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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.
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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4.
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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5.
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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6.
Surgical management of patients with von Willebrand Disease: summary of 2 systematic reviews of the literature
Brignardello-Petersen R, El Alayli A, Husainat N, Kalot MA, Shahid S, Aljabirii Y, Britt A, Alturkmani HJ, El Khechen H, Motaghi S, et al
Blood advances. 2021
Abstract
Von Willebrand disease (VWD) is the most common inherited bleeding disorder. The management of patients with VWD undergoing surgeries is crucial to prevent bleeding complications. To systematically summarize the evidence on the management of patients with VWD undergoing major and minor surgeries to support the development of practice guidelines. We searched Medline and EMBASE through October 2019 for randomized clinical trials (RCTs), comparative observational studies and case series comparing maintaining factor VIII levels or VWF levels >0.50 IU/mL for at least 3 days in patients undergoing major surgery, and options for perioperative management of patients undergoing minor surgery. Two authors screened, abstracted data, and assessed the risk of bias. We conducted meta-analysis when possible. We evaluated the certainty of the evidence using the GRADE approach. We included 7 case series for major surgeries and 2 RCTs and 12 case series for minor surgeries. Very low certainty evidence showed that maintaining factor VIII levels, or VWF levels > 0.50 IU/mL for at least 3 consecutive days showed excellent hemostatic efficacy (as labeled by the researchers) after 74-100% of major surgeries. Low to very low certainty evidence showed that prescribing tranexamic acid and increasing VWF levels to 0.50 IU/mL resulted in less bleeding complications after minor procedures compared to increasing VWF levels to 0.50 IU/mL alone. Given the low-quality evidence to guide management decisions, a shared-decision model leading to individualized therapy plans will be important in patients with VWD undergoing surgical and invasive procedures.
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7.
Delivery and neuraxial technique outcomes in patients with hemophilia and in hemophilia carriers: a systematic review
Togioka, B. M., Burwick, R. M., Kujovich, J. L.
Journal of Anesthesia. 2021;35(2):288-302
Abstract
Female carriers are more common than males with hemophilia and unrecognized factor VIII or IX deficiency is associated with intrauterine growth retardation, epidural hematomas, blood transfusion, and peripartum hemorrhage. A review was conducted to assess the evidence for professional society recommendations for > 50% factor levels during labor. Two searches of Pubmed, CINAHL, Cochrane, and Google Scholar were completed in October 2019. The first for case reports and series described neuraxial techniques in patients with hemophilia-regardless of sex, age, or pregnant status. The second for case reports and series described bleeding outcomes of parturients with hemophilia. Primary outcomes were diagnosis of neuraxial hematoma (first search) and postpartum bleeding complications (second search). Thirteen articles (n = 134) described neuraxial techniques in patients with hemophilia. Neuraxial hematoma with paraplegia occurred in 3/134 patients-all had a factor level of 1%. Nineteen articles (2712 deliveries in 2657 women) described bleeding outcomes. Postpartum hemorrhage occurred in 7.1% (193/2712) of deliveries, of which 60% necessitated blood transfusion. Postpartum bleeding complications were twice as likely (51.0% [25/49] vs. 25.6% [52/203], P < 0.001) with factor activity < 50%. Therefore, factor levels should be assessed and increased above 50% prior to neuraxial technique and delivery.Trial registration: PROSPERO 2018 CRD42018110215.
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8.
Effectiveness of ankle fusion in patients with hemophilia, advanced ankle degeneration, and unbearable pain for whom nonsurgical and surgical treatments have been ineffective
Rodriguez-Merchan EC, Encinas-Ullan CA, Giomez-Cardero P
Expert review of hematology. 2021
Abstract
INTRODUCTION In underdeveloped countries, patients with hemophilia often experience repetitive ankle joint hemorrhages due to a shortage of coagulation factors (factor VIII [FVIII] and factor IX [FIX] for hemophilia A and B, respectively). AREAS COVERED This is a narrative literature review in which we searched the Cochrane Library and MEDLINE for articles related to ankle arthrodesis in patients with hemophilia. The searches covered the period from the databases´ inception to February 28, 2021. In the event of unsuccessful hematologic prophylaxis and conservative measures (e.g., analgesics, cyclooxygenase-2 inhibitors, taping, intra-articular injections of hyaluronic acid and corticosteroids, physical and rehabilitation medicine, orthoses, radiosynovectomy, and joint-preserving surgery (e.g., removal of the distal tibia by open surgery or by arthroscopic surgery, joint debridement by arthroscopic surgery), the only surgical solution is ankle arthrodesis, which does not preserve the ankle joint. EXPERT OPINION Ankle pain is reduced after ankle arthrodesis (75% of patients experience no pain). Approximately 5% of patients require reoperation due to lack of fusion, and deep infection occurs in 2.5%. After tibiotalar fusion, a self-reported activity scale shows that approximately 12% of patients improve, 9% worsen, and 79% show no improvement. The results of ankle arthrodesis therefore appear to be poor.
