In this episode, I’ll discuss whether adding acetazolamide to loop diuretics improves the chance of successful decongestion in ADHF.
Monotherapy with carbonic anhydrase inhibitors in acute decompensated heart failure has not been studied in decades since the advent of loop diuretics supplanted carbonic anhydrase inhibitors as first-line treatment. Since acetazolamide is a proximal tubule-acting diuretic and sodium reabsorption in proximal tubules may be increased in patients who chronically take loop diuretic therapy or have decompensated heart failure, acetazolamide may be a particularly effective addition to standard loop diuretic therapy.
Previous case reports and pilot studies have suggested a potential benefit of acetazolamide in combination with loop diuretics in the treatment of fluid overload in heart failure. To investigate the topic further, a randomized, placebo-controlled multicenter trial was recently published in the New England Journal of Medicine.
The authors split just over 500 patients with acute decompensated heart failure, clinical signs of volume overload, and a BNP over 250 to receive either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose).
The primary endpoint was successful decongestion within 3 days after randomization. This was defined as the absence of signs of volume overload. Successful decongestion occurred in 42.2% of the patients in the acetazolamide group and in 30.5% of the patients in the placebo group. This difference was statistically significant.
Acetazolamide use was also associated with higher cumulative urine output and natriuresis, suggesting that the combination produced better diuretic efficiency than monotherapy with loop diuretics. The incidence of death from any cause, worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups.
The authors concluded:
The addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion.
One notable part of the design of this study is that it did not include patients receiving sodium–glucose cotransporter 2 (SGLT2) inhibitors. This is likely because such medications were not widely used at the time the study was designed. However SGLT2 inhibitors also work in the proximal tubule and application of these results to modern practice where SGLT2 inhibitors are now part of usual care presents an unknown that was not controlled for in the study.
Despite this limitation, expert opinion published in an editorial that accompanied this article state:
…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.
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