Natriuresis-guided diuretic therapy in acute heart failure: a pragmatic randomized trial

Abstract

Measurement of natriuresis has been suggested as a reliable, easily obtainable biomarker for assessment of the response to diuretic treatment in patients with acute heart failure (AHF). Here, to assess whether natriuresis-guided diuretic therapy in patients with AHF improves natriuresis and clinical outcomes, we conducted the pragmatic, open-label Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure trial, in which 310 patients (45% female) with AHF requiring treatment with intravenous loop diuretics were randomly assigned to natriuresis-guided therapy or standard of care (SOC). In the natriuresis-guided arm, natriuresis was determined at set timepoints, prompting treatment intensification if spot urinary sodium levels were <70 mmol l^-1. The dual primary endpoints were 24 h urinary sodium excretion and a combined endpoint of time to all-cause mortality or adjudicated heart failure rehospitalization at 180 days. The first primary endpoint was met, as natriuresis in the natriuresis-guided and SOC arms was 409 ± 178 mmol arm versus 345 ± 202 mmol, respectively (P = 0.0061). However, there were no significant differences between the two arms for the combined endpoint of time to all-cause mortality or first heart failure rehospitalization, which occurred in 46 (31%) and 50 (31%) of patients in the natriuresis-guided and SOC arms, respectively (hazard ratio 0.92 [95% confidence interval 0.62-1.38], P = 0.6980). These findings suggest that natriuresis-guided therapy could be a first step towards personalized treatment of AHF. ClinicalTrials.gov registration: NCT04606927 .

Fig. 1

Patient flow diagram. Created with BioRender.com.

Fig. 2. The urinary sodium and diuresis-based treatment protocol in PUSH-AHF.

Schematic of the treatment protocol, showing that loop diuretics were administered twice daily (in black), at 12 h intervals. At the timepoints at which natriuresis and diuresis was assessed, in the case of an insufficient response as determined by predetermined cutoffs (box 1), treatment was intensified according to the treatment algorithm (box 2). First step was the administration of an additional dose of loop diuretics (double the previous dose to a maximum of 5 mg of bumetanide). If an additional, increased dose of loop diuretic was administered, the maintenance dose (the twice-daily administered loop diuretic dose) was further increased to a level that was double the previous dose, to a maximum of 5 mg bumetanide. If response continued to be insufficient despite two consecutive maximum doses of loop diuretic, combination diuretic therapy was started. First choice for combination diuretic therapy was the addition of hydrochlorothiazide; however, if a patient for instance already used combination diuretic therapy with hydrochlorothiazide before admission or response remained insufficient after addition of hydrochlorothiazide, acetazolamide or an SGLT2i was added. T refers to the time in hours after start of loop diuretic treatment. ED, emergency department; LD, loop diuretic. Created with BioRender.com.

Fig. 3. Natriuresis, diuresis and the combined endpoint of all-cause mortality and HF rehospitalization according to randomization group.

a, Natriuresis at 24 and 48 h after start of loop diuretic (LD) treatment. Mean ± 95% CI. Student’s t-test. b, Kaplan–Meier plot for the combined primary endpoint of all-cause mortality and HF rehospitalization at 180 days. Cox regression. c, Diuresis at 24 and 48 h after start of LD treatment. Mean ± 95% CI. Student’s t-test.

Extended Data Fig. 1. Intensification of treatment during the first 36 hours in the natriuresis guided group.

Abbreviations: HCT: hydrochlorothiazide; SLGT2i: Sodium Glucose co-Transporter 2 inhibitor.

Extended Data Fig. 2. Spot urinary sodium values during the first 36 hours in the natriuresis guided group.

Median with interquartile ranges, whiskers and outliers.

Extended Data Fig. 3. Subgroup analyses 24- hour natriuresis.

Hazard ratio with 95% Confidence Intervals. Abbreviations: eGFR: estimated Glomerular Filtration Rate; HF: Heart Failure; NT-proBNP: N Terminal-pro Blood Natriuretic Peptide; SLGT2i: Sodium Glucose co-Transporter 2 inhibitor. Linear regression analysis with the inclusion of an interaction term.

Extended Data Fig. 4. Subgroup analyses combined endpoint of all-cause mortality and heart failure rehospitalization at 180 days.

Hazard ratio with 95% Confidence Intervals. Abbreviations: eGFR: estimated Glomerular Filtration Rate; HF: Heart Failure; NT-proBNP: N Terminal-pro Blood Natriuretic Peptide; SLGT2i: Sodium Glucose co-Transporter 2 inhibitor. Cox regression analysis with the inclusion of an interaction term.

Extended Data Fig. 5. Kaplan Meier plot for heart failure rehospitalization at 180 days.

Abbreviations: CI: Confidence Interval; HF: Heart Failure; HR: Hazard Ratio. Cox regression.

Extended Data Fig. 6. Kaplan Meier plot for all-cause mortality at 180 days.

Abbreviations: CI: Confidence Interval; HR: Hazard Ratio. Cox regression.

Extended Data Fig. 7. Natriuresis according to treatment group up to 72 hours.

Mean ± 95% Confidence Interval. Students T-test.

Extended Data Fig. 8. Diuresis according to treatment group up to 72 hours.

Mean ± 95% Confidence Interval. Students T-test.