In-Hospital Dapagliflozin Does Not Reduce CV Death or Worsening HF in Two Months, but Meta-Analysis Signals Potential Early Benefit

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By Leah Kosyakovsky on

Key Points:

  • Dapagliflozin is a key component of GDMT for heart failure, but it is unknown whether inpatient initiation improves outcomes.
  • The DAPA ACT HF-TIMI 68 was a randomized, double-blind trial which examined the efficacy and safety of in-hospital initiation of dapagliflozin in inpatients with HF.
  • Dapagliflozin did not significantly reduce the risk of CV death or worsening HF at two months, but a pre-specified meta-analysis inclusive of three SGLT2is indicated a potential early benefit.

While HF mortality continues to rise, uptake of GDMT is still not optimal. However, the evidence around timing of initiation of SGLT2is, one of the four pillars of GDMT, is still mixed. Specifically, it is unknown whether inpatient initiation of SGLT2is for hospitalized HF could improve short- or long-term outcomes. In a breaking presentation at the 2025 ACC ESC Congress today, Dr. David Berg and his team presented their study, “Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure -Thrombolysis in Myocardial Infarction 68,” or the DAPA ACT HF-TIMI 68 trial.

DAPA ACT HF-TIMI 68 (NCT04363697) was an international, randomized, double-blind trial that randomized 2,401 adults (age 18+) hospitalized with a primary HF diagnosis to inpatient initiation of dapagliflozin vs placebo. Initially, only patients with an EF <40% were included, but this was liberalized to individuals with an EF ≥40% in November 2021 after benefit was demonstrated with empagliflozin in ambulatory patients. Patients were randomized between 24 hours and two weeks of admission and were required to have elevated natriuretic peptides. The primary outcome was a composite of time to CV death or first worsening HF event over two months. Some relevant secondary outcomes included various composites of time to CV death, rehospitalization for HF, and urgent HF visit, as well as time to death from any cause. Important safety outcomes included symptomatic hypotension leading to hospitalization, drug discontinuation, and worsening kidney function. 

A total of 1,218 individuals were assigned to dapagliflozin and 1,183 to placebo. Dapagliflozin did not result in a significant reduction in the primary outcome relative to placebo (10.9% vs 12.7%; HR 0.86; 95% CI 0.68-1.08; p=0.20). There were also no significant differences in the individual endpoints of worsening HF, CV death, or all-cause death (all p>0.05). There were similar rates of symptomatic hypotension (3.6% v 2.2%) and worsening kidney function (5.9% vs 4,7%) between groups. After meta-analyzing the data from DAPA ACT HF-TIMI 68, EMPULSE, and SOLOIST-WHF, inpatient initiation of any SGLT2i resulted in a 29% significant reduction in the early risk of CV death or worsening HF (HR 0.71, 95% CI 0.54-0.93; p=0.012) and a 43% reduction in the risk of all-cause death (HR 0.57, 95% CI 0.41-0.80; p=0.001).

In conclusion, the authors stated “in-hospital initiation of dapagliflozin did not significantly reduce the risk of CV death or worsening HF…but the totality of RCT data suggests that in-hospital initiation of SGLT2i reduces high risk of adverse outcomes…in the early post-discharge period.”