Follow the EMPULSE: In-Hospital Initiation of Empagliflozin for Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction

This article refers to ‘Treatment effects of empagliflozin in hospitalized heart failure patients across the range of left ventricular ejection fraction – Results from the EMPULSE trial’ by J. Tromp et al., published in this issue on pages 963–970. Heart failure (HF) is a global pandemic expected to affect over 64 million people worldwide.1 In the United States, HF accounts for more than 1 million hospitalizations with costs exceeding $40 billion.1 Researchers and clinicians continue to investigate innovative and effective ways of treating HF. Sodium–glucose cotransporter 2 (SGLT2) inhibitors have emerged as a first-line treatment option for HF. Prior studies have evaluated the benefits of initiating SGLT2 inhibitors in stable ambulatory settings.2, 3 SOLOIST-WHF was the first trial to extrapolate efficacy of sodium–glucose cotransporter inhibition across left ventricular ejection fraction (LVEF) categories but was not exclusive to the acute setting.4 The landmark EMPULSE trial investigated the efficacy of early initiation of SGLT2 inhibitors specifically in hospitalized patients showing statistical and clinical significance in improving clinical and patient-centred outcomes.5 In this issue of the Journal, Tromp et al.6 conducted a post-hoc analysis of the EMPULSE trial and explored the efficacy, safety, and tolerability of empagliflozin across the full range of LVEF. EMPULSE enrolled 530 patients hospitalized for HF with symptoms regardless of LVEF. These patients were randomized in a double-blind, 1:1 ratio to receive empagliflozin 10 mg daily or a matching placebo. Of note, participants were initiated on therapy between 24 h and 5 days following admission and stabilization. Stabilization was defined as systolic blood pressure ≥100 mmHg with no symptoms of hypotension, no increase in intravenous diuretics or use of intravenous vasodilators within 6 h of randomization, and/or no use of inotropic therapies within 24 h of randomization. Benefits of empagliflozin initiated in the hospital setting, with parameters stated above measured via a composite hierarchical endpoint (i.e. death, worsening HF events, and quality of life over 90 days) and analysed using the novel win-ratio method. The individual components that comprised the composite hierarchical endpoint were further analysed as secondary endpoints at 90 days. These individual components included time to all-cause death, number of HF events, time to first HF event, or ≥5 point change from baseline in the Kansas City Cardiomyopathy Questionnaire total symptom score. The results showed that there was no heterogeneity of treatment effects by LVEF – the findings were largely consistent across LVEF for the primary endpoint, secondary endpoints, and safety endpoints.5 One of the notable aspects of EMPULSE lies within its design, which evaluated empagliflozin in the acute setting. The scientific rationale for the EMPULSE trial is rooted in numerous studies affirming the safety and efficacy of SGLT2 inhibitors in HF patients within the ambulatory setting. Here, patients are typically stable and titrated to their maximally tolerated guideline-directed medical therapy (GDMT) including SGLT2 inhibitor initiation to ensure optimal safety. Once SGLT2 inhibitors had established efficacy and safety on top of optimal GDMT, they were subsequently evaluated in the context of HF hospitalizations, a frequent occurrence amongst HF patients. The SOLOIST-WHF trial, which examined the initiation of sotagliflozin in patients either immediately prior to or within 3 days of discharge from a HF episode, was one of the groundbreaking trials to explore sodium–glucose cotransporter inhibition in the acute setting. It is noteworthy, however, that the trial exclusively enrolled patients with diabetes, and over half of the participants were recruited after discharge.4 EMPULSE further extends these findings by systematically analysing benefit amongst hospitalized patients and by emphasizing early initiation of SGLT2 inhibitors, with a median of 3 days into the hospitalization. Additionally, EMPULSE also included patients with no prior history of HF, distinguishing itself from prior studies by including the de novo HF population. This post-hoc analysis is not only one of the few to evaluate the impact of early initiation of SGLT2 inhibitors in acute HF hospitalizations amongst different LVEF groups, but also the first to show a