Add-on acetazolamide cuts congestion in acute decompensated HF

Adding acetazolamide to conventional loop diuretics led to a higher incidence of successful early decongestion in patients with acute decompensated heart failure (ADHF), according to the ADVOR* trial presented at ESC 2022.

“[Acetazolamide] has been used for >70 years … and it has shown a [favourable] safety profile over the last decades,” said Professor Wilfried Mullens from Ziekenhuis Oost-Limburg in Genk, Belgium. “[The findings of this current study suggest that it is a] very effective drug to improve decongestion.”

This trial randomized 519 hospitalized patients (mean age 78.2 years, 62.6 percent male) from 27 sites in Belgium with ADHF (median NT-proBNP** level of 6,173 pg/mL) and volume overload to receive either intravenous acetazolamide 500 mg once daily (n=259) or placebo (n=260) added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose). All patients had  been on oral loop diuretic at a dose equivalent of ≥40 mg of furosemide for at least 1 month previously. A comprehensive congestion score, including presence of oedema, pleural effusion, and ascites (maximum of 10, with higher scores indicating a worse condition), was used to determine the presence of volume overload. [ESC 2022, Hot Line Session 2]

The primary end point was successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy. Secondary end points included a composite of death from any cause or rehospitalization for HF during 3 months of follow-up.

Compared with the placebo arm, the acetazolamide arm had a higher incidence of successful decongestion (42.2 percent vs 30.5 percent; risk ratio [RR], 1.46; p=0.0009).

“The addition of 500 mg IV acetazolamide to standardized IV loop diuretic was associated with a 46 percent higher incidence of successful decongestion after 3 days [in this patient population],” said Mullens.

A similar trend favouring acetazolamide over placebo for successful decongestion was seen in an exploratory analysis of patients who were alive at discharge (78.8 percent vs 62.5 percent; RR, 1.27; p=0.0001).

Mullens noted that the benefit observed with acetazolamide was “overwhelming”, and was generally consistent across all prespecified subgroups, such as age, left ventricular ejection fraction, NT-proBNP level, sex, and estimated glomerular filtration rate.

In terms of the key secondary endpoints, acetazolamide recipients had a shorter duration of hospital stay than those on placebo (8.8 vs 9.9 days), but no between-group difference was seen in terms of the composite outcome of all-cause mortality and rehospitalization for HF at 3 months.

Acetazolamide recipients had more diuresis and natriuresis (absolute difference on day 2, 0.5 L; p=0.002 and 98 mmoL; p<0.001, respectively) than those on placebo. “[They were also] more likely to be discharged without residual signs of volume overload,” Mullens noted. “[These findings] highlight the importance of targeting congestion both early and aggressively, and support the use of natriuresis as an indicator of diuretic response.”

The incidence of adverse events and worsening kidney function, hypokalaemia, and hypotension were comparable between groups.

“ADVOR was the largest diuretic trial in ADHF ever performed with a very important clinical endpoint of decongestion, which is a class I recommendation for ADHF in EU/US guidelines. It is therefore expected that the results of ADVOR will lead to a paradigm shift in the way physicians worldwide treat ADHF,” said Mullens.

“Moreover, as acetazolamide is easy to use, safe, cheap, off patent, and very effective, we expect a worldwide adaptation,” Mullen told MIMS.

“[For] patients who have some degree of diuretic resistance, or have an inadequate initial response to loop-diuretic therapy, acetazolamide may be a reasonable adjunct to achieving more rapid decongestion,” wrote Dr Michael Felker from the Duke University School of Medicine and Duke Clinical Research Institute in Durham, North Carolina, US, in an editorial. [N Engl J Med 2022;doi:10.1056/NEJMe2209997]

“Future studies will further define the role of this strategy in the changing landscape of therapy for patients with HF,” added Felker.

*ADVOR: Acetazolamide in Decompensated heart failure with Volume OveRload