Efficacy and Safety of Anticoagulant Therapy in Patients with Sepsis: A Meta-Analysis of Randomized Controlled Trials

Efficacy and Safety of Anticoagulant Therapy in Patients with Sepsis: A Meta-Analysis of Randomized Controlled Trials | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 20 January 2025 V1 Latest version Share on Efficacy and Safety of Anticoagulant Therapy in Patients with Sepsis: A Meta-Analysis of Randomized Controlled Trials Authors : Qi Wang , jiayu wu 0000-0002-5837-2064 , Wenhao Tang , and Hong zhang [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.173734933.31991654/v1 Published Thrombosis Journal Version of record Peer review timeline 278 views 140 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: At present, a consistent and standardized method for evaluating the effectiveness and safety of anticoagulant treatment in such patients remains lacking. Objective: The purpose of this research was to assess the efficacy and safety of anticoagulant treatment for patients with sepsis. Methods: A comprehensive search was carried out on PubMed, Embase and Cochrane Library to identify Randomized Controlled Trials (RCTs) which compared the efficacy and safety of anticoagulants with placebo or no treatment in patients with sepsis. The reduction in 28/30-day all-cause mortality or the regression of disseminated intravascular coagulation (DIC) was regarded as effective, while bleeding complications constituted the most prevalent adverse events. Results: A sum of 19 RCTs encompassing 8,177 patients were incorporated. In all sepsis patients, the anticoagulant group exhibited an 8% decrease in the death risk when contrasted with the placebo group. The combined relative risk [RR] was 0.92 (with a 95% confidence interval [CI] of 0.86 - 0.98; P = 0.02). Anticoagulant therapy might potentially reduce patient mortality (RR 0.87, 95% CI 0.62 - 1.22, P = 0.42) and enhance the regression rate of DIC (RR 1.62, 95% CI 1.32 - 2, P < 0.00001) in 6 studies with a baseline of DIC. Nevertheless, the employment of anticoagulants augmented the bleeding risk in patients (RR 1.31, 95% CI 1.16 - 1.49, P < 0.0001). Conclusion: The research discovered that anticoagulant treatment lessened the mortality rate among patients with sepsis and enhanced the regression of DIC in those patients with sepsis - associated DIC. Efficacy and Safety of Anticoagulant Therapy in Patients with Sepsis: A Meta-Analysis of Randomized Controlled Trials Author: Qi Wang 1,2 ，JiaYu Wu 1 ，WenHao Tang 1 ，Hong Zhang 1* Affiliation: 1 The First Affiliated Hospital of Anhui Medical University, HeFei, AnHui, China; 2 The Second Hospital of JiaXing, JiaXing, ZheJiang, China; *Corresponding author: Hong Zhang(MD, PhD); ORCID iD: https://orcid.org/0000-0002-5837-2064; The First Affiliated Hospital of Anhui Medical University; HeFei(Zip-kod:230031), AnHui, China; Emai: [email protected] ; Formatting of funding sources: The research was funded by the Anhui Provincial Health Research Project (AHWJ2023A10095) and the Anhui Provincial University Natural Science Research Project (2023AH040079). Efficacy and Safety of Anticoagulant Therapy in Patients with Sepsis: A Meta-Analysis of Randomized Controlled Trials Qi Wang, JiaYu Wu,WenHao Tang, Hong Zhang* Abstract Background: Coagulation dysfunction exerts a substantial influence on the prognosis of patients suffering from sepsis. At present, a consistent and standardized method for evaluating the effectiveness and safety of anticoagulant treatment in such patients remains lacking. Objective: The purpose of this research was to assess the efficacy and safety of anticoagulant treatment for patients with sepsis. Methods: A comprehensive search was carried out on PubMed, Embase and Cochrane Library to identify Randomized Controlled Trials (RCTs) which compared the efficacy and safety of anticoagulants with placebo or no treatment in patients with sepsis. The reduction in 28/30-day all-cause mortality or the regression of disseminated intravascular coagulation (DIC) was regarded as effective, while bleeding complications constituted the most prevalent adverse events. Results: A sum of 19 RCTs encompassing 8,177 patients were incorporated. In all sepsis patients, the anticoagulant group exhibited an 8% decrease in