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BMJ (Clinical Research Ed.) Jul 2022To assess the benefits and harms of different types and doses of anticoagulant drugs for the prevention of venous thromboembolism in patients who are acutely ill and... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To assess the benefits and harms of different types and doses of anticoagulant drugs for the prevention of venous thromboembolism in patients who are acutely ill and admitted to hospital.
DESIGN
Systematic review and network meta-analysis.
DATA SOURCES
Cochrane CENTRAL, PubMed/Medline, Embase, Web of Science, clinical trial registries, and national health authority databases. The search was last updated on 16 November 2021.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Published and unpublished randomised controlled trials that evaluated low or intermediate dose low-molecular-weight heparin, low or intermediate dose unfractionated heparin, direct oral anticoagulants, pentasaccharides, placebo, or no intervention for the prevention of venous thromboembolism in acutely ill adult patients in hospital.
MAIN OUTCOME MEASURES
Random effects, bayesian network meta-analyses used four co-primary outcomes: all cause mortality, symptomatic venous thromboembolism, major bleeding, and serious adverse events at or closest timing to 90 days. Risk of bias was also assessed using the Cochrane risk-of-bias 2.0 tool. The quality of evidence was graded using the Confidence in Network Meta-Analysis framework.
RESULTS
44 randomised controlled trials that randomly assigned 90 095 participants were included in the main analysis. Evidence of low to moderate quality suggested none of the interventions reduced all cause mortality compared with placebo. Pentasaccharides (odds ratio 0.32, 95% credible interval 0.08 to 1.07), intermediate dose low-molecular-weight heparin (0.66, 0.46 to 0.93), direct oral anticoagulants (0.68, 0.33 to 1.34), and intermediate dose unfractionated heparin (0.71, 0.43 to 1.19) were most likely to reduce symptomatic venous thromboembolism (very low to low quality evidence). Intermediate dose unfractionated heparin (2.63, 1.00 to 6.21) and direct oral anticoagulants (2.31, 0.82 to 6.47) were most likely to increase major bleeding (low to moderate quality evidence). No conclusive differences were noted between interventions regarding serious adverse events (very low to low quality evidence). When compared with no intervention instead of placebo, all active interventions did more favourably with regard to risk of venous thromboembolism and mortality, and less favourably with regard to risk of major bleeding. The results were robust in prespecified sensitivity and subgroup analyses.
CONCLUSIONS
Low-molecular-weight heparin in an intermediate dose appears to confer the best balance of benefits and harms for prevention of venous thromboembolism. Unfractionated heparin, in particular the intermediate dose, and direct oral anticoagulants had the least favourable profile. A systematic discrepancy was noted in intervention effects that depended on whether placebo or no intervention was the reference treatment. Main limitations of this study include the quality of the evidence, which was generally low to moderate due to imprecision and within-study bias, and statistical inconsistency, which was addressed post hoc.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42020173088.
Topics: Anticoagulants; Bayes Theorem; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hospitals; Humans; Network Meta-Analysis; Randomized Controlled Trials as Topic; Thrombosis; Venous Thromboembolism
PubMed: 35788047
DOI: 10.1136/bmj-2022-070022 -
Cureus Jun 2022Hemophilia A, the most common hereditary disorder, is caused by clotting factor deficiency. Challenges encountered in the current treatment of hemophilia A [factor VIII... (Review)
Review
The Impact of Recombinant Versus Plasma-Derived Factor VIII Concentrates on Inhibitor Development in Previously Untreated Patients With Hemophilia A: A 2021 Update of a Systematic Review and Meta-Analysis.
Hemophilia A, the most common hereditary disorder, is caused by clotting factor deficiency. Challenges encountered in the current treatment of hemophilia A [factor VIII (FVIII) replacement therapy] due to inhibitor development have caused ineffective treatment as well as morbidity and mortality among patients. However, there are no studies comparing the two types of FVIII treatments in terms of inhibitor development rate. Therefore, we conducted this systematic review to devise a better treatment option with a lower risk of inhibitor development. The systematic review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and by searching several databases. Data extraction on study characteristics and outcomes was conducted. Reviewers also conducted a risk of bias assessment on all studies. All eligible studies for quantitative analysis were then processed using RevMan 5.4.1 and the data was extrapolated into cumulative outcomes and expressed in forest and funnel plots. Nine studies were included in the meta-analysis, involving a total of 2,531 hemophilia A patients who were followed up from birth until death. A higher incidence of inhibitor development was found to be associated with recombinant FVIII (rFVIII) [odds ratio (OR)=1.57, 95% confidence interval (CI): 0.95-2.59; hazard ratio (HR)=1.89, 95% CI: 1.15-3.12]. The same trend was also found for high-responding inhibitors (OR=1.38, 95% CI: 0.70-2.70; HR=1.42, 95% CI: 0.84-2.39). rFVIII is associated with a higher risk of overall and high-responding inhibitor development compared to plasma-derived FVIII (pdFVIII).
