The majority of hospitalizations for acute decompensated heart failure (ADHF) are driven by volume overload.¹ Practice guidelines recommend use of loop diuretics as the first step in relieving these symptoms/signs,^2,3 with guidance to promptly increase loop diuretic doses or add a second agent in cases when diuresis is inadequate. Unfortunately, contemporary, real-world data indicate that one-third of hospitalized AHF patients are discharged from the hospital with residual congestion and this negatively impacts their prognosis.^1,4 Yet, recent studies investigating approaches to augment decongestion in this setting have been neutral.^5-7

Acetazolamide (ACTZ), used since 1952, inhibits Na⁺ reabsorption in the proximal tubules of the nephron.⁸ Experimental data suggest that it also blocks Na⁺ reabsorption in the distal nephron and improves renal blood flow.⁸ ACTZ alone is a weak diuretic and its clinical use has been limited to specific indications like high altitude sickness and glaucoma.⁹ However, recent data from a small series of patients have shown a modest increase in diuresis/natriuresis with ACTZ when added to loop diuretics.^10,11

The ADVOR trial (Acetazolamide in Acute Decompensated Heart Failure with Volume Overload) was a parallel-group, double-blind, multi-center, randomized, placebo-controlled trial conducted in Belgium.¹² The study included 519 patients with ADHF to receive either intravenous ACTZ (500 mg once daily) or placebo in addition to standardized intravenous loop diuretics. The study's primary endpoint was successful decongestion within 3 days after randomization without an indication for escalation of decongestive therapy.

Inclusion criteria included age >18 years, admission for ADHF with at least one sign of congestion (more than trace edema, pleural effusion, or ascites), maintenance therapy with oral loop diuretics at a dose equivalent to ≥1 mg bumetanide for ≥1 month before enrollment, and NT-proBNP/BNP >1000/250 ng/mL at screening. Major exclusion criteria included concurrent use of sodium-glucose transporter-2 inhibitors (SGLT-2is), use of any non-protocol defined diuretic except for mineralocorticoid receptor antagonists, systolic blood pressure (SBP) <90 mmHg and eGFR <20mL/min/1.73m².

Over the 72-hour study treatment period, the primary outcome occurred in 42.2% of patients in the ACTZ versus 30.5% of patients in the placebo group (risk ratio [RR], 1.46; 95% confidence interval [CI] 1.17-1.82; P<0.001). Results were mostly consistent among pre-specified subgroups. Notably, patients with home diuretic dose >60 mg daily in furosemide equivalents seemed to have less benefit with ACTZ than patients with home dose ≤60 mg daily.

The pre-specified secondary outcomes of death from any cause and HF hospitalization were not different between groups, albeit a numerically greater number of deaths at 3 months in the ACTZ group (39 [15.2%] vs. 31 [12.0%], hazard ratio [HR], 1.28; 0.78-2.05). There was no difference in quality of life between the two study groups, as measured by the EuroQoL-5D instrument. ACTZ use was associated with a shorter hospitalization (8.8 vs. 9.9 days; 0.89; 0.81-0.98).

Among other study outcomes, cumulative diuresis and natriuresis on the morning of Day 3 were significantly higher with ACTZ compared to placebo. From a safety point of view, there was no significant difference regarding the rate of adverse events between the groups with the exception of 90-day hypokalemia (defined as serum K⁺≤3.0 mmol/l) which occurred more often in patients on ACTZ compared with patients in the control group (23.4% vs. 14.7%, P=0.0134).

ADVOR is an important trial. It is a sizeable randomized, placebo-controlled decongestion study that met its primary outcome with a HR of 1.46 and was relatively safe. However, the critical issue for clinicians is whether the results of ADVOR change clinical practice.

