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Determinants of successful immune tolerance induction in hemophilia A: systematic review and meta-analysis
Oomen I, Camelo RM, Rezende SM, Voorberg J, Mancuso ME, Oldenburg J, Carcao M, Matino D, Lillicrap D, Fischer K, et al
Research and practice in thrombosis and haemostasis. 2023;7(1):100020
Abstract
BACKGROUND Immune tolerance induction (ITI) aims to eradicate anti-factor VIII (FVIII) antibodies (inhibitors) in persons with hemophilia A. However, this burdensome treatment fails in 10% to 40%. To estimate the chance of ITI success in clinical decision making, it is important to identify the predictors of ITI success. OBJECTIVES We performed a systematic review and meta-analysis to summarize the current evidence on determinants of ITI outcome in persons with hemophilia A. METHODS A literature search was conducted to identify randomized controlled trials, cohort, or case-control studies reporting on the predictors for ITI outcome in persons with hemophilia A. The main outcome was ITI success. Methodological quality was assessed using an adapted Joanna Briggs Institute checklist, rating as high if ≥11 of 13 criteria were met. Pooled odds ratios (ORs) for ITI success were calculated for each determinant. ITI success was defined as negative inhibitor titer (<0.6 BU/mL), FVIII recovery ≥66% of expected, and FVIII half-life ≥6 hours in 16 (59.3%) studies. RESULTS We included 27 studies, involving 1,734 participants. Methodological quality of 6 (22.2%) studies (418 participants) was rated as high. Twenty different determinants were assessed. Historical peak titer ≤100 BU/mL (compared with >100 BU/mL, OR, 1.7; 95% CI, 1.4-2.1), pre-ITI titer ≤10 BU/mL (compared with >10 BU/mL, OR, 1.8; 95% CI, 1.4-2.3), and peak titer during ITI ≤100 BU/mL (compared with >100 BU/mL, OR, 2.7; 95% CI, 1.9-3.8) were associated with a higher chance of ITI success. CONCLUSION Our results suggest that determinants related to the inhibitor titer are associated with ITI success.
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Risk factors for bleeding in people living with Hemophilia A and B treated with regular prophylaxis: a systematic review of the literature
Germini F, Noronha N, Philip BA, Olasupo O, Pete D, Navarro T, Keepanasseril A, Matino D, de Wit K, Parpia S, et al
Journal of thrombosis and haemostasis : JTH. 2022
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Abstract
BACKGROUND Knowledge about the risk for bleeding in patients with hemophilia (PWH) would be relevant for patients, stakeholders, and policy makers. OBJECTIVES to perform a systematic review of the literature on risk assessment models (RAMs) and risk factors for bleeding in PWH on regular prophylaxis. METHODS We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from inception through August 2019. In duplicate, reviewers screened the articles for inclusion, extracted data, and assessed the risk for bias using the QUIPS tool. A qualitative synthesis of the results was not performed due to high heterogeneity in risk factors, outcomes definition and measurement, and statistical analysis of the results. RESULTS From 1843 search results, 10 studies met the inclusion criteria. No RAM for the risk for bleeding in PWH was found. Most studies included only PWH A or both PWH A and B and were conducted in North America or Europe. Only one study had a low risk for bias in all the domains. Eight categories of risk factors were identified. The risk for bleeding was increased when factor levels were lower and in people with a significant history of bleeding or who engaged in physical activities involving contact. CONCLUSIONS Our findings suggest that plasma factor levels, history of bleeds, and physical activity should be considered for the derivation analysis when building a RAM for bleeding in PWH, and the role of other risk factors, including antithrombotic treatment and obesity, should be explored.
PICO Summary
Population
People living with haemophilia (PWH) A and B treated with regular prophylaxis (10 studies).
Intervention
Systematic review on risk assessment models and risk factors for bleeding.
Comparison
Outcome
No risk assessment model for the risk for bleeding was found. Most studies included only PWH A or both PWH A and B and were conducted in North America or Europe. Only one study had a low risk for bias in all the domains. Eight categories of risk factors were identified. The risk for bleeding was increased when factor levels were lower and in people with a significant history of bleeding or who engaged in physical activities involving contact.