PubMed: 35859961
DOI: 10.7759/cureus.26015 -
The Cochrane Database of Systematic... Dec 2016Haemophilia is a genetic disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of... (Review)
Review
BACKGROUND
Haemophilia is a genetic disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of treatment are expensive, challenging and involve regular administration of clotting factors. Gene therapy has recently been prompted as a curative treatment modality. This is an update of a published Cochrane Review.
OBJECTIVES
To evaluate the safety and efficacy of gene therapy for treating people with haemophilia A or B.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis & Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Date of last search: 18 August 2016.
SELECTION CRITERIA
Eligible trials include randomised or quasi-randomised clinical trials, including controlled clinical trials comparing gene therapy (with or without standard treatment) with standard treatment (factor replacement) or other 'curative' treatment such as stem cell transplantation for individuals with haemophilia A or B of all ages who do not have inhibitors to factor VIII or IX.
DATA COLLECTION AND ANALYSIS
No trials of gene therapy for haemophilia were found.
MAIN RESULTS
No trials of gene therapy for haemophilia were identified.
AUTHORS' CONCLUSIONS
No randomised or quasi-randomised clinical trials of gene therapy for haemophilia were identified. Thus, we are unable to determine the safety and efficacy of gene therapy for haemophilia. Gene therapy for haemophilia is still in its nascent stages and there is a need for well-designed clinical trials to assess the long-term feasibility, success and risks of gene therapy for people with haemophilia.
Topics: Genetic Therapy; Hemophilia A; Hemophilia B; Humans
PubMed: 27996087
DOI: 10.1002/14651858.CD010822.pub3 -
Research and Practice in Thrombosis and... Feb 2023Predicting recurrent venous thromboembolic events (VTEs) is challenging in clinical practice for both adults and children, but it is relevant for clinical management....
BACKGROUND
Predicting recurrent venous thromboembolic events (VTEs) is challenging in clinical practice for both adults and children, but it is relevant for clinical management. Identifying laboratory risk factors for VTE recurrence may aid in clinical decision-making.
OBJECTIVE
The goal of this systematic review is to investigate the predictive role of FVIII, IX, or XI in recurrent VTE in adult and pediatric patients with a first VTE.
METHODS
A systematic review of the published literature was conducted in databases MEDLINE In-Process, Other Nonindexed Citations, MEDLINE Epub Ahead of Print, EMBASE Classic + EMBASE (OvidSP), and Cochrane (Wiley). We included observational and interventional studies that comprised adults or children with a first VTE, FVIII, FIX, and/or FXI and objectively confirmed VTE recurrence. The quality in prognosis studies tool was used to assess the risk of bias.
RESULTS
We identified 2177 unique studies, of which 19 were included (18 for adults and 1 for children). The risk of bias was overall low to moderate. The studies were heterogenous with regards to population (provoked/unprovoked primary VTE), exposure (type of assay and cut-off values), and statistical analysis results (measures of association and modeling strategy). In adults, contradictory evidence was found for FVIII and FXI as outcome predictors, while no research could establish if FIX predicts VTE recurrence. Data in pediatrics were limited. Given the extensive heterogeneity of the literature, a meta-analysis was not performed.
CONCLUSIONS
Overall, there is contradictory evidence that FVIII, FIX, or FXI predict recurrent VTE in adults and children. Addressing heterogeneity is a relevant aspect to consider in future studies investigating prognostic factors for VTE recurrence.
PubMed: 36852262
DOI: 10.1016/j.rpth.2023.100064 -
Clinical and Experimental Medicine Aug 2022The SARS-CoV-2 virus has spread to all corners of the world. Thrombosis is the cause of organ failure and subsequent death in COVID-19. The pathophysiology of thrombosis... (Meta-Analysis)
Meta-Analysis Review
The SARS-CoV-2 virus has spread to all corners of the world. Thrombosis is the cause of organ failure and subsequent death in COVID-19. The pathophysiology of thrombosis in COVID-19 needs to be further explored to shed light on its downside. For this reason, this meta-analysis of Von Willebrand Factor profile (VWF: Ag, VWF: activity, VWF: RCo), ADAMTS-13, and factor VIII levels in COVID-19 was performed. To obtain data on the status of the aforementioned hemostatic factors, a systematic literature review and meta-analysis were performed on COVID-19. After reviewing the evaluation of 348 papers, 28 papers included in the meta-analysis, which was performed using STATA. The analysis showed an increase in VWF: Ag levels in COVID-19 patients. VWF: Ac was higher in all COVID-19 patients, while it was lower in the COVID-19 ICU patients. The pooled mean of VWF: RCO in all patients with COVID-19 was 307.94%. In subgroup analysis, VWF: RCO was significantly higher in ICU patients than in all COVID-19 patients. The pooled mean of ADAMTS-13 activity was 62.47%, and 58.42% in ICU patients. The pooled mean of factor VIII level was 275.8%, which was significantly higher in ICU patients with COVID-19 than all patients with COVID-19. Levels of VWF: Ag, VWF: activity, VWF: ristocetin, and factor VIII are increased in patients with COVID-19. The elevated levels in ICU patients with COVID-19 suggest that these markers may have prognostic value in determining the severity of COVID-19. New therapeutic programs can be developed as a result.
