Background Tranexamic acid (TXA) reduces surgical bleeding and reduces death from bleeding after trauma and childbirth. However, its effects on thrombotic events and seizures are less clear. We conducted a systematic review and meta-analysis to examine the safety of TXA in bleeding patients. Methods For this systematic review and meta-analysis, we searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled trials from inception until June 1, 2020. We included randomized trials comparing intravenous tranexamic acid and placebo or no intervention in bleeding patients. The primary outcomes were thrombotic events, venous thromboembolism, acute coronary syndrome, stroke and seizures. A meta-analysis was performed using a random effects model and meta-regression analysis was performed to evaluate how effects vary by dose. We assessed the certainty of evidence using the grading of recommendations, assessment, development and evaluations (GRADE) approach. Results A total of 234 studies with 102,681 patients were included in the meta-analysis. In bleeding patients, there was no evidence that TXA increased the risk of thrombotic events (RR = 1.00 [95% CI 0.93–1.08]), seizures (1.18 [0.91–1.53]), venous thromboembolism (1.04 [0.92–1.17]), acute coronary syndrome (0.88 [0.78–1.00]) or stroke (1.12 [0.98–1.27]). In a dose-by-dose sensitivity analysis, seizures were increased in patients receiving more than 2 g/day of TXA (3.05 [1.01–9.20]). Meta-regression showed an increased risk of seizures with increased dose of TXA (p = 0.011). Conclusion Tranexamic acid did not appear to increase the risk of thrombotic events in bleeding patients. However, because there may be dose-dependent increase in the risk of seizures, very high doses should be avoided.
Background Clinical effectiveness of recombinant human soluble thrombomodulin (rhTM) in sepsis or sepsis-induced coagulopathy remains a matter of dispute. Recently, the Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin (SCARLET) trial, the latest multinational multi-centre phase III randomized controlled trial, was completed. Objective This article assesses the benefits and harms of rhTM therapy in sepsis-induced coagulopathy by updating our previous systematic review. Methods We performed a systematic review and meta-analysis of rhTM therapy for sepsis-induced coagulopathy in randomized controlled trials. All-cause 28-day mortality as efficacy and serious bleeding complications as the adverse effect were measured as primary outcomes. We assessed the certainty of a body of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation approach. Results We analysed five trials enrolling 1,762 patients. Approximately 13% reduction in the risk of mortality was observed in the rhTM group, but the difference was not significant (relative risk, 0.87; 95% confidence interval, 0.74–1.03; p = 0.10; I 2 = 0%). Risk of serious bleeding complications did not increase with rhTM administration. We judged the certainty of evidence as moderate for mortality and low for serious bleeding. Trial sequential analysis indicated that only 42.0% of the required information size is actually available at this stage to reject or accept low risk-of-bias trials examining the anticipated effect for all-cause mortality. Conclusion Even in this updated review including the latest SCARLET trial, we currently cannot make any declarative judgments about the beneficial effects of rhTM in sepsis-induced coagulopathy, although some favourable effects were suggested.
Optimizing diagnostic criteria to detect specific patients likely to benefit from anticoagulants is warranted. A cutoff of 5 points for the International Society on Thrombosis and Haemostasis overt disseminated intravascular coagulation (DIC) scoring system was determined in the original article, but its validity was not evaluated. This study aimed to explore the optimal cutoff points of DIC scoring systems and evaluate the effectiveness of early intervention with anticoagulants. We used a nationwide retrospective registry of consecutive adult patients with sepsis in Japan to develop simulated survival data, assuming anticoagulants were conducted strictly according to each cutoff point. Estimated treatment effects of anticoagulants for in-hospital mortality and risk of bleeding were calculated by logistic regression analysis with inverse probability of treatment weighting using propensity scoring. Of 2663 patients with sepsis, 1247 patients received anticoagulants and 1416 none. The simulation model showed no increase in estimated mortality between 0 and 3 cutoff points, whereas at ≥4 cutoff points, mortality increased linearly. The estimated bleeding tended to decrease in accordance with the increase in cutoff points. The optimal cutoff for determining anticoagulant therapy may be 3 points to minimize nonsurvival with acceptable bleeding complications. The findings of the present study suggested a beneficial association of early intervention with anticoagulant therapy and mortality in the patients with sepsis-induced DIC. Present cutoff points of DIC scoring systems may be suboptimal for determining the start of anticoagulant therapy and delay its initiation.
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.
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