Key Points:
- Residual decongestion after a hospitalization for acute decompensated heart failure is associated with poor outcomes.
- In this double-blinded, placebo-controlled study, patients admitted to the hospital with heart failure were randomized to receive either acetazolamide or placebo in addition to standard high-dose loop diuretics.
- Acetazolamide was associated with improved decongestion at 3 days and discharge, resulting in shorter hospital stays.
- This is the first diuretic trial to use successful decongestion as a primary outcome.
Residual decongestion after a heart failure exacerbation is associated with poorer outcomes. Despite this, many patients show signs and symptoms of volume overload days after presentation and upon discharge. In the DOSE trial, 85% of patients had clinical congestion 72 hours into diuretic therapy, and in the ADHERE registry, 20% of patients were discharged with an increased weight from baseline. Given these data, the need to augment our current understanding of effective diuretic therapy exits. In a Hot Line Session at the European Science of Cardiology Congress today, Dr. Wilfried Mullens (University Hasselt, Belgium) presented the results of the ADVOR trial, in which a diuretic strategy including acetazolamide was tested against standard loop diuretic therapy in acute decompensated heart failure exacerbations.
In this multicenter, randomized, double-blind, placebo-controlled trial, patients were eligible for enrollment if they were admitted to the hospital with heart failure and had at least one sign of volume overload, i.e, edema, pleural effusion or ascites, as well as a NT-proBNP level of more than 1000 pg/mL or BNP of more than 250 pg/mL. Importantly, participants must have been on oral loop diuretic therapy equivalent to at least 40 mg of furosemide for thirty days prior to randomization. Participants already taking acetazolamide or other diuretics including SGLT2 inhibitors, were excluded. Also excluded were those with low GFR, and low blood pressure (systolic less than 90 mmHg). Participants were randomized in a 1:1 fashion using the following protocol: oral diuretic therapy was stopped at randomization and patients were given intravenous loop diuretics at double the oral maintenance dose, escalated to achieve a urine output of 3.5 liters over 24 hours; a single bolus of either placebo or 500 mg acetazolamide was administered intravenously after randomization, and this was continued on a daily basis until the physician was satisfied with the decongestion achieved. Physicians were instructed not to change neurohormonal therapies, including beta blockers, if clinically acceptable.
519 participants were randomized, of which 259 were in the acetazolamide group. Median age for the study was 78.5 years, and only 5 participants were not white. Over 90% of patients had peripheral edam to start, and over half had pleural effusions as well.
This is the first large, randomized clinical trial in which the primary endpoint was successful decongestion, defined as the absence of volume overload as assessed by a cardiologist within 3 days of randomization. At 3 days, a greater proportion of the acetazolamide patients achieved successful decongestion (42.2% versus 30.5%, RR 1.46 (95% CI 1.17-1.82), p<0.001). Furthermore, these patients had a more dramatic decrease in congestion scores when compared to patients in the placebo group at 3 days. This trend continued to hold at discharge, where 78.8% of the acetazolamide group had achieved successful decongestion, compared to just 62.5% in the placebo group. These differences translated into a shorter length of hospital stay for the acetazolamide group (8.8 days versus 9.9 days) and no difference in all cause death. In a safety analysis, the addition of acetazolamide posed no significant difference in combined renal and cardiac adverse events.
In response to the results, which were applauded at the Congress, Dr. Mullens stated that acetazolamide is “safe and effective”, adding that “participants in this trial represented real-world patients, with advanced age and many comorbidities”.
The study had a simultaneous publication in the New England Journal of Medicine.
