Dapagliflozin Did Not Meet Primary Endpoint in DICTATE-AHF Trial of Patients with Acute Decompensated Heart Failure

Early initiation of dapagliflozin did not result in a statistically significant improvement in diuretic efficiency relative to structured usual care in patients hospitalized with acute decompensated heart failure (ADHF), according to new research presented at the European Society of Cardiology (ESC) 2023 Congress in Amsterdam.

Findings from the DICTATE-AHF clinical trial were presented in a Hot Line session today, according to an ESC press release.

Results also showed that early initiation of the sodium glucose co-transporter 2 (SGLT2) inhibitor did not worsen any prespecified safety outcomes, “indicating dapagliflozin can be safely started upon hospital admission to rapidly optimize guideline directed medical therapy (GDMT),” stated the release. Moreover, data from exploratory analyses showed that dapagliflozin improved decongestion and was associated with an earlier discharge from the hospital.

According to the ESC release, the 2 primary therapeutic goals for patients hospitalized with ADHF are complete decongestion and optimization of GDMT.

“Previous studies of diuretic combinations improved decongestion, but these diuretic combinations inherently did not optimize GDMT and were not associated with improved post-discharge outcomes,” wrote the ESC. “Early initiation of dapagliflozin could improve both GDMT optimization and decongestion, but the efficacy and safety of this strategy is unknown.”

Authors of the DICTATE-AHF trial examined the efficacy and safety of dapagliflozin 10 mg when initiated within 24 hours of hospital admission on diuretic response in adults with hypervolemic ADHF.

Participants with type 2 diabetes (T2D) and an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73m² admitted to the hospital with ADHF and current or planned treatment with intravenous (IV) loop diuretics were initially included in the study. In September 2021, an amendment was added to the study protocol to address new safety data that allowed enrollment of patients with or without T2D and an eGFR of at least 25 mL/min/1.73m², according to the ESC statement.

Within 24 hours of hospital admission, participants were randomly assigned to either daily dapagliflozin or structured usual care until day 5 or hospital discharge. Researchers assessed natriuretic peptide concentration, standing weight, and congestion at baseline.

“A standardized protocol for IV loop diuretic dosing and titration every 12-24 hours was used for both study arms throughout the study period to target a urine output of 3-5 L/day. Loop diuretic doses were titrated to a dose of at least 960 mg/day of IV furosemide equivalents before a thiazide diuretic was added,” stated the press release.

To measure baseline diuretic-induced urine sodium, investigators collected a spot urine sample after the initial IV loop diuretic dose, but before administration of dapagliflozin. On day 2, spot urine collections and a 24-hour urine collection were done. At day 5 or hospital discharge, natriuretic peptide concentration, final standing weight, and a congestion assessment were performed. Patients were followed after discharge to analyze 30-day post-discharge outcomes, according to the ESC statement.

“The primary outcome was diuretic efficiency (diuretic response) expressed as the cumulative change in weight per cumulative loop diuretic dose (IV and oral) from enrolment to day 5 or discharge, if sooner,” wrote the ESC. “The primary outcome was compared across treatment assignment using a proportional odds regression model adjusting for baseline weight.”

FINDINGS

A total of 240 patients (mean age, 65 years; 39% women) were included in the study.

Researchers observed, after adjusting for baseline weight, that the odds ratio (OR) for diuretic efficiency with dapagliflozin compared to structured care was 0.65 (95% CI 0.41-1.01; P=.06); in the unadjusted analysis, the OR was 0.64 (95% CI 0.41-1.00; P=.05).

“The secondary endpoints of in-hospital worsening heart failure and 30-day readmission for heart failure or diabetes-related reasons did not differ between early dapagliflozin initiation compared to usual care,” said the ESC.

In regard to the exploratory endpoints, investigators found that dapagliflozin significantly increased 24-hour natriuresis (P=.025) and 24-hour urine output (P=.005), and decreased time to completing IV diuretic therapy (P=.006) and time to hospital discharge (P=.007).

“Although our study did not show statistical significance for its primary endpoint, the totality of data from this trial supports the early initiation of dapagliflozin in ADHF to facilitate decongestion while rapidly and safely optimizing GDMT,” said study coauthor Zachary Cox, PharmD, a professor in the Department of Pharmacy Practice at Lipscomb University College of Pharmacy, in Nashville, Tennessee, in the press release.

In addition, early initiation of dapagliflozin was found to be safe across all diabetic and cardiorenal in-hospital outcomes, with no differences between groups in the change in eGFR from baseline to end-of-study, incidence of adverse events, inpatient mortality, symptomatic hypotension, total or serious hypoglycemia events, genitourinary infections, or severe hypokalemia.

"Our findings of safety across inpatient diabetes, cardiovascular and renal outcomes should encourage in-hospital use, which can translate to improved chronic SGLT2 inhibitor prescription, adherence, and long-term benefits," noted Cox.

Source: DICTATE-AHF trial fails to meet primary endpoint with dapagliflozin in acute heart failure. European Society of Cardiology. News release. August 28, 2023. Accessed August 28, 2023. https://www.escardio.org/The-ESC/Press-Office/Press-releases/DICTATE-AHF-trial-fails-to-meet-primary-endpoint-with-dapagliflozin-in-acute-heart-failure