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1.
A systematic review of efficacy and safety of plasma-derived von Willebrand factor/Factor VIII concentrate (Voncento®) in von Willebrand Disease
Rugeri, L., Thomas, W., Schirner, K., Heyder, L., Auerswald, G.
Thrombosis and haemostasis. 2024
Abstract
BACKGROUND For the treatment of von Willebrand disease (VWD), von Willebrand Factor (VWF) concentrates can be used in on-demand, long-term prophylaxis and surgical prophylaxis regimens. METHODS This systematic literature review was conducted to evaluate the efficacy, consumption and safety of plasma-derived human coagulation FVIII/human VWF (pdVWF/FVIII; Voncento®/Biostate®) for the treatment of patients with any inherited VWD type. An electronic search was conducted in MEDLINE® and Cochrane Library databases on VWD therapies. All retrieved publications were assessed against predefined inclusion/exclusion criteria following the Cochrane group recommendations. Associated pharmacovigilance data were collected across the same time period. RESULTS Eleven publications from eight study cohorts were identified for data retrieval. All were from multicenter studies and included both pediatric and adult patients. Eight publications included evaluations of the efficacy of pdVWF/FVIII for on-demand treatment, eight included long-term prophylactic treatment, and eight included surgical prophylaxis. Treatment protocols and VWF administration methods differed between studies, as did safety evaluations. The clinical response was rated as excellent/good for on-demand treatment in 67-100% of non-surgical bleeds, 88.9-100% in the treatment of breakthrough bleeds during long-term prophylaxis treatment, and hemostatic efficacy in surgical procedures was 75-100%. Pharmacovigilance data confirmed a low incidence of adverse events in treated patients. CONCLUSIONS This review provides a comprehensive summary of studies that evaluated the use of pdVWF/FVIII in VWD demonstrating the long-term effectiveness and safety of this pdVWF/FVIII across all ages, types of VWD and treatment settings.
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2.
Pharmacokinetic-guided versus standard prophylaxis in hemophilia- A systematic review and meta-analysis
Kraemmer, D., Königsbrügge, O., Moik, F., Wildner, B., Ay, C., Pabinger, I.
Journal of thrombosis and haemostasis : JTH. 2023
Abstract
BACKGROUND With population pharmacokinetic (PK) modeling more readily available and PK-guided prophylaxis endorsed by current hemophilia guidelines, we conducted a systematic review to summarize current evidence in the literature. OBJECTIVE To assess the efficacy of PK-guided compared to non-PK-guided prophylaxis. METHODS We did not restrict inclusion to specific study design labels and included all studies consisting of at least one distinct cohort arm receiving PK-guided prophylaxis. We searched the following databases from inception to date of search: MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the EU Clinical Trial Register. Following title, abstract, and full text screening conducted independently by two review authors, we summarized studies qualitatively and synthesized included randomized clinical trials (RCT) quantitatively by fitting random-effects models. RESULTS Search of databases on 3 February 2023 yielded 25 studies fitting our inclusion criteria. Of those, only two RCT and 17 non-randomized studies included a standard prophylaxis comparator group. Furthermore, risk of bias in the latter was substantial, primarily due to before-after study designs and retrospective comparator groups. Thus, non-randomized studies were only presented qualitatively. A random-effects meta-analysis of the two identified RCT remained inconclusive with regards to bleeding outcomes (ratio of means 1.15; 95%CI, 0.85-1.56) and factor consumption (ratio of means 0.82; 95%CI, 0.58-1.18). CONCLUSION Evidence in the literature suggesting a clinical benefit of PK-guided over standard fixed-dose prophylaxis was weak and mainly found in non-randomized studies limited by lack of concurrent controls, heterogeneity in outcome reporting, small sample sizes, and high risk of bias.
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3.
Access and use of immunoglobulins in secondary supportive cancer care: A systematic literature review
Counihan, M., Cervenakova, L., Misztela, D., Van Baelen, M., Naughton, B. D.
