Add on Acetazolamide to loop diuretics decreases congestion in patients with acute decompensated HF

Acetazolamide is a carbonic anhydrase inhibitor with diuretic effects which is a drug commonly used in the treatment of mountain sickness and some types of glaucoma. Researchers have found a new indication for this 70 years old drug.

Researchers have found in a new randomized ADVOR trial that addition of acetazolamide to conventional loop diuretics can improve the rate of decongestion in hospitalized acute decompensated heart failure (HF) patients better than diuretics alone. Further among patients of heart failure addition of IV acetazolamide to loop diuretics, facilitated their discharge sooner and these patients were less likely to have residual clinical signs of volume overload. 

The research has been presented in a Hot Line session today at ESC Congress 2022.

Principal investigator Professor Wilfried Mullens of Hospital Oost-Limburg (ZOL), Genk, Belgium said: "ADVOR was the largest randomised diuretic trial ever performed in patients with acute decompensated heart failure. Acetazolamide is easy to use, safe, effective, off-patent and cheap. It is therefore expected that the results of ADVOR will lead to a paradigm shift in the way physicians worldwide treat acute decompensated heart failure."

Acute heart failure is a life-threatening condition requiring urgent evaluation and treatment. It is usually due to an acute deterioration of chronic heart failure. Acute decompensated heart failure is the most common form, accounting for up to 70% of presentations.

Acetazolamide is a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption. The ADVOR trial examined whether the addition of acetazolamide to intravenous loop diuretics improves decongestion in patients with acute decompensated heart failure.

The trial enrolled 519 adults hospitalised with acute decompensated heart failure at 27 centres in Belgium. The average age was 78 years and 63% were men. Patients had at least one clinical sign of volume overload (i.e. ascites, pleural effusion, or oedema), elevated natriuretic peptide levels, and had been taking oral diuretics for at least one month.

Patients were randomised (1:1) to intravenous acetazolamide (500 mg once daily) or placebo, administered as a bolus upon randomisation and during the next two days or until successful decongestion. At randomisation, oral loop diuretics were stopped and all patients received high-dose intravenous loop diuretics.

The primary endpoint was successful decongestion, defined as no clinical signs of fluid overload (other than trace oedema) within three days of randomisation without needing escalation of decongestive therapy. The primary outcome occurred in 108 of 256 patients (42.2%) in the acetazolamide group and 79 of 259 patients (30.5%) in the placebo group, for a relative risk (RR) of 1.46 (95% confidence interval [CI] 1.17-1.82; p=0.0009). Of those alive at discharge, 190 of 241 in the acetazolamide group (78.8%) and 145 of 232 in the placebo group (62.5%) had successful decongestion (RR 1.27; 95% CI 1.13–1.43; p=0.0001).

Regarding key secondary endpoints, patients in the acetazolamide group had a shorter hospital stay (an average of 8.8 days) compared with those in the placebo group (average of 9.9 days; p=0.02) but there was no difference between groups in the composite outcome of all-cause mortality and hospitalisation for heart failure within three months.

Professor Mullens said: "Patients treated with acetazolamide had more diuresis and natriuresis, and were more likely to be discharged without residual signs of volume overload. There did not appear to be an increase in adverse events with the drug. Participants had similar characteristics to patients in real world practice, including a high degree of congestion, advanced age and many comorbidities."

References:

1. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–3726.

2. Felkner GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364:797–805.

3. Mullens W, Damman K, Harjola VP, et al. The use of diuretics in heart failure with congestion-a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019;21:137-155.

4. Mullens W, Verbrugge FH, Nijst P, et al. Rationale and design of the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial. Eur J Heart Fail. 2018;20:1591-1600.