Empagliflozin effective and well tolerated in acute heart failure

Prof. Adriaan Voors
University Medical Centre Groningen
Netherlands
Prof. Stefan Anker
Charité University Hospital Berlin
Germany
30 Dec 2021
Empagliflozin effective and well tolerated in acute heart failure

Empagliflozin is shown to provide a significant clinical benefit without safety concerns in patients hospitalized for acute heart failure (HF) in the EMPULSE trial. An analysis of the EMPEROR-Preserved trial showed consistent benefit of empagliflozin in patients with HF with left ventricular ejection fraction (LVEF) ≥50 percent (ie, true HF with preserved ejection fraction [HFpEF]). These findings, presented at the American Heart Association Scientific Sessions 2021 (AHA 2021), together with earlier results of the EMPEROR-Reduced trial in patients with HF with reduced ejection fraction (HFrEF), support empagliflozin as an effective and well-tolerated treatment for HF across the LVEF spectrum and in both inpatient and outpatient settings.

EMPULSE trial in acute HF

The EMPULSE trial included 530 patients hospitalized with a primary diagnosis of acute HF (de novo or decompensated chronic HF), with N-terminal pro-B-type natriuretic peptide (NT-proB-NP) ≥1,600 pg/mL or B-type natriuretic peptide (BNP) ≥400 pg/mL (50 percent more for patients with atrial fibrillation) during index hospitalization or within 72 hours before admission, regardless of LVEF or diabetes status. [Voors AA, et al, AHA 2021]

Patients in the trial were randomized at ≥24 hours to ≤5 days after admission and in-hospital stabilization to receive treatment with empagliflozin 10 mg (n=265; median age, 71 years; female, 32.5 percent) or placebo (n=265; median age, 70 years; female, 35.1 percent) for 90 days. In-hospital stabilization criteria included systolic blood pressure ≥100 mm Hg and no symptoms of hypotension within 6 hours, no increase in intravenous (IV) diuretic dose within 6 hours, no IV vasodilators including nitrates within 6 hours, and no IV inotropic drugs within 24 hours.

“At baseline, 46.8 percent of patients in the empagliflozin group vs 43.8 percent of those in the placebo group had diabetes. LVEF was ≤40 percent in 68.7 percent vs 64.9 percent of the patients and was >40 percent in 28.7 percent vs 35.1 percent of the patients. About two-thirds of patients [66.8 percent vs 67.2 percent] had decompensated chronic HF, while one-third [33.2 percent vs 32.8 percent] had acute de novo HF,” said lead author Professor Adriaan Voors of the University Medical Centre Groningen in Groningen, the Netherlands.

“The patients had very severe disease at baseline, as indicated by very low median Kansas City Cardiomyopathy Questionnaire Total Symptom Score [KCCQ-TSS] of 37.5 vs 39.6 in the empagliflozin vs placebo group,” said Voors.

Empagliflozin of clinical benefit

The primary endpoint of clinical benefit, defined as a composite of death, number of HF events (ie, hospitalizations for HF [HHFs], urgent HF visits, and unplanned outpatient visits), time to first HF event, and change from baseline in KCCQ-TSS after 90 days of treatment, was assessed by a stratified win ratio. [Voors AA, et al, AHA 2021]

“Results demonstrated a significant clinical benefit with empagliflozin vs placebo within 90 days of treatment. Patients in the empagliflozin group were 36 percent more likely to experience a clinical benefit within 90 days compared with those in the placebo group [stratified win ratio, 1.36; 95 percent confidence interval (CI), 1.09 to 1.68; p=0.0054],” reported Voors. (Figure 1)

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“Empagliflozin’s effect on the primary endpoint was consistent across subgroups, including in patients with de novo HF [win ratio, 1.29; 95 percent CI, 0.89 to 1.89] or decompensated chronic HF [win ratio, 1.39; 95 percent CI, 1.07 to 1.81] [pinteraction, 0.7590], those with diabetes [win ratio, 1.47; 95 percent CI, 1.07 to 2.02] or without diabetes [win ratio, 1.30; 95 percent CI, 0.97 to 1.73] [pinteraction, 0.5683], and those with baseline LVEF ≤40 percent [win ratio, 1.35; 95 percent CI, 1.04 to 1.75] or >40 percent [win ratio, 1.39; 95 percent CI, 0.95 to 2.03] [pinteraction, 0.9008],” Voors continued.

