Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction

Abstract

Background: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure. Methods: We randomly assigned 3730 patients with class II-IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite endpoints. Results: Empagliflozin reduced the combined risk of death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (415 vs 519 patients; empagliflozin vs placebo, respectively; hazard ratio 0.76, 95% CI: 0.67-0.87), P <0.0001. This benefit reached statistical significance at 12 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio 0.67, 95% CI 0.50-0.90, P=0.008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (hazard ratio 0.64, 95% CI: 0.47-0.87, P=0.005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 vs 414), hazard ratio 0.67, 95% CI: 0.56-0.78, P<0.0001. Additionally, patients assigned to empagliflozin were 20-40% more likely to experience an improvement in NYHA functional class and were 20-40% less likely to experience worsening of NYHA functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up. The risk of any inpatient or outpatient worsening heart failure event in the placebo group was high (48.1 per 100 patient-years of follow-up), and it was reduced by empagliflozin (hazard ratio 0.70, 95% CI: 0.63-0.78), P<0.0001. Conclusions: In patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT03057977

Heart failure drug treatment: the fantastic four

“…Thus, the detailed analyses from two large outcome trials in HFrEF with SGLT2 inhibitors 6 , 7 now substantiate the first crude data already reported in the original publications 4 , 5 as well as in the meta-analysis of DAPA-HF and EMPEROR-Reduced showing that patients treated with an ARNI derive at least the same benefit from additional SGLT2 inhibitor treatment as patients not on an ARNI. 8 …”

“…Patients taking a neprilysin inhibitor at baseline, for example, had slightly lower blood pressure, and were more likely to be treated with implantable cardioverter-defibrillator and/or cardiac resynchronization therapy. 7 Side effects were similar in patients taking or not taking an ARNI; symptomatic hypotension non-significantly tended to be more frequent in patients on sacubitril/valsartan.…”

“…In the current issue of the European Heart Journal , Packer et al . 7 provide a detailed analysis of the influence of ARNI pre-treatment on the effects of SGLT2 inhibition with empagliflozin in patients with HFrEF included in EMPEROR-Reduced. In this trial, 19.5% of the patients received sacubitril/valsartan at baseline.…”

Early initiation of SGLT2 inhibitors is important, irrespective of ejection fraction: SOLOIST‐WHF in perspective

“…Several mechanism(s) have been put forward to help explain the benefits of SGLT2 inhibition on heart failure 14,36–39 . The early separation of the curves (within days)—which is also seen for dapagliflozin in DAPA‐HF 40 and for empagliflozin in EMPEROR‐Reduced 30 — may point toward an important haemodynamic effect of SGLT2 inhibition in patients with heart failure. Indeed, recent human physiological studies in heart failure have indicated that SGLT2 inhibition promotes fractional sodium excretion within a few hours of treatment initiation—an effect that is exaggerated in the context of a loop diuretic 41 .…”

Lo mejor del 2020: Estudios que marcarán nuestra práctica clínica

“…El estudio EMPEROR-Reduced (5) encontró que el inhibidor del cotransportador sodio -glucosa 2 (iSGLT2): empaglifozina disminuyó el combinado de muerte CV o primera hospitalización por IC en pacientes con fracción de eyección (FEVI) ≤40%, con un número necesario a tratar (NNT) de 19 a 16 meses, y un efecto significativo desde el día 12 de iniciado el medicamento (6) . Asimismo, con un efecto añadido de nefro protección (menor tasa de disminución en la función renal, con ↓ en riesgo relativo [RR] de 50%), hace que los iSGLT2 se posicionen con un beneficio de clase, que anticipa sean un pilar de tratamiento de los pacientes con IC con fracción de eyección reducida (IC-FEr) para la próxima guía de IC de la Sociedad Europea de Cardiología 2021 (Figura 1).…”