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PHILADELPHIA – Two clinical trials of the combination therapy of the neprilysin inhibitor sacubitril and the angiotensin II receptor blocker valsartan in patients with heart failure and reduced ejection fraction found that it lowered rates of all-cause death, compared to a renin-angiotensin-system inhibitor alone.
Furthermore, the treatment produced a more beneficial effect in women, who are more prone to heart failure and preserved ejection fraction (HFpEF), lead investigators reported at the American Heart Association scientific sessions.
A prespecified subgroup analysis of 4,796 patients in the PARAGON-HF trial found that the sacubitril/valsartan, or sac/val, combination had a significantly more beneficial risk reduction of first and recurrent hospitalizations for heart failure, as well as cardiovascular death, in women than men. A prespecified pooled analysis of 13,195 patients in the PARAGON-HF and the PARADIGM-HF trials also found women derived a greater benefit from the combination therapy than men, but also concluded that patients with heart failure and even mildly reduced ejection fraction had better outcomes. The results of both studies were published simultaneously with the presentations on Nov. 17 in Circulation (doi: 10.1161/circulationaha.119.044491; doi: 10.1161/circulationaha.119.044586).
The findings underscore the effectiveness of sac/val combination in patients with HF and EF in the lower ranges, defined as 40% or less, commented discussant Lynne Warner Stevenson, MD, of Vanderbilt Heart and Vascular Institute in Nashville, Tenn. “We all agree now that the use of sacubitril/valsartan is very appropriate to improve outcomes in those patients, even if they’ve never been hospitalized,” she said in an interview.
PARAGON-HF subanalysis
John J.V. McMurray, MD, of the University of Glasgow presented the PARAGON-HF subgroup analysis. He said it initially focused on 12 subgroups, but that only two baseline variables showed a modified effect of sac/val: sex and left-ventricle ejection fraction (LVEF). The findings, he said, “stood up in a very robust, multivariable analysis.”
The women in the subgroup analysis were older, had higher baseline New York Heart Association class status, and worse quality of life as measured by Kansas City Cardiomyopathy Questionnaire clinical summary score. At baseline, women also had higher average LVEF (59% vs. 56%), lower N-terminal prohormone brain natriuretic peptide levels, and higher rates of renal dysfunction and chronic kidney disease, but lower incidence of a previous MI and coronary artery disease. Prestudy treatments were similar between the sexes.
In terms of the primary outcome – a composite of total hospitalizations for heart failure and cardiovascular death – “there was an apparent 27% relative risk reduction in women and no overall effect in men,” Dr. McMurray said of the treatment group. “The difference was driven completely by hospitalizations.” Rates of CV death were similar between the valsartan-only and sac/val groups in both men and women, he said.
In the analysis of LVEF, women in the treatment group seemed to cross over to a heightened risk of hospitalization and CV death at an LVEF in the 60%-65% range, Dr. McMurray said, whereas men made that cross over in the 50%-55% range. “It looks as though women might be getting more benefit from this treatment up to a higher EF than in men,” he said.
However, the differences between men and women did not hold up in the analysis of secondary outcomes. At 8 months, women in the sac/val group had a 0.6-point greater decline than did the valsartan-only patients in KCCQ-CSS score, whereas men on sac/val had a 2.8-point lesser decline than did those on valsartan only. Similar differences were seen between the treatment and valsartan-only groups within the sexes, with women showing a noticeable improvement surpassing the men.
Posttreatment hypotension rates in both sexes were higher in the sac/val groups, and the risk of renal dysfunction was a bit less in both treatment groups. Women in the treatment group had significantly higher rates of angioedema than did the valsartan-only group and men in either group.
“Compared to valsartan, it’s important to say that sacubitril/valsartan seemed to reduce the risk of heart failure and hospitalization more in women than men, but we didn’t find a similar differential for other endpoints,” Dr. McMurray said. “Therefore, we’re not sure this is a real effect or a chance finding. It’s very statistically robust, but it could still be a chance finding.”
A possible explanation could be than men may not be responding to sac/val, or that valsartan alone may be more effective in men than women, he said. “This possible effect modification of sac/val vs. valsartan by sex deserves further investigation,” he said.
PARAGON-HF and PARADIGM-HF pooled analysis
Likewise, the prespecified pooled analysis of the PARADIGM-HF and PARAGON-HF trials found a greater benefit of sac/val in women, according to results presented by Scott D. Solomon, MD, of Brigham and Women’s Hospital in Boston. Where PARAGON-HF compared combination therapy with valsartan 160 mg twice daily alone, PARADIGM-HF used enalapril 10 mg twice daily alone as the comparator renin-angiotensin-system (RAS) inhibitor.
