To the editor:

The Research of Determinants of Inhibitor Development (RODIN) study published a higher risk for inhibitors by a second-generation full-length recombinant factor VIII (rFVIII) (adjusted for several potential confounders) (hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.08-2.37) as compared with third-generation full-length rFVIII, based on 547 previously untreated patients (PUPs) with severe hemophilia A.1  Recently, these findings were confirmed by 2 independent cohort studies from France and the United Kingdom.2,3  The French group reported on 303 PUPs with severe hemophilia and found adjusted HR of 1.55 (CI, 0.97-2.49), and in the United Kingdom report, the adjusted HR of inhibitor development for the second-generation full-length rFVIII product compared with the third-generation full-length rFVIII product was 1.75 (95% CI, 1.11-2.76). Recently, it was suggested that the preference for certain products in a hemophilia treatment center might lead to an additional confounder, a so-called “center effect.”4  A “center effect” might arise when centers differentially choose to prescribe certain products for predefined patients. In a recent letter in Blood by Iorio and Berntorp, our group was requested to share data on a potential “center effect.”4  The leading hypothesis was that larger centers might include more patients with a higher initial risk. The PedNet Study Group is a collaboration of 29 centers and for this analysis, the most recent update of January 2015 was used.

We identified 10 large centers (≥25 patients) that included a median of 35 patients (range, 25-49) over a 10-year period. The 19 smaller centers included a median of 13 patients (range, 2-23) (Table 1).1  Large centers showed a higher incidence of inhibitor development as compared with small centers: 34.5% vs 24.0% (P = .006). Overall, large centers had significantly more patients with a high-risk gene mutation. Dosing during the first peak treatment moment was higher in large centers (P = .001) (Table 1).

Table 1

Comparison of large and small centers

Large centersSmall centersP2*
Number of centers 10 19 –— 
Number of patients 354 250 — 
Median (range) 35 (25-49) 13 (2-23) — 
Positive family history for inhibitors 39 (11.0) 18 (7.2) .114 
High-risk FVIII gene mutation 228 (64.4) 138 (55.2) .023 
Age (y) at diagnosis; median (IQR) 0.5 (0.0-0.9) 0.3 (0.0-0.8) .703 
Age at first exposure; median (IQR) 0.8 (0.5-1.1) 0.8 (0.3-1.1) .239 
Intensive treatment (≥5 EDs) at first exposure 53 (15.0) 40 (16.0) .680 
Dose (IU/kg/ED) in first 5 EDs; median (IQR) 82 (50-133) 68 (50-92) .001 
Product at first exposure    
 Plasma-derived 62 (17.5) 43 (17.2) .895 
 Recombinant 290 (81.9) 207 (82.8) — 
Recombinant product at first exposure    
 1st generation full-length 49 (13.8) 19 (7.6) .017 
 2nd generation full-length 106 (29.9) 81 (32.4) .520 
 2nd generation B-domain–deleted 37 (10.5) 40 (16.0) .044 
 3rd generation full-length 96 (27.1) 66 (26.4) .844 
 3rd generation B-domain–deleted 2 (0.6) 1 (0.4) .776 
ED at start prophylaxis; median (IQR) 12 (5-22) 13 (5-21) .631 
Patients with clinically relevant inhibitors 122 (34.5) 60 (24.0) .006 
Number of EDs at inhibitor development; median (IQR) 14 (10-19) 14 (8-19) .938 
Patients with high-titer inhibitors 82 (23.1) 45 (18.0) .125 
Patients with low-titer inhibitors 40 (11.3) 15 (6.0) .026 
Frequency of testing3    
 Tests per year; median (IQR) 4.1 (2.3-8.2) 2.6 (1.1-4.1) .001 
 Tests per 50 EDs; median (IQR) 5 (3-7) 3 (1-6) .002 
Large centersSmall centersP2*
Number of centers 10 19 –— 
Number of patients 354 250 — 
Median (range) 35 (25-49) 13 (2-23) — 
Positive family history for inhibitors 39 (11.0) 18 (7.2) .114 
High-risk FVIII gene mutation 228 (64.4) 138 (55.2) .023 
Age (y) at diagnosis; median (IQR) 0.5 (0.0-0.9) 0.3 (0.0-0.8) .703 
Age at first exposure; median (IQR) 0.8 (0.5-1.1) 0.8 (0.3-1.1) .239 
Intensive treatment (≥5 EDs) at first exposure 53 (15.0) 40 (16.0) .680 
Dose (IU/kg/ED) in first 5 EDs; median (IQR) 82 (50-133) 68 (50-92) .001 
Product at first exposure    
 Plasma-derived 62 (17.5) 43 (17.2) .895 
 Recombinant 290 (81.9) 207 (82.8) — 
Recombinant product at first exposure    
 1st generation full-length 49 (13.8) 19 (7.6) .017 
 2nd generation full-length 106 (29.9) 81 (32.4) .520 
 2nd generation B-domain–deleted 37 (10.5) 40 (16.0) .044 
 3rd generation full-length 96 (27.1) 66 (26.4) .844 
 3rd generation B-domain–deleted 2 (0.6) 1 (0.4) .776 
ED at start prophylaxis; median (IQR) 12 (5-22) 13 (5-21) .631 
Patients with clinically relevant inhibitors 122 (34.5) 60 (24.0) .006 
Number of EDs at inhibitor development; median (IQR) 14 (10-19) 14 (8-19) .938 
Patients with high-titer inhibitors 82 (23.1) 45 (18.0) .125 
Patients with low-titer inhibitors 40 (11.3) 15 (6.0) .026 
Frequency of testing3    
 Tests per year; median (IQR) 4.1 (2.3-8.2) 2.6 (1.1-4.1) .001 
 Tests per 50 EDs; median (IQR) 5 (3-7) 3 (1-6) .002 

