Acetazolamide in Decompensated Heart Failure With Volume Overload - ADVOR

Contribution To Literature:

Among patients with acute decompensated heart failure in the ADVOR trial, addition of acetazolamide to loop diuretic therapy resulted in a greater incidence of successful early decongestion as compared with placebo.

Description:

The goal of the trial was to compare incidence of successful decongestion among patients with acute decompensated heart failure receiving intravenous (IV) loop diuretics with IV acetazolamide versus placebo.

Study Design

The ADVOR trial was a multicenter, randomized, parallel-group, double-blind, placebo-controlled trial of patients hospitalized with acute decompensated heart failure. Patient were randomized in 1:1 fashion to IV bolus of acetazolamide (500 mg daily, n = 259) or matching placebo (n = 260). Oral loop diuretics were given intravenously at double the oral maintenance dose over split doses. Participants received acetazolamide or placebo simultaneously with first dose of loop diuretics each day.

  • Total number screened: 2,915
  • Total number randomized: 519
  • Median duration of follow-up: 3 months
  • Mean patient age: 78 years
  • Percentage female: 37.4%

Inclusion criteria:

  • Clinical signs of volume overload (edema, pleural effusion, ascites)
  • N-terminal pro–B-type natriuretic peptide (NT-proBNP) >1000 pg/mL or BNP >250 pg/mL
  • Oral maintenance therapy with 40 mg of furosemide, 20 mg of torsemide, 1 mg of bumetanide or more for ≥1 month prior to randomization

Exclusion criteria:

  • Receipt of acetazolamide maintenance therapy
  • Treatment with a sodium–glucose cotransporter 2 inhibitor (SGLT2i)
  • Systolic blood pressure <90 mm Hg
  • Estimated glomerular filtration rate <20 mL/min/1.73 m2
  • Treatment with dose >80 mg IV furosemide equivalent during index hospitalization

Other salient features/characteristics:

  • Median home furosemide maintenance dose: 60 mg
  • Mean left ventricular ejection fraction: 43%
  • Median NT-proBNP: 6173 pg/mL
  • Median creatinine: 1.5 mg/dL

Principal Findings:

The primary outcome, successful decongestion within 3 days after randomization, for acetazolamide vs. placebo, was: 42.2% vs. 30.5% (p < 0.001).

Key secondary outcomes for IV acetazolamide vs. placebo:

  • Duration of hospital stay: 8.8 days vs. 9.9 days (p = 0.016)
  • All-cause mortality or rehospitalization for heart failure during 3-month follow-up: 29.7% vs. 27.8% (not statistically significant)
  • Combined renal safety endpoint: 2.7% vs. 0.8% (p = 0.10)
  • Hypokalemia: 5.5% vs. 3.9% (p = 0.39); hypotension: 6.6% vs. 3.5% (p = 0.11)

Interpretation:

The results of this trial showed that, among patients with acute decompensated heart failure, treatment with IV acetazolamide in addition to IV loop diuretics led to significantly greater incidence of successful decongestion within 3 days of randomization as compared with placebo. Acetazolamide is a carbonic anhydrase inhibitor, which inhibits sodium and bicarbonate ion resorption in the renal proximal tubule. Patients who received acetazolamide also had shorter length of stay without a significant difference in adverse event rate between both study groups. The study is limited in that it was exclusively performed in Belgium, which may limit generalizability across other racial/ethnic groups, and that concurrent SGLT2i use was excluded. It is also relatively small. Given SGLT2i also function at the level of the renal proximal tubule, efficacy of acetazolamide in conjunction with SGLT2i is unknown and will require further study.

However, achieving successful decongestion is a widespread challenge among patients with acute decompensated heart failure. Patients with residual congestion have a higher risk of post-discharge adverse outcomes. The current study provides strong evidence to support use of IV acetazolamide to achieve decongestion among patients with decompensated heart failure.

References:

Mullens W, Dauw J, Martens P, et al., on behalf of the ADVOR Study Group. Acetazolamide in Acute Decompensated Heart Failure With Volume Overload. N Engl J Med 2022;387:1185-95.

Editorial: Felker GM. New Decongestion Strategies in an Evolving Heart Failure Landscape. N Engl J Med 2022;387:1231-3.

Presented by Dr. Wilfried Mullens at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 27, 2022.

Clinical Topics: Geriatric Cardiology, Heart Failure and Cardiomyopathies, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: ESC22, ESC Congress, Acetazolamide, Diuretics, Edema, Furosemide, Geriatrics, Heart Failure, Hypokalemia, Hypotension, Length of Stay, Natriuretic Peptide, Brain, Pleural Effusion, Torsemide, Ventricular Function, Left


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