ADVOR: remarkable advance in acute congestive heart failure

Barcelona, ​​Spain – In patients with acute congestive heart failure, acetazolamide in combination with IV loop diuretics dramatically and rapidly reduces congestion, the study found ADVOR presented in the hotline session at the ESC Congress 2022 .[1] and simultaneously published in the NEJM .

“This academic study, involving patients who resemble those in real life, answers a question of daily hospital practice. It should have implications for heart failure practice and future recommendations. Although the study is quite small, it is positive. Keep in mind that there has been no therapeutic advance in acute congestive heart failure in the last three decades. Only the DOSE study ten years ago led to therapeutic advances,” he commented Professor Damien Logeart (Hospital Lariboisière, Paris) for French edition of Medscape.

This scientific study, which involved patients similar to those in real life, answers a question of daily hospital practice.
Professor Damien Logeart

Current recommendations for the treatment of patients with acute congestive heart failure are largely based on studies DOSE Published in 2011 showing the benefits of sequential administration of high-dose furosemide. However, many patients still have residual congestion after treatment, which is a factor in poor prognosis.

Acetazolamide is a drug that has been used for decades to treat metabolic alkalosis, ocular hypertension, altitude sickness, and post-traumatic and post-surgical edema. This carbonic anhydrase inhibitor, which reduces proximal tubular reabsorption of sodium, has never been tested in heart failure.

When evaluated in acute heart failure, researchers hypothesized that acetazolamide and loop diuretics such as furosemide could potentially have complementary effects through their effects on different segments of the nephron.

In the ADVOR study, the Professor Wilhelm Mullens (Hospital Oost-Limburg, Genk, Belgium) et al. therefore investigated whether the addition of acetazolamide to intravenous loop diuretics improved decongestion in patients with acute congestive heart failure.

The study involved 519 adults hospitalized for acute congestive heart failure in 27 centers in Belgium.

The median age was 78 years and 63% were male. Patients had at least one clinical sign of volume overload (ascites, pleural effusion, or edema), elevated natriuretic peptide levels, and had been taking oral diuretics for at least one month.

Patients were randomized to receive intravenous acetazolamide (500 mg once daily) and placebo, administered as a bolus at randomization and for the next two days or until successful decongestion.

+ 50% of patients improved after 3 days

The primary endpoint was decongestive success, defined as the absence of clinical signs of fluid overload (other than signs of edema) within three days of randomization without requiring an increase in the dose of decongestant treatment.

This good result occurred in 108 of the 256 patients (42.2%) in the acetazolamide group and in 79 of the 259 patients (30.5%) in the placebo group, ie a relative risk (RR) of 1.46 (95% CI: 1.17-1.82). ;p=0.0009).

“We had to treat 6 patients in order to achieve the decongestion of one patient,” specified Professor Mullens when presenting the results at a press conference.

Regarding the secondary endpoints, patients in the acetazolamide group had a shorter hospital stay (mean 8.8 days) than patients in the placebo group (mean 9.9 days; p=0.02). Also, there was no difference between the groups for the composite endpoint, which associated all-cause mortality and hospitalization for heart failure within three months.

“The main objective of this study was not to assess a benefit in terms of mortality and rehospitalization in heart failure, but to achieve decongestion before leaving the hospital, which is often quite a guarantee of a better prognosis, as several exploratory studies have shown . Keep in mind that strong and rapid decongestion, as observed in this study, is a strong recommendation,” notes Professor Logeart, adding that tolerability with acetazolamide was very good. “No ionic disorders or hypotension were observed”.

What about gliflozines?

In an editorial accompanying the article, the dr G.Michael Felker (Duke University in Durham, USA) points out that the ADVOR study has “several notable strengths”. This is a multi-center, placebo-controlled study “relatively large compared to other studies testing diuretics in patients with heart failure and evaluating a clinically relevant endpoint.”

However, for the editor, the exclusion of patients receiving SGLT2 inhibitors (at the time of the study, gliflozines were not widely available) poses a problem for the application of these results in clinical practice today.

“We can only speculate about the efficacy of acetazolamide in patients treated with SGLT2 inhibitors, which could potentially be additive, subadditive, or synergistic,” he says.

A rating weighted by the Professor Gabriel Steg (read here) and by Pr Logeart. “Compared to acetazolamide, SGLT2 inhibitors induce a more modest sodium reabsorption in the proximal part of the nephron. Theoretically, their actions could therefore be more complementary,” explains the latter.

“In summary, this study promotes the use of acetazolamide as an inexpensive, patent-free, easy-to-use, and highly effective treatment to improve decongestion,” said Prof. Mullens.

This study promotes the use of acetazolamide as an inexpensive, patent-free, easy-to-use, and highly effective treatment to improve decongestion.
Professor Wilhelm Mullens

The study was not funded by industry.

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