In-hospital initiation of SGLT2 inhibitors in acute heart failure: Why?

Patients hospitalized for acute heart failure (HF) have high risks of readmission and mortality in the first few months after discharge. At Advances in Medicine (AIM) 2023, Professor Christiane Angermann of Comprehensive Heart Failure Centre, University Hospital of Würzburg, Würzburg, Germany, discussed recent evidence supporting in-hospital initiation of guideline-directed medical therapies (GDMT) in patients hospitalized for acute HF, focusing on clinical benefits of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, demonstrated in the EMPULSE trial.

High readmission & death rates 1–3 months after discharge
Patients hospitalized for acute HF face high risks of readmission and mortality in the vulnerable phase during the first 4–6 months after discharge. [Circ Heart Fail 2012;5:398-400; Am J Ther 2018;25:e456-e464] “Mortality rate within 1 month after discharge is approximately 10 percent, while readmission rate in the first 3 months after discharge is as high as 30 percent,” Angermann pointed out. [Am J Cardiol 2008;101:1016-1022; JAMA 2010;303:2141-2147; J Am Coll Cardiol 2007;50:768-777]

“The high risks during this vulnerable phase can be explained by the organ damage that occurs during acute cardiac decompensation, which may take weeks or months to recover from and has a major impact on longer-term prognosis,” she continued.

In a phase III study of 1,161 patients hospitalized for acute HF, substantial changes in surrogate markers of organ function and/or indicators of congestion (ie, ≥20 percent increase in troponin, aspartate transaminase or alanine transaminase, ≥22 nmol/L increase in cystatin C, ≥30 percent decrease in N-terminal pro-brain natriuretic peptide [NT-proBNP]) that occurred at 24–48 hours following hospital admission for acute cardiac decompensation or in-hospital worsening HF episodes occurring until day 5 after admission were each associated with a significantly increased risk of all-cause mortality at day 180. [J Am Coll Cardiol 2013;61:196-206]

In-hospital initiation of GDMT in acute HF
Early initiation of GDMT, including SGLT2 inhibitors, after acute decompensation can improve longer-term outcomes. “However, appropriate timing is crucial. The new paradigm is in-hospital initiation of foundational HF therapies after patients are stabilized,” said Angermann. [J Card Fail 2022;28:e1-e167; Ponikowski P, et al, ESC 2022]

This new paradigm is supported by randomized controlled trials including PIONEER-HF, SOLOIST-WHF, STRONG-HF, and EMPULSE, which demonstrated improved outcomes with in-hospital initiation of foundational therapies in patients hospitalized for acute HF. [N Engl J Med 2019;380:539-548; N Engl J Med 2021;384;117-128; Lancet 2022;400:1938-1952; Nat Med 2022;28:568-574]

In-hospital initiation of empagliflozin: Beneficial and well tolerated
The EMPULSE trial evaluated the effect of in-hospital initiation of empagliflozin in patients hospitalized for acute (de novo or decompensated chronic) HF regardless of left ventricular ejection fraction (LVEF). After clinical stabilization, 530 patients (median age, 71 years; female, 34 percent) were randomized 1:1 (median time from admission to randomization, 3 days) to receive empagliflozin 10 mg QD or placebo for up to 90 days. At baseline, about half of the patients had diabetes, and two-thirds had mean LVEF ≤40 percent. “Results showed significant clinical benefit and no safety concerns with in-hospital initiation of empagliflozin in patients hospitalized for acute HF,” said Angermann. [Nat Med 2022;28:568-574]

Significant clinical benefit at 90 days
The primary outcome of clinical benefit (a hierarchical composite of all-cause death, number of HF events [HFEs], time to first HFE, or a ≥5-point difference in change from baseline in Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days), assessed using a win ratio, was 36 percent more likely with empagliflozin vs placebo (stratified win ratio, 1.36; 95 percent confidence interval [CI], 1.09–1.68; p=0.0054). (Figure) Clinical benefit of empagliflozin was observed for both acute de novo and decompensated chronic HF, regardless of baseline LVEF, presence or absence of diabetes, or baseline estimated glomerular filtration rate (eGFR).

