Meeting NewsPerspective

PARAGON-HF: Sacubitril/valsartan misses primary endpoint for HFpEF; may still provide insight into unmet need

Scott D. Solomon

PARIS — Sacubitril/valsartan 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%, according to a hot line trial presented at the European Society of Cardiology Congress.

Results from this trial were also published in The New England Journal of Medicine.

“These findings suggest that in this disease with no evidence-based therapy currently and a huge unmet need, some patients with heart failure with preserved ejection fraction, particularly those with ejection fractions below normal but not frankly reduced for whom there is currently no evidence-based therapy, may benefit from sacubitril/valsartan,” 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 trial, said during a press conference.

Study design

Researchers analyzed data from 4,822 patients aged 50 years or older with signs and symptoms of HF, an EF of 45% or greater within the past 6 months, NYHA class II to IV, evidence of structural heart disease, elevated level of natriuretic peptides and diuretic therapy.

“We enrolled patients who were very representative of what we see in general in patients with HFpEF,” Solomon said during the Q&A portion of the press conference. “In contrast to prior studies, we required that patients in this study have evidence of structural heart disease. We required them to have some elevation of natriuretic peptides, so we were pretty confident that they in fact did have heart failure.”

Patients (mean age, 73 years; 52% women) initially underwent a run-in period when they received a half dose of valsartan then a half dose of sacubitril/valsartan (Entresto, Novartis). If no side effects occurred, patients were assigned either 97 mg of sacubitril with 103 mg of valsartan twice per day or 160 mg of valsartan twice per day.

“One-hundred and three mg of valsartan in sacubitril/valsartan is biologically equivalent to 160 mg of standard valsartan,” Solomon said during the press conference. “This was on top of optimal background medications for all their comorbidities, excluding ACE inhibitors or ARBs.”

The primary outcome was a composite of CV death and total hospitalizations for HF. Secondary outcomes included a change from baseline to 8 months in NYHA class, change from baseline to 8 months in the Kansas City Cardiomyopathy Questionnaire, all-cause death and first occurrence of a decline in renal function. Evaluations were performed every 4 weeks to 16 weeks for a median of 35 months.

Events during follow-up

During follow-up, 894 primary outcome events occurred in 526 patients in the sacubitril/valsartan group vs. 1,009 primary outcome events in 557 patients in the valsartan group (rate ratio [RR] = 0.87; 95% CI, 0.75-1.01).

There were 690 hospitalizations for HF in patients assigned sacubitril/valsartan compared with 797 HF hospitalizations in those assigned valsartan (RR = 0.85; 95% CI, 0.72-1). CV death occurred in 8.5% of patients in the sacubitril/valsartan group compared with 8.9% of those in the valsartan group (HR = 0.95; 95% CI, 0.79-1.16).

At 8 months, 15% of patients assigned sacubitril/valsartan had an improvement in NYHA class, compared with 12.6% of those assigned valsartan (OR = 1.45; 95% CI, 1.13-1.86). Renal function worsened in 1.4% of patients in the sacubitril/valsartan group and 2.7% of those assigned valsartan (HR = 0.5; 95% CI, 0.33-0.77). The sacubitril/valsartan group had a greater change in Kansas City Cardiomyopathy Questionnaire clinical summary score compared with the valsartan group (mean change = 1; 95% CI, 0-2.1).

The incidence of hypotension and angioedema was higher in patients assigned sacubitril-valsartan compared with valsartan alone. In contrast, these patients had lower incidence of hyperkalemia.

“The safety and tolerability was similar to that in PARADIGM with more hypotension, but less elevation in serum creatinine and less elevation in potassium with sacubitril-valsartan compared with valsartan,” Solomon said during the press conference.

There was a suggestion of heterogeneity among 12 prespecified subgroups, and those analyses showed a possible benefit from sacubitril/valsartan in women and in those with EF at or below the median of 57%, Solomon said.

