Ghatalia P, Je Y, Kaymakcalan M D, Sonpavde G, Choueiri T K
Department of Internal Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
Department of Food and Nutrition, Kyung Hee University, Seoul, Republic of Korea.
Br J Cancer. 2015 Jan 20;112(2):296-305. doi: 10.1038/bjc.2014.564. Epub 2014 Nov 6.
Multi-targeted vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are known to cause cardiac toxicity, but the relative risk (RR) of QTc interval prolongation and serious arrhythmias associated with them are not reported.
We conducted a trial-level meta-analysis of randomised phase II and III trials comparing arms with and without a US Food and Drug Administration-approved VEGFR TKI (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib and regorafenib). A total of 6548 patients from 18 trials were selected. Statistical analyses were conducted to calculate the summary incidence, RR and 95% CIs.
The RR for all-grade and high-grade QTc prolongation for the TKI vs no TKI arms was 8.66 (95% CI 4.92-15.2, P<0.001) and 2.69 (95% CI 1.33-5.44, P=0.006), respectively, with most of the events being asymptomatic QTc prolongation. Respectively, 4.4% and 0.83% of patients exposed to VEGFR TKI had all-grade and high-grade QTc prolongation. On subgroup analysis, only sunitinib and vandetanib were associated with a statistically significant risk of QTc prolongation, with higher doses of vandetanib associated with a greater risk. The rate of serious arrhythmias including torsades de pointes did not seem to be higher with high-grade QTc prolongation. The risk of QTc prolongation was independent of the duration of therapy.
In the largest study to date, we show that VEGFR TKI can be associated with QTc prolongation. Although most cases were of low clinical significance, it is unclear whether the same applies to patients treated off clinical trials.
多靶点血管内皮生长因子受体（VEGFR）酪氨酸激酶抑制剂（TKIs）已知会导致心脏毒性，但与之相关的QTc间期延长和严重心律失常的相对风险（RR）尚未见报道。
我们对随机II期和III期试验进行了试验水平的荟萃分析，比较了使用和未使用美国食品药品监督管理局批准的VEGFR TKI（舒尼替尼、索拉非尼、帕唑帕尼、阿昔替尼、凡德他尼、卡博替尼、波纳替尼和瑞戈非尼）的组。共纳入了18项试验中的6548例患者。进行统计分析以计算汇总发病率、RR和95%置信区间（CIs）。
TKI组与非TKI组相比，所有级别和高级别QTc延长的RR分别为8.66（95%CI 4.92 - 15.2，P<0.001）和2.69（95%CI 1.33 - 5.44，P = 0.006），大多数事件为无症状性QTc延长。分别有4.4%和0.83%暴露于VEGFR TKI的患者出现所有级别和高级别QTc延长。亚组分析显示，只有舒尼替尼和凡德他尼与QTc延长的统计学显著风险相关，较高剂量的凡德他尼风险更大。包括尖端扭转型室速在内的严重心律失常发生率在高级别QTc延长时似乎并未更高。QTc延长的风险与治疗持续时间无关。
在迄今为止最大规模的研究中，我们表明VEGFR TKI可与QTc延长相关。尽管大多数病例临床意义不大，但尚不清楚这是否适用于非临床试验中的患者。
