Furosemide Versus Torsemide: May the Highest Dose Win!

Since furosemide first gained US Food and Drug Administration approval in 1966, loop diuretics have been central to the role of the management of heart failure. In nearly 60 years, there has been significant development in the pharmacologic treatment of heart failure. However, furosemide remains the dominant loop diuretic on the market, followed by bumetanide and torsemide (1). There has been accumulating data that torsemide has a superior pharmacologic profile to furosemide, including increased and more consistent bioavailability, a significantly longer half-life, and favorable effects on neurohormones such as decreased aldosterone (2). This has led to speculation as to the superiority of torsemide compared with other available loop diuretics. The recently published TRANSFORM-HF (Torsemide Comparison With Furosemide for Management of Heart Failure) trial sought to answer this question by examining all-cause mortality in 2859 patients who were hospitalized across 60 hospitals in the United States in cohorts randomized to torsemide versus furosemide, demonstrating no significant difference (3). This culminated into reconsideration of the possible pharmacologic benefits of torsemide over furosemide. The TRANSFORM-Mechanism (Torsemide Comparison With Furosemide for Management of Patients With Stable Heart Failure) trial was designed to investigate the pharmacodynamic differences between these two drugs (4).

The TRANSFORM-Mechanism substudy randomized patients 1:1 to oral furosemide versus oral torsemide. Eighty-eight patients were enrolled from July 2019 to March 2022 via the TRANSFORM-HF trial and the TRANSFORM-Outpatient parent study (3). During the TRANSFORM-Mechanism study, clinicians largely used a 2:1 dosing conversion for furosemide to torsemide. In the study, excretion of the unchanged diuretic was measured using liquid chromatography with more furosemide (median, 24.8% [interquartile range, 16.6%–34.1%]) recovered in the urine than torsemide (median, 17.1% [interquartile range, 12.3%–23.5%]), suggesting higher kidney bioavailability of furosemide. As expected, furosemide had a slower onset of action and prolonged delivery versus torsemide, with a greater percentage of drug excreted after the initial 2 hours (p = 0.003). Notably, oral dosing equivalence was found to be 4:1 when comparing the natriuretic effect of furosemide versus torsemide rather than the 2:1 conversion used in the study. Higher torsemide doses did result in higher natriuresis, but this was accompanied by higher neurohormonal activation with significant increases in aldosterone (p = 0.002), renin (p < 0.001), and norepinephrine (p = 0.039). In other words, the neurohormonal activation negated the diuretic effects of torsemide, as there was an absence of differences in blood volume or body weight at 30 days compared with furosemide.

The TRANSFORM-Mechanism trial demonstrated the importance of kidney-specific bioavailability. Despite greater availability of torsemide in the blood, this did not reflect delivery of the drug to the luminal side of the kidney tubular epithelium, which determines the natriuretic effect. This may be secondary to the hepatic metabolism of torsemide affecting its overall delivery to the tubule. Furthermore, furosemide's slower gastrointestinal absorption may prove advantageous, given that it minimizes the effect of its short half-life. A prior study with extended-release preparations of torsemide demonstrated greater natriuretic effects with greater preservation of kidney function (5). Furosemide's slower onset of action may be beneficial compared with torsemide's rapid onset of action. In terms of real-world clinical use, TRANSFORM-Mechanism demonstrated that furosemide's diuretic effects were similar to torsemide when dosed in a 4:1 ratio.

The limitations of the study were that this was an open-label trial, influencing clinician and patient bias, involving both hospitalized and stable outpatients (which could affect pharmacodynamic results), and had unsupervised 24-hour urine collection. Overall, this study dispels the belief that torsemide is superior to furosemide and reiterates that ultimately, it is the dosing of the diuretic that should take precedence over the choice of the loop diuretic.

View Full Size

• Download Figure
• Download figure as PowerPoint slide