中国循证医学杂志

中国循证医学杂志

不同酪氨酸激酶抑制剂治疗慢性髓性白血病不良反应发生风险的 Meta 分析

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目的 系统评价不同酪氨酸激酶抑制剂(TKIs)治疗慢性髓性白血病(CML)后动脉缺血与代谢异常不良事件的发生风险。 方法 计算机检索 PubMed、EMbase、The Cochrane Library、CNKI、WanFang Data 和 VIP 数据库,搜集有关 TKIs 治疗 CML 后不良反应情况的临床试验、观察性研究和病例系列报告,检索时限从建库至 2017 年 2 月。由 2 名研究者独立筛选文献、提取资料和评价纳入研究的偏倚风险后,采用 Stata 12.0 软件进行 Meta 分析。 结果 最终纳入 22 个研究,包括 4 223 例患者。Meta 分析结果显示各终点事件发生率分别如下:① 所有级别缺血性心脏病:尼洛替尼组 2/100 人年[95%CI(2,3)]、伊马替尼组 0/100 人年[95%CI(0,3)];3/4 级缺血性心脏病:尼洛替尼组 1/100 人年[95%CI(0,2)]。② 所有级别周围动脉闭塞性疾病:尼洛替尼组 3/100 人年[95%CI(0,14)]、伊马替尼组 0/100 人年[95%CI(0,2)]。③ 所有级别高血压:尼洛替尼组 1/100 人年[95%CI(0,3)]、帕纳替尼组 44/100 人年[95%CI(27,71)],3/4 级高血压:尼洛替尼组 2/100 人年[95%CI(0,15)]、帕纳替尼组 22/100 人年[95%CI(8,58)]。④ 所有级别高脂血症:尼洛替尼组 17/100 人年[95%CI(5,59)]。⑤ 所有级别血糖升高:尼洛替尼组 11/100 人年[95%CI(9,15)]、伊马替尼组 2/100 人年[95%CI(1,4)]、达沙替尼组 1/100 人年[95%CI(0,5)]、博舒替尼组 19/100 人年[95%CI(19,20)],3/4 级血糖升高:尼洛替尼组 4/100 人年[95%CI(3,5)]、博舒替尼组 1/100 人年[95%CI(1,2)]。 结论 尼洛替尼组 CML 患者缺血性心脏病和周围动脉闭塞性疾病的发生率高于伊马替尼组,帕纳替尼组患者高血压发生率较高,尼洛替尼组患者高脂血症发生率较高,博舒替尼和尼洛替尼组患者血糖升高的发生率较高,而伊马替尼和达沙替尼组患者血糖升高的发生率相对较低。受纳入研究数量和质量所限,以上结论尚需高质量大样本的队列研究结果证实。

Objective To systematically review the risk of arterial ischemic and metabolic adverse events in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). Methods PubMed, EMbase, The Cochrane Library, CNKI, WanFang Data and VIP databases were searched to collect clinical trials, observational studies and case reports of adverse events in CML patients treated with TKIs from inception to February 2017. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, meta-analysis was performed by using Stata 12.0 software. Results A total of 22 studies involving 4 223 patients were included. The incidence rates of ischemic heart disease in any grade were 2 per 100 patient-years (95%CI 2 to 3) for nilotinib, and 0 per 100 patient-years (95%CI 0 to 3) for imatinib. The incidence of ischemic heart disease in grade 3 or 4 was 1 per 100 patient-years (95%CI 0 to 2) for nilotinib. The incidence of peripheral arterial occlusive disease in any grade was 2 per 100 patient-years (95%CI 0 to 14) for nilotinib, and 0 per 100 patient-years (95%CI 0 to 2) for imatinib. The incidence of hypertension in any grade was 1 per 100 patient-years (95%CI 0 to 3) for nilotinib, and 44 per 100 patient-years (95%CI 27 to 71) for ponatinib. The incidence of hypertension in grade 3 or 4 was 2 per 100 patient-years (95%CI 0 to 15) for nilotinib, and 22 per 100 patient-years (95%CI 8 to 58) for ponatinib. The incidence of hyperlipidemia in any grade was 17 per 100 patient-years (95%CI 5 to 59) for nilotinib. The incidence of hyperglycemia in any grade was 11 per 100 patient-years (95%CI 9 to 15) for nilotinib, 2 per 100 patient-years (95%CI 1 to 4) for imatinib, 1 per 100 patient-years (95%CI 0 to 5) for dasatinib, and 19 per 100 patient-years (95%CI 19 to 20) for bosutinib. The incidence of hyperglycemia in grade 3 or 4 was 4 per 100 patient-years (95%CI 3 to 5) for nilotinib, and 1 per 100 patient-years (95%CI 1 to 2) for bosutinib. Conclusion Patients treated with nilotinib have a greater possibility of ischemic heart and peripheral arterial occlusive disease compared with patients treated with imatinib. Patients treated with ponatinib have a high incidence rate of hypertension, and patients treated with nilotinib have a high incidence rate of hyperlipidemia. Patients treated with bosutinib and nilotinib have a more probability of hyperglycemia compared with patients treated with imatinib or dasatinib.

关键词: 酪氨酸激酶抑制剂; 慢性髓性白血病; 动脉缺血事件; 代谢异常

Key words: Tyrosine kinase inhibitors; Chronic myeloid leukemia; Arterial ischemic event; Metabolic disorder

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