Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
National Poisons Information Centre, Tox Info Suisse, Associated Institute of the University of Zurich, Zurich, Switzerland.
Drug Saf. 2020 Sep;43(9):881-891. doi: 10.1007/s40264-020-00958-9.
The Janus kinase (JAK) inhibitors tofacitinib and baricitinib are new treatments for rheumatic diseases. Recent concerns regarding the risk of thrombosis have led to warnings by competent authorities. We therefore aimed to examine the thromboembolic safety signal for tofacitinib and baricitinib.
Individual case safety reports (ICSRs) for tofacitinib and baricitinib were retrieved from the World Health Organization global database VigiBase in April 2019. Primary outcomes were deep vein thrombosis (DVT) and pulmonary thrombosis (PT) or pulmonary embolism (PE). Patient demographics were summarized and then stratified by outcome. Disproportionality analyses were conducted by estimating the reporting odds ratios (RORs) and 95% confidence intervals (CIs) worldwide, and stratified by either Europe or the US.
In both the tofacitinib (n = 40,017) and baricitinib (n = 2138) ICSRs, patients with reported DVT or PT/PE were older and had higher reporting of prothrombotic medications or antithrombotic treatments, suggesting a pre-existing thromboembolic risk/event. In Europe, tofacitinib was associated with increased reporting for DVT (ROR 2.37, 95% CI 1.23-4.56) and PT/PE (ROR 2.38. 95% CI 1.45-3.89). For baricitinib, a threefold increased reporting odds was observed for DVT (ROR 3.47, 95% CI 2.18-5.52) and PT/PE (ROR 3.44, 95% CI 2.43-4.88) in Europe. In the US, tofacitinib was only associated with an elevated ROR of PT (ROR 2.05, 95% CI 1.45-2.90) and no baricitinib ICSRs were reported.
This study supports the current recommendation for cautious use of tofacitinib in patients with high thromboembolic risk. Moreover, with a similar patient profile and elevated reporting for baricitinib, a potential class effect of JAK inhibitors cannot be ruled out.
Janus 激酶（JAK）抑制剂托法替尼和巴瑞替尼是风湿性疾病的新疗法。最近人们对血栓形成风险的担忧导致主管当局发出警告。因此，我们旨在检查托法替尼和巴瑞替尼的血栓栓塞安全性信号。
我们于 2019 年 4 月从世界卫生组织全球数据库 VigiBase 中检索到托法替尼和巴瑞替尼的个别病例安全报告（ICSR）。主要结局为深静脉血栓形成（DVT）和肺血栓形成（PT）或肺栓塞（PE）。总结患者人口统计学资料，并按结局分层。通过估计全球范围内的报告比值比（ROR）和 95%置信区间（CI），以及按欧洲或美国进行分层，进行了不成比例性分析。
在托法替尼（n=40017）和巴瑞替尼（n=2138）的 ICSR 中，报告 DVT 或 PT/PE 的患者年龄较大，且更常报告存在血栓形成风险的药物或抗血栓治疗，表明存在预先存在的血栓栓塞风险/事件。在欧洲，托法替尼与 DVT（ROR 2.37，95%CI 1.23-4.56）和 PT/PE（ROR 2.38，95%CI 1.45-3.89）的报告增加相关。对于巴瑞替尼，在欧洲，DVT（ROR 3.47，95%CI 2.18-5.52）和 PT/PE（ROR 3.44，95%CI 2.43-4.88）的报告比值增加了三倍。在美国，托法替尼仅与 PT 的 ROR 升高相关（ROR 2.05，95%CI 1.45-2.90），且没有报告巴瑞替尼的 ICSR。
这项研究支持目前对高血栓栓塞风险患者谨慎使用托法替尼的建议。此外，由于巴瑞替尼具有相似的患者特征和较高的报告率，不能排除 JAK 抑制剂的潜在类别效应。
