Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: A systematic review

A. Iorio, S. Halimeh, S. Holzhauer, Neil Goldenberg, E. Marchesini, M. Marcucci, G. Young, C. Bidlingmaier, L. R. Brandao, C. E. Ettingshausen, A. Gringeri, G. Kenet, R. Knöfler, W. Kreuz, K. Kurnik, D. Manner, E. Santagostino, P. M. Mannucci, U. Nowak-Göttl

Research output: Contribution to journalArticle

Abstract

Background: Different rates of inhibitor development after either plasma-derived (pdFVIII) or recombinant (rFVIII) FVIII have been suggested. However, conflicting results are reported in the literature. Objectives: To systematically review the incidence rates of inhibitor development in previously untreated patients (PUPs) with hemophilia A treated with either pdFVIII or rFVIII and to explore the influence of both study and patient characteristics. Methods: Summary incidence rates (95% confidence interval) from all included studies for both pdFVIII and rFVIII results were recalculated and pooled. Sensitivity analysis was used to investigate the effect of study design, severity of disease and inhibitor characteristics. Meta-regression and analysis-of-variance were used to investigate the effect of covariates (testing frequency, follow-up duration and intensity of treatment). Results: Two thousand and ninety-four patients (1167 treated with pdFVIII, 927 with rFVIII; median age, 9.6 months) from 24 studies were investigated and 420 patients were observed to develop inhibitors. Pooled incidence rate was 14.3% (10.4-19.4) for pdFVIII and 27.4% (23.6-31.5) for rFVIII; high responding inhibitor incidence rate was 9.3% (6.2-13.7) for pdFVIII and 17.4% (14.2-21.2) for rFVIII. In the multi-way anova study design, study period, testing frequency and median follow-up explained most of the variability, while the source of concentrate lost statistical significance. It was not possible to analyse the effect of intensity of treatment or trigger events such as surgery, and to completely exclude multiple reports of the same patient or changes of concentrate. Conclusions: These findings underscore the need for randomized controlled trials to address whether or not the risk of inhibitor in PUPs with hemophilia A differs between rFVIII and pdFVIII.

Original languageEnglish (US)
Pages (from-to)1256-1265
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume8
Issue number6
DOIs
StatePublished - Jun 2010
Externally publishedYes

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Factor VIII
Hemophilia A
Incidence
Meta-Analysis
Analysis of Variance
Randomized Controlled Trials
Regression Analysis
Confidence Intervals
Therapeutics

Keywords

  • Factor VIII concentrates
  • Hemophilia A
  • Inhibitor development
  • Previously untreated patients
  • Systematic review

ASJC Scopus subject areas

  • Hematology

Cite this

Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates : A systematic review. / Iorio, A.; Halimeh, S.; Holzhauer, S.; Goldenberg, Neil; Marchesini, E.; Marcucci, M.; Young, G.; Bidlingmaier, C.; Brandao, L. R.; Ettingshausen, C. E.; Gringeri, A.; Kenet, G.; Knöfler, R.; Kreuz, W.; Kurnik, K.; Manner, D.; Santagostino, E.; Mannucci, P. M.; Nowak-Göttl, U.

In: Journal of Thrombosis and Haemostasis, Vol. 8, No. 6, 06.2010, p. 1256-1265.

Research output: Contribution to journalArticle

Iorio, A, Halimeh, S, Holzhauer, S, Goldenberg, N, Marchesini, E, Marcucci, M, Young, G, Bidlingmaier, C, Brandao, LR, Ettingshausen, CE, Gringeri, A, Kenet, G, Knöfler, R, Kreuz, W, Kurnik, K, Manner, D, Santagostino, E, Mannucci, PM & Nowak-Göttl, U 2010, 'Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: A systematic review', Journal of Thrombosis and Haemostasis, vol. 8, no. 6, pp. 1256-1265. https://doi.org/10.1111/j.1538-7836.2010.03823.x
Iorio, A. ; Halimeh, S. ; Holzhauer, S. ; Goldenberg, Neil ; Marchesini, E. ; Marcucci, M. ; Young, G. ; Bidlingmaier, C. ; Brandao, L. R. ; Ettingshausen, C. E. ; Gringeri, A. ; Kenet, G. ; Knöfler, R. ; Kreuz, W. ; Kurnik, K. ; Manner, D. ; Santagostino, E. ; Mannucci, P. M. ; Nowak-Göttl, U. / Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates : A systematic review. In: Journal of Thrombosis and Haemostasis. 2010 ; Vol. 8, No. 6. pp. 1256-1265.
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T1 - Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates

T2 - A systematic review

AU - Iorio, A.

AU - Halimeh, S.

AU - Holzhauer, S.

AU - Goldenberg, Neil

AU - Marchesini, E.

AU - Marcucci, M.

AU - Young, G.

AU - Bidlingmaier, C.

AU - Brandao, L. R.

AU - Ettingshausen, C. E.

AU - Gringeri, A.

AU - Kenet, G.

AU - Knöfler, R.

AU - Kreuz, W.

AU - Kurnik, K.

AU - Manner, D.

AU - Santagostino, E.

AU - Mannucci, P. M.

AU - Nowak-Göttl, U.

PY - 2010/6

Y1 - 2010/6

N2 - Background: Different rates of inhibitor development after either plasma-derived (pdFVIII) or recombinant (rFVIII) FVIII have been suggested. However, conflicting results are reported in the literature. Objectives: To systematically review the incidence rates of inhibitor development in previously untreated patients (PUPs) with hemophilia A treated with either pdFVIII or rFVIII and to explore the influence of both study and patient characteristics. Methods: Summary incidence rates (95% confidence interval) from all included studies for both pdFVIII and rFVIII results were recalculated and pooled. Sensitivity analysis was used to investigate the effect of study design, severity of disease and inhibitor characteristics. Meta-regression and analysis-of-variance were used to investigate the effect of covariates (testing frequency, follow-up duration and intensity of treatment). Results: Two thousand and ninety-four patients (1167 treated with pdFVIII, 927 with rFVIII; median age, 9.6 months) from 24 studies were investigated and 420 patients were observed to develop inhibitors. Pooled incidence rate was 14.3% (10.4-19.4) for pdFVIII and 27.4% (23.6-31.5) for rFVIII; high responding inhibitor incidence rate was 9.3% (6.2-13.7) for pdFVIII and 17.4% (14.2-21.2) for rFVIII. In the multi-way anova study design, study period, testing frequency and median follow-up explained most of the variability, while the source of concentrate lost statistical significance. It was not possible to analyse the effect of intensity of treatment or trigger events such as surgery, and to completely exclude multiple reports of the same patient or changes of concentrate. Conclusions: These findings underscore the need for randomized controlled trials to address whether or not the risk of inhibitor in PUPs with hemophilia A differs between rFVIII and pdFVIII.

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