title: Benefit profile of recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis.
abstract: BACKGROUND
  The safety and efficacy of recombinant human soluble thrombomodulin (rhTM) have been demonstrated, with promising evidence suggestive of efficacy for patients with severe sepsis involving coagulopathy in a phase IIb randomized controlled trial. However, the benefit profiles of rhTM have not been elucidated. The purpose of this study was to explore whether patients with greater disease severity, determined according to the Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores, would experience treatment benefit from rhTM administration.
  
  
  METHODS
  This was a post hoc, subgroup analysis of a multicenter retrospective cohort study conducted in three Japanese tertiary referral hospitals. Patients with sepsis-induced disseminated intravascular coagulation (DIC) who required ventilator management were included. We stratified patients into several strata according to disease severity, determined by APACHE II and SOFA scores, using classification and regression trees for survival data. Intervention effects, expressed as hazard ratios (HR), were analyzed using Cox regression analysis adjusted for a propensity model to detect subgroup heterogeneity of the effects of rhTM on in-hospital mortality.
  
  
  RESULTS
  Participants were 162 patients with sepsis-induced DIC; 68 of these patients received rhTM and 94 did not. After adjusting for imbalances, rhTM administration was significantly associated with reduced mortality in high-risk patients (APACHE II: 24 to 29; HR: 0.281; 95% confidence interval (CI): 0.093 to 0.850; P = 0.025). A similar nonsignificant tendency was observed in the very high-risk subset (APACHE II: ≥30; HR: 0.529; 95% CI: 0.202 to 1.387; P = 0.195) but was not evident in the moderate-risk subset of patients (APACHE II: <24; HR: 0.814; 95% CI: 0.351 to 1.884; P = 0.630). A similar tendency was observed in analysis of SOFA scores (moderate-risk subset (SOFA: <11), P = 0.368; high-risk subset (SOFA: ≥11), P = 0.042).
  
  
  CONCLUSIONS
  Survival benefit was observed with rhTM treatment in sepsis-induced DIC and high risk of death according to baseline APACHE II and SOFA scores.
authors.affiliation: Department of Emergency and Critical Care, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558, Japan. jumpei.y0210@gmail.com.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Yoshimura
authors.affiliation: Department of Emergency and Critical Care, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558, Japan. k.yamakawa0911@gmail.com.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Yamakawa
authors.affiliation: Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan. ogura@hp-emerg.med.osaka-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ogura
authors.affiliation: Department of Emergency and Critical Care, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558, Japan. plum00022@gmail.com.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Umemura
authors.affiliation: Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan. thirokikmu@yahoo.co.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Emergency and Critical Care Medicine, Juntendo University, Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan. tsumiki@juntendo-urayasu.jp.
authors.forename: Miki
authors.initials: M
authors.lastname: Morikawa
authors.affiliation: Department of Emergency and Critical Care Medicine, Juntendo University, Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan. yinoue@juntendo-urayasu.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Emergency and Critical Care, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558, Japan. fujimis@opho.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujimi
authors.affiliation: Department of Emergency and Critical Care Medicine, Juntendo University, Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan. htanaka@juntendo-urayasu.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Office of Biostatistics and Data Management, National Cerebral and Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan. toshi.hamasaki@ncvc.go.jp.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Hamasaki
authors.affiliation: Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan. shimazu@hp-emerg.med.osaka-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimazu
mesh_terms: D018806:APACHE; D000368:Aged; D004211:Disseminated Intravascular Coagulation / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D057216:Propensity Score; D011994:Recombinant Proteins / Q000627:therapeutic use; D012044:Regression Analysis; D012189:Retrospective Studies; D018805:Sepsis / Q000150:complications* / Q000401:mortality; D018180:Thrombomodulin / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D011994:Recombinant Proteins; D018180:Thrombomodulin