARADIGM trial -HF.

Earlier this year, the FDA expanded the indication to include certain chronic heart failure patients with below normal LVEF, but did not specify a threshold to define abnormal.

The expanded indication was based on the results of the PARAGON-HF trial. Although the trial did not meet its primary endpoint, secondary subgroup analyzes showed a significant interaction between LVEF and treatment efficacy, with patients with a mean (below the median ) from 45% to 57% appearing to benefit from treatment with sacubitril / valsartan.

In their analysis, Solomon and colleagues set out to quantify the number of patients with HF newly eligible for sacubitril / valsartan treatment under the new label using data from approximately 4.7 million US adults. living with CI (mean age, 66.3; 42.6% female).

When using a broad definition of lower-than-normal LVEF of 41% to 60%, an additional 1.8 million patients could be considered for treatment with sacubitril / valsartan, with the potential to prevent 182,592 HF events. Worsening over 3 years of treatment (main outcome measure), they report.

Using the more conservative interpretation of 41% to 50% below normal LVEF would result in fewer potential new treatment candidates (643,000), with the potential to prevent 69,268 HF events which worsen over 3 years, they estimate.

They also calculate that the number of patients to be treated to avoid a worsening of a HF event over 3 years of sacubitril / valsartan treatment ranges from seven to 12 within the LVEF ranges potentially encompassed by the expanded labeling. of the FDA.

“Hope is palpable”

Weighing in on this research in an editorial, Clyde W. Yancy, MD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois, states: “The urgent need for effective therapies for [heart failure with preserved ejection fraction (HFpEF)] cannot be ruled out, and it is likely that sacubitril / valsartan is a new treatment for some patients with ICFpEF. “

“Clearly, the exploratory data analyzes from the PARAGON-HF trial are intriguing, made even more intriguing by examining the results by gender (results in women versus men: ratio rate, 0, 73; 95% confidence interval, 0.59 – 0.90; P ) “, notes Yancy.

However, several “non-trivial” questions remain, says Yancy, who is deputy editor of JAMA Cardiology.

For example, he asks, “Are the secondary data from the PARAGON-HF trial, clearly quite provocative, still subject to a statistical game of chance?” sacubitril / valsartan for symptomatic heart failure seen in the secondary analysis of the PARAGON-HF trial? Will clinicians have confidence in these expectations? “

“For now,” concludes Yancy, “a new, reasonable evidence-based therapy in ICFpF is emerging, and for patients at both the morbidity and mortality risks of ICFpEF, hope is palpable. . “

The PARAGON-HF trial was sponsored by Novartis. The Get With The Guidelines – Heart Failure program is offered by the American Heart Association and is sponsored, in part, by Novartis, Boehringer Ingelheim, Eli Lilly Diabetes Alliance, NovoNordisk, Sanofi, AstraZeneca and Bayer. Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, the National Heart, Lung, and Blood Institute, NeuroTronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur and Theracos; and the personal consulting fees of Abbott, Action Pharma, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Ironwood, Lilly, Merck , MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProthera, Moderna, American Regent and Sarepta. Several other authors have disclosed financial relationships with pharmaceutical companies. A full list of disclosures is available with the original article. Yancy did not disclose any relevant financial relationship.

JAMA Cardiol. Published online September 15, 2021. Article, Editorial.

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