The impact of prophylactic treatment on children with severe haemophilia
TL;DR: Twenty‐seven children with severe haemophilia receiving regular prophylactic factor concentrate were evaluated to examine the overall effectiveness of prophYLaxis in modern haemophile care.
Abstract: Twenty-seven children with severe haemophilia receiving regular prophylactic factor concentrate were evaluated to examine the overall effectiveness of prophylaxis in modern haemophilia care. The median age at the start of prophylaxis was 6.2 years (range 1.3-15.9 years) and the cumulative length of follow-up was 808 months (mean 30, rang 7-76 months). Nine patients required a central venous catheter for venous access (age range 1.3-5.2 years), eight boys could cannulate themselves and in 10 the parents performed regular venepuncture. The mean dose of concentrate given at the time of study was 31.8 U/kg three times weekly (range 12.5.6 U/kg) or 4900 U/kg/year (range 1900-8200). None developed an inhibitor on prophylaxis, though four had previously had an antibody. The median average annual number of bleeds in the 27 patients prior to prophylaxis was 14.7 (range 3.7-35.4). On prophylaxis this fell to 1.5 (range 0-12.5) (P<0.001) and in the group as a whole the frequency of bleeds diminished in successive years on prophylaxis. All 20 children with evidence of arthropathy improved on prophylaxis and eight had reversal of chronic damage such that their joints appeared normal at the time of study. There were reductions in the need for walking aids, in hospital admissions, and in numbers of school days lost for bleeding episodes. All families feel that prophylaxis has brought about an improvement in quality of life.
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TL;DR: In the past, men with haemophilia were likely to die in their youth, but with advances in diagnosis, and especially with development of safe and effective treatment, affected individuals can now look forward to a normal life expectancy.
625 citations
University of Minnesota1, Icahn School of Medicine at Mount Sinai2, Yale University3, University of North Carolina at Chapel Hill4, University of California, San Diego5, Harvard University6, Mayo Clinic7, Great Lakes Institute of Management8, Stanford University9, University of Texas MD Anderson Cancer Center10, University of Iowa11, Boston Children's Hospital12, Tufts University13, Riley Hospital for Children14, Children's Memorial Hospital15, Albany Medical College16
TL;DR: In this paper, the authors evaluated the safety and efficacy of a fixed dose of recombinant activated factor VII (rFVIIa) in the home setting for mild to moderately severe joint, muscle, and mucocutaneous bleeding episodes in patients with haemophilia A or B with inhibitors.
Abstract: Objective. To assess the safety and efficacy of a fixed dose of recombinant activated factor VII (rFVIIa; NovoSeven™) in the home setting for mild to moderately severe joint, muscle, and mucocutaneous bleeding episodes in patients with haemophilia A or B with inhibitors. Design. Multicentre, open-label, single arm, phase III study of one year duration. Methods. Patients or their caregivers administered up to three doses of rFVIIa (90 μg/kg i.v.) at 3 h intervals within 8 h of the onset of a mild to moderate bleeding episode. Once the subject considered that rFVIIa had been “effective” with regard to haemostasis (after 1-3 injections), one further (maintenance) dose of rFVIIa was administered. Results. Of 60 patients enrolled, 56 experienced at least one bleed, and 46 completed the one year study. 614 of 877 bleeds (70%) were evaluable according to protocol definitions. Haemostasis was rated as “effective” in 92% (566/614) of evaluable bleeds after a mean of 2.2 injections. For successfully treated episodes, the time from onset of bleeding until administration of the first injection was 1.1 ± 2.0 h (mean ± SD). Twenty-four hours after initial successful response, haemostasis was reported as having been maintained in 95% of cases. Efficacy was comparable for muscle, joint and target joint, and muco-cutaneous bleeding episodes. In an intent-to-treat analysis of all 877 bleeding events, efficacy outcomes were equivalent to the evaluable bleeds, with an effective response in 88% of treated episodes. Treatment-related adverse events occurred in 32 (3% of all) bleeding episodes and consisted of re-bleeds/new bleeds in more than 50% (18/32) of these events. A single episode of superficial thrombophlebitis was the only thrombotic complication encountered, and there were no patient withdrawals due to adverse events. Development of FVII(a) antibodies could not be detected, and hypersensitivity reactions to rFVIIa were not reported. Conclusion. rFVIIa is effective and well tolerated when used in the home setting to treat mild to moderate bleeding episodes in patients with haemophilia A or B with inhibitors.
