ESC 2021: EMPEROR-Preserved and EMPEROR-Pooled: Empagliflozin in HFpEF and the effect of empagliflozin on major renal outcomes in HFrEF and HFpEF

Debra L. Beck and Eugene Braunwald, MD 

SGLT2 inhibitors have been shown to reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction (HFrEF), but their effects in patients with heart failure and a preserved ejection fraction (HFpEF) have not been well studied and are uncertain. The EMPEROR-Preserved trial evaluated the effects of the SGLT2 inhibitor empagliflozin on major HF outcomes in patients with HFpEF.

A total of 5,988 patients with class II-IV HF and an ejection fraction >40% were randomly assigned to empagliflozin (10 mg once daily) or matching placebo, in addition to their usual therapies.

Mean age of participants was 72 years, 45% were women and median left ventricular ejection fraction was 54%. Most, 82%, had NYHA class II heart failure. About half of patients had diabetes and half had an estimated glomerular filtration rate (EGFR) of <60 ml/minute/1.73 m2. Median follow-up was 26.2 months

The primary outcome, a composite of cardiovascular death or hospitalization for heart failure, occurred in 13.8% of the empagliflozin arm and in 17.1% of the placebo arm, yielding a hazard ratio of 0.79 in favor of treatment with empagliflozin (p<0.001). Most of this effect was due to a lower risk of HF hospitalization in the empagliflozin group.

The effects of the drug were generally consistent across patient subgroups, including in patients with and without diabetes.

The total number of HF hospitalizations was reduced with empagliflozin (407 vs. 541; hazard ratio, 0.73; p<0.001). No between-group differences were seen in all-cause or cardiovascular death.

No difference was seen in the occurrence of serious adverse events or in adverse events leading to discontinuation of the treatment. Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin.

The rate of decline in eGFR was slower in the empagliflozin group compared with the placebo group (–1.25 vs. –2.62ml/min/1.73 m2/year; p<0.0001).

Summary

The investigators concluded that in patients with HFpEF, empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure, in both those with and without diabetes.

“This drug has the potential to become a new standard treatment for these patients, who currently have few therapeutic options,” said Dr. Anker in his presentation of the findings.

Comments

In the discussion that followed the presentation of the findings, the trial was called “landmark,” “practice changing,” and “a feast for science.”

In an editorial comment, Dr. M Drazner noted that based on a subgroup analysis, there appeared to be some decrement in benefit in patients with the highest ejection fractions, a question that will be clarified in further analysis of this trial and in the ongoing DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial.

EMPEROR-Pooled:

EMPEROR-Reduced and EMPEROR-Preserved had similar protocols and endpoints, mostly separated by an ejection fraction of 40%. To determine the effect of treatment on renal outcomes, the investigators planned a prospective, patient-level, pooled analysis of the results of the EMPEROR-Reduced and EMPEROR-Preserved trials (n=9718).

The effects of empagliflozin to reduce heart failure outcomes in EMPEROR-Preserved and EMPEROR-Reduced were highly concordant. Empagliflozin reduced heart failure hospitalizations by about 30% across a broad range of ejection fractions from < 25% to < 65%, with attenuation of the effect at higher ejection fractions.

For the primary outcome of a composite of major adverse renal outcomes (i.e. profound and sustained decreases in eGFR or renal-replacement therapy), the rates were 2.8% in the empagliflozin group and 3.5% in the placebo group. The hazard ratios for serious renal outcomes were 0.51 in EMPEROR-Reduced (p<0.05) and 0.95 (p=NS) in EMPEROR-Preserved, respectively.

This observed lack of benefit in the HFpEF group, despite a slowing in the rate of decline in eGFR, suggests that ejection fraction influences the effect of empagliflozin on major renal outcomes. It also suggests that the eGFR slope analysis has limitations as a surrogate for predicting the effects of drugs on renal outcomes in patients with HF, said the investigators.

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