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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).
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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.
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3.
Efficacy and Safety of Andexanet Alfa for Bleeding Caused by Factor Xa Inhibitors: A Systematic Review and Meta-Analysis
Shrestha DB, Budhathoki P, Adhikari A, Shrestha S, Khati N, Mir WAY, Joshi T, Shrestha A
Cureus. 2021;13(12):e20632
Abstract
Direct oral anticoagulants (DOAC) including factor Xa inhibitors are associated with bleeding events which can lead to severe morbidity and mortality. Reversal agents like andexanet alfa (AA) and 4F-PCC (Four-factor prothrombin concentrate complex) are available for treating bleeding that occurs with DOAC therapy but a comparison on their efficacy is lacking. In this study, we analyzed the efficacy and safety of patients treated with andexanet alfa for bleeding events from DOAC. Databases were searched for relevant studies where AA was used to determine efficacy and safety in bleeding patients who were on factor Xa inhibitors. Published papers were screened independently by two authors. RevMan 5.4 (The Cochrane Collaboration, 2020) was used for data synthesis. Odds ratio (OR) and mean difference (MD) was used to estimate the outcome with a 95% confidence interval (CI). Among 1245 studies were identified after a thorough database search and three studies were included for analysis. AA resulted in lower odds of mortality compared to 4F- PCC (OR, 0.37; 95% CI, 0.20-0.71) among patients with intracerebral hemorrhage. There was no difference in thrombotic events between patients receiving AA and 4F-PCC (OR, 2.40; 95% CI, 0.36-15.84). No differences in length of hospital stay and intensive care unit (ICU) stay were seen between patients receiving AA and 4F-PCC. In conclusion, andexanet alfa reduced in-hospital mortality in patients who had bleeding due to factor Xa inhibitors compared to 4F-PCC. However, there were no differences in thrombotic events, length of ICU, and hospital stay between patients treated with AA and 4F-PCC.
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4.
A meta-analysis of andexanet alfa and prothrombin complex concentrate in the treatment of factor Xa inhibitor-related major bleeding
Jaspers T, Shudofsky K, Huisman MV, Meijer K, Khorsand N
Research and Practice in Thrombosis and Haemostasis. 2021;5(4):e12518
Abstract
BACKGROUND Andexanet alfa (andexanet) and prothrombin complex concentrate (PCC) are both reversal agents for major bleeding in patients using factor Xa inhibitors (FXaIs). Our aim was to evaluate the current evidence for the effectiveness and safety of andexanet and PCC in a systematic review and meta-analysis. OBJECTIVES Primary objective was hemostatic effectiveness. Secondary objectives were thromboembolic event rate and mortality. METHODS A systematic review was performed in PubMed and Embase. Studies describing the effectiveness and/or safety of PCC or andexanet in patients with major bleeding using FXaIs were included. Meta-analysis was performed using a random-effects model. RESULTS Seventeen PCC studies, 3 andexanet studies, and 1 study describing PCC and andexanet were included, comprising 1428 PCC-treated and 396 andexanet-treated patients. None of the included studies had control groups, hampering a pooled meta-analysis to compare the two reversal agents. Separate analyses for andexanet and PCC were performed. In subgroup analysis, the pooled proportion of patients with effective hemostasis in studies that used Annexa-4 criteria demonstrated a hemostatic effectiveness of 0.85 (95% confidence interval [CI], 0.80-0.90) in PCC and 0.82 (95% CI, 0.78-0.87) in andexanet studies. The pooled proportion of patients with thromboembolic events was 0.03 (95% CI, 0.02-0.04) in PCC and 0.11 (95% CI, 0.04-0.18) in andexanet studies. CONCLUSION Based on the available evidence with low certainty from observational studies, PCC and andexanet demonstrated a similar, effective hemostasis in the treatment of major bleeding in patients using FXaIs. Compared to PCC, the thromboembolic event rate appeared higher in andexanet-treated patients.
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5.
The incidence of thromboembolism formation following the use of recombinant factor VIIa in patients suffering from blunt force trauma compared with penetrating trauma: a systematic review
Devlin R, Bonanno L, Badeaux J
Jbi Database of Systematic Reviews and Implementation Reports. 2016;14((3)):116-38.
