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PHILADELPHIA -- The benefits of angiotensin receptor-neprilysin inhibition (ARNI) therapy extend beyond heart failure (HF) with reduced ejection fraction (HFrEF), according to investigators revisiting the PARAGON-HF and PARADIGM-HF trials.

In two separate analyses, two patient groups -- women with HF with preserved ejection fraction (HFpEF) and people who have HF with mid-range ejection fraction (HFmEF) -- were identified as having HF hospitalizations and cardiovascular (CV) deaths reduced by sacubitril/valsartan (Entresto).

The new data were presented at the American Heart Association (AHA) meeting. Results from both studies were published online in .

ARNI therapy should be considered the fifth class of life-saving drugs in HF along with angiotensin-converting enzyme inhibitors, beta blockers, aldosterone antagonists, and sodium-glucose cotransporter-2 inhibitors, according to John McMurray, MD, of the British Heart Foundation Cardiovascular Research Centre at University of Glasgow in Scotland.

Ideally, these drugs would be used to complement each other, McMurray said at an AHA press conference. However, he posed the questions of how patients would use these drugs together and how they could afford them all -- sacubitril/valsartan being especially pricey.

AHA discussant Clyde Yancy, MD, of Northwestern University Feinberg School of Medicine in Chicago, noted the consistent evidence of sacubitril/valsartan's efficacy and safety, and suggested it even gain a Class I indication for HFmEF with level of evidence rising to "A" in future guidelines.

"I too embrace the concept now of five pillars in the treatment of heart failure," Yancy said, though he said the priority should be optimizing the titration of current guideline-directed medical therapy.

Effect of Sex in PARAGON-HF

The "near miss" of PARAGON-HF shifted to a finding that sacubitril/valsartan benefited women, not men, in reducing the risk of HF hospitalizations and CV deaths.

Sex interacted with treatment efficacy to give women a significant reduction in the primary composite outcome over 35 months if they were randomized to the combination therapy over valsartan (Diovan) alone (RR 0.73, 95% CI 0.59-0.90, P=0.017 for interaction), according to a prespecified of the trial.

In particular, it was the reduced risk of HF hospitalizations that drove the benefit of sacubitril/valsartan in women (RR 0.67, 95% CI 0.53-0.85), McMurray reported.

On the other hand, sacubitril/valsartan cut neither hospitalizations nor CV deaths for men (RR 1.03, 95% CI 0.84-1.25).

These findings are notable because HFpEF has no approved therapies, but is the most common type of heart failure in women, McMurray told the audience.

"While the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding," the study authors wrote. "Therefore, not clear whether this was a chance finding or a real difference."

"As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men, but the effects on KCCQ [Kansas City Cardiomyopathy Questionnaire], NYHA [New York Heart Association] class and worsening kidney function were not greater in women," McMurray said.

The PARAGON-HF trial was a "near miss" in which sacubitril/valsartan failed to significantly reduce hospitalization for HF and death from CV causes compared with valsartan alone in HFpEF (LVEF ≥45%).

PARAGON-HF included nearly 4,800 patients in a cohort that was 52% women. Among other differences at baseline, women who entered the trial were older and with worse HF symptoms, worse kidney function, and less coronary disease compared to men.

Adverse event differences between sacubitril/valsartan and valsartan were consistent between women and men in the trial.

It was a limitation of the trial that LVEF was all the investigators had to assess LV systolic function, they said. There was also no information on certain biomarkers, such as neprilysin levels or sex hormones.

"It is tempting to jump on the signal of gender, but I am reluctant to ride. My guess is that the female gender enriches HFpEF for some pathophysiology that is sensitive to some peptides degraded by neprilysin, but I don't know," said AHA discussant Lynne Warner Stevenson, MD, of Vanderbilt Heart and Vascular Institute in Nashville, Tennessee.

Outcomes Across Spectrum of EF

HF patients with mid-range EF appear to be one group that may also benefit from ARNI therapy, a pooling of PARADIGM-HF and PARAGON-HF suggested.

This showed that sacubitril/valsartan was better than RAS inhibition alone overall in terms of:

• Time to first CV death or HF hospitalization (HR 0.84, 95% CI 0.78-0.90)
• CV death (HR 0.84, 95% CI 0.76-0.92)
• HF hospitalization (HR 0.84, 95% CI 0.77-0.91)
• All-cause mortality (HR 0.88, 95% CI 0.81-0.96)

"The therapeutic effects of sacubitril/valsartan, compared with a RAS inhibitor alone, vary by LVEF, with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction," according to Scott Solomon, MD, of Brigham and Women's Hospital in Boston.

Solomon noted that LVEF, as a continuous variable, modified the effect of sacubitril/valsartan (P=0.02). The combination was protective mainly for people with lower EF -- roughly 20% to 55% was where ARNI therapy maintained a significant advantage in total HF hospitalizations and CV deaths.

The effect of LVEF was observed in men and women alike. However, women kept their benefit with sacubitril/valsartan out to a higher EF.

was a 8,400-person HFrEF trial in which people with LVEF 40% or less did better with sacubitril/valsartan compared with enalapril (Vasotec) alone.

Based on how different the PARAGON-HF and PARADIGM-HF populations were in their baseline characteristics and their response to ARNI therapy, the question is "whether we are truly looking at a continuum of one disease as described by EF," said Warner Stevenson.

"I see two different etiologies," she said.

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