Natriuretic Response to Acetazolamide in Patients With Acute Heart Failure and Volume Overload

Verbrugge, Frederik H.; Martens, Pieter; Dauw, Jeroen; Nijst, Petra; Meekers, Evelyne; Augusto, Silvio Nunes; Maaten, Jozine M. ter; Damman, Kevin; Filippatos, Gerasimos; Lassus, Johan; Mebazaa, Alexandre; Ruschitzka, Frank; Dupont, Matthias; Mullens, Wilfried

doi:10.1016/j.jacc.2023.03.400

Cited by 20 publications

(14 citation statements)

References 25 publications

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“…The achieved natriuresis in the PUSH-AHF trial was much higher, also in the SOC group compared with previous observations from ENACT even in the active arm, and also from a subanalysis from the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) study, where addition of acetazolamide resulted in total natriuresis of 258 ± 133 mmol in 24 h (refs. 16 , 17 ). These differences might be due to the inclusion of a different patient population where in the ADVOR trial patients were required to use loop diuretics at home, whereas the PUSH-AHF trial enrolled 44% of patients with de novo HF, frequently loop diuretic naïve with a higher likelihood of sufficient response to loop diuretic therapy.…”

Section: Discussionmentioning

confidence: 99%

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

ter Maaten,

Beldhuis,

van der Meer

et al. 2023

Nat Med

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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.

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Section: Discussionmentioning

confidence: 99%

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

ter Maaten,

Beldhuis,

van der Meer

et al. 2023

Nat Med

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“…This difference was observed even though acetazolamide-treated patients experienced only a modest incremental diuresis after 2 days (between-group difference of ≈0.5 L in urine volume and only ≈100 mmol in cumulative urinary sodium excretion). 15 Such modest effects cannot account for reported striking resolution of signs of fluid retention attributed to acetazolamide, especially since effects on symptoms and body weight during the treatment period were not noted by the investigators. After 90 days, a total of 76 patients in the acetazolamide group and 72 patients in the placebo group died or were hospitalized for heart failure (hazard ratio 1.07, 95% CI 0.78-1.48).…”

Section: Trials With Acetazolamide: Diuresis-chf and Advormentioning

confidence: 93%

Similarities and distinctions between acetazolamide and sodium–glucose cotransporter 2 inhibitors in patients with acute heart failure: Key insights into ADVOR and EMPULSE

Packer

Butler

2023

European J of Heart Fail

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Both acetazolamide and sodium–glucose cotransporter 2 (SGLT2) inhibitors block sodium reabsorption in the proximal renal tubule primarily through inhibition of sodium–hydrogen exchanger isoform 3 (NHE3), but neither SGLT2 inhibitors nor acetazolamide produce a sustained natriuresis due to compensatory upregulation of sodium reabsorption at distal nephron sites. Nevertheless, acetazolamide and SGLT2 inhibitors have been used as adjunctive therapy to loop diuretics in states where NHE3 is upregulated, e.g. acute heart failure. Two randomized controlled trials have been carried out with acetazolamide in acute heart failure (DIURESIS‐CHF and ADVOR). In ADVOR, acetazolamide improved physical signs of fluid retention, but this finding could not be explained by the modest observed diuretic effect. Acetazolamide did not produce a natriuresis in the DIURESIS‐CHF trial, and in ADVOR, immediate effects on symptoms and body weight were not reported, and the drug had no effect on morbidity or mortality after 90 days. Three randomized controlled trials have been carried out with empagliflozin (EMPAG‐HF, EMPA‐RESPONSE‐AHF and EMPULSE) in acute heart failure. The EMPULSE trial did not report effects on diuresis or in changes in physical signs of congestion during the first week of treatment, but in EMPAG‐HF and EMPA‐RESPONSE‐AHF, empagliflozin had no effect of dyspnoea, urinary sodium excretion or body weight during the first 4 days. In the EMPULSE trial, empagliflozin improved health status at 15 days and reduced the risk of worsening heart failure events at 90 days, but these effects are similar in magnitude and time course to the early statistical significance on the risk of heart failure hospitalizations achieved within 14–30 days in the major trials of SGLT2 inhibitors in patients with chronic heart failure. Neurohormonal inhibitors produce this early effect in the absence of a diuresis. Additionally, in numerous randomized controlled trials, in‐hospital diuretic intensification has not reduced the risk of major heart failure events, even when treatment is sustained. These findings, taken collectively, suggest that any immediate diuretic effects of acetazolamide and SGLT2 inhibitors in acute heart failure are not likely to influence the short‐ or long‐term clinical course of patients.

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“…At 48 h, the cumulative diuresis and natriuresis were only modestly higher in the acetazolamide arm as well (by 0.5 L of urine and 98 mmol of sodium). Later, Verbrugge et al [40] showed that allocation to acetazolamide in ADVOR strongly and independently predicted natriuresis with a 16 mmol/L (19%) increase in spot urine sodium and 115 mmol (32%) greater total natriuresis. Higher natriuresis and enhanced decongestion translated into a shorter hospital stay ( p < 0.001).…”

Section: Targeting Proximal Tubule For Decongestionmentioning

confidence: 99%

“…Higher natriuresis and enhanced decongestion translated into a shorter hospital stay ( p < 0.001). Every 10 mmol/L increase in urine sodium was independently associated with a lower risk of all-cause death or heart failure readmission (HR: 0.92; 95% CI: 0.85–0.99) [40]. In another post hoc analysis of ADVOR, Martens et al [41] reported that acetazolamide improved decongestive response over the entire range of serum bicarbonate levels, but the treatment response was magnified in patients with baseline or loop diuretic-induced elevated bicarbonate concentrations.…”

Section: Targeting Proximal Tubule For Decongestionmentioning

confidence: 99%

Cardiorenal Interactions in Acute Heart Failure; Renal Proximal Tubules in the Spotlight

Kazory,

Ronco,

Koratala

2024

Cardiorenal Med

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Background: The maladaptive neurohormonal activation, an integral mechanism in the pathophysiology of heart failure (HF) and cardiorenal syndrome, has a profound impact on renal sodium handling. Congestion is the primary reason for hospitalization of patients with HF and the main target of therapy. As sodium is the main determinant of extracellular volume, the goal is to enhance urinary sodium excretion in order to address excess fluid. The interventions to increase natriuresis have conventionally been focused on distal nephron as the primary segment that counterbalances the effects of loop diuretics. Summary: Recent developments in the field of cardiorenal medicine have resulted in a shift of attention to renal proximal tubules (e.g., emerging evidence on proximal tubular dysfunction beyond handling of sodium). Herein, we discuss the three main mechanisms of sodium transport in the proximal tubules with emphasis on their intrinsic links to one another as well as to more distal transporters of sodium. Then, we provide an overview of the findings of the most recent clinical studies that have tried to enhance the conventional decongestive strategies through simultaneous blockade of these mechanisms. Key Message: Interventions aiming at renal proximal tubules have the potential to significantly improve our ability to decongest patients with acute HF.

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Natriuretic Response to Acetazolamide in Patients With Acute Heart Failure and Volume Overload

Cited by 20 publications

References 25 publications

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

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

Similarities and distinctions between acetazolamide and sodium–glucose cotransporter 2 inhibitors in patients with acute heart failure: Key insights into ADVOR and EMPULSE

Cardiorenal Interactions in Acute Heart Failure; Renal Proximal Tubules in the Spotlight

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