“These data suggest that the therapeutic effect of sacubitril/valsartan vs. RAS inhibition alone appear to extend to patients with heart failure and mildly reduced EF, with therapeutic benefits that extend to a higher left-ventricle EF range in women compared to men,” Dr. Solomon said.
The pooled analysis divided patients into six different EF groups: up to 22.5%, then in 10-point increments from 22.5% to 62.5%, and 62.5% or greater. PARADIGM-HF enrolled patients age 18 years and older, whereas PARAGON-HF involved those aged 50 years and older.
The analysis showed that, as LVEF rates increased across the EF groups, the rates of the primary composite outcome – HF hospitalizations, CV death, and all-cause mortality – decreased, but the decline was greatest for CV death and less so for HF hospitalization. And while rates of all-cause mortality decreased as EF increased, rates of non-CV death increased substantially with increasing LVEF.
“For each of these endpoints, there are significant benefits to sacubitril/valsartan in the pooled analysis, and this includes HF hospitalization, CV death, either total or first events, and all-cause mortality, which was reduced overall by 12% in the combination group,” Dr. Solomon said. That benefit was seen in the first five categories of EF, but all but disappeared in the highest category (at least 62.5%), he said.
At the lower end of the EF spectrum, the effect of sac/val is more pronounced and similar for men and women, Dr. Solomon said. “But as EF goes up, we see an attenuation of that effect in both men and women, but it occurs at a different point,” he said. “Women seem to derive a benefit to a higher ejection fraction than men.” As in Dr. McMurray’s research, the benefit seems to extend to LVEF of 55%-60% in men and 65%-70% in women.
“These findings were driven by an observed benefit in patients with chronic heart failure and LVEF below the normal range,” he said. “The benefit in the EF range above the ranking ‘reduced’ but below normal was driven primarily by reduction in HF hospitalization.”
Dr. Stevenson said that these findings indicate that a previous hospitalization for HF with preserved EF may be a telling marker for the effectiveness of sac/val. “As opposed to the patient who has exertional dyspnea but has never decompensated to the level needing hospitalization, if they have pEF, our current analyses would suggest sac/val may not offer them much benefit,” she said.
In real-world practice, cost would be an issue, Dr. Stevenson said. “This drug is very expensive; the majority of patients pay more than $100 a month in out-of-pocket costs, and we have to recognize this is not a therapy that everyone can afford,” she said in an interview. “In many areas, and particularly in the disadvantaged populations, this is not going to be a therapy that we’re going to be able to offer everyone, and that gives me great concern as we move toward trying to treat the whole disease that we’re developing therapies that will be limited by finance rather than by physiology. That’s a major call to action for all of us.”
Novartis sponsored the studies. Dr. McMurray has no disclosures. Dr. Solomon disclosed financial relationships with trial sponsor Novartis along with numerous pharmaceutical companies and the National Heart, Lung, and Blood Institute.
SOURCE: McMurray JJ and Solomon SD. AHA 2019, Late Breaking Science Session 5.
PHILADELPHIA – Two clinical trials of the combination therapy of the neprilysin inhibitor sacubitril and the angiotensin II receptor blocker valsartan in patients with heart failure and reduced ejection fraction found that it lowered rates of all-cause death, compared to a renin-angiotensin-system inhibitor alone.
Furthermore, the treatment produced a more beneficial effect in women, who are more prone to heart failure and preserved ejection fraction (HFpEF), lead investigators reported at the American Heart Association scientific sessions.
A prespecified subgroup analysis of 4,796 patients in the PARAGON-HF trial found that the sacubitril/valsartan, or sac/val, combination had a significantly more beneficial risk reduction of first and recurrent hospitalizations for heart failure, as well as cardiovascular death, in women than men. A prespecified pooled analysis of 13,195 patients in the PARAGON-HF and the PARADIGM-HF trials also found women derived a greater benefit from the combination therapy than men, but also concluded that patients with heart failure and even mildly reduced ejection fraction had better outcomes. The results of both studies were published simultaneously with the presentations on Nov. 17 in Circulation (doi: 10.1161/circulationaha.119.044491; doi: 10.1161/circulationaha.119.044586).
The findings underscore the effectiveness of sac/val combination in patients with HF and EF in the lower ranges, defined as 40% or less, commented discussant Lynne Warner Stevenson, MD, of Vanderbilt Heart and Vascular Institute in Nashville, Tenn. “We all agree now that the use of sacubitril/valsartan is very appropriate to improve outcomes in those patients, even if they’ve never been hospitalized,” she said in an interview.
