Empagliflozin reduces CV death or HHF in HFpEF

Empagliflozin significantly reduces the risk of cardiovascular (CV) death or hospitalization for heart failure (HHF) vs placebo in patients with heart failure with preserved ejection fraction (HFpEF) with or without diabetes, according to results of the EMPEROR-Preserved trial presented at the European Society of Cardiology (ESC) Congress 2021

“EMPEROR-Preserved is the first trial to show unequivocal clinical benefits with a drug in HFpEF. It sets a new standard for what we want to achieve in HFpEF,” said principal investigator, Professor Stefan Anker of the Charité University Hospital Berlin, Germany.

The trial included 5,988 patients with New York Heart Association (NYHA) class II–IV chronic heart failure and a left ventricular ejection fraction (LVEF) of >40 percent, with or without type 2 diabetes mellitus, who had an N-terminal pro–B-type natriuretic peptide (NT-proBNP) level of >300 pg/mL (or >900 pg/mL for patients with atrial fibrillation) at baseline. The patients, recruited from 23 countries, were randomized 1:1 to receive empagliflozin 10 mg once daily (n=2,997; mean age, 71.8 years; female, 44.6 percent) or placebo (n=2,991; mean age, 71.9 years; female, 44.7 percent) on top of standard of care. At baseline, about 49 percent of patients in each arm had diabetes, mean LVEF was 54.3 percent, while mean estimated glomerular filtration rate (eGFR) was 60.6 mL/min/1.73 m². [Anker SD, et al, ESC 2021; N Engl J Med 2021;doi:10.1056/NEJMoa2107038]

“Interestingly, at baseline, patients in the trial were treated in many ways that were similar to those with heart failure with reduced ejection fraction [HFrEF],” noted Anker. “For example, 80–81 percent of patients in each arm were on a renin-angiotensin-aldosterone system [RAAS] inhibitor with or without an angiotensin receptor-neprilysin inhibitor [ARNI], 37–38 percent were on a mineralocorticoid receptor antagonist [MRA], while 86–87 percent were on a beta-blocker.”

Significant clinical benefits

“After a median follow-up of 26.2 months, a statistically significant and clinically meaningful 21 percent relative risk reduction [RRR] in the primary composite endpoint of CV death or HHF was shown with empagliflozin vs placebo,” reported Anker. “CV death or HHF occurred in 13.8 percent of patients in the empagliflozin group vs 17.1 percent of those in the placebo group [hazard ratio (HR), 0.79; 95 percent confidence interval (CI), 0.69 to 0.90; p<0.001].”

“The RRR in the primary composite endpoint was driven by a 29 percent RRR in first HHF with empagliflozin vs placebo [8.6 percent vs 11.8 percent; HR, 0.71; 95 percent CI, 0.60 to 0.83],” said Anker. “CV death occurred in 7.3 percent vs 8.2 percent of patients treated with empagliflozin vs placebo [HR, 0.91; 95 percent CI, 0.76 to 1.09].”

“The number of patients needed to be treated with empagliflozin to prevent one primary outcome event was 31 during a median trial period of 26 months,” he noted.

Of note, empagliflozin’s effect on the primary composite endpoint was consistent across prespecified subgroups, including in patients with or without diabetes at baseline (HR, 0.79 [95 percent CI, 0.67 to 0.94] and 0.78 [95 percent CI, 0.64 to 0.95], respectively; p_interaction=0.92), male or female patients (HR, 0.81 [95 percent CI, 0.69 to 0.96] and 0.75 [95 percent CI, 0.61 to 0.92], respectively; p_interaction=0.54), and patients with LVEF <50 percent, ≥50 to <60 percent, or ≥60 percent at baseline (HR, 0.71 [95 percent CI, 0.57 to 0.88], 0.80 [95 percent CI, 0.64 to 0.99] and 0.87 [95 percent CI, 0.69 to 1.10], respectively; p_trend=0.21).

“In terms of secondary endpoints, empagliflozin showed a very significant and meaningful 27 percent RRR in total [first and recurrent] HHFs vs placebo [HR, 0.73; 95 percent CI, 0.61 to 0.33; p<0.001], as well as a slower rate of eGFR decline [mean, -1.25 vs -2.62 mL/min/1.73 m²/year; difference in eGFR slope, +1.36 mL/min/1.73 m²/year; 95 percent CI, 1.06 to 1.66; p<0.0001],” said Anker. “Among 3,176 patients who underwent reassessment of eGFR at 23–42 days after withdrawal of double-blind therapy, eGFR deterioration over 28 months was 3.3 mL/min/1.73 m² in the empagliflozin group vs 5.7 mL/min/1.73 m² in the placebo group [p<0.0001].”

In addition, significant changes in haematocrit (+1.94 percent vs -0.41 percent; treatment difference, +2.36 percent; 95 percent CI, 2.17 to 2.54; p<0.0001) and body weight (-1.39 kg vs -0.11 kg; treatment difference, -1.28 kg; 95 percent CI, -1.54 to -1.03; p<0.001) were observed with empagliflozin vs placebo, while the effect on NT-proBNP levels was modest (-29 pg/mL vs -9 pg/mL; treatment difference [geometric mean ratio], +0.95; p=0.0071).

“The safety profile of empagliflozin was positive,” Anker noted. “Serious adverse events [AEs] occurred in 47.9 percent vs 51.6 percent of patients in the empagliflozin vs placebo group. Symptomatic hypotension [6.6 percent vs 5.2 percent] and genital infections [2.2 percent vs 0.7 percent] were more commonly reported with empagliflozin vs placebo, but these AEs were manageable and not surprising.”

First evidence-based treatment for HFpEF

“EMPEROR-Preserved is a landmark study and a giant step forward for patients for whom we did not have treatment before. The results suggest empagliflozin as the first evidence-based treatment for patients with heart failure and a LVEF of >40 percent,” commented discussant Professor Frank Ruschitzka of the University Heart Centre, Zurich, Switzerland.

“A tipping point for attenuation of benefit was observed at LVEF of around 60 percent, which is similar to the gradient of treatment effect seen in studies of ARNI,” he continued. [Circulation 2020;141:352-361]

“Perhaps it is time now that we see heart failure as a global cardiac dysfunction, and rename LVEF >60 percent as normal and LVEF <60 percent as reduced ejection fraction,” he suggested. “Focus should be on identification of aetiology and better understanding of pathophysiology to further improve treatment of patients with heart failure.”