the death risk when contrasted with the placebo group. The combined relative risk [RR] was 0.92 (with a 95% confidence interval [CI] of 0.86 - 0.98; P = 0.02). Anticoagulant therapy might potentially reduce patient mortality (RR 0.87, 95% CI 0.62 - 1.22, P = 0.42) and enhance the regression rate of DIC (RR 1.62, 95% CI 1.32 - 2, P < 0.00001) in 6 studies with a baseline of DIC. Nevertheless, the employment of anticoagulants augmented the bleeding risk in patients (RR 1.31, 95% CI 1.16 - 1.49, P < 0.0001). Conclusion: Although anticoagulant therapy might lead to a rise in the occurrence rate of bleeding complications, it has been correlated with a survival advantage for patients with sepsis. The research discovered that anticoagulant treatment lessened the mortality rate among patients with sepsis and enhanced the regression of DIC in those patients with sepsis - associated DIC. Keywords: Sepsis; Disseminated Intravascular Coagulation; Anticoagulants; Meta-analysis. 1.Background Sepsis is currently considered to be a serious and potentially fatal clinical syndrome caused by the host’s immune response to infection disorders or dysfunction [1,2] . In 2017, the World Health Organization (WHO) carried out an extensive study on sepsis [3] . The findings indicated that there were around 48.9 million occurrences of sepsis globally. Alarmingly, among these cases, 11 million led to fatalities, accounting for a staggering 19.7% of all deaths worldwide. Evidently, sepsis persists as a principal contributor to the loss of global health. Despite the fact that adherence to the Surviving Sepsis Campaign has led to a decline in sepsis mortality in recent times, the diagnosis and treatment of sepsis continue to constitute a central focus within global health research endeavors [4,5] . The onset and progression of sepsis are highly intricate, being associated with factors such as inflammatory response and coagulation dysfunction. Patients with sepsis display aberrant coagulation function, giving rise to distinctive clinical manifestations. In the initial phase of sepsis, the inflammatory response triggers the activation of the coagulation system, which assists the host in eradicating microorganisms and serves a defensive purpose. Nevertheless, protracted inflammation induces extensive activation of the coagulation system, overpowering the anticoagulation system and culminating in coagulation dysfunction. This can lead to the formation of intravascular thrombosis and the excessive depletion of platelets and coagulation factors. In severe cases, it develops into disseminated intravascular coagulation (DIC), resulting in extensive bleeding and organ dysfunction [6] . Research has demonstrated [7] that the likelihood of organ dysfunction and mortality in patients with sepsis and septic shock rises with the worsening of coagulation abnormalities. Rough statistics indicate [8] that patients with sepsis have an incidence of coagulation dysfunction ranging from 50% to 70%, and an incidence of DIC of approximately 35%. In 2017, the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Hemostasis (ISTH) proposed the concept and diagnostic criteria of sepsis-induced coagulopathy (SIC) [9] . It is employed for the early detection of coagulation dysfunction in patients with sepsis and for the determination of target groups for treatment. At present, the mechanism of SIC is thought to involve excessive activation of the coagulation system, relative insufficiency of the physiological anticoagulation system, inhibition of the fibrinolysis system, activation of platelets, formation of neutrophil extracellular traps, release of microsomes and alteration of the vascular endothelial glycocalyx structure [10,11] . Therefore, it is plausible to hypothesize that the application of anticoagulants to restrain the overactivated coagulation cascade might be conducive to the alleviation of DIC and the diminution of mortality among patients with sepsis. In recent decades, several anticoagulants have been used as adjuvant therapy for patients with sepsis and have been evaluated [12-17] . These encompass recombinant human thrombomodulin (rhTM), recombinant human activated protein C (rhAPC), antithrombin (AT), tissue factor pathway inhibitor (TFPI), unfractionated