Empagliflozin reduces CV death, HF hospitalization in HFrEF patients

In patients with chronic heart failure with reduced ejection fraction (HFrEF), empagliflozin reduced the risk of cardiovascular (CV) death or heart failure hospitalization (HHF) and decline in estimated glomerular filtration rate (eGFR), results of the EMPEROR-Reduced* trial showed.

“Empagliflozin reduced the risk of serious HF events by 30 percent and decreased the risk of serious adverse renal outcomes by 50 percent. This trial extends the benefits of SGLT2** inhibitors to higher-risk patients and shows a meaningful benefit on renal outcomes in patients with HF for the first time,” said principal investigator Dr Milton Packer from Baylor University Medical Center, Dallas, Texas, US, who presented the results at ESC 2020.

In this multinational, double-blind trial, 3,730 patients with HFrEF (left ventricular ejection fraction [LVEF] ≤30 percent***) with or without diabetes were randomized 1:1 to empagliflozin (10 mg QD; mean age 67.2 years, 23.5 percent female) or placebo (mean age 66.5 years, 24.4 percent female) plus usual care. Patients were followed up for a median 16 months.

Approximately 75 percent of patients had NYHA^# class II. Mean LVEF was 27.7 and 27.2 percent in the empagliflozin and placebo groups, respectively, median NT-proBNP 1,887 and 1,926 pg/mL, mean eGFR 61.8 and 62.2 mL/min/1.73 m², and 18.3 and 20.7 percent, respectively, were on angiotensin receptor neprilysin inhibitors (ARNIs).

The composite of CV death or HHF was significantly reduced in the empagliflozin vs placebo group (19.4 percent vs 24.7 percent; 15.8 vs 21.0 per 100 patient-years; hazard ratio [HR], 0.75, 95 percent confidence interval [CI], 0.65–0.86; p<0.0001). [ESC 2020, Hot Line Session]

The magnitude of benefit was comparable between diabetic (HR, 0.72) and nondiabetic (HR, 0.78) patients, said Packer.

The reduction in events was driven by a decrease in first HHF (13.2 percent vs 18.3 percent; 10.7 vs 15.5 per 100 patient-years; HR, 0.69, 95 percent CI, 0.59–0.81), with an 8 percent reduction in the risk of CV death (10.0 percent vs 10.8 percent; HR, 0.92, 95 percent CI, 0.75–1.12). Total (first and recurrent) HHF was also reduced with empagliflozin vs placebo (HR, 0.70, 95 percent CI, 0.58–0.85; p=0.0003).

The composite renal endpoint^## also occurred in fewer empagliflozin vs placebo recipients (1.6 percent vs 3.1 percent; HR, 0.50, 95 percent CI, 0.32–0.77; p=0.0019). 

Among 966 patients whose eGFR were assessed 23–42 days following withdrawal of double-blind therapy, there was significantly less eGFR deterioration with empagliflozin vs placebo (-0.9 vs -4.2 mL/min/1.73 m²; p<0.0001).

“EMPEROR-Reduced achieved all three endpoints prespecified as key outcomes by hierarchical testing, each with a p<0.001,” Packer pointed out.

Serious adverse events (AEs) occurred in fewer empagliflozin than placebo recipients (41.4 percent vs 48.1 percent), specifically serious AEs related to cardiac disorders (26.8 percent vs 34.0 percent) or worsening renal function (3.2 percent vs 5.1 percent).

Comparison with DAPA-HF 

Notably, there were difference between the patients in this study and dapagliflozin recipients in the DAPA-HF^### trial, namely lower LVEF (mean 31.2 percent in dapagliflozin recipients in DAPA-HF) as well as higher NT-proBNP levels (1,428 pg/mL) and worse renal function (mean 66.0 mL/min/1.73 m²).

“With respect to the primary endpoint and for the risk of HHF, the results of DAPA-HF and EMPEROR-Reduced trials are virtually superimposable, with a 25–30 percent reduction in risk,” said Packer.

“The composite renal endpoint was reduced numerically more and was nominally significant in the EMPEROR-Reduced trial but not in DAPA-HF [HR, 0.50 vs 0.71]. CV death was reduced numerically more and was nominally significant in DAPA-HF but not in EMPEROR-Reduced,” he continued, noting the potential heterogeneity pertaining to the effects of these drugs on survival.

The lower eGFR in the EMPEROR-Reduced cohort “probably accounted for the decrease in the renal endpoint which reached statistical significance,” said discussant Professor Marco Metra from the University of Brescia in Brescia, Italy. He also noted the consistent improvement in the primary outcome among patients on ARNIs. [https://www.youtube.com/watch?v=HOYGg7nf4CI, accessed 11 September 2020] However, analysing the different effects of the two drugs would require a direct comparison, he added.

“Taken together, we believe that the concordant results of DAPA-HF and EMPEROR-Reduced should be sufficient to establish SGLT2 inhibitors as a new standard of care for patients with HFrEF,” said Packer.