Benefit profile of anticoagulant therapy in sepsis: a nationwide multicentre registry in Japan

Abstract

Background: Little evidence supports anticoagulant therapy as effective adjuvant therapy to reduce mortality overall in sepsis. However, several studies suggest that anticoagulant therapy may reduce mortality in specific patients. This study aimed to identify a subset of patients with high benefit profiles for anticoagulant therapy against sepsis.

Methods: This post hoc subgroup analysis of a nationwide multicentre retrospective registry was conducted in 42 intensive care units in Japan. Consecutive adult patients with sepsis were included. Treatment effects of anticoagulants, e.g. antithrombin, recombinant thrombomodulin, heparin, and protease inhibitors, were evaluated by stratifying patients according to disseminated intravascular coagulation (DIC) and Sequential Organ Failure Assessment (SOFA) score. Intervention effects of anticoagulant therapy on in-hospital mortality and bleeding complications were analysed using Cox regression analysis stratified by propensity scores.

Results: Participants comprised 2663 consecutive patients with sepsis; 1247 patients received anticoagulants and 1416 received none. After adjustment for imbalances, anticoagulant administration was significantly associated with reduced mortality only in subsets of patients diagnosed with DIC, whereas similar mortality rates were observed in non-DIC subsets with anticoagulant therapy. Favourable associations between anticoagulant therapy and mortality were observed only in the high-risk subset (SOFA score 13-17; adjusted hazard ratio 0.601; 95 % confidence interval 0.451, 0.800) but not in the subsets of patients with sepsis with low to moderate risk. Although the differences were not statistically significant, there was a consistent tendency towards an increase in bleeding-related transfusions in all SOFA score subsets.

Conclusions: The analysis of this large database indicates anticoagulant therapy may be associated with a survival benefit in patients with sepsis-induced coagulopathy and/or very severe disease.

Trial registration: University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR ID: UMIN000012543 ). Registered on 10 December 2013.

Keywords: Anticoagulants; DIC; Disseminated intravascular coagulation; Retrospective studies; Sepsis; Subgroup analysis.

Fig. 1

Patient flow diagram. J-Septic DIC Japan Septic Disseminated Intravascular Coagulation, SCCM/ACCP Society of Critical Care Medicine/American College of Chest Physicians, SOFA Sequential Organ Failure Assessment, APACHE Acute Physiology and Chronic Health Evaluation

Fig. 2

Patient stratification according to baseline Sequential Organ Failure Assessment (SOFA) score using the classification and regression tree method

Fig. 3

Adjusted estimated survival curves in patients with or without disseminated intravascular coagulation (DIC) diagnosed by ISTH overt DIC criteria (a) and JAAM DIC criteria (b). The solid line represents patients in the anticoagulant group, and the dotted line represents patients in the control group. ISTH International Society on Thrombosis and Haemostasis, JAAM Japanese Association for Acute Medicine

Fig. 4

Adjusted estimated survival curves in 4 subsets stratified according to baseline Sequential Organ Failure Assessment (SOFA) score (a-d). The solid line represents patients in the anticoagulant group, and the dotted line represents patients in the control group

Fig. 5

In-hospital mortality across subsets defined according to several baseline characteristics. HR hazard ratio, CI confidence interval, ISTH International Society on Thrombosis and Hemostasis, DIC disseminated intravascular coagulation, JAAM Japanese Association for Acute Medicine, SOFA Sequential Organ Failure Assessment, APACHE Acute Physiology and Chronic Health Evaluation