Old but Effective – Acetazolamide Makes a Comeback

A new study presented at the European Society of Cardiology found that the addition of acetazolamide to intravenous loop diuretics in patients hospitalized with acute decompensated heart failure resulted in a significant increase in successful decongestion.[1]

Acetazolamide was first introduced into clinical practice in the early 1950s as an oral diuretic via “alkaline diuresis”.[2] Previous small observational studies have suggested that acetazolamide might improve natriuresis and neurohormonal blockade in decompensated heart failure.[3]

In the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial, investigators assessed the effectiveness of acetazolamide 500mg daily for three days in addition to loop diuretic therapy for volume overload due to heart failure. The primary endpoint was successful decongestion, assessed by tabulating the presence of peripheral edema, pleural effusion, and ascites. Secondary endpoints included death, 3-month rehospitalization, and duration of index hospitalization, in addition to safety endpoints of composite renal injury and hypokalemia.

The investigators found that successful decongestion at three days occurred in 42.2% versus 30.5% in the acetazolamide versus placebo group, with 78.8% versus 62.5% of patients achieving euvolemia at discharge. There was no statistically significant difference in death or 3-month rehospitalization, though the duration of index hospitalization was 8.8 days in the treatment group as compared to 9.9 days in the placebo group. Likewise, the incidence of hypotension, hypokalemia, and renal injury were similar.

Dr. Michael Felker, Professor of Medicine in the Division of Cardiology at Duke University states, “despite the fact that decongestion therapy for patients hospitalized with heart failure is something that happens every day in clinical practice, there are surprisingly little high quality data to guide best practice…The addition of acetazolamide to standard diuretic therapy showed a clear improvement in decongestion without any obvious safety concerns. Since acetazolamide is already clinically available, these are data that could be readily incorporated into clinical practice.”

Despite growing evidence to support SGLT2 inhibitors, it should be noted that patients taking SGLT2 inhibitors were excluded from this trial. The trial also lacked racial and ethnic diversity, with 99.0% of enrolled patients identifying as White. Future studies may seek to assess the impact of acetazolamide on patient symptoms or quality of life and may be powered to assess long term endpoints including rehospitalization and death.

Wilfried Mullens and colleagues present compelling evidence that acetazolamide may be added to the growing toolkit for patients hospitalized with volume overload in acute decompensated heart failure.

Importantly, can't make up for a missed opportunity! AFTER randomised treatment period, decongestion curves keep separating. Remember that #acetazolamide is a break on the neurohumoral system. You don't break when Your already over the cliff! pic.twitter.com/NBrMamFA0z

— Frederik H. Verbrugge (@FH_Verbrugge) August 27, 2022

References:

1. Mullens W, Dauw J, Martens P, Verbrugge FH, Nijst P, Meekers E, et al. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload. N Engl J Med. 2022. doi: 10.1056/NEJMoa2203094.
2. Sneader W. Drug Discovery: A History. John Wiley & Sons. p. 390. 2005. ISBN 9780471899792. .
3. Verbrugge FH, Dupont M, Bertrand PB, Nijst P, Penders J, Dens J, et al. Determinants and impact of the natriuretic response to diuretic therapy in heart failure with reduced ejection fraction and volume overload. Acta Cardiol. 2015;70(3):265-73. doi: 10.1080/ac.70.3.3080630.