NEJM.

ORG SEPTEMBER 29, 2022

JC, 17.05.2023
Ivana Begic
 Acute decompensation of CHF

Klinische Präsentation Therapeutische Optionen

BACKGROUND

Acetazolamide - carbonic anhydrase inhibitor

Known: reduces proximal tubular sodium reabsorption - increased urinary sodium excretion - objective metric of
diuretic efficiency

Q: Can it improve the efficiency of loop diuretics - faster decongestion in patients with acute decompensated heart
Q: Can it improve the efficiency of loop diuretics - faster decongestion in patients with acute
failure?
decompensated heart failure?

The attainment of successful decongestion (euvolemia) has a class I recommendation from the European and
American guidelines for the diagnosis and treatment of heart failure

Current guidelines recommend the use of intravenous loop diuretics – Praxis: sequential diuretic therapy
Problem: despite high-dose loop diuretics (dose equivalent, 2 to 2.5 times the oral maintenance dose), many patients are discharged from the hospital with
residual clinical signs of volume overload, a strong predictor of poor outcome
Diuretic Optimization Strategies Evaluation (DOSE) trial: 15% free from clinical congestion
Acute Decompensated Heart Failure National Registry (ADHERE): 20% of the patients were discharged from the hospital with an increase in body
weight.
Acetazolamid
 ADVOR
Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial

• Scope: examined whether the addition of acetazolamide to standardized intravenous loop-diuretic therapy would
improve the incidence of successful decongestion among patients with acute decompensated heart failure

Trial Design and Oversight

• multicenter, randomized, parallel-group, double-blind, placebo-controlled, investigator-initiated, academic,

clinical trial without industry involvement («sounds promising!»)
• A steering committee consisting of 14 academic members, one patient representative, and one independent statistician
• central ethics committee and the Belgian Federal Agency for Medicines and Health Products
• written informed consent
• Supported by the Belgian Health Care Knowledge Center un- der the KCE Trials Program (KCE-17001).
 ADVOR
Patients
• Patients
• Between November 11, 2018, and January 17, 2022
• a total of 2915 patients underwent screening
• 519 were randomly assigned to receive either acetazolamide (259 patients) or placebo (260 patients) at 27
sites in Belgium
• Time: 72 h for primary endpoint, 3 months for secondary endpoint - death from any cause and
rehospitalization for heart failure
 ADVOR
Patients
• Adult patients – hospitalisation- acute decompensated chr.
heart failure
• at least one clinical sign of volume overload (i.e., edema,
pleural effusion, or ascites): Rx +/- Sono
• NT-proBNP more than 1000 pg/ml or a BNP >250 pg/ml
• oral maintenance therapy with at least 40 mg of furosemide
or an equivalent dose (1 mg of bumetanide or 20 mg of
torasemide) for at least 1 month before randomization
• The main exclusion criteria: acetazolamide maintenance
therapy or treatment with another proximal tubular diuretic
including: SGLT2i and systolic blood pressure of less than
90mmHg; eGFR < 20 ml/min per 1.73 m2 BSA and i.v. -loop
diuretics > 80mg of furosemide equivalent during the index
hospitalization
The characteristics of the patients at baseline were well
balanced between the two groups
 ADVOR
Patients

Congestion score: scale from 0 to 10

degree of edema (0 to 4)
pleural effusion (0 to 3)
ascites (0 to 3)
ADVOR
Study Design and Randomization
At randomization
• At the moment of randomization, oral loop diuretics are stopped and the patient receives an IV
bolus of loop diuretics at a dose equal to the double of his oral daily maintenance dose with a
maximal dose of 5 mg bumetanide (=200 mg furosemide). Bumetanide is the preferred loop diuretic
agent to be used in this trial.
• Conversion factor:
1 mg bumetanide po = 1 mg bumetanide IV
40 mg furosemide po = 40 mg furosemide IV
20 mg torsemide po = 40 mg furosemide IV = 1 mg bumetanide IV

START DOSE (IV) = 2 x orally daily maintenance dose of loop diuretics (max. 5 mg of
bumetanide)
+
500 mg acetazolamide or placebo
 ADVOR
Trial Procedures
• diuretic protocol, a timed urine collection
• If the cumulative urinary output less than 3.5 liters and signs of fluid
overload were still present, an escalation of decongestive th
• congestion score: scale from 0 to 10
degree of edema (0 to 4)
pleural effusion (0 to 3)
ascites (0 to 3)
calculated before the administration of the morning dose of diuretics during the
treatment phase, at discharge, and during 3 months of follow-up.
 ADVOR
Trial Procedures

