Identifying Sepsis Populations Benefitting from Anticoagulant Therapy: A Prospective Cohort Study Incorporating a Restricted Cubic Spline Regression Model

Abstract

Background Anticoagulant therapy has seldom been achieved in randomized trials targeting nonspecific overall sepsis patients. Although the key components to identify the appropriate target in sepsis may be disseminated intravascular coagulation (DIC) and high disease severity, the interaction and relation of these two components for the effectiveness of therapy remain unknown.

Objective This article identifies the optimal target of anticoagulant therapy in sepsis.

Methods We used a prospective nationwide cohort targeting consecutive adult severe sepsis patients in 59 intensive care units in Japan to assess associations between anticoagulant therapy and in-hospital mortality according to DIC (International Society on Thrombosis and Haemostasis [ISTH] overt and Japanese Association for Acute Medicine DIC scores) and disease severity (Acute Physiology and Chronic Health Evaluation II [APACHE II] and Sequential Organ Failure Assessment scores). Multivariable Cox proportional hazard regression analysis with nonlinear restricted cubic spline including a two-way interaction term (treatment × each score) and three-way interaction term (treatment × ISTH overt DIC score × APACHE II score) was performed.

Results The final study cohort comprised 1,178 sepsis patients (371 received anticoagulants and 768 did not). The regression model including the two-way interaction term showed significant interaction between intervention and disease severity as indicated by the ISTH overt DIC score and APACHE II score (p = 0.046 and p = 0.101, respectively). Three-way interaction analysis revealed that risk hazard was suppressed in the anticoagulant group compared with the control group in the most severe subset of both scores.

Conclusion Anticoagulant therapy was associated with better outcome according to the deterioration of both DIC and disease severity, suggesting that anticoagulant therapy should be restricted to patients having DIC and high disease severity simultaneously.

Keywords

anticoagulants - critically ill - disseminated intravascular coagulation - sepsis - septic shock

Authors' Contributions

K.Y. conceived and designed this study; contributed to acquisition, analysis, and interpretation of the data; and was responsible for drafting, editing, and submission of the manuscript. S.G., H..O., and Y.U. had a significant influence on the interpretation of the data and critical appraisal of the manuscript. D.K. and A.S. played a significant role in the analysis of the data and helped to draft the manuscript. All of the authors contributed to the acquisition of data, reviewed, discussed, and approved the final manuscript.

Investigators of the JAAM FORECAST Sepsis Study Group

1. Nagasaki University Hospital (Osamu Tasaki)

2. Osaka City University Hospital (Yasumitsu Mizobata)

3. Tokyobay Urayasu Ichikawa Medical Center (Hiraku Funakoshi)

4. Aso Iizuka Hospital (Toshiro Okuyama)

5. Tomei Atsugi Hospital (Iwao Yamashita)

6. Hiratsuka City Hospital (Toshio Kanai)

7. National Hospital Organization Sendai Medical Center (Yasuo Yamada)

8. Ehime University Hospital (Mayuki Aibiki)

9. Okayama University Hospital (Keiji Sato)

10. Tokuyama Central Hospital (Susumu Yamashita)

11. Fukuyama City Hospital (Susumu Yamashita)

12. JA Hiroshima General Hospital (Kenichi Yoshida)

13. Kumamoto University Hospital (Shunji Kasaoka)

14. Hachinohe City Hospital (Akihide Kon)

15. Osaka City General Hospital (Hiroshi Rinka)

16. National Hospital Organization Disaster Medical Center (Hiroshi Kato)

17. University of Toyama (Hiroshi Okudera)

18. Sapporo Medical University (Eichi Narimatsu)

19. Okayama Saiseikai General Hospital (Toshifumi Fujiwara)

20. Juntendo University Nerima Hospital (Manabu Sugita)

21. National Hospital Organization Hokkaido Medical Center (Yasuo Shichinohe)

22. Akita University Hospital (Hajime Nakae)

23. Japanese Red Cross Society Kyoto Daini Hospital (Ryouji Iiduka)

24. Maebashi Red Cross Hospital (Mitsunobu Nakamura)

25. Sendai City Hospital (Yuji Murata)

26. Subaru Health Insurance Society Ota Memorial Hospital (Yoshitake Sato)

27. Fukuoka University Hospital (Hiroyasu Ishikura)

28. Ishikawa Prefectural Central Hospital (Yasuhiro Myojo)

29. Shiga University of Medical Science (Yasuyuki Tsujita)

30. Nihon University School of Medicine (Kosaku Kinoshita)

31. Seirei Yokohama General Hospital (Hiroyuki Yamaguchi)

32. National Hospital Organization Kumamoto Medical Center (Toshihiro Sakurai)

33. Saiseikai Utsunomiya Hospital (Satoru Miyatake)

34. National Hospital Organization Higashi-Ohmi General Medical Center (Takao Saotome)

35. National Hospital Organization Mito Medical Center (Susumu Yasuda)

36. Tsukuba Medical Center Hospital (Toshikazu Abe)

37. Osaka University Graduate School of Medicine (Hiroshi Ogura, Yutaka Umemura)

38. Kameda Medical Center (Atsushi Shiraishi)

39. Tohoku University Graduate School of Medicine (Shigeki Kushimoto)

40. National Defense Medical College (Daizoh Saitoh)

41. Keio University School of Medicine (Seitaro Fujishima, Junichi Sasaki)

42. University of Occupational and Environmental Health (Toshihiko Mayumi)

43. Kawasaki Medical School (Yasukazu Shiino)

44. Chiba University Graduate School of Medicine (Taka-aki Nakada)

45. Kyorin University School of Medicine (Takehiko Tarui)

46. Kagawa University Hospital (Toru Hifumi)

47. Tokyo Medical and Dental University (Yasuhiro Otomo)

48. Hyogo College of Medicine (Joji Kotani)

49. Saga University Hospital (Yuichiro Sakamoto)

50. Aizu Chuo Hospital (Shin-ichiro Shiraishi)

51. Kawasaki Municipal Kawasaki Hospital (Kiyotsugu Takuma)

52. Yamaguchi University Hospital (Ryosuke Tsuruta)

53. Center Hospital of the National Center for Global Health and Medicine (Akiyoshi Hagiwara)

54. Osaka General Medical Center (Kazuma Yamakawa)

55. Aichi Medical University Hospital (Naoshi Takeyama)

56. Kurume University Hospital (Norio Yamashita)

57. Teikyo University School of Medicine (Hiroto Ikeda)

58. Rinku General Medical Center (Yasuaki Mizushima)

59. Hokkaido University Graduate School of Medicine (Satoshi Gando)

Note

The data that support the findings of this study are available from the authors upon reasonable request.

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