The journal of medicine access. 2023;7:27550834231197315
Abstract
BACKGROUND Immunoglobulin replacement therapy (IgRT) benefits patients with primary immuno deficiency (PID) originating from the innate or polygenic defects in the immune system. However, evidence supporting their therapeutic role is not as explicit in secondary immuno deficiency (SID) resulting from the treatment of haematological malignancies. OBJECTIVES This study aimed to (1) create a dataset of relevant research papers, which explore the use of IgRT in SID for analysis, (2) assess the risk of bias within this dataset and (3) study the characteristics of these papers. DESIGN This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. In addition to the risk of bias, the study characteristics explored in this article included study design, study geographical location and year of publication. DATA SOURCES AND METHODS To identify studies relevant to the research question, EMBASE and PubMed databases were searched. The Population, Intervention, Comparison and Outcome (PICO) framework was used to assess study quality. Risk of bias and quality of studies were assessed in accordance with the study design. As one model was not appropriate to assess bias in all articles, several tools were used. RESULTS A total of 43 studies were identified from the literature search as relevant to the research objective. The most common study design was a retrospective case-control cohort study (n = 16/43), and randomised trials were among the least commonly used approaches (n = 1). Research in this area is occurring around the globe including the United States (n = 7), Italy (n = 7), China, India, Japan and throughout Europe. The annual number of papers in this area has varied from 2012 (n = 1) to 2021 (n = 7). The studies in this article demonstrated a varied risk of bias, with 9 of the 20 cohort studies scoring less than 5 out of 9 stars. CONCLUSIONS Randomised controlled trials are less frequently used to assess access and use of immunoglobulins. More commonly, a retrospective case-control cohort study was used which correlates with the higher risk of bias seen in the studies in this article. Most of the research concerning immunoglobulin use and access occurs in higher-income countries.
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4.
3-Factor versus 4-Factor Prothrombin Complex Concentrates for the Reversal of Vitamin K Antagonist-Associated Coagulopathy: A Systematic Review and Meta-analysis
Puchstein, D., Kork, F., Schöchl, H., Rayatdoost, F., Grottke, O.
Thrombosis and Haemostasis. 2023;123(1):40-53
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Abstract
Long-term anticoagulation is used worldwide to prevent or treat thrombotic events. Anticoagulant therapy using vitamin K antagonists (VKAs) is well established; however, anticoagulants carry an increased risk of potentially life-threatening bleeding. In cases of bleeding or need for surgery, patients require careful management, balancing the need for rapid anticoagulant reversal with risk of thromboembolic events. Prothrombin complex concentrates (PCCs) replenish clotting factors and reverse VKA-associated coagulopathy. Two forms of PCC, 3-factor (3F-PCC) and 4-factor (4F-PCC), are available. Using PRISMA methodology, we systematically reviewed whether 4F-PCC is superior to 3F-PCC for the reversal of VKA-associated coagulopathy. Of the 392 articles identified, 48 full texts were reviewed, with 11 articles identified using criteria based on the PICOS format. Data were captured from 1,155 patients: 3F-PCC, n = 651; 4F-PCC, n = 504. ROBINS-I was used to assess bias. Nine studies showed international normalized ratio (INR) normalization to a predefined goal, ranging from ≤1.5 to ≤1.3, following PCC treatment. Meta-analysis of the data showed that 4F-PCC was favorable compared with 3F-PCC overall (odds ratio [OR]: 3.50; 95% confidence interval [CI]: 1.88-6.52, p < 0.0001) and for patients with a goal INR of ≤1.5 or ≤1.3 (OR: 3.45; 95% CI: 1.42-8.39, p = 0.006; OR: 3.25; 95% CI: 1.30-8.13, p = 0.01, respectively). However, heterogeneity was substantial (I (2) = 62%, I (2) = 70%, I (2) = 64%). Neither a significant difference in mortality (OR: 0.72; 95% CI: 0.42-1.24, p = 0.23) nor in thromboembolisms was reported. These data suggest that 4F-PCC is better suited than 3F-PCC for the treatment of patients with VKA-associated coagulopathy, but further work is required for a definitive recommendation.
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Efficacy/Effectiveness and safety of emicizumab prophylaxis of people with hemophilia A: a systematic review and meta-analysis
Muniz, R. L., Camelo, R. M., Araújo, M. S., Barbosa, M. M., Guerra, A. A., de Assis Acurcio, F., Alvares-Teodoro, J.
