International Journal of Clinical Pharmacy

, Volume 37, Issue 1, pp 139–147 | Cite as

Observational study to compare antithrombin and thrombomodulin for disseminated intravascular coagulation

  • Atsuhiko MurataEmail author
  • Kohji Okamoto
  • Toshihiko Mayumi
  • Keiji Muramatsu
  • Shinya Matsuda
Research Article


Background There have been no studies comparing the effects of antithrombin (AT-III) and recombinant human soluble thrombomodulin (rhs-TM) on outcomes in patients with disseminated intravascular coagulation (DIC) associated with infectious diseases. Objective The aim of this observational study is to compare AT-III and rhs-TM in terms of outcomes such as mortality, length of hospitalization, and medical costs in patients with DIC associated with infectious diseases based on a Japanese administrative database. Setting A total of 7,535 patients with DIC associated with infectious diseases in 886 hospitals from 2010 to 2012 in Japan. Methods We collected patients’ data from the administrative database to compare clinical and medical economic outcomes of patients with DIC. Patients were divided into two groups according to treatment of DIC: AT-III (n = 3,601) and rhs-TM (n = 3,934). Main outcomes measure In-hospital mortality (within 14 days, within 28 days, and overall mortality), length of stay (LOS), and medical costs during hospitalization. Results Multilevel logistic regression analysis showed that there were no significant differences with regard to in-hospital mortality between AT-III and rhs-TM within 14 days (odds ratio (OR) of rhs-TM 0.97, 95 % confidence interval (CI) 0.85–1.11, p = 0.744), within 28 days (OR 1.00, 95 % CI 0.89–1.13, p = 0.919), and overall (OR 0.95, 95 % CI 0.85–1.07, p = 0.470). However, multilevel linear regression analysis revealed that use of rhs-TM significantly decreased LOS and medical costs during hospitalization. The coefficient for LOS was −2.92 days (95 % CI −4.79 to −1.04 days; p = 0.002) whereas that for medical costs during hospitalization was −798.3 Euro (95 % CI −1,515.7 to −81.0 Euro; p = 0.029). Conclusion This study demonstrated no significant difference in in-hospital mortality between AT-III and rhs-TM. However, use of rhs-TM was significantly associated with decreased LOS and medical costs during hospitalization in patients with DIC associated with infectious diseases.


Antithrombin Database Disseminated intravascular coagulation Healthcare costs Length of stay Mortality Thrombomodulin 



This study was funded by Grants-in-Aid for Research on Policy Planning and Evaluation from the Ministry of Health, Labour and Welfare, Japan.

Conflicts of interest

None of the authors have any conflicts of interest to declare.


