ADVOR

Published

Mullens W, et al. "Acetazolamide in Acute Decompensated Heart Failure with Volume Overload". NEJM. 2022. Epub 2022-08-27:1-11.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In adult patients with acute decompensated heart failure characterized by volume overload, does acetazolamide in combination with loop diuretics as compared to loop diuretics alone improve time to successful decongestion within 72 hours?

Bottom Line

In adult patients with acute decompensated heart failure characterized by volume overload on diuretics, addition of acetazolamide improves proportion who achieve decongestion when compared to placebo.

Major Points

Loop diuretics (so called because they act in the loop of henle) are the cornerstone of acute decompensated heart failure (ADHF) treatment. (Strategies for administration of the loop diuretic furosemide in ADHF were evaluated in the 2011 DOSE trial.) The carbonic anhydrase inhibitor, acetazolamide (brand name Diamox), acts in the proximal convoluted tubule, and was a commonly used diuretic until the more potent loop diuretics were released. More recently, pilot studies suggested that acetazolamide might augment loop diuretics in promoting more effective diuresis among adults with ADHF. A larger trial was needed to confirm this effect.

Published in 2022, the Acetazolamide in Decompensated Heart Failure With Volume OveRload (ADVOR) trial randomized 519 adults with ADHF on ≥40 mg of furosemide at home as a chronic stable dose to acetazolamide 500 mg IV daily or placebo in addition to a doubling of their home loop diuretic dose, given as an IV formulation. After the first day, acetazolamide was given simultaneously with loop diuretics. The intervention was continued for 3 days or until the time of decongestion. As compared to placebo, 11.7% more patients in the acetazolamide group achieved successful decongestion at day 3 (30.5% vs. 42.2%; RR 1.46, 95% CI 1.17-1.82; P<0.001). The acetazolamide arm also had a shorter hospital length of stay (9.9 days vs. 8.8 days; RR 0.89, 95% CI 0.81-0.98; p=0.02).

There are a few challenges generalizing the results of this trial to clinical practice. It was conducted in Northern Europe and nearly all patients were White. New HF patients were excluded, as were those on SGLT-2 inhibitors as they were not yet approved for treatment in HF when the trial was planned. (The 2022 EMPULSE trial found benefit for SGLT-2 inhibitors in ADHF.) It is unknown what would occur when acetazolamide is added to loop diuretics and an SGLT-2 inhibitor, theoretically they could be synergistic but could also feasibly lead to no greater outcomes and worse adverse effects. Thiazide diuretics (ie metolazone, chlorothiazide), which are accepted adjuncts for loop diuretic refractory volume overload, were also not compared to acetazolamide. Additionally, the amount of diuresis per day was conservative and patients in the comparator group could have potentially been treated with higher doses of loop diuretics to target a higher urine output and shorter length of stay. Overall, this trial indicates that acetazolamide in addition to double-dose loop diuretics improves decongestion among adults with ADHF.

Guidelines

As of September 2022, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, double-blind, randomized, placebo-controlled trial
• N=519
  • Acetazolamide (n=259)
  • Placebo (n=260)
• Setting: 27 sites in Belgium
• Enrollment: 2018-2022
• Follow-up: 3 months
• Analysis: Intention-to-treat
• Primary outcome: successful decongestion within 3 days

Population

Inclusion Criteria

• Aged ≥18 years
• Admitted for acute decompensated heart failure and ≥1 of clinical sign of volume overload:
  • 2+ or worse edema
  • Pleural effusion on CXR
  • Ascites on ultrasound
• Elevated natriuretic peptide, defined as either:
  • N-terminal pro–B-type natriuretic peptide (NT-proBNP) >1,000 pg/mL
  • B-type natriuretic peptide level >250 pg/mL
• Oral maintenance diuretic, minimum dose, for ≥1 month:
  • Furosemide 40mg/day
  • Bumetanide 1mg/day
  • Torasemide 20mg/day
• Known LVEF on imaging in the prior year

Exclusion Criteria

• Admission for known or suspected ACS
• Expected to require pressors
• Prior surgical correction for congenital heart disease
• Prior heart transplant or LVAD
• On acetazolamide in the prior month
• Treatment with another proximal tubular diuretic, including SGLT-2 inhibitors
• SBP <90 or MAP <65 mmHg
• On RRT
• eGFR <20 mL/min/1.73m²
• IV loop diuretic >80mg furosemide, >2 mg bumetanide, or >20 mg torsemide during that hospitalization
• Anticipated exposure to IV contrast or other nephrotoxin in the coming 3 days
• SGLT2-inhibitor use
• Breastfeeding
• Incontinence or not willing to have foley or similar catheter placed

