Big Impact Anticipated With HFpEF Expansion of Sacubitril/Valsartan Label

Opening up the indication for sacubitril/valsartan (Entresto; Novartis) to include at least some patients with heart failure with preserved ejection fraction (HFpEF) greatly expands the population eligible for the therapy and has the potential to avert many adverse outcomes, researchers project.

The US Food and Drug Administration initially approved the angiotensin receptor-neprilysin inhibitor (ARNI) for patients with heart failure with reduced ejection fraction (HFrEF) based on the results of the PARADIGM-HF trial, which enrolled those with an LVEF of 40% or lower. Earlier this year, the FDA removed language restricting use to those with reduced EF, but included a note that the “benefits are most clearly evident” when LVEF is below normal.

That change was spurred by the PARAGON-HF trial in patients with HFpEF—which in this case required an EF of 45% or higher. The trial missed its primary endpoint, but subgroup analyses suggested that sacubitril/valsartan was beneficial among patients with EFs of 45% to 57%.

Researchers led by Muthiah Vaduganathan, MD (Brigham and Women’s Hospital, Boston, MA), estimated the implications of expanding the indication for ARNI therapy into higher LVEFs. Under the broadest definition of “below-normal” LVEF (41% to 60%), the more-permissive indication makes treatment available to an additional 1.8 million patients, with the possibility of staving off up to 180,000 more worsening HF events over 3 years of treatment compared with the previous labeled indication.

Even when the below-normal threshold is narrowed to an LVEF between 41% and 50%, there are an estimated 643,000 newly eligible treatment candidates, with the potential to prevent or postpone up to about 69,000 worsening HF events, they report in a study published online this week in JAMA Cardiology.

“The community at large—including end users like clinicians, guideline committees, and payers—will ultimately help define exactly what ejection fraction threshold may [be] ‘below normal’ and so we offer, really, a number of different ranges to help inform that conversation,” Vaduganathan told TCTMD. “But regardless of the exact cutoff that one chooses, there’s a substantial number of newly eligible individuals and there’s a large potential for reduction in worsening heart failure events if the therapy can be fully and appropriately implemented in that cohort of patients.”

The estimates represent the maximum number of potential treatment candidates and not necessarily the amount of patients who will actually receive sacubitril/valsartan, senior author Scott Solomon, MD (Brigham and Women’s Hospital), pointed out, noting that uptake of beneficial new therapies is inherently slow. That “underscores the fact that we don’t just need trial evidence,” he told TCTMD. “We need to understand why new therapies are or are not being implemented and consider ways in which we might be able to augment that implementation.”

Greatest Effects Seen for Women

The investigators brought together data from three sources for this study. Based on National Health and Nutrition Examination Survey data, they estimated that roughly 4.7 million US adults (mean age 66.3; 42.6% women) were living with heart failure, after excluding those less likely to tolerate the drug (systolic BP below 100 mm Hg and/or an estimated glomerular filtration rate of less than 30 mL/min/1.73 m2). They then projected how many patients would be newly eligible for sacubitril/valsartan by applying LVEF distributions from the Get With The Guidelines – Heart Failure registry. Finally, they used treatment effects from PARAGON-HF to estimate the potential impact on clinical events.

The number needed to treat (NNT) to prevent a worsening HF event over 3 years of treatment with sacubitril/valsartan ranged from 7 to 12, regardless of the LVEF range deemed below normal. Over the same span, the number needed to harm (NNH) for hemodynamic hypotension ranged from 20 to 21.

Of note, the expanded indication would have a disproportionate effect on women versus men. Overall, an additional 1.2 million women and 478,000 men would be eligible for treatment, the researchers estimated. And based on analyses from PARAGON-HF suggesting greater benefits in women, they calculated an NNT of just 5 for women and 27 to 34 for men across endpoints, with NNHs for hemodynamic hypotension of 18 and 27, respectively.

“We estimate that not only a much larger group of women are eligible for the drug under the revised FDA labeling, but also in fact more heart failure events may be averted if implemented in women compared to men,” Vaduganathan said.

‘Hope is Palpable’

In an accompanying editorial, Clyde Yancy, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), deputy editor of JAMA Cardiology, says that “given the prevailing evidence-based treatment void for HFpEF, there is reason for cautious optimism” when it comes to sacubitril/valsartan.

But several questions remain unanswered, he points out, including those surrounding how secondary analyses of trials should be interpreted when it comes to making regulatory decisions about indications for therapy.

“Careful secondary analyses of clinical importance for heart failure (or other diseases), subjected to high-level expert public scrutiny, may provide the impetus for new FDA considerations, and the same troika of editorial critique, FDA regulatory review, and guideline committee assessment remains operational,” Yancy states.

Referring to considerations for sacubitril/valsartan in a wider group of patients, he explains, “Editorial critique by this journal finds the current data reasonable. Regulatory review by the FDA asserts the reasonableness of these data. Deliberations of guideline-writing committees remain pending but will likely align with a permissive statement of indication supported by a level of evidence of at least moderate certainty.”

He adds that “evolution of the FDA evidence bar is appropriate,” pointing to various study designs beyond traditional RCTs while stressing the importance of the FDA remaining committed to ensuring the safety and effectiveness of new therapies.

Giving a nod to the “intriguing” exploratory analyses from PARAGON-HF, Yancy notes that “the urgency of need for effective therapies for HFpEF cannot be discounted, and it is likely that sacubitril/valsartan is a new therapy for certain patients with HFpEF.

“Clinical implementation will resolve any residual uncertainties and will test the integrity of this evolved FDA evidence bar,” he continues. “Unfailingly, the correct approach remains further discovery science, but for now, 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.”