Intravenous acetazolamide for acute decompensated heart failure – ADVOR Study

Intravenous acetazolamide for acute decompensated heart failure – ADVOR Study

Acetazolamide in Decompensated Heart Failure With Volume OveRload (ADVOR) study assessed whether intravenous acetazolamide can improve the efficacy of loop diuretics in acute decompensated heart failure with volume overload. Acetazolamide is a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption. It was a multicenter, double blind randomized, placebo controlled trial. Edema, pleural effusion and ascites were the important features of volume overload [1].

Ascites was confirmed by abdominal ultrasound and pleural effusion by chest X-ray or ultrasound. Intravenous acetazolamide or placebo were added to standardized intravenous loop diuretics at a dose equivalent to twice the oral maintenance dose [1]. Randomization was stratified according to left ventricular ejection fraction to those with LVEF over 40% or those with LVEF 40% or lower.

Primary endpoint was successful decongestion defined as absence of signs of volume overload within 3 days without an indication for escalation of decongestive therapy. This would mean no more than trace edema assessed on the third morning after hospital admission, no residual pleural effusion, and no residual ascites. An important secondary endpoint was a composite of death from any cause or hospitalization for heart failure during 3 months of follow up. Other secondary endpoints planned were length of hospital stay for the index admission, and longitudinal changes in the EuroQol-5 dimensions questionnaire [2].

Successful decongestion occurred in 108 of 256 patients in the acetazolamide group and in 79 of the 259 patients in the placebo group. Secondary endpoint occurred in 76 of the acetazolamide group and 72 of the placebo group. There was also associated higher cumulative urine output and natriuresis, consistent with better diuretic efficacy on adding acetazolamide. Worsening of kidney function, hypokalemia and hypotension were similar in the two groups [1].

An editorial note in another journal [3] mentioned that the impact of the drug has massive implications with number needed to treat of 8.5 and an outcome difference between groups of about 12% of patients. They also emphasized the fact that the reported treatment effect was demonstrated in real world patients with a mean age of 78 years and about 43% having heart failure with reduced ejection fraction [4].

The large treatment effect is probably due to the mechanism of action which inhibits sodium and bicarbonate reabsorption in the proximal renal tubule causing natriuresis and diuresis, complementing the action of loop diuretics. A point of concern was the exclusion of those on SGLT2 inhibitors. Both acetazolamide and SGLT2 inhibitors act on the proximal renal tubule, unlike the loop diuretics. So it is hard to predict the potential cumulative effect if the two are combined [3]. We need a study to assess this aspect as the role of SGLT2 inhibitors in the treatment of heart failure is now well established.

References

1. Mullens W, Dauw J, Martens P, Verbrugge FH, Nijst P, Meekers E, Tartaglia K, Chenot F, Moubayed S, Dierckx R, Blouard P, Troisfontaines P, Derthoo D, Smolders W, Bruckers L, Droogne W, Ter Maaten JM, Damman K, Lassus J, Mebazaa A, Filippatos G, Ruschitzka F, Dupont M; ADVOR Study Group. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload. N Engl J Med. 2022 Aug 27. doi: 10.1056/NEJMoa2203094. Epub ahead of print. PMID: 36027559.
2. Mullens W, Verbrugge FH, Nijst P, Martens P, Tartaglia K, Theunissen E, Bruckers L, Droogne W, Troisfontaines P, Damman K, Lassus J, Mebazaa A, Filippatos G, Ruschitzka F, Dupont M. Rationale and design of the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial. Eur J Heart Fail. 2018 Nov;20(11):1591-1600. doi: 10.1002/ejhf.1307. Epub 2018 Sep 21. PMID: 30238574.
3. Rossello X, Menon V, Vranckx P. Acetazolamide for patients with acute decompensated heart failure with volume overload. Eur Heart J Acute Cardiovasc Care. 2022 Sep 12:zuac108. doi: 10.1093/ehjacc/zuac108. Epub ahead of print. PMID: 36093748.
4. Mullens W, Dauw J, Martens P, Meekers E, Nijst P, Verbrugge FH, Chenot F, Moubayed S, Dierckx R, Blouard P, Derthoo D, Smolders W, Ector B, Hulselmans M, Lochy S, Raes D, Van Craenenbroeck E, Vandekerckhove H, Hofkens PJ, Goossens K, Pouleur AC, De Ceuninck M, Gabriel L, Timmermans P, Prihadi EA, Van Durme F, Depauw M, Vervloet D, Viaene E, Vachiery JL, Tartaglia K, Ter Maaten JM, Bruckers L, Droogne W, Troisfontaines P, Damman K, Lassus J, Mebazaa A, Filippatos G, Ruschitzka F, Dupont M. Acetazolamide in Decompensated Heart Failure with Volume Overload trial (ADVOR): baseline characteristics. Eur J Heart Fail. 2022 Jun 22. doi: 10.1002/ejhf.2587. Epub ahead of print. PMID: 35733283.