Randomized, open-label, blinded-endpoint, crossover, single-dose study to compare the pharmacodynamics of torasemide-PR 10 mg, torasemide-IR 10 mg, and furosemide-IR 40 mg, in patients with chronic heart failure

Abstract

PurposeDiuretics are the primary treatment for the management of chronic heart failure (HF) symptoms and for the improvement of acute HF symptoms. The rate of delivery to the site of action has been suggested to affect diuretic pharmacodynamics. The main objective of this clinical trial was to explore whether a prolonged release tablet formulation of torasemide (torasemide-PR) was more natriuretically efficient in patients with chronic HF compared to immediate-release furosemide (furosemide-IR) after a single-dose administration. Moreover, the pharmacokinetics of torasemide-PR, furosemide-IR, and torasemide-IR were assessed in chronic HF patients as well as urine pharmacodynamics.MethodsRandomized, open-label, blinded-endpoint, crossover, and single-dose Phase I clinical trial with three experimental periods. Torasemide-PR and furosemide-IR were administered as a single dose in a crossover fashion for the first two periods, and torasemide-IR 10 mg was administered for the third period. Blood and urine samples were collected at fixed timepoints. The primary endpoint was the natriuretic efficiency after administration of torasemide-PR and furosemide-IR, defined as the ratio between the average drug-induced natriuresis and the average drug recovered in urine over 24 hours.ResultsTen patients were included and nine completed the study. Here, we present the results from nine patients. Torasemide-PR was more natriuretically efficient than furosemide-IR (0.096±0.03 mmol/μg vs 0.015±0.0007 mmol/μg; P<0.0001). Mictional urgency was lower and more delayed with torasemide-PR than with furosemide-IR.ConclusionIn a study with a limited sample size, our results suggest that 10 mg of torasemide-PR is more natriuretically efficient than 40 mg of furosemide-IR after single-dose administration in patients with chronic HF over a 24-hour collection period. Further studies are necessary to evaluate potential pharmacodynamic differences between torasemide formulations and to assess its impact on clinical therapeutics.

Prognostic Impact of Loop Diuretics in Patients With Chronic Heart Failure – Effects of Addition of Renin-Angiotensin-Aldosterone System Inhibitors and β-Blockers –

“…We assumed that 60 mg azosemide is equivalent to approximately 40 mg furosemide 19 and 8 mg torasemide to approximately 40 mg furosemide, considering the smaller body mass index (BMI) of Japanese patients compared with the previous Western study. 20 …”

Comparative effectiveness of torasemide versus furosemide in symptomatic therapy in heart failure patients: Preliminary results from the randomized TORNADO trial

“…Heart failure patients on a stable dose of furosemide were randomized to the treatment with torasemide or unchanged treatment with furosemide (randomization 1:1). After randomization, furosemide has been continued in its current fixed-dose or was replaced by equipotential dose of torasemide (4:1, according to the previous studies and manufacturer's data [6]). Figure 1 shows the flow chart of the study design.…”

“…Moreover, torasemide potency is 4 times greater than furosemide. Torasemide also has anti-aldosterone activity and inhibits myocardial fibrosis and remodeling [4][5][6][7][8]. According to previous studies, torasemide decreases rates of HF hospitalizations and hospital stay, improves exercise tolerance, quality of life, left ventricular function, cardiac sympathetic nerve activity, myocardial fibrosis, pulmonary congestion, peripheral edema, and blood pressure compared with furosemide [9][10][11][12].…”

Pharmacokinetic and pharmacodynamic properties of orally administered torsemide in healthy horses

“…Once the active reabsorption of sodium, potassium, and chloride is blocked, diuresis is promoted by excretion of water, sodium, potassium, and chloride. Intravenously administered furosemide is commonly used to resolve pulmonary edema secondary to acute CHF, whereas PO administered diuretics are the mainstay for successful long‐term management of CHF . Diuretics also are indicated to increase urine output in horses with acute renal failure, oliguria, anuria, poisoning, envenomation, and severe hypercalcemia or hyperkalemia …”

“…Intravenously administered furosemide is commonly used to resolve pulmonary edema secondary to acute CHF, 5 whereas PO administered diuretics are the mainstay for successful longterm management of CHF. 6 Diuretics also are indicated to increase urine output in horses with acute renal failure, oliguria, anuria, 7 poisoning, envenomation, 8 and severe hypercalcemia 4 or hyperkalemia. 9 Torsemide is a high ceiling loop diuretic that is 10 times more potent than furosemide, and has a consistently high bioavailability after PO administration in humans and dogs.…”