A review of the trial's limitations is worthwhile in this context. First, congestion in the study was defined by limited criteria as it only included edema, pleural effusion, and ascites, but not other common symptoms and signs of volume overload, such as dyspnea, orthopnea, and jugular vein distention. This limitation may explain why fewer patients with NYHA IV were enrolled in this study relative to other ADHF trials. For example, orthopnea was prevalent in >85% of patients in DOSE, ROSE and ATHENA-HF.^6,7,13

The same criteria were used to evaluate decongestion in the study. Thus, in a hypothetical scenario, a patient who had trace pedal edema, no pleural effusion and no ascites after treatment would be considered decongested for the purpose of the study, even if they continued to have dyspnea and/or jugular vein distention. These limited criteria may have led to the ADVOR-reported, high rates of decongestion at 72 hours (33% in the control and 45% in the intervention arm) when compared to the respective rates in the high-dose arm of DOSE (18% at 72 hours) and the pharmacologic arm of CARRESS-HF (9% at 96 hours).^5,13

The decongestion protocol of ADVOR did not allow diuretic therapy escalation earlier than Day 3, which was less aggressive than other ADHF trials and as suggested in contemporary guidelines (Table 1).^2,3

Table 1: Courtesy of Kapelios CJ, Drakos SG, Fang JC.

Study*, First Author, Year	Decongestion Therapy
ADVOR,8 Mullens, 2022	Daily intravenous loop diuretic dose = 2 x oral dose for Days 1 and 2. On morning of Day 3 escalation was mandatory if patient was overloaded and decongestion target (cumulative urine output >3.5 L for the first 2 days) was not achieved. Escalation could be doubling of loop diuretic dose, adding chlorthalidone 50mg orally or ultrafiltration/renal replacement therapy.
DOSE,13 Felker, 2011	Daily intravenous loop diuretic dose = 2.5 x oral dose for 72 hours. At 48 hours, the treating physician could adjust the diuretic strategy on the basis of clinical response (increase dose by 50%, maintain same strategy, or discontinue iv treatment and change to oral diuretics).
CARRESS-HF,5 Bart, 2012	Prespecified stepped pharmacologic protocol up to a total daily dose of intravenous furosemide of 800 mg + metolazone 10 mg.
ROSE,6 Chen, 2013	Intravenous loop diuretic dose recommendation for the first 24 hours = 2.5 x PO dose and up to 600 mg/day. Use of other medications and diuretic dosing after 24 hours were at the discretion of the clinician.
ATHENA-HF,7 Butler, 2017	Prescription of all medications except spironolactone, including diuretics, was left at the discretion of the treating physician.

Consequently, diuresis was lower in the control arm of ADVOR compared to the respective arms of recent ADHF trials (Table 2).^5-7,12,13

Table 2: Courtesy of Kapelios CJ, Drakos SG, Fang JC.

Study*, First Author, Year	N	Diuresis	Body Weight Loss	Proportion of Decongested Patients
ADVOR,12 Mullens, 2022	260	Cumulative urine output on morning of day 3: 4.1 ± 1.8 L	Not reported	33.2% at 72 hours
DOSE,13 Felker, 2011	157	Net** fluid loss at 72 hours: 4.9 ± 3.5 L	At 72 hours: 3.9 ± 3.9 kg	18% at 72 hours
CARRESS-HF,5 Bart, 2012	94	Cumulative urine output after 2nd day ≈ 6.1 L	At 96 hours: 5.5 ± 5.1 kg	9% at 96 hours
ROSE,6 Chen, 2013	119	Cumulative urine output after 48 hours: 5.5 ± 2.2 L	At 72 hours: 3.5 kg (2.9;4.1)	Not reported
ATHENA-HF,7 Butler, 2017	178	Net cumulative urine output after 48 hours: 2.3 L (1.2;4.1)	At 96 hours: 2.8 kg (0.8;5.1)	Not reported

In ADVOR, weight loss was not reported, although it was a pre-specified study outcome and is a common metric of decongestion in clinical practice and previous studies.¹⁴

Additionally, the per protocol maximum daily intravenous dose of bumetanide 10 mg/furosemide 200 mg and discontinuation of thiazides/thiazide-like diuretics during the study treatment phase in ADVOR did not allow comparison of ACTZ with higher doses of loop diuretics frequently used in clinical practice and with the addition of thiazide, which is a common approach for patients not responding to loop diuretics. This might explain why ACTZ showed less benefit in the subgroup of patients with higher pre-admission diuretic doses, while limiting clinical practice implications, particularly since clinicians frequently use thiazides to augment diuresis in loop diuretic resistant ADHF.