Expert review of hematology. 2023
Abstract
BACKGROUND Emicizumab is a monoclonal antibody approved for prophylaxis against bleeds for people with hemophilia A (PwHA). A systematic review was conducted evaluating the efficacy/effectiveness and the safety of emicizumab as prophylaxis for PwHA compared to prophylaxis with factor VIII (FVIII) or bypassing agents (BPA), respectively in patients without and with inhibitors. RESEARCH DESIGN AND METHODS Database-directed search strategies were performed in Aug/26/22 and updated in Mar/16/2023. Studies evaluating the prophylaxis with emicizumab versus prophylaxis with FVIII or BPA in PwHA without or with inhibitors, respectively, were selected by two independent reviewers. Data were extracted by two independent reviewers. Annualized bleeding rates for total treated bleeding events (ABR-all) were evaluated by meta-analysis. The quality of studies and certainty of evidence were assessed. RESULTS A total of 11 studies were included. The standard mean differences for ABR-all were -0.6 (95%CI -1.0 to -0.2, p-value = 0.0002), among PwHA without inhibitors, and -1.7 (95%CI -2.4 to -0.9, p-value <0.00001), among PwHA with inhibitors. However, there was moderate heterogeneity in both meta-analyses. The most frequent adverse event was injection site reaction. CONCLUSIONS Emicizumab prophylaxis was superior in reducing the ABR-all when compared with prophylaxis with FVIII or BPA.
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Bleeding events in people with congenital haemophilia A without factor VIII inhibitors receiving prophylactic factor VIII treatment: A systematic literature review
Mannucci, P. M., Kessler, C. M., Germini, F., Nissen, F., Ofori-Asenso, R., Brocchieri, C., Bendinelli, S., Iorio, A.
Haemophilia : the official journal of the World Federation of Hemophilia. 2023
Abstract
BACKGROUND Evidence on bleeding rates in people with congenital haemophilia A (PwcHA) without inhibitors on factor VIII (FVIII) replacement products is inconsistent. AIM: This systematic literature review assessed bleeding outcomes in PwcHA using FVIII-containing products as prophylactic treatment. METHODS A search was conducted using the bibliographic databases Medline, Embase and Cochrane Central Register of Controlled Trials on the Ovid platform. The search involved a bibliographic review of clinical trial studies, routine clinical care studies and registries and a search of ClinicalTrials.gov, EU Clinical Trials Register and conference abstracts. RESULTS The search yielded 5548 citations. A total of 58 publications were included for analysis. In 48 interventional studies, the pooled estimated mean (95% confidence interval [CI]) annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR) and proportion of participants with zero bleeding events were 3.4 (3.0-3.7), 2.0 (1.6-2.5), and 38.5% (33.1-43.9), respectively. In 10 observational studies, the pooled estimated mean (95% CI) ABR, AJBR and proportion of participants with zero bleeding events were 4.8 (4.0-5.5), 2.6 (2.1-3.2), and 21.8% (19.9-47.5), respectively. A large variation in mean effect size for ABR, AJBR and zero bleeding event data across cohorts and cohort types was observed. Funnel plots indicated potential reporting bias for publications incorporating ABR and AJBR data across both interventional and observational studies. CONCLUSION This meta-analysis shows that PwcHA without inhibitors still have bleeds despite FVIII prophylaxis. Improved standardization on capturing and reporting bleeding outcomes is needed so that effective comparisons between treatments can be made.
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Outcomes of long-term von Willebrand factor prophylaxis use in von Willebrand disease: A systematic literature review
El Alayli A, Brignardello Petersen R, Husainat NM, Kalot MA, Aljabiri Y, Turkmani H, Britt A, El-Khechen H, Shahid S, Roller J, et al
Haemophilia : the official journal of the World Federation of Hemophilia. 2022;28(3):373-387
Abstract
BACKGROUND Von Willebrand Disease (VWD) is a common inherited bleeding disorder. Patients with VWD suffering from severe bleeding may benefit from the use of secondary long-term prophylaxis. AIM: Systematically summarize the evidence on the clinical outcomes of secondary long-term prophylaxis in patients with VWD and severe recurrent bleedings. METHODS We searched Medline and EMBASE through October 2019 for relevant randomized clinical trials (RCTs) and comparative observational studies (OS) assessing the effects of secondary long-term prophylaxis in patients with VWD. We used Cochrane Risk of Bias (RoB) tool and the RoB for Non-Randomized Studies of interventions (ROBINS-I) tool to assess the quality of the included studies. We conducted random-effects meta-analyses and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS We included 12 studies. Evidence from one placebo controlled RCT suggested that VWD prophylaxis as compared to no prophylaxis reduced the rate of bleeding episodes (Rate ratio [RR], .24; 95% confidence interval [CI], .17-.35; low certainty evidence), and of epistaxis (RR, .38; 95%CI, .21-.67; moderate certainty evidence), and may increase serious adverse events RR 2.73 (95%CI .12-59.57; low certainty). Evidence from four before-and-after studies in which researchers reported comparative data suggested that VWD prophylaxis reduced the rate of bleeding (RR .34; 95%CI, .25-.46; very low certainty evidence). CONCLUSION VWD prophylaxis treatment seems to reduce the risk of spontaneous bleeding, epistaxis, and hospitalizations. More RCTs should be conducted to increase the certainty in these benefits.
