Reviwer: Dr. Duygu İnan

Name of the study : Empagliflozin in Heart Failure with a Preserved Ejection Fraction- EMPEROR- Preserved

Presented congress : 2021 ESC/EAST

Link : https://www.nejm.org/doi/full/10.1056/NEJMoa2107038

Background:

Sodium–glucose cotransporter 2 (SGLT-2) inhibitors reduce the risk of  cardiovacular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their certain effects in patients with heart failure and a preserved ejection fraction are unknown

Objective:

The aim of the trial was to evaluate the safety and efficacy of empagliflozin, a SGLT-2 inhibitor, in patients with symptomatic heart failure and a preserved ejection fraction (HFpEF), irrespective of diabetes status.

 Method:

In this double-blind trial, investigators randomly assigned 5,988 patients with NYHA class II to IV heart failure and an ejection fraction greater than 40% (mean age 72 years; 45% women; mean LVEF 54%) to empagliflozin 10 mg once daily or placebo, in addition to usual therapy, at 622 centers in 23 countries. Patients were required to have an estimated glomerular filtration rate (eGFR )≥ 20 mL/min/1.73 m2 along with either structural heart disease or documented history of heart failure hospitalization within the past year. Nearly half (49%) of patients also had diabetes. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. The first secondary outcome was hospitalizations for heart failure, including first and recurrent events. The second secondary outcome was the rate of decline in the glomerular filtration rate (eGFR) during study treatment.

Results :

During a median follow-up of 26 months, primary outcome for empagliflozin vs. placebo, was 13.8% vs. 17.1% (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.69-0.90, p < 0.001. This effect was mainly associated with a lower risk of hospitalization for heart failure in empagliflozin group. The number of patients who needed to be treated with empagliflozin to prevent one primary outcome event during a median study period of 26 months was 31 (95% CI 20–69). The effects of empagliflozin on the primary outcome appeared consistent in patients with or without diabetes and those with a left ventricular ejection fraction of less than 50%, 50% to less than 60%, or 60% or more. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). The rate of decline in eGFR was slower in the empagliflozin group compared with the placebo group (–1.25 vs. –2.62 ml/min/1.73 m2/year; p<0.0001). Uncomplicated genital and urinary tract infections and hypotension were more common in empagliflozin therapy.

Interpretation :

Empagliflozin convincingly reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. This benefit was primarily driven by a reduction in HF hospitalizations, not mortality. A non-significant 9% relative risk reduction was observed in the incidence of cardiovascular death, with no discernible effect on death from any cause. There was also a benefit in eGFR, but not in renal outcomes per se. However, from a system or patient perspective, reducing hospitalizations for heart failure is a major challenge in patients with HFpEF. This is where empagliflozin shows significant benefit in HEpEF patients. Most routinely used drugs for HFrEF have not shown to be effective among patients with HFpEF, and some drugs such as candesartan, spironolactone, and sacubitril/valsartan appear to mostly have a benefit among patients with EF between 40-49% rather than true HFpEF. Empagliflozin has the potential to become a new standard treatment for these patients. This tiral results represented the unequivocal benefit of any drug on major heart failure outcomes for the first time in patients with heart failure and a preserved ejection fraction. Empagliflozin appears to be the first and only clinically proven therapy to improve outcomes for the full spectrum of heart failure patients regardless of ejection fraction.

A pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved combined the results of these two trials at the individual patient level. This was possible because of the similarities in that both studies were conducted in parallel with nearly identical protocols, case report forms, investigte sites, and administrative committees. A total of 9,718 patients in these two studies were included in the analysis. Empagliflozin has been shown to reduce the risk of heart failure hospitalization by approximately 30% in EMPEROR-Reduced and EMPEROR-Preserved. The power of the effect on hospitalizations for heart failure was similar across a broad ejection fraction range of EF < 65%, with attenuation of drug effect at higher ejection fractions ( EF >65% ). At a 40-60% ejection fraction range, the effect size was greater than in the PARAGON-HF study comparing empagliflozin with sacubitril/valsartan with valsartan. The EMPEROR- pooled also shows that the renal benefit is primarily among patients with HFrEF, and the eGFR slope analysis may not predict renal outcomes in patients with HF.