Empagliflozin beneficial in ‘true’ HFpEF with higher ejection fraction
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In a new analysis of the EMPEROR-Preserved trial, the SGLT2 inhibitor empagliflozin reduced CV death or HF hospitalization by 17% among those with a left ventricular ejection fraction of at least 50%.
“This trial shows that for patients with a 50% of higher EF — what the guidelines consider the ‘true’ HFpEF patients — the primary endpoint of CV mortality and first HF hospitalization is reduced significantly and in a meaningful way by 17%,” Stefan D. Anker, MD, PhD, heart failure cardiologist at Charité Berlin, Germany, said during a presentation at the American Heart Association Scientific Sessions. “First hospitalizations are the driver of this, down 32%. Quality of life and kidney function ... are also significantly improved. We have a successful trial overall, but also for this specific population that is now considered the HFpEF population by most recent guidelines.”
As Healio previously reported, the EMPEROR-Preserved trial demonstrated empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) improved clinical outcomes in patients with HF with an EF above 40% — the first agent to be shown to do so. Empagliflozin also improved clinical outcomes in patients with HF with reduced EF with or without diabetes in the EMPEROR-Reduced trial.
Benefit according to EF
EMPEROR-Preserved initially enrolled 5,988 patients with NYHA class II to IV HF and an EF above 40% who underwent random assignment to empagliflozin 10 mg daily or placebo. The primary outcome was CV death or hospitalization for HF. The mean age of participants was 72 years, 45% were women and 49% had type 2 diabetes.
During a median follow-up of 26.2 months, the primary outcome occurred in 13.8% of the empagliflozin group compared with 17.1% of the placebo group (HR = 0.79; 95% CI, 0.69-0.9; P < .0003; number needed to treat to prevent one event = 31), driven by HF hospitalization (HR = 0.71; 95% CI, 0.6-0.83). Results did not differ according to EF (41% to 49%, 50% to 59% or 60% or more), with a P value for trend of .21.
“When we set up the study it was clear many patients were recruited with a 41% to 49% EF,” Anker said. “That is, of course, HF with mid-range EF, and is not really considered HFpEF in the true sense. Hence, we created a stratification of 50% or higher EF vs. all other patients.”
The new analyses compared outcomes in 4,005 participants with HF with a preserved EF of at least 50% with 1,983 participants with HR and preserved EF or 41% to 49%. Patients with a higher preserved EF were more likely to be women (50% vs. 33%); almost half had type 2 diabetes.
Patients in the higher EF subgroup experienced a 17% reduction in the primary endpoint compared with those assigned placebo (HR = 0.83; 95% CI, 0.71-0.98; P = .024). That benefit was driven primarily by first HF hospitalization (HR = 0.78; 95% CI, 0.64-0.95; P = .013).
There were no significant reductions in CV death, all-cause death or total HF hospitalizations among those with a higher EF vs. placebo.
Among participants with an EF between 41% and 49%, the HR for the primary endpoint was 0.71 (95% CI, 0.57-0.88; P = .002), also driven primarily by first HF hospitalization (HR = 0.58; 95% CI, 0.44-0.77; P = .001). This subgroup also saw a benefit for total HF hospitalizations (HR = 0.57; 95% CI, 0.42-0.79).
Quality of life, symptom measures
Patients with both HF with mid-range EF and HF with an EF of 50% or greater had similar improvements in quality of life as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score, as well as reduced symptom burden as measured by NYHA functional class, Anker said. Kidney function also improved for patients assigned empagliflozin with an EF of 50% of greater; the mean slope of decline in eGFR over time was 1.24 mL/min/1.73m2 per year (P < .0001), Anker said.
“This is the first large-scale evidence of any drug improving the outcomes specifically for what we today consider HFpEF patients,” Anker said.
‘Refer less to EF’
Discussing the study findings, Cardiology Today Editorial Board Member Mary Norine Walsh, MD, MACC, medical director of heart failure and cardiac transplantation at Ascension St. Vincent Heart Center in Indianapolis and past president of the American College of Cardiology, said the new EMPEROR-Preserved analyses demonstrate the benefits of this agent across the wide range of LVEF.
“It is important to underscore that 50% of the patients enrolled with LVEF greater than 50% were women,” Walsh said. “Women are differentially disadvantaged by a lack of information on guideline-directed medical therapies, so this is good news for our women patients.”
The benefits of empagliflozin were not attenuated at higher EFs, as was seen in the PARAGON-HF trial of sacubitril/valsartan (Entresto, Novartis), Walsh said. Curves separated early and patient-centered outcomes were emphasized, she said.
“Patients felt better, as was manifested by NYHA functional class measures and KCCQ scores,” Walsh said.
“Clinicians who are busy can now refer less to EF and to what the phenotype of their patient is regarding whether to use this important therapy,” Walsh said. “We do not have to stop and reassess LVEF with echocardiology or other imaging modalities before we decide what we need for our patients.”
Perspective
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Christopher M. O’Connor, MD, MACC, FESC, FHFSA, FHFA
The EMPEROR-Preserved study included almost 6,000 patients with HF and an EF of more than 40%, which is what we would consider a mix of pure HFpEF — our classic definition is 50% — and this mid-range EF. It turns out many therapies show stronger signals in that mid-range group because it is closer to HFrEF. That has been a concern in HFpEF trials, because the two groups are mixed.
The objective of this new analysis was to look at the mid-range EF group vs. the 50% EF or greater group, with additional information on quality of life and other parameters.
The results stand up nicely in the group of patients with an EF greater than or equal to 50%. That is important because that is the traditional space we think of as HFpEF.
This is an absolute blockbuster breakthrough for patients. This population has been void of any strong therapies, and patients will benefit immediately and significantly.
The real challenge for our community is how quickly can we implement this therapy in clinical practice? My hope is we can get significant implementation in less than 5 years.
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Anker S, et al. LBS.05: Building on the Foundations of Treatment: Advances in Heart Failure Therapy. Presented at: American Heart Association Scientific Sessions; Nov. 13-15, 2021 (virtual meeting).
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