Letter to the Editor Regarding “Cost-Effectiveness Analysis of Pharmacokinetic-Guided Prophylaxis Versus Standard Prophylaxis in Adults with Severe Hemophilia A in China”

Dear Editor,

With great interest, I carefully read the paper by Gu et al., which aimed to compare the cost-effectiveness between standard prophylaxis and pharmacokinetic (PK)-guided prophylaxis among Chinese patients with hemophilia A [1]. However, some important points need to be noticed during the interpretation of this study.

This study “enrolled” patients from a previous study which only contained 35 patients with hemophilia A from one local hospital in China [2]. Although hemophilia is a rare disease, the sample size (N = 35) is insufficient to draw a very firm conclusion, especially in a cost-effectiveness analysis. Considering the large number and uneven distribution of population in China, the authors may choose other multicenter studies with more patients included, which would obviously enhance the extrapolation ability in further studies.

For reference, several publications have conducted more PK tests in Chinese patients with hemophilia A [3]. In the study series from Beijing, a total of more than 200 PK tests were conducted in Chinese patients with hemophilia A, which hopefully Gu et al. may benefit from [4–6]. In addition, the authors may also seek help from the commonly used PK tool (WAPPS-Hemo), because its rich and comprehensive data may help the study to reach a more representative goal [7].

In Gu et al.’s paper, the PK-guided prophylaxis was defined as using the PK tool to adjust patients’ dose to locate at the target trough FVIII level (1–5 IU/dL). According to the latest guideline from the World Federation of Hemophilia (WFH) recommends, the target trough level has changed to 3 IU/dL because the previous standard (1 IU/dL) could not prevent the progression of chronic joint injury [8]. According to previous studies, even the patients with trough level range 1–3 IU/dL could have a low zero bleeding proportion (less than 50%). And the trough level over 3 IU/dL could decrease the median annual bleeding rate to zero as previously reported [4]. In Gu et al.’s study, the setting of the minimum target trough level to 1 IU/dL instead of 3 IU/dL could potentially underestimate the necessary FVIII consumption. The extra FVIII consumption caused by the increment of minimum target trough level (from 1  to 3 IU/dL) may not show a very different clinical outcome in the short term [9]. However, increasing evidence has shown that occasional clinical and subclinical bleeds could occur in these patients and result in gradual and irreversible joint damage [4, 9, 10]. Also, considering the short interval of infusions (48 h) in this study, it would not be hard to reach the WFH-recommended target FVIII level (3 IU/dL) in routine prophylaxis. Thus, the authors may consider using this new target FVIII level for further analysis so that the results will be closer to reality in hemophilia treatment.

In the PK parameter section, the research used data from the study conducted by Iannazzo et al. which was based on a simulated patient cohort of 1000 patients with severe hemophilia A [11]. Although their median age was similar to the “enrolled patients” in this study (27.8 vs. 29.3 years), the age ranges were quite different (19–44 vs. 12–63 years) [2]. And the median weights of these two cohorts were also not similar (59.1 vs. 73.7 kg). Therefore, careful interpretation of the result and clear statements in the limitations section could be important. Further, considering the potential variability of FVIII PK parameters among different races, it may be a better choice to draw PK data from the Chinese population. Although this paper mentioned “MyPKFit” a lot, the involved FVIII concentrates in this study do not seem to be limited to ADVATE only. Thus, the authors could also seek PK parameters of different FVIII concentrates in published clinical trials as they are conducted in the Chinese population. Actually, the variability of PK parameters among different FVIII concentrates was also reported, which could be a potential bias for this study and there could have been better relevant descriptions in the limitations section [12, 13].

In summary, Gu et al. reported the advances of PK-guided prophylaxis over standard prophylaxis, along with lower total costs and slightly higher quality-adjusted life years. Readers should be aware of some important points in the methods section and careful interpretation of the results is required.

Author Contributions

Kun Huang was the sole writer of this publication. Kun Huang meets the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, takes responsibility for the integrity of the work as a whole, and gave his approval for this version to be published.

Funding

No funding or sponsorship was received for this study or publication of this article.

Declarations

Conflict of Interest

Kun Huang has nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any studies with human patients or animals performed by the author.