ADVOR: Acetazolamide for Acute Decompensated Heart Failure
Acetazolamide in Acute Decompensated Heart Failure with Volume Overload.
Mullens W, Dauw J, Martens P, et al. for the ADVOR Study Group.
N Engl J Med. 2022 Sep 29;387(13):1185-1195. [Full text]
Loop diuretics are the mainstay of management for decongestion in acute decompensated heart failure (ADHF). The 2011 Diuretic Optimization Strategies Evaluation (DOSE) trial established that bolus furosemide was no different than a continuous infusion, and that high dose boluses (2.5 times the total daily oral loop diuretic dose) achieved more diuresis than low dose [1].
While this management strategy continues to be to standard of care, there is a subset of patients that will not respond to high dose loop diuretics, that have developed “diuretic resistance“. The mechanisms for diuretic resistance are complex. As outlined by Georgetown’s own Dr. Christopher Wilcox et al., these include (1) pharmacokinetic mechanisms related to loop diuretics – variable bioavailability, a short duration of action allowing that the kidneys to restore diuretic-induced Na+ losses between doses, (2) pathophysiological mechanisms – high daily salt, hyponatremia, hypokalemic+hypochloremic metabolic alkalosis, and reflex activation of the renal nerves, and finally (3) nephron mechanisms include tubular tolerance that leads to enhanced reabsorption in the proximal tubule, downstream distal tubule, or collecting ducts [2].
Sequential blockade involves the addition of diuretic agents that do not act in the loop of Henle. ATHENA-HF did not find that the addition of spironolactone improved congestion [3] while the small (n=60) cohort of patients with diuretic resistance in the 3T trial had good urine output with the addition of metolazone, chlorthalidone or tolvaptan [4].
This Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial was a designed as a large randomized trial to assess whether the addition of acetazolamide to standardized intravenous loop-diuretic therapy improved decongestion in patients with ADHF, not just those with diuretic resistance.
Patient population and Design
This was multicenter, randomized, parallel-group, double-blind, placebo-controlled, investigator-initiated, academic, clinical trial without industry involvement, though all centers were in Belgium.
Adult patients who were admitted to the hospital because of ADHF and had at least one clinical sign of volume overload (i.e., edema, pleural effusion, or ascites) and an N-terminal pro–B-type natriuretic peptide (NT-proBNP) level of >1000 pg.mL or a BMP > 250 pg/mL were eligible. Receipt of at least 40 mg furosemide oral maintenance therapy (or equivalent: 1 mg of bumetanide, 20 mg torsemide) for at least 1 month before randomization was required.
Patients were excluded if they were on acetazolamide maintenance therapy or another proximal tubular diuretic including sodium–glucose cotransporter 2 (SGLT2) inhibitors, had a SBP <90 mm Hg, or an eGFR <20 ml/min/1.73 m2 BSA. The maximum IV loop diuretics dose before randomization was 80 mg of furosemide or equivalent.
Patients were randomly assigned in a 1:1 ratio to receive acetazolamide 500 mg once daily or matching placebo, administered after randomization and for the next 2 days or until the occurrence of complete decongestion (defined as the absence of any clinical sign of fluid overload other than trace edema). If the cumulative urinary output over the period of 30 to 48 hours on that morning was less than 3.5 liters and signs of fluid overload were still present, an escalation of decongestive treatment was mandated by the protocol.
All patients received the same maintenance infusion of 500 ml of 5% dextrose and 3 g of magnesium sulfate over 24 hours during the treatment phase of the trial.
Outcomes
The primary end point was successful decongestion within 3 days after randomization, defined as the absence of signs of volume overload (i.e., no more than trace edema, no residual pleural effusion, and no residual ascites) as assessed by a cardiologist trained in the completion of the congestion score (0-10 with the degree of edema = 0 to 4, pleural effusion = 0 to 3, and ascites = 0 to 3), with higher scores indicating a worse condition, without an indication for escalation of decongestive therapy. Secondary end points included the composite end point of death from any cause or rehospitalization for heart failure during 3 months of follow-up, the duration of the index hospital admission (i.e., the number of days from randomization until the date of discharge).
Results
A total of 2915 patients were screened, and 519 were randomly assigned to receive either acetazolamide (259 ) or placebo (260). The groups were well balanced and had with a median NT-proBNP of 6173 pg/mL and a median congestion score of 4.
Successful decongestion occurred in more patients in the acetazolamide group, 108 of 256 patients (42.2%) compared to 79 of 259 (30.5%) in receiving placebo (RR 1.46; 95% CI 1.17-1.82; P<0.001). In subgroup analysis a benefit was not detected in those with a higher baseline maintenance diuretic dose, >60 mg furosemide. or those with a lower systolic function (LVEF ≤ 40%).
In regards to secondary outcomes, death from any cause or re-hospitalization for heart failure within 3 months occurred with similar frequency. The duration of the hospital stay was slightly shorter in the acetazolamide group, 8.8 days vs. 9.9 days. There were no safety difference between the groups and no patients receiving acetazolamide developed severe metabolic acidosis.
Discussion
In this large randomized trial, the addition of 500 mg IV acetazolamide to standardized IV loop-diuretic therapy was associated with a higher incidence of successful decongestion within 3 days, with possibly a shorter length of stay and no increase in adverse events. As the study authors note, residual congestion is associated with worse outcomes and readmission, and acetazolamide may offer better and early decongestion in ADHF.
The study participants were generally a homogeneous population recruited in Belgium. Additionally, these patients had established heart failure and were on maintenance diuretics, so the results may not apply to newly decompensated HF. Furthermore, it may not be standard practice in many places to administer 500 ml of 5% dextrose daily to patients with ADHF, again limiting generalizability.
Of note, SGLT2 inhibitors were not allowed during the study and were an exclusion criteria. SGLT2 inhibitors also act on the proximal tubule and have mild diuretic activity. As these agents have important mortality benefits (EMPEROR-Reduced, DAPA-HF) and/or decrease hospitalization (EMPORER-preserved), it remains unclear whether acetazolamide may have additional benefit over an SGLT2i or if it is safe to combine them.
For now, standard 2-2.5 times maintance dose loop diuretic likely remains the initial management strategy for ADHF. Based here on ADVOR, for those patients with diuretic resistance, or an inadequate initial response to loop-diuretics, the addition of acetazolamide is reasonable and may achieve more rapid decongestion.
| F: Follow up | Yes, 73 hrs after randomization and then 3 months |
| R: Randomization | Yes, permuted blocks, stratification according to LVEF (≤40% or >40%) and center |
| I: Intention to treat | Yes |
| S: Similar at baseline | Yes |
| B: Blinding | Yes |
| E: Equal treatment | Yes, except as by design |
| S: Source (funding) | Belgian Health Care Knowledge Center |
- Felker GM, Lee KL, Bull DA, et al.; NHLBI Heart Failure Clinical Research Network. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011 Mar 3;364(9):797-805.
- Wilcox CS, Testani JM, Pitt B. Pathophysiology of Diuretic Resistance and Its Implications for the Management of Chronic Heart Failure. Hypertension. 2020 Oct;76(4):1045-1054.
- Butler J, Anstrom KJ, Felker GM, et al.; National Heart Lung and Blood Institute Heart Failure Clinical Research Network. Efficacy and Safety of Spironolactone in Acute Heart Failure: The ATHENA-HF Randomized Clinical Trial. JAMA Cardiol. 2017 Sep 1;2(9):950-958.
- Cox ZL, Hung R, Lenihan DJ, Testani JM. Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure: The 3T Trial. JACC Heart Fail. 2020 Mar;8(3):157-168.