PARAGON-HF subanalysis
John J.V. McMurray, MD, of the University of Glasgow presented the PARAGON-HF subgroup analysis. He said it initially focused on 12 subgroups, but that only two baseline variables showed a modified effect of sac/val: sex and left-ventricle ejection fraction (LVEF). The findings, he said, “stood up in a very robust, multivariable analysis.”
The women in the subgroup analysis were older, had higher baseline New York Heart Association class status, and worse quality of life as measured by Kansas City Cardiomyopathy Questionnaire clinical summary score. At baseline, women also had higher average LVEF (59% vs. 56%), lower N-terminal prohormone brain natriuretic peptide levels, and higher rates of renal dysfunction and chronic kidney disease, but lower incidence of a previous MI and coronary artery disease. Prestudy treatments were similar between the sexes.
In terms of the primary outcome – a composite of total hospitalizations for heart failure and cardiovascular death – “there was an apparent 27% relative risk reduction in women and no overall effect in men,” Dr. McMurray said of the treatment group. “The difference was driven completely by hospitalizations.” Rates of CV death were similar between the valsartan-only and sac/val groups in both men and women, he said.
In the analysis of LVEF, women in the treatment group seemed to cross over to a heightened risk of hospitalization and CV death at an LVEF in the 60%-65% range, Dr. McMurray said, whereas men made that cross over in the 50%-55% range. “It looks as though women might be getting more benefit from this treatment up to a higher EF than in men,” he said.
However, the differences between men and women did not hold up in the analysis of secondary outcomes. At 8 months, women in the sac/val group had a 0.6-point greater decline than did the valsartan-only patients in KCCQ-CSS score, whereas men on sac/val had a 2.8-point lesser decline than did those on valsartan only. Similar differences were seen between the treatment and valsartan-only groups within the sexes, with women showing a noticeable improvement surpassing the men.
Posttreatment hypotension rates in both sexes were higher in the sac/val groups, and the risk of renal dysfunction was a bit less in both treatment groups. Women in the treatment group had significantly higher rates of angioedema than did the valsartan-only group and men in either group.
“Compared to valsartan, it’s important to say that sacubitril/valsartan seemed to reduce the risk of heart failure and hospitalization more in women than men, but we didn’t find a similar differential for other endpoints,” Dr. McMurray said. “Therefore, we’re not sure this is a real effect or a chance finding. It’s very statistically robust, but it could still be a chance finding.”
A possible explanation could be than men may not be responding to sac/val, or that valsartan alone may be more effective in men than women, he said. “This possible effect modification of sac/val vs. valsartan by sex deserves further investigation,” he said.
PARAGON-HF and PARADIGM-HF pooled analysis
Likewise, the prespecified pooled analysis of the PARADIGM-HF and PARAGON-HF trials found a greater benefit of sac/val in women, according to results presented by Scott D. Solomon, MD, of Brigham and Women’s Hospital in Boston. Where PARAGON-HF compared combination therapy with valsartan 160 mg twice daily alone, PARADIGM-HF used enalapril 10 mg twice daily alone as the comparator renin-angiotensin-system (RAS) inhibitor.
“These data suggest that the therapeutic effect of sacubitril/valsartan vs. RAS inhibition alone appear to extend to patients with heart failure and mildly reduced EF, with therapeutic benefits that extend to a higher left-ventricle EF range in women compared to men,” Dr. Solomon said.
The pooled analysis divided patients into six different EF groups: up to 22.5%, then in 10-point increments from 22.5% to 62.5%, and 62.5% or greater. PARADIGM-HF enrolled patients age 18 years and older, whereas PARAGON-HF involved those aged 50 years and older.
The analysis showed that, as LVEF rates increased across the EF groups, the rates of the primary composite outcome – HF hospitalizations, CV death, and all-cause mortality – decreased, but the decline was greatest for CV death and less so for HF hospitalization. And while rates of all-cause mortality decreased as EF increased, rates of non-CV death increased substantially with increasing LVEF.
“For each of these endpoints, there are significant benefits to sacubitril/valsartan in the pooled analysis, and this includes HF hospitalization, CV death, either total or first events, and all-cause mortality, which was reduced overall by 12% in the combination group,” Dr. Solomon said. That benefit was seen in the first five categories of EF, but all but disappeared in the highest category (at least 62.5%), he said.
At the lower end of the EF spectrum, the effect of sac/val is more pronounced and similar for men and women, Dr. Solomon said. “But as EF goes up, we see an attenuation of that effect in both men and women, but it occurs at a different point,” he said. “Women seem to derive a benefit to a higher ejection fraction than men.” As in Dr. McMurray’s research, the benefit seems to extend to LVEF of 55%-60% in men and 65%-70% in women.