Empagliflozin-treated patients also had greater improvements in symptoms, as measured by the secondary endpoint of change in KCCQ-TSS score at day 90 (placebo-adjusted mean difference, 4.5 points; 95 percent CI, 0.3 to 8.6; p=0.0347).

In addition, all-cause death or first HF event was reduced by 35 percent with empagliflozin vs placebo (hazard ratio [HR], 0.65; 95 percent CI, 0.43 to 0.99; p=0.0423). (Figure 2) Cardiovascular death or first HF event showed a 31 percent reduction (HR, 0.69; 95 percent CI, 0.45 to 1.08; p=0.1021), which did not reach statistical significance.

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Patients in the empagliflozin group also had greater reduction in body weight vs those in the placebo group (placebo-adjusted mean difference at day 90, -1.5 kg; 95 percent CI, -2.8 to -0.3; p=0.0137).

No safety concerns

“Empagliflozin demonstrated a very benign safety profile, with no safety concerns, in this very vulnerable and sick population of patients hospitalized for acute HF,” said Voors.

Adverse events (AEs) and serious AEs were reported in 70.0 percent vs 77.3 percent and 32.3 percent vs 43.6 percent of patients in the empagliflozin vs placebo group, respectively. (Table 1) Rates of acute renal failure and genital infection were 7.7 percent vs 12.1 percent and 1.2 percent vs 0.4 percent, respectively. (Table 2)

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“Rates of volume depletion, hypotension and confirmed hypoglycaemia were similar between the empagliflozin and placebo groups,” said Voors. “Importantly, no cases of ketoacidosis were reported.”  (Table 2)

Estimated glomerular filtration rate (eGFR) decreased slightly, by approximately 2 mL/min/1.73 m2, in the empagliflozin group shortly after treatment initiation, and normalized from day 30. Placebo-adjusted mean difference in eGFR at day 90 was 0.9 mL/min/1.73 m2 (95 percent CI, -2.2 to 4.0; p=0.5714).

Empagliflozin effective in HF with LVEF ≥50 percent

The EMPEROR-Preserved trial in patients with HF with LVEF >40 percent with or without diabetes (n=5,988) showed a 21 percent relative risk reduction (RRR) in the primary composite outcome of cardiovascular (CV) death or HHF with empagliflozin vs placebo. [N Engl J Med 2021;385:1451-1461]

With HFpEF redefined as LVEF ≥50 percent in the European Society of Cardiology’s 2021 HF guidelines, an analysis of the trial’s results was conducted to evaluate empagliflozin’s effects in the subgroup of patients with baseline LVEF ≥50 percent (ie, true HFpEF). [Eur Heart J 2021;doi:10.1093/eurheartj/ehab368; Anker SD, et al, AHA 2021]

“EMPEROR-Preserved is the first large-scale study to document meaningful and significant improvements in outcomes associated with drug therapy in patients with true HFpEF,” said study author Professor Stefan Anker of the Charité University Hospital Berlin, Germany.

Among 4,005 patients with baseline LVEF ≥50 percent (mean age, 72.8 years; female, 50 percent), empagliflozin demonstrated a 17 percent RRR in the primary composite outcome (HR, 0.83; 95 percent CI, 0.71 to 0.98; p=0.024) and a 22 percent RRR in first HHF (HR, 0.78; 95 percent CI, 0.64 to 0.95; p=0.013) vs placebo.

“Results on the primary outcome, total HHF, CV death and first HHF showed no significant interaction between patients with true HFpEF and those with baseline LVEF of 41–49 percent [ie, now redefined as HF with mildly reduced ejection fraction (HFmrEF)],” said Anker. “Improvements in health-related quality of life, measures of kidney function and symptom status were also observed in patients with baseline LVEF ≥50 percent.”

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