Clinical Edge

Summaries of Must-Read Clinical Literature, Guidelines, and FDA Actions

Sacubitril/valsartan suggests HFpEF benefit in neutral PARAGON-HF

Key clinical point: Sacubitril/valsartan treatment showed a suggestion of benefit in selected patients with heart failure with preserved ejection fraction.

Major finding: Among 2,495 patients with an ejection fraction of 57% or less, treatment with sacubitril/valsartan cut the primary endpoint by a statistically significant 22% relative to controls.

Study details: PARAGON-HF, a multicenter, randomized trial with 4,796 evaluable patients.

Disclosures: PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). The presenter has been a consultant to and has received research funding from Novartis and from several other companies.


Solomon SD. ESC 2019.


PARAGON-HF was a well-designed and well-conducted trial that unfortunately showed a modest treatment effect, with sacubitril/valsartan treatment reducing the overall primary endpoint by 13%, compared with control patients, a difference that was not statistically significant. One factor to consider when interpreting this outcome was that the study used an active control arm in which patients received valsartan even though no treatment is specifically approved for or is considered to have proven efficacy in patients with heart failure with preserved ejection fraction. The investigators felt compelled to use this active control because many patients with this form of heart failure receive a drug that inhibits the renin-angiotensin system. It’s possible that if sacubitril/valsartan had been compared with placebo the treatment effect would have been greater.

The hypothesis that sacubitril/valsartan may have exerted a real benefit in at least some patients is supported by positive, statistically significant benefits for several secondary endpoints, such as quality of life, improvement in functional class, and reduced worsening of renal function.

Although caution is required when interpreting subgroup outcomes in a study that lacks a positive primary endpoint, the data indicate a positive signal in the subgroup analysis that Dr. Solomon presented that took into account left ventricular ejection fraction at entry into the study. Patients with a baseline ejection fraction of 57% or less, roughly half the entire study group, showed a statistically significant benefit in a prespecified analysis, and a finding with some level of biological plausibility. This was a compelling analysis, and it suggested that with this treatment it may be possible to reduce a key outcome – the incidence of heart failure hospitalizations – in patients with modestly reduced ejection fractions.

Stuart J. Connolly, MD , is a professor of medicine at McMaster University, Hamilton, Ont. He had no disclosures. He made these comments as the designated discussant for PARAGON-HF.