Key takeaways:

• Dapagliflozin did not improve diuretic efficiency for patients hospitalized with acute HF.
• It did, however, require fewer diuretic doses, fewer daily uptitrations and shorter hospital stay vs. usual care.

Despite dapagliflozin not improving diuretic efficiency in the setting of acute HF hospitalization, it was associated with fewer diuretic doses to achieve the same weight change as usual care and shorter hospital stay, researchers reported.

“Dapagliflozin facilitates achievement of both acute HF goals, decongestion and guideline-directed medical therapy optimization, which is unique from other guideline-directed medical therapies or diuretic therapies,” Zachary L. Cox, PharmD, professor of pharmacy at Lipscomb University College of Pharmacy in Nashville, Tennessee, told Healio. “There is no one definitive metric to measure ‘diuretic efficacy,’ so we measured multiple measures of diuretic efficacy in DICTATE-AHF. We observed a treatment effect in the primary outcome of weight-based diuretic efficiency that failed to meet statistical significance but observed significant improvement in several other measures of diuretic effect with dapagliflozin, consistent with other smaller trials of SGLT2 inhibition in acute HF. Clinicians should start a SGLT2 inhibitor on the first day of acute HF hospitalization, which can provide a modest acute diuretic benefit in combination with IV loop diuretics. More rapidly achieving decongestion and guideline-directed medical therapy optimization may translate to reduced hospital lengths of stay.”

To assess the efficacy and safety of early dapagliflozin (Farxiga, AstraZeneca) in the setting of acute HF hospitalization, Cox and colleagues conducted a multicenter, open-label study that enrolled 240 patients who presented with hypervolemic acute HF.

Within 24 hours of hospitalization, participants were randomly assigned to dapagliflozin 10 mg once daily or structured usual care with protocolized diuretic titration until day 5 or hospital discharge.

Participants’ average age was approximately 65 years, roughly one-third were Black, and the majority were men.

Approximately 87% of participants has a history of HF, whereas 71% had diabetes and about 41% had atrial fibrillation/flutter.

The primary outcome was diuretic efficiency expressed as cumulative weight change per cumulative loop diuretic dose.

Reduced diuretic doses, titrations, hospital stay

After adjustment for baseline weight, researchers observed no difference in diuretic efficiency between early dapagliflozin and usual care (OR = 0.65; 95% CI, 0.41-1.02; P = .06); however, early dapagliflozin was associated with lower loop diuretic doses (560 mg vs. 800 mg; P = .006) and fewer daily IV diuretic uptitrations (P .05) to achieve the same weight loss as usual care.

Early dapagliflozin initiation was not associated with any significant difference in 30-day readmission for acute HF or diabetes-related reasons, change in estimated glomerular filtration rate, ketoacidosis, hypovolemic hypotension and inpatient death compared with usual care.

Moreover, early dapagliflozin initiation was associated with improved:

• median 24-hour natriuresis (50 vs. 35 mmol/40 mg IV furosemide; P = .025);
• median urine output (634 vs. 403 mL/40 mg IV furosemide; P = .005); and
• proportion of patients discharged by day 5 (52% vs. 33%; P = .007).

“Collectively, we now have substantial clinical trial evidence across multiple trials that initiation of SGLT2 inhibition during acute HF hospitalization is safe and provides both acute in-hospital benefits along with rapid and sustained post-discharge benefits on morbidity and mortality across the range of left ventricular ejection fraction,” Cox told Healio. “The concerns of increased infection risk, acute kidney injury and ketoacidosis have been demonstrated to be much lower than the substantial acute and chronic benefits. These concerns should not hinder clinicians from starting a SGLT2 inhibitor early in the acute HF hospitalization and continuing it chronically.”

Reassurance of SGLT2 safety in acute HF

In a related editorial, Maria Rosa Costanzo, MD, advanced heart failure cardiologist at the Midwest Cardiovascular Institute in Naperville, Illinois, and James L. Januzzi, MD, the Hutter Family Professor of Medicine at Harvard Medical School, cardiologist at Massachusetts General Hospital and director of heart failure and biomarker trials at the Baim Institute for Clinical Research in Boston, discussed the significance of reduced loop diuretic doses conferred by dapagliflozin as well as an important limitation of the DICTATE-AHF trial.

“Despite having only transient diuretic effects, the addition of dapagliflozin to IV loop diuretics resulted in equivalent cumulative weight change as usual care, but the dapagliflozin arm required significantly less loop diuretics to achieve this weight loss,” the authors wrote. “The importance of reduced IV loop diuretics doses is not insignificant: Lowering loop diuretics doses may attenuate detrimental cardiorenal interactions.

“DICTATE-AHF did not meet its primary endpoint of superior dapagliflozin diuretic efficiency. … The choice of such primary endpoint is unfortunate, because it has long been recognized that weight measurements are unreliable in HF patients in both hospital and outpatient settings,” they wrote. “Despite these unresolved challenges, the DICTATE-AHF trial provides reassurance that initiation of SGLT2 inhibitors amid acute HF decompensation is safe, may promote decongestion with lower loop diuretics doses, and facilitates optimization of GDMT, the only approach able to produce sustained inhibition of key pathophysiologic mechanisms leading to cardiorenal dysfunction.”