350 citations
TL;DR: Clinically relevant reductions in bleeding frequency during prophylaxis as compared to conventional on‐demand therapy were achieved without raising safety concerns, providing evidence for the concept of secondary rFVIIa prophyllaxis in inhibitor patients with frequent bleeds.
317 citations
TL;DR: The frequency of joint bleeds and orthopaedic joint scores were evaluated in 121 patients with severe haemophilia who had started prophylactic treatment with clotting factor concentrates at least once weekly before the age of 10.
Abstract: The frequency of joint bleeds and orthopaedic joint scores were evaluated in 121 patients with severe haemophilia who had started prophylactic treatment with clotting factor concentrates at least once weekly before the age of 10. 75 of the patients started before the age of 3, 31 at the age of 3-5 and 15 at the age of 6-9. Each subgroup was evaluated separately. In addition, a regimen of one infusion weekly was compared with that of two (haemophilia B) or three (haemophilia A) infusions weekly in each patient. A significant decrease in the overall number of joint bleeds per year was found after shortening the infusion interval (P<0.005), but the individual bleeding pattern varied. In survival analysis of the first pathologic joint score event, those who started prophylaxis before the age of 3 had a better outcome overall than those starting at later ages (P=0.001). However, in subgroup analysis, no significant difference was seen in the annual number of joint bleeds and the development of arthropathy between those starting with, or shifting to, the more intensive regimen before the age of 3 and those that were put on this regimen at the age of 3-5. Age at start of prophylaxis was found to be an independent predictor for the development of arthropathy (P=0.0002), whereas dose and infusion interval at start were not. Our data emphasize the importance of starting replacement therapy during the first years of life. However, it seems that when beginning the regimen it can be individualized and adjusted according to the bleeding pattern. In this way, the need for a venous access system may be assessed on an individual basis.
267 citations
Cites background from "The impact of prophylactic treatmen..."
...Moreover, Liesner et al (1996) have pointed out that it is important to evaluate whether a severe haemophilia patient, in terms of the factor VIII or IX clotting activity, behaves as a severely ill subject clinically....
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...…it has been clearly shown that it is important to minimize the amounts of joint bleeds and to start treatment before arthropathy has developed (Petrini et al, 1991; Nilsson et al, 1992; van den Berg et al, 1994; Manco-Johnson et al, 1994; Aledort et al, 1994; Berntorp, 1995; Liesner et al, 1996)....
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...…for three decades and the benefits of this treatment compared to the on-demand regimen have been described elsewhere (Petrini et al, 1991; Nilsson et al, 1992; van den Berg et al, 1994; MancoJohnson et al, 1994; Aledort et al, 1994; Berntorp, 1995; Liesner et al, 1996; Löfqvist et al, 1997)....
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TL;DR: In this article, the authors investigated the safety and pharmacokinetics of Factor VIII (FVIII) in patients with severe hemophilia A and found that rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing.
257 citations
References
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TL;DR: It appears to be possible to prevent haemophilic arthropathy by giving effective continuous prophylaxis from an early age, and preventing the VIII:C or IX:C concentration from falling below 1% of normal.
Abstract: In Sweden, prophylactic treatment of boys with severe haemophilia has been practised since 1958 in an attempt to convert the disease from a severe to a milder form. The present study population consisted of 60 severe haemophiliacs (52 A, 8 B), aged 3-32 years. Treatment is started when the boys are 1-2 years of age, the regimens used being 24-40 IU F VIII kg-1 three times weekly in haemophilia-A cases (i.e. greater than 2000 IU kg-1 annually) and 25-40 IU F IX kg-1 twice weekly in haemophilia-B cases. The orthopaedic and radiological joint scores (maximum scores of 90 and 78, respectively) are evaluated as recommended by the World Federation of Haemophilia. Of those subjects aged 3-17 years, 29 out of 35 individuals had joint scores of zero. The oldest group had only minor joint defects. The VIII:C and IX:C concentrations had usually not fallen below 1% of normal. All 60 patients are able to lead normal lives. In conclusion, it appears to be possible to prevent haemophilic arthropathy by giving effective continuous prophylaxis from an early age, and preventing the VIII:C or IX:C concentration from falling below 1% of normal.