• Assigned in a 1:1 ratio to receive an intravenous bolus of

acetazolamide (500 mg once daily) or matching placebo
• Randomization: automated, Web-based system,per-muted
blocks, stratification according to the left ventricular ejection
fraction (≤40% or >40%) and trial center
• Immediately and during the next 2 days or until the occurrence
of complete decongestion
• oral loop diuretics stopped
• intravenous loop diuretic at double the oral maintenance dose
(single bolus immediately after randomization and split into
two doses on each of the next 2 days)
• The bolus of acetazolamide or matching placebo was
administered simultaneously with the first dose of loop
diuretics each day
• All the patients: maintenance infusion with 500 ml of 5%
dextrose and 3 g of magnesium sulfate/24h
 ADVOR
End Points
• The primary end point:
successful decongestion, within 3 days after randomization
(score)
• Key secondary end points:
the composite end point of death from any cause or
rehospitalization for heart failure during 3 months of follow-up
and the duration of the index hospital admission (i.e., the
number of days from randomization until the date of discharge)
• Exploratory tertiary end points
death from any cause and rehospitalization for heart failure
during 3 months of follow-up
• Data regarding adverse events
severe metabolic acidosis (BIC <12mmol/l), renal events (eGFR
50% reducion), hypokalemia (3mmol/l), and hypotension
(sys.<85mmHg)
 ADVOR
Primary End Points
Dropout after randomization:
only 4 patients - did not receive the assigned
acetazolamide or placebo

one owing to the patient’s decision

one owing to the physician’s decision
one who was withdrawn because the patient did not
meet the inclusion criteria
one patient withdrew informed consent)
 ADVOR
Primary End Points
 ADVOR
Primary End Points
 ADVOR
Secondary End Points

The duration of the index hospitalization:

8.8 days (95% CI, 8.0 to 9.5) in the acetazolamide group and
9.9 days (95% CI, 9.1 to 10.8) in the placebo group

Death from any cause or rehospitalization for

heart failure

76 of 256 patients (29.7%) in the acetazolamide group and in

72 of 259 patients (27.8%) in the placebo group (hazard
ratio, 1.07; 95% CI, 0.78 to 1.48)

Safety and Adverse Events

Safety was assessed in the 515 patients (99%) who received
acetazolamide or placebo
 ADVOR
Results – Subgroup Analysis
.
 ADVOR
Discussion
•In this multicenter, randomized, placebo-controlled trial
•Acute decompensated heart failure and volume overload-addition of acetazolamide to standardized intravenous loop-
diuretics: higher incidence of successful decongestion within 3 days after randomization
•More diuresis and natriuresis, had a shorter hospital stay, and were more likely to be discharged without residual signs
of volume overload
•There did not appear to be a higher incidence of adverse events with acetazolamide treatment
•Higher percentage of patients being discharged from the hospital without residual congestion (difference vs. placebo,
16.3 percentage points)
•Sustained increase in diuresis and natriuresis that were associated with the addition of acetazolamide
•The use of natriuresis as an indicator of diuretic respons
•The improvement with regard to successful decongestion with acetazolamide was generally consistent across all the
prespecified subgroups

However, the risk of death from any cause or rehospitalzation for heart failure (secondary
composite end point) did not differ significantly between the two trial groups
 ADVOR
Discussion - Limitations
• Nearly all the patients who participated in the trial were White -recruited exclusively in Belgium -
generalizability???
• Patients also had a history of chronic heart failure and had been receiving long-term outpatient treatment
with at least 40 mg of furosemide equivalent - applicable to patients with newly diagnosed heart
failure???
• Two trial groups received similar standardized loop diuretics - similar results may have been obtained with
other dose regimens of loop diuretics?
• The congestion score that was used for the assessment of the primary end point focused on the presence of
edema in the lower limb, pleural effusion, and ascites — findings - only extracellular volume overload
• SGLT2 inhibitors were not indicated - natriuretic and diuretic effects on the proximal tubules, their mode
of action and potency differ substantially from acetazolamide (5% of proximal sodium uptake is mediated
by SGLT2, whereas 60% is mediated by the apical sodium–hydrogen exchange that is inhibited by
acetazolamide)
• Follow-up time? Too short?
 ADVOR

Danke für Eure Aufmerksamkeit….

Time for Q and A…

Manneken Pis, famous fountain statue in Brussels, Belgium

Unnecessary to Champagner-
know… but still
Blues???
• Earl Carstens und seine Kollegen von der University of California in Davis
machten ihre Entdeckung mit Hilfe von Acetazolamid, einem Medikament, das
zur Bekämpfung von Höhenkrankheit eingenommen wird. Eine der
Nebenwirkungen des Medikamentes ist, daß es das durch kohlensäurehaltige
Getränke verursachte Prickeln dämpft…
• Probanden - Zungen 15 Sekunden lang in kohlensäurehaltiges Wasser gesteckt
• Dann die Hälfte der Zunge jedes Freiwilligen mit Acetazolamid bedeckt und das
Experiment wiederholt
• Auf der mit dem Medikament überzogenen Seite war die Empfindung eines
Prickelns bedeutend geringer
Carboanhydrase, ein Enzym, das Kohlendioxid in Kohlensäure umwandelt – der
sprudelnde Reiz