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
Recenzirano
This editorial describes the science behind a clinical trial of concizumab, an inhibitor of a naturally occurring anticoagulant, to treat hemophilia A and B.
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.
Inhibitory antibodies to factor VIII develop in about a third of patients with severe hemophilia A, complicating therapy. In this study, factor VIII type, von Willebrand factor content, and product ...switching had no significant effect on inhibitory antibodies.
Patients with severe hemophilia A have a deficiency of functional clotting factor VIII (<0.01 IU per milliliter) and have bleeding in the joints and muscles. To prevent joint destruction, the current standard of care for children with severe hemophilia A is primary prophylaxis. This includes regular infusions of factor VIII, which are initiated at the time of the first episode of bleeding in a joint or earlier, aiming at the prevention of joint damage.
1
However, in about 30% of children, inhibitory antibodies to infused factor VIII products develop, making usual treatment with factor VIII and prophylaxis impossible. There are multiple . . .
A Cure for Hemophilia within Reach van den Berg, H. Marijke
The New England journal of medicine,
12/2017, Letnik:
377, Številka:
26
Journal Article
Recenzirano
Severe hemophilia has changed from a debilitating disease to a condition that is compatible with normal life, provided that patients receive a diagnosis early and also receive prophylactic therapy.
1
...The disease burden is now related largely to the demanding infusions and the development of alloantibodies that can neutralize the effect of exogenously administered clotting factors (so-called inhibitors). Products with an extended half-life have reduced the burden of treatment. In patients with hemophilia B, therapeutic levels can be obtained with infusions every 2 weeks.
2
Yet, the high costs of lifelong prophylactic therapy and the continuous bleeding risk that is due to . . .
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.
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.
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