Data are N (%), unless otherwise stated.

ED, exposure days; IQR, interquartile range.

*

χ2 test for categorical variables and independent samples t tests for continuous variables.

For large centers, determined in 65 of 323 (20%) randomly selected non-inhibitor patients; for small centers, determined in all 73 non-inhibitor patients of 8 randomly selected centers.

However, the higher total inhibitor incidence of large as compared with small centers was mainly due to the detection of more low-titer inhibitors: 11.3% for the large centers vs 6% for the small centers (P = .026). The incidence of high-titer inhibitors was not significantly different: 23.1% (large centers) vs 18% (small centers) (P = .125). It is likely that the higher number of low-titer inhibitors found in the large centers is at least partly due to the observed higher testing rate for inhibitors. Large centers tested a median of 5 times in 50 EDs, whereas small centers tested only 3 times (P = .002).

The difference in inhibitor incidence between large and small centers did not affect the higher risk for inhibitors found with a second-generation rFVIII product. The percentage of patients using second-generation full-length rFVIII products was similar: 29.9% in large centers and 32.4% in small centers (P = .520). This contradicts the hypothesis of an additional “center effect” caused by a preferential use or avoidance of second-generation products. A factor that has been suggested to influence treatment choice is a positive family history for inhibitors. As is clear from Table 1, however, a positive family history for inhibitors was present in only a small percentage of our patients. It is highly unlikely, therefore, that a preferential choice of product could have had an impact on our results. In conclusion, no “center effect” was found comparing small and large centers that contributed to the higher inhibitor incidence with a second-generation full-length rFVIII product.

The online version of this article contains a data supplement.

Acknowledgments: The PedNet Study Group was supported by unrestricted research grants from Baxter Healthcare Cooperation (Deerfield, IL), Bayer Healthcare, Novo Nordisk, Sobi, and Biogen.

Contribution: H.M.v.d.B. and R.L. designed the research, analyzed and interpreted the data, and wrote the manuscript.

Conflict-of-interest disclosure: H.M.v.d.B. received unrestricted research support from Novo Nordisk, Wyeth, Baxter, and Bayer. R.L. received research grants, speaker fees, and consultation fees from Bayer, Baxter, Novo Nordisk, and Octapharma.

A complete list of the members of the PedNet Study Group appears in the online data supplement.

Correspondence: H. M. van den Berg, Julius Centre for Health Sciences and Primary Care, PO Box 85500, 3508 GA Utrecht, The Netherlands; e-mail: h.m.vandeberg@umcutrecht.nl.

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Author notes

*

H.M.v.d.B. and R.L. contributed equally.

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