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

Kazuma Yamakawa; Satoshi Gando; Hiroshi Ogura; Yutaka Umemura; Daijiro Kabata; Ayumi Shintani; Atsushi Shiraishi; Daizoh Saitoh; Seitato Fujishima; Toshihiko Mayumi; Shigeki Kushimoto; Toshikazu Abe; Yasukazu Shiino; Taka-aki Nakada; Takehiko Tarui; Toru Hifumi; Yasuhiro Otomo; Kohji Okamoto; Joji Kotani; Yuichiro Sakamoto; Junichi Sasaki; Shin-ichiro Shiraishi; Kiyotsugu Takuma; Ryosuke Tsuruta; Akiyoshi Hagiwara; Tomohiko Masuno; Naoshi Takeyama; Norio Yamashita; Hiroto Ikeda; Masashi Ueyama; Satoshi Fujimi; 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

doi:10.1055/s-0039-1693740

Thrombosis and Haemostasis, Table of Contents

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

¹Division of Trauma and Surgical Critical Care, Osaka General Medical Center, Osaka, Japan

²Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

,

Satoshi Gando

³Department of Anesthesiology and Critical Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan

⁴Acute and Critical Care Center, Department of Acute and Critical Care Medicine, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan

,

Hiroshi Ogura

²Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

,

Yutaka Umemura

²Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

,

Daijiro Kabata

⁵Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan

,

Ayumi Shintani

⁵Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan

,

Atsushi Shiraishi

⁶Emergency and Trauma Center, Kameda Medical Center, Kamogawa, Chiba, Japan

,

Daizoh Saitoh

⁷Division of Traumatology, Research Institute, National Defense Medical College, Tokorozawa, Saitama, Japan

,

Seitato Fujishima

⁸Center for General Medicine Education, Keio University School of Medicine, Kanagawa, Japan

,

Toshihiko Mayumi

⁹Department of Emergency Medicine, School of Medicine, University of Occupational and Environmental Health Japan, Fukuoka, Japan

,

Shigeki Kushimoto

¹⁰Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, Sendai Japan

,

Toshikazu Abe

¹¹Department of General Medicine, Juntendo University, Tokyo, Japan

¹²Health Services Research and Development Center, University of Tsukuba, Tokyo, Japan

,

Yasukazu Shiino

¹³Department of Acute Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan

,

Taka-aki Nakada

¹⁴Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan

,

Takehiko Tarui

¹⁵Department of Trauma and Critical Care Medicine, Kyorin University School of Medicine, Mitaka, Tokyo, Japan

,

Toru Hifumi

¹⁶Department of Emergency and Critical Care Medicine, St. Luke's International Hospital, Tokyo, Japan

,

Yasuhiro Otomo

¹⁷Trauma and Acute Critical Care Center, Medical Hospital, Tokyo Medical and Dental University, Tokyo, Japan

,

Kohji Okamoto

¹⁸Department of Surgery, Center for Gastroenterology and Liver Disease, Kitakyushu City Yahata Hospital, Kitakyushu, Japan

,

Joji Kotani

¹⁹Division of Disaster and Emergency Medicine, Department of Surgery Related, Kobe University Graduate School of Medicine, Kobe, Japan

,

Yuichiro Sakamoto

²⁰Emergency and Critical Care Medicine, Saga University Hospital, Saga, Japan

,

Junichi Sasaki

²¹Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan

,

Shin-ichiro Shiraishi

²²Department of Emergency and Critical Care Medicine, Aizu Chuo Hospital, Aizu, Japan

,

Kiyotsugu Takuma

²³Emergency & Critical Care Center, Kawasaki Municipal Hospital, Kawasaki, Kanagawa, Japan

,

Ryosuke Tsuruta

²⁴Advanced Medical Emergency and Critical Care Center, Yamaguchi University Hospital, Yamaguchi, Japan

,

Akiyoshi Hagiwara

²⁵Center Hospital of the National Center for Global Health and Medicine, Tokyo, Japan

,

Tomohiko Masuno

²⁶Department of Emergency and Critical Care Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan

,

Naoshi Takeyama

²⁷Advanced Critical Care Center, Aichi Medical University Hospital, Aichi-gun, Aichi, Japan

,

Norio Yamashita

²⁸Advanced Emergency Medical Service Center, Kurume University Hospital, Kurume, Fukuoka, Japan

,

Hiroto Ikeda

²⁹Department of Emergency Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan

,

Masashi Ueyama

³⁰Department of Trauma, Critical Care Medicine, and Burn Center, Japan Community Healthcare Organization, Chukyo Hospital, Nagoya, Aichi, Japan

,

Satoshi Fujimi

¹Division 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

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

Full Text

References

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Supplementary Material