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Starting dapagliflozin (Farxiga) early during acute heart failure hospitalization didn't boost decongestion, although it appeared to spare loop diuretic doses and increase diuresis compared with usual care, the DICTATE-AHF trial showed.

Diuretic efficiency -- cumulative weight change per cumulative loop diuretic dose -- wasn't significantly better with the SGLT2 inhibitor (SGLT2i) than with standard diuretic titration (OR 0.65, 95% CI 0.41-1.02, P=0.06), Zachary Cox, PharmD, of the Lipscomb University College of Pharmacy in Nashville, Tennessee, and colleagues reported in the .

However, dapagliflozin-treated patients in the open-label trial had those effects at lower loop diuretic doses (560 vs 800 mg, P=0.006) and with fewer IV diuretic up-titrations (P≤0.05).

Additionally, the strategy of initiation within 24 hours of hospitalization appeared safe, without excess diabetic, renal, or cardiovascular safety events, the researchers emphasized. Despite the neutral results for the primary endpoint, the "safety findings should encourage early in-hospital use, which can translate into improved chronic SGLT2i prescription, adherence, and long-term benefits."

In-hospital initiation of SGLT2 inhibitors only reaches about 20% of eligible acute HF patients due in large part to safety concerns, Cox and colleagues wrote. Indeed, "Endocrinology guidelines and international diabetes experts recommend against the routine use of SGLT2i during hospitalization, citing concerns about increased risks of genitourinary infections, ketoacidosis, and acute kidney injury."

Clinical trial evidence is strong for their use in chronic HF and for initiation in-hospital with acute HF, Maria Rosa Costanzo, MD, of the Midwest Cardiovascular Institute in Naperville, Illinois, and James Januzzi, MD, of Massachusetts General Hospital and Harvard University in Boston, noted in an .

With prior trial evidence, "the rationale for why an SGLT2i should be initiated during hospitalization has been that the treatment is safe and facilitates adherence," they wrote. This trial confirms similar pilot trial findings with fellow SGLT2 inhibitor empagliflozin (Jardiance), adding the rationale of reduced IV loop diuretics doses, which Costanzo and Januzzi noted may attenuate their contribution to the "vicious circle of neurohormonal activation that hastens progression of cardiorenal failure."

Additionally, "the effects of these medications go far beyond enhanced decongestion: SGLT2is produce distinctive benefits on the progression of cardiomyopathy and nephropathy," with proven long-term benefits on outcomes, the editorialists wrote.

Nevertheless, they cautioned about limitations of the study that cannot be overlooked. "Of 3,672 patients screened for eligibility, only 7% were randomized. This raises questions on whether the enrolled subjects are representative of the AHF [acute heart failure] population seen in clinical practice and therefore on the generalizability of the study results."

The researchers chalked that up to screening procedures with enrollment during the COVID-19 pandemic and noted that one-third of the screen failures were patients without acute HF and another one-fifth without type 2 diabetes before the trial protocol was amended to allow them.

The multicenter open-label study included 238 persons with acute HF who were randomized in the first 24 hours of hospitalization to either take 10 mg dapagliflozin daily or have protocol-driven diuretic titration until day 5 or discharge. The trial initially included only adult patients with type 2 diabetes and an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m² along with at least two objective measures of hypervolemia, but the protocol was amended to allow those without type 2 diabetes and an eGFR as low as 25 mL/min/1.73 m² after publication of safety data from the DAPA-HF trial.

Indeed, Cox and colleagues noted: "Despite aggressive IV diuresis in DICTATE-AHF, dapagliflozin did not worsen eGFR or cause significant acute kidney injury events compared to usual care. Importantly, this was not the result of empiric IV loop diuretic down-titration in the dapagliflozin arm. It may be that the acute, mild changes in eGFR with SGLT2i are obscured by the common underlying fluctuations in eGFR increases and decreases during decongestion in AHF."

Adverse event incidence overall was similar between randomized groups. Dapagliflozin did not increase the risk of hypoglycemia (seven vs nine cases), and no ketoacidosis occurred in either treatment arm.

The researchers noted that, among the secondary endpoints, the "usual care arm required an additional 80 mg of IV furosemide to achieve equivalent 24-hour natriuresis as the dapagliflozin arm." Dapagliflozin also significantly increased 24-hour urine output (median 634 vs 403 mL per 40-mg IV furosemide, P=0.005).

The researchers acknowledged the open-label design as a limitation, as well as the modest sample size that might have led to lack of statistical significance for the moderate treatment effect favoring dapagliflozin.

The editorialists also pointed to missing data on the doses of relevant background therapies, lack of objective measurement of hypervolemia and of decongestion as a condition for discharge, and a lamentable choice of primary endpoint, "because it has long been recognized that weight measurements are unreliable in HF patients in both hospital and outpatient settings."

"At this stage, clinicians should now understand both when to start proven treatments for AHF and what treatments, such as SGLT2is, can be initiated early," Costanzo and Januzzi concluded. "Now we know why: SGLT2is improve decongestion and ensure long-term favorable outpatient use."

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