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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.
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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Prothrombin complex concentrates and andexanet for management of direct factor Xa inhibitor related bleeding: a meta-analysis
Luo C, Chen F, Chen YH, Zhao CF, Feng CZ, Liu HX, Luo DZQ
European review for medical and pharmacological sciences. 2021;25(6):2637-2653
Abstract
There are potential concerns related to bleeding caused by oral anticoagulants, especially in the elderly. Andexanet alfa has been authorized for use to reverse the effects of oral anticoagulants. Off-label use of four factor prothrombin complex concentrate (4F-PCC) for the reversal of oral factor Xa inhibitors is common. However, not much is known about their efficacy and safety profile. The intent of this meta-analysis was to evaluate the efficacy and safety of 4F-PCC and andexanet alfa for management of major bleeding due to oral factor Xa inhibitors. Comprehensive searches were done systematically through PubMed, Scopus and Google scholar databases. Studies that were retrospective record based or adopted prospective cohort approach and reported either of the three main outcomes, i.e., achieved hemostasis rate or rate of thrombotic events or mortality rate were included in the meta-analysis. Statistical analyses were done using STATA version 13.0. A total of 22 studies were included in the meta-analysis. All the studies had a single arm with no control/comparator group. The pooled rate of good to excellent hemostatic control upon use of andexanet was 80% (95% CI; 72% to 88%) and for 4F-PCC, it was 76% (95% CI; 70% to 83%). A comparatively higher pooled rate of thrombotic complications upon use of andexanet [13% (95% CI; 5% to 20%) was noted, compared to use of aPCC/4F-PCC [4% (95% CI; 3% to 5%). The pooled all-cause mortality rate within 30 days of administration was 24% (95% CI; 12% to 35%) with andexanet use and 19% (95% CI; 14% to 25%) for aPCC/4F-PCC. The findings suggest that use of both andexanet and aPCC/4F-PCC achieves a good hemostasis but there is an associated risk of thrombotic events and mortality. Future studies should have a control group to better establish evidence on efficacy and safety of these agents.
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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.