title: Reevaluation of the efficacy and safety of the neutrophil elastase inhibitor, Sivelestat, for the treatment of acute lung injury associated with systemic inflammatory response syndrome; a phase IV study.
abstract: BACKGROUND
  Sivelestat, a neutrophil elastase inhibitor, has been approved in Japan for the treatment of patients with acute lung injury (ALI) associated with systemic inflammatory response syndrome (SIRS). The Pharmaceuticals and Medical Devices Agency (PMDA) has ordered to conduct a postmarket clinical study in order to reevaluate the efficacy and safety of Sivelestat in actual clinical settings in Japan.
  
  
  METHODS
  According to the PMDA's order, we evaluated the efficacy and safety of Sivelestat in Japanese patients with ALI associated with SIRS using ventilator-free days (VFD) as the primary endpoint. The surrogate endpoints are ventilator-weaning rate, ICU discharge rate, and 180-day survival rate. Study design was an open-label, non-randomized, multi-center clinical trial. Sivelestat was intravenously administered at 0.2 mg/kg/h continuously for a maximum of 14 days. Sivelestat group and control group were compared by adjusting the outcome values using an inverse probability of treatment weighted method based on the propensity scores.
  
  
  RESULTS
  Four hundred and four Sivelestat group patients and 177 control group patients were enrolled. The adjusted mean number of VFD was 15.7 and 12.1 in the Sivelestat group and control group, respectively (P = 0.0022). Both the adjusted ventilator-weaning rate and ICU discharge rate were significantly higher in the Sivelestat group than in the control group (P = 0.0028 and P = 0.019, respectively). The adjusted 180-day survival rate was significantly higher in the Sivelestat group than in the control group (71.8 percent vs. 56.3 percent).
  
  
  CONCLUSIONS
  Sivelestat contributed to early weaning from the mechanical ventilation, while showing no negative effect on the long-term outcomes of ALI associated with SIRS. The results of this study suggest the clinical usefulness of Sivelestat in this patient population.
authors.affiliation: Department of Emergency and Critical Care Medicine, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, Japan. aikawa7@rc4.so-net.ne.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Aikawa
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Ishizaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirasawa
authors.forename: Shuji
authors.initials: S
authors.lastname: Shimazaki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hisashi
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shinozaki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Taenaka
authors.forename: Shigeatsu
authors.initials: S
authors.lastname: Endo
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawasaki
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000503:physiopathology; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005998:Glycine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D053491:Proteinase Inhibitory Proteins, Secretory / Q000009:adverse effects / Q000494:pharmacology; D012121:Respiration, Artificial; D015842:Serine Proteinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology*; D015996:Survival Rate; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D015300:Ventilator Weaning
chemical_list: D053491:Proteinase Inhibitory Proteins, Secretory; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D005998:Glycine