Interpreting results

Although patients with HFpEF may not have benefitted from sacubitril/valsartan as much as anticipated, this trial helped determine who may benefit from this therapy, Solomon said.

“Our data suggest that in patients with what has been recently termed ‘heart failure with mid-range ejection fraction’ and somewhat higher, basically the point at which ejection fraction becomes normal, that these patients would indeed benefit from sacubitril/valsartan,” Solomon said during the Q&A portion of the press conference. “Both the relative risk reduction and the absolute risk reduction was quite high in those patients. It’s a group of patients with currently unmet needs.”

Although several P values in this study did not reach statistical significance, data from this trial should still be seen in a positive light, experts said.

“In view of clinical trials as being totally positive because you were at 0.049 and totally negative because you’re at 0.051 is misleading,” P. Gabriel Steg, MD, professor at Université Paris-Diderot and at the National Heart and Lung Institute at Imperial College in London, said during the Q&A portion of the press conference. “This is why many in the field are moving into different types of analyses, which gives us a little more leeway in interpreting the data. Second, the unmet need in this population is absolutely huge. We have nothing that we can show benefit. Everything in this trial points to substantial potential benefit.”

Deepak L. Bhatt

Cardiology Today’s Intervention Chief Medical Editor Deepak L. Bhatt, MD, MPH, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs in the Heart and Vascular Center at Brigham and Women’s Hospital, added, “These results are really fascinating. I look at the totality of the evidence, as most good practicing physicians do. PARADIGM was clearly a very positive trial. ... We often say, ‘We have 55%, it’s not so bad,’ but that’s an abnormal ejection fraction. The way that I interpret the [PARAGON-HF] trial is that the drug worked in those patients with an ejection fraction that was low-ish, but not conventionally ... reduced ejection fraction.” – by Darlene Dobkowski

References:

Solomon SD, et al. Hot Line Session 1. Presented at: European Society of Cardiology Congress; Aug. 31 to Sept. 4, 2019; Paris.

Solomon SD, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1908655.

Disclosures: The trial was supported by Novartis. Solomon reports he received 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 personal fees from Akros, Alnylam, Amgen, AoBiome, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardiac Dimensions, Corvia, Cytokinetics, Daiichi Sankyo, Gilead, GlaxoSmithKline, Ironwood, Janssen, Merck, MyoKardia, Novartis, Quantum Genomics, Roche, Takeda, Tenaya and Theracos. Bhatt reports he has financial ties with numerous drug and device companies. Steg reports he has financial ties with Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Idorsia, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi and Servier. Please see the study for all other authors’ relevant financial disclosures.

Scott D. Solomon

PARIS — Sacubitril/valsartan 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%, according to a hot line trial presented at the European Society of Cardiology Congress.

Results from this trial were also published in The New England Journal of Medicine.

“These findings suggest that in this disease with no evidence-based therapy currently and a huge unmet need, some patients with heart failure with preserved ejection fraction, particularly those with ejection fractions below normal but not frankly reduced for whom there is currently no evidence-based therapy, may benefit from sacubitril/valsartan,” 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 trial, said during a press conference.

Study design

Researchers analyzed data from 4,822 patients aged 50 years or older with signs and symptoms of HF, an EF of 45% or greater within the past 6 months, NYHA class II to IV, evidence of structural heart disease, elevated level of natriuretic peptides and diuretic therapy.

“We enrolled patients who were very representative of what we see in general in patients with HFpEF,” Solomon said during the Q&A portion of the press conference. “In contrast to prior studies, we required that patients in this study have evidence of structural heart disease. We required them to have some elevation of natriuretic peptides, so we were pretty confident that they in fact did have heart failure.”

Patients (mean age, 73 years; 52% women) initially underwent a run-in period when they received a half dose of valsartan then a half dose of sacubitril/valsartan (Entresto, Novartis). If no side effects occurred, patients were assigned either 97 mg of sacubitril with 103 mg of valsartan twice per day or 160 mg of valsartan twice per day.

