suggests a new randomized trial. The drugs were given to the study’s loop diuretic–resistant patients on top of furosemide.
Changes in volume status and measures of pulmonary congestion and risk for serious adverse events were similar for those assigned to take dapagliflozin, an SGLT2 inhibitor, or metolazone, a quinazoline diuretic. Those on dapagliflozin zone ultimately received a larger cumulative furosemide dose in the 61-patient trial, called DAPA-RESIST.
“The next steps are to assess whether a strategy of using SGLT2 inhibitors up front in patients with HF reduces the incidence of diuretic resistance, and to test further combinations of diuretics such as thiazide or thiazide-like diuretics, compared with acetazolamide, when used in addition to an IV loop diuretic and SGLT2 inhibitors together,” Ross T. Campbell, MBChB, PhD, University of Glasgow and Queen Elizabeth University Hospital, also in Glasgow, said in an interview.
Dr. Campbell presented the findings at the annual meeting of the Heart Failure Association of the European Society of Cardiology and is senior author on its simultaneous publication in the European Heart Journal.
The multicenter trial randomly assigned 61 patients with AHF to receive dapagliflozin at a fixed dose of 10 mg once daily or metolazone 5 mg or 10 mg (starting dosage at physician discretion) once daily for 3 days of treatment on an open-label basis.
Patients had entered the trial on furosemide at a mean daily dosage of 260 mg in the dapagliflozin group and 229 mg for those assigned metolazone; dosages for the loop diuretic in the trial weren’t prespecified.
Their median age was 79 and 54% were women; 44% had HF with reduced ejection fraction. Their mean glomerular filtration rate was below 30 mL/min per 1.73 m2 in 26%, 90% had chronic kidney disease, 98% had peripheral edema, and 46% had diabetes.
The mean cumulative furosemide dose was significantly higher among the dapagliflozin group’s 31 patients, 976 mg versus 704 mg for the 30 on acetazolamide (P < .05), 96 hours after the start of randomized therapy. However, patients on dapagliflozin experienced a lesser increase in creatinine (P < .05) and in blood urea (P < .01), a greater change in serum sodium (P < .05), and a smaller reduction in serum potassium (P < .01).
Although the trial wasn’t powered for those outcomes, Dr. Campbell said, “less biochemical upset could be associated with better outcomes in terms of less medium- to long-term renal impairment, and in the short-term length of stay.”
The mean decrease in weight at 96 hours, the primary endpoint, reached 3 kg on dapagliflozin, compared with 3.6 kg with metolazone (P = .082), a difference that fell short of significance.
Loop diuretic efficiency, that is weight change in kg per 40 mg furosemide, “was smaller with dapagliflozin than with metolazone at each time point after randomization, although the difference was only significant at 24 hours,” the published report states.
Changes in pulmonary congestion (by lung ultrasound) and fluid volume were similar between the groups.
“This trial further adds to the evidence base and safety profile for using SGLT2 inhibitors in patients with acute heart failure,” and “gives further confidence to clinicians that this class can be started in ‘sicker’ patients with HF who also have diuretic resistance,” Dr. Campbell said.
Asked during his presentation’s question and answer whether dapagliflozin might have shown a greater effect had the dosage been higher, Dr. Campbell explained that the drug was investigational when the trial started. Adding a higher-dose dapagliflozin arm, he said, would have made for an excessively complex study. But “that’s a great research question for another trial.”
DAPA-RESIST was funded by AstraZeneca. Dr. Campbell disclosed receiving honoraria from AstraZeneca for speaking and from Bayer for serving on an advisory board.
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