Acetazolamide in Acute Decompensated Heart Failure with Volume Overload

Abstract

BACKGROUNDWhether acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption, can improve the efficiency of loop diuretics, potentially leading to more and faster decongestion in patients with acute decompensated heart failure with volume overload, is unclear. METHODSIn this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned patients with acute decompensated heart failure, clinical signs of volume overload (i.e., edema, pleural effusion, or ascites), and an N-terminal pro-B-type natriuretic peptide level of more than 1000 pg per milliliter or a B-type natriuretic peptide level of more than 250 pg per milliliter 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). Randomization was stratified according to the left ventricular ejection fraction (≤40% or >40%). 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 heart failure during 3 months of follow-up. Safety was also assessed. RESULTSA total of 519 patients underwent randomization. Successful decongestion occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; P<0.001). Death from any cause or rehospitalization for heart failure occurred in 76 of 256 patients (29.7%) in the acetazolamide group and in 72 of 259 patients (27.8%) in the placebo group (hazard ratio, 1.07; 95% CI, 0.78 to 1.48). Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. The incidence of worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups. CONCLUSIONSThe addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion. (Funded by the Belgian Health Care Knowledge Center; ADVOR ClinicalTrials.gov number, NCT03505788.

Acetazolamide for patients with acute decompensated heart failure with volume overload

“… 2 Patients receiving SGLT2 inhibitors were excluded from the ADVOR trial given the evidence and availability of the drug at the time. 1 Now, there is a huge body of evidence supporting the use of SGLT2 inhibitors in HF patients. 8 Unlike loop diuretics, both acetazolamide and SGLT2 inhibitors has the mechanism of action in the proximal renal tubule, making harder to predict a potential cumulative effect.…”

“…The primary outcome of successful decongestion (no more than trace oedema, no residual pleural effusion, and no residual ascites within 3 days after randomization without an indication for escalation of decongestive therapy) occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; P < 0.001). 1 The primary end point of successful decongestion could not be assessed in four patients.…”

“…The effect of acetazolamide on the primary end point was generally consistent across prespecified subgroups, although the patients who were receiving a higher maintenance dose of loop diuretics appeared to have less benefit than those who were receiving a lower maintenance dose. 1 …”

“…the number of days from randomization until the date of discharge) was a geometric mean of 8.8 days (95% CI, 8.0–9.5) in the acetazolamide group and 9.9 days (95% CI, 9.1–10.8) in the placebo group. 1 …”

“…The Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial showed that the addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure (ADHF) in a greater incidence of successful decongestion. 1 , 2 …”