Expanded Label of Sacubitril/Valsartan for HF Could Drastically Expand Eligible Population

The FDA recently expanded the label for sacubitril/valsartan for additional use in individuals with chronic heart failure (HF) with left ventricular ejection fraction (LVEF) lower than normal, which has the potential to substantially increase the population eligible for the therapy by up to 1.8 million individuals, according to a study published in JAMA Cardiology.

In addition to quantifying the newly eligible candidates for sacubitril/valsartan, the researchers estimated the number needed to treat (NNT) to prevent a worsening HF event, as well as the number needed to harm to cause a safety event.

FDA made the regulatory change based on data from the Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARAGON-HF) trial.

“Notably, in the PARAGON-HF trial, there was a significant interaction between LVEF and treatment efficacy, whereby participants with an LVEF at or below the median value of 57% appeared to garner greater clinical benefit,” the authors explained. “Indeed, the FDA emphasized that benefits are most clearly evident in patients with LVEF lower than normal.”

The researchers estimated the prevalence of HF using the National Health and Nutrition Examination Survey from 2015 to 2018 and then leveraged data from the American Heart Association Get With The Guidelines-Heart Failure (GWTG-HF) registry to identify the distribution of LVEF among adults patients who were hospitalized between January 1, 2014, and September 30, 2019.

There were 559,520 patients hospitalized with HF in the GWTG-HF registry who had LVEF measurements; of those, 45.4% would have met the criteria for the prior indication for sacubitril/valsartan. The new eligibility would make an additional 14% to 39% eligible depending on how LVEF was considered. However, they found large variation in the newly eligible population based on 4 LVEF ranges (45%-50%, 45%-55%, 45%-57%, and 45%-60%).

The 3-year NNT in the PARAGON-HF trial was 20 for total HF hospitalizations, 19 for total HF hospitalizations and cardiovascular (CV) death, and 17 for total worsening HF and CV death. Across LVEF ranges, the expanded FDA label would change the 3-year NNT to:

• 45%-50%: 10 for total HF hospitalizations, 10 for total HF hospitalizations and CV death, and 9 for total worsening HF and CV death
• 45%-55%: 8 for total HF hospitalizations, 8 for total HF hospitalizations and CV death, and 7 for total worsening HF and CV death
• 45%-57%: 9 for total HF hospitalizations, 9 for total HF hospitalizations and CV death, and 9 for total worsening HF and CV death
• 45%-60%: 12 for total HF hospitalizations, 10 for total HF hospitalizations and CV death, and 10 for total worsening HF and CV death

The 3-year number needed to harm, which wasn’t estimated for PARAGON-HF, was estimated to range from 20 to 21 for hypotension due to the expanded FDA label.

As a result, the authors estimated that 3 years of treatment with the expanded eligibility for sacubitril/valsartan would prevent or postpone up to 69,268 (95% CI, 57,558-80,978) worsening HF events for LVEF of 41% to 50% and up to 182,592 (95% CI, 151,725-213,460) worsening HF events for LVEF of 41% to 60%. Expanded eligibility over 3 years of treatment would cause up to 32,029 (95% CI, 26,614-37,443) hemodynamic hypotensive events for LVEF of 41% to 50% and up to 86,164 (95% CI, 71,598-100,730) hemodynamic hypotensive events for LVEF of 41% to 60%.

“In light of the substantial variation in estimates of newly eligible patients with HF encompassed by the expanded label, the use of sacubitril/valsartan in real-world settings should be carefully monitored,” the authors noted.

Reference

Vaduganathan M, Claggett BL, Greene SJ, et al. Potential implications of expanded US Food and Drug Administration labeling for sacubitril/valsartan in the US. JAMA Cardiol. 2021;6(12):1415-1423. doi:10.1001/jamacardio.2021.3651