Abstract Body (Do not enter title and authors here): Background: Patients with severe heart failure (HF) experience debilitating clinical symptoms and worse cardiovascular (CV) outcomes with an excess mortality risk. Until recently, severe HF has largely been considered only in those with reduced ejection fraction. The ESC HFA has put forth a consensus definition for severe or advanced HF that may be applicable across the ejection fraction (EF) spectrum.

Hypothesis: Patients with severe HF experience a higher rate of CV outcomes. The safety and efficacy of SGLT2i dapagliflozin is consistent regardless of the severe HF status.

Aims: To assess the prevalence, CV outcome risk, and treatment response to the SGLT2i dapagliflozin among patients with severe HF.

Methods: DAPA-HF and DELIVER were randomized, double-blind trials, testing dapagliflozin vs placebo in 11,007 patients with symptomatic HF across the full spectrum of EF. Severe HF was adapted from the ESC HFA definition: NYHA class III/IV, evidence of HF with reduced, mildly reduced or preserved EF, elevated natriuretic peptides, HF hospitalization within previous 12 months, and adverse patient-reported symptom burden (KCCQ-TSS<75). Outcomes were assessed and the treatment effect of dapagliflozin was measured for the primary endpoint of CV death or first worsening HF event (including HF hospitalization and urgent HF visit) by severe HF status.

Results: Overall, 730 (6.6%) fulfilled the severe HF definition (296 [40.6%] with EF ≤40%, 192 [26.3%] with EF 41-49%, and 232 [33.2%] with EF ≥50%). Patients with severe HF had a higher comorbidity burden and higher NT-proBNP values. Over a median follow-up of 22.4 months, the primary endpoint occurred in 231 patients, at a rate of 20 (17-23) per 100py. Patients with severe HF experienced a higher rate of events compared to patients without severe HF (adjusted hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.20-1.75), across the spectrum of LVEF (P_interaction=0.85). Treatment with dapagliflozin was consistently beneficial in reducing the risk of the primary endpoint regardless of the severe HF status (P_interaction=0.10, Figure 1). The safety profile of dapagliflozin was also consistent irrespective of the severe HF status (Figure 2).

Conclusions: In a large, global contemporary HF trial population, “severe HF” was associated with excess risk of CV events across the spectrum of EF. Treatment with the SGLT2i dapagliflozin appears safe and effective in reducing the risk of CV death or worsening HF in this population.