Furthermore, nearly all the patients in the trial were White, which may limit the generalizability of the results to other racial or ethnic groups.

Finally, patients receiving SGLT-2is were excluded from the study, a practice that does not reflect contemporary standard of care and creates uncertainty regarding the safety and efficacy of ACTZ in patients treated with background SGLT-2is.¹⁵ Hence, data on use of ACTZ in addition to SGTL2i and/or thiazide for sequential nephron blockade on background loop diuretics is needed.

Regardless, ADVOR was an important trial and highlights the need for randomized clinical trials in ADHF. In the meantime, ACTZ could be considered as adjunctive decongestive therapy in ADHF and it will be interesting to see where it will ultimately land in the landscape of contemporary decongestive therapies.

References

1. Chioncel O, Mebazaa A, Maggioni AP, et al. Acute heart failure congestion and perfusion status - impact of the clinical classification on in-hospital and long-term outcomes; insights from the ESC-EORP-HFA Heart Failure Long-Term Registry. Eur J Heart Fail 2019;21:1338-52.
2. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2022;24:4-131.
3. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022;79:e263-e421.
4. Rubio-Gracia J, Demissei BG, Ter Maaten JM, et al. Prevalence, predictors and clinical outcome of residual congestion in acute decompensated heart failure. Int J Cardiol 2018;258:185-91.
5. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012;367:2296-304.
6. Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013;310:2533-43.
7. Butler J, Anstrom KJ, Felker GM, et al. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiol 2017;2:950-58.
8. Mullens W, Verbrugge FH, Nijst P, et al. Rationale and design of the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial. Eur J Heart Fail 2018;20:1591-1600.
9. Tang WHW, Kiang A. Acute cardiorenal syndrome in heart failure: from dogmas to advances. Curr Cardiol Rep 2020;22:143.
10. Imiela T, Budaj A. Acetazolamide as add-on diuretic therapy in exacerbations of chronic heart failure: a pilot study. Clin Drug Investig 2017;37:1175-81.
11. Verbrugge FH, Martens P, Ameloot K, et al. Acetazolamide to increase natriuresis in congestive heart failure at high risk for diuretic resistance. Eur J Heart Fail 2019;21:1415-22.
12. Mullens W, Dauw J, Martens P, et al. Acetazolamide in acute decompensated heart failure with volume overload. N Engl J Med 2022;387:1185-95.
13. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364:797-805.
14. Acetazolamide in Decompensated Heart Failure With Volume OveRload (ADVOR) (ClinicalTrials.gov.). 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT03505788. Accessed 10/10/2022.
15. Felker GM. New Decongestion strategies in an evolving heart failure landscape. N Engl J Med 2022;387:1231-33.

Clinical Topics: Heart Failure and Cardiomyopathies, Statins

Keywords: ESC Congress, ESC22, Acetazolamide, Diuretics, Furosemide, Bumetanide, Mineralocorticoid Receptor Antagonists, Sodium Potassium Chloride Symporter Inhibitors, Natriuresis, Patient Discharge, Hypokalemia, Sodium-Glucose Transporter 2 Inhibitors, Quality of Life, Confidence Intervals, Jugular Veins, Random Allocation, Edema, Dyspnea, Sodium, Nephrons, Prognosis, Glaucoma, Glucose, Randomized Controlled Trials as Topic, Multicenter Studies as Topic, Review Literature as Topic, Thiazides

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