Early empagliflozin initiation after hospitalization for heart failure in the United States: a target trial emulation
S J Greene, G Tskhvarashvil, C Carlsen, P Tran, R Hermans, S Enshaeifar, A Adam, M Martinez Traba, N Schmedt, A AlhamdowAbstract
Background
Sodium-glucose cotransporter-2 inhibitors (SGLT2i), such as empagliflozin, have been shown to reduce mortality and heart failure (HF) events across the entire spectrum of ejection fraction. Despite evidence from the EMPULSE trial and guideline recommendations for early initiation, real-world implementation varies substantially, with many patients experiencing delays in treatment initiation.
Purpose
This study aimed to evaluate real-world 1-year clinical outcomes of early versus delayed empagliflozin initiation after HF hospitalisation.
Methods
This retrospective cohort study utilised Optum’s de-identified Clinformatics Data Mart database (Sep 2021–Dec 2023). Adults (≥18 years) hospitalised with HF in the U.S., with ≥1-year continuous enrolment and no prior SGLT2i use were included. Patients with type 1 diabetes, diabetic ketoacidosis, dialysis, LVAD, cardiac/renal transplant, or eGFR <20 mL/min/1.73m² were excluded. Follow-up began at hospital discharge until death, end of insurance plan, or up to 365 days post-discharge. The Clone-Censor-Weighting approach was used to emulate a target trial. Each patient was cloned into three empagliflozin initiation arms: initiation during hospitalisation or ≤7 days post-discharge; initiation 8–91 days post-discharge; initiation >91 days or no initiation. Study outcomes were all-cause mortality, HF events (HF rehospitalisation and emergency department visits with HF), and all-cause hospitalisation. Risk Ratios (RR) were calculated using a pooled logistic regression model with 95% confidence intervals (CI), using robust sandwich variance estimators. Initiation >91 days or no initiation served as a reference.
Results
Among 99,738 patients hospitalised for HF (mean age 78 y; 54% female), 3,873 initiated empagliflozin pre-discharge or within 7 days post-discharge, 3,087 initiated between 8–91 days, and 92,778 had delayed or no initiation. Baseline characteristics were well-balanced after weighting (Table 1). Compared with delayed initiation >91 days or no initiation, early empagliflozin initiation was associated with a 42% lower risk of all-cause mortality (adjusted RR=0.58, 95% CI: 0.54–0.62), 11% lower risk of HF events (RR=0.89, 95% CI: 0.86–0.93), and 16% lower risk of all-cause hospitalisation (RR=0.84, 95% CI: 0.81–0.87). Initiation at 8–91 days showed intermediate benefits for mortality (RR=0.74, 95% CI: 0.70–0.77) and HF events (RR=0.91, 95% CI: 0.88–0.95), suggesting a graded relationship between earlier initiation and improved 1-year post-discharge outcomes (Table 2).
Conclusion(s)
Early initiation of empagliflozin within 7 days following hospital discharge for HF is associated with lower risks for all-cause mortality, HF-related events, and all-cause hospitalisation, compared to delayed empagliflozin initiation. These findings support guideline recommendations for early initiation of SGLT2i therapy in HF patients and suggest the need to reduce treatment delays in clinical practice.Baseline Patient CharacteristicsFor image description, please refer to the figure legend and surrounding text.Relative Risks of Clinical OutcomesFor image description, please refer to the figure legend and surrounding text.