Influence of ARNI on the Efficacy and Safety of Empagliflozin in the Treatment of Heart Failure with Reduced Ejection Fraction

Study Methodology, Population and Course

The randomized double-blind placebo-controlled EMPEROR-Reduced trial included a total of 3730 individuals with heart failure with reduced ejection fraction, NYHA class II–IV. Patients were treated with all available indicated pharmacological and non-pharmacological procedures. Preferentially, patients with a left ventricular ejection fraction (LVEF) < 30% were included in the study. Inclusion of patients with LVEF 30–40% was conditional on a recent hospitalization for heart failure in the past 12 months or significantly elevated levels of the N-terminal prohormone of brain natriuretic peptide (NT-proBNP ≥ 1000 pg/ml for LVEF 31–35% and ≥ 2500 pg/ml for LVEF 36–40%).

In the EMPEROR-Reduced trial, patients were randomized in a 1:1 ratio to receive either 10 mg of empagliflozin daily or placebo in addition to their existing chronic heart failure therapy. The median follow-up was 16 months. The primary endpoints were hospitalization for decompensated chronic heart failure and CV mortality. Also compared were changes in symptoms, functional capacity, NYHA classification, hematocrit, uric acid levels, glycated hemoglobin (HbA1c), NT-proBNP, weight and blood pressure, as well as the effect on glomerular filtration and the need for changes in chronic therapy.

Results

Out of the 3730 patients, 727 (19.5%) were taking sacubitril/valsartan at the study entry. This was a pre-specified group for a subset analysis of the results. Their baseline characteristics and initial parameters (gender, age, NYHA functional classification, renal function, and others) were comparable to patients treated with beta-blockers and mineralocorticoid receptor antagonists. Patients on ARNI had lower systolic blood pressure, heart rate, NT-proBNP levels, and a higher likelihood of having an implanted cardioverter-defibrillator or having undergone resynchronization therapy compared to those not receiving sacubitril/valsartan.

Empagliflozin use was associated with a reduction in the composite endpoint of CV mortality and hospitalization for heart failure by 23% in patients without sacubitril/valsartan (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.66–0.90, p = 0.0008) and by 36% in those concurrently using ARNI (HR 0.64, 95% CI 0.45–0.89, p = 0.009). The risk of hospitalization for heart failure was reduced by 29% in patients not on ARNI (HR 0.71, 95% CI 0.58–0.88, p = 0.002) and by 35% in those using ARNI (HR 0.65, 95% CI 0.42–1.00, p = 0.052).

The risk of serious renal outcomes (a composite endpoint including the need for dialysis, transplantation, persistent eGFR decline > 40%, persistent eGFR < 0.15 ml/min/1.73 m² in patients with baseline GFR ≥ 30 ml/min/1.73 m² or eGFR < 10 ml/min/1.73 m² in those with baseline GFR < 30 ml/min/1.73 m²) was reduced by 49% in patients not on ARNI (HR 0.51, 95% CI 0.32–0.81) and by 61% in those on concurrent ARNI (HR 0.39, 95% CI 0.11–1.45).

Due to the different mechanisms of action of the two medications, no significant drug interactions were observed.

Conclusion

This sub-analysis of the EMPEROR-Reduced trial showed that the benefit of empagliflozin in reducing CV mortality and heart failure risk, as well as the risk of serious renal events in patients with heart failure with reduced ejection fraction, is unaffected by co-medication with sacubitril/valsartan. Significant effects on studied outcomes were demonstrated both in patients on concurrent ARNI therapy and in those not on this treatment. The combination of these two classes of medication is well tolerated and their cumulative benefit can also be anticipated.

(kali)

Source: Packer M., Anker S. D., Butler J. et al. Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J 2021 Feb; 42 (6): 671–680, doi: 10.1093/eurheartj/ehaa968.