Washington University Emergency Medicine Journal Club– February 23rd, 2022
You are working a steady shift in EM-2 one Friday afternoon when you encounter Mr. X, a 50-year-old gentleman with a history of congestive heart failure who presents with 2 days of worsening bilateral lower extremity edema, dyspnea on exertion, and orthopnea. He reports compliance with his home medications, including his diuretic (furosemide 40 mg daily), but does report a higher salt intake over the last few days as he was celebrating his birthday (hamburger, French fries, barbecue ribs, and a huge bowl of ramen).
Mr. X’s vitals are as follows:
BP 156/89 HR 86 Temp 36.8 RR 18 O2 sat 92% ORA
His lab work reveals a serum sodium of 147 mmol/L, a troponin < 6 ng/L, and pro-BNP of 3000. Review of records reveals an echocardiogram 6 months previously on which his ejection fraction was 40%.
You elect to initiate diuresis with IV furosemide (initial dose 80 mg) but remember hearing about a recent article that suggested some benefit from the addition of acetazolamide for acute decompensated heart failure (https://rebelem.com/the-advor-trial-acetazolamide-in-acute-decompensated-heart-failure). After the patient is admitted to the cardiology service, you decide to review the article yourself and see what other literature there is on this subject…
Adult patients admitted to the hospital for decompensated heart failure requiring diuresis
Intervention: Addition of acetazolamide to inpatient diuretics
Comparison: Monotherapy with IV loop diuretics
Outcome: Improved diuresis, change in daily weight, improvement in symptoms of volume overload (dyspnea, extremity edema, abdominal ascites), hospital length of stay, patient satisfaction, acute renal failure, need for renal replacement therapy
PubMed was searched using the terms acetazolamide AND “heart failure” which
resulted in 235 citations (https://tinyurl.com/tzwc7srv). Of these, the four most
relevant articles were selected for inclusion.
Article 1: Mullens W, Dauw J, Martens P, Verbrugge FH, Nijst P, Meekers E, Tartaglia K, Chenot F, Moubayed S, Dierckx R, Blouard P, Troisfontaines P, Derthoo D, Smolders W, Bruckers L, Droogne W, Ter Maaten JM, Damman K, Lassus J, Mebazaa A, Filippatos G, Ruschitzka F, Dupont M, ADVOR Study Group. Acetazolamide in acute decompensated heart failure with volume overload. New Engl J Med. 2022;387(13):1185-95. Answer Key.
Article 2: Martens P, Dauw J, Verbrugge FH, Nijst P, Meekers E, Augusto SN Jr, Ter Maaten JM, Damman K, Mebazaa A, Filippatos G, Ruschitzka F, Tang WHW, Dupont M, Mullens W. Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Prespecified Analysis From the ADVOR Trial. Circulation. 2023 Jan 17;147(3):201-211. doi: 10.1161/CIRCULATIONAHA.122.062486. Epub 2022 Nov 6. PMID: 36335479. Answer Key.
Article 3: Imiela T, Budaj A. Acetazolamide as Add-on Diuretic Therapy in Exacerbations of Chronic Heart Failure: a Pilot Study. Clin Drug Investig. 2017 Dec;37(12):1175-1181. doi: 10.1007/s40261-017-0577-1. PMID: 28965280; PMCID: PMC5684277. Answer Key.
Article 4: Verbrugge FH, Martens P, Ameloot K, Haemels V, Penders J, Dupont M, Tang WHW, Droogné W, Mullens W. Acetazolamide to increase natriuresis in congestive heart failure at high risk for diuretic resistance. Eur J Heart Fail. 2019 Nov;21(11):1415-1422. doi: 10.1002/ejhf.1478. Epub 2019 May 9. PMID: 31074184. Answer Key.
The 2022 ACEP clinical policy on management of adult patients with congestive heart failure (CHF) recommends the use of loop diuretics to increase renal sodium and water excretion (natriuresis and diuresis, respectively) with concomitant reduction of preload on the heart. While there is no mention of adjunct use of acetazolamide to help promote natriuresis and diuresis, there have been a handful of recent papers suggesting a possible benefit in this patient population. Acetazolamide reduces sodium reabsorption in the proximal renal tubules, theoretically leading to increased sodium excretion and improved diuresis (Mullens 2019). We looked at a handful of studies assessing the clinical benefit to the addition of acetazolamide to loop diuretics for patients admitted with decompensated heart failure, with primary emphasis on the results of the most recent ADVOR trial.
Two small studies published in 2017 and 2019 (Imiela 2017, Verbrugge 2019) evaluated the addition of acetazolamide to diuresis in small patient populations in Poland and Belgium, respectively. Neither study found a significant improvement in natriuresis or diuretic volume. While there was a trend toward higher rates of euvolemia within 72 hours with high-dose loop diuretics compared to combination therapy in the 2019 paper (22% vs. 38%), this study was vastly underpowered and this difference was not statistically significant.
The more recent ADVOR trial was a large, multi center study conducted in Belgium between November 11, 2018 and January 17, 2022 (Mullens 2022). All patients received a loop diuretic at twice the home maintenance dose, and were randomized to receive either placebo or a 500 mg bolus of IV acetazolamide daily. The primary outcome—successful diuresis, defined as the absence of signs of volume overload as assessed by a cardiologist trained in completion of a novel congestion score—occurred more frequently in the acetazolamide group (42.2%) than the monotherapy group (30.5%): RR 1.46, 95% CI 1.17 to 1.82. There was no difference in mortality between groups, and a statistically nonsignificant trend toward higher rates of adverse renal events was seen in the combined therapy group (2.7% vs. 0.8%). There was also a small reduction in hospital length of stay with the use of acetazolamide (difference 0.89 days, 95% CI 0.81 to 0.98). The primary limitations of the study were the use of a non-validated congestion score, without assessment of inter-rater reliability, and completion of the study in Belgium alone. Differences in provision of healthcare, especially in the outpatient setting, make it difficult to generalize these results to similar centers in the US (external validity).
A secondary analysis of the ADVOR trial was subsequently undertaken to assess the results across the spectrum of heart failure patients (Martens 2023). Patients were analyzed based on dichotomized baseline left ventricular ejection fraction (≤ 40% and > 40%) as well as heart failure categories: HFrEF (LVEF ≤40%), HFmrEF (LVEF 41% to 49%), and HFpEF (LVEF >50%). While the primary endpoint occurred more frequently in the acetazolamide group across all subgroups of LVEF, it is interesting to note that this difference only achieved statistical significance for those with more maintained ejection fracture. For those with an EF > 40% the odds ratio was 1.98 (95% CI 1.22-3.21); for those with HFpEF, the odds ratio was 2.15 (95% CI 1.16-4.00). While the initial two studies evaluated were limited by small sample size, the subsequent ADVOR trial showed promising results suggesting improved “decongestion” with the addition of acetazolamide to standard treatment with loop diuretics for heart failure exacerbation. This study was primarily limited by the use of a nonvalidated scoring system for the primary outcome and conduction in a single country. Overall, the current data data were isolated to patients in Belgium and Poland, two heterogenous patient populations in Central Europe. Additional research in disparate populations (particularly the US) with objective, validated outcomes would help clinicians decide whether addition of acetazolamide to traditional diuretic regimens would be beneficial in our patient population.