METHODS AND RESULTS: The Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure (ENACT-HF) study is an international, multicentre, non-randomized, open-label, pragmatic study in AHF patients on chronic loop diuretic therapy, admitted to the hospital for intravenous loop diuretic therapy, aiming to enrol 500 patients. Inclusion criteria are as follows: at least one sign of volume overload (oedema, ascites, or pleural effusion), use ≥ 40 mg of furosemide or equivalent for >1 month, and a BNP > 250 ng/L or an N-terminal pro-B-type natriuretic peptide > 1000 pg/L. The study is designed in two sequential phases. During Phase 1, all centres will treat consecutive patients according to the local standard of care. In the Phase 2 of the study, all centres will implement a standardized diuretic protocol in the next cohort of consecutive patients. The protocol is based upon the recently published HFA algorithm on diuretic use and starts with intravenous administration of two times the oral home dose. It includes early assessment of diuretic response with a spot urinary sodium measurement after 2 h and urine output after 6 h. Diuretics will be tailored further based upon these measurements. The study is powered for its primary endpoint of natriuresis after 1 day and will be able to detect a 15% difference with 80% power. Secondary endpoints are natriuresis and diuresis after 2 days, change in congestion score, change in weight, in-hospital mortality, and length of hospitalization.

METHODS: ENACT-HF was an international, multicenter, open-label, pragmatic, 2-phase study, comparing the current standard of care of each center with a standardized diuretic protocol, including urinary sodium to guide therapy. The primary end point was natriuresis after 1 day. Secondary end points included cumulative natriuresis and diuresis after 2 days of treatment, length of stay, and in-hospital mortality. All end points were adjusted for baseline differences between both treatment arms.

RESULTS: Four hundred one patients from 29 centers in 18 countries worldwide were included in the study. The natriuresis after 1 day was significantly higher in the protocol arm compared with the standard of care arm (282 versus 174 mmol; adjusted mean ratio, 1.64; P<0.001). After 2 days, the natriuresis remained higher in the protocol arm (538 versus 365 mmol; adjusted mean ratio, 1.52; P<0.001), with a significantly higher diuresis (5776 versus 4381 mL; adjusted mean ratio, 1.33; P<0.001). The protocol arm had a shorter length of stay (5.8 versus 7.0 days; adjusted mean ratio, 0.87; P=0.036). In-hospital mortality was low and did not significantly differ between the 2 arms (1.4% versus 2.0%; P=0.852).

METHODS: In this systematic review and individual participant data meta-analysis, we searched PubMed, Cochrane Central Register of Controlled Trials, Scopus, and the International Clinical Trials Registry Platform from inception to July 6, 2026, without language restrictions, for randomised trials comparing the safety and efficacy of 0/1 h versus 0/3 h pathways (blood draws at 0 h and 3 h, ie, standard care). Individual participant data were obtained and outcome definitions were harmonised. The primary analysis used a two-stage random-effects meta-analysis. After receipt of the individual participant data but before data harmonisation or analysis, the primary safety outcome was refined to a composite of all-cause death or new type 1 myocardial infarction within 30 days, from the originally specified composite of all-cause death or any new myocardial infarction. The primary efficacy outcomes were emergency department length of stay and direct discharge from the emergency department. This meta-analysis is registered with PROSPERO (CRD420261383452).

FINDINGS: Our systematic review identified five randomised trials, all of which provided individual participant data. Among these, the definition of the primary safety outcome varied, and in four trials emergency department length of stay was not reported for the whole analysis population. We included 110 933 patient presentations (55 489 managed with the 0/1 h pathway and 55 444 managed with the 0/3 h pathway). Within 30 days, all-cause death or new type 1 myocardial infarction occurred in 446 patient presentations (0·8%) with the 0/1 h pathway versus 562 patient presentations (1·0%) with the 0/3 h pathway (random-effects pooled odds ratio [OR] 0·83 [95% CI 0·45-1·53]; I2=62·9%; τ2=0·143). Emergency department length of stay was 314 min (IQR 211-481) in the 0/1 h pathway group versus 308 min (209-453) in the 0/3 h pathway group (random-effects pooled geometric mean ratio 1·03 [95% CI 0·85-1·25]; I2=99·2%; τ2=0·024). Direct discharge from the emergency department occurred in 37 190 patient presentations (67·0%) with the 0/1 h pathway versus 36 485 patient presentations (65·8%) with the 0/3 h pathway (random-effects pooled OR 1·31 [95% CI 0·79-2·16]; I2=97·8%; τ2=0·156).

INTERPRETATION: Across the available randomised trials, short-term adverse event rates were low with both pathways, but the pooled safety estimate remained imprecise. On average, earlier cardiac troponin retesting did not reduce emergency department length of stay or clearly increase direct discharge, and substantial between-study heterogeneity indicates that treatment effects might not translate uniformly across health-care systems. For hospitals considering transitioning from a 0/3 h to a 0/1 h pathway, implementation decisions should take broader diagnostic and organisational considerations into account.