PARAGON-HF: Sacubitril/valsartan benefit in HFpEF most prominent in women, lower EF
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PHILADELPHIA — Sacubitril/valsartan reduced the risk for HF hospitalization more in women compared with men, and the overall benefit of sacubitril/valsartan was driven by a benefit in patients with chronic HF and a left ventricular ejection fraction below the normal range, according to two analyses of the PARAGON-HF trial of patients with HF with preserved EF presented at the American Heart Association Scientific Sessions.
The sex difference was not observed for quality of life, NYHA class and worsening renal function, according to the researchers. Both analyses were simultaneously published in Circulation.
As Healio previously reported at the European Society of Cardiology Congress in September, sacubitril/valsartan (Entresto, Novartis) did not reduce the rate of hospitalizations for CV-related death and HF in patients with HF with preserved ejection fraction, defined as at least 45%. In the subgroup analyses of the trial, only sex and left ventricular ejection fraction modified the effect of sacubitril/valsartan compared with valsartan alone for the primary outcome, which was CV death and total first and recurrent HF hospitalizations.
Women vs. men
In this analysis, researchers analyzed data from 2,479 women (mean age, 74 years; mean LVEF, 59%) and 2,317 men (mean age, 72 years; mean LVEF, 56%).
“We don’t have any effective treatments for [HFpEF], and that is the type of heart failure that affects women more than the other major phenotype, HFrEF, which is more of a male disease,” John J.V. McMurray, MD, professor of cardiology at the Institute of Cardiovascular and Medical Sciences at University of Glasgow in Scotland, said during the press conference. “There is, in a way, a greater therapeutic deficit for women with heart failure than for men with heart failure because women are more afflicted by the HFpEF phenotype.”
Sacubitril/valsartan was linked to a further reduction in the primary outcome (RR = 0.73; 95% CI, 0.59-0.9) compared with men (RR = 1.03; 95% CI, 0.84-1.25; P for interaction = .017)), which was mainly driven by total HF hospitalizations (RR in women = 0.67; 95% CI, 0.53-0.85; RR in men = 1.07; 95% CI, 0.85-1.34; P for interaction = .0046). There was no difference in CV mortality in women (HR = 1.02; 95% CI, 0.76-1.36) and men (HR = 0.9; 95% CI, 0.7-1.17; P for interaction = .5763).
“What we think we’ve seen is that sacubitril/valsartan compared to valsartan reduces the risk of HF hospitalizations,” McMurray said during the press conference.
There was a small reduction in Kansas City Cardiomyopathy Questionnaire score in both men and women, which indicates a deterioration in quality of life.
“We didn’t see any advantage in women over men with sacubitril/valsartan looking at quality of life,” McMurray said during the press conference.
There were also no advantages between women and men for NYHA class, although it tended to improve with sacubitril/valsartan compared with valsartan alone. No advantages were observed in women compared with men regarding worsening renal function. There were also no differences for all-cause mortality in women (HR = 0.96; 95% CI, 0.77-1.2) compared with men (HR = 0.97; 95% CI, 0.8-1.19; P for interaction = .904).
Women had fewer adverse events with sacubitril/valsartan compared with men except for angioedema (0.9% vs. 0.3%). Hypotension was more common in patients assigned sacubitril/valsartan (15.7% for women and 15.9% for men) compared with those assigned valsartan alone (9.9% for women and 11.7% for men).
“Our conclusion is that we need to look into this question more probably not just for sacubitril/valsartan, but actually for all treatments used in heart failure,” McMurray said during the press conference.
Range of EF
In a separate analysis, researchers assessed data in which patients from both the PARAGON-HF and PARADIGM-HF trials were stratified by EF.
“We have recently completed the PARAGON-HF trial, and that allows us to take the data from both the PARAGON and the PARADIGM trials, which are the two large outcomes trials with sacubitril/valsartan and pooled them in a prespecified pooled analysis,” Scott D. Solomon, MD, Edward D. Frohlich Distinguished Chair and professor of medicine at Harvard Medical School, senior physician at Brigham and Women’s Hospital and executive committee co-chair of the PARAGON-HF trial, said during the press conference. “This allows for examination of the effect of sacubitril/valsartan across the full spectrum of ejection fraction.”
PARADIGM-HF was similar in design to PARAGON-HF, in which sacubitril/valsartan was compared with enalapril for the reduction of death and HF hospitalization in patients with HF with reduced EF.
This analysis included 13,195 patients from both trials whose EFs were measured at sites. Patients were then divided into the following EF groups:
- 22.5% (n = 1,269; mean age, 61 years; 19% women),
- > 22.5% to 32.5% (n = 3,987; mean age, 63 years; 21% women);
- > 32.5% to 42.5% (n = 3,143; mean age, 66 years; 24% women);
- > 42.5% to 52.5% (n = 1,427; mean age, 71 years; 40% women);
- > 52.5% to 62.5% (n = 2,166; mean age, 73 years; 54% women); and
- > 62.5% (n = 1,202; mean age, 74 years; 63% women).
Researchers assessed time to first composite of CV death or HF hospitalization — PARADIGM’s primary endpoint — and a composite of total HF hospitalizations and CV death, which was PARAGON’s primary endpoint.
