Datos obtenidos en la observación

A key issue in treating individuals with primary prophylaxis is when treatment should commence. A number o f studies have suggested that treatment should begin between the ages o f 1-3 years o f age prior to any signs o f repeated joint bl eedi ng^’ However , it has also been suggested that treatment should be withheld until an individual has experienced three joint bleeds or two successive bleeds in the same joint, because not all individuals with severe haemophilia ‘behave’ as clinically severe^*.

In one study from the Malmo Centre, joint bleeding frequency and WFH orthopaedic joint scores were evaluated in 121 individuals with severe haemophilia who had started prophylactic treatment with clotting factor concentrates at least once a week before the age o f 10 years” ^. No significant differences were seen in the annual num ber o f joint bleeds and the development o f arthropathy before the age o f 3 years. However, age at

start o f prophylaxis was found to be an independent predictor for the development o f arthropathy (P=0.0002), whereas dose size and infusion interval at were not.*®^’’’®

2.3.2.2.6 Methods of reducing dotting factor use

Although the evidence suggests that prophylaxis with 24-40 iu/kg o f clotting factor 2-3 times per week may prevent haemophilic arthropathy in patients with severe haemophilia, treatment is thought to be extremely costly because it involves the use of large amounts o f clotting factor. Interest is growing, therefore, in developing techniques that reduce the amount o f clotting factor required for prophylaxis without compromising the effectiveness o f treatment.

Once infused, clotting factors are known to show wide intersubject variability in terms o f pharmacokinetic b e h a v i o u r ^ I t has been suggested, therefore, that tailoring prophylactic regimes to individual patient’s pharmacokinetic properties might be one method o f reducing clotting factor use. Pharmacokinetic dosing, as this process is known, can be seen as a method o f ‘fine-tuning’ clotting factor requirements in terms o f size and frequency o f dose.

The feasibility o f using pharmacokinetic dosing to fine-tune prophylactic regimes has been assessed by Carlsson et a l in two separate studies performed at the Malmo Centre^^^’'^^’^^'^’*^'^. One o f these two studies was a prospective crossover study that comprised 21 individuals with haemophilia A. With the exception o f one individual who had a baseline clotting factor level o f 1.5 iu/dl, all patients had severe haemophilia A; participants were a median o f 17 years o f age (range 8-42 years). At the beginning o f the study, participants were randomised to receive either 25-40 iu/kg o f FVIII three times per week or a modified schedule based on individual pharmacokinetic data requiring a dosing interval o f two days. The aim o f both treatment regimes was to prevent in vivo FVIII levels from falling below 1 iu/dl. The study lasted for a total o f 12 months; patients switched treatment regimes after 6 months. Spontaneous joint

levels were assessed each time a participant required maintenance infusion. Doses were calculated as;

/• = !

W here C is the in vivo clotting factor concentration at time t, A is the y-axis intercepts and kn is the rate constants o f the exponential term (half-life=ln2/k).

Data from only 14 participants were analysed, as the remainder did not complete the treatment protocol. During the periods o f pharmacokinetic dosing the m ean in vivo

trough level increased from 0.89 iu/dl to 2.2 iu/dl (P<0.005); a slight decrease in bleeding frequency was also observed but the difference was not significant. Furthermore, during these periods, reported FVIII consumption decreased from a mean o f 124,000 iu to 84,000 iu (P<0.005), a reduction o f 32% over the six month period.

Although no adverse events, such as inhibitor development, were observed in any o f the 21 patients, 7 (33%) patients did not complete the study. Two individuals were withdrawn from the study, one following an (unrelated) accident and the other because he changed treatment centres. One individual did not consent to using the reduced rate pharmacokinetic regime, one individual did not wish to receive injections every two days and in another patient it was not possible to maintain an in vivo clotting factor level above 1 iu/dl with a dosing interval o f two days. O f the remaining two individuals, one started with the modified regime and subsequently refused to allow longer intervals between doses and the other individual found that attempting to reduce clotting factor use when starting the pharmacokinetic regime was not worthwhile given the size o f the clotting factor vials. Therefore, although this non-completion rate is high (33%) and there is some concern as to patient acceptability due to the increased need for venipuncture, reduced rate treatment regimes based on individual pharmacokinetic details were technically feasible in all but one person.

Carlsson et al. also performed a similar crossover study in eight individuals w ith severe haemophilia B over two two-week peri ods’ The results showed that compared to infusing with FIX every 3 days, infusing every 2 days reduced total clotting factor use

by 25%. Moreover, compared to the 3-day programme, infusing every day reduced the total amount o f FIX used by 34%.

Based on the same pharmacokinetic principles, it has been suggested that supplying patients with a continuous infusion (Cl) o f FVIII would further reduce consumption during standard prophylaxis (ie. 24-40 iu/kg 2-3 times per week) and bolusing using pharmacokinetic information every other day by as much as 92% and 86% respectively'^^'^^^. However, a practical application o f this process, which would probably require the use o f an implantable micro-pump and reservoir system, is yet to be marketed. Additionally, although the Swedish series o f studies suggest that it is possible to prevent the onset o f degenerative haemophilic arthritis in individuals with severe haemophilia, studies have shown that a small number o f individuals with mild / moderate forms o f the condition have developed HA^^. Thus, it is yet to be proved that reducing or removing the peaks in in vivo clotting factor activity would be clinically insignificant^^.

Although long-term Cl is yet to become a practical treatment option, an alternative to bolusing during surgery is to use short-term Cl. Indeed, Cl has previously been used as a method o f supplying clotting factor during a range o f different invasive procedures and has also been used to treat potentially life-threatening bleeds such as cerebral haemorrhage in individuals with and without inhibitors^^'^^^'^^^.

The theoretical advantage o f Cl over bolusing is that it maintains a constant in vivo

clotting factor level above which there is little or no risk o f bleeding and in some instances has reduced clotting factor consumption by 30% -75% ' ^ ^427,132,134,139,140

also been suggested that Cl may allow individuals to be discharged earlier from hospital compared to bolusing because wounds are thought to heal quicker and because o f the use o f more ambulant therapy programmes

same objective. There is some evidence to suggest that clearance rates reduce during the course o f treatment meaning that progressively less clotting factor is required in order to maintain a given in vivo clotting factor level. M artinowitz et a lP ^

demonstrated in 10 patients with haemophilia A that clearance rates decreased from a median post-operative level o f 3.2 ml/kg/hour to 1.7 ml/kg/hour on day 5 after which time the clearance rate levelled o ff for the remainder o f treatment (range o f treatment 4- 21 days). In a separate study o f 4 individuals with severe and moderate haemophilia B, 3 patients experienced a progressive decrease in clearance rates^\ W hen infusion rates are adjusted to take account o f decreased clearance rates, the process is usually referred to as adjusted dose CL

One o f the reported side effects o f Cl has been local thrombophlebitis around the cannula site. However, there is reason to believe that in the majority o f instances infusing a small dose o f diluted heparin concurrently with the clotting factor can prevent cannula irritations and infections. A further limitation o f this approach is that Cl requires clotting factor to remain in solution in plastic containers for periods o f time. Efficacy must be established and a license granted before a clotting factor can be stored and used in this manner. At present the greatest published experience is for M onoclate P (a very high purity FVIII) and Mononine (a very high purity FIX). However, the suitability o f using a recombinant FVIII for Cl is currently being investigated.