Benefit of Adding Empagliflozin to Standard Therapy in Heart Failure with Reduced Ejection Fraction

Monitored Parameters and Considered Standard Treatment

The aim of the post hoc analysis of the EMPEROR-Reduced study was to evaluate the efficacy and safety of empagliflozin in patients with HFrEF as an additive therapy depending on the underlying disease-modifying treatment and its dose.

The randomized double-blind, parallel-group EMPEROR-Reduced study included patients with NYHA class II–IV heart failure with reduced left ventricular ejection fraction (LVEF) ≤ 40%, who were receiving adequate therapy (diuretics, renin-angiotensin-aldosterone system inhibitors /RAASi = ACEi or ARBs, i.e., sartans/, angiotensin II receptor and neprilysin inhibitors /ARNi/, beta-blockers /BB/, mineralocorticoid receptor antagonists /MRA/, and, if indicated, pacemakers). The study was conducted in a total of 520 centers in 20 countries across continents.

Patients were randomized in a 1:1 ratio to receive empagliflozin 10 mg once daily or placebo. The primary composite endpoint was the occurrence of CV death and hospitalization for heart failure, with the secondary endpoint being the total number of heart failure hospitalizations. The study also evaluated an extended composite endpoint including outpatient treatments or hospitalizations associated with HFrEF.

The results of the study were analyzed in relation to the administration of angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs, i.e., sartans), ARNi, BB, and MRA at doses <50% or ≥50% of the target dose, including various combinations of this therapy.

Results

A total of 3730 patients monitored from March 6, 2017, to May 28, 2020, were included in the post hoc analysis of the study, of which 1863 were taking empagliflozin (49.9%) and 1867 placebo (50.1%). The average age of the evaluated population was 66.8 ± 11.0 years, with women accounting for 23.9% (n = 893).

Administering empagliflozin resulted in a significant reduction in the occurrence of the primary endpoint compared to placebo, regardless of the baseline therapy with ACEi or ARBs (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.65–0.85) or their administered doses: for patients on <50% of the target dose, HR was 0.85 (95% CI 0.69–1.06), for patients on ≥50% of the target dose, HR was 0.67 (95% CI 0.52–0.88; p = 0.18). A similar result in favor of adding empagliflozin was observed with BB: for those on <50% of the target dose, HR was 0.66 (95% CI 0.54–0.80); for those on ≥50% of the target dose, HR was 0.81 (95% CI 0.66–1.00; p = 0.15).

Adding empagliflozin also reduced the risk of the primary endpoint independently of the standard triple combination of ACEi/ARB/ARNi + BB + MRA (HR with this triple combination 0.73; 95% CI 0.61–0.88; HR without this triple combination 0.76; 95% CI 0.62–0.94; p = 0.77). Similar results were also observed for the secondary and expanded endpoints.

Empagliflozin was well-tolerated in the study, with the occurrence of hypotension, symptomatic hypotension, and hyperkalemia being similar across all subgroups.

Conclusion

The results of the post hoc analysis of the EMPEROR-Reduced study indicate that empagliflozin reduces the risk of CV death or hospitalization for heart failure in patients with HFrEF regardless of the underlying disease-modifying therapy and its dose. The available clinical data suggest that empagliflozin can be considered a beneficial additive therapy for all patients with HFrEF regardless of standard disease-modifying treatment.

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Source: Verma S., Dhingra N. K., Butler J. et al.; EMPEROR-Reduced trial committees and investigators. Empagliflozin in the treatment of heart failure with reduced ejection fraction in addition to background therapies and therapeutic combinations (EMPEROR-Reduced): a post-hoc analysis of a randomized, double-blind trial. Lancet Diabetes Endocrinol 2022; 10 (1): 35–45, doi: 10.1016/S2213-8587(21)00292-8.