Reported inhibitor incidence in FVIII PUP studies: comparing apples with oranges?

We have read with great interest the paper by Wight and Paisley The epidemiology of inhibitors in haemophilia A: a systematic review [1]. With inhibitor development being the most serious complication of haemophilia treatment to date, the elucidation of the epidemiology of inhibitors is of critical importance for rational patient management. There are, however, several methodological flaws in the analysis of Wight and Paisley, which unfortunately impact some of the conclusions drawn by the authors. During the last two decades, it has become apparent that a number of variables greatly influence individual patients risk of developing an inhibitor. Some of the most important factors are haemophilia severity, type of gene mutation, race, age at first treatment and exposure to FVIII product [2]. Furthermore, the frequency and sensitivity of assaying for factor VIII inhibitors in patients plasma have a substantial impact on inhibitor detection. Our primary concern with the work of Wight and Paisley is that clinical trials with very different probabilities of inhibitor detection are being compared, and that the (expected) observed differences in detected inhibitor incidence are interpreted as product-related. For example, one of the authors conclusions is that clinical trials using single plasma-derived FVIII (pdFVIII) preparations reported lower inhibitor incidence than those using multiple pdFVIII preparations or single recombinant FVIII (rFVIII) preparations. One of the studies with a single pdFVIII preparation in previously untreated patients (PUP’s) [3], supposedly providing supportive data for this conclusion, enrolled 15 patients with FVIII levels <3% (with no further specification on how many of these patients had severe disease) and reported to have a zero percentage inhibitor rate after a median number of 8 exposure days (EDs). It is impossible to utilize the results of this study for a meaningful comparison with the well-designed and large studies with rFVIII [4,5]. The futile nature of such a comparison is illustrated by the following considerations: only six of the 22 inhibitors detected in a rFVIII PUP-study (72 evaluable patients in total) were detected within the first 8 EDs (Baxter BioScience, Vienna, Austria, data on file), i.e. within the median number of EDs in the study with the pdFVIII preparation [3]. Clearly, the upper limits of the 95% confidence interval (95% CI) are much better suited for an assessment of inhibitor risk than the point estimates, and in the given example these limits are 21.8% for the pdFVIII preparation and 17.3% for the rFVIII preparation. As pointed out by Mannucci in a letter to the editor [6] following the publication of this trial with pdFVIII, this study as well as other recent studies quoted by the author cannot truly answer the question whether or not concentrate purity affects inhibitor development . This view is exemplified by the fact that two relatively large studies with similar rFVIII products and with similar study designs reported inhibitor incidences of 15 and 29% in severe haemophiliacs, respectively [5,7]. Even if it was possible to exactly match the patient populations between studies with respect to risk factors, such a difference in outcome is not surprising, e.g. in a 60 patient study with 15 inhibitors (25%), the 95% CI is 14.7–37.9%. In summary, we continue to believe that the wide range of reported incidences of inhibitory antibodies to FVIII in PUPs with haemophilia A is due in part to several methodological differences and difficulties in the design and conduct of studies to assess inhibitor risk, rendering a meaningful comparison of data virtually impossible [8]. This view is consistent with that of the International Society on Thrombosis and Haemostasis (ISTH) scientific subcommittee on FVIII and FIX. Correspondence: Inge Scharrer, University Hospital Frankfurt/ Main, Hemostaseology, Theodor-Stern-Kai 7, 60590 Frankfurt/M, Germany. Tel. : +49(0)69 6301 5051; fax: +49(0)69 6301 6738; e-mail: scharrer@em.uni-frankfurt.de