Mechanistic Differences between Torsemide and Furosemide

Abstract

Key Points:

1. Oral torsemide was not superior to furosemide in measures of renal tubular delivery or duration of action.

2. A dose equivalence of approximately 40 mg oral furosemide:10 mg oral torsemide resulted in similar natriuresis.

3. The two-fold higher doses of torsemide did not improve fluid status due to the kidney’s compensation.

Background: Torsemide is proposed to have clinically important pharmacokinetic and pharmacodynamic advantages over furosemide. However, clinical outcomes did not differ in the Torsemide Comparison with Furosemide for Management of Heart Failure (TRANSFORM) randomized trial.

Methods: We conducted a multicenter mechanistic substudy of patients with heart failure randomized to oral furosemide or torsemide (TRANSFORM-Mechanism trial). At baseline and 30 days, participants underwent detailed assessments of pharmacokinetic and pharmacodynamic parameters.

Results: The TRANSFORM-Mechanism trial enrolled 88 participants. Kidney bioavailability, or the proportion of dose delivered to the tubular site of action, was significantly less with torsemide compared with furosemide (median, 17.1% [interquartile range, 12.3%–23.5%] versus 24.8% [16.6%–34.1%], P < 0.001). Furosemide had a longer duration of kidney drug delivery and natriuresis (P ≤ 0.004 for both). Prescribed doses of furosemide and torsemide in the TRANSFORM-Mechanism trial were similar to the TRANSFORM trial, with clinicians on average using a 2:1 dose equivalence conversion between drugs. However, these doses resulted in a substantially greater natriuresis with torsemide (P < 0.001). A dose equivalence of approximately 4:1 resulted in similar natriuresis. Higher diuretic doses in the torsemide group resulted in mild perturbations in kidney function and significant increases in renin, aldosterone, and norepinephrine (P < 0.05 for all). Plasma volume (P = 0.52) and body weight (P = 0.89) did not improve with torsemide versus furosemide.

Conclusions: We observed no meaningful pharmacokinetic/pharmacodynamic advantages for torsemide versus furosemide. The greater natriuresis from higher diuretic doses in the torsemide group was offset by greater neurohormonal activation and kidney dysfunction.

Clinical Trial registry name and registration number:: TRANSFORM-HF: ToRsemide compArisoN With furoSemide FORManagement of Heart Failure (TRANSFORM-HF), NCT03296813; Torsemide Comparison With Furosemide for Management of Patients With Stable Heart Failure (TFO), NCT05093621.

Graphical abstract

Figure 1

Pharmacokinetics of oral furosemide and torsemide. (A) Furosemide displayed greater kidney bioavailability, defined as the percentage of the oral dose excreted unchanged in urine during the timed urine collection (i.e., diuretic delivered to the site of action), compared with torsemide. (B) Kinetics of diuretics reaching the urinary site of action displayed as the percentage of total kidney delivery over time. Furosemide had a significantly slower initial onset of delivery to urine, followed by a longer duration of delivery. The number of urine samples analyzed at each time point, and when a urine sample was not available, the median volume of urine in the bladder (quantitated by formal bladder ultrasound) was HR1: n=134, 28 ml (1–90 ml); H2: n=123, 26 ml (0–181 ml); HR4: n=132, 41 ml (0–98 ml); HR6: n=97, 1 ml (0–36 ml); and HR8: n=91, 37 ml (3–98 ml). Results were consistent across various sensitivity analyses (Figure 1B and Supplemental Statistical Analysis Methods). Data are presented as median (IQR) and mean±SEM of the mean in (A) and (B), respectively. (C) Population variability in kidney bioavailability between patients expressed as interleaved histograms. (D) Variability in kidney bioavailability within individual patients from baseline to the 30-day visit. (C and D) Standardized data with mean (0) and SDs from the mean; P values represent comparisons of distributions between treatment groups. IQR, interquartile range.

Figure 2

Oral diuretic dose equivalence. (A) Quantity of loop diuretic administered using a 2:1 equivalence ratio for furosemide to torsemide was similar. (B) However, the observed natriuresis was substantially greater with torsemide. (C) The oral dose equivalence ratio of furosemide to torsemide is varied from 2:1 to 5:1; diuretic response is equivalent with approximately a 4:1 ratio. *FENa diuretic efficiency represents the increase in FENa per 2× increase in diuretic dose. Data are presented as median (IQR) (A and B) and mean±SEM of the mean (C). FENa, fractional excretion of sodium.

Figure 3

Pharmacodynamics of oral furosemide and torsemide. (A) Torsemide produced a greater cumulative sodium excretion (mmol) over the entire study visit. (B) Natriuresis over time with each drug is shown. Torsemide produced a greater proportion of its total sodium excretion during the first 2 hours compared with furosemide. After hour 2, furosemide produced a greater proportion of its natriuresis compared with torsemide. Data are presented as median (IQR) (A) and mean±SEM of the mean (B).

Figure 4

Change in plasma norepinephrine, total renin, and aldosterone from baseline to 30 days. Data are presented as median (IQR).

Figure 5

Change in blood volume, plasma volume, and body weight from baseline to 30 days. Data are presented as median (IQR).