Optimal Diuretic Therapies for Acute Heart Failure With Volume Overload

This trial aims to identify the best strategy for treating acute heart failure (AHF) with volume overload in patients at risk of diuretic resistance. It is a double-blinded, randomized, controlled, multicenter study comparing loop-diuretics combined with metolazone, loop-diuretics combined with acetazolamide, and loop-diuretics with matching placebos. Eligible participants are adults aged 18 years or older who are hospitalized with AHF and have clinical signs of congestion and a risk of diuretic resistance. The primary outcome is the number of days alive and out of hospital through day 30. Secondary outcomes are clinical benefit at 30 days, assessed using a hierarchical win ratio; days alive and out of hospital through day 90; and the duration of the index hospital admission. The trial aims to enroll 939 participants across three treatment arms (313 per arm). The sample size is based on detecting a clinically relevant between-group difference of two days alive and out of hospital through day 30, with 80% power and adjustment for comparisons between the three groups.

Inclusion Criteria: 1. Age ≥ 18 years 2. Acute hospital admission with a clinical diagnosis of acute heart failure with volume overload. 3. Display risk of diuretic resistance, characterized by: 1. Daily loop-diuretics administration for a minimum of 7 days before admission, or 2. Insufficient decongestion observed in the preceding 24 hours (weight reduction \