Topics: ADAMTS13 Protein; Biomarkers; COVID-19; Factor VIII; Humans; SARS-CoV-2; von Willebrand Factor
PubMed: 34741678
DOI: 10.1007/s10238-021-00769-x -
Journal of Thrombosis and Haemostasis :... Jun 2018Essentials Data on product-related immunogenicity in previously treated haemophilia A patients is scarce. A systematic review and meta-analysis of all currently... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Essentials Data on product-related immunogenicity in previously treated haemophilia A patients is scarce. A systematic review and meta-analysis of all currently available evidence was conducted. The overall incidence rate was 2.06 per 1000 person-years (95% confidence interval: 1.06-4.01). Some recombinant factor VIII products were associated with increased immunogenicity.
SUMMARY
Background Patients with severe hemophilia A who have been treated extensively with factor VIII products have a low but potentially serious risk of inhibitor development. It is unknown why these patients develop inhibitors, and data on product-related immunogenicity are scarce. Aims To summarize the currently available evidence on the relationship between inhibitor development and recombinant FVIII product type in previously treated patients (PTPs) with severe hemophilia A. Methods Longitudinal studies were included that reported on de novo inhibitor formation in patients with baseline FVIII activity levels of < 0.02 IU mL who had been treated with FVIII for at least 50 days. Pooled incidence rates of inhibitor development according to product types were calculated with a random intercept Poisson regression model. Results Forty-one independent cohorts were included; 39 patients developed de novo inhibitors during 19 157 person-years of observation. The overall incidence rate was 2.06 per 1000 person-years, with a 95% confidence interval (CI) of 1.06-4.01. According to product type, the pooled incidence rates were 0.99 (95% CI 0.37-2.70) per 1000 person-years for patients treated with Advate, 5.86 (95% CI 0.25-134.92) per 1000 person-years for those treated with Kogenate/Helixate, 1.35 (95% CI 0.66-2.77) per 1000 person-years for those treated with Kogenate FS/Helixate NexGen, 12.05 (95% CI 1.53-94.78) per 1000 person-years for those treated with Refacto, and 4.64 (95% CI 0.82-26.43) per 1000 person-years for those treated with Refacto AF. Conclusion These results suggest that some products may be associated with increased immunogenicity. However, the low incidence of inhibitors in PTPs and the differences in study design may cause significant variation in estimates of risk.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Neutralizing; Child; Child, Preschool; Coagulants; Factor VIII; Hemophilia A; Hemostasis; Humans; Infant; Infant, Newborn; Middle Aged; Recombinant Proteins; Risk Assessment; Risk Factors; Severity of Illness Index; Treatment Outcome; Young Adult
PubMed: 29665204
DOI: 10.1111/jth.14124 -
The Cochrane Database of Systematic... Apr 2020Haemophilia is a genetic disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of...
BACKGROUND
Haemophilia is a genetic disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of treatment are expensive, challenging and involve regular administration of clotting factors. Gene therapy for haemophilia is a curative treatment modality currently under investigation. This is an update of a published Cochrane Review.
OBJECTIVES
To evaluate the safety and efficacy of gene therapy for treating people with haemophilia A or B.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis & Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Date of last search: 17 April 2020.
SELECTION CRITERIA
Eligible trials include randomised or quasi-randomised clinical trials, including controlled clinical trials comparing gene therapy (with or without standard treatment) with standard treatment (factor replacement) or other 'curative' treatment such as stem cell transplantation for individuals with haemophilia A or B of all ages who do not have inhibitors to factor VIII or IX.
DATA COLLECTION AND ANALYSIS
No trials of gene therapy for haemophilia matching the inclusion criteria were identified.
MAIN RESULTS
No trials of gene therapy for haemophilia matching the inclusion criteria were identified.
AUTHORS' CONCLUSIONS
No randomised or quasi-randomised clinical trials of gene therapy for haemophilia were identified. Thus, we are unable to determine the safety and efficacy of gene therapy for haemophilia. Gene therapy for haemophilia is still in clinical investigation and there is a need for well-designed clinical trials to assess the long-term feasibility, success and risks of gene therapy for people with haemophilia.
