Ma Zidong, Cao Fei, Liao Mingjuan, Min Rui, Zheng Rui, Sun Xiaolin, Chen Xinlin, Gong Yabin, Ai Sizhi, Kang Xiaohong
Department of Oncology, the First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, Henan, China.
Department of Traditional Chinese Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
BMJ. 2025 Sep 2;390:e082834. doi: 10.1136/bmj-2024-082834.
To evaluate the risk of cardiovascular adverse events associated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with mutated non-small cell lung cancer (NSCLC).
Systematic review and network meta-analysis.
PubMed, Embase, Web of Science, Scopus, Cochrane Central Register of Controlled Trials, and three clinical trial registries, from inception to 20 November 2024.
Randomised controlled trials comparing EGFR tyrosine kinase inhibitor monotherapy with placebo or other treatments in patients with mutated NSCLC.
Pairs of reviewers extracted data and assessed risk of bias. A random effects network meta-analysis using a frequentist approach compared adverse drug reactions across different treatments. Certainty of evidence was evaluated using the confidence in network meta-analysis approach. Pairwise meta-analyses were done to compare the three generations of EGFR tyrosine kinase inhibitors.
The network meta-analysis comprised 89 randomised controlled trials involving 29 813 participants, mean follow-up 2.18 years. Compared with placebo, both first generation (odds ratio 1.51, 95% confidence interval 1.01 to 2.26; high certainty; pooled incidence 3.2%) and third generation EGFR tyrosine kinase inhibitors (2.18, 1.46 to 3.27; high certainty; 9.5%) were associated with increased risks of cardiac adverse events. Among third generation inhibitors, osimertinib (2.53, 1.53 to 4.19; high certainty; 8.9%) and lazertinib (2.84, 1.17 to 6.91; moderate certainty; 2.7%) were associated with cardiac adverse events. Combined therapies, such as antiangiogenesis with erlotinib or gefitinib, were associated with vascular adverse events (high certainty), whereas antiangiogenesis with osimertinib was associated with cardiovascular adverse events (moderate to high certainty). Also, the risk of arrhythmias was significantly higher with third generation inhibitors (3.26, 1.83 to 5.81; high certainty; 7.3%), such as osimertinib alone (3.35, 1.75 to 6.40; high certainty; 6.2%) and in combination with antiangiogenesis. Almonertinib was associated with vascular toxicity. In pairwise meta-analysis, third generation inhibitors were associated with higher risks of any grade and grade ≥3 cardiovascular adverse events compared with first generation inhibitors.
In patients with mutated NSCLC, first and third generation EGFR tyrosine kinase inhibitors, as well as combination therapies with antiangiogenesis, were associated with increased risks of cardiovascular adverse events. Risks were significantly higher with third generation compared with first generation inhibitors.
PROSPERO CRD42023433003.
评估表皮生长因子受体（EGFR）酪氨酸激酶抑制剂与非小细胞肺癌（NSCLC）突变患者心血管不良事件的相关性。
系统评价和网状Meta分析。
从创刊至2024年11月20日的PubMed、Embase、科学引文索引、Scopus、Cochrane对照试验中央注册库以及三个临床试验注册库。
比较EGFR酪氨酸激酶抑制剂单药治疗与安慰剂或其他治疗方法在NSCLC突变患者中的随机对照试验。
由两名评价员提取数据并评估偏倚风险。采用频率学派方法进行随机效应网状Meta分析，比较不同治疗方法的药物不良反应。使用网状Meta分析的置信度方法评估证据的确定性。进行成对Meta分析以比较三代EGFR酪氨酸激酶抑制剂。
网状Meta分析纳入了89项随机对照试验，涉及29813名参与者，平均随访2.18年。与安慰剂相比，第一代（比值比1.51，95%置信区间1.01至2.26；高确定性；合并发生率3.2%）和第三代EGFR酪氨酸激酶抑制剂（2.18，1.46至3.27；高确定性；9.5%）均与心脏不良事件风险增加相关。在第三代抑制剂中，奥希替尼（2.53，1.53至4.19；高确定性；8.9%）和拉泽替尼（2.84，1.17至6.91；中等确定性；2.7%）与心脏不良事件相关。联合治疗，如厄洛替尼或吉非替尼联合抗血管生成治疗，与血管不良事件相关（高确定性），而奥希替尼联合抗血管生成治疗与心血管不良事件相关（中至高确定性）。此外，第三代抑制剂导致心律失常的风险显著更高（3.26，1.83至5.81；高确定性；7.3%），如单独使用奥希替尼（3.35，1.75至6.40；高确定性；6.2%）以及与抗血管生成联合使用时。阿美替尼与血管毒性相关。在成对Meta分析中，与第一代抑制剂相比，第三代抑制剂发生任何级别和≥3级心血管不良事件的风险更高。
在NSCLC突变患者中，第一代和第三代EGFR酪氨酸激酶抑制剂以及联合抗血管生成治疗均与心血管不良事件风险增加相关。与第一代抑制剂相比，第三代抑制剂的风险显著更高。
PROSPERO CRD42023433003
Zotero 插件
