Acetazolamide in Decompensated Heart Failure With Volume Overload - ADVOR

Oct 05, 2023
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC; Neil Keshvani, MD
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC; Kim A. Eagle, MD, MACC
Trial Sponsor:
Belgian Health Care Knowledge Center
Date Presented:
08/25/2023
Date Published:
08/24/2023
Date Updated:
10/05/2023
Original Posted Date:
08/27/2022
References

Contribution To Literature:

Highlighted text has been updated as of August 25, 2023.

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 (eGFR) <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 (LVEF): 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)

Effect across baseline LVEF: Heart failure with reduced ejection fraction (HFrEF: EF ≤40%; n = 224); HF with mildly reduced EF (HFmrEF: EF 41-49%; n = 75); HF with preserved EF (HFpEF: EF ≥50%, n = 220). No interaction on the overall beneficial treatment effect of acetazolamide on the primary endpoint of successful decongestion (p for interaction >0.05) was found when LVEF was assessed per randomization stratum (≤/>40%), or as HFrEF, HFmrEF, and HFpEF, or on a continuous scale. Acetazolamide resulted in improved diuretic response measured by higher cumulative diuresis and natriuresis and shortened length of stay without treatment effect modification by baseline LVEF (p for interaction > 0.05).

Pre-treatment bicarbonate levels: Continuous HCO3 modeling illustrated a higher proportional treatment effect for acetazolamide if baseline HCO3 ≥27 mmol/L. Patients with baseline HCO3 ≥27 mmol/L (45%) exhibited a significant higher response to acetazolamide (primary endpoint: no vs. elevated HCO3; odds ratio 1.37 [0.79–2.37] vs. odds ratio 2.39 [1.35–4.22], p for interaction = 0.065), with higher proportional diuretic and natriuretic response (both p for interaction <0.001), greater reduction in congestion score on consecutive days (treatment × time by HCO3-interaction <0.001) and length of stay (p for interaction = 0.019). The larger proportional treatment effect was mainly explained by the development of diminished decongestive response in the placebo arm, especially with loop diuretics.

Renal function: No difference between acetazolamide vs. placebo based on eGFR ≤ or >40 mL/min/m2 for the primary endpoint (p for interaction = 0.67), complete decongestion at discharge (p for interaction = 0.47), and all-cause mortality/HF hospitalization (p for interaction = 0.64). There was a significant interaction for total natriuresis (p for interaction < 0.001) and total urinary output (p for interaction = 0.006) for acetazolamide vs. placebo based on baseline renal function, with greater effects of acetazolamide among patients with eGFR ≤40 mL/min/m2. Renal function was worsened to a greater extent with acetazolamide: 41% vs. 19% (p < 0.001).

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, irrespective of baseline LVEF and renal function. Response was magnified among patients with higher baseline HCO3 levels; urine output and natriuresis was greater among patients with eGFR ≤40 at baseline. 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 with the exception of worsening renal function defined by serum creatinine. 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:

Meekers E, Dauw J, Martens P, et al. Renal Function and Decongestion With Acetazolamide in Acute Decompensated Heart Failure: The ADVOR Trial. Eur Heart J 2023;44:3672-82.

Editorial: Bueno H, Packer M. Acetazolamide for Acute Heart Failure: Is ADVOR a Riddle Wrapped in a Mystery Inside an Enigma? Eur Heart J 2023;44:3683-5.

Presented by Dr. Jeroen Dauw at the European Society of Cardiology Congress, Amsterdam, Netherlands, August 25, 2023.

Martens P, Verbrugge FH, Dauw J, et al. Pre-treatment bicarbonate levels and decongestion by acetazolamide: the ADVOR trial. Eur Heart J 2023;44:1995-2005.

Editorial: Campbell RT, Docherty KF. Serum bicarbonate and congestion: a potential biomarker for identifying and guiding management in diuretic resistance? Eur Heart J 2023;44:2006-8.

Martens P, Dauw J, Verbrugge FH, et al. Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Pre-specified Analysis From the ADVOR Trial. Circulation 2022;387:1185-95.

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: Cardiovascular Care Team, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: ESC22, ESC23, ESC Congress, Acetazolamide, Diuretics, Edema, Furosemide, Geriatrics, Heart Failure, Hypokalemia, Hypotension, Length of Stay, Natriuretic Peptide, Brain, Pleural Effusion, Renal Insufficiency, Stroke Volume, Torsemide, Ventricular Function, Left


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