The ACETAZ-HF trial: intravenous furosemide plus oral acetazolamide for rapid decongestion in acute HFrEF and sustained outpatient benefit

Background Rapid and sustained decongestion in acute heart failure with reduced ejection fraction (HFrEF) remains a therapeutic challenge, particularly in patients with diuretic resistance. Sequential nephron blockade with acetazolamide may enhance decongestion during hospitalization and, when continued intermittently after discharge, reduce long-term events. Purpose To evaluate whether adding oral acetazolamide to intravenous furosemide during hospitalization, followed by intermittent outpatient therapy, improves decongestion and reduces 3-month heart failure (HF) hospitalizations and mortality. Methods This single-centre, randomised, open-label, blinded-endpoint trial enrolled 600 patients admitted for acute HFrEF (LVEF ≤40%) with persistent congestion despite initial IV furosemide. Patients were randomised 1:1 to: (A) IV furosemide alone or (B) IV furosemide plus oral acetazolamide 250 mg daily (first 3–5 days of admission). After discharge, both groups continued oral furosemide; the acetazolamide group additionally received intermittent oral acetazolamide 250 mg on days 1–5 monthly for 3 months. The primary outcome was time to complete decongestion (VExUS ≤1 and ≥50% B-lines reduction) during hospitalization. Key secondary outcomes included the composite of HF hospitalization or cardiovascular death at 3 months. Results Baseline characteristics were balanced (mean age 68 years, 62% male, mean LVEF 32%). Acetazolamide accelerated decongestion: median time 2.1 vs. 3.8 days (HR 1.82; 95% CI 1.52–2.18; p<0.001). NT-proBNP reduction at discharge was greater with acetazolamide (58% vs. 31%; p<0.001). Over 3 months, the composite of HF hospitalization or cardiovascular death occurred in 12.3% of the acetazolamide group versus 18.7% of controls (HR 0.66; 95% CI 0.44–0.99; p=0.049). Safety profiles were comparable; metabolic acidosis occurred in 1.8% vs. 2.1% (p=0.68). Conclusion In patients hospitalized for acute HFrEF, adding oral acetazolamide to IV furosemide accelerated decongestion. Continued intermittent outpatient therapy was associated with a significant reduction in 3-month HF hospitalizations and cardiovascular mortality. This safe, low-cost strategy warrants confirmation in a multicentre trial.