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Background: The use of urinary sodium to guide diuretics in acute heart failure is recommended by experts and the most recent European Society of Cardiology guidelines. However, there are limited data to support this recommendation. The ENACT-HF study (Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure) investigated the feasibility and efficacy of a standardized natriuresis-guided diuretic protocol in patients with acute heart failure and signs of volume overload., 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)., Conclusions: A standardized natriuresis-guided diuretic protocol to guide decongestion in acute heart failure was feasible, safe, and resulted in higher natriuresis and diuresis, as well as a shorter length of stay., Competing Interests: Disclosures Dr Dauw received speaker fees from AstraZeneca, Boehringer-Ingelheim, and Bayer; Dr Lelonek received speaker and consulting fees from Novartis, Novo Nordisk, Servier, AstraZeneca, Boehringer-Ingelheim, Bausch Health, Bayer, Ewopharma, and Gedeon Richter and was involved in clinical trials from Amgen, Novartis, Novo Nordisk, and Boehringer-Ingelheim; Dr Borbély received speaker fees from Astra Zeneca, Bayer, Boehringer-Ingelheim, and Novartis; Dr Cobo-Marcos received speaker fees from Astra Zeneca, Boehringer-Ingelheim, Novartis, Vifor Pharma, Novo Nordisk, and Bayer; Dr Barge-Caballero received travel grants and speaker fees from Astra Zeneca, Boehringer-Ingelheim, Novartis, Viatris, and Pfizer and received research grants from Pfizer; Dr Barker received speaker fees from AstraZeneca, Novartis, and Medtronic; Dr Doghmi received speaker fees from Novartis, Boehringer-Ingelheim, and Pfizer; Dr Nijst received speaker fees from Novartis, Boehringer-Ingelheim, and Bayer; and Dr Martens received consultancy fees from Novartis and CLS Vifor and is supported by a research grant from the Belgian American Educational Foundation and the Frans Van de Werf Fund. The other authors report no conflicts. more...