“These findings were driven by an observed benefit in patients with chronic heart failure and LVEF below the normal range,” he said. “The benefit in the EF range above the ranking ‘reduced’ but below normal was driven primarily by reduction in HF hospitalization.”
Dr. Stevenson said that these findings indicate that a previous hospitalization for HF with preserved EF may be a telling marker for the effectiveness of sac/val. “As opposed to the patient who has exertional dyspnea but has never decompensated to the level needing hospitalization, if they have pEF, our current analyses would suggest sac/val may not offer them much benefit,” she said.
In real-world practice, cost would be an issue, Dr. Stevenson said. “This drug is very expensive; the majority of patients pay more than $100 a month in out-of-pocket costs, and we have to recognize this is not a therapy that everyone can afford,” she said in an interview. “In many areas, and particularly in the disadvantaged populations, this is not going to be a therapy that we’re going to be able to offer everyone, and that gives me great concern as we move toward trying to treat the whole disease that we’re developing therapies that will be limited by finance rather than by physiology. That’s a major call to action for all of us.”
Novartis sponsored the studies. Dr. McMurray has no disclosures. Dr. Solomon disclosed financial relationships with trial sponsor Novartis along with numerous pharmaceutical companies and the National Heart, Lung, and Blood Institute.
SOURCE: McMurray JJ and Solomon SD. AHA 2019, Late Breaking Science Session 5.
PHILADELPHIA – Two clinical trials of the combination therapy of the neprilysin inhibitor sacubitril and the angiotensin II receptor blocker valsartan in patients with heart failure and reduced ejection fraction found that it lowered rates of all-cause death, compared to a renin-angiotensin-system inhibitor alone.
Furthermore, the treatment produced a more beneficial effect in women, who are more prone to heart failure and preserved ejection fraction (HFpEF), lead investigators reported at the American Heart Association scientific sessions.
A prespecified subgroup analysis of 4,796 patients in the PARAGON-HF trial found that the sacubitril/valsartan, or sac/val, combination had a significantly more beneficial risk reduction of first and recurrent hospitalizations for heart failure, as well as cardiovascular death, in women than men. A prespecified pooled analysis of 13,195 patients in the PARAGON-HF and the PARADIGM-HF trials also found women derived a greater benefit from the combination therapy than men, but also concluded that patients with heart failure and even mildly reduced ejection fraction had better outcomes. The results of both studies were published simultaneously with the presentations on Nov. 17 in Circulation (doi: 10.1161/circulationaha.119.044491; doi: 10.1161/circulationaha.119.044586).
The findings underscore the effectiveness of sac/val combination in patients with HF and EF in the lower ranges, defined as 40% or less, commented discussant Lynne Warner Stevenson, MD, of Vanderbilt Heart and Vascular Institute in Nashville, Tenn. “We all agree now that the use of sacubitril/valsartan is very appropriate to improve outcomes in those patients, even if they’ve never been hospitalized,” she said in an interview.
PARAGON-HF subanalysis
John J.V. McMurray, MD, of the University of Glasgow presented the PARAGON-HF subgroup analysis. He said it initially focused on 12 subgroups, but that only two baseline variables showed a modified effect of sac/val: sex and left-ventricle ejection fraction (LVEF). The findings, he said, “stood up in a very robust, multivariable analysis.”
The women in the subgroup analysis were older, had higher baseline New York Heart Association class status, and worse quality of life as measured by Kansas City Cardiomyopathy Questionnaire clinical summary score. At baseline, women also had higher average LVEF (59% vs. 56%), lower N-terminal prohormone brain natriuretic peptide levels, and higher rates of renal dysfunction and chronic kidney disease, but lower incidence of a previous MI and coronary artery disease. Prestudy treatments were similar between the sexes.
In terms of the primary outcome – a composite of total hospitalizations for heart failure and cardiovascular death – “there was an apparent 27% relative risk reduction in women and no overall effect in men,” Dr. McMurray said of the treatment group. “The difference was driven completely by hospitalizations.” Rates of CV death were similar between the valsartan-only and sac/val groups in both men and women, he said.
In the analysis of LVEF, women in the treatment group seemed to cross over to a heightened risk of hospitalization and CV death at an LVEF in the 60%-65% range, Dr. McMurray said, whereas men made that cross over in the 50%-55% range. “It looks as though women might be getting more benefit from this treatment up to a higher EF than in men,” he said.
