Abstract
Many systematic reviews have been published regarding anticoagulant therapy in sepsis, among which there is substantial heterogeneity. This study aimed to provide an overview of existing systematic reviews of randomized controlled trials by using a comprehensive search method. We searched MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews. Of 895 records screened, 19 systematic reviews were included. The target agent was as follows: antithrombin (n = 4), recombinant thrombomodulin (n = 3), heparin (n = 3), recombinant activated protein C (n = 8), and all anticoagulants (n = 1). Antithrombin did not improve mortality in critically ill patients but indicated a beneficial effect in sepsis-induced disseminated intravascular coagulation (DIC), although the certainty of evidence was judged as low. Recombinant thrombomodulin was associated with a trend in reduced mortality in sepsis with coagulopathy with no increased risk of bleeding, although the difference was not statistically significant and the required information size for any declarative judgement insufficient. Although three systematic reviews showed potential survival benefits of unfractionated heparin and low-molecular-weight heparin in patients with sepsis, trials with low risk of bias were lacking, and the overall impact remains unclear. None of the meta-analyses of recombinant activated protein C showed beneficial effects in sepsis. In summary, a beneficial effect was not observed in overall sepsis in poorly characterized patient groups but was observed in sepsis-induced DIC or sepsis with coagulopathy in more specific patient groups. This umbrella review of anticoagulant therapy suggests that characteristics of the target populations resulted in heterogeneity among the systematic reviews.
Highlights
Sepsis is a life-threatening condition with high morbidity and mortality that remains an important public health problem
We found four published systematic reviews of antithrombin [10,11,13,28], among which we observed significant heterogeneity
Two systematic reviews focused on patients with sepsis-induced disseminated intravascular coagulation (DIC) and reported beneficial effects on mortality [11,13]. In this meta-analysis, post hoc analyses of the KyperSept trial accounted for 51% relative weight. This sub-analysis evaluated the antithrombin effect in KyperSept patients with DIC who did not receive concomitant heparin, and antithrombin-treated patients were associated with reduced mortality (28-day mortality: 22.2% with antithrombin vs. 40.0% with placebo, p < 0.01) [29]
Summary
Sepsis is a life-threatening condition with high morbidity and mortality that remains an important public health problem. Systemic activation of the coagulation system is frequently observed in patients with sepsis, and mortality increases in accordance with the increased severity of the coagulopathy [1,2,3]. Several anticoagulants agents, such as antithrombin, recombinant activated protein C (rAPC), recombinant thrombomodulin (rTM), heparin, and tissue factor pathway inhibitor, have been expected and evaluated as adjunctive therapy for the management of sepsis [4,5,6]. There is substantial heterogeneity among these systematic reviews, and clinical evidence for the therapy remains controversial
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