Research Methods & Reporting

Use of GRADE for assessment of evidence about prognosis: rating confidence in estimates of event rates in broad categories of patients

BMJ 2015; 350 doi: (Published 16 March 2015) Cite this as: BMJ 2015;350:h870

The SIPPET trial and the economic consequences of developing high-titre inhibitors in hemophilia A

The SIPPET trial [1] 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 [3] 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 [5] recorded a monthly cost of EUR 18,000 in patients with inhibitors (i.e. about EUR 215,000 yearly). The oldest of these studies [7] 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. [2], 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 [8]. 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 [11], 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. [12] 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 [8].

Although other estimates much higher than this value have been reported (e.g. an increase in lifetime costs of about US$1million or EUR 891,500 according to Colowick et al [9]), the figure of US$ 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.


1. Peyvandi F, Mannucci PM, Garagiola I, et al. Source of Factor VIII replacement (plasmatic or recombinant) and incidence of inhibitory alloantibodies in previously untreated patients with severe hemophilia A: the multicenter randomized SIPPET study. 57th ASH Annual Meeting & Exposition, Orlando, FL, December 5-8, 2015,

2. Di Minno MN, Di Minno G, Di Capua M, Cerbone AM et al. Cost of care of haemophilia with inhibitors. Haemophilia. 2010; 16:e190-201. doi:10.1111/j.1365-2516.2009.02100.x.

3. Bohn RL, Aledort LM, Putnam KG, Ewenstein BM et al. The economic impact of Factor VIII inhibitors in patients with haemophilia. Haemophilia 2004; 10:63-8.

4. Negrini C, Daniele F, Mancuso ME, Rivolta GF et al. Implicazioni economiche del trattamento dei pazienti emofilici con inibitori: una revisione sistematica della letteratura PharmacoEconomics - Italian Research Articles 2006; 8:1-12. DOI:10.1007/BF03320556

5. Gringeri A, Mantovani LG, Scalone L, Mannucci PM; COCIS Study Group. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood. 2003; 102:2358-6.

6. Ullman M, Hoots WK. Assessing the costs for clinical care of patients with high-responding factor VIII and IX inhibitors. Haemophilia 2006 ; 12:74-9; discussion 79-80.

7. Chang H, Sher GD, Blanchette VS, Teitel JM. The impact of inhibitors on the cost of clotting factor replacement therapy in Haemophilia A in Canada. Haemophilia 1999; 5:247-51.

8. Valentino LA, Pipe SW, Tarantino MD, Ye X et al. Healthcare resource utilization among haemophilia A patients in the United States. Haemophilia. 2012; 18:332-8.

9. Colowick AB, Bohn RL, Avorn J, Ewenstein BM. Immune tolerance induction in hemophilia patients with inhibitors: costly can be cheaper. Blood. 2000; 96:1698-702.

10. Athale AH, Marcucci M, Iorio A. Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B. Cochrane Database Syst Rev. 2014 24; 4:CD010561.

11. Hay CR, DiMichele DM; International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2012 Feb 9; 119:1335-44.

12. Auerswald G, von Depka Prondzinski M, Ehlken B, Kreuz W et al. Treatment patterns and cost-of-illness of severe haemophilia in patients with inhibitors in Germany. Haemophilia 2004; 10:499-508.

Competing interests: No competing interests

17 November 2015
Andrea Messori
HTA Unit, ESTAR Toscana
Sabrina Trippoli, Claudio Marinai
Regional Health Service
50100 Firenze
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