Department of Clinical Pharmacology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.
Department of Clinical Pharmacy, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Br J Clin Pharmacol. 2024 Sep;90(9):2166-2179. doi: 10.1111/bcp.16127. Epub 2024 Jun 3.
Bruton's tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib and zanubrutinib, may be involved in the mechanisms of action related to adverse events (AEs) of the cardiovascular system. We aimed to characterize the cardiovascular AEs of BTKIs reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System, and to compare the cardiovascular risks of BTKIs.
Across all indications of three FDA-approved BTKIs, primary suspect drugs were extracted over two periods: from January 2013 to December 2022 (after the approval of the first BTKI), and from January 2020 to December 2022 (all three BTKIs on the market). Disproportionality was measured by reporting odds ratios (RORs) and information components. Additional analyses were performed without incorporating patients with underlying cardiovascular disease (CVD).
A total of 10 353 cases included the uses of ibrutinib, acalabrutinib and zanubrutinib. Ibrutinib was significantly associated with 47 cardiovascular AEs. Acalabrutinib was associated with new signals, including cardiac failure (ROR = 1.82 [1.13-2.93]), pulmonary oedema (ROR = 2.15 [1.19-3.88]), ventricular extrasystoles (ROR = 5.18 [2.15-12.44]), heart rate irregular (ROR = 3.05 [1.53-6.11]), angina pectoris (ROR = 3.18 [1.71-5.91]) and cardiotoxicity (ROR = 25.22 [17.14-37.10]). In addition, cardiovascular events had an earlier onset in acalabrutinib users. Zanubrutinib was only associated with atrial fibrillation. Acalabrutinib and zanubrutinib had lower ROR values than ibrutinib. The AE signals were generally consistent between the population receiving and not receiving CVD medications.
Potential cardiovascular risks identified in this study were not clearly noted on the label of marketed acalabrutinib. Caution should be paid to the cardiovascular risks of BTKIs having been or being developed.
布鲁顿酪氨酸激酶抑制剂（BTKIs），包括第一代伊布替尼、第二代阿卡替尼和泽布替尼，可能与心血管系统不良事件（AE）的作用机制有关。我们旨在描述美国食品药品监督管理局（FDA）不良事件报告系统中报告的 BTKI 的心血管 AE，并比较 BTKI 的心血管风险。
在三种经 FDA 批准的 BTKI 的所有适应证中，在两个时期提取主要嫌疑药物：从 2013 年 1 月至 2022 年 12 月（第一种 BTKI 批准后），以及从 2020 年 1 月至 2022 年 12 月（三种 BTKI 均在市场上）。通过报告比值比（ROR）和信息成分来衡量比例失调。在不纳入患有基础心血管疾病（CVD）的患者的情况下进行了额外的分析。
共纳入 10353 例使用伊布替尼、阿卡替尼和泽布替尼的病例。伊布替尼与 47 例心血管 AE 显著相关。阿卡替尼与新的信号相关，包括心力衰竭（ROR=1.82[1.13-2.93]）、肺水肿（ROR=2.15[1.19-3.88]）、室性期外收缩（ROR=5.18[2.15-12.44]）、心率不规则（ROR=3.05[1.53-6.11]）、心绞痛（ROR=3.18[1.71-5.91]）和心脏毒性（ROR=25.22[17.14-37.10]）。此外，阿卡替尼使用者的心血管事件更早发生。泽布替尼仅与心房颤动相关。阿卡替尼和泽布替尼的 ROR 值均低于伊布替尼。在接受和未接受 CVD 药物治疗的人群中，AE 信号基本一致。
本研究中发现的潜在心血管风险在已上市的阿卡替尼标签中并未明确指出。应注意正在或即将开发的 BTKI 的心血管风险。