“One-hundred and three mg of valsartan in sacubitril/valsartan is biologically equivalent to 160 mg of standard valsartan,” Solomon said during the press conference. “This was on top of optimal background medications for all their comorbidities, excluding ACE inhibitors or ARBs.”

The primary outcome was a composite of CV death and total hospitalizations for HF. Secondary outcomes included a change from baseline to 8 months in NYHA class, change from baseline to 8 months in the Kansas City Cardiomyopathy Questionnaire, all-cause death and first occurrence of a decline in renal function. Evaluations were performed every 4 weeks to 16 weeks for a median of 35 months.

PAGE BREAK

Events during follow-up

During follow-up, 894 primary outcome events occurred in 526 patients in the sacubitril/valsartan group vs. 1,009 primary outcome events in 557 patients in the valsartan group (rate ratio [RR] = 0.87; 95% CI, 0.75-1.01).

There were 690 hospitalizations for HF in patients assigned sacubitril/valsartan compared with 797 HF hospitalizations in those assigned valsartan (RR = 0.85; 95% CI, 0.72-1). CV death occurred in 8.5% of patients in the sacubitril/valsartan group compared with 8.9% of those in the valsartan group (HR = 0.95; 95% CI, 0.79-1.16).

At 8 months, 15% of patients assigned sacubitril/valsartan had an improvement in NYHA class, compared with 12.6% of those assigned valsartan (OR = 1.45; 95% CI, 1.13-1.86). Renal function worsened in 1.4% of patients in the sacubitril/valsartan group and 2.7% of those assigned valsartan (HR = 0.5; 95% CI, 0.33-0.77). The sacubitril/valsartan group had a greater change in Kansas City Cardiomyopathy Questionnaire clinical summary score compared with the valsartan group (mean change = 1; 95% CI, 0-2.1).

The incidence of hypotension and angioedema was higher in patients assigned sacubitril-valsartan compared with valsartan alone. In contrast, these patients had lower incidence of hyperkalemia.

“The safety and tolerability was similar to that in PARADIGM with more hypotension, but less elevation in serum creatinine and less elevation in potassium with sacubitril-valsartan compared with valsartan,” Solomon said during the press conference.

There was a suggestion of heterogeneity among 12 prespecified subgroups, and those analyses showed a possible benefit from sacubitril/valsartan in women and in those with EF at or below the median of 57%, Solomon said.

Interpreting results

Although patients with HFpEF may not have benefitted from sacubitril/valsartan as much as anticipated, this trial helped determine who may benefit from this therapy, Solomon said.

“Our data suggest that in patients with what has been recently termed ‘heart failure with mid-range ejection fraction’ and somewhat higher, basically the point at which ejection fraction becomes normal, that these patients would indeed benefit from sacubitril/valsartan,” Solomon said during the Q&A portion of the press conference. “Both the relative risk reduction and the absolute risk reduction was quite high in those patients. It’s a group of patients with currently unmet needs.”

Although several P values in this study did not reach statistical significance, data from this trial should still be seen in a positive light, experts said.

“In view of clinical trials as being totally positive because you were at 0.049 and totally negative because you’re at 0.051 is misleading,” P. Gabriel Steg, MD, professor at Université Paris-Diderot and at the National Heart and Lung Institute at Imperial College in London, said during the Q&A portion of the press conference. “This is why many in the field are moving into different types of analyses, which gives us a little more leeway in interpreting the data. Second, the unmet need in this population is absolutely huge. We have nothing that we can show benefit. Everything in this trial points to substantial potential benefit.”

