Inhibitor development in previously treated hemophilia A patients: a systematic review, meta‐analysis, and meta‐regression

Xi, Menchen; Makris, Michael; Marcucci, Maura; Santagostino, Elena; Mannucci, Pier Mannuccio; Iorio, Alfonso

doi:10.1111/jth.12335

Cited by 62 publications

(80 citation statements)

References 28 publications

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“…First, the overall inhibitor rate was 2.8 per thousand patient-years, remarkably close to what was found in the published literature by Xi et al [10]. First, the overall inhibitor rate was 2.8 per thousand patient-years, remarkably close to what was found in the published literature by Xi et al [10].…”

supporting

confidence: 87%

Answering relevant research questions via careful observation of clinical practice: a fresh look at the old way forward

Matino

Iorio

2014

Haemophilia

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Although many aspects of inhibitor development have been elucidated, the role of switching FVIII product concentrate in the risk of inhibitors development in previously treated patients is still under discussion. To provide their contribution, Aznar et al [9] transparently showed the numerous different brands used over time and the number of patients treated with one or another class of concentrates in their center. This way of inclusively reporting data as generated in routine clinical practice would need to be adopted more broadly among hemophilia treater and scientists. Strength and limitations of the approach are discussed.

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supporting

confidence: 87%

Answering relevant research questions via careful observation of clinical practice: a fresh look at the old way forward

Matino

Iorio

2014

Haemophilia

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“…A more recent meta‐analysis from 2013 did not report any differences in immunogenicity . Thirteen of 33 studies in this previous meta‐analysis were also included in the current meta‐analysis.…”

Section: Discussionmentioning

confidence: 99%

Factor VIII products and inhibitor development in previously treated patients with severe or moderately severe hemophilia A: a systematic review

Hassan

Cannavó

Gouw

et al. 2018

Journal of Thrombosis and Haemostasis

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Background Patients with severe hemophilia A who have been treated extensively with factor VIII products have a low but potentially serious risk of inhibitor development. It is unknown why these patients develop inhibitors, and data on product-related immunogenicity are scarce. Aims To summarize the currently available evidence on the relationship between inhibitor development and recombinant FVIII product type in previously treated patients (PTPs) with severe hemophilia A. Methods Longitudinal studies were included that reported on de novo inhibitor formation in patients with baseline FVIII activity levels of < 0.02 IU mL who had been treated with FVIII for at least 50 days. Pooled incidence rates of inhibitor development according to product types were calculated with a random intercept Poisson regression model. Results Forty-one independent cohorts were included; 39 patients developed de novo inhibitors during 19 157 person-years of observation. The overall incidence rate was 2.06 per 1000 person-years, with a 95% confidence interval (CI) of 1.06-4.01. According to product type, the pooled incidence rates were 0.99 (95% CI 0.37-2.70) per 1000 person-years for patients treated with Advate, 5.86 (95% CI 0.25-134.92) per 1000 person-years for those treated with Kogenate/Helixate, 1.35 (95% CI 0.66-2.77) per 1000 person-years for those treated with Kogenate FS/Helixate NexGen, 12.05 (95% CI 1.53-94.78) per 1000 person-years for those treated with Refacto, and 4.64 (95% CI 0.82-26.43) per 1000 person-years for those treated with Refacto AF. Conclusion These results suggest that some products may be associated with increased immunogenicity. However, the low incidence of inhibitors in PTPs and the differences in study design may cause significant variation in estimates of risk.

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“…To this scope, we sought relevant comparable priors and tested two different sets of informative priors. The first set 1) comprised the data obtained during the treatment with a certain molecule (eg, rAHF-PFM) in different studies; specifically i) estimates of inhibitor rates from the manufacturer’s pivotal studies35; ii) estimates of inhibitor rates from a meta-analysis36; and iii) estimates of inhibitor rates from an independent prospective multicentric cohort 37. The second set of informative priors 2) comprised pooled inhibitor rates for any FVIII concentrate, including: i) a meta-analysis36 and ii) an independent prospective multicenter cohort 37.…”

Section: Methodsmentioning

confidence: 99%

Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study

Cheng

Iorio

Marcucci

et al. 2016

JBM

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BackgroundDeveloping inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information.MethodsWe built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs) or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population – patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A) post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1) or random-effects (Case 2 and Case 3) logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical significant inhibitor (10/100, 5/100 [high rates], and 1/86 [the Food and Drug Administration mandated cutoff rate in PTPs]) were calculated. The effect of discounting prior information or scaling up the study data was evaluated.ResultsResults based on noninformative priors were similar to the classical approach. Using priors from PTPs lowered the point estimate and narrowed the 95% credible intervals (Case 1: from 1.3 [0.5, 2.7] to 0.8 [0.5, 1.1]; Case 2: from 1.9 [0.6, 6.0] to 0.8 [0.5, 1.1]; Case 3: 2.3 [0.5, 6.8] to 0.7 [0.5, 1.1]). All probabilities of satisfying a threshold of 1/86 were above 0.65. Increasing the number of patients by two and ten times substantially narrowed the credible intervals for the single cohort study (1.4 [0.7, 2.3] and 1.4 [1.1, 1.8], respectively). Increasing the number of studies by two and ten times for the multiple study scenarios (Case 2: 1.9 [0.6, 4.0] and 1.9 [1.5, 2.6]; Case 3: 2.4 [0.9, 5.0] and 2.6 [1.9, 3.5], respectively) had a similar effect.ConclusionBayesian approach as a robust, transparent, and reproducible analytic method can be efficiently used to estimate the inhibitor rate of hemophilia A in complex clinical settings.

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Inhibitor development in previously treated hemophilia A patients: a systematic review, meta‐analysis, and meta‐regression

Cited by 62 publications

References 28 publications

Answering relevant research questions via careful observation of clinical practice: a fresh look at the old way forward

Answering relevant research questions via careful observation of clinical practice: a fresh look at the old way forward

Factor VIII products and inhibitor development in previously treated patients with severe or moderately severe hemophilia A: a systematic review

Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study

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