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9.
Factor VIII replacement prophylaxis in patients with hemophilia A transitioning to adults: a systematic literature review
Sun, J., Zhou, X., Hu, N.
Orphanet Journal of Rare Diseases. 2021;16(1):287
Abstract
BACKGROUND Despite the advantages of prophylactic treatment for hemophilia, patients tend to discontinue or not adhere to it because of several challenges such as long-term use, high cost, young patients transitioning to adolescents, and switch to self-infusion or self-care. The goal of this systematic literature review is to emphasize adherence to and efficiency of prophylactic treatment in adults. METHODS A literature review was conducted in PubMed, Embase, and Cochrane databases until April 2021 according to PRISMA guidelines, and the protocol was registered with PROSPERO (CRD42020220085). Studies evaluating the efficacy of prophylaxis in enhancing the quality of life were included. RESULTS A total of 31 articles involving 2379 patients with hemophilia were included in this systematic review. Of these, 26 studies were observational, questionnaire-based studies, and 5 were randomized controlled trials. The majority of studies reported lower annualized bleeding rates in patients receiving prophylaxis compared with those receiving on-demand treatment or those who discontinued prophylaxis. Standard-dose prophylaxis was reported to be effective in most of the studies. In developing countries like China, data suggest that low doses were administered because of limited available resources. However, standard dose or individualized prophylaxis should be provided to prevent joint damage in the long term. Compared with adults, greater adherence to treatment was observed in patients aged < 16 years. CONCLUSION This systematic review emphasizes the importance of adherence to prophylaxis among young adults transitioning from childhood. In countries like China, low-dose prophylaxis can help in preventing joint bleeds in the short term, but in the long term, standard-dose therapy has shown high adherence among young adults and better joint health, in turn improving the quality of life.
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10.
Prevalence and Incidence of Non-neutralizing Antibodies in Congenital Hemophilia A- A Systematic Review and Meta-Analysis
Abdi, A., Bordbar, M. R., Hassan, S., Rosendaal, F. R., van der Bom, J. G., Voorberg, J., Fijnvandraat, K., Gouw, S. C.
Frontiers in Immunology. 2020;11:563
Abstract
Objectives: In hemophilia A the presence of non-neutralizing antibodies (NNAs) against Factor VIII (FVIII) may predict the development of neutralizing antibodies (inhibitors) and accelerate the clearance of administrated FVIII concentrates. This systematic review aimed to assess: (1) the prevalence and incidence of NNAs in patients with congenital hemophilia without inhibitors and (2) the association between NNAs and patient and treatment characteristics. Methods: We conducted a search in MEDLINE, Embase, Web of Science and the Cochrane database. We included cross-sectional and longitudinal studies reporting on NNAs in patients with hemophilia A and B, who were inhibitor-negative at the start of the observation period. Data were extracted on: hemophilia type and severity, patient and treatment characteristics, NNA prevalence and incidence, NNA assays and inhibitor development. Two independent reviewers performed study selection, data extraction and risk of bias assessment, using adapted criteria of the Joanna Briggs Institute. Studies were classified as high-quality when ≥5/9 criteria were met. NNA assays were classified as high-quality when both quality criteria were met: (1) use of positive controls and (2) competition with FVIII to establish FVIII-specificity. We reported NNA prevalence and incidence for each study. The pooled NNA prevalence was assessed for well-designed studies in previously treated patients, employing high-quality NNA assays. Results: We included data from 2,723 inhibitor-negative patients with hemophilia A, derived from 28 studies. Most studies were cross-sectional (19/28) and none reported on NNAs in hemophilia B. Study design was of high quality in 16/28 studies and the NNA assay quality was high in 9/28 studies. Various NNA assays were used, predominantly ELISA (18/28) with different cut-off values. We found a large variety in NNA prevalence (Range, 0-100%). The pooled NNA prevalence in high-quality studies was 25% (95% CI, 16-38%). The incidence of new NNA development was reported in one study (0.01 NNA per person-exposure day). Conclusion: This systematic review identified studies that were heterogeneous in study design, patient population and NNA assay type, with NNA prevalence ranging from 0 to 100% in inhibitor-negative patients with hemophilia A. The pooled NNA prevalence was 25% in high-quality studies including only previously treated patients and performing high-quality NNA assays.