Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study.
Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study.
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DOI：
10.1016/s1470-2045(18)30608-9
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发表时间：
2018-12
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影响因子：
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通讯作者：
Moslehi JJ
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作者：
Salem JE;Manouchehri A;Moey M;Lebrun-Vignes B;Bastarache L;Pariente A;Gobert A;Spano JP;Balko JM;Bonaca MP;Roden DM;Johnson DB;Moslehi JJ
免疫检查点抑制剂（ICI）在多种癌症类型中显着改善了临床结果，并越来越多地用于早期疾病环境和组合。然而，ICI也可引起严重甚至致命的免疫介导的不良事件（irAE）。在这里，我们确定并表征与ICI相关的显著心血管irAE（CV-irAE）。我们使用VigiBase（世卫组织的全球个体病例安全性报告数据库）识别截至2018年1月与ICI（n：31，321）和其他药物（n：16，343，451）相关的药物AE。我们使用报告比值比（ROR）和信息成分（IC）评估ICI和CV事件之间的关联。IC是不成比例贝叶斯报告的指标值，比较观察值和预期值以发现药物-AE相关性。IC 025是IC 95%可信区间的下限，并且IC 025>0被认为是统计学显著的。使用这种不可知的方法，我们确定了多个CV实体ICI治疗后过度报告相比，整个数据库。ICI治疗与心肌炎（n：122，ROR：11.21 [9.36-13.43]，IC 025：3.2）、心包疾病（n：95，ROR：3.8 [3.08-4.62]，IC 025：1.63）和血管炎（n：82，ROR：1.56 [1.25-1.94]，IC 025：0.03），包括颞动脉炎（n：18，ROR：12.99 [8.12-20.77]，IC 025：2.59）的较高报告率相关。这些CV-irAE主要累及男性（58-67%），年龄范围较广（20-90岁），发生在ICI给药后早期（40-80%在首次ICI给药后1个月内）。心包疾病在肺癌患者中更常见（56.3%），而心肌炎和血管炎在黑色素瘤患者中更常见（分别为40.7%和60%; p<0.001）。颞动脉炎患者视力损害占27.8%。CV-irAE在大多数病例中是严重的（>80%），50%的心肌炎病例、21.1%的心包疾病和6.1%的血管炎病例发生死亡（p<0.0001）。在心肌炎病例中，与ICI单药治疗相比，ICI联合治疗的死亡率最高（65.6% vs. 44.4%，p：0.04）。ICI可能在治疗早期导致重度和致残性炎性CV-irAE。除了危及生命的心肌炎外，这些毒性还包括心包疾病以及有失明风险的颞动脉炎。
Immune-checkpoint-inhibitors (ICIs) have dramatically improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations. However, ICIs can also cause severe or even fatal immune-mediated adverse-events (irAE). Here, we identify and characterize significant cardiovascular irAE (CV-irAEs) associated with ICIs. We used VigiBase, the WHO’s global Individual-Case-Safety-Report database to identify drug-AE related to ICIs (n:31,321) and related to other drugs (n:16,343,451) through 01/2018. We evaluated the association between ICI and CV events using Reporting-Odds-Ratio (ROR) and Information-Component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find drug-AE associations. IC025 is the lower-end of IC 95% credibility-interval and an IC025>0 is considered statistically significant. Using this agnostic approach, we identified multiple CV entities over-reported after ICI treatment compared to the entire database. ICI treatment was associated with higher reporting of myocarditis (n:122, ROR: 11.21 [9.36–13.43], IC025:3.2), pericardial diseases (n:95, ROR: 3.8 [3.08–4.62], IC025:1.63), and vasculitis (n:82, ROR: 1.56 [1.25–1.94], IC025:0.03), including temporal-arteritis (n:18, ROR: 12.99 [8.12–20.77], IC025:2.59). These CV-irAE affected mostly men (58–67%), with a wide age range (20–90 years) and occurred early after ICI administration (40–80% within one month of first ICI administration). Pericardial disorders were reported more often in patients with lung cancer (56.3%) whereas myocarditis and vasculitis were more commonly reported in patients with melanoma (40.7% and 60%, respectively; p<0.001). Vision was impaired in 27.8% of temporal-arteritis cases. CV-irAE were serious in the majority of cases (>80%), with fatalities occurring in 50% of myocarditis cases, 21.1% of pericardial disorders and 6.1% of vasculitis (p<0.0001). Among myocarditis cases, fatality was most frequent in ICI combination therapy compared to ICI monotherapy (65.6% vs. 44.4%, p:0.04). ICI may lead to severe and disabling inflammatory CV-irAEs early during therapy. Besides life-threatening myocarditis, these toxicities include pericardial disorders, as well as temporal arteritis with a risk for blindness.