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Randomized Controlled Trial
. 2021 Feb 11;42(6):671-680.
doi: 10.1093/eurheartj/ehaa968.

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

Milton Packer  1   2 , Stefan D Anker  3 , Javed Butler  4 , Gerasimos Filippatos  5 , Joao Pedro Ferreira  6 , Stuart J Pocock  7 , Hans-Peter Brunner-La Rocca  8 , Stefan Janssens  9 , Hiroyuki Tsutsui  10 , Jian Zhang  11 , Martina Brueckmann  12 , Waheed Jamal  13 , Daniel Cotton  14 , Tomoko Iwata  15 , Janet Schnee  14 , Faiez Zannad  6 ; EMPEROR-Reduced Trial Committees and Investigators
Affiliations
Randomized Controlled Trial

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

Milton Packer et al. Eur Heart J. .

Abstract

Aims: We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction.

Methods and results: The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P < 0.001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril/valsartan [hazard ratio 0.64 (95% CI 0.45-0.89), P = 0.009 and hazard ratio 0.77 (95% CI 0.66-0.90), P = 0.0008, respectively, interaction P = 0.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m2/year in patients taking a neprilysin inhibitor (P = 0.016) and by 1.71 ± 0.35 mL/min/1.73 m2/year in patients not taking a neprilysin inhibitor (P < 0.0001), interaction P = 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated.

Conclusion: The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.

Keywords: Empagliflozin; Heart failure; Sacubitril/valsartan.

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Figures

None
Graphical abstract
Figure 1
Figure 1
Effect of empagliflozin on total (first and recurrent) hospitalizations for heart failure, according to use of neprilysin inhibition at baseline. P-value for the interaction of the effect of empagliflozin and the background use of a neprilysin inhibitor was 0.72. A number of patients at risk at specific time points in each treatment group are displayed below each graph. CI, confidence intervals; HR, hazard ratio. In accordance with usual practice, cumulative function plots were truncated when the number of patients being followed in individual subgroups became extremely sparse.
Figure 2
Figure 2
Effect of empagliflozin on composite of serious adverse renal outcomes, according to use of neprilysin inhibition at baseline. P-value for the interaction of the effect of empagliflozin and the background use of a neprilysin inhibitor was 0.71. A number of patients at risk at specific time points in each treatment group are displayed below each graph. Between-group difference in estimated glomerular filtration rate represents a slowing of the decline in renal function in the empagliflozin group. CI, confidence intervals; eGFR, estimated glomerular filtration rate; HR, hazard ratio. In accordance with usual practice, cumulative incidence plots were truncated when the number of patients being followed in individual subgroups became extremely sparse.
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Comment in

References

    1. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. - PubMed
    1. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang C-E, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde A-M; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. - PubMed
    1. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F, EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–1424. - PubMed
    1. Vaduganathan M, Claggett BL, Jhund PS, Cunningham JW, Pedro Ferreira J, Zannad F, Packer M, Fonarow GC, McMurray JJV, Solomon SD. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet 2020;396:121–128. - PubMed
    1. Solomon SD, Jhund PS, Claggett BL, Dewan P, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Inzucchi SE, Desai AS, Bengtsson O, Lindholm D, Sjostrand M, Langkilde AM, McMurray JJV. Effect of dapagliflozin in patients with HFrEF treated with sacubitril/valsartan: the DAPA-HF trial. JACC Heart Fail 2020;8:811–818. - PubMed

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