1.
Effects of combination therapy of antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation: a systematic review and meta-analysis
Totoki, T., Makino, Y., Yamakawa, K., Koami, H., Wada, T., Ito, T., Iba, T.
Thrombosis journal. 2024;22(1):10
Abstract
BACKGROUND Disseminated intravascular coagulation (DIC) syndrome is a highly lethal condition characterized by the complication of multiple organ damage. Although the effects of combined antithrombin (AT) and recombinant thrombomodulin (rTM) on DIC syndrome have previously been examined, the results are inconsistent and inconclusive. Therefore, we conducted a systematic review on the combined administration of AT and rTM for the treatment of septic DIC to investigate the superiority of the combination therapy over either AT or rTM monotherapy using a random-effects analysis model. METHOD We searched electronic databases, including Medline, Cochrane Central Register of Controlled Trials, Scopus, and Igaku-Chuo Zasshi (ICHU-SHI) Japanese Central Review of Medicine Web from inception to January 2022. Studies assessing the efficacy of combined AT and rTM were included. The primary outcome was all-cause mortality, and the secondary outcome was occurrence of serious bleeding complications compared to monotherapy. We presented the pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence intervals (CI) depending on reporting results in each primary study. RESULTS We analyzed seven enrolled clinical trials, all of which were observational studies. Combination therapy had a non-significant favorable association with lower 28-day mortality compared to monotherapy (HR 0.67 [0.43-1.05], OR 0.73 [0.45-1.18]). The I(2) values were 60% and 72%, respectively, suggesting high heterogeneity. As a secondary outcome, bleeding complications were similar between the two groups (pooled OR 1.11 [0.55-2.23], I(2) value 55%). CONCLUSIONS Although the findings in this analysis could not confirm a statistically significant effect of AT and rTM combination therapy for septic DIC, it showed a promising effect in terms of improving mortality. The incidence of bleeding was low and clinically feasible. Further research is warranted to draw more conclusive results. TRIAL REGISTRATION This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID 000049820).
2.
Efficacy and safety of recombinant human soluble thrombomodulin in patients with sepsis-induced disseminated intravascular coagulation - A meta-analysis
Kato H, Hagihara M, Asai N, Umemura T, Hirai J, Mori N, Yamagishi Y, Iwamoto T, Mikamo H
Thrombosis research. 2023;226:165-172
Abstract
BACKGROUND Recombinant human soluble thrombomodulin (rhTM) is used to treat sepsis-induced disseminated intravascular coagulation (DIC). However, no consistent clinical guidelines exist regarding the administration of rhTM in patients with sepsis-induced DIC. Therefore, we conducted this meta-analysis to evaluate the efficacy and safety of rhTM therapy in patients with sepsis-induced DIC. METHODS EMBASE, PubMed, Scopus, Ichushi, and CINAHL databases were used to search for relevant articles that met the inclusion criteria of patients with sepsis-induced DIC treated with and without rhTM through November 2022. Mortality, DIC resolution, and incidence of bleeding complications were evaluated. DIC resolution was defined as the recovery from DIC after the start of DIC treatment. RESULTS Of the 1697 citations identified for screening, 17 studies involving 2296 patients were included. Administering rhTM significantly reduced mortality (odds ratio (OR) 0.54, 95 % confidence interval (CI) 0.42-0.71) and improved DIC resolution (OR 2.88, 95 % CI 1.83-4.52). There were no significant differences in the incidence of bleeding complications between the rhTM and control groups (OR 0.92, 95 % CI 0.66-1.28). CONCLUSIONS Our meta-analysis revealed that rhTM could reduce mortality and improve DIC resolution without increasing the risk of bleeding in patients with sepsis-induced DIC. Our findings suggest that rhTM is a relatively effective and safe anticoagulant for the treatment of sepsis-induced DIC. SUMMARY Recombinant human soluble thrombomodulin reduced mortality without increasing the bleeding risk in the treatment of sepsis-induced disseminated intravascular coagulation.
3.
Outcomes of cancer patients treated with drotrecogin alfa (activated) for severe sepsis
Joyce D, Leclerc J, Nelson D, Levy H, Garg R
Journal of Clinical Oncology. 2004;22((14_suppl)):6055
Abstract
6055 Background: Drotrecogin alfa (activated) (Xigris; DAA), was approved for the treatment of severe sepsis in many countries based on a pivotal phase 3 trial of 1690 patients. DAA, has antithrombotic, profibrinolytic and anti-inflammatory properties and may improve microvascular thrombosis to reduce organ dysfunction in sepsis. We are reporting 1-month mortality outcomes among 303 patients with any prior or current history of malignancy enrolled in this pivotal trial (PROWESS). METHODS A post-hoc subgroup analysis was preformed on the 303 PROWESS cancer patients with acute sepsis-related organ dysfunction and who received standard therapy and either DAA at 24ug/kg/hr or placebo for 96 hrs. Patients were excluded for increased bleeding risk, including platelet count<30K/mm3, history of bone marrow transplant, poorly controlled neoplasm, or likely death from a non-sepsis cause within 28-days. Mortality and bleeding were evaluated at the 28-day PROWESS endpoint and mortality at 1-year. RESULTS Compared to the entire cohort cancer patients were older, had more chronic health points, and higher APACHE II scores. Cancer patients had a lower survival rate than the overall PROWESS group. Cancer patients experienced a significant treatment effect (28-day relative risk: 0.68) similar to the overall trial population (RR: 0.80). This benefit was similar at one year. Cancer and PROWESS patients experienced a similar rate of serious adverse bleeding events. CONCLUSIONS CONCLUSION DAA is efficacious and safe in patients with severe sepsis and early stage cancer or a history of malignancy. Despite increased baseline morbidity, DAA produced an increase in 28-day survival in cancer patients that was similar to the overall trial population. This treatment effect appeared to persist over the first year following the severe sepsis episode. [Figure: see text] [Table: see text].