Fluid retention is one of the most common causes of hospitalization in heart failure patients. Standard therapy consists of intravenous (IV) loop diuretics to increase natriuresis and diuresis to resolve signs of fluid retention (decongestion). Sometimes these loop diuretics prove ineffective and treatment lasts for several days, especially in patients with renal insufficiency. In the old DOSE study, successful decongestion was achieved in only 15% of patients after 3 days of therapy.¹ Therefore, additional therapeutic options have long been sought.

The nephrons of the kidneys produce urine and regulate how much sodium is reabsorbed or excreted. Sodium reabsorption from the urine back to the body occurs for 65% in the proximal tubule , in patients with heart failure even for 75%.² Classical diuretics inhibit sodium reabsorption further along the nephron and therefore cannot influence the majority of sodium reabsorption.

Acetazolamide ( Diamox ) is an old diuretic that inhibits sodium reabsorption in the proximal tubules of the nephrons. For many years it was only used in the treatment of altitude sickness and glaucoma, among other conditions. However, acetazolamide increases the sodium concentration in the urine further along the nephron , making loop diuretics much more effective.²

The ADVOR study is a Belgian multicenter study, initiated by the team of Prof. Dr. Wilfried Mullens of the Ziekenhuis-Oost Limburg in Genk. 519 patients were included. They were hospitalized with acute heart failure and signs of congestion. On admission, they were double-blind randomized to acetazolamide 500 mg IV once daily versus placebo, in addition to standard therapy with IV loop diuretics . The patients were treated for 3 days according to the study protocol. The primary endpoint was successful decongestion (disappearance of edema, pleural effusion or ascites) after these 3 days.³

Results:

In the Acetazolamide group there was a significantly higher cumulative urine output and a higher natriuresis. On day 3, successful decongestion was achieved in 42.2% of the patients versus 30.5% in the placebo group (p<0.001). Thereafter, the patients were allowed to be treated freely according to the judgement of the treating cardiologist. At discharge, this difference in successful decongestion was maintained (acetazolamide 78.8% versus placebo 62.5%). In addition, the hospital stay was shortened by treatment with acetazolamide from 9.9 days to 8.8 days.³

Conclusion:

In patients hospitalized for cardiac decompensation with fluid retention, the combination of intravenous (IV) acetazolamide ( Diamox ) with IV loop diuretics increases natriuresis and diuresis. As a result, the symptoms of fluid retention disappear more quickly and effectively in these patients. This also shortened the hospital stay. The combination of acetazolamide also appeared to be safe with a low risk of ion disturbances. In addition, IV acetazolamide is inexpensive.

Read also : Diuretics

General comment: combination of diuretics

Treatment with a combination of different types of diuretics increases the diuretic effect and can help to achieve or maintain euvolemia in patients with persistent fluid retention despite an already good dose of loop diuretic. Renal function and the ionogram should then be monitored after a few days and regularly thereafter. In case of insufficient effect and persistent fluid retention, a short-term or intermittent combination of oral acetazolamide can be considered in selected patients. Oral use of acetazolamide in heart failure and its use in the outpatient setting has not yet been studied. Combination of a thiazide diuretic is another option. This also increases diuresis (CLOROTIC trial ⁴ ), although with a higher risk of hypokalemia.

Heart failure patients are best treated with a MRA ( HFrEF and HFmrEF ) and an SGLT2 inhibitor (independent of LVEF) if possible to improve the prognosis. The MRA do not significantly increase the diuresis (ATHENA-HF trial ⁵).

References

1. Felker G. et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364:797-805.
2. Mullens W. 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 of Heart Fail 2019;21:137-155.
3. Mullens W. et al. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload. N Engl J Med 2022; 387:1185-1195.
4. Trullas et al. Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial. Eur Heart J 2023;44(5):411-421.
5. Butler et al. Efficacy and Safety of Spironolactone in Acute Heart Failure: The ATHENA-HF Randomized Clinical Trial. JAMA Cardiol 2017;2(9):950-958.