heparin (UFH) and low-molecular weight heparin (LMWH). However, they have not led to a substantial reduction in mortality, and the potential risk of bleeding cannot be overlooked. However, several observational studies and subgroup analyses of RCTs suggest [18-20] that anticoagulant therapy may reduce mortality in patients with disseminated intravascular coagulation caused by sepsis. Studies have demonstrated [21-23] that administering rhTM or AT to patients with sepsis-induced DIC can decrease patient mortality. The possible reasons for this include differences in the timing of anticoagulant therapy and significant patient heterogeneity. Overall, there is a lack of a unified understanding regarding the efficacy and safety of anticoagulant therapy in sepsis patients. The objective of this study is to carry out a meta-analysis of the currently available RCTs, with the intention of comparing the efficacy and safety of anticoagulant therapy in patients afflicted with sepsis and thereby providing theoretical underpinning for the clinical management of this condition. 2.1 Search strategy A methodical search was carried out on PubMed, Embase, and Cochrane Library to identify randomized controlled trials (RCTs) that were published prior to November 2023. The following search keywords were utilized: ((sepsis) OR (bloodstream infection) OR (pyemia) OR (pyemias) OR (septicemia) OR (SARS-CoV-2) OR (2019 Novel Coronavirus) OR (COVID-19 viruses) OR (Severe Acute Respiratory Syndrome Coronavirus 2) OR (Wuhan Coronavirus)) AND ((anticoagulants) OR (blood coagulation factor inhibitors) OR (heparin) OR (LMWH) OR (rTM) OR (ART- 123) OR (TFPI) OR (antithrombins) OR (APC) OR (dabigatran) OR (rivaroxaban) OR (warfarin) OR (fondaparinux) OR (gabexate)). 2.2 Inclusion and exclusion criteria The study’s inclusion criteria were as follows: (1) Randomized controlled trials (RCTs); (2) Patients with sepsis and novel coronavirus infection; (3) Evaluation of the impact of anticoagulant therapy on mortality, DIC regression rate and bleeding complications in patients with sepsis; (4) Age ≤ 18 years; (5) Access to the full text. Exclusion criteria for this study are: (1) Repetition of previous studies; (2) Review articles, meta-analyses, case reports, and observational studies; (3) Animal experiments; (4) Inconsistent research content; (5) Combined use of multiple anticoagulants; (6)A age < 18 years; (7) Full text not available. 2.3 Literature screening and data extraction Two independent reviewers carried out a comprehensive literature search and meticulously read the retrieved literature in its entirety. The data were systematically screened and precisely extracted in accordance with the pre-defined inclusion and exclusion criteria. In the event of any disagreements or discrepancies, they were resolved through in-depth discussion and mutual consensus. If the discrepancies still remained unresolved, a third-party expert opinion was solicited for final adjudication. The process of data extraction involved collecting information on the author’s name, year of publication, research location, number of research centers, number of patients, type of anticoagulant administered, and measurement of results. The definition of DIC must meet the diagnostic criteria. Various definitions of DIC have been proposed by individual study authors, such as the Japanese Ministry of Health and Welfare (JMHW) DIC standard, the International Society of Thrombosis and Hemostasis (ISTH) dominant DIC standard, the ISTH non-dominant DIC standard, and the Japan Acute Medical Association (JAAM) DIC standard or the author’s original standard. The study’s primary outcome was the all-cause mortality rate at 28 days. If this value was not available, the mortality rate at 30 or 90 days or another time point was used for the meta-analysis. Secondary outcomes included the rate of DIC regression and bleeding complications. DIC was diagnosed based on a diverse range of criteria. Regression of DIC was regarded as having been attained when the specific criteria could no longer be fulfilled subsequent to anticoagulant therapy. Bleeding complications are defined as any complication that aligns with the criteria detailed in the respective individual manuscripts. All reported severe or minor bleeding incidents are categorized as bleeding complications. 