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Comparative Efficacy of Rivaroxaban and Immunoglobulin Therapy in the Treatment of Livedoid Vasculopathy: A Systematic Review
Ramphall S, Rijal S, Prakash V, Ekladios H, Mulayamkuzhiyil Saju J, Mandal N, Kham NI, Shahid R, Naik SS, Venugopal S
Cureus. 2022;14(8):e28485
Abstract
Livedoid vasculopathy (LV) is an uncommon chronic coagulation disorder whose underlying etiology is not yet fully understood. It predominantly affects females, especially those in late adolescence. There is currently limited research on treatment options for those with this diagnosis. The present systematic review aims to compare the efficacy of rivaroxaban and intravenous immunoglobulin (IVIG) therapy in the treatment of livedoid vasculopathy. A detailed search was conducted from April 20, 2022, to May 1, 2022, using four databases: Elsevier, Medline Complete, Medline Ovid, and PubMed. Out of these, 20 relevant articles were used, and the data was extracted and analyzed. Both rivaroxaban and IVIG were shown to be effective treatment options with similar treatment response times. However, future large-scale clinical trials are needed to determine an established treatment regimen for these patients.
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Measuring Factor XIII Inhibitors in Patients with Factor XIII Deficiency: A Case Report and Systematic Review of Current Practices in Japan
Amano S, Oka K, Sato Y, Sano C, Ohta R
Journal of clinical medicine. 2022;11(6)
Abstract
Factor XIII (FXIII) deficiency is a rare but serious coagulopathy. FXIII is critical in blood coagulation, and FXIII deficiencies can lead to uncontrolled or spontaneous bleeding. FXIII deficiencies can be congenital or acquired; acquired FXIII deficiency can be categorized as autoimmune and non-autoimmune. Immunological tests to measure FXIII inhibitors are required to diagnose acquired FXIII deficiency; however, appropriate test facilities are limited, which increases the turnaround time of these tests. In the case of critical bleeding, delayed test results may worsen prognosis due to delayed treatment. Here, we report a case of acquired FXIII deficiency, followed by a review of FXIII deficiency cases in Japan. We performed a systematic review to investigate the present conditions of the diagnosis and treatment of FXIII deficiency, including the measurement of FXIII inhibitors in Japan. FXIII inhibitor testing was only performed in 29.7 of acquired FXIII deficiency cases. Clinical departments other than internal medicine and pediatrics were often involved in medical treatment at the time of onset. Therefore, it is important for doctors in clinical departments other than internal medicine and pediatrics to consider FXIII deficiency and perform FXIII inhibitor testing when examining patients with prolonged bleeding of unknown cause or persistent bleeding after trauma.
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Systemic therapy of necrobiotic xanthogranuloma: a systematic review
Steinhelfer L, Kühnel T, Jägle H, Mayer S, Karrer S, Haubner F, Schreml S
Orphanet journal of rare diseases. 2022;17(1):132
Abstract
BACKGROUND Even though a plethora of systemic therapies have been proposed for necrobiotic xanthogranuloma (NXG), there is no systematic review on this topic in literature. OBJECTIVE To review all existing literature on the systemic therapy of NXG in order to identify the most effective therapies. METHODS All reported papers in the literature were screened for systemic treatments of NXG. Papers without proper description of the therapies, papers describing topical therapy, and articles without assessment of effectiveness were excluded. Subsequently, we analyzed 79 papers and a total of 175 cases. RESULTS The most effective treatments for NXG are intravenous immunoglobulins (IVIG), corticosteroids, and combination therapies including corticosteroids. CONCLUSIONS Corticosteroids and IVIG should therefore be considered first-line treatments in patients with NXG.