Efficacy of Empagliflozin in HFpEF Patients – Comparison of Subpopulations with Preserved and Mid-Range LV EF

Stratification of Patients with Heart Failure

Historically, patients with heart failure (HF) have been classified into 2 groups based on their left ventricular ejection fraction (LV EF): heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF). Given the imprecision of the LV EF boundary defining pEF and rEF, which remains uncertain, heart failure societies today often classify an LV EF of 41–49% as “mid-range” or “mildly reduced” ejection fraction (mrEF). 

The EMPEROR-Preserved clinical trial studied the efficacy of empagliflozin in patients with HF with an LV EF > 40% and identified clinically significant and statistically significant reductions in the number of CV deaths and HHFs. The aim of the presented pre-specified sub-analysis was to evaluate the efficacy of empagliflozin in patients with HFpEF (i.e., LV EF ≥ 50%) compared to the group with HFmrEF (i.e., LV EF 41–49%).

Study Methodology and Population Assessed

The study was randomized, double-blind, placebo-controlled, pre-specified, and event-driven. The primary composite endpoint was the time to CV death or first HHF. Secondary endpoints included total (first and recurrent) HHF and estimated glomerular filtration rate (eGFR) decline.   

A total of 5988 participants were included in the study, receiving standard therapy and randomized in a 1:1 ratio to receive 10 mg of empagliflozin or placebo. A total of 66.9% of patients had pEF at study entry, while 33.1% had an LV EF in the range of 41–49%. The median follow-up time was 26.2 months.

Results

Treatment with empagliflozin resulted in a statistically significant risk reduction of the primary endpoint by 17% in patients with an LV EF ≥ 50% compared to placebo (6.7 vs. 8.0/100 patient-years; hazard ratio [HR] 0.83; 95% confidence interval [CI] 0.71–0.98; p = 0.024). Empagliflozin significantly reduced the number of first HHFs by 22% compared to placebo (4.5 vs. 5.7/100 patient-years; HR 0.78; 95% CI 0.64–0.95; p = 0.013), but not CV mortality (3.0 vs. 3.4/100 patient-years; HR 0.89; 95% CI 0.70–1.13; p = 0.34).

In patients with an LV EF of 41–49%, empagliflozin reduced the risk for the primary endpoint by 29% compared to placebo (7.2 vs. 10.0/100 patient-years; HR 0.71; 95% CI 0.57–0.88; p = 0.002), reduced the risk of first hospitalization by 42% (3.8 vs. 6.5/100 patient-years; HR 0.58; 95% CI 0.44–0.77; p < 0.001), with no effect on CV mortality (HR 0.92; p = 0.54).

HR for the effect of empagliflozin on first and recurrent hospitalization for heart failure was 0.83 (95% CI 0.66–1.04; p = 0.11) in patients with an LV EF ≥ 50% and 0.57 (95% CI 0.42–0.79; p < 0.001) in patients with an LV EF of 41–49% (p_interaction = 0.06). Empagliflozin slowed the decline in eGFR similarly in patients with an LV EF between 50% and 41–49% and significantly improved quality of life regardless of LV EF. 

Conclusion

The study results indicated that empagliflozin significantly reduced the composite risk of CV death or HHF in patients with heart failure with an LV EF > 40%. The observed benefit was mainly due to a reduction in HF hospitalizations, and there was also an improvement in the quality of life of patients. These observations were the first to demonstrate clinically significant and statistically significant improvement in patients with an LV EF ≥ 50% due to the administration of the study drug, empagliflozin. Combined with the results of the EMPEROR-Reduced study, the presented findings support the use of empagliflozin in patients with HF across the entire spectrum of LV EF. 

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Source: Anker S. D., Butler J., Usman M. S. et al. Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-Preserved. Nat Med 2022 Dec 5; 28 (12): 2512–2520, doi: 10.1038%2Fs41591-022-02041-5.