The SIPPET trial and the economic consequences of developing high-titre inhibitors in hemophilia A
The SIPPET trial  has provided a quite strong evidence that, in patients with severe haemophilia A, recombinant Factor VIII increases the risk of developing high-titre inhibitors as compared with plasma-derived Factor VIII. These findings have important clinical implications, but also the economic consequences deserve to be considered.
If one examines the absolute incidence of high-titre inhibitor development, the SIPPET trial found 28.4% (95%CI: 19.6 to 37.2%) with recombinant Factor VIII and 18.5% (95%CI: 12.1 to 26.9%) with plasma-derived Factor VIII. The number needed to harm, calculated from these data, is 10. In other words, for every 10 patients who are treated with recombinant Factor VIII as opposed to plasma-derived factor VIII, one patient is expected to develop high-titre inhibitors.
From an economic point of view, this means that the use of recombinant Factor VIII can be associated with an average increase in the treatment cost per patient equal to the average cost of treating 1 case of high titre inhibitors divided by 10. This in turn raises the need to estimate the average cost to treat 1 patient who develops high-titre inhibitors.
Although numerous studies have addressed this issue [2-10], the current information on this point still shows important differences from study to study. The analysis by Bohn et al  found a mean cost per patient per year of $141,000 (EUR 125,701; US$ 1 = EUR 0.8915) for patients with inhibitors vs $80,000 (EUR 71,320) for patients without inhibitors (difference = $61,000 per patient per year). In the same period, Gringeri et al  recorded a monthly cost of EUR 18,000 in patients with inhibitors (i.e. about EUR 215,000 yearly). The oldest of these studies  found an average yearly cost of Can$96,000 (EUR 63,859; Can$ 1 = EUR 0.6652) as compared with Can$43,000 (EUR 28,604) without inhibitors. As pointed out by DiMinno et al. , the wide variability of these cost estimates is intrinsically related to the clinical variability of the disease course in these patients.
In our view, the best economic estimate for the management of patients with inhibitors is represented by the most recent analysis in this area published by Valentino et al . These authors examined a large US sample including 981 patients without inhibitors and 63 with inhibitors and found a median annual drug cost of US$47,626 (EUR 42,459) for patients without inhibitors and a median annual drug cost of US$191,301 (EUR 170,545) for patients with inhibitors. According to these estimates, the presence of inhibitors implies a median increase in the annual drug cost of about US$138,000 per patient (EUR 123,027).
To draw a lifetime estimate of the economic consequences of inhibitor development, this latter estimate of annual cost increase should be extended over an appropriate duration representing the duration of tolerance induction. According to the controlled trial by Hay et al , these interventions can have a duration up to 33 months (i.e. 2.75 years). Hence, if one multiplies the annual cost increase of US$138,000 (EUR 123,027) by 2.75, the resulting estimate (US$ 380,000; EUR 338,770) can represent the median lifetime increase in cost per patient that can be attributed to the development of inhibitors. This figure is quite in keeping with the findings of Auesrwald et al.  indicating an annual cost of EUR 354,000 per patient. Furthermore, it has been observed that medians represent an underestimate of true costs because outlier patients showing extremely high costs are not accounted for .
Although other estimates much higher than this value have been reported (e.g. an increase in lifetime costs of about US$1million or EUR 891,500 according to Colowick et al ), the figure of US$ 380,000 or EUR 338,770 seems to be the most reasonable estimate.
According to our estimate of the number needed to harm, dividing the above amount of money by 10 gives US$ 38,000 or EUR 33,877 per patient. In this framework, the clinical implications raised by the SIPPET trial obviously remain the main priority. However, if one focuses the analysis only on the economic aspects, using recombinant Factor VIII as opposed to plasma-derived products implies an increase in the expenditure per patient of about US$ 38,000 or EUR 33,877. This increased expenditure, which has an important practical impact, directly reflects the economic consequences of the expected increase in the incidence of inhibitors.
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Competing interests: No competing interests