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

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)

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.

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

 
  • References

  • 1 Singer M, Deutschman CS, Seymour CW. , et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
  • 2 Shankar-Hari M, Phillips GS, Levy ML. , et al; Sepsis Definitions Task Force. Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315 (08) 775-787
  • 3 Seymour CW, Liu VX, Iwashyna TJ. , et al. Assessment of clinical criteria for sepsis: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315 (08) 762-774
  • 4 Vincent JL, de Mendonça A, Cantraine F. , et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med 1998; 26 (11) 1793-1800
  • 5 Iba T, Levy JH. Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis. J Thromb Haemost 2018; 16 (02) 231-241
  • 6 Levi M, van der Poll T. Coagulation and sepsis. Thromb Res 2017; 149: 38-44
  • 7 Gando S, Levi M, Toh C-H. Disseminated intravascular coagulation. Nat Rev Dis Primers 2016; 2: 16037
  • 8 Warren BL, Eid A, Singer P. , et al; KyberSept Trial Study Group. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286 (15) 1869-1878
  • 9 Abraham E, Reinhart K, Opal S. , et al; OPTIMIST Trial Study Group. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 2003; 290 (02) 238-247
  • 10 Abraham E, Laterre P-F, Garg R. , et al; Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005; 353 (13) 1332-1341
  • 11 Ranieri VM, Thompson BT, Barie PS. , et al; PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366 (22) 2055-2064
  • 12 Hoffmann JN, Wiedermann CJ, Juers M. , et al; KyberSept investigators. Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin. Thromb Haemost 2006; 95 (05) 850-856
  • 13 Kienast J, Juers M, Wiedermann CJ. , et al; KyberSept investigators. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost 2006; 4 (01) 90-97
  • 14 Yoshimura J, Yamakawa K, Ogura H. , et al. Benefit profile of recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. Crit Care 2015; 19: 78
  • 15 Yamakawa K, Umemura Y, Hayakawa M. , et al; Japan Septic Disseminated Intravascular Coagulation (J-Septic DIC) study group. Benefit profile of anticoagulant therapy in sepsis: a nationwide multicentre registry in Japan. Crit Care 2016; 20 (01) 229
  • 16 Ogura H, Gando S, Iba T. , et al; Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Study Group. SIRS-associated coagulopathy and organ dysfunction in critically ill patients with thrombocytopenia. Shock 2007; 28 (04) 411-417
  • 17 Saito S, Uchino S, Hayakawa M. , et al; Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study group. Epidemiology of disseminated intravascular coagulation in sepsis and validation of scoring systems. J Crit Care 2019; 50: 23-30
  • 18 Umemura Y, Yamakawa K. Optimal patient selection for anticoagulant therapy in sepsis: an evidence-based proposal from Japan. J Thromb Haemost 2018; 16 (03) 462-464
  • 19 Abe T, Ogura H, Shiraishi A. , et al; JAAM FORECAST group. Characteristics, management, and in-hospital mortality among patients with severe sepsis in intensive care units in Japan: the FORECAST study. Crit Care 2018; 22 (01) 322
  • 20 Levy MM, Fink MP, Marshall JC. , et al; International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 2003; 29 (04) 530-538
  • 21 Yang Y, Yang KS, Hsann YM, Lim V, Ong BC. The effect of comorbidity and age on hospital mortality and length of stay in patients with sepsis. J Crit Care 2010; 25 (03) 398-405
  • 22 Taylor Jr FB, Toh C-H, Hoots WK, Wada H, Levi M. ; Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86 (05) 1327-1330
  • 23 Gando S, Saitoh D, Ogura H. , et al; Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Study Group. Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: results of a multicenter, prospective survey. Crit Care Med 2008; 36 (01) 145-150
  • 24 Gando S, Iba T, Eguchi Y. , et al; Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Study Group. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med 2006; 34 (03) 625-631
  • 25 Harell Jr FE. Regression Modeling Strategies Package ‘rms.’. Published 2018 . Available at: https://cran.r-project.org/web/packages/rms/rms.pdf . Accessed December 18, 2018
  • 26 Ramos LF, Shintani A, Ikizler TA, Himmelfarb J. Oxidative stress and inflammation are associated with adiposity in moderate to severe CKD. J Am Soc Nephrol 2008; 19 (03) 593-599
  • 27 Bernard GR, Vincent JL, Laterre PF. , et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344 (10) 699-709
  • 28 Asahi Kasei Pharma America Corporation. Phase 3 Safety and Efficacy Study of ART-123 in Subjects With Severe Sepsis and Coagulopathy. Available at: https://clinicaltrials.gov/ct2/show/NCT01598831?cond=ART-123&rank=5 . Accessed August 2, 2018
  • 29 Asahi Kasei Pharma Corporation. Preliminary results of overseas Phase III clinical study for ART-123. Published 2018 . Available at: https://www.asahi-kasei.co.jp/asahi/en/news/2018/e180802.html . Accessed August 2, 2018
  • 30 Umemura Y, Yamakawa K, Ogura H, Yuhara H, Fujimi S. Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials. J Thromb Haemost 2016; 14 (03) 518-530
  • 31 Wiedermann CJ, Hoffmann JN, Juers M. , et al; KyberSept Investigators. 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 (02) 285-292
  • 32 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
  • 33 van der Poll T, Herwald H. The coagulation system and its function in early immune defense. Thromb Haemost 2014; 112 (04) 640-648
  • 34 Ito T. PAMPs and DAMPs as triggers for DIC. J Intensive Care 2014; 2 (01) 67