Topics: Genetic Therapy; Hemophilia A; Hemophilia B; Humans
PubMed: 32342499
DOI: 10.1002/14651858.CD010822.pub4 -
Journal of Internal Medicine Jan 2015Congenital haemophilia A and B are genetic disorders affecting factor VIII and factor IX production, respectively. Factor replacement is the only effective treatment for... (Review)
Review
Congenital haemophilia A and B are genetic disorders affecting factor VIII and factor IX production, respectively. Factor replacement is the only effective treatment for these deficiencies, but a patient's immune system can develop inhibitory antibodies which bind and interfere with the function of the replaced factor in a variety of ways. The main treatment goal for patients with inhibitors is to induce immune tolerance to the injected factor. If not successful, a different treatment termed bypass therapy is needed to treat bleeds. The goal of this review is to demonstrate the usefulness of haemophilia registries as information sources to supplement available evidence regarding predictors of inhibitor development and immune tolerance induction (ITI) outcomes. In this systematic review, relevant keywords were used to search online academic databases during February 2014. Inclusion criteria were original publication and data obtained from a haemophilia or ITI registry with a minimum of 30 patients. A data collection form was created to extract information from selected manuscripts. Titles, abstracts and then full texts were screened to determine the eligibility of reports for this review. Eleven manuscripts from nine registries were determined eligible and included in the study. Registries have reported on some core variables, but are inconsistent in reporting less practiced predicting variables. Variables that may affect inhibitor and ITI outcomes were each divided into two categories: patient characteristics (such as age and family history) and treatment-related variables (including exposure days, treatment duration and dose). It is recommended that, in addition to exploratory hypothesis testing, a minimum set of variables should be collected and reported by registries. International collaboration and well-designed prospective registries are of major importance to advance this field in order to determine inhibitor risks and ITI outcomes and facilitate the development of new treatments.
Topics: Age Factors; Child; Evidence-Based Medicine; Factor VIII; Female; Follow-Up Studies; Hemophilia A; Hemophilia B; Humans; Immune Tolerance; Infant; Infant, Newborn; International Cooperation; Male; Registries; Risk Assessment; Severity of Illness Index; Sex Factors; Time Factors; Treatment Outcome
PubMed: 25169114
DOI: 10.1111/joim.12301 -
Journal of Medical Economics Dec 2020Long-acting (LA) recombinant FVIII (rFVIII) products with extended dosing intervals have been developed for the treatment of hemophilia A; however, no direct...
AIMS
Long-acting (LA) recombinant FVIII (rFVIII) products with extended dosing intervals have been developed for the treatment of hemophilia A; however, no direct head-to-head trial has been conducted to compare the efficacy of these products.
MATERIALS AND METHODS
A systematic literature search was conducted to identify published Phase III clinical trials of prophylactic LA rFVIII treatment in previously treated patients aged ≥12 years, with moderate-to-severe hemophilia A (endogenous FVIII levels ≤2%). Studies that did not meet these criteria, or did not report the included outcomes, were excluded. Bleeding rates and consumption were extracted and summarized; only data for the dosing frequencies indicated in the US product labels (which are similar to those indicated in the European Medicines Agency labels) were included.
RESULTS
Five articles met the inclusion criteria; these studies only included patients with severe hemophilia A. Treatment length, reported outcomes and dose (range: 20-65 IU/kg) varied between studies. Median annualized bleeding rate (ABR) (IQR) reported in the relevant studies was 1.14 (0.00-4.30), rVIII-SingleChain 2 or 3 times weekly; 1.6 (0.0-4.7), rFVIIIFc 2 times weekly followed by every 3-5 days; 1.9 (0.0-5.8), BAX855 2 times weekly; 1.18 (0.00-4.25), N8-GP every 4 days; 1.9 (0.0-5.2) and 4.1 (2.0-10.6), BAY 94-9027 2 times weekly for the cohort who experienced >1 or <1 bleed in the study run-in phase, respectively. Median spontaneous ABR was 0.0 across studies reporting relevant data. Reported consumption was comparable among all LA products.
LIMITATIONS
The primary limitation of this systematic review was the variation in study design and not all studies reported all desired outcomes, which limited the quantity of data available.
CONCLUSIONS
This systematic review identified pivotal trial data for LA rFVIII products. Real-world evidence is needed to understand how these products perform in clinical practice.
Topics: Factor VIII; Hemophilia A; Hemorrhage; Humans; Immunotherapy, Adoptive; Treatment Outcome
PubMed: 32969738
DOI: 10.1080/13696998.2020.1828092