Sex Differences, EF Thresholds Probed for Sacubitril/Valsartan in Heart Failure

PHILADELPHIA, PA—Investigators have taken a deeper dive into the PARAGON-HF and PARADIGM-HF trials to try to tease out a number of secondary findings and, in particular, to understand a differential effect of sacubitril/valsartan (Entresto; Novartis) in women versus men, as well as to get a better appreciation of the impact of this agent across the spectrum of ejection fractions.

As previously reported by TCTMD, PARAGON-HF was unveiled at the European Society of Cardiology (ESC) Congress 2019 in September and showed that sacubitril/valsartan, an angiotensin receptor/neprilysin inhibitor (ARNI), failed to significantly reduce the risk of hospitalization for heart failure or cardiovascular death in patients with heart failure with preserved ejection fraction (HFpEF) compared with valsartan, an ARB, alone. That’s in contrast to the 2014 PARADIGM-HF trial, which helped cement the original approval of this agent after showing that it significantly reduced heart failure hospitalizations/CV death in patients with reduced HF (HFrEF) based on an ejection fraction threshold of 40%.

At the American Heart Association (AHA) 2019 Scientific Sessions earlier this week, John McMurray, MD (University of Glasgow, Scotland), presented a detailed analysis of one of those two signals identified at ESC, namely that women with preserved EF may have benefited more than men from sacubitril/valsartan. And indeed, the primary endpoint of total HF hospitalizations or CVD death was significantly reduced in women (RR 0.73; 95% CI: 0.59-0.90), a reduction that was not seen in men. That difference, said McMurray, appeared to be driven by HF hospitalizations. Women also appeared to derive a benefit from the newer agent over valsartan at higher ejection fractions than did men.

But in additional findings that cast a shadow over those intriguing differences for the primary endpoint, women did not report a higher quality of life in the sacubitril/valsartan arm, nor were there marked improvements in NYHA class in women as compared with men, in favor of the ARNI therapy.

Adverse events were also similar between groups. A range of biological mechanisms could potentially explain the difference in primary outcome events by sex, McMurray noted, including differences in intercellular signaling pathways, systolic function, or drug response/efficacy based on underlying mechanisms of heart failure. But without having insights into any potential mechanisms that would explain why women with HFpEF responded better to the drug, he concluded, “we’re not sure whether this is a real finding or a chance finding.”

Commenting on the analysis for TCTMD, Shelley Zieroth, MD (University of Manitoba, Winnipeg, Canada), said she, too, worried that the primary outcome difference by sex might be a chance finding, given the lack of corroborating signals in the secondary endpoints. “In the absence of a mechanistic explanation that explains the differential effect that we’re seeing in women, it’s really hard to know how to interpret this difference. . . . I think clinicians and payers as well as those writing the guidelines are still looking for a little bit more in terms of biologic plausibility, and that just means we need to include more women in HFpEF trials and we need more research to understand those sex-based differences in heart failure.”

Across the Spectrum of Ejection Fraction

Scott Solomon, MD (Brigham and Women’s Hospital, Boston, MA), looked into what he called the “spectrum” of ejection fraction and how that appeared to interact with ARNI therapy. For this analysis, Solomon and colleagues pooled the data from both PARADIGM-HF and PARAGON-HF, yielding a cohort of 13,264 patients from 56 countries.

In this pooled group of HFrEF and HFpEF patients, sacubitril/valsartan was overall superior to treatment with an ARB alone. These findings, however, “were driven by benefit in patients with chronic HF and an LVEF below the normal range,” Solomon said. “Benefit in the ejection fraction range above frankly ‘reduced’ but below normal was driven primarily by a reduction in heart failure hospitalization.” And echoing what was seen in McMurray’s analysis, women appeared to continue to derive benefit from the ARNI at higher LVEF levels than men, Solomon concluded.

Discussing both subanalyses following their presentation at AHA 2019, Clyde Yancy, MD (Northwestern Medicine, Chicago, IL), put this newer class of agents in the context of other available therapies and urged better tailoring of heart failure management with an “especially sharp focus” on age, sex, race, and comorbidities.

Part of that, he predicted, might be a “thought experiment” involving the creation of a new category of heart failure that he dubbed HFmEF, or heart failure with midrange ejection fraction. Based on evidence presented at AHA, he continued, these patients with borderline or intermediate ejection fraction appear to respond to guideline-directed medical therapy in a fashion more similar to patients with HFrEF, yet they are clearly a distinct patient group from those with either preserved or reduced EF. That, he added, might have implications for first-line therapies, a question guideline-writing committees will no doubt wrestle with in the months to come.

For Harriette Van Spall, MD, MPH (McMaster University, Hamilton, Canada), the insights into ejection fraction and its interplay with sacubitril/valsartan are what unite the two reports. She won’t, for example, be using an ARNI in female patients with HFpEF, but she will be watching for further research into what may be a shifting threshold for initiating therapy based on EF.

“What these analyses show us is that there’s an interaction with EF such that the patients with the lower EFs derive the greatest benefit,” she told TCTMD. “The benefit of the drug diminishes as your EF increases, but females continue to derive benefit at higher ejection fractions than males did.”

All of these analyses are exploratory, Van Spall cautioned, given that the primary endpoint for PARAGON-HF was negative. “These newer findings to me are consistent with the older findings: it’s a great drug in patients with reduced EF, with a threshold of 40%, and there might be a continuation of benefit in the midrange of EFs but that effect diminishes as you approach persevered EF. We need more clinical trials to test the hypothesis that females might derive benefit at higher but reduced EF, but what the threshold should be is unknown.”

Both analyses, presented as late-breaking clinical trials at AHA 2019, were published simultaneously in Circulation.

Photo Credit: Copyright, American Heart Association. Used with permission.