November 14, 2021—Patients with true heart failure with preserved ejection fraction (HFpEF), meaning their left ventricular ejection fraction is at least 50%, experience cardiovascular protection with the SGLT2 inhibitor empagliflozin, according to research presented at the American Heart Association’s Scientific Sessions, which took place virtually from November 13 to 15.
The EMPEROR-Preserved trial was designed to evaluate the efficacy and safety of empagliflozin among patients with and without diabetes who had heart failure with a preserved ejection fraction. For the study, 5988 patients with New York Heart Association (NYHA) class II to IV chronic heart failure, an ejection fraction > 40%, an estimated glomerular filtration rate (eGFR) ≤ 20, and raised N-terminal-pro hormone B-type natriuretic peptide (NT-proBNP) were randomized to empagliflozin 10 mg or placebo once daily. Both groups of patients additionally received standard of care and were followed up for a median of 26 months. Patients with and without type 2 diabetes were included in the study.
“When we set up this study, it was clear that many patients were recruited with a 41% to 49% ejection fraction, that is, heart failure with mid-range ejection fraction. This is [now] considered, maybe, not so much heart failure with a preserved ejection fraction in the true sense.” said lead author Stefan D. Anker, MD, PhD, of the Charité-Universitätsmedizin Berlin in Germany, during his presentation of the data. “Hence, we created a stratification … for 50% and higher ejection fraction versus all the other patients.”
The primary endpoint of the trial was the composite of time to the first event of adjudicated cardiovascular death or adjudicated heart failure. The secondary endpoints were first and recurrent adjudicated heart failure hospitalization events and slope in the change in eGFR. Additional clinical outcomes included the change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and NYHA class at 52 weeks.
Among the patients included in the trial, 1983 had a left ventricular ejection fraction < 50%, and 4005 had left ventricular ejection fraction ≥ 50%. The analysis presented by Dr. Anker at AHA 2021 focused specifically on the 4005 patients with an ejection fraction ≥ 50%, who are considered to be “true HFpEF,” according to recent guidelines on heart failure. The investigators also compared the results of patients with true HFpEF from those with ejection fractions of 41% to 49%.
Regarding baseline characteristics, HFpEF patients were older and more likely to be female than patients with mildly reduced ejection fractions. HFpEF patients were also less likely to have diabetes and ischemic heart failure and more likely to have atrial fibrillation or flutter. Baseline eGFR and NT-proBNP were both lower in HFpEF patients. At baseline, the majority of patients in both groups were taking ACE inhibitors/angiotensin receptor blockers/ARN inhibitors, beta-blockers, and/or diuretics.
Among HFpEF patients, empagliflozin reduced the risk of the primary endpoint by 17% (hazard ratio 0.83, 95% confidence interval 0.71–0.98, P = .0244). This was mainly driven by a reduction in first heart failure hospitalization (hazard ratio 0.78, 95% confidence interval 0.64–0.95, P = .013). There was no significant impact of empagliflozin on cardiovascular death, all-cause mortality, or total heart failure hospitalization in this subgroup analysis.
Among patients with mildly reduced ejection fractions, empagliflozin also reduced the risk of the primary endpoint (hazard ratio 0.71, 95% confidence interval 0.57–0.88, P = .002) and first heart failure hospitalization (hazard ratio 0.58, 95% confidence interval 0.44–0.77, P < .001). In this group, it additionally reduced total heart failure hospitalizations (hazard ratio 0.57, 95% confidence interval 0.42–0.79, P < .001).
In the HFpEF group, empagliflozin produced meaningful improvement in the KCCQ-CSS, with an adjusted mean difference of 1.46 points (P = .006). Finally, HFpEF patients treated with empagliflozin had a 34% higher likelihood of being in a lower NYHA class (P = .0004) and had a slower decline in kidney function, as determined by eGFR.
“Here, we have a successful trial overall, but also a successful trial for the specific population that is now considered the HFpEF population by most recent guidelines,” concluded Dr. Anker. “These benefits … also extend to quality of life, symptoms, and kidney function. This is the first large-scale evidence of any drug improving the outcomes specifically for what we today consider HFpEF.”
In an independent comment, Mary N. Walsh, MD, of the St. Vincent Cardiovascular Research Institute in Indianapolis, said that “this [analysis] extends our knowledge of the benefits of empagliflozin across the wide range of left ventricular ejection fraction. It is really important to underscore the fact that 50% of the patients enrolled with a left ejection fraction ≥ 50% were women. Women are differentially disadvantaged by lack of information on guideline-directed medical therapy, so this is good news for our women patients. The benefits were not attenuated at a higher ejection fraction, … as was seen in the PARAGON-HF trial, … and patient-centric outcomes were emphasized. … Clinicians who are busy can now refer less to ejection fraction than to what the phenotype of their patient is with regard to whether or not they can use this important therapy.” She noted that it is crucial to work on patient barriers to access to SGLT2 inhibitors, such as high cost.
The EMPEROR-Preserved trial was sponsored and conducted in collaboration with Boehringer Ingelheim.