Cardiovascular Toxicities Associated with Anaplastic Lymphoma Kinase Inhibitors: A Disproportionality Analysis of the WHO Pharmacovigilance Database (VigiBase)
Cardiovascular Toxicities Associated with Anaplastic Lymphoma Kinase Inhibitors: A Disproportionality Analysis of the WHO Pharmacovigilance Database (VigiBase)
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DOI：
10.1007/s40264-023-01300-9
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发表时间：
2023-04-27
期刊：
影响因子：
4.2
通讯作者：
Ishizawa，Keisuke
中科院分区：
文献类型：
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作者：
Niimura，Takahiro;Miyata，Koji;Ishizawa，Keisuke
简介最近，有报道称间变性淋巴瘤激酶（ALK）抑制剂引起心包炎等心血管毒性病例；然而，这些不良事件是否在所有 ALK 抑制剂中常见仍不清楚。目的本研究旨在使用不良事件自发报告数据库阐明 ALK 抑制剂的心血管毒性特征。方法我们分析了 WHO 全球个体安全报告数据库 VigiBase 从 1968 年成立到 2021 年 12 月的数据。我们计算了报告比值比，以评估 ALK 抑制剂（克唑替尼、色瑞替尼、艾来替尼、布加替尼、和劳拉替尼）和 21 项心血管不良事件。分析了 ALK 抑制剂给药至心包炎发作的时间。结果 在 27,994,584 份报告中，19,911 份涉及 ALK 抑制剂治疗。在 21 种心血管毒性中，所有五种 ALK 抑制剂仅检测到心包炎信号（克唑替尼 [报告比值比 (ROR)，4.7；95% CI 3.63–6.15]、色瑞替尼 [ROR，12.9；95% CI 9.37–17.79]、艾乐替尼 [ROR，4.8；95% CI]） 3.15–7.42]、布加替尼 [ROR，3.5；95% CI 1.33–9.46] 和劳拉替尼 [ROR，6.4；95% CI 3.60–11.22]）。对于尖端扭转型室性心动过速/QT 延长，使用克唑替尼（ROR，5.0；95% CI 3.72–6.77）和色瑞替尼（ROR，4.2；95% CI 2.17–8.05）检测到信号，而对于高血压，仅使用布加替尼（ROR，3.9；95% CI 2.88–5.20）检测到信号。心力衰竭，他们使用艾来替尼（ROR，2.2；95% CI 1.60-2.90）、克唑替尼（ROR，2.1；95% CI 1.72-2.48）和劳拉替尼（ROR，2.0；95% CI 1.27-3.23）进行检测。关于从给药到不良事件报告的发病时间分析，对于心包炎，艾来替尼的发病时间为 52.5 天，克唑替尼的为 166.5 天。 结论 对 ALK 抑制剂相关不良事件的系统评估揭示了 ALK 抑制剂心脏毒性特征的差异。了解每种 ALK 抑制剂心血管毒性特征的差异将有助于在 ALK 抑制剂之间转换时实现安全的药物治疗。
IntroductionRecently, cases of cardiovascular toxicities, such as pericarditis, caused by anaplastic lymphoma kinase (ALK) inhibitors have been reported; however, whether these adverse events are common among all ALK inhibitors remains unclear.AimsThis study aimed to clarify the cardiovascular toxicity profile of ALK inhibitors using an adverse event spontaneous report database.MethodsWe analyzed data from VigiBase, the WHO global database of individual safety reports, from its inception in 1968 to December 2021. We calculated the reporting odds ratio to evaluate the association between ALK inhibitors (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib) and 21 cardiovascular adverse events. Time to onset of pericarditis from ALK inhibitor administration was analyzed.ResultsOf the 27,994,584 reports, 19,911 involved treatment with ALK inhibitors. Among the 21 cardiovascular toxicities, only pericarditis signals were detected with all five ALK inhibitors (crizotinib [reporting odds ratios (ROR), 4.7; 95% CI 3.63–6.15], ceritinib [ROR, 12.9; 95% CI 9.37–17.79], alectinib [ROR, 4.8; 95% CI 3.15–7.42], brigatinib [ROR, 3.5; 95% CI 1.33–9.46], and lorlatinib [ROR, 6.4; 95% CI 3.60–11.22]). For torsade de pointes/QT prolongation, signals were detected with crizotinib (ROR, 5.0; 95% CI 3.72–6.77) and ceritinib (ROR, 4.2; 95% CI 2.17–8.05), whereas for hypertension, they were identified only with brigatinib (ROR, 3.9; 95% CI 2.88–5.20), and for heart failure, they were detected with alectinib (ROR, 2.2; 95% CI 1.60–2.90), crizotinib (ROR, 2.1; 95% CI 1.72–2.48), and lorlatinib (ROR, 2.0; 95% CI 1.27–3.23). Regarding time-to-onset analysis from drug administration to adverse event reporting, for pericarditis, it ranged from 52.5 days for alectinib to 166.5 days for crizotinib.ConclusionsSystematic evaluation of ALK inhibitor-associated adverse events revealed differences in the cardiotoxicity profiles among ALK inhibitors. Understanding the differences in the cardiovascular toxicity profile of each ALK inhibitor will contribute to safe drug therapy when switching between ALK inhibitors.