Protective effect of prophylaxis on inhibitor development in children with haemophilia A: more convincing studies are required. Response to Calvez and Laurian

Abstract

. (2005) Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study. British Journal of Haematology, 130,[422][423][424][425][426][427] Keywords: haemophilia, inhibitors, prophylaxis, case-control studies, time-varying risk factors.doi:10.1111/j. 1365-2141.2006.05989.x Protective effect of prophylaxis on inhibitor development in children with haemophilia A: more convincing studies are required. Response to Calvez and Laurian Our case-control study was originally designed to investigate the impact of environmental factors on inhibitor development in children with severe haemophilia A (Santagostino et al, 2005). The impact of prophylaxis was a secondary goal, and we are fully aware of the limits of this part of the study, for the following reasons. As inhibitor development prevented the start of prophylaxis in the majority of cases, prophylaxis was, as expected, more frequently started in controls. In order to evaluate prophylaxis as a risk factor, a secondary analysis was carried out in a subgroup of 25 cases consisting of all those eligible to start prophylaxis within the age of 35 months, i.e. the upper limit of the age range at prophylaxis start in cases and the median age at prophylaxis start in controls. We are aware that the small sample size and large confidence intervals give some degree of statistical instability to the data. However, we are convinced that no selection bias was introduced by the treatment modality because cases who started prophylaxis (n ¼ 7) and those treated on demand (n ¼ 18) were all included in the multivariate analysis, which showed a protective effect of starting prophylaxis before 35 months of age. An additional univariate analysis was carried out excluding 16 of 48 controls who started prophylaxis later than cases after the age of 35 months, in order to take into account that these children were at lower risk of inhibitor development. We are aware that bias may not be completely controlled in a subgroup analysis performed to handle time-varying risk factors. However, the proper tool to overcome this issue, i.e. time-dependent survival analysis, can only be used in cohort studies. To date, only one retrospective cohort study evaluated the effect of prophylaxis on the inhibitor risk and a protective effect of prophylaxis was observed (Morado et al, 2005). However, at variance with our study, the other genetic and environmental risk factors were not taken into account. Adjusted survival analysis considering environmental and genetic risk factors for inhibitor development is underway in the frame of an international retrospective cohort study (Gouw, 2005) and it may represent a further step in clarifying the relative role of an array of putative risk factors, such as age at first factor-VIII exposure, type of bleeding or surgery as reason for treatment, treatment intensity and prophylactic regimen.On the whole, we are fully aware that the effect of early prophylaxis on inhibitor risk can be truly assessed only by directly comparing t...

Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study

“…We had data on breastfeeding in 132 patients (36%). Ninety-one patients had been breastfed, for a median of 13 (IQR, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] weeks. The inhibitor risk was similar in patients with and without breastfeeding.…”

“…21 A protective effect has been suggested for prophylactic treatment, 18,22 but additional studies are required to confirm this association. 23,24 Modifiable risk factors of inhibitors provide the key to predict and perhaps even prevent inhibitor development in hemophilia patients. Therefore, in collaboration with investigators from 13 European and 1 Canadian hemophilia treatment centers, we set up a study to examine whether age at first exposure, intensity of treatment, and regular prophylaxis are associated with clinically relevant inhibitor development in previously untreated patients with severe hemophilia A.…”

Von Willebrand factor in high‐purity factor VIII complex concentrates: chaperone protein or key to therapies? A meeting report

“…continuous infusion) [16]. In contrast, FVIII prophylaxis may reduce inhibitor risk by as much as 50% [17,18].…”

Pharmacovigilance studies in haemophilia

“…Multicentre studies of haemophilia patients, designed with the involvement of international agencies, appear to be the most effective way of assessing different regimens in various patient populations (3). Over the past few years various registries have been created to record comprehensively demographic, clinical, genetic and laboratory data from large haemophilia patient populations.…”