WFH Guidelines for the Management of Hemophilia, 3rd edition Srivastava, Alok; Santagostino, Elena; Dougall, Alison ...
Haemophilia : the official journal of the World Federation of Hemophilia,
August 2020, 2020-08-00, 20200801, 2020-08-01, Letnik:
26, Številka:
S6
Journal Article
Hemostasis - A Balancing Act van den Berg, H Marijke; Srivastava, Alok
The New England journal of medicine,
08/2023, Letnik:
389, Številka:
9
Journal Article
Introduction
The prophylactic regimen in children with severe haemophilia is suggested in various publications and guidelines. Few data exist on its implementation in clinical practice.
Aim
To ...investigate the implementation of primary prophylaxis based on real‐life data from PedNet during the last 20 years.
Methods
All children from the PedNet cohort (n = 1260) with severe haemophilia A (SHA) or severe haemophilia B (SHB), FVIII/IX < .01 IU/mL, born between 2000 and 2009 (Cohort I; SHA n = 662; SHB n = 88) and 2010–2019 (Cohort II; SHA n = 598; SHB n = 94) were included.
Results
In SHA, the median age at start of prophylaxis was 17.3 months (IQR; 12.5–26.1) in Cohort I which decreased to 13.1 months (IQR; 10.4–19.1) in Cohort II (p < .000). “Once‐a‐week” prophylaxis at start increased from 49% to 68% (SHA) and 38% to 70% (SHB). FVIII doses were reduced from median 43.5 (IQR; 34.6–49.0) to 30.9 IU/kg (IQR; 26.3–46.3), while dosing with FIX did not change. After 2010 approximately 60% of the patients with SHA and SHB started prophylaxis before any joint bleed. The number of CVADs needed in both cohorts was around 30%. Incidences of inhibitors were unchanged: SHA (∼31%) and SHB (∼10%). Sporadic cases were diagnosed significantly later (median 8.3 months; IQR; 3.7–11.9) and they had more joint bleeds before start of prophylaxis.
Conclusion
Primary prophylaxis nowadays starts at an earlier age: before any joint bleed (60% of patients with SHA and SHB). Approximately 70% started on a once‐weekly schedule with significantly reduced doses in SHA but unchanged in SHB.
This systematic review was designed to provide more precise effect estimates of inhibitor development for the various types of F8 gene mutations in patients with severe hemophilia A. The primary ...outcome was inhibitor development and the secondary outcome was high-titer-inhibitor development. A systematic literature search was performed to include cohort studies published in peer-reviewed journals with data on inhibitor incidences in the various F8 gene mutation types and a mutation detection rate of at least 80%. Pooled odds ratios (ORs) of inhibitor development for different types of F8 gene mutations were calculated with intron 22 inversion as the reference. Data were included from 30 studies on 5383 patients, including 1029 inhibitor patients. The inhibitor risk in large deletions and nonsense mutations was higher than in intron 22 inversions (pooled OR = 3.6, 95% confidence interval 95% CI, 2.3-5.7 and OR = 1.4, 95% CI, 1.1-1.8, respectively), the risk in intron 1 inversions and splice-site mutations was equal (pooled OR = 0.9; 95% CI, 0.6-1.5 and OR = 1.0; 95% CI, 0.6-1.5), and the risk in small deletions/insertions and missense mutations was lower (pooled OR = 0.5; 95% CI, 0.4-0.6 and OR = 0.3; 95% CI, 0.2-0.4, respectively). The relative risks for developing high titer inhibitors were similar.
For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of ...clinically relevant inhibitory antibodies (inhibitor development).
We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels.
Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval CI, 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development.
Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.).
Prophylactic treatment in severe hemophilia is very effective but is limited by cost issues. The implementation of 2 different prophylactic regimens in The Netherlands and Sweden since the 1970s may ...be considered a natural experiment. We compared the costs and outcomes of Dutch intermediate- and Swedish high-dose prophylactic regimens for patients with severe hemophilia (factor VIII/IX < 1 IU/dL) born between 1970 and 1994, using prospective standardized outcome assessment and retrospective collection of cost data. Seventy-eight Dutch and 50 Swedish patients, median age 24 years (range, 14-37 years), were included. Intermediate-dose prophylaxis used less factor concentrate (median: Netherlands, 2100 IU/kg per year interquartile range (IQR), 1400-2900 IU/kg per year vs Sweden, 4000 IU/kg per year IQR, 3000-4900 IU/kg per year); (P < .01). Clinical outcome was slightly inferior for the intermediate-dose regimen (P < .01) for 5-year bleeding (median, 1.3 IQR, 0.8-2.7 vs 0 IQR, 0.0-2.0 joint bleeds/y) and joint health (Haemophilia Joint Health Score >10 of 144 points in 46% vs 11% of participants), although social participation and quality of life were similar. Annual total costs were 66% higher for high-dose prophylaxis (mean, 180 95% confidence interval, 163 - 196 × US$1000 for Dutch vs 298 95% confidence interval, 271-325) × US$1000 for Swedish patients; (P < .01). At group level, the incremental benefits of high-dose prophylaxis appear limited. At the patient level, prophylaxis should be tailored individually, and many patients may do well receiving lower doses of concentrate without compromising safety.