PAGE BREAK
Deepak L. Bhatt

Cardiology Today’s Intervention Chief Medical Editor Deepak L. Bhatt, MD, MPH, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs in the Heart and Vascular Center at Brigham and Women’s Hospital, added, “These results are really fascinating. I look at the totality of the evidence, as most good practicing physicians do. PARADIGM was clearly a very positive trial. ... We often say, ‘We have 55%, it’s not so bad,’ but that’s an abnormal ejection fraction. The way that I interpret the [PARAGON-HF] trial is that the drug worked in those patients with an ejection fraction that was low-ish, but not conventionally ... reduced ejection fraction.” – by Darlene Dobkowski

References:

Solomon SD, et al. Hot Line Session 1. Presented at: European Society of Cardiology Congress; Aug. 31 to Sept. 4, 2019; Paris.

Solomon SD, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1908655.

Disclosures: The trial was supported by Novartis. Solomon reports he received 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 personal fees from Akros, Alnylam, Amgen, AoBiome, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardiac Dimensions, Corvia, Cytokinetics, Daiichi Sankyo, Gilead, GlaxoSmithKline, Ironwood, Janssen, Merck, MyoKardia, Novartis, Quantum Genomics, Roche, Takeda, Tenaya and Theracos. Bhatt reports he has financial ties with numerous drug and device companies. Steg reports he has financial ties with Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Idorsia, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi and Servier. Please see the study for all other authors’ relevant financial disclosures.

    Perspective
    Ileana L. Pina

    Ileana L. Pina

    I am not surprised with the results of this trial because I don’t think that we have even defined HFpEF truly. It is probably a mixture of syndromes. The definition that was used here was that they had to have some diastolic dysfunction and an EF of over 45%, but some patients ended up with a little bit lower EF in the group.

    Researchers are comparing it to valsartan, so the only advantage would be the sacubitril piece. The fact that the N-terminal pro-B natriuretic peptide went down doesn’t surprise me. It’s the sacubitril that is doing that.

    This trial did not have a lot of patients from the U.S., including almost no African Americans. In the practices that I’ve been in, most of my HFpEF patients are women, they’re older, they’re obese. The trial excluded patients with obesity. I was an investigator for PARAGON when I was in New York, and I had a hard time recruiting because a lot of my patients were overweight. I’ve spoken with Dr. Solomon about why he excluded patients with obesity, and he said it was due to the fact that they didn’t want to have obesity as the disease entity so the patients were limited in symptoms because of the obesity. Excluding those patients may have excluded an important population.

    We know what angiotensin receptor blockers do in HFpEF because we did the CHARM-Preserved trial (Yusef S, et al. Lancet. 2003;doi:10.1016/S0140-6736(03)14285-7.). The population here is very similar to CHARM-Preserved, and CHARM-Preserved had a very modest reduction in endpoints, but it had a lot of reduction in symptoms.

    The amount of mineralocorticoid receptor antagonists used was not that high. It was 24%, which is very low. Right now, I as a practicing HF doctor use a lot of mineralocorticoid receptor antagonists with the angiotensin receptor blockers and it works. You wonder what the results could have looked like if there had been more.

    The mortality rate was very low in this study, so this was not a very sick group of patients. If you look at the NYHA class, most patients are class I and a few in class II. If these were sicker patients with obesity, the results may have been better.

    The other interesting thing was that the Kansas City Cardiomyopathy Questionnaire score didn’t change much of anything. We changed it more with exercise. I found the Kansas City Cardiomyopathy Questionnaire score difference striking because I do a lot of things with that score. I’m sure researchers are going to review the women separately, but women always come in with a worse quality of life and more symptoms, but yet better survival.

    It’s the wrong population. And to say that those closer to midrange EF (45%) or a bit lower EF did better, it approximates PARADIGM-HF, ie, that’s HF with reduced EF where the drug is known to work.

    • Ileana L. Pina, MD, MPH
    • Cardiology Today Editorial Board Member
      Detroit Medical Center

    Disclosures: Pina reports she is on the steering committee for PROVE-HF, a study of sacubitril/valsartan sponsored by Novartis.

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