SGLT2 inhibition leads to early decongestion and clinical benefit in acute HF
Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trialLiterature - Biegus J, Voors AA, Collins SP, et al. - Eur Heart J. 2022 Oct 18;ehac530. doi: 10.1093/eurheartj/ehac530
Introduction and methods
In patients with acute HF (AHF), residual congestion at hospital discharge contributes to readmission and predicts poor outcome . Therefore, effective and safe decongestion remains the main goal of AHF therapy [2-4]. Although diuretics are the first-line treatment for AHF patients, their use be limited due to, among others, impaired kidney function or poor response to the particular diuretic . As SGLT2i tend to facilitate decongestion in patients with chronic HF [6,7], the question is whether they can achieve the same decongestive efficacy in AHF.
Previously, the EMPULSE (EMPagliflozin in patients hospitalized with acUte heart faiLure who have been StabilizEd) trial showed that early treatment with the SGLT2i empagliflozin resulted in a statistically significant and clinically meaningful benefit within 90 days in hospitalized AHF patients compared with placebo [8,9].
Aim of the study
The aim of the study was to evaluate the effect of empagliflozin on several prespecified decongestion-related endpoints in the EMPULSE trial and to examine whether decongestion itself was associated with clinical benefit at day 90.
The EMPULSE trial was a multinational, multicenter, randomized, double-blind study in which 530 patients hospitalized for AHF were randomized, after initial stabilization, to treatment with empagliflozin 10 mg once daily or placebo for 90 days. Inclusion criteria were: hospital admission with primary diagnosis of AHF, treatment with minimum dose of 40 mg of intravenous furosemide or equivalent, dyspnea (exertional or at rest), and ≥2 of 4 signs of congestive HF. One of the key exclusion criteria was AHF primarily triggered by pulmonary embolism, CVA, or acute MI.
The primary endpoint of the EMPULSE trial was clinical benefit as measured by the stratified win ratio. The order and components of the primary endpoint were: time to all-cause death, number of HF events (including HF hospitalizations, urgent HF visits, and unplanned outpatient visits), time to first HF event, and ≥5-point difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire – total symptom score at day 90.
For the current analysis, changes from baseline to days 15, 30, and 90 of treatment in the following decongestion-related endpoints were evaluated: weight loss, weight loss adjusted per mean daily loop diuretic dose, area under the curve (AUC) of change from baseline in log-transformed NT-proBNP level (over 30 days of treatment), hemoconcentration (measured as hematocrit changes), and clinical congestion score.
Changes in decongestion-related endpoints
- From baseline to day 15, patients in the empagliflozin group had lost more body weight than those in the placebo group: The means (adjusted for HF status and baseline value by visit interaction) were –3.20 kg (standard error (SE): 0.32) and –1.23 kg (SE: 0.32), respectively (adjusted mean difference: −1.97 kg; 95%CI: −2.86 to −1.08; P<0.0001).
- The adjusted mean difference in body weight between the empagliflozin and placebo groups was −1.74 kg (95%CI: −2.73 to −0.74; P=0.0007) at day 30 and −1.53 kg (95%CI: −2.75 to −0.31; P=0.014) at day 90.
- As for body weight change per mean daily loop diuretic dose from baseline, the adjusted mean difference between the empagliflozin and placebo groups was −2.31 kg per 40 mg of furosemide or equivalent (95%CI: −3.77 to −0.85; P=0.002) at day 15, −2.79 kg/40 mg of furosemide or equivalent (95%CI: −5.03 to −0.54; P=0.015) at day 30, and −3.18 kg/40 mg of furosemide or equivalent (95%CI: −6.08 to −0.28; P=0.032) at day 90.
- The adjusted geometric mean ratio of the AUC of NT-proBNP change from baseline between the empagliflozin and placebo groups was 0.92 pg/mL (95%CI: 0.86–0.98; P=0.010) at day 15 and 0.90 pg/mL (95%CI: 0.82–0.98; P=0.018) at day 30. At day 90, the adjusted geometric mean ratio was not statistically significant (0.89 pg/mL; 95%CI: 0.79–1.00; P=0.056).
- The adjusted mean difference in hematocrit change from baseline between the empagliflozin and placebo groups was 1.71% (95%CI: 1.02–2.40; P<0.0001) at day 15, 1.62% (95%CI: 0.88–2.35; P<0.0001) at day 30, and 1.94% (95%CI: 1.11–2.76; P<0.0001) at day 90.
- The clinical congestion score showed a larger reduction from baseline in the empagliflozin group than in the placebo group at day 15 (adjusted mean difference: –0.34; 95%CI: –0.60 to –0.09; P=0.008) but not at day 90 (adjusted mean difference: –0.23; 95%CI: –0.47 to 0.02; P=0.067).
Effect of body weight loss or hematocrit change on clinical benefit at day 90
- In the entire study population, patients with more body weight loss (i.e., weight reduction >overall median) at days 15 and 30 were more likely to have a clinical benefit at day 90 than those with less weight loss (i.e., weight reduction ≤overall median); the win ratios were 1.75 (95%CI: 1.37–2.23; 2-sided P<0.0001) and 1.55 (95%CI: 1.22–1.98; 2-sided P=0.0004), respectively. Similar results were seen when the empagliflozin and placebo arms were analyzed separately.
- In the overall population, patients with a larger hematocrit increase (i.e., hematocrit change >overall median) at days 15 and 30 were more likely to experience a clinical benefit at day 90 than those with a hematocrit change ≤overall median; the win ratios were 1.40 (95%CI: 1.09–1.80; 2-sided P=0.008) and 1.30 (95%CI: 1.01–1.67; 2-sided P=0.042), respectively.
- In both the empagliflozin and placebo groups, there was a (strong) trend toward a more pronounced clinical benefit at day 90 among patients with a larger hematocrit increase compared with those with a smaller or no hematocrit increase. At days 15 and 30, the win ratios were 1.33 (95%CI: 0.93–1.90; 2-sided P=0.121) and 1.42 (95%CI: 1.00–2.01; 2-sided P=0.047) in the empagliflozin group, respectively, and 1.36 (95%CI: 0.96–1.92; 2-sided P=0.085) and 1.36 (95%CI: 0.96–1.92; 2-sided P=0.085) in the placebo group, respectively.
In patients hospitalized for AHF, empagliflozin treatment initiated after initial in-hospital stabilization resulted in early (at day 15), clinically meaningful, and sustained (present at day 90) decongestion compared with placebo. The magnitude of the decongestion (as proxied by more body weight loss) was associated with a clinical benefit at day 90. According to the authors, their “findings suggest that empagliflozin added to standard therapy improves diuretic efficacy,” which becomes evident at day 15 and is sustained until day 90.