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

https://doi.org/10.1016/j.jacc.2023.03.400Get rights and content

Abstract

Background

Acetazolamide facilitates decongestion in acute decompensated heart failure (ADHF).

Objectives

This study sought to investigate the effect of acetazolamide on natriuresis in ADHF and its relationship with outcomes.

Methods

Patients from the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial with complete data on urine output and urine sodium concentration (UNa) were analyzed. Predictors of natriuresis and its relationship with the main trial endpoints were evaluated.

Results

This analysis included 462 of 519 patients (89%) from the ADVOR trial. During 2 days after randomization, UNa was 92 ± 25 mmol/L on average, and total natriuresis was 425 ± 234 mmol. Allocation to acetazolamide strongly and independently predicted natriuresis with a 16 mmol/L (19%) increase in UNa and 115 mmol (32%) greater total natriuresis. Higher systolic blood pressure, better renal function, higher serum sodium levels, and male sex also independently predicted both a higher UNa and greater total natriuresis. A stronger natriuretic response was associated with faster and more complete relief of signs of volume overload, and this effect was already significant on the first morning of assessment (P = 0.022). A significant interaction was observed between the effect of allocation to acetazolamide and UNa on decongestion (P = 0.007). Stronger natriuresis with better decongestion translated into a shorter hospital stay (P < 0.001). After multivariable adjustments, every 10 mmol/L UNa increase was independently associated with a lower risk of all-cause death or heart failure readmission (HR: 0.92; 95% CI: 0.85-0.99).

Conclusions

Increased natriuresis is strongly related to successful decongestion with acetazolamide in ADHF. UNa may be an attractive measure of effective decongestion for future trials. (Acetazolamide in Decompensated Heart Failure with Volume Overload [ADVOR]; NCT03505788)

Section snippets

Study design

This is a prespecified analysis from the ADVOR trial. Detailed methods and results of this trial have been published previously.6,7 The ADVOR trial protocol was approved by the Institutional Review Board at every participating center and by the Belgian Federal Agency for Medicines and Health Products. In brief, ADVOR was a Belgian academic, multicenter, randomized, parallel-arm, double-blind, placebo-controlled trial that tested intravenous acetazolamide (500 mg once daily) on top of

Study group

In the overall ADVOR group of 519 patients, 502 patients (96.7%) had complete urine collections. Twelve patients (2.3%) had a urine sample <500 mL over 24 hours and were excluded (Supplemental Table 1). Full UNa results were lacking in another 28 patients (5.4%), resulting in a final study population of 462 patients or 89% of the overall ADVOR group. A comparison with excluded patients is presented in Supplemental Table 2. Excluded patients were more often women and less often had undergone

Discussion

This analysis from the ADVOR trial offers a unique perspective on the impact of acetazolamide on natriuresis in ADHF and its relationship with decongestion and clinical outcomes. Key findings are as follows: 1) allocation to acetazolamide in the ADVOR trial was the strongest independent predictor of a greater natriuretic response; 2) a stronger natriuretic response was associated with faster and more successful decongestion, translating into a shorter length of stay; 3) the interaction between

Conclusions

Acetazolamide leads to faster and more complete decongestion in patients with ADHF and clear clinical signs of volume overload, which is mediated by its effect on natriuresis. UNa may be an attractive measure of effective decongestion for future ADHF trials because it is simple to assess, objective, strongly related to decongestion, and associated with clinical outcome. Further randomized studies should investigate whether a decongestive strategy titrated on the basis of UNa further improves

Funding Support and Author Disclosures

This work was supported by the Belgian Health Care Knowledge Center under the KCE Trials Program (KCE 17001). Dr Damman has received speaker fees from AstraZeneca, Abbott, and Boehringer Ingelheim. Dr Ruschitzka has not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years (remuneration for the time spent in activities, such as participation as steering committee member of clinical trials and member of the Pfizer Research Award selection committee in

Acknowledgments

The authors express their gratitude to Katrien Tartaglia and her team from the Clinical Trial Unit Ziekenhuis Oost-Limburg Genk, who played a pivotal role in completing the ADVOR trial.

References (23)

  • W. Mullens et al.

    Acetazolamide in Acute Decompensated Heart Failure with Volume Overload

    N Engl J Med

    (2022)

    • Listen to this manuscript's audio summary by Editor-in-Chief Dr Valentin Fuster on www.jacc.org/journal/jacc.

    The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

    View full text
    © 2023 by the American College of Cardiology Foundation. Published by Elsevier.