Acetazolamide in Acute Decompensated Heart Failure with Volume Overload (ADVOR)

Authors, Journal, Affiliations, Type, DOI

• Authors: Wilfried Mullens, Jeroen Dauw, Pieter Martens, Frederik H. Verbrugge, et al., for the ADVOR Study Group
• Journal: New England Journal of Medicine
• Lead Affiliation: Ziekenhuis Oost-Limburg and Hasselt University, Genk/Hasselt, Belgium
• Funding: Belgian Health Care Knowledge Centre (KCE Trials Program); no industry involvement
• Type: Multicentre, parallel-group, double-blind, randomised, placebo-controlled investigator-initiated trial
• Published: August 27, 2022
• DOI: https://doi.org/10.1056/NEJMoa2203094

Overview

ADVOR randomised 519 patients with acute decompensated HF, clinical signs of volume overload, and elevated natriuretic peptides (NT-proBNP >1000 pg/mL or BNP >250 pg/mL) to IV acetazolamide 500mg once daily or placebo, both added to standardised IV loop diuretics (twice the oral maintenance dose), across 27 Belgian centres. Acetazolamide — a carbonic anhydrase inhibitor blocking the apical sodium-hydrogen exchanger responsible for ~60% of proximal tubular sodium reabsorption — significantly increased the rate of successful decongestion within 3 days (42.2% vs 30.5%; RR 1.46; P<0.001), with higher natriuresis, higher urine output, and shorter hospital stay. However, the secondary composite of death or HF rehospitalization at 3 months was not significantly different (HR 1.07; NS). Safety was comparable, with no severe metabolic acidosis and similar rates of AKI, hypokalemia, and hypotension.

Keywords

Heart failure; acute decompensated heart failure; volume overload; decongestion; acetazolamide; loop diuretics; natriuresis; diuretic resistance; carbonic anhydrase inhibitor; sequential nephron blockade

Key Takeaways

Background and Rationale

• Despite high-dose IV loop diuretic therapy, successful decongestion in acute HF is uncommon: the DOSE trial showed only 15% of patients were free from clinical congestion at 72 hours; the ADHERE registry found ~20% discharged with weight gain.
• Residual congestion at discharge is strongly linked to worse outcomes (readmission, mortality).
• Sequential nephron blockade — targeting multiple nephron segments simultaneously — may improve diuretic efficiency. Evidence for specific agents (thiazides, spironolactone) had been inconsistent.
• Acetazolamide inhibits carbonic anhydrase at the proximal tubule, blocking the apical sodium-hydrogen exchanger (NHE3) responsible for ~60% of proximal tubular Na⁺ reabsorption. This mechanism is mechanistically complementary to loop diuretics (which target the thick ascending limb) and distinct from SGLT2 inhibitors (which block only ~5% of proximal sodium uptake via SGLT2).
• Prior observational data and a small prospective RCT (Verbrugge et al.) suggested IV acetazolamide 500mg increased urinary sodium excretion in HF patients, justifying a large trial.

Methods

• Population: Adults hospitalised for ADHF with ≥1 sign of volume overload (oedema, pleural effusion, or ascites); NT-proBNP >1000 pg/mL or BNP >250 pg/mL; on oral loop diuretic ≥40mg furosemide equivalent for ≥1 month before randomisation.
• Key exclusions: Active SGLT2i use (excluded — both act on proximal tubule; SGLT2i not approved for HF during most of trial); SBP <90 mmHg; eGFR <20 mL/min/1.73m²; pre-trial IV loop diuretic >80mg furosemide equivalent.
• Intervention: IV acetazolamide 500mg OD bolus (simultaneously with first daily loop diuretic dose) for up to 3 days or until complete decongestion; IV loop diuretic standardised at twice oral maintenance dose.
• Stratification: LVEF ≤40% vs >40%; trial centre.
• Congestion score (0–10): Edema 0–4 + pleural effusion 0–3 + ascites 0–3. Assessed daily.
• Primary endpoint: Successful decongestion within 3 days — defined as absence of signs of volume overload (≤trace oedema, no pleural effusion, no ascites) AND no escalation of decongestive therapy triggered by urine output <3.5L on morning of day 2.
• Key secondary endpoint: Composite of all-cause death or HF rehospitalization at 3 months.
• Other secondary endpoint: Duration of index hospitalisation.
• Sample size: 519 patients (powered assuming 15% vs 25% decongestion rate; 80% power; two-sided α=0.05).
• Enrollment: November 2018 – January 2022; 27 sites in Belgium.

