Department of Internal Medicine, Mount Sinai Hospital, Chicago, Illinois.
Department of Internal Medicine, Mount Sinai Hospital, Chicago, Illinois.
Clin Ther. 2024 Feb;46(2):134-145. doi: 10.1016/j.clinthera.2023.11.014. Epub 2023 Dec 14.
Cardiovascular adverse events (CVAEs) are common adverse effects of first-generation Bruton tyrosine kinase inhibitors (BTKis) and limit their use considerably. This led to the development of second-generation BTKis-acalabrutinib and zanubrutinib-which are more selective, potent, and presumed to have better safety profiles than the previous group of medications. However, there have been sporadic reports of CVAEs associated with second-generation BTKis in clinical practice. To address this issue, a comprehensive meta-analysis to pool the documented CVAEs was performed, including major hemorrhage, any bleeding, atrioventricular block, atrial fibrillation/flutter, pericardial effusion, pericarditis, heart failure, cardiac arrest, myocardial infarction, hypertension, hypotension, and stroke. This meta-analysis incorporated 8 studies. Among these, 6 were Phase III trials and 2 were Phase II trials. These studies collectively enrolled a total of 2938 patients.
Multiple databases, including PubMed, MEDLINE, Cochrane Library, Scopus, and EMBASE, were systematically searched for relevant clinical trials from inception through January 14, 2023. The effect measure used was odds ratio (OR) and 95% CI.
Of a total of 1774 studies identified during the initial database search, 8 were included in the meta-analysis. The incidence of overall and cardiovascular mortality was comparable between the 2 groups. There were no significant differences observed for cardiovascular mortality (OR = 0.36; 95% CI, 0.08-1.65; n = 2588; I = 45%; P = 0.19). Similar results were found for all-cause mortality (OR = 0.85; 95% CI, 0.67-1.07), any bleeding (OR = 1.90; 95% CI, 0.88-4.09), major bleeding (OR = 1.07; 95% CI, 0.65-1.76), atrioventricular block (OR = 0.74; 95% CI, 0.15-3.68), atrial fibrillation/flutter (OR = 0.74; 95% CI, 0.37-1.50), and other CVAEs associated with second-generation BTKis.
Based on the available evidence, there is no indication of worse cardiovascular outcomes or superiority of second-generation BTKis compared with standard treatments in terms of safety profile. However, additional large-scale controlled trials are needed to provide robust support for the superior tolerability of new-generation BTKis.
心血管不良事件（CVAEs）是第一代 Bruton 酪氨酸激酶抑制剂（BTKis）的常见不良反应，极大地限制了其应用。这导致了第二代 BTKis-阿卡鲁替尼和泽布替尼的开发，它们比前一组药物更具选择性、更强效，且假定具有更好的安全性。然而，在临床实践中，已有零星报告称第二代 BTKis 与 CVAEs 相关。为了解决这个问题，进行了一项全面的荟萃分析，以汇总有记录的 CVAEs，包括大出血、任何出血、房室传导阻滞、心房颤动/扑动、心包积液、心包炎、心力衰竭、心脏骤停、心肌梗死、高血压、低血压和中风。这项荟萃分析纳入了 8 项研究。其中，6 项为 III 期临床试验，2 项为 II 期临床试验。这些研究共纳入了 2938 名患者。
系统检索了包括 PubMed、MEDLINE、Cochrane 图书馆、Scopus 和 EMBASE 在内的多个数据库，以查找截至 2023 年 1 月 14 日的相关临床试验。使用的效应量为比值比（OR）和 95%置信区间。
在最初的数据库搜索中，共确定了 1774 项研究，其中 8 项纳入了荟萃分析。两组的总体和心血管死亡率无显著差异。心血管死亡率无显著差异（OR = 0.36；95%CI，0.08-1.65；n = 2588；I = 45%；P = 0.19）。全因死亡率也有类似结果（OR = 0.85；95%CI，0.67-1.07）、任何出血（OR = 1.90；95%CI，0.88-4.09）、大出血（OR = 1.07；95%CI，0.65-1.76）、房室传导阻滞（OR = 0.74；95%CI，0.15-3.68）、心房颤动/扑动（OR = 0.74；95%CI，0.37-1.50）和其他与第二代 BTKis 相关的 CVAEs。
基于现有证据，在安全性方面，第二代 BTKis 与标准治疗相比，并没有心血管结局恶化的迹象，也没有优于标准治疗的证据。然而，需要更多的大规模对照试验来为新一代 BTKis 的更高耐受性提供有力支持。