  1. 1.
    Bick RL. Disseminated intravascular coagulation: a review of etiology, pathophysiology, diagnosis, and management: guidelines for care. Clin Appl Thromb Hemost. 2002;8(1):1–31.PubMedCrossRefGoogle Scholar
  2. 2.
    Levi M, van der Poll T. Disseminated intravascular coagulation: a review for the internist. Intern Emerg Med. 2013;8(1):23–32.PubMedCrossRefGoogle Scholar
  3. 3.
    Levi M, Schultz M, van der Poll T. Disseminated intravascular coagulation in infectious disease. Semin Thromb Hemost. 2010;36(4):367–77.PubMedCrossRefGoogle Scholar
  4. 4.
    Nakagawa M, Tsuji H. Current trends in the diagnosis of disseminated intravascular coagulation in Japan: findings of questionnaire survey. Rinsho Ketsueki. 1999;40(5):362–4.PubMedGoogle Scholar
  5. 5.
    Gogos CA, Lekkou A, Papageorgiou O, Siagris D, Skoutelis A, Bassaris HP. Clinical prognostic markers in patients with severe sepsis: a prospective analysis of 139 consecutive cases. J Infect. 2003;47(4):300–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Cartin-Ceba R, Kojicic M, Li G, Kor DJ, Poulose J, Herasevich V, et al. Epidemiology of critical care syndromes, organ failures, and life-support interventions in a suburban US community. Chest. 2011;140(6):1447–55.PubMedCrossRefGoogle Scholar
  7. 7.
    Wada H, Asakura H, Okamoto K, Iba T, Uchiyama T, Kawasugi K, et al. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res. 2010;125(1):6–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Nishiyama T, Matsukawa T, Hanaoka K. Is protease inhibitor a choice for the treatment of pre-or mild disseminated intravascular coagulation? Crit Care Med. 2000;28(5):1419–22.PubMedCrossRefGoogle Scholar
  9. 9.
    Wiedermann CJ, Kaneider NC. A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis. Blood Coagul Fibrinolysis. 2006;17(7):521–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Iba T, Saito D, Wada H, Asakura H. Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: a prospective multicenter survey. Thromb Res. 2012;130(3):e129–33.PubMedCrossRefGoogle Scholar
  11. 11.
    Tagami T, Matsui H, Horiguchi H, Fushimi K, Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J Thromb Haemost. 2014;12(9):1470–9.PubMedGoogle Scholar
  12. 12.
    Shirahata A, Mimuro J, Takahashi H, Kitajima I, Tsuji H, Eguchi Y, et al. Recombinant soluble human thrombomodulin (thrombomodulin alfa) in the treatment of neonatal disseminated intravascular coagulation. Eur J Pediatr. 2014;173(3):303–11.PubMedCrossRefGoogle Scholar
  13. 13.
    Ogawa Y, Yamakawa K, Ogura H, Kiguchi T, Mohri T, Nakamori Y, et al. Recombinant human soluble thrombomodulin improves mortality and respiratory dysfunction in patients with severe sepsis. J Trauma Acute Care Surg. 2012;72(5):1150–7.PubMedGoogle Scholar
  14. 14.
    Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost. 2007;5(1):31–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Vincent JL, Ramesh MK, Ernest D, LaRosa SP, Pachl J, Aikawa N, et al. A randomized, double-blind, placebo-controlled, phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Care Med. 2013;41(9):2069–79.PubMedCrossRefGoogle Scholar
  16. 16.
    Murata A, Matsuda S. Association between ambulance distance to hospitals and mortality from acute diseases in Japan: national database analysis. J Public Health Manag Pract. 2013;19(5):E23–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Murata A, Matsuda S, Kuwabara K, Ichimiya Y, Matsuda Y, Kubo T, et al. Association between hospital volume and clinical outcomes of elderly patients with acute biliary diseases: a national administrative database analysis. Geriatr Gerontol Int. 2013;13(3):731–40.PubMedCrossRefGoogle Scholar
  18. 18.
    Murata A, Okamoto K, Muramatsu K, Kubo T, Fujino Y, Matsuda S. Effects of additional laparoscopic cholecystectomy on outcomes of laparoscopic gastrectomy in patients with gastric cancer based on a national administrative database. J Surg Res. 2014;186(1):157–63.PubMedCrossRefGoogle Scholar
  19. 19.
    Murata A, Muramatsu K, Ichimiya Y, Kubo T, Fujino Y, Matsuda S. Endoscopic submucosal dissection for gastric cancer in elderly Japanese patients: an observational study of financial costs of treatment based on a national administrative database. J Dig Dis. 2014;15(2):62–70.PubMedCrossRefGoogle Scholar