Primary Outcome

• Successful decongestion in 42.2% (108/256) acetazolamide vs 30.5% (79/259) placebo: RR 1.46 (95% CI 1.17–1.82; P<0.001).
• Progressive reduction in congestion score over consecutive days was more pronounced in the acetazolamide group.
• At discharge among survivors: 78.8% (190/241) acetazolamide vs 62.5% (145/232) placebo were successfully decongested (RR 1.27; 95% CI 1.13–1.43) — absolute difference of 16.3 percentage points.

Diuretic Efficacy

• Mean urine output by morning of day 2: 4.6±1.7L (acetazolamide) vs 4.1±1.8L (placebo).
• Mean natriuresis by morning of day 2: 468±234 mmol (acetazolamide) vs 369±231 mmol (placebo).
• Total administered loop diuretic dose was similar between groups — confirming that the benefit was attributable to acetazolamide, not diuretic dose escalation.

Secondary Outcomes

• All-cause death or HF rehospitalization at 3 months: 29.7% (acetazolamide) vs 27.8% (placebo) — HR 1.07 (95% CI 0.78–1.48); NS. No mortality or readmission benefit.
• Duration of index hospitalisation: Geometric mean 8.8 days (acetazolamide) vs 9.9 days (placebo) — shorter stay with acetazolamide.

Subgroup Analyses

• Benefit on primary endpoint was generally consistent across prespecified subgroups including LVEF ≤40% vs >40%, higher congestion score, lower eGFR, and higher NT-proBNP.
• One signal of possible heterogeneity: patients on a higher oral maintenance dose of loop diuretics appeared to derive less benefit — potentially because higher baseline diuretic load implies more established diuretic resistance where a single complementary mechanism may be insufficient.

Safety

• Severe metabolic acidosis (bicarbonate <12 mmol/L): occurred in zero patients in either group.
• Combined renal safety endpoint (serum creatinine doubling, eGFR decrease ≥50%, or renal replacement therapy): similar between groups.
• Hypokalemia (K⁺ ≤3 mmol/L): similar between groups.
• Hypotension (SBP <85 mmHg): similar between groups.
• Adverse events leading to discontinuation: rare and comparable.

Mechanistic Context

• Acetazolamide blocks carbonic anhydrase in proximal tubular cells → impairs NHE3-mediated Na⁺/H⁺ exchange → reduces proximal tubular sodium and bicarbonate reabsorption (~60% of filtered sodium load) → enhances sodium delivery to downstream nephron segments → augments loop diuretic effect at the thick ascending limb.
• This is mechanistically synergistic with loop diuretics (thick ascending limb blockade) — the combined proximal + loop blockade is the basis of sequential nephron blockade in HF.
• Contrast with SGLT2i: SGLT2 mediates only ~5% of proximal tubular sodium uptake. Despite superficial similarities as proximal tubular agents, acetazolamide and SGLT2i have substantially different potency and mode of action.

Limitations of the document

• Single-country trial (all 27 sites in Belgium) — near-exclusively White population; generalisability to other racial/ethnic groups and healthcare systems is uncertain.
• Patients required pre-existing loop diuretic therapy (≥40mg furosemide equivalent) for ≥1 month — results may not apply to de novo acute HF.
• Congestion score (primary endpoint) measures extracellular/clinical congestion only (oedema, pleural effusion, ascites); does not capture intravascular or pulmonary vascular congestion directly.
• SGLT2 inhibitors were excluded by design — interaction between acetazolamide and SGLT2i on decongestion and outcomes is unknown. Most patients enrolled pre-dating SGLT2i approval for HF.
• Secondary composite endpoint (death/rehospitalization at 3 months) was not significantly improved despite the decongestion benefit — the trial was likely underpowered for hard outcomes.
• Loop diuretic dose standardisation at 2× oral maintenance (rather than higher titration) may have limited generalisability to sicker/more diuretic-resistant patients.

Key Concepts Mentioned

• concepts/Diuretic-Resistance — acetazolamide as proximal tubular blockade strategy; ADVOR is the first large RCT demonstrating decongestion benefit
• entities/Heart-Failure — acute decompensated HF management

Key Entities Mentioned

• DOSE trial — prior acute HF decongestion benchmark (15% successful decongestion at 72h); provided control event rate assumption for ADVOR
• CARRESS-HF — ultrafiltration vs pharmacologic decongestion; referenced as comparator
• SGLT2 inhibitors — excluded from ADVOR; proximal tubular overlap but different mechanism and potency

Wiki Pages Updated

• wiki/sources/acetazolamide-acutehf-nejm-2022.md — created
• wiki/concepts/Diuretic-Resistance.md — added acetazolamide/ADVOR as proximal tubular blockade strategy; new contradiction on absence of hard outcome benefit; source_count updated
• wiki/entities/Heart-Failure.md — added ADVOR to Acute HF section
• wiki/sourceindex.md — new entry added
• wiki/wikiindex.md — Diuretic-Resistance entry updated