928 citations
"The impact of prophylactic treatmen..." refers background or result in this paper
...There also has to be some doubt as to whether such a trial is ethically justified in view of some encouraging results of prophylaxis from the Swedish haemophilia centre in Malmö (Nilsson et al, 1992) where a form of prophylaxis was first introduced in 1958....
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...However, the only published literature on larger series are the Swedish study from Malmö (Nilsson et al, 1992) and the recently published prospective orthopaedic outcome study from 21 centres worldwide which examined 477 children and young adults receiving varied treatment programmes (Aledort et…...
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...However, the only published literature on larger series are the Swedish study from Malmö (Nilsson et al, 1992) and the recently published prospective orthopaedic outcome study from 21 centres worldwide which examined 477 children and young adults receiving varied treatment programmes (Aledort et al, 1994)....
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...The Malmö group (Carlsson et al, 1993) have studied the pharmacokinetics of factor VIII and IX in order to try to find a schedule which would achieve this, and by decreasing the dosage interval it has apparently been possible to give an overall lower dose, though there is considerable individual variation....
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TL;DR: It is hypothesized that no direct relationship exists between increasing factor dosage and orthopaedic outcomes over time and optimal therapeutic regimens for persons with haemophilia are established.
Abstract: . Objective. Arthropathy is the major cause of morbidity in haemophilia. In an attempt to establish optimal therapeutic regimens for persons with haemophilia, we hypothesized that no direct relationship exists between increasing factor dosage and orthopaedic outcomes over time.
Design. A longitudinal uncontrolled 6 year study was carried out. Ankles, knees and elbows of patients were studied using physical and X-ray examination scores. Bleeding episodes and treatment regimens were determined. The amount of time lost from work and school, as well as days in hospital, was also monitored.
Setting. Twenty-one international haemophilia centres were used to accrue and follow patients over the 6 year period.
Subject. Severe (< 1 %) factor VIII deficient patients under the age of 25 without inhibitors were recruited into the study.
Intervention. The status of the six major joints of these patients were measured annually for mobility. X-ray evaluation of these joints was carried out at the beginning and end of the study. Using a World Federation of Haemophilia joint and X-ray score, stability, progression or regression of arthropathy was evaluated.
Results. Physical and X-ray examination scores increased significantly with age, and the number of joint bleeds were significant in determining the Δ score. Approximately 10% of patients entered with all six joints normal. Of these, 50% remained so. Year-long prophylaxis significantly reduced the rate at which joints deteriorate both on physical (P = 0.02) and X-ray examination (P = < 0.001). Patients on prophylaxis had significantly fewer days lost from work or school, as well as fewer days spent in hospital (P = < 0.01).
Conclusions. Higher doses of factor per se do not necessarily produce improved orthopaedic outcomes. However, full time prophylaxis is likely to produce the best orthopaedic outcome. The most critical factor for a good orthopaedic outcome is the reduction of joint bleeds.
608 citations
TL;DR: The feasibility of the method to generally raise trough levels with a decreased consumption of FVIII was confirmed, and dosing of coagulation factors according to kinetic principles can result in more cost‐effective utilization of these very expensive preparations.
Abstract: The aim of this study was to investigate individual pharmacokinetics as a tool for dosing of factor VIII (FVIII) in severe hemophilia A. It is assumed that effective prophylaxis against bleedings is maintained if the plasma FVIII:C activity is kept above 1 U/dl, and the present study is based on this assumption. A current standard dosage regimen for FVIII is 25-40 U/kg up to three times weekly. However, there is considerable individual variation in the pharmacokinetics of FVIII:C. Individual pharmacokinetic data were used to computer-simulate plasma activity curves after repeated doses in 8 patients. Going from prophylaxis regimens of normally 2-3 infusions per week to dosing every 2 days would theoretically reduce their average FVIII consumption by 43% with maintained or increased trough levels of FVIII:C. Daily dosing would reduce their mean FVIII usage by 82%. Modified dosage regimens, infusions every 2 days, were implemented in the patients, and plasma samples were drawn to verify the pharmacokinetic models. The feasibility of the method to generally raise trough levels with a decreased consumption of FVIII was confirmed. Dosing of coagulation factors according to kinetic principles can result in more cost-effective utilization of these very expensive preparations.
