ADVOR Backs Add-On Acetazolamide for Cutting Congestion in Decompensated HF

BARCELONA — The addition of IV acetazolamide to loop diuretic therapy led to a greater incidence of successful early decongestion in patients with acute decompensated heart failure (HF), according to the ADVOR trial.

The primary outcome of successful decongestion within 3 days after randomization was 42.2% with acetazolamide versus 30.5% with placebo (P<0.001), reported Wilfried Mullens, MD, PhD, of Ziekenhuis Oost-Limburg, in Genk, Belgium at the European Society of Cardiology (ESC) meeting. The results were simultaneously published in the New England Journal of Medicine (NEJM).

“ADVOR was the largest diuretic trial in acute decompensated heart failure ever performed with a very important clinical end point of decongestion,” Mullens said at an ESC press conference. “In these patients, the addition of acetazolamide to standardized intravenous loop diuretic was associated with 46% [risk ratio 1.46] higher incidence of decongestion after 3 days.”

Patients who received IV acetazolamide also saw better outcomes for the following versus placebo:

• Duration of hospital stay: 8.8 days vs 9.9 days (P=0.016)
• All-cause mortality or rehospitalization for HF during 3-month follow-up: 29.7% vs 27.8% (not statistically significant)
• Combined renal safety endpoint: 2.7% vs 0.8% (P=0.10)
• Hypokalemia: 5.5% vs 3.9% (P=0.39)
• Hypotension: 6.6% vs 3.5% (P=0.11)

“The study was underpowered to determine a mortality benefit,” Mullens told MedPage Today. “But we saw we could get more patients to be dry — that is, resolution of edema and ascites.” Other study limitations included the fact that it was done only in Belgium (vast majority of patients were white), so the findings may not be generalizable to other racial/ethnic groups. Also, at the time of the trial (November 2018-January 2022), sodium–glucose cotransporter 2 (SGLT2) inhibitors were not indicated and had not been approved as drugs to treat HF so “the trial design excluded their use,” the researchers wrote.

In an accompanying NEJM editorial, G. Michael Felker, MD, of Duke University in Durham, North Carolina, said that ADVOR had “several notable strengths; it was a relatively large as compared with other trials testing diuretics in patients with heart failure, multicenter, placebo-controlled trial that assessed a clinically relevant end point.”

But the exclusion of patients taking SGLT2 inhibitors “presents a conundrum for applying these results in contemporary clinical care…we can only speculate as to the efficacy of acetazolamide in patients treated with background SGLT2 inhibitors, which could potentially be additive, subadditive, or synergistic,” he stated.

Felker suggested that younger patients, those with less severe or new-onset HF, and those with normal kidney function are more likely to respond to loop diuretics, and that treatment may be enough for successful decongestion.

“However, for the large group of patients who have some degree of diuretic resistance, or for those who have an inadequate initial response to loop-diuretic therapy, these data suggest the use of acetazolamide as a reasonable adjunct to achieving more rapid decongestion,” Felker stated. “Future studies will further define the role for this strategy in the changing landscape of therapy for patients with heart failure.”

ADVOR had 519 patients (age around 78; more than half male) hospitalized with acute decompensated HF who were randomized 1:1 to IV bolus of acetazolamide (500 mg daily) or matching placebo. IV oral loop diuretics were given at double the oral maintenance dose over split doses. Patients had to have clinical signs of volume overload, N-terminal pro-B-type natriuretic peptide >1000 pg/mL or BNP >250 pg/mL, and be on oral maintenance therapy with furosemide/torsemide/bumetanide for at least a month prior to randomization. They received acetazolamide or placebo simultaneously with first dose of loop diuretics each day. Follow-up was done for 3 months.

As for adverse events (AEs), the researchers emphasized that the “incidence of worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups.” During 3-month follow-up, about 48% in both groups experienced serious AEs. Serious cardiovascular AEs occurred in 47.1% of the study-drug group and 44.1% of the placebo group.

Acetazolamide, an inhibitor of the enzyme carbonic anhydrase, is FDA approved to treat glaucoma, drug-induced edema, altitude sickness, and intraocular pressure after surgery. Mullens said that generic acetazolamide costs about $8 per dose.