No abstract

TM-α is effective and safe for DIC-ST. This agent is the treatment of choice for the management of DIC-ST.

SummaryRecombinant human soluble thrombomodulin (ART-123) is a novel anticoagulant for patients with disseminated intravascular coagulation (DIC). It is widely used in clinical settings throughout Japan. Furthermore, a global Phase 3 study is currently being conducted. In healthy subjects, ART-123 is excreted mainly via the kidneys. Therefore, ART-123 dose decrease was recommended in DIC patients with severe renal dysfunction. However, the pharmacokinetics of ART-123 in DIC patients with severe acute renal dysfunction has not been elucidated. In an open-label, multicentre, prospective, clinical pharmacological study, we investigated the pharmacokinetics and safety of ART-123 upon repeated administration to DIC patients. ART-123 was administered to patients at a dose of 130 or 380 U/kg/day for six consecutive days. Plasma concentrations of ART-123 were measured at 21 time points until eight days after the final administration. Urinary excretion rates during the first 24 hours (h) were calculated. Patient renal functions were evaluated by measuring 24-h creatinine clearance (Ccr). Forty-three patients were enrolled in the present study. The urinary excretion rates of ART-123 correlated closely with 24-h Ccr. Total body clearance of ART-123 was also weakly related with 24-h Ccr. However, the plasma concentrations of ART-123 were not considerably different among patients with different renal function. Two patients had subcutaneous haemorrhage as an adverse event related to ART-123. In conclusion, plasma concentrations of ART-123 may not be different among patients with different renal functions. ART-123 was well tolerated in these patients.

No abstract

The current trial (1) was the only randomized trial. Three observational studies provided data for survival rate difference on Day 90 (3, 5, 6). Because baseline patient characteristics were not significantly different in any item of these three studies, we believe using raw comparison data is allowed. A random-model meta-analysis on the basis of these three reports with 109 patients yielded Day 90 survival rate difference of 26% in favor of the rhTM arm (95% CI, 13-39%; P , 0.001) without heterogeneity (I 2 = 0%; P for heterogeneity = 0.39). Baseline data were different in another observational study with 40 cases (4); however, this study provided adjusted OR for 90-day survival, which made this article eligible for a meta-analysis. Pooled ORs for 90-day survival on the basis of these four studies (3-6) were 3.1 in favor of rhTM-treated patients (95% CI, 1.8-5.3; P , 0.001; I 2 = 0%; P for heterogeneity = 0.54). Most of the control subjects in the non-rhTM arm of these four studies were treated with high-dose corticosteroids with a tapering dose. Some of them were also treated with low-molecular-weight heparin, cyclosporine, immunosuppressants, anticoagulants, antiplatelets, and polymyxin. Two studies adopted 0.06 mg/kg/d rhTM, and the other two adopted 380 U/kg/d rhTM on Days 1-6. In short, there was no clear difference of treatment strategy between the current trial (1) and previous observational studies (3-6). Notably, most of the key authors in the four included articles were named in the author list of the recent article by Kondoh and colleagues (1). We suppose many readers would like to know what introduced this large discrepancy between the current trial (1) and previous observations (3-6). Four additional reports that were excluded from our analysis also revealed favorable outcomes for the rhTM arm; three were excluded because they might include the same patients as an included article (3), and one was excluded because of including nonspecific interstitial pneumonia cases. In any case, we are grateful to Kondoh and colleagues (1) for providing the most up-to-date survival data of AE-IPF cases and alerting us not to use rhTM for AE-IPF. n Author disclosures are available with the text of this letter at www.atsjournals.org.