However, the differences between men and women did not hold up in the analysis of secondary outcomes. At 8 months, women in the sac/val group had a 0.6-point greater decline than did the valsartan-only patients in KCCQ-CSS score, whereas men on sac/val had a 2.8-point lesser decline than did those on valsartan only. Similar differences were seen between the treatment and valsartan-only groups within the sexes, with women showing a noticeable improvement surpassing the men.
Posttreatment hypotension rates in both sexes were higher in the sac/val groups, and the risk of renal dysfunction was a bit less in both treatment groups. Women in the treatment group had significantly higher rates of angioedema than did the valsartan-only group and men in either group.
“Compared to valsartan, it’s important to say that sacubitril/valsartan seemed to reduce the risk of heart failure and hospitalization more in women than men, but we didn’t find a similar differential for other endpoints,” Dr. McMurray said. “Therefore, we’re not sure this is a real effect or a chance finding. It’s very statistically robust, but it could still be a chance finding.”
A possible explanation could be than men may not be responding to sac/val, or that valsartan alone may be more effective in men than women, he said. “This possible effect modification of sac/val vs. valsartan by sex deserves further investigation,” he said.
PARAGON-HF and PARADIGM-HF pooled analysis
Likewise, the prespecified pooled analysis of the PARADIGM-HF and PARAGON-HF trials found a greater benefit of sac/val in women, according to results presented by Scott D. Solomon, MD, of Brigham and Women’s Hospital in Boston. Where PARAGON-HF compared combination therapy with valsartan 160 mg twice daily alone, PARADIGM-HF used enalapril 10 mg twice daily alone as the comparator renin-angiotensin-system (RAS) inhibitor.
“These data suggest that the therapeutic effect of sacubitril/valsartan vs. RAS inhibition alone appear to extend to patients with heart failure and mildly reduced EF, with therapeutic benefits that extend to a higher left-ventricle EF range in women compared to men,” Dr. Solomon said.
The pooled analysis divided patients into six different EF groups: up to 22.5%, then in 10-point increments from 22.5% to 62.5%, and 62.5% or greater. PARADIGM-HF enrolled patients age 18 years and older, whereas PARAGON-HF involved those aged 50 years and older.
The analysis showed that, as LVEF rates increased across the EF groups, the rates of the primary composite outcome – HF hospitalizations, CV death, and all-cause mortality – decreased, but the decline was greatest for CV death and less so for HF hospitalization. And while rates of all-cause mortality decreased as EF increased, rates of non-CV death increased substantially with increasing LVEF.
“For each of these endpoints, there are significant benefits to sacubitril/valsartan in the pooled analysis, and this includes HF hospitalization, CV death, either total or first events, and all-cause mortality, which was reduced overall by 12% in the combination group,” Dr. Solomon said. That benefit was seen in the first five categories of EF, but all but disappeared in the highest category (at least 62.5%), he said.
At the lower end of the EF spectrum, the effect of sac/val is more pronounced and similar for men and women, Dr. Solomon said. “But as EF goes up, we see an attenuation of that effect in both men and women, but it occurs at a different point,” he said. “Women seem to derive a benefit to a higher ejection fraction than men.” As in Dr. McMurray’s research, the benefit seems to extend to LVEF of 55%-60% in men and 65%-70% in women.
“These findings were driven by an observed benefit in patients with chronic heart failure and LVEF below the normal range,” he said. “The benefit in the EF range above the ranking ‘reduced’ but below normal was driven primarily by reduction in HF hospitalization.”
Dr. Stevenson said that these findings indicate that a previous hospitalization for HF with preserved EF may be a telling marker for the effectiveness of sac/val. “As opposed to the patient who has exertional dyspnea but has never decompensated to the level needing hospitalization, if they have pEF, our current analyses would suggest sac/val may not offer them much benefit,” she said.
In real-world practice, cost would be an issue, Dr. Stevenson said. “This drug is very expensive; the majority of patients pay more than $100 a month in out-of-pocket costs, and we have to recognize this is not a therapy that everyone can afford,” she said in an interview. “In many areas, and particularly in the disadvantaged populations, this is not going to be a therapy that we’re going to be able to offer everyone, and that gives me great concern as we move toward trying to treat the whole disease that we’re developing therapies that will be limited by finance rather than by physiology. That’s a major call to action for all of us.”
Novartis sponsored the studies. Dr. McMurray has no disclosures. Dr. Solomon disclosed financial relationships with trial sponsor Novartis along with numerous pharmaceutical companies and the National Heart, Lung, and Blood Institute.
SOURCE: McMurray JJ and Solomon SD. AHA 2019, Late Breaking Science Session 5.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS