Sacubitril/Valsartan Benefits Extend to HF With Mildly Reduced EF

Sue Hughes  

November 17, 2019

PHILADELPHIA — Further analyses of the PARADIGM and PARAGON heart failure trials of sacubitril/valsartan (Entresto, Novartis) appear to show that the benefits of the drug combination established in patients with low ejection fraction (EF) appear to extend to patients with mildly reduced EF, and to a higher EF range in women than men.

These latest analyses from the two trials were presented today at the American Heart Association (AHA) Scientific Sessions 2019 and simultaneously published online in Circulation.

PARADIGM, reported in 2014, showed clear benefits of sacubitril/valsartan in patients with heart failure who have reduced ejection fraction versus enalapril, with a 20% reduction in cardiovascular (CV) death/heart failure hospitalization and a similar reduction in all-cause mortality.

However, in the more recent PARAGON trial in patients with symptomatic heart failure but preserved EF, the sacubitril/valsartan combination was associated with a more modest reduction in events that failed to meet statistical significance (P = .059) compared with valsartan alone.  

Presenting the latest findings from PARAGON, John McMurray, MD, said, "We are talking today about the interesting finding from PARAGON HF that women appeared to get more benefit from the sacubitril/valsartan combination for the primary outcome than men."

McMurray is professor of cardiology at the University of Glasgow, United Kingdom.

He noted that heart failure with preserved EF, for which no effective treatment is available, affects women more than men, "so women with heart failure have a greater therapeutic deficit than men."

"Subgroup analysis suggested only two baseline characteristics seemed to modify the effect of treatment: sex and ejection fraction. We actually think these two things are possibly inter-related."

Latest data show that women and men were different at baseline, McMurray reported. Women were a little older, had higher EFs, slightly higher blood pressure, and worse kidney function. Baseline treatments were similar in the two sexes apart from a little less use of mineralocorticoid receptor antagonists in women.

Results were also different in men and women. Women showed a benefit of treatment with sacubitril/valsartan, with a rate ratio for the primary endpoint of 0.73 (95% CI, 0.59 - 0.90), whereas there was no effect in men: rate ratio 1.03 (95% CI, 0.84 - 1.25).

The benefit in women was driven by congestive heart failure (CHF) hospitalization, with no difference in cardiovascular mortality among men or women.

When the results were examined according to baseline EF, women showed a benefit of sacubitril/valsartan across the range of EFs up to about 65%. But in men, the benefit was attenuated at around 55%.  

"So it appears that women get a benefit of sacubitril/valsartan over valsartan alone up to a higher ejection fraction than men," McMurray concluded.     

Other outcomes, including quality-of-life scores, New York Heart Association (NYHA) class, worsening kidney function, and mortality, did not differ between women and men.     

"We are not sure whether the differences between women and men is a real finding or a chance finding," McMurray commented.   

He suggested several potential biological mechanisms may explain the differences: for example, a deficit in cyclic guanosine monophosphate–protein kinase G signaling in postmenopausal women and more systolic dysfunction in women than men in the EF range of 40% to approximately 65%.

Conversely, there may be more male "nonresponders" because of alternative pathology, such as cardiac amyloidosis, and/or the active comparator, valsartan, may have been more effective in men than women, he added.

"The possible modification of the effect of sacubitril/valsartan by sex requires further investigation," he said.


In a separate presentation, Scott Solomon, MD, Brigham and Women's Hospital, Boston, Massachusetts, reported a pooled analysis of the PARADIGM and PARAGON trials "allowing us to look at the effects of the drug across the whole spectrum of EF."

The analyses included 13,195 patients from both trials and divided patients into EF categories.

Results showed a highly significant reduction for all primary endpoints in the overall pooled analysis.  

"But when we look at ejection fraction categories, we see overall benefit CV death/CHF hospitalizations is similar in the first five lower categories," Solomon reported. "Until you get to the highest ejection fraction category of greater than 62.5%, when we see an attenuation of a treatment effect."  

Table. Treatment Effect of Sacubitril/Valsartan Across Spectrum of Left Ventricular EF

EF (%) Rate Ratio Number of CV Deaths/CHF Hospitalizations Prevented per 1000 Patient-Years
<22.5 0.79 53
22.5 - 32.5 0.77 46
32.5 - 42.5 0.82 28
42.5 - 52.5 0.81 34
52.5 - 62.5 0.83 23
>62.5 1.06 -


And corresponding to McMurray's presentation, when the results were considered according to men and women, the same overall pattern was seen, but the curves are shifted so that women were deriving benefit up to a higher EF than men, Solomon said.  

Designated discussant of these presentations, Lynne Warner Stevenson, MD, Vanderbilt University Medical Center, Nashville, Tennessee, said these additional analyses were commendable.

"Sacubitril/valsartan showed a remarkable benefit in low ejection fraction heart failure in PARADIGM," she said. "When we started using the drug we saw clear benefits in patients as to how they felt, and we were expecting a benefit similar or even larger in preserved ejection fraction, so we were all surprised when we didn't see that benefit in the PARAGON trial."

She suggested that the current results show that despite less demonstrable benefit above EFs of 45%, "there is indeed a continuum across EF."

"The beneficial effect is driven equally by CV death/CHF hospitalizations in the low EF PARADIGM group but only by CHF hospitalization in the higher EF PARAGON group," she said.

Warner Stevenson noted, though, that she was "reluctant to ride" the gender issue.

"I'm not sure what that's due to," she pointed out. "Female gender may enrich for some specific heart failure etiologies which may respond better to this agent, but I don't think this is intrinsically a gender-related issue."

Warner Stevenson added that a larger question remains of whether there is a continuum of one disease across the spectrum of EF.

"I feel the data fit with two different physiologies and two different targets of benefit in lower EF and higher EF groups," she said.   

She pointed out that the benefit in PARADIGM was not dependent on sex or EF and was equally split between CV death and hospitalization, whereas in PARAGON the benefit was seen only in CHF hospitalization among patients with an EF less than 57% and only women.

In PARADIGM, the benefit was more obvious in NYHA class 1 and 2, but in PARAGON it was more obvious in class 3 and 4. 

"And what I'm most struck by is that in PARADIGM, the benefit was seen regardless of previous CHF hospitalizations, whereas in PARAGON it was only evident in those patients with prior CHF hospitalizations."  

"I'm thinking about it by dividing patients both by EF and by history of CHF hospitalization," she added.

"To me it appears that sacubitril/valsartan reduces hospitalizations for congestion across EF whether reduced or preserved, but perhaps disease progression and CV mortality present better targets if you have a low EF than if you have a preserved EF," she concluded.

PARADIGM-HF and PARAGON-HF were sponsored by Novartis. Both McMurray and Solomon report receiving research grants from the company.

American Heart Association (AHA) Scientific Sessions 2019. Presented November 17, 2019.

Circulation. Published online November 17, 2019.  McMurray paper; Solomon paper.

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