Sacubitril/Valsartan Label Expansion Could Increase Patient Base by Nearly 2 Million

Muthiah Vaduganathan, MD

The US FDA’s label expansion for sacubitril/valsartan (Entresto) in February 2021 could increase the potential patient population by nearly 2 million patients and prevent or postpone up to 180,000 heart failure events with comprehensive implementation, according to the results of a new study.

A decision analytical model study using data from NHANES, the GWTG-HF registry, and PARAGON-HF, results provide clinicians with insight into the newly eligible patient population outlined in the FDA’s label expansion for patients with heart failure with an ejection fraction below normal.

“We undertook this analysis to really study a range of ejection fractions that may define what below normal may mean and how that may influence the potential population who may be eligible for use of sacubitril/valsartan, as well as the potential benefits we may see in clinical practice with the full implementation of this therapy,” said Muthiah Vaduganathan, MD, MPH, cardiologist at Brigham and Women’s Hospital and lead investigator of the study, in an interview with Practical Cardiology.

With the FDA’s expanded label creating uncertainty around the specific ejection fraction range considered appropriate, Vaduganathan and a team of colleagues from multiples institutions in the US and abroad sought to provide clinicians with an overview of the potential impact of optimal implementation based on a range of ejection fractions. The study was designed to use data from the National Health and Nutrition Examination Survey (NHANES) from 2015-2018 and left ventricular ejection fraction (LVEF) distribution data from the Get With The Guidelines-Heart Failure (GWTG-HF) registry to quantify newly eligible candidates and apply treatment effects observed in PARAGON-HF to assess the impact of implementation.

While the trial failed to meet its primary end point, PARAGON-HF provided valuable insight into the treatment effects of sacubitril/valsartan among patients with an ejection fraction of 45% or greater. Briefly, the PARAGON-HF trial concluded the 3-year number-needed-to-treat (NNT) was 20 for heart failure hospitalizations, 19 for total heart failure hospitalizations and cardiovascular death, and 17 for worsening heart failure events and cardiovascular death.

From NHANES, investigators identified 19,255 patients with self-reported heart failure, which investigators noted correlates to an estimated patient population of 5,604,076 (95% CI, 4,674,944-6,533,208). From the GWTG-HF registry, investigators obtained data related to LVEF measurements for 559,520 patients. Of these, 45.4%, which correlates to an estimated 2,124,182 individuals, would have already been considered eligible for sacubitril/valsartan prior to the February 2021 label expansion.

Results of the investigators analysis suggested the new FDA label for sacubitril/valsartan could expand the patient population by 643,161 (95% CI, 534,433-751,888) when below normal was considered 41-50% and by 1,838,756 (95% CI, 1,527,911-2,149,601) when below normal was considered 41-60%. Based on the treatment effects observed in PARAGON-HF, investigators estimated comprehensive implementation could prevent up to 69,268 (95% CI, 57,558-80,978) worsening heart failure events using the 41-50% definition of below normal and 182,592 (95% CI, 151,725-213,460) using the 41-60% definition.

“Our estimates are likely over-optimistic in that many of those patients who may be eligible and may stand to benefit may, in fact, ultimately go untreated. So, this does provide that optimistic estimate, however, as perhaps a goalpost that, as a community, if we were to achieve this degree of implementation, these are the potential resultant averted hospitalizations and averted worsening heart failure events that we may be able to achieve,” Vaduganathan added.

In an editorial comment, Clyde Yancy, MD, MSc, chief of cardiology at Northwestern Medicine and deputy editor of JAMA Cardiology, provides perspective on the need for therapies in HFpEF and explores what he describes as the “evolution of the FDA evidence bar”.

“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,” wrote Yancy. “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.”

This study, “Potential Implications of Expanded US Food and Drug Administration Labeling for Sacubitril/Valsartan in the US,” was published in JAMA Cardiology.