2.4 literature quality assessment The quality of the literature was evaluated using the Cochrane Systematic Evaluation manual’s recommended quality evaluation method. The evaluation method included seven aspects: (1) Random sequence generation; (2) Allocation concealment; (3) Blinding of participants and personnel; (4) Blinding of outcome assessment; (5) Incomplete outcome data; (6) Selective reporting; (7) Other bias. Each aspect was evaluated independently and strictly. According to the criteria recommended by the Cochrane Collaboration, we applied a uniform standard for assessing the risk of bias associated with a single randomized controlled trial, and determined ’low risk of bias’, ’unclear’ and ’high risk of bias’ for each item. 2.5 Statistical analysis Data analysis was performed using Review Manager 5.4.1. The Mantel-Haenszel method was used to analyze the dichotomous variables. The results for relative risk (RR) were presented with a 95% confidence interval (CI). Statistical significance was considered at a P value of less than 0.05. Heterogeneity was assessed using the I 2 index and P value [24,25] . If I 2 was less than 50% and the P value was greater than 0.1, the results for each group were considered to have no statistical heterogeneity or only small heterogeneity, and the fixed effect model was used for analysis. On the contrary, it means that there is at least moderate heterogeneity, and the reliability of the results can be ensured by subgroup analysis or sensitivity analysis, changing the model, and removing the maximum weight or minimum weight method. The existence of publication bias was assessed by visual inspection of the funnel plot. 3.Results 3.1 literature search The PRISMA flow diagram, as shown in Figure 1, was selected for the meta-analysis. A total of 10,590 studies were retrieved. After excluding reviews, meta-analyses, case reports, and retrospective studies, 919 studies remained. After title and abstract screening, 748 studies were excluded. The remaining 171 studies were read in full, and 94 of these were excluded because they were duplicates, full text was not available, they were ongoing, or they did not meet our inclusion criteria. Ultimately, we included 19 studies, which involved a total of 8177 patients. 3.2 Basic characteristics of the included studies Table 1 displays the fundamental features of the studies included, with 8 international multicenter RCTs [17,26-32] . One multicenter randomized controlled trial was conducted in Japan [14] and another in the United States [33] . The remaining 9 RCTs were single-center studies conducted in various countries [12,13,15,16,34-38] . All studies focused on sepsis patients. 3.3 Results of bias risk assessment Figure 2 and Figure 3 present the results of the bias risk assessment in detail. Overall, only three studies were found to have a high risk of bias due to non-double-blind or random allocation based on hospitalization numbers. Eight studies had a low risk of bias, and the remaining eight studies had an unknown bias risk. Of these, six studies were randomly assigned, but the authors did not specify, and two studies did not describe whether they were double-blind. The primary source of bias in the trials included was the insufficient description of allocation concealment. 3.4 Mortality rate All 19 RCTs reported all-cause mortality either at 28/30 days or at the end of the study. The RR of the included RCTs ranged from 0.57 to 1.76. Only one trial found a protective effect of anticoagulant therapy on mortality, while the other 18 studies found no effect. Figure 4 displays the pooled RR of all eligible patients with death, indicating that anticoagulant therapy is associated with lower mortality (1153/4171 [27.6 %] vs. 1198/4006 [29.9 %]; RR 0.92, 95% CI 0.86 to 0.98, P = 0.02). The anticoagulant group showed a 8% reduction in the risk of death. The difference between the two groups was statistically significant, and no heterogeneity as observed ( I 2 = 0%, P = 0.49). The pooled RR of anticoagulants in each subgroup ranged from 0.67 to 0.99, and the heterogeneity among different anticoagulants was not statistically significant ( I 2 = 0%, P = 0.78). The mortality rate of each