Date Published: January 10, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Mineji Hayakawa, Kota Ono.
Over the past few decades, the large, international, randomized controlled trials of anticoagulant therapies for patients with sepsis have not yielded any improvement in mortality rates. However, in Japan, anticoagulant therapies are administered for sepsis patients with disseminated intravascular coagulation (DIC), but not for sepsis patients without DIC. Furthermore, epidemiological data regarding sepsis in Japan are scarce. Therefore, a nationwide multicenter retrospective observational study, the Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study, was undertaken. The JSEPTIC DIC study enrolled 42 intensive care units and included 3,195 patients with sepsis. The results of the JSEPTIC DIC study indicated the following: (i) anticoagulant therapy may be effective in sepsis‐induced DIC patients at high risk for death, (ii) recombinant human soluble thrombomodulin administration and antithrombin supplementation are associated with survival benefits in patients with sepsis‐induced DIC.
In cases of sepsis and septic shock, the dysregulation of systemic coagulation and fibrinolytic systems frequently leads to disseminated intravascular coagulation (DIC).1, 2, 3 Moreover, DIC often induces multiple organ failure, which is associated with a high mortality rate, owing to the development of microthrombi that cause tissue hypoperfusion.1, 2, 3
The JSEPTIC DIC study involved 42 intensive care units (ICUs) from 40 institutions throughout Japan. The ICU characteristics are presented in Table 1. The JSEPTIC DIC study included 3,195 consecutive adult patients with severe sepsis or septic shock, which was defined on the basis of the International Sepsis Definitions Conference criteria,22 diagnosed between January 2011 and December 2013. The JSEPTIC DIC study excluded patients who were <16 years old or patients who developed severe sepsis or septic shock following ICU admission. The JSEPTIC DIC study included 1,916 men (60%) and 1,279 women (40%). The mean age was 70 ± 15 years. The mean Acute Physiology and Chronic Health Evaluation II score was 23 ± 9. The median Sequential Organ Failure Assessment (SOFA) score was 9 (interquartile range, 6–12). The primary infection sites are presented in Table 2. The in‐hospital mortality rate was 33%. These characteristics of the septic patients treated in the ICU were almost the same as that previously reported in Japanese published works.16, 17 We previously reported that anticoagulant therapy is significantly associated with lower in‐hospital mortality in sepsis patients with DIC, but not in sepsis patients without DIC (Fig. 1).19 We found that the associations between anticoagulant therapy and lower in‐hospital mortality were not significant, regardless of the DIC diagnosis criteria applied. We also evaluated the relationship between the effects of anticoagulant therapy and disease severity. A significant association between anticoagulant therapy and lower in‐hospital mortality was observed in high‐risk sepsis patients (SOFA score 13–17) but not in low‐risk to moderate‐risk sepsis patients (SOFA score ≤12; Fig. 2). These results indicate that anticoagulant therapies may be effective in sepsis‐induced DIC patients at high risk of death. Recombinant human soluble thrombomodulin (rhTM), like AT, is frequently used as an anticoagulant for treating DIC.18, 23 Thrombomodulin is a receptor of thrombin and protein C on the endothelial cell surface and plays an important role in the regulation of coagulation and the innate immune system.24 Recombinant human soluble thrombomodulin was developed and approved in Japan in 2008 for treating patients with DIC.25 However, there is very limited clinical evidence supporting the use of rhTM in patients with sepsis‐induced DIC. Therefore, we evaluated the effect of rhTM treatment on sepsis‐induced DIC using a propensity score analysis for the dataset of the JSEPTIC DIC study.20 Antithrombin is among the most important physiologic anticoagulants.26 However, in sepsis‐induced DIC, a decrease in AT activity is frequently observed27, 28, 29, 30 and is associated with high mortality rates.31, 32 Several RCTs to investigate the effects of high‐dose AT administration in patients with sepsis have been carried out.4, 33, 34, 35, 36 Although some RCTs indicated benefits of high‐dose AT administration in patients with sepsis,33, 34, 35 a large RCT (the KyberSept trial) failed to show any survival benefits.4 However, a subgroup analysis of the KyberSept trial indicated that AT administration significantly improved survival rates in patients with sepsis‐induced DIC.9 The results of the JSEPTIC DIC study indicated that anticoagulant therapies, mainly rhTM and AT, were associated with survival benefits among patients with sepsis‐induced DIC in real world clinical settings. Mineji Hayakawa received a grant for the basic research and a lecturer's fee from Asahi Kasei Pharma Co. The other authors have no conflict of interest. Source: http://doi.org/10.1002/ams2.326