Rao Veena S, Cox Zachary L, Ivey-Miranda Juan B, Neville Daniel, Balkcom Natasha, Moreno-Villagomez Julieta, Ramos-Mastache Daniela, Maulion Christopher, Bellumkonda Lavanya, Tang W H Wilson, Collins Sean P, Velazquez Eric J, Mentz Robert J, Wilson F Perry, Turner Jeffrey M, Wilcox Christopher S, Ellison David H, Fang James C, Testani Jeffrey M
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
Department of Pharmacy Practice, Lipscomb University College of Pharmacy, Nashville, Tennessee.
J Am Soc Nephrol. 2025 Jan 1;36(1):99-107. doi: 10.1681/ASN.0000000000000481. Epub 2024 Aug 28.
Oral torsemide was not superior to furosemide in measures of renal tubular delivery or duration of action. A dose equivalence of approximately 40 mg oral furosemide:10 mg oral torsemide resulted in similar natriuresis. The two-fold higher doses of torsemide did not improve fluid status due to the kidney’s compensation.
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.
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.
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%], < 0.001). Furosemide had a longer duration of kidney drug delivery and natriuresis ( ≤ 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 ( < 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 ( < 0.05 for all). Plasma volume ( = 0.52) and body weight ( = 0.89) did not improve with torsemide versus furosemide.
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.
: 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.
在肾小管输送或作用持续时间方面，口服托拉塞米并不优于呋塞米。口服呋塞米40mg与口服托拉塞米10mg的剂量等效性可导致相似的利钠作用。由于肾脏的代偿作用，两倍剂量的托拉塞米并未改善液体状态。
托拉塞米被认为在药代动力学和药效学方面比呋塞米具有重要的临床优势。然而，在心力衰竭管理中托拉塞米与呋塞米比较（TRANSFORM）随机试验中，临床结果并无差异。
我们对随机接受口服呋塞米或托拉塞米的心力衰竭患者进行了一项多中心机制亚研究（TRANSFORM - 机制试验）。在基线和30天时，参与者接受了药代动力学和药效学参数的详细评估。
TRANSFORM - 机制试验纳入了88名参与者。与呋塞米相比，托拉塞米的肾脏生物利用度，即输送到作用肾小管部位的剂量比例显著降低（中位数，17.1%[四分位间距，12.3% - 23.5%]对24.8%[16.6% - 34.1%]，<0.001）。呋塞米的肾脏药物输送和利钠作用持续时间更长（两者均≤0.004）。TRANSFORM - 机制试验中规定的呋塞米和托拉塞米剂量与TRANSFORM试验相似，临床医生平均使用2:1的药物剂量等效转换。然而，这些剂量导致托拉塞米的利钠作用显著增强（<0.001）。约4:1的剂量等效性可导致相似的利钠作用。托拉塞米组更高的利尿剂剂量导致肾功能轻度紊乱，肾素、醛固酮和去甲肾上腺素显著增加（所有均<0.05）。与呋塞米相比，托拉塞米并未改善血浆容量（P = 0.52）和体重（P = 0.89）。
我们观察到托拉塞米与呋塞米相比没有有意义的药代动力学/药效学优势。托拉塞米组更高利尿剂剂量带来的更大利钠作用被更大的神经激素激活和肾功能障碍所抵消。
TRANSFORM - HF：心力衰竭管理中托拉塞米与呋塞米比较（TRANSFORM - HF），NCT03296813；稳定心力衰竭患者管理中托拉塞米与呋塞米比较（TFO），NCT05093621。
Zotero 插件