106 citations
"The impact of prophylactic treatmen..." refers background in this paper
...The Malmö group (Carlsson et al, 1993) have studied the pharmacokinetics of factor VIII and IX in order to try to find a schedule which would achieve this, and by decreasing the dosage interval it has apparently been possible to give an overall lower dose, though there is considerable individual…...
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TL;DR: Twenty-three children with severe congenital coagulopathy had a total of 27 port‐a‐cath devices inserted to facilitate factor VIII or IX prophylaxis, domiciliary therapy, immunotolerance, or a combination thereof, from two U.K. centres.
Abstract: Summary From two U.K. centres 23 children with severe congenital coagulopathy had a total of 27 port-a-cath devices inserted to facilitate factor VIII or IX prophylaxis (eight patients), domiciliary therapy (seven patients), immunotolerance (four patients), or a combination thereof (four patients). Six children had a factor VIII inhibitor at the time of insertion. The mean age at operation was 30 months, with a range of 9–76 months. The cumulative length of follow-up is 639 months with a mean of 27–8 months and a range of 5–79 months.
Haemostasis was achieved peri- and post-operatively with high-purity concentrate in the majority of patients without an inhibitor. All those with an inhibitor had porcine factor VIII, except one who had recombinant factor Vila.
The post-operative complication rate was 27% (6/23): three had a port-site haematoma (one required removal and replacement), two had post-operative infection, and one had swelling caused by extravasation.
To date there have been 13 documented infections in 10/ 23 patients (five with inhibitor): a rate of 0–24 per follow-up year or 0–67 per 1000 patient-days. Six were caused by Gram-positive and seven by Gram-negative organisms. Six infections could not be eradicated by antibiotics and the port-a-cath system had to be removed; in three it was replaced by a second port-a-cath.
Although there are risks involved in the use of port-a-caths in this population, both clinicians and parents involved in the care of these children believe that the benefits are considerable and the potential hazards are acceptable.
71 citations
"The impact of prophylactic treatmen..." refers background in this paper
...One third of the children (9/27) required the insertion of a right atrial indwelling catheter in order to enable prophylaxis to be given; eight had a port-a-cath and one has had a Hickman line (Liesner et al, 1995)....
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...Since prophylaxis was introduced, none of the children has had an admission for a bleed, but there have been admissions for minor surgery, dental treatment and catheter-related complications such as sepsis (Liesner et al, 1995)....
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...The main complications of bleeding during insertion and infection occur particularly in patients with inhibitors, but we have found that the benefit of being able to give prophylaxis to young children outweighs the associated risks of these catheters (Liesner et al, 1995)....
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...…catheters in order to give the treatment to young children, and as more and more of these are being used in children with bleeding diatheses it is becoming apparent that it is possible to do it safely without undue risk to the child (Ljung et al, 1992; Lilleyman et al, 1994; Liesner et al, 1995)....
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TL;DR: Nine of the 12 children with a severe form of haemophilia A's parents learned how to use the Port‐A‐Cath system, thus enabling optimal prophylactic home treatment with factor VIII to be begun early in life.
Abstract: Twelve children with a severe form of haemophilia A received a totally implantable venous access system (Port-A-Cath) to facilitate regular prophylactic treatment with factor VIII. The indication for implantation was difficulty in obtaining regular access to a peripheral vein. Postoperative bleeding around the portal site occurred in two of 12 cases. After a median duration of follow-up of 26 months (range 5-79 months), one of the systems had needed replacement due to bleeding, septicaemia or thrombosis. One child, with an inhibitor against factor VIII, had an infection at the portal site and this system was removed. None of the other children had any serious side effects. Nine of the 12 children's parents learned how to use the Port-A-Cath system, thus enabling optimal prophylactic home treatment with factor VIII to be begun early in life. (Less)
65 citations
"The impact of prophylactic treatmen..." refers background in this paper
...…catheters in order to give the treatment to young children, and as more and more of these are being used in children with bleeding diatheses it is becoming apparent that it is possible to do it safely without undue risk to the child (Ljung et al, 1992; Lilleyman et al, 1994; Liesner et al, 1995)....
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