Abstract：
With population pharmacokinetic (PK) modeling more readily available and PK-guided prophylaxis endorsed by current hemophilia guidelines, we conducted a systematic review to summarize current evidence in the literature.
To assess the efficacy of PK-guided compared with non-PK-guided prophylaxis.
We did not restrict inclusion to specific study design labels and included all studies consisting of at least one distinct cohort arm receiving PK-guided prophylaxis. We searched the following databases from inception to date of search: MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the EU Clinical Trial Register. Following title, abstract, and full-text screening conducted independently by 2 review authors, we summarized studies qualitatively and synthesized included randomized clinical trials (RCTs) quantitatively by fitting random-effects models.
Search of databases on February 3, 2023, yielded 25 studies fitting our inclusion criteria. Of those, only 2 RCTs and 17 nonrandomized studies included a standard prophylaxis comparator group. Furthermore, risk of bias in the latter was substantial, primarily due to before-after study designs and retrospective comparator groups. Thus, nonrandomized studies were only presented qualitatively. A random-effects meta-analysis of the 2 identified RCT remained inconclusive with regards to bleeding outcomes (ratio of means, 1.15; 95% CI, 0.85-1.56) and factor consumption (ratio of means, 0.82; 95% CI, 0.58-1.18).
Evidence in the literature suggesting a clinical benefit of PK-guided over standard fixed-dose prophylaxis was weak and mainly found in nonrandomized studies limited by lack of concurrent controls, heterogeneity in outcome reporting, small sample sizes, and high risk of bias.
To assess the efficacy of PK-guided compared with non-PK-guided prophylaxis.
We did not restrict inclusion to specific study design labels and included all studies consisting of at least one distinct cohort arm receiving PK-guided prophylaxis. We searched the following databases from inception to date of search: MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the EU Clinical Trial Register. Following title, abstract, and full-text screening conducted independently by 2 review authors, we summarized studies qualitatively and synthesized included randomized clinical trials (RCTs) quantitatively by fitting random-effects models.
Search of databases on February 3, 2023, yielded 25 studies fitting our inclusion criteria. Of those, only 2 RCTs and 17 nonrandomized studies included a standard prophylaxis comparator group. Furthermore, risk of bias in the latter was substantial, primarily due to before-after study designs and retrospective comparator groups. Thus, nonrandomized studies were only presented qualitatively. A random-effects meta-analysis of the 2 identified RCT remained inconclusive with regards to bleeding outcomes (ratio of means, 1.15; 95% CI, 0.85-1.56) and factor consumption (ratio of means, 0.82; 95% CI, 0.58-1.18).
Evidence in the literature suggesting a clinical benefit of PK-guided over standard fixed-dose prophylaxis was weak and mainly found in nonrandomized studies limited by lack of concurrent controls, heterogeneity in outcome reporting, small sample sizes, and high risk of bias.
摘要：
背景：随着人群药代动力学（PK）建模更容易获得，并且PK指导的预防被当前的血友病指南认可，我们进行了系统综述,以总结文献中的现有证据.
目的：评估PK指导的预防与非PK指导的预防的疗效。
方法：我们没有将纳入限制在特定的研究设计标签上，并且纳入了由至少一个接受PK指导预防的不同队列组组成的所有研究。从开始到搜索日期，我们搜索了以下数据库：MEDLINE，Embase,中部,ClinicalTrials.gov,和欧盟临床试验注册。标题之后,abstract,以及由两位综述作者独立进行的全文筛选，我们通过拟合随机效应模型对研究进行了定性总结,并对纳入的随机临床试验(RCT)进行了定量综合.
结果：在2023年2月3日的数据库搜索中，有25项研究符合我们的纳入标准。其中,只有2项RCT和17项非随机研究纳入了标准预防比较组.此外，后者的偏见风险很大，主要是由于前后研究设计和回顾性比较组。因此，非随机研究仅定性地进行.对两个确定的RCT的随机效应荟萃分析在出血结局（均值1.15的比率；95CI，0.85-1.56）和因子消耗（均值0.82的比率；95CI，0.58-1.18）方面仍然没有定论。
结论：文献中的证据表明PK指导优于标准固定剂量预防的临床益处是微弱的，主要见于缺乏并行对照的非随机研究。结果报告中的异质性，小样本量，和高风险的偏见。
目的：评估PK指导的预防与非PK指导的预防的疗效。
方法：我们没有将纳入限制在特定的研究设计标签上，并且纳入了由至少一个接受PK指导预防的不同队列组组成的所有研究。从开始到搜索日期，我们搜索了以下数据库：MEDLINE，Embase,中部,ClinicalTrials.gov,和欧盟临床试验注册。标题之后,abstract,以及由两位综述作者独立进行的全文筛选，我们通过拟合随机效应模型对研究进行了定性总结,并对纳入的随机临床试验(RCT)进行了定量综合.
结果：在2023年2月3日的数据库搜索中，有25项研究符合我们的纳入标准。其中,只有2项RCT和17项非随机研究纳入了标准预防比较组.此外，后者的偏见风险很大，主要是由于前后研究设计和回顾性比较组。因此，非随机研究仅定性地进行.对两个确定的RCT的随机效应荟萃分析在出血结局（均值1.15的比率；95CI，0.85-1.56）和因子消耗（均值0.82的比率；95CI，0.58-1.18）方面仍然没有定论。
结论：文献中的证据表明PK指导优于标准固定剂量预防的临床益处是微弱的，主要见于缺乏并行对照的非随机研究。结果报告中的异质性，小样本量，和高风险的偏见。