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Clotting factor concentrates for preventing bleeding and bleeding-related complications in previously treated individuals with haemophilia A or B
Olasupo OO, Lowe MS, Krishan A, Collins P, Iorio A, Matino D
The Cochrane database of systematic reviews. 2021;8:Cd014201
Abstract
BACKGROUND The hallmark of severe hemophilia (A or B) is recurrent bleeding into joints and soft tissues with progressive joint damage, despite on-demand treatment. Prophylaxis has long been used, but not universally adopted, because of medical, psychosocial, and cost controversies. OBJECTIVES To determine the effectiveness of clotting factor concentrate prophylaxis in managing previously-treated individuals with hemophilia A or B. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. In addition, we searched MEDLINE and Embase and online trial registries. Most recent search of Group's Coagulopathies Trials Register: 24 February 2021. SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs evaluating people with hemophilia A or hemophilia B, who were previously treated with clotting factor concentrates to manage their hemophilia. DATA COLLECTION AND ANALYSIS Two authors independently reviewed trials for eligibility, assessed risk of bias and extracted data. The authors used the GRADE criteria to assess the certainty of the evidence. MAIN RESULTS Ten trials (including 608 participants) were eligible for inclusion. Eight of the trials (477 participants) had arms comparing two or more prophylactic regimens to one another and four of the trials (n = 258) compared prophylaxis to on-demand treatment (two trials had multiple arms and were included in both comparisons). Comparison of two or more prophylactic regimens For trials comparing one prophylaxis regimen to another, given the heterogeneity of the data, none of the data were pooled for this comparison. Considering the individual trials, three trials reported the primary outcome of joint bleeding, and none showed a dfference between dosing regimens (low-certainty evidence). For the secondary outcome of total bleeding events, prophylaxis with a twice-weekly regimen of FIX likely results in reduced total bleeds compared to a once-a-week regimen of the same dose, mean difference (MD) 11.2 (5.81 to 16.59) (one trial, 10 participants, low-certainty evidence). Transient low-titer anti-FVIII inhibitors were reported in one of the trials. Blood-transmitted infections were not identified. Other adverse events reported include hypersensitivity, oedema, and weight gain. These were, however, rare and unrelated to study drugs (very low-certainty evidence). Comparison of prophylactic and on-demand regimens Four of the trials (258 participants) had arms that compared prophylaxis to on-demand treatment. Prophylaxis may result in a large decrease in the number of joint bleeds compared to on-demand treatment, MD -30.34 (95% CI -46.95 to -13.73) (two trials, 164 participants, low-certainty evidence). One of these trials (84 participants) also reported the long-term effects of prophylaxis versus on-demand therapy showing improved joint function, quality of life, and pain; but no differences between groups in joint structure when assessed by magnetic resonance imaging (MRI). In one trial (84 participants) validated measures for joint health and pain assessment showed that prophylaxis likely improves joint health compared to an on-demand regimen with an estimated change difference of 0.94 points (95% CI 0.23 to 1.65) and improves total pain scores, MD -17.20 (95% CI -27.48 to -6.92 (moderate-certainty evidence). Two trials (131 participants) reported that prophylaxis likely results in a slight increase in adverse events, risk ratio 1.71 (1.24 to 2.37) (moderate-certainty evidence). No inhibitor development and blood-transmitted infections were identified. Overall, the certainty of the body of evidence was judged to be low because of different types of bias that could have altered the effect. AUTHORS' CONCLUSIONS There is evidence from RCTs that prophylaxis, as compared to on-demand treatment, may reduce bleeding frequency in previously-treated people with hemophilia. Prophylaxis may also improve joint function, pain and quality of life, even though this does not translate into a detectable improvement of articular damage when assessed by MRI. When comparing two different prophylaxis regimens, no significant differences in terms of protection from bleeding were found. Dose optimization could, however, result in improved efficacy. Given the heterogeneity of the data, pooled estimates were not obtained for most comparisons. Well-designed RCTs and prospective observational controlled studies with standardised definitions and measurements are needed to establish the optimal and most cost-effective treatment regimens.
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Recombinant factor VIIa concentrate versus plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors
Matino D, Makris M, Dwan K, D'Amico R, Iorio A
Cochrane Database of Systematic Reviews.. 2015;((12)):CD004449.
