ADVOR: A multi-center, randomized, double-blind, phase IV

Summary (Dutch or French)

Two percent of the Belgian population has heart failure (HF), with 15.000 new cases being diagnosed annually and 3% of the annual health care budget spent on HF, of which most is related to recurrent hospitalisation for decompensated HF with a tremendous negative impact on quality of life. Therefore, strategies that reduce the number of hospital admittances / length of stay will have an immediate impact on the health care budget and patients’ quality of life.

Treatment of decompensated HF mainly focuses on symptomatic relief of signs and symptoms of congestion (‘increased filling pressures’) and edema (‘fluid retention’) through administration of diuretics (‘water pills’), although clear evidence on the optimal agent, dosing schedule, and administration route is lacking. Importantly, persistent congestion and volume overload at discharge, has been consistently associated with higher mortality and more frequent readmissions for HF. Therefore, an important therapeutic target in HF is to achieve better decongestion.

The ADVOR study is a multi-centre randomised double blind trial (neither patients nor their doctors will know which treatment they receive). It will investigate if an improved application of existing decongestive therapies, based on strong scientific reasoning, will result in a better decongestion which should lead to improved outcome for patients and society. More specifically, ADVOR will investigate if the addition of a very easy to use diuretic agent (acetazolamide) which is off-patent and available at a very low cost (less than 10€) will reduce the average length of hospital stay and rehospitalisation rate, which could be accompanied by improved quality of life and a cost saving of 2,500€ per hospitalised patient.

Summary of results
Episodes of acute heart failure are caused by water and sodium retention, leading to signs and symptoms (shortness of breath, swollen legs, ..) with often the need for hospitalization in order to administer diuretic therapy. Acetazolamide is an old diuretic agent that blocks the sodium reabsorption in the kidney, resulting an increase in sodium and consequently water excretion. In the ADVOR trial, the benefit of the addition of acetazolamide to the classical diuretic therapy was investigated in patients with acute heart failure with fluid overload. The ADVOR study was conducted in 27 hospitals in Belgium. In total, 519 patients participated in the trial and were randomized towards classical diuretic therapy in combination with acetazolamide or towards the combination of classical diuretic therapy with placebo. The patient as well as the physician did not know the assigned group of the patient. After three days of treatment, patients were assessed whether they were successful decongested. This occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group, meaning that the addition of acetazolamide to classical diuretic therapy leads to a faster and better decongestion. This is explained by the fact that patients in the acetazolamide group excreted more water and sodium than patients in the placebo group. Furthermore, the duration of hospitalization was on average a day shorter in these patients than in the patients who received the placebo. The ADVOR study has demonstrated that the addition of acetazolamide to the classic diuretic therapy leads to a faster and better decongestion in patients with acute heart failure and fluid overload.

Summary of results

Episodes of acute heart failure are caused by water and sodium retention, leading to signs and symptoms (shortness of breath, swollen legs, ..) with often the need for hospitalization in order to administer diuretic therapy. Acetazolamide is an old diuretic agent that blocks the sodium reabsorption in the kidney, resulting an increase in sodium and consequently water excretion. In the ADVOR trial, the benefit of the addition of acetazolamide to the classical diuretic therapy was investigated in patients with acute heart failure with fluid overload.

The ADVOR study was conducted in 27 hospitals in Belgium. In total, 519 patients participated in the trial and were randomized towards classical diuretic therapy in combination with acetazolamide or towards the combination of classical diuretic therapy with placebo. The patient as well as the physician did not know the assigned group of the patient. After three days of treatment, patients were assessed whether they were successful decongested. This occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group, meaning that the addition of acetazolamide to classical diuretic therapy leads to a faster and better decongestion. This is explained by the fact that patients in the acetazolamide group excreted more water and sodium than patients in the placebo group. Furthermore, the duration of hospitalization was on average a day shorter in these patients than in the patients who received the placebo.

The ADVOR study has demonstrated that the addition of acetazolamide to the classic diuretic therapy leads to a faster and better decongestion in patients with acute heart failure and fluid overload.

Trial Description

Title	A multi-center, randomized, double-blind, phase IV clinical trial on the diuretic effects of Acetazolamide (Diamox ®) in patients with Decompensated heart failure and Volume OveRload (ADVOR) (KCE-17001)
Participants (P)	Patients with decompensated heart failure and volume overload admitted to hospital
Intervention (I)	Acetazolamide combination therapy with high-dose loop diuretics
Control (C)	Placebo combination therapy with high-dose loop diuretics
Outcome (O)	Treatment success (decongestion achieved) on the morning of day 4 without the need for escalating diuretic strategy (doubling loop diuretic dose, addition of chlorthalidone, or ultrafiltration) on the morning of day 3
Trial Design	Prospective, multi-center, randomised double blind placebo controlled phase IV clinical trial
Sample Size	519 patients
Trial duration	28 Months
Budget	€ 2 600 000 (incl. VAT)

Trial team

Sponsor	Ziekenhuis Oost Limburg Autonome Verzorgingsinstelling
Chief Investigator	Wilfried Mullens MD, PhD
Trial coordinator	Katrien Tartaglia Clinical Trial Unit, Ziekenhuis Oost-Limburg, Autonome Verzorgingsinstelling
Participating centres	24 hospitals from Flanders, Wallonia and Brussels including both University and regional hospitals