Abstract
BACKGROUND Rapid replacement of blood loss is critical in patients suffering from traumatic hemorrhage. When the availability of blood products is limited, certain interventions have shown promise in conserving blood supplies. Recombinant factor (rF) VIIa has been administered, as an off-label use, to assist in controlling hemorrhage in trauma patients. Although rFVIIa has a tendency to remain localized to areas of vascular insult, there may be an increase in thromboembolism formation when patients suffer multiple sites of injury as seen in blunt force trauma. OBJECTIVES This review aimed to synthesize the best available evidence regarding the incidence of thromboembolism formation after receiving rFVIIa as an adjunct to hemorrhage control measures (standard resuscitation efforts consisting of varying amounts of packed red blood cells [PRBCs], fresh frozen plasma [FFP], platelets and crystalloid solutions) in patients suffering from traumatic injuries (blunt force and penetrating trauma). INCLUSION CRITERIA TYPES OF PARTICIPANTS Civilian and combat trauma patients who were 15 years and older suffering from blunt force and penetrating traumatic injuries. TYPES OF INTERVENTION(S)/PHENOMENA OF INTEREST Use of rFVIIa as an adjunct to hemorrhage control measures (standard resuscitation efforts consisting of varying amounts of PRBCs, FFP, platelets and crystalloid solutions). TYPES OF STUDIES This review considered both experimental and epidemiological study designs. TYPES OF OUTCOMES Confirmed formation of thromboembolism (confirmation based on specific diagnostic tests such as ultrasound, ventilation-perfusion scan or angiography). SEARCH STRATEGY The databases searched included CINAHL, Ovid MEDLINE, Web of Science, EMBASE and the Cochrane Control Register of Clinical Trials. Studies published after June 1986 were considered for inclusion in this review. Search for unpublished studies was performed. METHODOLOGICAL QUALITY Studies selected for inclusion were critically appraised by two independent reviewers using standardized critical appraisal instruments from the Joanna Briggs Institute (JBI). DATA EXTRACTION Data was extracted from articles using standardized data extraction instruments from the JBI. DATA SYNTHESIS Quantitative results were pooled in statistical meta-analysis using the Joanna Briggs software for meta-analysis. RESULTS Two studies with a total of 831 participants were included. Both the studies were randomized, placebo-controlled, double-blind trials. No studies of combat trauma patients met the inclusion criteria for this review. A meta-analysis was performed. In blunt force trauma patients, the incidence of thromboembolism formation on administering rFVIIa revealed an overall relative risk of 1.17 with a 95% confidence interval (CI) from 0.77 to 1.79; results not statistically significant (P = 0.4594); large CI and imprecise estimate. In penetrating trauma patients, the incidence of thromboembolism formation on administering rFVIIa revealed an overall relative risk of 0.77 with a 95% CI from 0.27 to 2.20; results not statistically significant (P = 0.6242); very large CI and imprecise estimate. CONCLUSIONS The estimates of the effects are imprecise, results are compatible with effects in opposite directions, increase or decrease of thromboembolism formation, and an increase of thromboembolism formation cannot be excluded. IMPLICATIONS FOR PRACTICE When rFVIIa is administered to trauma patients, there does not appear to be an increased risk of thromboembolism formation favoring one type of injury over the other (blunt force versus penetrating trauma). Owing to large CIs and imprecise estimates, the overall risk of thromboembolism cannot be excluded. The use of rFVIIa does appear to decrease the overall need for blood products in trauma patients with no statistically significant improvement in survival rates. With the high cost of rFVIIa, its use is limited to those facilities that can afford it. In situations wherein blood supply is limited, rFVIIa could conserve limited supplies of
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6.
The efficacy of recombinant activated factor VII in severe trauma
Nishijima DK, Zehtabchi S
Annals of Emergency Medicine. 2009;54((5):):737-744.
Abstract
STUDY OBJECTIVE The use of recombinant activated factor VII (rFVIIa) in severe trauma is controversial. This evidence-based emergency medicine review evaluates the existing evidence about the efficacy and safety of rFVIIa for the management of severe trauma. METHODS We searched MEDLINE, EMBASE, the Cochrane Library, and other databases. We limited our review to prospective, controlled trials that involved the therapeutic use of rFVIIa in the emergency department phase of care. We included studies with blunt and penetrating severe trauma. The primary outcome measure of interest was mortality. Secondary patient-important outcome measures included neurologic outcome, delayed surgical intervention, and adverse effects. Standard criteria were used to evaluate the quality of published trials. RESULTS One randomized, blinded trial met the inclusion criteria. There was no significant difference in mortality or adverse effects between rFVIIa and placebo. Our other selected secondary outcome measures of interest were not reported. CONCLUSION Existing evidence suggests that there is no significant difference in mortality between rFVIIa and placebo. Further research is needed to better understand the efficacy and safety of rFVIIa in patients with severe trauma.