Disclosures: The members of the Cardiovascular and Renal Drugs Advisory Committee report no relevant financial disclosures. Soergel is an employee of Novartis.
December 15, 2020
4 min read

FDA panel supports expanded indication for sacubitril/valsartan in some with HFpEF

Disclosures: The members of the Cardiovascular and Renal Drugs Advisory Committee report no relevant financial disclosures. Soergel is an employee of Novartis.
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The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 12-1 that an expanded indication is warranted for sacubitril/valsartan, which could allow it as a treatment for certain patients with HF with preserved ejection fraction.

However, the panel members did not achieve consensus on how to define the population for whom the expanded indication would apply.

Heart Failure
Source: Adobe Stock

There are no medical therapies specifically approved for treatment of HFpEF in the United States. The panel on Wednesday will consider whether spironolactone should also be approved for such patients.

Sacubitril/valsartan (Entresto, Novartis) was previously approved for treatment of patients with HF with reduced EF. The application for an indication for HFpEF was primarily based on the PARAGON-HF trial, in which sacubitril/valsartan was not superior to valsartan for reduction of total CV death and HF hospitalization events in an overall cohort of patients with EF at least 45%, but which showed certain groups benefited from sacubitril/valsartan, including women and patients in the lower range of the EF spectrum. In addition, sacubitril/valsartan was superior to valsartan in an analysis combining the primary endpoint with urgent HF visits.

‘Potential for an indication’

Steven E. Nissen

“The rate ratio of 0.78 in the group that had the below-median ejection fraction compared with 0.99 in the group that was above median, I found to be compelling in the context of what we learned from PARADIGM-HF,” the trial of sacubitril/valsartan in patients with HFrEF, panel member Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic and Cardiology Today Editorial Board Member, said after the vote. “I do see the potential for an indication for those people. How we define the group that would benefit is going to be very important.”

Although the panel agreed that the indication should be expanded to include the populations that received the most benefit from sacubitril/valsartan in PARAGON-HF, some panelists wanted an EF range specified because having one makes the indication easier to implement in clinical practice, whereas some did not, citing the complexity of the HF spectrum and noting that EF does not tell the whole story of who could benefit from a medication like sacubitril/valsartan.

In addition, among those who wanted a range, there was disagreement over what the range should be, and among those who did not want a range, there was disagreement over the best wording to describe the population. Among those who wanted a range, some advocated the upper limit of EF be 55%, the median in many HFpEF trials, whereas others said it should be 57%, the median in PARAGON-HF, or higher to capture more women. Among those who did not want a range, some preferred the term “mildly reduced EF” because the mild-moderate-severe gradation is familiar to clinicians, whereas others preferred “EF below the lower limit of normal” because it is more precise without giving specific numbers.

Panel chairperson Julia B. Lewis, MD, professor of medicine in the division of nephrology at Vanderbilt Medical Center, was the only panelist to vote against an expanded indication and said she did so because PARAGON-HF “didn’t study mildly reduced or middle-range EF. It studied everybody above a certain level, including people with truly normal EF. The drug has a side effect of hypotension and I’m not sure it couldn’t cause harm in some of those patients.”

Unmet medical need

“Heart failure with preserved ejection fraction remains a huge unmet medical need,” David Soergel, MD, global head of cardiovascular, renal and metabolic drug development for Novartis, told Healio. “About 3.25 million people in the United States have HFpEF — about half the heart failure population — and there is no approved therapy. What we have from the PARAGON trial, plus the adjacent population in HFrEF in the PARADIGM-HF study, as well as the evolution of clinical research in HFpEF over the last 10 to 15 years, puts light on the data from PARAGON and gives us confidence that this medication can work for those patients.”

He told Healio that “when we look at the [PARAGON] data with more granularity, there is a very consistent beneficial treatment effect proven by heart failure hospitalization and urgent heart failure metrics in patients with HFpEF. [There is a] level of consistency that is comforting. All of the analyses ... point in the direction of a true and consistent benefit.”

The company initially asked for an indication for all patients with HFpEF, “but when we started digging into the data more and had more conversations with medical experts in the community, we started focusing more on the population with lower-than-normal ejection fraction,” Soergel told Healio, noting that devising a precise definition of HF with preserved but lower-than-normal EF was one of the goals of the panel meeting.

In a briefing document prepared for the panel, the FDA staff wrote that “the prevalence of HF with LVEF ≥ 45% is increasing in the U.S., with increasing life expectancy, and epidemics of metabolic syndrome and [diabetes]. These patients experience significant morbidity associated with recurrent [HF hospitalization] with no approved treatment. The overall benefit-risk considerations may support approval of sacubitril/valsartan to treat patients with HF with LVEF ≥ 45%.”

In the briefing document, the FDA staff also stated that: “Although there are underlying differences in the pathophysiology and epidemiology of patients with HFrEF and HFpEF, the LVEF boundaries separating the two patient populations is ill-defined. ... It is conceivable that there is some overlap in pathophysiology between patients with LVEF < 40% and LVEF ≥ 45% evaluated in PARADIGM and PARAGON-HF, respectively. In PARAGON-HF, the relationship of RR with LVEF as a continuous variable indicates that the patients in the lower LVEF range benefit the most with sacubitril/valsartan.”

After the panel meeting, Novartis released the following statement: “We are encouraged by the committee’s response today and look forward to the [FDA] decision on the potential approval of Entresto (sacubitril/valsartan) for use in the treatment of patients with heart failure with preserved ejection fraction. Novartis remains committed to the goal of reimagining medicine and to Entresto through our extensive clinical trials program in heart failure.”

The FDA is not required to follow the recommendations of its advisory panels, but it usually does.


For more information:

David Soergel, MD, can be reached at One Health Plaza, East Hanover, NJ 07936.