•Compared with intermediate-dose prophylaxis (3 × 1000 IU/wk), high-dose prophylaxis (3 × 2000 IU/wk) resulted in a 66% higher total cost.•At age 24 years, high-dose prophylaxis resulted in a small reduction in bleeding and hemophilic arthropathy, but equal quality of life.
Objective
Repeated hemarthrosis in hemophilia causes arthropathy with pain and dysfunction. The Hemophilia Joint Health Score (HJHS) was developed to be more sensitive for detecting arthropathy than ...the World Federation of Hemophilia (WFH) physical examination scale, especially for children and those using factor prophylaxis. The HJHS has been shown to be highly reliable. We compared its validity and sensitivity to the WFH scale.
Methods
We studied 226 boys with mild, moderate, and severe hemophilia at 5 centers. The HJHS was scored by trained physiotherapists. Study physicians at each site blindly determined individual and total joint scores using a series of visual analog scales.
Results
The mean age was 10.8 years. Sixty‐eight percent were severe (93% of whom were treated with prophylaxis), 15% were moderate (24% treated with prophylaxis), and 17% were mild (3% treated with prophylaxis). The HJHS correlated moderately with the physician total joint score (rs = 0.42, P < 0.0001) and with overall arthropathy impact (rs = 0.42, P < 0.0001). The HJHS was 97% more efficient than the WFH at differentiating severe from mild and moderate hemophilia. The HJHS was 74% more efficient than the WFH at differentiating subjects treated with prophylaxis from those treated on demand. We identified items on the HJHS that may be redundant or rarely endorsed and could be removed from future versions.
Conclusion
Both the HJHS and WFH showed evidence of strong construct validity. The HJHS is somewhat more sensitive for mild arthropathy; its use should be considered for studies of children receiving prophylaxis.
Registries supporting new drug applications Jonker, Carla J.; Berg, H. Marijke; Kwa, Marcel S.G. ...
Pharmacoepidemiology and drug safety,
December 2017, Letnik:
26, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Purpose
Knowledge of the benefits and risks of new drugs is incomplete at the time of marketing approval. Registries offer the possibility for additional, post‐approval, data collection. For all new ...drugs, which were approved in the European Union between 2007 and 2010, we reviewed the frequency, the type, and the reason for requiring a registry.
Methods
The European Public Assessment Reports, published on the website of the European Medicine Agency, were reviewed for drugs approved by the Committee for Medicinal Products for Human Use. We searched for key characteristics of these drugs, including therapeutic area (ATC1 level), level of innovation (the score is an algorithm based on availability of treatment and therapeutic effect), and procedural characteristics. In addition, we identified if these registries were defined by disease (disease registry) or exposure to a single drug (drug registry).
Results
Out of 116 new drugs approved in the predefined period, for 43 (37%), 1 to 6 registry studies were identified, with a total of 73 registries. Of these 46 were disease registries and 27 (single) drug registries. For 9 drugs, the registry was a specific obligation imposed by the regulators. The level of innovation and the orphan status of the drugs were determinants positively predicting post‐approval registries (OR 10.3 95% CI 1.0‐103.9 and OR 2.8 95% CI 1.0‐7.5, respectively).
Conclusions
The majority of registries required by regulators are existing disease registries. Registries are an important and frequently used tool for post‐approval data collection for orphan and innovative drugs.
The CANAL Study (Concerted Action on Neutralizing Antibodies in severe hemophilia A) was designed to describe the relationship between treatment characteristics and inhibitor development in ...previously untreated patients with severe hemophilia A. This multicenter retrospective cohort study investigated 366 consecutive patients born between 1990 and 2000. The outcome was clinically relevant inhibitor development, defined as the occurrence of at least 2 positive inhibitor titers combined with a decreased recovery. Eighty-seven (24%) patients developed inhibitors (69 high titer 19%). The incidence of inhibitors appeared to be associated with age at first treatment, decreasing from 41% for those treated within the first month of age to 18% in those treated after 18 months; after adjustment for treatment intensity, this association largely disappeared. Surgical procedures and peak treatment moments at start of treatment increased inhibitor risk (relative risk RR, 3.7; 95% confidence interval CI, 2.0-7.1; and RR, 3.3; CI, 2.1-5.3, respectively). Regular prophylaxis was associated with a 60% lower risk than on-demand treatment (RR, 0.4; CI, 0.2-0.8). Our findings suggest that the previously reported associated between an early age at first exposure and the risk of inhibitor development is largely explained by early, intensive treatment. The latter appears to be an independent risk factor for inhibitor development. In addition, early, regular prophylaxis may protect patients with hemophilia against the development of inhibitors.
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