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Thromb Haemost 2019; 119(11): 1740-1751
DOI: 10.1055/s-0039-1693740
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

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

Kazuma Yamakawa 
1   Division of Trauma and Surgical Critical Care, Osaka General Medical Center, Osaka, Japan
2   Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
,
Satoshi Gando
3   Department of Anesthesiology and Critical Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
4   Acute and Critical Care Center, Department of Acute and Critical Care Medicine, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
,
Hiroshi Ogura
2   Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
,
Yutaka Umemura
2   Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
,
Daijiro Kabata
5   Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan
,
Ayumi Shintani
5   Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan
,
Atsushi Shiraishi
6   Emergency and Trauma Center, Kameda Medical Center, Kamogawa, Chiba, Japan
,
Daizoh Saitoh
7   Division of Traumatology, Research Institute, National Defense Medical College, Tokorozawa, Saitama, Japan
,
Seitato Fujishima
8   Center for General Medicine Education, Keio University School of Medicine, Kanagawa, Japan
,
Toshihiko Mayumi
9   Department of Emergency Medicine, School of Medicine, University of Occupational and Environmental Health Japan, Fukuoka, Japan
,
Shigeki Kushimoto
10   Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, Sendai Japan
,
Toshikazu Abe
11   Department of General Medicine, Juntendo University, Tokyo, Japan
12   Health Services Research and Development Center, University of Tsukuba, Tokyo, Japan
,
Yasukazu Shiino
13   Department of Acute Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan
,
Taka-aki Nakada
14   Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
,
Takehiko Tarui
15   Department of Trauma and Critical Care Medicine, Kyorin University School of Medicine, Mitaka, Tokyo, Japan
,
Toru Hifumi
16   Department of Emergency and Critical Care Medicine, St. Luke's International Hospital, Tokyo, Japan
,
Yasuhiro Otomo
17   Trauma and Acute Critical Care Center, Medical Hospital, Tokyo Medical and Dental University, Tokyo, Japan
,
Kohji Okamoto
18   Department of Surgery, Center for Gastroenterology and Liver Disease, Kitakyushu City Yahata Hospital, Kitakyushu, Japan
,
Joji Kotani
19   Division of Disaster and Emergency Medicine, Department of Surgery Related, Kobe University Graduate School of Medicine, Kobe, Japan
,
Yuichiro Sakamoto
20   Emergency and Critical Care Medicine, Saga University Hospital, Saga, Japan
,
Junichi Sasaki
21   Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
,
Shin-ichiro Shiraishi
22   Department of Emergency and Critical Care Medicine, Aizu Chuo Hospital, Aizu, Japan
,
Kiyotsugu Takuma
23   Emergency & Critical Care Center, Kawasaki Municipal Hospital, Kawasaki, Kanagawa, Japan
,
Ryosuke Tsuruta
24   Advanced Medical Emergency and Critical Care Center, Yamaguchi University Hospital, Yamaguchi, Japan
,
Akiyoshi Hagiwara
25   Center Hospital of the National Center for Global Health and Medicine, Tokyo, Japan
,
Tomohiko Masuno
26   Department of Emergency and Critical Care Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
,
Naoshi Takeyama
27   Advanced Critical Care Center, Aichi Medical University Hospital, Aichi-gun, Aichi, Japan
,
Norio Yamashita
28   Advanced Emergency Medical Service Center, Kurume University Hospital, Kurume, Fukuoka, Japan
,
Hiroto Ikeda
29   Department of Emergency Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
,
Masashi Ueyama
30   Department of Trauma, Critical Care Medicine, and Burn Center, Japan Community Healthcare Organization, Chukyo Hospital, Nagoya, Aichi, Japan
,
Satoshi Fujimi
1   Division of Trauma and Surgical Critical Care, Osaka General Medical Center, Osaka, Japan
,
on behalf of the Japanese Association for Acute Medicine (JAAM) Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis Trauma (FORECAST) Study Group › Author Affiliations Funding This work was supported by the Japanese Association for Acute Medicine.
Further Information

Publication History

11 January 2019

13 June 2019

Publication Date:
13 August 2019 (online)

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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.


Supplementary Material

 

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