s 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....

中文翻译：

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托拉塞米和呋塞米之间的机理差异


由于肾脏的代偿。背景 托拉塞米被认为比呋塞米具有临床上重要的药代动力学和药效学优势。然而，在托拉塞米与呋塞米治疗心力衰竭 （TRANSFORM） 随机试验中，临床结局没有差异。方法 我们对随机分配至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子研究 （TRANSFORM-Mechanism 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。结果 TRANSFORM-Mechanism 试验招募了 88 名参与者。与呋塞米相比，托拉塞米的肾脏生物利用度或输送到肾小管作用部位的剂量比例显着降低（中位数，17.1% [四分位距，12.3%–23.5%] 对 24.8% [16.6%–34.1%]，P < 0.001）。呋塞米的肾脏药物输送和利钠持续时间更长 （P ≤ 0.004）。TRANSFORM-Mechanism 试验中处方剂量的呋塞米和托拉塞米与 TRANSFORM 试验相似，临床医生平均使用药物之间的 2：1 剂量等效转换。然而，这些剂量导致托拉塞米的利钠作用明显增加 （P < 0.001）。大约 4：1 的剂量等效性导致相似的利钠。托拉塞米组较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着增加 （P < 0.05）。与呋塞米相比，托拉塞米的血浆体积 （P = 0.52） 和体重 （P = 0.89） 没有改善。结论 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。 托拉塞米组较高利尿剂剂量产生的较大利钠作用被更大的神经激素激活和肾功能障碍所抵消。临床试验注册名称和注册号：TRANSFORM-HF：ToRsemide compArisoN 与 furoSemide FORM心力衰竭管理 （TRANSFORM-HF），NCT03296813;托拉塞米与呋塞米治疗稳定型心力衰竭 （TFO） 患者的比较，NCT05093621....