similar safety profile and tolerability of in-hospital initiation of empagliflozin when compared to matching placebo regardless of baseline LVEF.6 The novelty of this analysis, however, comes from its ability to demonstrate notable clinical benefits and safety profiles across various clinical settings, including ambulatory and acute care, and in patients with different LVEF levels.6 GDMT includes multiple treatment options that have shown to provide benefit in HF patients, yet that benefit can be limited by a patient's LVEF. For example, a post-hoc analysis of the TOPCAT trial revealed that LVEF levels largely influence efficacy of spironolactone with greatest benefit for patients on the lower end of the LVEF spectrum.7-9 The dichotomy between clinical benefit of therapy for patients with LVEF ≤40% or 40–50% compared to LVEF >50% seems to be a common theme throughout the studies evaluating many agents (i.e. angiotensin converting enzyme inhibitors and angiotensin receptor–neprilysin inhibitors indicated for HF with reduced and mildly reduced ejection fraction).10-12 However, SGLT2 inhibitors demonstrate uniqueness in previous trials, where HF patients consistently benefitted regardless of their LVEF status.2, 3, 5 This is further supported by this analysis, which found that baseline LVEF did not modify empagliflozin effect. This aligns with pooled analyses from previous landmark randomized controlled trials.2, 3, 13, 14 It is this potential benefit that contributes to the therapy's IIa class of recommendation, while its counterparts retain a IIb class of recommendation. These data have huge implications as they identify a therapy that is appropriate to be initiated without delay irrespective of clinical setting and LVEF. The EMPULSE trial, along with this post-hoc analysis, contributes more evidence to the emerging paradigm in HF management, emphasizing the critical nature of early initiation and rapid sequence up-titration of GDMT. These findings underscore the significance of prompt intervention and support the concept of early rapid-sequence initiation of GDMT in HF patients on a broader scale. The STRONG-HF trial, comparing high-intensity care to usual care in hospitalized HF patients, observed mortality benefit with high-intensity care.15 High-intensity care involved rapid up-titration to 100% of recommended doses of GDMT (including renin–angiotensin system inhibitors, beta-blockers, and mineralocorticoid receptor antagonists) within 2 weeks of discharge, whereas usual care followed a more moderate titration approach in line with the established guidelines of the time. A secondary analysis of STRONG-HF found that the benefits from high-intensity care reduced HF hospitalization and all-cause mortality at 180 days consistently across the full spectrum of LVEF.16 The data also showed that LVEF had no impact on occurrence of adverse events. Although SGLT2 inhibitors were not part of the GDMT regimen during the STRONG-HF trial, the data on SGLT2 inhibitors also suggest that high-intensity care is a viable strategy, independent of LVEF, to optimize its benefits as the data demonstrated infrequent adverse events. Notably, prior trials have revealed higher rates of adverse events in the high-intensity care groups compared to the usual care groups. However, despite these occurrences, the high-intensity care group exhibited significantly greater utilization of GDMT and superior clinical outcomes. This suggests that while adverse events may be more prevalent, they should be expected and not overshadow the overall net clinical benefit. This analysis by Tromp et al.6 highlights the unique characteristics of SGLT2 inhibitors in the treatment of HF that influence the way we think about HF management. Despite other therapies indicated for HF, SGLT2 inhibitors have distinguished themselves from their counterparts within GDMT. The evidence from EMPULSE complements prior trials to show that SGLT2 inhibitors are safe and effective in the acute settings independent of LVEF. This analysis also adds evidence to the growing phenomenon of early initiation and rapid-sequence up-titration when initiating GDMT. Intriguingly, the promise of early rapid-sequence initiation of SGLT2 inhibitors following a de novo diagnosis or hospitalization with HF can potentially alter the natural history of HF. This thorough post-hoc analysis validates this approach warranting the need for future research to incorporate SGLT2 inhibitors into high-intensity care strategies. Conflict of interest: none declared.