Novartis PARAGON-HF trial suggests Entresto benefit in HFpEF patients but narrowly misses primary endpoint

Novartis announced full results from its global Phase III PARAGON-HF study, investigating the efficacy and safety of Entresto (sacubitril/valsartan) versus the active comparator valsartan in heart failure patients with preserved ejection fraction (HFpEF). Entresto reduced the composite primary endpoint of total (first and recurrent) heart failure hospitalizations and cardiovascular (CV) death by 13 percent (p = 0.059).
The result was primarily driven by a nearly 15 percent reduction (p = 0.056) in total heart failure hospitalizations (first and recurrent).

The full body of evidence from the trial suggests that treatment with Entresto may result in clinically important benefits in HFpEF, a heterogeneous type of heart failure with no approved treatment, in particular subgroups. Pre-specified subgroup analyses suggest even greater effects in individuals with a left ventricular ejection fraction equal to or below the median of 57% (22 percent reduction in primary endpoint; 95% CI: 0.641, 0.949) and in women (27.5 percent reduction in primary endpoint; 95% CI: 0.588, 0.895). Safety and tolerability were consistent with previously reported findings in HFrEF patients. Currently, Entresto is an approved and essential treatment for patients with HFrEF, which is typically defined as ejection fraction less than 40%. These results were presented at the ESC Congress 2019, the annual meeting of the European Society of Cardiology, and published in The New England Journal of Medicine.

“Novartis is proud of PARAGON-HF’s significant contribution to the body of scientific evidence in HFpEF. This study highlights the critical need for treatment options for this complex disease,” said David Soergel, M.D., Global Head of Cardiovascular, Renal and Metabolic Drug Development at Novartis. “Novartis is committed to reimagining heart failure treatment, and our next step is to further explore these results from PARAGON-HF. We also look forward to continuing conversations with clinical experts and regulators to determine next steps.”

“While the reduction in the primary endpoint was not statistically significant, the totality of evidence from PARAGON-HF suggests potential overall benefit of sacubitril/valsartan compared with valsartan in HFpEF, particularly in patients with ejection fraction below normal. It also highlights the complexity of HFpEF and may suggest that some treatments have a more pronounced impact in certain patient groups, including women, who are more likely to suffer from this condition than men,” said Scott Solomon, M.D., Director of Noninvasive Cardiology at Brigham and Women’s Hospital, Professor, Harvard Medical School, and PARAGON-HF Executive Committee Co-Chair.

“PARAGON-HF provides a wealth of data that will advance our understanding of HFpEF and the patients it affects,” said John McMurray, M.D., Professor of Medical Cardiology at University of Glasgow and PARAGON-HF Executive Committee Co-Chair. “When considered in the context of the PARADIGM-HF trial, it is not surprising that sacubitril/valsartan might have a greater treatment effect in HFpEF patients with an ejection fraction in the lower part of the range we studied in PARAGON-HF.”

Sacubitril/valsartan (approved as Entresto since 2015) is a first-choice and essential treatment in HFrEF, based on its superiority to the angiotensin-converting enzyme (ACE) inhibitor enalapril and its ability to significantly reduce CV death and HF hospitalizations.