  20. 20.
    Murata A, Okamoto K, Muramatsu K, Matsuda S. Endoscopic submucosal dissection for gastric cancer: the influence of hospital volume on complications and length of stay. Surg Endosc. 2014;28(4):1298–306.PubMedCrossRefGoogle Scholar
  21. 21.
    Fukuda T, Yasunaga H, Horiguchi H, Ohe K, Fushimi K, Matsubara T, et al. Health care costs related to out-of-hospital cardiopulmonary arrest in Japan. Resuscitation. 2013;84(7):964–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Ministry of Health, Welfare and Labor of Japan. Stat. Chuikyo. 26.3.26 Accessed 8 Nov 2014.
  23. 23.
    Murata A, Okamoto K, Muramastu K, Matsuda S. Time trend of medical economic outcomes of endoscopic submucosal dissection for gastric cancer in Japan: a national database analysis. Gastric Cancer. 2014;17(2):294–301.PubMedCrossRefGoogle Scholar
  24. 24.
    Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165–228.PubMedCrossRefGoogle Scholar
  25. 25.
    Murata A, Okamoto K, Mayumi T, Muramatsu K, Matsuda S. The recent time trend of outcomes of disseminated intravascular coagulation in Japan: an observational study based on a national administrative database. J Thromb Thrombolysis. 2014;38(3):364–71.PubMedCrossRefGoogle Scholar
  26. 26.
    Kato T, Sakai T, Kato M, Hagihara M, Hasegawa T, Matsuura K, et al. Recombinant human soluble thrombomodulin administration improves sepsis-induced disseminated intravascular coagulation and mortality: a retrospective cohort study. Thromb J. 2013;11(1):3.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Yamakawa K, Fujimi S, Mohri T, Matsuda H, Nakamori Y, Hirose T, et al. Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study. Crit Care. 2011;15(3):R123.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Yamakawa K, Ogura H, Fujimi S, Morikawa M, Ogawa Y, Mohri T, et al. Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. Intensive Care Med. 2013;39(4):644–52.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Wiedermann CJ, Hoffmann JN, Juers M, Ostermann H, Kienast J, Briegel J, et al. High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety. Crit Care Med. 2006;34(2):285–92.PubMedCrossRefGoogle Scholar
  30. 30.
    Sawamura A, Gando S, Hayakawa M, Hoshino H, Kubota N, Sugano M. Effects of antithrombin III in patients with disseminated intravascular coagulation diagnosed by newly developed diagnostic criteria for critical illness. Clin Appl Thromb Hemost. 2009;15(5):561–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Sakamoto Y, Inoue S, Iwamura T, Yamashita T, Nakashima A, Nishimura Y, et al. Studies on therapeutic effects and pathological features of an antithrombin preparation in septic disseminated intravascular coagulation patients. Yonsei Med J. 2013;54(3):686–9.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Okamoto K, Takada T, Strasberg SM, Solomkin JS, Pitt HA, Garden OJ, et al. TG13 management bundles for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20(1):55–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Mimuro J, Takahashi H, Kitajima I, Tsuji H, Eguchi Y, Matsushita T, et al. Impact of recombinant soluble thrombomodulin (thrombomodulin alfa) on disseminated intravascular coagulation. Thromb Res. 2013;131(5):436–43.PubMedCrossRefGoogle Scholar
  34. 34.
    Murata A, Matsuda S, Mayumi T, Yokoe M, Kuwabara K, Ichimiya Y, et al. A descriptive study evaluating the circumstances of medical treatment for acute pancreatitis before publication of the new JPN guidelines based on the Japanese administrative database associated with the Diagnosis Procedure Combination system. J Hepatobiliary Pancreat Sci. 2011;18(5):678–83.PubMedCrossRefGoogle Scholar

Copyright information

© Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014

Authors and Affiliations

  • Atsuhiko Murata
    • 1
    Email author
  • Kohji Okamoto
    • 2
  • Toshihiko Mayumi
    • 3
  • Keiji Muramatsu
    • 1
  • Shinya Matsuda
    • 1
  1. 1.Department of Preventive Medicine and Community Health, School of MedicineUniversity of Occupational and Environmental HealthKitakyushuJapan
  2. 2.Department of SurgeryYahata Municipal HospitalKitakyushuJapan
  3. 3.Department of Emergency MedicineUniversity of Occupational, Environmental and HealthKitakyushuJapan

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