Baseline Characteristics

From the entire population

• Demographics: Mean age 78.2 years, 37.4% female, 99% Caucasian, mean weight 84.8 kg
• Physiologic parameters: BP 127/72 mmHg, HR 78 BPM, LVEF 43%, LVEF ≤40% in 43.2%, hgb 119 g/L, Na 139 mmol/L, estimated GFR 30, eGFR <60 in 81.7%
• Signs of congestion: Median congestion 4 (0 to 10, 10 being worst), 92.1% edema, 52.6% pleural effusion, 8.9% ascites, median NT-proBNP 6173 pg/mL
• Heart Failure: NYHA Class II 12.7%, NYHA Class III 57%, NYHA Class IV 30.3%, ischemic cause 44.7%,
• Co-morbidities: AF 72.4%, DM 47.2%, HTN 75%
• Current medications: ACE/ARB/ARNI 52%, beta blocker 80.7%, mineralocorticoid 41.6%, loop diuretic 100%, ICD 15.2%, CRT 11.8%

Interventions

• All patients had maintenance loop diuretics stopped, given IV loop diuretic double the maintenance dose divided into two doses given ≥6 hours apart
• Acetazolamide 500mg IV daily, given with first loop diuretic dose and for two additional days or until complete decongestion
  • If urinary output over 30-48 hours less than 3.5 L and still congested, then escalation of diuretics per protocol
• Maintenance fluid of 500mL D5W with 3g MgSO4 given over 24 hours

Outcomes

Comparisons are placebo vs. acetazolamide.

Primary Outcomes

Successful decongestion within 3 days

Defined as absence of signs of volume overload, except trace edema.

30.5% vs. 42.2% (RR 1.46, 95% CI 1.17-1.82) p<0.001

Secondary Outcomes

Hospital length of stay

9.9 days vs. 8.8 days (RR 0.89, 95% CI 0.81-0.98) p=0.02

Death from any cause or rehospitalization for heart failure during 3 months of follow-up

27.8% vs. 29.7% (RR 1.07, 95% CI 0.78-1.48)

Exploratory Analyses

Successful decongestion at discharge among patients who were alive at 3 months

62.5% vs. 78.8% (RR 1.27, 95% CI 1.13-1.43)

All-cause mortality at 3 months

12% vs. 15.2% (HR 1.28, 95% CI 0.78-2.05)

Rehospitalization for HF at 3 months

17.4% vs. 18.4% (HR 1.07, 95% CI 0.71-1.59)

Subgroup Analysis

The subgroup analyses are shown in Figure 2. In general, the point estimates for the primary outcome were similar between groups, except for the following:

Primary outcome

LVEF

≤40%: RR 1.24; 95% CI 0.88-1.75

>40%: RR 1.63; 95% CI 1.22-2.19

Home loop dose (converted to furosemide equivalent if not taking furosemide):

≤60 mg/d: RR 1.78; 95% CI 1.33-2.36

>60 mg/d: RR 1.08; 95% CI 0.76-1.55

Adverse Events

No safety endpoints reached statistical significance between treatment and placebo groups during treatment or at 3 months follow-up, however the trial may not have been powered to detect a clinically significant difference.

Combined renal safety endpoint (doubling of creatinine, ≥50% decrease in eGFR, or RRT)

0.8% vs 2.7% (P=0.10)

Hypotension

3.5% vs 6.6% (P=0.11)

Hypokalemia

3.9% vs 5.5% (P=0.39)

Adverse event during 3 months of follow-up

1.2% vs 3.1% (P=0.14)

Criticisms

• Unclear how many participants with HFrEF were on goal directed therapy at baseline.
• Generalizability hampered since almost completely white race participants included.
• New diagnosed HF were excluded from the trial so results cannot be applied to them.
• Unknown or unclear the interaction between acetazolamide and SGLT-2 inhibitors, whether synergistic or antagonistic, nor the potential adverse effects of this combination

Funding

• Belgian Health Care Knowledge Center under the KCE Trials Program (KCE-17001)