Indication, Resource Consumption and Clinical Outcomes of Prophylaxis in Adult Patients with Severe Hemophilia a in Routine Clinical Practice

Background:

Prophylaxis is the treatment of choice in patients with severe hemophilia A to prevent the development of haemophilic arthropathy and to preserve musculoskeletal function. In adult patients, there is no defined consensus on the indication, dose and frequency of prophylaxis. Because of the high cost of this scheme of treatment, it is basic to optimize it in routine practice.

Objectives:

To describe the profile of adult severe hemophilia A patients treated on prophylaxis, the reasons to indicate it and type of prophylaxis dose and frequency of infusions.

In patients on tertiary prophylaxis, to assess the annual rate of bleeding and factor VIII (FVIII) consumption during prophylaxis scheme and to compare them with the period on demand.

To analyze whether the implementation of programs of pharmacokinetics (PK) and trough levels adjustment optimize the results of prophylaxis.

To evaluate adherence to prophylaxis and safety of this scheme of treatment.

Patients and Methods:

We included in our study adult patients (older than 18 years old) who suffer from severe hemophilia A (less than 1% of FVIII), with no history of inhibitor at the moment of the inclusion. These patients have been treated with a long term prophylaxis in our center between January 2006 and December 2013. We define the type of prophylaxis according to WFH criteria. Tertiary prophylaxis is defined by Petterson score higher than 3. The dose and frequency of prophylaxis is based on PK study. The program is a Bayesian PK analysis. FVIII levels were determined by one-stage method. Samples were taken 30 minutes (recovery, not used for PK), 6, 12, 24 and 48 hours after FVIII 50ui/kg infusion. After PK study, subjects were evaluated every two months to adjust scheme of treatment using trough FVIII levels between 1% and 3% in absence of bleeding. After getting the established dose, patients were reviewed every 6 months. Adherence has been calculated as a percentage (number of weeks each year with the right dose and frequency of infusions divided into the number of weeks of the year in which the subject has no active bleeding or is subjected to invasive procedures, then multiply the result by 100). Demographic and diagnostic data of patients were recorded for inclusion in the program. Information about FVIII consumption and bleeding events comes from patient diaries (PD) and records from Hospital Pharmacy Department. Our Centre Ethics Committee approved the project. Everything has been done according to the Declaration of Helsinki. Patients signed written informed consent.

Results:

We evaluated 18 patients, median age at starting prophylaxis 30 years old (IQR, 17 to 40.5 years old). The type of prophylaxis was primary in 2 patients, secondary in 2 and tertiary in the rest. The reasons to indicate tertiary prophylaxis included prevent progression of hemophilia joint disease (11), central nervous system haemorrhage (2) and antiplatelet drugs needed because of stroke (1). 16 patients have been treated with recombinant FVIII and 2 with plasma derived FVIII. FVIII individual patient dose was calculated based on PK study (mean volume of distribution 51.1±6.0 mL/kg, half-life 13.2 ±5.8 hours and plasma clearance 3.0 ±1.0 mL/kg). Prophylaxis dose frequency was twice a week (8), three times a week (7) and every 48 hours (3). No dose increases were required after trough levels adjustment. Thanks to through levels adjustment, FVIII consumption of these patients was reduced in 31.3%. Tertiary prophylaxis reduces annual rate of bleedings in 88.3% (mean 2.3 on prophylaxis vs 20.8 on demand, p <0.0001). Median annual consumption of FVIII in patients on tertiary prophylaxis was 2557.8 IU/kg/year vs 1696.8 IU/kg/ year on demand period (p. 0.312). This 50,7% increase in FVIII consumption is smaller if the indication of tertiary prophylaxis is the prevention of joint disease. In this case the increase in consumption is 24.5%. The median adherence was 84% (IQR, 69-95%), with no difference between types of prophylaxis (p, 0.125). We report no adverse events.

Conclusions:

In our experience, the majority of adult patients with hemophilia A are on tertiary prophylaxis. In this group of patients, prophylaxis reduces ostensibly the incidence of bleedings but with a higher economic cost. The reason to indicate a scheme of prophylaxis may change the cost-effectiveness of this treatment. Adult patients have a good adhesion to treatment, similar to the one reported in children.