Expanded Entresto Label Makes 1.8 Million More HF Patients Eligible

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

“If prior implementation barriers to sacubitril/valsartan are swiftly overcome, population-level impact on worsening HF events in this high-risk population is certainly possible with a favorable safety/efficacy margin 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, challenges based on access, cost, and therapeutic inertia should not be underestimated,” they caution.

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

Anticipated Impact of the Expanded Label

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

Earlier this year, the FDA expanded the indication to include some patients with chronic HF with LVEF lower than normal but did not specify a cutoff to define abnormal. 

The expanded indication was based on results of the PARAGON-HF trial. While the trial missed its primary endpoint, secondary subgroup analyses showed a significant interaction between LVEF and treatment efficacy, with patients with a mid-range (below-median) LVEF of 45% to 57% appearing to benefit from sacubitril/valsartan therapy. 

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

When they used 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 worsening HF events over 3 years of treatment (main outcome measure), they report.

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

They also calculate that the number needed to treat to prevent one worsening HF event over 3 years of sacubitril/valsartan therapy ranges from seven to 12 across the LVEF ranges potentially encompassed by the expanded FDA labeling.

“Hope is Palpable”

Weighing in on this research in an editorial, Clyde W. Yancy, MD, from Northwestern University Feinberg School of Medicine in Chicago, Illinois, says, “The urgency of need for effective therapies for cannot be discounted, and it is likely that sacubitril/valsartan is a new therapy for certain patients with HFpEF.”

“Clearly, the exploratory data analyses of the PARAGON-HF trial are intriguing, made even more intriguing by review of the results as a function of sex (outcomes in women compared with men: rate ratio, 0.73; 95% confidence interval, 0.59 – 0.90; P <.006>),” Yancy notes.

However, several “nontrivial” questions remain, says Yancy, who serves as 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 play of chance? Will patients with heart failure and an LVEF less than 0.57 actually experience the suggested magnitude of benefit from sacubitril/valsartan for symptomatic heart failure observed in the secondary analysis of the PARAGON-HF trial? Will clinicians have confidence in these expectations?”

“For now,” Yancy concludes, “a new, reasonably evidence-based therapy in HFpEF emerges, and for those patients with both the morbidity and mortality risks of HFpEF, hope is palpable.”

The PARAGON-HF trial was sponsored by Novartis. The Get With The Guidelines–Heart Failure program is provided 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 personal fees for consulting from 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 disclosed financial relationships with pharmaceutical companies. A complete list of disclosures is available with the original article. Yancy disclosed no relevant financial relationships.

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

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