EMPEROR-Preserved: Empagliflozin reduces CV death or HHF in HFpEF

Prof. Stefan Anker
Charité University Hospital, Berlin
Germany
11 Oct 2021
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 type 2 diabetes mellitus (T2DM), according to results of the EMPEROR-Preserved trial presented at the European Society of Cardiology Congress 2021 (ESC 2021). Results of this landmark study – the first positive drug trial in HFpEF – support empagliflozin as an evidence-based therapy for patients with HFpEF, for whom treatment options have been limited.

First positive drug trial in HFpEF
Treatment options for patients with HFpEF have been limited as previous trials have demonstrated either modest effects of therapies under investigation or benefits that were apparent only in subgroups of patients. [N Engl J Med 2014;370:1383-1392; Eur Heart J 2016;37:455-462; N Engl J Med 2019;381:1609-1620]

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

The phase III, randomized, double-blind, placebo-controlled 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 T2DM, 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) and an estimated glomerular filtration rate (eGFR) of ≥20 mL/min/1.73 m2 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) in addition to usual therapy. [Anker SD, et al, ESC 2021; N Engl J Med 2021;doi:10.1056/NEJMoa2107038]

At baseline, 48.9 percent vs 49.2 percent of patients in the empagliflozin vs placebo group had diabetes. Mean LVEF was 54.3 percent and mean eGFR was 60.6 mL/min/1.73 m2 in both groups.

“Interestingly, treatments received by the patients at baseline were similar to those for heart failure with reduced ejection fraction,” said Anker. “For example, 80–81 percent of patients in each group were on a renin-angiotensin-aldosterone system inhibitor with or without an angiotensin receptor-neprilysin inhibitor, 37–38 percent were on a mineralocorticoid receptor antagonist, while 86–87 percent were on a beta-blocker.”

Significant reductions in CV death or HHF
“After a median follow-up of 26.2 months, empagliflozin demonstrated a statistically significant and clinically meaningful 21 percent relative risk reduction [RRR] in the primary composite outcome of CV death or HHF 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].” (Figure 1) [Anker SD, et al, ESC 2021; N Engl J Med 2021;doi:10.1056/NEJMoa2107038]

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“The RRR in the primary composite outcome 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 in the empagliflozin vs placebo group [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.”

Of note, empagliflozin’s effect on the primary composite outcome was consistent across prespecified subgroups. These include patients with or without diabetes at baseline (pinteraction=0.92), male or female patients (pinteraction=0.54), and patients with baseline LVEF <50 percent, ≥50–<60 percent, or ≥60 percent (ptrend=0.21). (Figure 2)

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Reductions in total HHF, kidney protection
“In terms of secondary outcomes, empagliflozin demonstrated a very significant and meaningful 27 percent RRR in total [first and recurrent] HHF vs placebo [HR, 0.73; 95 percent CI, 0.61 to 0.33; p<0.001],” said Anker. (Figure 3) [Anker SD, et al, ESC 2021; N Engl J Med 2021;doi:10.1056/NEJMoa2107038]

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Rate of decline in eGFR, another secondary outcome of the trial, was significantly slower with empagliflozin vs placebo (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<0.001), suggesting a kidney- protective effect of empagliflozin. (Figure 4)

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“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/1.73m2 in the empagliflozin group vs 5.7mL/min/1.73 m2 in the placebo group [p<0.0001],” said Anker

Exploratory endpoints
Adjusted mean difference in change in Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score at 52 weeks was 1.32 (95 percent CI, 0.45 to 2.19), in favour of empagliflozin. [Anker SD, et al, ESC 2021; N Engl J Med 2021;doi:10.1056/NEJMoa2107038]

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. However, empagliflozin’s effect on NT-proBNP levels was modest (-29 pg/mL vs -9 pg/mL; treatment difference [geometric mean ratio], 0.95; p=0.0071).

Safety profile
“The safety profile of empagliflozin was positive,” Anker noted. “Serious adverse events [AEs] occurred in 47.9 percent of patients in the empagliflozin group vs 51.6 percent of those in the 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 the observed increase of approximately 1.5 percent with empagliflozin vs placebo was not surprising.” [Anker SD, et al, ESC 2021; N Engl J Med 2021;doi:10.1056/NEJMoa2107038]

First evidence-based treatment for HFpEF
“Empagliflozin significantly reduced the risk of CV death or HHF in patients with HFpEF. The effect was consistent across prespecified LVEF subgroups and in patients with or without T2DM at baseline,” concluded Anker.
 
“EMPEROR-Preserved is a landmark study and an important step forward for patients with HFpEF. 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, who was not involved in the trial.

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