Novartis presented detailed findings from the Phase III PARAGON-HF trial on Sunday at the annual European Society of Cardiology (ESC) conference, saying Entresto (sacubitril/valsartan) reduced the composite primary endpoint of total heart failure hospitalisations and cardiovascular (CV) deaths by 13% in patients with preserved ejection fraction (HFpEF). The company, which previously reported that the study had "narrowly missed statistical significance" on its main goal, said the decline was mostly due to a nearly 15% reduction in total heart failure hospitalisations.
PARAGON-HF enrolled 4822 patients with HFpEF who were randomised to receive Entresto twice daily or valsartan, which Novartis markets as Diovan. Participants represented ambulatory patients with established HFpEF being treated for symptoms and comorbidities, approximately half of whom had a history of heart failure hospitalisations.
Novartis indicated that the findings, which were also published in the NEJM, showed "more pronounced effects" on the primary endpoint in certain subgroups, including patients with a median ejection fraction of 57% or less, who saw a 22% reduction in heart failure hospitalisations and CV deaths. Similarly, more pronounced effects were observed in women and in non-adjudicated investigator-reported events, where the reductions were 27.5% and 15.7%, respectively.
The drugmaker noted that "exploratory" secondary endpoint analyses showed that Entresto-treated patients experienced less worsening in quality of life than those in the valsartan group based on the KCCQ Clinical Summary Score (CSS) at eight months. Changes in the New York Heart Association (NYHA) class were also "more favourable" in the Entresto arm than for valsartan, the company said. In addition, Entresto resulted in a significant decrease in the risk of the composite renal endpoint, although there was no difference in all-cause mortality between the groups.
"Our data strongly imply that one size might not fit all in HFpEF," commented co-principal investigator Scott Solomon. "We've known for some time that patients with this disorder have different characteristics and aetiologies. The PARAGON-HF results suggest that the impact of treatment may also vary," he said, adding that "some secondary endpoints suggested a modest overall benefit with Entresto."
Solomon noted that the results at the lower end of the ejection fraction range should be considered in light of the PARADIGM-HF trial, which demonstrated substantial benefit of Entresto, formerly known as LCZ696, in those with heart failure and ejection fraction below 40%. Aside from ejection fraction, the entry criteria for PARADIGM-HF and PARAGON-HF were nearly identical. "Our findings indicate that the benefit of Entresto observed in PARADIGM-HF could extend to heart failure patients with ejection fraction below the normal range, including those designated HFmrEF [heart failure with mid-range ejection fraction]," he said.
The researcher also described the benefit seen in women in PARAGON-HF as "intriguing" as they make up a much greater proportion of patients with HFpEF compared to heart failure with reduced ejection fraction. "Further analyses will explore these subgroup findings in detail and help determine which patients with heart failure across a broad range of ejection fraction might benefit the most from Entresto," he said.
The angiotensin receptor neprilysin inhibitor is currently approved in the US for the treatment of heart failure in patients with systolic dysfunction, and in the EU for the treatment of symptomatic chronic heart failure in adults with reduced ejection fraction.
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