anticoagulant intervention group was lower than that of the control group, and the RR value of the gabexate group was the lowest (0.67). The RR value of the TFPI group was the highest (0.99). However, only the AT group was statistically significant ( P = 0.04), and no heterogeneity was observed within the group ( I 2 = 0%, P = 0.85). Six studies analyzed the mortality of patients with DIC at baseline, with a total of 356 patients. Figure 5 shows that anticoagulant therapy could reduce the mortality of patients with sepsis and DIC, but the results were not statistically significant. The pooled RR was 0.87 (95% CI 0.62 ~ 1.22, P = 0.42), and no heterogeneity was observed ( I 2 = 0%, P = 0.55). AT can significantly reduce the mortality of sepsis patients with DIC, but the difference was not statistically significant ( P = 0.06). 3.5 DIC regression Six RCTs reported on the regression of DIC during treatment in patients with DIC at baseline. The included RCTs had an RR ranging from 1.18 to 15, and four trials found a positive effect of anticoagulant therapy on DIC regression. Figure 6 displays the pooled RR of DIC regression in all eligible patients. The incidence of DIC regression in the anticoagulant group increased by 62%, and the difference between the two groups was statistically significant ( P < 0.00001; RR 1.62, 95% CI 1.32-2). No significant heterogeneity was observed ( I 2 = 45%, P = 0.11). The pooled RR of anticoagulants in each subgroup ranged from 0.67 to 0.97, and there was significant heterogeneity among different anticoagulants ( I 2 = 85.9%, P = 0.008). Both the AT and rhTM groups showed positive results with a P value of less than 0.05. 3.6 Bleeding complications Bleeding complications were reported in 13 trials involving 8064 patients. The risk ratio (RR) of the included randomized controlled trials (RCTs) ranged from 0.34 to 7.43, with three trials showing a significant increase in the risk of bleeding complications associated with anticoagulant therapy. Figure 7 displays the incidence of bleeding complications in all eligible patients, as pooled with RR. The pooled RR indicates that anticoagulant therapy is associated with bleeding (RR 1.31, 95% CI 1.16-1.49; P < 0.0001), with no observed heterogeneity ( I 2 = 0%, P = 0.59). The pooled RR of anticoagulants in each subgroup ranged from 0.34 to 7.43, with no heterogeneity observed between different anticoagulants ( I 2 = 0%, P = 0.55). Except for the Garadacimab group, the incidence of bleeding complications in each subgroup of anticoagulant therapy was higher than that in the control group, and the difference between the AT group and the APC group was statistically significant ( P = 0.01 and 0.008). 3.7 Publication bias Through the funnel plot of visual assessment, we found no evidence of publication bias (Figure. 8). 4.Discussions Sepsis represents a life-threatening condition whose outcome is highly time-dependent and continues to be associated with a generally unfavorable prognosis. Diffuse intravascular coagulation is a confirmed complication that leads to a high fatality rate in sepsis. Nevertheless, contemporary research concerning anticoagulant therapy in the context of sepsis remains a subject of intense debate and contention. The meta-analysis reveals that anticoagulants possess a potential protective influence on the mortality of sepsis patients. The results manifest that anticoagulant therapy confers a statistically remarkable benefit regarding the mortality of such patients, diminishing the death risk by 15%. Moreover, anticoagulant therapy might curtail the mortality in sepsis patients with DIC, albeit without statistical significance. Secondly, both antithrombin (AT) and recombinant human thrombomodulin (rhTM) can substantially enhance DIC regression in patients with sepsis-induced coagulopathy (SIC), and the disparity is statistically significant. Although anticoagulant therapy can reduce mortality and improve DIC regression in patients with sepsis, our analysis also shows that anticoagulant therapy is associated with an increased risk of bleeding adverse events. A meta-analysis [39] of 24 RCTs on the efficacy of anticoagulant therapy for sepsis showed that anticoagulant therapy did not significantly reduce mortality, and there was no statistical