Liu Huiyi, Fu Lu, Jin Shuyu, Ye Xingdong, Chen Yanlin, Pu Sijia, Xue Yumei
Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou Guangdong China.
The Second School of Clinical Medicine Southern Medical University Guangzhou Guangdong China.
Cancer Innov. 2024 Apr 16;3(3):e116. doi: 10.1002/cai2.116. eCollection 2024 Jun.
With the emergence of cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitors, the outcomes of patients with malignant tumors have improved significantly. However, the incidence of cardiovascular adverse events has also increased, which can affect tumor treatment. In this study, we evaluated the incidence and severity of adverse cardiovascular events caused by CTLA-4 inhibitors by analyzing reported trials that involved CTLA-4 inhibitor therapy.
Randomized clinical trials published in English from January 1, 2013, to November 30, 2022, were searched using the Cochrane Library and PubMed databases. All included trials examined all grade and grades 3-5 cardiac and vascular adverse events. These involved comparisons of CTLA-4 inhibitors to placebo, CTLA-4 inhibitors plus chemotherapy to chemotherapy alone, CTLA-4 inhibitors combined with PD-1/PD-L1 inhibitors to PD-1/PD-L1 inhibitors alone, and CTLA-4 inhibitors plus target agent to PD-1/PD-L1 inhibitors plus target agent. The odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method.
Overall, 20 trials were included. CTLA-4 inhibitors significantly increased the incidence of all-grade cardiovascular toxicity (OR = 1.33, 95% CI: 1.00-1.75, = 0.05). The incidence of all-grade cardiovascular toxicity increased in malignant tumor patients who received single-agent CTLA-4 inhibitors (OR = 1.73, 95% CI: 1.13-2.65, = 0.01), as well as the incidence rate of grades 3-5 cardiovascular adverse events (OR = 2.00, 95% CI: 1.08-3.70, = 0.03). Compared with the non-CTLA-4 inhibitor group, CTLA-4 inhibitors plus chemotherapy, PD-1/PD-L1 inhibitors, or target agent did not significantly affect the incidence of cardiac and vascular toxicity. The incidence of grades 3-5 cardiac failure, hypertension, pericardial effusion, myocarditis, and atrial fibrillation were much higher among patients exposed to CTLA-4 inhibitor, but the data were not statistically significant.
Our findings suggest that the incidence rate of all cardiovascular toxicity and severe cardiovascular toxicity increased in patients who were administered CTLA-4 inhibitors. In addition, the risk of serious cardiovascular toxic events was independent of the type of adverse event. From these results, physicians should assess the benefits and risks of CTLA-4 inhibitors when treating malignancies.
随着细胞毒性T淋巴细胞相关蛋白4（CTLA-4）抑制剂的出现，恶性肿瘤患者的治疗结果有了显著改善。然而，心血管不良事件的发生率也有所增加，这可能会影响肿瘤治疗。在本研究中，我们通过分析涉及CTLA-4抑制剂治疗的已报道试验，评估了CTLA-4抑制剂所致心血管不良事件的发生率和严重程度。
使用Cochrane图书馆和PubMed数据库检索2013年1月1日至2022年11月30日以英文发表的随机临床试验。所有纳入的试验均考察了所有级别以及3-5级心脏和血管不良事件。这些试验包括CTLA-4抑制剂与安慰剂的比较、CTLA-4抑制剂加化疗与单纯化疗的比较、CTLA-4抑制剂联合PD-1/PD-L1抑制剂与单纯PD-1/PD-L1抑制剂的比较，以及CTLA-4抑制剂加靶向药物与PD-1/PD-L1抑制剂加靶向药物的比较。采用Mantel-Haenszel方法计算比值比（OR）及相应的95%置信区间（CI）。
共纳入20项试验。CTLA-4抑制剂显著增加了所有级别心血管毒性的发生率（OR = 1.33，95%CI：1.00-1.75，P = 0.05）。接受单药CTLA-4抑制剂治疗的恶性肿瘤患者中，所有级别心血管毒性的发生率增加（OR = 1.73，95%CI：1.13-2.65，P = 0.01），3-5级心血管不良事件的发生率也增加（OR = 2.00，95%CI：1.08-3.70，P = 0.03）。与非CTLA-4抑制剂组相比，CTLA-4抑制剂加化疗、PD-1/PD-L1抑制剂或靶向药物对心脏和血管毒性的发生率没有显著影响。暴露于CTLA-4抑制剂的患者中，3-5级心力衰竭、高血压、心包积液、心肌炎和心房颤动的发生率更高，但数据无统计学意义。
我们的研究结果表明，接受CTLA-4抑制剂治疗的患者中，所有心血管毒性和严重心血管毒性的发生率均增加。此外，严重心血管毒性事件的风险与不良事件类型无关。基于这些结果，医生在治疗恶性肿瘤时应评估CTLA-4抑制剂的利弊。
