Acetazolamide as a Decongestion Strategy in Acute Decompensated Heart Failure: Balancing Fluid Removal and Electrolyte Disturbances

This article refers to ‘Sodium and potassium changes during decongestion with acetazolamide – A pre-specified analysis from the ADVOR trial’ by S. Dhont et al., published in this issue on pages 1310–1319. Heart failure (HF) is a global public health problem with about one-third of Europeans developing HF over the age of 55.1, 2 Furthermore, hospitalizations for HF account for over a million admissions annually in Europe and may carry a risk of mortality as high as 20–30% in the subsequent year.3, 4 A major component of inpatient HF management is volume control, and patients often struggle with residual congestion at discharge resulting in impairments in quality of life and functional limitations as an outpatient.5, 6 Currently, there is a lack of evidence-based decongestion strategies and clearly defined endpoints to guide treatment duration, although loop diuretics remain the cornerstone of inpatient HF management. The Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial evaluated the efficacy and safety of acetazolamide as an adjunct to loop diuretic therapy in patients with acute decompensated HF (ADHF) compared to usual standard of care. In short, the patients randomly assigned to receive acetazolamide reached successful clinical decongestion on day 3, as well as had a shorter length of stay, but did not have a meaningful difference in rehospitalization for HF or all-cause mortality at 3 months. Furthermore, there was no evidence of clinically significant hypokalaemia or hyponatraemia when treated with acetazolamide in addition to loop diuretics.7-9 The ADVOR study was a multicentre, double-blind, randomized controlled trial set across 27 sites in Belgium between 2018 and 2022.7-9 Patients were eligible for enrolment if they were adult patients >18 years admitted for ADHF and presented with (i) more than one clinical sign of volume overload (i.e. defined as >2+ pitting oedema, ascites on ultrasound, or pleural effusion on chest X-ray), (ii) elevated natriuretic peptide, and (iii) prior low-dose oral maintenance diuretic therapy for more than 1 month, which was defined as 40mg of furosemide or an equivalent dose (1mg bumetanide or 20mg torsemide). Patients were excluded if they had newly diagnosed HF (i.e. de novo), were on sodium–glucose cotransporter 2 inhibitor therapy, or if they received higher doses of intravenous loop diuretics during hospitalization, which was defined as either >2 mg bumetanide, >80 mg furosemide, or >20 mg torsemide. Patients received either 500 mg acetazolamide once daily or matching placebo, both in addition to the standardized loop diuretic therapy, which was twice the oral daily home dose administered intravenously. The primary endpoint was defined as successful decongestion (i.e. defined as the absence of signs of volume overload) within 3 days after randomization and without indication for escalation of decongestive therapy. A total of 519 patients were enrolled in the ADVOR trial, with a mean age of 78.2 ± 8.9 years, 37.4% female patients, and 99.0% of participants self-reporting as non-Hispanic White. The mean left ventricular ejection fraction (LVEF) was 43 ± 15%, with 43.2% of patients having a LVEF <40%, and 87.3% of patients reported New York Heart Association (NYHA) functional class III or IV symptoms. At 3 days, 42.2% in the acetazolamide group reached the primary endpoint (i.e. successful decongestion) compared to 30.5% of patients in the placebo group (risk ratio [RR] 1.46, 95% confidence interval [CI] 1.17–1.82; p < 0.001), and length of stay was 1.1 days shorter in the acetazolamide group (9.9 vs. 8.8 days; RR 0.89, 95% CI 0.81–0.98; p = 0.02). The results remained robust in a pre-specified sensitivity analysis excluding the component of need for escalation therapy in the primary endpoint (successful decongestion: 44.9% acetazolamide vs. 33.2% placebo). There were no statistically significant differences in adverse events (i.e. hypotension, hypokalaemia, acute kidney injury, etc.), rehospitalization, or all-cause mortality at 3 months. In this issue of the Journal, Dhont et al.10 performed a secondary analysis to elucidate if acetazolamide affects serum sodium and potassium levels when used in conjunction with loop diuretics, and if baseline electrolyte values impact the efficacy and/or safety of acetazolamide. Electrolyte abnormalities frequently accompany decongestion therapy, which is observed due to the mechanism of action of loop diuretics. By blocking the Na-K-2Cl cotransporter in the loop of Henle, sodium and potassium cannot be resorbed, which facilitates water excretion.11 Additionally, the increased sodium delivery in the collecting duct results in further potassium loss. While the desired effect of fluid loss is key to decongestion, both loop and thiazide-type diuretics exacerbate electrolyte loss. Close electrolyte monitoring is crucial to correct hypokalaemia, which