Adding acetazolamide to intravenous loop diuretics improves decongestion in patients with acute decompensated heart failure, a major study has shown.

While loop diuretics are recommended in guidelines for acute decompensated heart failure, many patients have residual clinical signs of volume overload, a strong predictor of poor outcome, researchers from Belgium told the ESC 2022 meeting in Barcelona.

But results from the ADVOR trial of the carbonic anhydrase inhibitor acetazolamide showed that it resulted in more and faster decongestion compared to use of loop diuretics alone.

The trial enrolled 519 adults hospitalised with acute decompensated heart failure, with an average age of 78 years and 63% of whom were men. Patients had at least one clinical sign of volume overload, elevated natriuretic peptide levels, and had been taking oral diuretics for at least one month.

All patients received high-dose intravenous loop diuretics and were randomised to intravenous acetazolamide (500 mg once daily) or placebo, administered as a bolus upon randomisation and during the next two days or until successful decongestion.

The primary endpoint was successful decongestion, defined as no clinical signs of fluid overload (other than trace oedema) within 72 hours days without needing escalation of decongestive therapy.

Successful decongestion occurred in 42.2% of patients in the acetazolamide group and 30.5% in the placebo group, for a relative risk (RR) of 1.46 (95% confidence interval [CI] 1.17–1.82; p=0.0009).

Of those alive at discharge, 78.8% in the acetazolamide group had successful decongestion compared with 62.5% in the placebo group (RR 1.27; 95% CI 1.13–1.43; p=0.0001).

Use of acetazolamide was also associated with a shorter hospital stay (8.8 vs 9.9 days) compared with placebo, but there was no difference between groups in the composite outcome of all-cause mortality and hospitalisation for heart failure within three months.

Principal investigator Professor Wilfried Mullens of Hospital Oost-Limburg, Genk, Belgium, said it was reassuring that acetazolamide treatment was not associated with higher incidences of hypokalemia, hypotension, or renal end points.

It was also notable that the improvement with regard to successful decongestion with acetazolamide was generally consistent across all the prespecified subgroups, except for one comparison suggesting less treatment benefit among patients receiving a higher oral maintenance dose of loop-diuretic therapy.

He said the carbonic anhydrase inhibitor reduces proximal tubular sodium reabsorption and may improve diuretic efficiency when added to loop diuretics, thereby potentially facilitating decongestion.

“ADVOR was the largest randomised diuretic trial ever performed in patients with acute decompensated heart failure. Acetazolamide is easy to use, safe, effective, off-patent and cheap. It is therefore expected that the results of ADVOR will lead to a paradigm shift in the way physicians worldwide treat acute decompensated heart failure,” he concluded.

The findings were also published in the NEJM.