“Baseline eGFR did not modify empagliflozin’s effect on the primary outcome. Even patients with severely impaired kidney function obtained clinical benefit,” said Angermann. Win ratios for clinical benefit in patients with baseline eGFR ≥60 mL/min/1.73 m², 45–<60 mL/min/1.73 m², and <45 mL/min/1.73 m² were 1.48 (95 percent CI, 1.04–2.13), 1.14 (95 percent CI, 0.73–1.78), and 1.56 (95 percent CI, 1.08–2.25) (p_interaction=0.54), respectively. [Eur J Heart Fail 2022;24:1844-1852]

Lower risk of death or HFEs
In EMPULSE, empagliflozin significantly reduced the risk of all-cause death or HFEs by 35 percent vs placebo (hazard ratio [HR], 0.65; 95 percent CI, 0.43–0.99; p=0.042).“The number needed to treat of 15 is impressive, although this is an exploratory outcome,” said Angermann. [Voors AA, et al, AHA 2021; Angermann CE, AIM 2023]

Numerically lower risks were observed with empagliflozin vs placebo in time to HFE (HR, 0.72; 95 percent CI, 0.44–1.17; p=0.183), time to all-cause death (HR, 0.52; 95 percent CI, 0.25–1.07; p=0.074), time to cardiovascular (CV) death (HR, 0.59; 95 percent CI, 0.25–1.40; p=0.227), and time to CV death or HFE (HR, 0.69; 95 percent CI, 0.45–1.08; p=0.102). [Nat Med 2022;28:568-574; Angermann CE, AIM 2023]

Early and sustained decongestion
Decongestion is a key therapeutic target in acute HF. Weight loss, a surrogate of decongestion, was significantly greater in empagliflozin vs placebo recipients on days 15, 30 and 90 in EMPULSE (adjusted mean difference: -1.97 kg [95 percent CI, -2.86 to -1.08], -1.74 kg [95 percent CI, -2.73 to -0.74] and -1.53 kg [95 percent CI, -2.75 to -0.31], respectively; all p<0.05). “Greater weight loss on day 15 was associated with a significantly higher probability of clinical benefit on day 90 [win ratio, 1.75; 95 percent CI, 1.37–2.23; p<0.0001],” said Angermann. [Eur Heart J 2023;44:41-50]

Reduction in clinical congestion score (a measure of dyspnoea, orthopnoea and fatigue) was also significantly greater in the empagliflozin vs placebo group on day 15 (adjusted mean difference, -0.34; 95 percent CI, -0.60 to -0.09; p<0.01), with a numerical advantage maintained on day 90 (adjusted mean difference, -0.23; 95 percent CI, -0.47 to 0.02; p=0.067).

Safety & tolerability
In EMPULSE, rates of serious adverse events were lower with empagliflozin vs placebo (32.3 percent vs 43.6 percent).“Rates of hepatic injury [3.8 percent vs 4.9 percent] and acute renal failure [7.7 percent vs 12.1 percent] were also lower with empagliflozin vs placebo,” noted Angermann. [Nat Med 2022;28:568-574]

Optimal sequence and rapid uptitration of GDMT
The Heart Failure Association–European Society of Cardiology consensus recommends tailoring HF therapy based on clinical profiles and maintaining SGLT2 inhibitors across all HF phenotypes. [Eur J Heart Fail 2021;23:872-881]

“The use of four foundational therapies provides the best results,” said Angermann. [JACC Heart Fail 2022;10:73-84]“If we start with an SGLT2 inhibitor [in the four-drug regimen] and go fast [with uptitration], we can halve the risk of HF hospitalization or CV death [at 1 year vs conventional approach of GDMT].” [Eur Heart J 2022;43:2573-2587]