if left untreated can lead to unstable cardiac arrhythmias. Furthermore, electrolyte abnormalities are often a barrier to achieving adequate decongestion therapy, and hypokalaemia has been associated with a worse overall prognosis.12 In this pre-specified secondary analysis, the investigators' primary objectives were to determine if baseline sodium and potassium levels impacted acetazolamide therapeutic benefit, and if there was an increased risk for hypokalaemia or hyponatraemia with acetazolamide as an adjunct to loop diuretic therapy. At randomization, mean potassium and sodium levels were 4.2 ± 0.6 and 139 ± 4 mmol/L in the acetazolamide arm versus 4.2 ± 0.6 and 140 ± 4 mmol/L in the placebo arm, respectively. The presence of hypokalaemia (i.e. defined as <3.5 mmol/L) on admission in either treatment group was not associated with any clinical outcome overall and in adjusted demographic subgroup analyses. Although the decrease in serum potassium levels during decongestion was marginally greater in the acetazolamide arm compared to placebo (0.4 ± 0.3 mmol/L vs. 0.2 ± 0.2 mmol/L, p = 0.022) the between-group difference was completely attenuated at 3 months (p = NS). Finally, severe hypokalaemia (i.e. defined as <3.0 mmol/L) occurred in only 7 (1%) patients between the two treatment groups (p = 0.676). Acetazolamide, a carbonic anhydrase inhibitor, acts in the proximal convoluted tubule (PCT) of the nephron.7-9 In the PCT, hydrogen secretion is closely tied to sodium resorption; carbonic anhydrase is found in both the nephron lumen and PCT to increase hydrogen ion production. By blocking carbonic anhydrase, the hydrogen ion gradient is disrupted and the sodium–hydrogen exchanger becomes non-functional and results in natriuresis and subsequently, diuresis. Acetazolamide also increases the excretion of bicarbonate ions, leading to a metabolic acidosis. This effect may be useful in the management of certain medical conditions, such as metabolic alkalosis, which is frequently seen in loop diuretic therapy. The main lesson learned from the ADVOR trial is that acetazolamide improves symptoms faster than loop therapy alone, without an increased adverse event profile. This is in contrast to other prior trials that aimed to evaluate the role of other adjunctive diuretics, all of which showed either that adjunctive therapies were not effective or that they had an increased risk of treatment-limiting side effects (Table 1).13-15 While the data presented in the ADVOR trial support the notion that acetazolamide may be both effective and safe in comparison to other adjunctive therapies, there are a few key limitations that are worth identifying. Notably, patients enrolled in this trial were on electrolyte replacement scales, with 3 g intravenous magnesium sulfate given daily and 40 mmol of potassium chloride if potassium was <4 mmol/L, but data were not collected on what quantities or how frequently electrolytes needed to be repleted while receiving decongestion therapy. However, these data suggest that there is likely minimal additional risk of electrolyte abnormalities when using acetazolamide if proactive monitoring and appropriate repletion goals are set. Furthermore, the risk of electrolyte abnormalities may be appreciably higher in real-world settings outside the context of a trial with pre-specified laboratory testing. Another aspect worth highlighting is the short duration of acute decongestion therapy. The management of decongestion in the acute versus chronic HF setting may differ, and the findings from the ADVOR study should not be generalized to ambulatory populations or for long-term use. Finally, this study population was relatively homogeneous, with 99% of participants identifying as non-Hispanic White, and the response to decongestion therapy may vary based on race and ethnicity. ADVOR is a rigorous randomized controlled trial establishing acetazolamide as both a safe and effective adjunct to standard decongestion therapy for ADHF. Although electrolyte abnormalities and acute kidney injury are often a barrier to adequate decongestion therapy, acetazolamide may be safely added to loop diuretics with proactive monitoring and electrolyte repletion. However, the frequency and dosing required to mitigate the risk of electrolyte abnormalities outside of the context of a clinical trial require further investigation. Future clinical trials with larger sample sizes that are adequately powered are necessary to clarify the impact of acetazolamide and other decongestion strategies on patient-reported outcomes (i.e. health-related quality of life) and clinical endpoints (i.e. hospitalizations and mortality). Conflict of interest: Z.B. has nothing to disclose. A.P.A. is supported by a Mentored Patient-Oriented Research Career Development Award (K23HL150159) through the National Heart, Lung, and Blood Institute and has received relevant research support through grants to his institution from Abbott, Amarin Pharma, Edwards Lifesciences, Esperion, Lexicon, and Novartis.