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New EMPEROR-Preserved findings show the SGLT-2 inhibitor significantly reduced heart failure-related hospitalizations, regardless of patient diabetes status.
Once-daily add-on empagliflozin was associated with a 21% decreased risk of cardiovascular death or hospitalization due to heart failure (HF) over 2-plus years among patients with HF with preserved ejection fraction (HFpEF), according to new findings from EMPEROR-Preserved.
In the new phase 3 trial data presented at the European Society of Cardiology (ESC) 2021 Congress this weekend, the international team of investigators reported the SGLT-2 inhibitor provided benefit for decreased severe cardiovascular event risk, regardless of patients’ diabetes status.
The understanding of clinical benefit with SGLT-2 inhibitors in patients with HFpEF is lesser than that of the drug class in patients with HF with reduced ejection fraction (HFrEF), investigators wrote. In fact, post hoc analyses of large-scale trials involving dapagliflozin have shown serious adverse HF outcomes may not be reduced by the agent in patients with HFpEF.
Led by Stefan D. Anker, MD, PhD, of Charité Universitätsmedizin in Germany and Javed Butler, MD, of the University of Mississippi Medical Center, investigators sought to compare 10 mg daily empagliflozin plus usual therapy to placebo plus usual therapy in patients with New York Heart Association functional class II-IV HFpEF.
The Boehringer Ingelheim and Eli Lilly-sponsored randomized, double-blind clinical trial assigned 5988 patients 1:1 to either therapy regimen. Eligible participants were aged 18 years or older and had an N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of >300 pg/mL, or an NT-proBNP level of >900 pg/mL for patients with baseline atrial fibrillation. Baseline diabetes was prevalent in 48.9% of patients randomized to empagliflozin, and 49.2% of patients randomized to placebo.
Anker, Butler and colleagues sought a primary outcome of composite cardiovascular-related death or HF-related hospitalization in patients.
Patients were observed for a median 26.2 months. Investigators observed the primary outcome in 415 (13.8%) patients treated with empagliflozin and 511 (17.1%) of patients provided placebo, indicating a hazard ratio (HR) of 0.79 for the therapy (95% CI, 0.69 – 0.90; P <.001). HF-related hospitalization was particularly decreased among patients treated with empagliflozin: just 259 events per 100 patient-years (8.6%), versus 352 (11.8%) in patients on placebo (HR, 0.71; 95% CI, 0.60 – 0.83).
Patients with diabetes at baseline treated with empagliflozin reported a consistent risk for the composite outcome (HR, 0.79; 95% CI, 0.67 – 0.95) as patients without diabetes (HR, 0.78; 95% CI, 0.64 – 0.95).
Investigators observed serious adverse events in 47.9% of patients treated with empagliflozin, versus 51.6% in patients on placebo. Adverse events leading to treatment discontinuation occurred in 19.1% and 18.4% of the treatment arms, respectively.
Investigators concluded the benefit of empagliflozin in patients with HFpEF are consistent with those showing SLGT2 inhibitor effect on reduced hospitalization risk for HF.
“However, in these earlier trials, most patients did not have heart failure at the time of enrollment,” they wrote. “Post hoc characterization of the heart failure phenotype, either at the time of randomization or at the onset of a post-randomization heart failure event, suggested that patients with (HFpEF) might have benefited from treatment, but these analyses had a small number of events and substantial missing data.”
Moreover, the significant rate of treatment discontinuation may have driven the effect size toward the study’s null hypothesis, and the death of reduced cardiovascular deaths remained insignificant versus placebo.
Nonetheless, the team concluded that empagliflozin provided a consistent benefit of composite reduced cardiovascular death and HF-related hospitalization among patients with HFpEF, both with and without diabetes.
The study, “Empagliflozin in Heart Failure with a Preserved Ejection Fraction,” was published online in The England Journal of Medicine.