significance, with a pooled RR of 0.97 (95% CI 0.92-1.02, P = 0.25). However, anticoagulant therapy was found to significantly reduce the mortality of sepsis-associated DIC patients (RR = 0.72, 95% CI = 0.62-0.85; P < 0.01). A key distinction of our analysis from the meta-analysis conducted by Umemura Y et al. is that our study neither encompasses the research on the combined use of multiple anticoagulants nor focuses solely on the population using a single anticoagulant within the selected studies for analysis. In contrast to the conclusions drawn by Umemura Y et al.’s meta-analysis, our analysis demonstrates that anticoagulant therapy contributes to a decrease in the mortality rate among patients with sepsis or sepsis-associated DIC. However, among sepsis-associated DIC patients, the reduction in mortality failed to attain statistical significance. Intriguingly, the rhTM and AT groups presented contrasting results. We hypothesize that this discrepancy may originate from the differences in the diagnostic criteria for sepsis-associated DIC across various studies, consequently leading to inconsistent findings concerning the effectiveness of different anticoagulants in patients with sepsis-associated DIC. Furthermore, the timing of anticoagulant treatment exerts a profound and substantial impact on the prognosis of sepsis patients. In an observational study [40] involving 1787 patients with sepsis-related DIC, the 28-day survival rates were 66.4%, 48.5%, and 31.1% when anticoagulant therapy was commenced on the same day, 4 days, and more than 7 days after DIC diagnosis, respectively. These findings imply that an earlier initiation of rhTM following the diagnosis of coagulopathy might confer more pronounced survival advantages. The coagulation phenotype of the sepsis population differs significantly from that of the non-sepsis population. Studies have shown [41,42] that the coagulation process in sepsis is related to the body’s innate immune system. Immune cells and complements are capable of interacting with platelets, thereby giving rise to local thrombosis within the microvessels. This physiological process is referred to as ’immunothrombosis’, which serves to identify and constrain tissue invasion as well as pathogen dissemination, consequently diminishing their survival rate. The local nature of immune thrombosis ensures that it does not significantly interfere with overall organ perfusion. While the innate immune response might initially confer benefits upon the body, persistent and excessive inflammation can trigger the uncontrolled activation of thrombus, which represents the initial physiological phase in the development of DIC [43,44] . This can culminate in extensive thrombosis, thereby giving rise to the emergence of thrombotic diseases that deviate from the scope of host defense mechanisms. Our analysis demonstrates that anticoagulant therapy has the capacity to enhance DIC regression in patients who already have DIC at the baseline level. A meta-analysis previously published by Umemura Y et al.showed [39] that anticoagulant therapy was associated with a significantly increased risk of bleeding complications in patients with sepsis. Although our results are different from those of Umemura Y et al.in terms of survival benefits, the risk of bleeding complications is similar to their previous meta-analysis. The decision to use anticoagulant therapy depends on the efficacy and safety of balanced anticoagulant therapy for sepsis. Based on our analysis, it is important to consider the potential risks of anticoagulant therapy, such as an increased risk of bleeding, despite its potential to reduce patient mortality. Further large randomized controlled trials are necessary to establish a stronger theoretical basis. Our research has several advantages. Firstly, we only included randomized controlled trials (RCTs), which enhances the credibility of our research findings. Secondly, our study enriches the existing literature on sources of infection in sepsis patients by incorporating the recent outbreak of novel coronavirus infection. Lastly, this study excludes investigations involving the combined usage of multiple anticoagulants or solely focusing on a specific subset of individuals using a single anticoagulant