Abstract
BACKGROUND In people with haemophilia, therapeutic clotting agents might be recognised as a foreign protein and induce anti-factor VIII antibodies, known as 'inhibitors'. Drugs insensitive to such antibodies, either recombinant or plasma-derived, are called factor VIII 'by-passing' agents and used for treatment of bleeding in people with inhibitors. OBJECTIVES To determine the clinical effectiveness of recombinant factor VIIa concentrate compared to plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Coagulopathies Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Coagulopathies Trials Register: 23 September 2015. SELECTION CRITERIA Randomised and quasi-randomised controlled clinical trials comparing recombinant factor VIIa concentrate to human plasma-derived concentrates (high-dose human or recombinant factor VIII or factor IX concentrate; non-activated prothrombin complex concentrates; activated prothrombin complex concentrates) in people with haemophilia. Comparisons with animal-derived products were excluded. DATA COLLECTION AND ANALYSIS Two authors independently assessed the trials (eligibility and risk of bias) and extracted data. No combined meta-analyses were performed due to the unavailability of outcomes and comparisons common to the included trials. MAIN RESULTS A total of 15 trials were identified, two of which (with data for a total of 69 participants) were eligible for analysis. Both trials showed methodological flaws and did not show superiority of one treatment over the other. Both the treatments showed that recombinant factor VIIa and activated prothrombin complex concentrate appeared to have a similar haemostatic effect in both trials, without increasing thromboembolic risk. AUTHORS' CONCLUSIONS Based on the separate analysis of the two available randomised trials, recombinant factor VIIa and activated prothrombin complex concentrate were found to be similar in efficacy and safety. However, there is a need for further, well-designed, adequately-powered, randomised controlled trials to assess the relative benefits and risks of using recombinant factor VIIa compared to human plasma-derived concentrates in people with haemophilia with inhibitors. It is advisable that researchers in the field define commonly agreed objective outcome measures in order to enable the pooling of their results, thus increasing the power of comparisons. To date, data could not be combined in a formal meta-analysis. For the same reason reporting concordant and discordant pairs in cross-over trials is recommended.
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Recombinant factor VIIa concentrate versus plasma derived concentrates for the treatment of acute bleeding episodes in people with haemophilia and inhibitors
Iorio A, Matino D, D'Amico R, Makris M
Cochrane Database of Systematic Reviews. 2010;((8):):CD004449.
Abstract
BACKGROUND In people with haemophilia, therapeutic clotting agents might be recognised as a foreign protein and induce anti-FVIII antibodies, known as 'inhibitors'. Drugs insensitive to such antibodies, either recombinant or plasma-derived, are called factor VIII by-passingagents and used for treatment of bleeding in people with inhibitors. OBJECTIVES To determine the clinical effectiveness of recombinant FVIIa concentrate in comparison to plasma-derived concentrates for the treatment of acute bleeding episodes in people with haemophilia and inhibitors. SEARCH STRATEGY We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Coagulopathies Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Trials Register: 07 July 2010. SELECTION CRITERIA Randomised (RCTs) and quasi-randomised controlled clinical trials comparing recombinant FVIIa concentrate (rFVIIa) to human plasma-derived concentrates (high-dose human or recombinant FVIII or FIX concentrate; prothrombin complex concentrates (PCCs); activated prothrombin complex concentrate (aPCC)) in persons with haemophilia. Comparisons with animal derived products were excluded. DATA COLLECTION AND ANALYSIS Two authors independently assessed trials (eligibility and risk of bias) and extracted data. No meta-analysis was performed due to unavailability of outcomes and comparisons common to the included studies. MAIN RESULTS A total of ten trials were identified, two of which (total of 69 participants) were eligible for analysis. Both trials showed methodological flaws and did not show superiority of one treatment over the other. Both the treatments showed that (rFVIIa and aPCC appeared to have a similar haemostatic effect in both studies, without increasing thromboembolic risk. AUTHORS' CONCLUSIONS Although the main conclusion should be the need for further randomised controlled trials, we conclude that both rFVIIa and aPCC can be used to treat bleeding in haemophiliacs with inhibitors.