Rationale and design of the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial

Abstract

Aims Decisive evidence on the optimal diuretic agent, dosing schedule, and administration route is lacking in acute heart failure (AHF) with congestion. The Acetazolamide in Decompensated heart failure with Volume OveRload (ADVOR) trial is designed to test the hypothesis that the carbonic anhydrase inhibitor acetazolamide, a potent inhibitor of proximal tubular sodium reabsorption, improves decongestion when combined with loop diuretic therapy in AHF, potentially leading to better clinical outcomes. Methods The ADVOR trial is set up as a multicentre, randomized, double‐blind, placebo‐controlled study, aiming to recruit 519 patients with AHF and clinically evident volume overload. All study participants receive high‐dose intravenous loop diuretics as background therapy and are randomized towards intravenous acetazolamide at a dose of 500 mg once daily vs. placebo, stratified according to including study centre and ejection fraction (< 40% vs. ≥ 40%). The primary endpoint is successful decongestion with no more than trace oedema assessed on the third morning after hospital admission, with good diuretic efficacy defined as a urine output > 3.5 L during the first 30–48 h of decongestive treatment. Secondary endpoints include all‐cause mortality or heart failure readmission after 3 months, length of hospital stay for the index admission, and longitudinal changes in the EuroQol‐5 dimensions questionnaire. Conclusion ADVOR will investigate if acetazolamide combined with loop diuretic therapy improves decongestion in AHF with volume overload.

The use of diuretics in heart failure with congestion — a position statement from the Heart Failure Association of the European Society of Cardiology

“…Additionally, acetazolamide efficiently boosts the diuretic response in combination with loop diuretics, as illustrated by one small randomized trial including 24 patients with acute volume overload refractory to loop diuretic therapy . A multicentre, randomized, double‐blind, phase IV clinical trial of the diuretic effects of Acetazolamide in Decompensated heart failure with Volume OveRload (ADVOR, NCT03505788) will investigate if combination therapy with acetazolamide improves loop diuretic response to increase diuresis in decompensated heart failure patients . Observational studies have only assessed the role of intravenous acetazolamide, and no data are available supporting the role of oral acetazolamide.…”

Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology

“…No new evidence was published since 2016 for diuretic therapy. The ADVOR (Acetazolamide in Decompensated Heart Failure With Volume Overload) trial with acetazolamide is ongoing …”

Acetazolamide to increase natriuresis in congestive heart failure at high risk for diuretic resistance

“…Anyhow, results of this small pilot study can only be considered hypothesis‐generating and warrant confirmation by larger independent studies with adequate statistical power. The Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR, NCT03505788) is currently recruiting and aims to randomise a population of 519 AHF patients with clinical signs of volume overload to acetazolamide or matching placebo in addition to standard of care with high‐dose loop diuretics . This trial – constituting the largest randomised diuretic study in AHF if successfully performed – is powered for achievement of complete clinical decongestion without the need for diuretic therapy escalation because of poor diuretic response.…”