for analysis. There are limitations to this meta-analysis. Firstly, the RCT included in this study spans a long period, resulting in differences in the diagnostic criteria of sepsis and no standardized definition of DIC. Various DIC diagnostic criteria proposed in the original study were accepted, such as the JMHW DIC standard, the ISTH dominant DIC standard, the ISTH non-dominant DIC standard, and the JAAM DIC standard or the author’s original standard. Secondly, the anticoagulants used in each study vary in type, dosage form, dose, and duration, and their pharmacological effects differ. Thirdly, bleeding complications are described differently in various studies. Some studies only report the incidence of severe bleeding adverse events, and different studies have different definitions of severe bleeding adverse events. Therefore, this study considers bleeding complications to include all bleeding events mentioned in each study. It is important to note that there may be variations in the degree of bleeding between different studies, which could introduce bias in the results of bleeding complications. Additionally, the sample size of patients with DIC at baseline is small, with only 356 patients. Therefore, more large RCTs are needed to compare the potential effects of anticoagulants on the mortality of sepsis-associated DIC patients. 5.Conclusion Our meta-analysis reveals that, notwithstanding the fact that anticoagulant therapy augments the incidence of bleeding complications, it can enhance the prognoses of patients afflicted with sepsis and sepsis-induced DIC. It is of paramount importance to strike a balance between the advantages of anticoagulant therapy and the bleeding risk in clinical practice, particularly when dealing with patients suffering from sepsis. Additional evidence is essential to buttress the assessment of the merits and demerits of anticoagulant therapy for this specific patient cohort. Acknowledgements None. DISCLOSURE All authors have no potential conflicts of interest. Data Availability The datasets analyzed in the present study are available from the published papers that have been cited in this manuscript. 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[36] 1997 Germany 1 40 20 20 AT placebo Warren,B.L.et al. [28] 2001 Multinational 211 698 352 346 AT placebo Gando,S.et al. [14] 2013 Japan 13 60 30 30 AT w/o AT APC Bernard,G.R.et al. [29] 2001 Multinational 164 1690 850 840 APC placebo Bernard, G. R. et al. [30] 2001 Multinational 40 131 90 41 APC placebo Ranieri,V.M.et al. [31] 2012 Multinational 208 1680 846 834 APC placebo Pappalardo,F.et al. [13] 2016 Italy 1 37 19 18 APC placebo Gabexate Hsu,J.T.et al. [37] 2004 China 1 50 25 25 Gabexate placebo Garadacimab Papi,A.et al. [33] 2023 U.S 14 124 63 61 Garadacimab placebo LMWH Ai,Y.H.et al. [15] 2005 China 1 40 22 18 LMWH placebo Heparin Fabia´n.et al. [38] 2009 Cuba 1 317 158 159 Heparin placebo Liu,X.L.et al. [16] 2014 China 1 37 22 15 Heparin placebo TFPI Abraham,E.et al. [32] 2001 Multinational 38 210 141 69 TFPI placebo Abraham,E.et al. [17] 2003 Multinational 245 1754 880 874 TFPI placebo Supplementary Material File (table1.docx) Download 61.49 KB Information & Authors Information Version history V1 Version 1 20 January 2025 Peer review timeline Published Thrombosis Journal Version of Record 2 Dec 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords adverse drug reactions clinical pharmacology clinical pharmacy medication safety Authors Affiliations Qi Wang The First Affiliated Hospital of Anhui Medical University View all articles by this author jiayu wu 0000-0002-5837-2064 The First Affiliated Hospital of Anhui Medical University View all articles by this author Wenhao Tang The First Affiliated Hospital of Anhui Medical University View all articles by this author Hong zhang [email protected] The First Affiliated Hospital of Anhui Medical University View all articles by this author Metrics & Citations Metrics Article Usage 278 views 140 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Qi Wang, jiayu wu, Wenhao Tang, et al. Efficacy and Safety of Anticoagulant Therapy in Patients with Sepsis: A Meta-Analysis of Randomized Controlled Trials. Authorea . 20 January 2025. 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