Sacubitril/valsartan was superior to renin-angiotensin system inhibition for CV death (HR = 0.84; 95% CI, 0.76-0.92), all-cause mortality (HR = 0.88; 95% CI, 0.81-0.96), HF hospitalization (HR = 0.84; 95% CI, 0.77-0.91) and first CV death or HF hospitalization (HR = 0.84; 95% CI, 0.78-0.9), according to the researchers.
However, the treatment effect of sacubitril/valsartan was greatest in patients with LVEF below the normal range (P for interaction = .02), though the CV death benefit of sacubitril/valsartan was diminished in patients in the lower EF range.
The incidence of non-CV death was similar across all EF categories, although the proportion of patients with non-CV death when considered among total deaths was higher in patients at the highest end of the EF spectrum.
Patients with lower EF had higher rates of hypotension and hyperkalemia. Serum creatinine elevations were similar across EFs.
“These data suggest that the benefits of sacubitril/valsartan compared to RAS inhibitors alone appear to extend to patients with heart failure and mildly reduced ejection fraction with benefits that may even go higher in women than in men,” Solomon said during the press conference.
In a discussant presentation, Lynne Warner Stevenson, MD, Lisa M. Jacobson Professor of Cardiovascular Medicine at Vanderbilt Heart and Vascular Institute, said “It appears that sacubitril/valsartan has impact to decrease hospitalizations for congestion across ejection fraction whether it’s reduced or preserved, but perhaps disease progression and cardiac mortality present better targets if you have a low EF than if you have a preserved EF. It’s particularly important that we understand the patients who benefit and how they benefit for all of the new therapies we’re considering both for this and for dapagliflozin.”
“These new data suggesting potential benefit of Entresto beyond HFrEF represent our ongoing work to develop treatments for patients, including for HFpEF, a complex condition with high unmet patient need,” David Soergel, MD, global head of cardiovascular, renal and metabolic drug development at Novartis, said in a press release.– by Darlene Dobkowski
References:
McMurray JJV, et al.
Solomon SD, et al. Late Breaking Science V: Challenges in Heart Failure Management. Both presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.
McMurray JJV, et al. Circulation. 2019;doi:10.1161.CIRCULATIONAHA.119.044491.
Solomon SD, et al. Circulation. 2019;doi:10.1161/CIRCULATIONAHA.119.044586.
Disclosures: The PARAGON-HF and PARADIGM-HF trials were supported by Novartis. McMurray reports his institution has financial relationships with Abbvie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardiorentis, DalCor Pharmaceuticals, Glaxosmithkline, Merck, Novartis, Oxford University, Pfizer and Theracos. Solomon reports he received institutional research grants from Alnylam, Amgen, AstraZeneca, Bayer, Bellerophon, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur and Theracos and consultant fees from Alnylam, Amgen, AoBiome, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardiac Dimensions, Corvia, Cytokinetics, Daichi Sankyo, Gilead, GlaxoSmithKline, Ironwood, Janssen, Merck, MyoKardia, Novartis, Quantum Genomics, Roche, Takeda, Tenaya and Theracos. Please see the studies for all other authors’ relevant financial disclosures. Soergel is an employee of Novartis. Stevenson reports she serves on a data safety monitoring board for LivaNova.
Perspective
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Mark Drazner, MD
In the current guidelines, we look at EFs and classify patients with HF based on their LVEF. For the patients who have higher EFs (> 40%), we don’t really have a strong evidence base. PARAGON-HF took patients with an EF of more than 45%, and although the overall trial did not quite reach its primary endpoint, when the investigators published their results, they noted that two of the 12 subgroups seem to derive particular benefit from angiotensin receptor-neprilysin inhibitor therapy: women and those who had an EF below their median, which was 57%.
What we learned at AHA was that there was not consistency of the apparent greater benefit in women than men across multiple outcomes. Specifically, we did not see that women derived more benefit than men regarding NYHA class, Kansas City Cardiomyopathy Questionnaire score and renal preservation.
There is biological plausibility that women may redrive more benefit than men in patients with LVEFs greater than 45%. For example, in the general population, women have an LVEF about three points higher than men. We published that from the Dallas Heart Study in Circulation a number of years ago. That observation suggests that when you move down to a slightly less than normal EF, maybe there’s more dysfunction in the hearts of women than men (since the women started higher).
However, whenever you start looking at many different subgroups and you come up with some that stand out, you have to be cautious. There’s always the possibility that if you look at enough subgroups, just by change, you’re going to find something that looks interesting, but then when you repeat the experiment prospectively, you don’t confirm the finding. Based on the totality of evidence now available, it is plausible that the apparent benefit in women seen in PARAGON-HF may have been due to a play of chance. We definitely need additional studies because this is an important question.
The second analysis presented combined PARADIGM-HF and PARAGON-HF. That analysis showed that the benefit of angiotensin receptor-neprilysin inhibitors seemed to persist even in patients with LVEFs higher than 40% but less than approximately 60%. It is somewhere in what has been called midrange or mildly reduced LVEF. Is it possible that angiotensin receptor-neprilysin inhibitors would be effective in that subgroup? That would be very important because we don’t have any proven therapies for patients with HF and LVEFs greater than 40%.
In my opinion, this analysis is hypothesis-generating. I believe that you need to do a trial specifically in patients with HF who have an LVEF in the 40% to 55% range to show that the benefits being demonstrated in this combined PARADIGM-HF/PARAGON-HF analysis can be replicated in a prospective trial.
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