EMPEROR - Reduced (empagliflozin in reduced ejection fraction heart failure)

Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure - Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced)

BACKGROUND

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. This study investigated the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction.

METHODS

• double-blind trial
• randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy
• primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure

RESULTS

• during a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001) effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes
• total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001)
• annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (–0.55 vs. –2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes
• uncomplicated genital tract infection was reported more frequently with empagliflozin

Study authors concluded that:

• among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes
• during the trial period, the number of patients who would need to have been treated with empagliflozin to prevent one primary event was
  19 (95% CI, 13 to 37).

Commentary (2):

Why was the dose of 10mg rather than 25 mg chosen for EMPEROR-Reduced? - the study authors state the dose of empagliflozin was selected on the basis of the reduction in the risk of cardiovascular death or hospitalization for heart failure that had been previously reported with this dose in patients with type 2 diabetes (3)

The findings of EMPEROR-Reduced support those seen in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial showed a reduction in the risk of cardiovascular death or hospitalization for heart failure with dapagliflozin in patients regardless of the presence or absence of diabetes (4).

As in DAPA-HF, a substantial proportion of the patients (50.2%) did not have diabetes.

The patients in EMPEROR-Reduced had on average more severe heart failure than those in the DAPA-HF trial, with a mean ejection fraction of 27% versus 31% and a median level of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) of 1907 versus 1437; in addition, more than 70% of the patients enrolled in EMPEROR-Reduced had an ejection fraction of 30% or less.

In both EMPEROR-Reduced and the DAPA-HF trial, the benefit of the SGLT2 inhibitor on the primary composite outcome was driven mainly by a reduction in hospitalizations for heart failure.

DAPA-HF did show statistical evidence of a reduction in the risk of cardiovascular death with a reduction of 18% with dapagliflozin in the dapagliflozin group compared to placebo (hazard ratio, 0.82; 95% CI, 0.69 to 0.98). This measure however did not achieve statistical significance in EMPEROR-Reduced with a reduction of 8% empagliflozin compared to placebo but a non-significannt hazard ratio (hazard ratio, 0.92; 95% CI, 0.75 to 1.12).

Why the difference in cardiovascular death from these two trials? It is noteworthy that the patients in EMPEROR-Reduced had on average more severe heart failure than those in DAPA-HF and perhaps these drugs are less effective in more advanced heart failure? Possibly this result reflects that there is a difference in the reduction of likelihood of cardiovascular death given by these two different molecules in the context of heart failure? Perhaps this difference is the result of statistical chance? The only true way to ascertain the significance, or not, of this statistical difference is via a head-to-head trial which is unlikely.

So in conclusion, the evidence base suggesting benefit of SGLT2 inhibitors of being a beneficial therapeutic intervention in heart failure with reduced ejection fraction, in the presence or absence of diabetes, has been enhanced by EMPEROR-Reduced. The benefit of both dapagliflozin and empagliflozin in treating reduced ejection fraction heart failure is now well established - with the EMPEROR-Reduced having such similar results to DAPA-HF, this emphasises the potential benefits of these therapies in the reduced ejection fraction heart failure cohort.

Notes:

• use of neprisylin inhibitor and SGLT2 inhibitor in heart failure
  • further analysis investigated the concurrent use of empagliflozin and neprilysin inhibition on empagliflozin to reduce the risk of heart failure and renal events (5)
    • the study showed that the risk of heart failure and renal events is 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

Reference:

• Packer S et al.Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure . NEJM 2020; DOI: 10.1056/NEJMoa2022190
• Commentary (August 31st 2020). Dr Jim McMorran, Editor in Chief, GPnotebook.
• Fitchett D et al. Empagliflozin reduced mortality and hospitalization for heart failure across the spectrum of cardiovascular risk in the EMPA-REG OUTCOME trial. Circulation
  2019; 139: 1384-95.
• McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381: 1995-2008
• Packer M 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. European Heart Journal, ehaa968, https://doi.org/10.1093/eurheartj/ehaa968