Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Prespecified Analysis From the ADVOR Trial

Abstract

Background: Acetazolamide inhibits proximal tubular sodium reabsorption and improved decongestion in the Acetazolamide in Decompensated heart failure with Volume OveRload (ADVOR) trial. It remains unclear whether the decongestive effects of acetazolamide differ across the spectrum of left ventricular ejection fraction (LVEF). Methods: This is a pre-specified analysis of the randomized, double blind, placebo-controlled ADVOR trial that enrolled 519 patients with acute heart failure, clinical signs of volume overload (edema, pleural effusion or ascites), NTproBNP >1,000 ng/L or BNP >250 ng/ml, to receive intravenous acetazolamide (500 mg once daily) or placebo on top of standardized intravenous loop diuretics (twice oral home maintenance dose). Randomization was stratified according to LVEF (≤40% or >40%). The primary endpoint was successful decongestion, defined as the absence of signs of volume overload within three days from randomization without the need for mandatory escalation of decongestive therapy because of poor urine output. Results: Median LVEF was 45% (25-75 th percentile: 30-55%) and 43% had a LVEF ≤40%. Patients with lower LVEF were younger, more likely to be male, with a higher prevalence of ischemic heart disease, a higher NTproBNP, less atrial fibrillation, and lower estimated glomerular filtration rate. No interaction on the overall beneficial treatment effect of acetazolamide on the primary endpoint of Successful decongestion (OR=1.77, 95% CI=[1.18-2.63], p=0.005, all p-values for interaction >0.401) was found when LVEF was assessed per randomization stratum (≤/ >40%), or as HFrEF, HFmrEF and HFpEF, or on a continuous scale. Acetazolamide resulted in improved diuretic response measured by higher cumulative diuresis and natriuresis and shortened length of stay without treatment effect modification by baseline LVEF (all p-values for interaction >0.160). Conclusions: Acetazolamide when added to treatment with loop diuretics in patients with AHF improves the incidence of successful decongestion, improves diuretic response and shortens length of stay, without treatment effect modification by baseline LVEF.

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes

“…Yet, assuming that the effect of SGLT2 inhibitor on volume homeostasis occur and are durable, it is difficult to know if treatmentmediated changes in the volume set point (if any) contribute to the effect of these drugs to reduce the risk of major heart failure events. Short-or long-term use of many conventional natriuretic and aquaretic drugs has not reduced cardiovascular death or hospitalizations for heart failure, 136,[138][139][140]157 demonstrating that immediate changes in urinary sodium or water excretion do not yield long-term clinical benefits. It is possible that the effects of SGLT2 inhibitors on sodium avidity may differ from other agents, but the volume effect of these drugs is small.…”

“…Although intensive short-term diuresis to achieve hemoconcentration in hospitalized patients is associated with lower cardiac filling pressures, 153 early decongestion has not been associated with improved outcomes in observational studies or clinical trials. 138–141,154,155 More intensive treatment with intravenous loop diuretics yields a greater short-term diuresis, but does not reduce heart failure events at 60 days. 138 The addition of hydrochlorothiazide to a loop diuretic yields a modest diuretic effect, but no effect on death or rehospitalization at 90 days.…”

Decongestion (instead of ultrafiltration?)

“…Posthoc analyses suggested that the observed decongestive effects of acetazolamide were chiefly mediated by its effect on natriuresis [36 & ]. Acetazolamide use increased the chance of successful decongestion across the entire spectrum of left ventricular ejection fraction [37]. Its use in the ADVOR trial prevented the development of loop diuretic induced metabolic alkalosis, which reflects neurohumoral activation and might play an important role in the occurrence of diuretic resistance [38].…”

Improving therapeutic outcomes in heart failure with reduced nonvalvular ejection fraction: A clinical study of heart failure education intervention

“…9,10 In cases of HF with reduced nonvalvular ejection fraction, timely and effective treatment is essential, as failure to control the condition promptly may lead to complications that severely jeopardize the patients' life. 11 While medications for treating HF with reduced nonvalvular ejection fraction can provide temporary relief of clinical symptoms in patients, their long-term treatment outcomes are not always optimal, impacting patients' prognosis and overall quality of life. [12][13][14] Following HF education intervention, the treatment outcomes for HF patients showed significant improvement, aligning with findings from previous studies.…”