Thrombotic events after start of ICPi use.

BackgroundImmune checkpoint inhibitors (ICPi) have been associated with a prothrombotic and pro-atherogenic tendency which could lead to an increased risk of thrombosis. The aim of this study was to investigate the incidence of venous and arterial thrombosis (myocardial infarction or ischemic stroke) in patients who used ICPi as compared with the general population. Furthermore, we investigated the association between the occurrence of venous or arterial thrombosis and mortality.MethodsPatients receiving immune checkpoint inhibitors ICPi between January 1, 2013, and May 31, 2020, at the University Medical Center Utrecht, the Netherlands, were included in this study. Indirect standardization was used to compare the incidence rates of venous and arterial thrombosis in patients who used ICPi to the age- and sex weighted incidence rates in the general population. Time-dependent Cox proportional hazard regression model was used to calculate Hazard ratios (HRs) with 95% CIs to investigate the association between the occurrence of a venous or arterial event after start of an ICPi and mortality.ResultsThe age- and sex weighted incidence rates in 663 patients who used ICPi as compared to the general population was 22.7-fold (95% CI 16.6–31.0) increased for venous thrombosis, 3.0-fold (95% CI 1.2–7.1) increased for myocardial infarction, and 3.2-fold (95% CI 1.6–5.7) increased for ischemic stroke. After adjustment, the all-cause mortality risk was 2.3-fold (95% CI 1.5–3.5) increased for patients who were diagnosed with venous thrombosis during follow-up and 2.2-fold (95% CI 1.1–4.1) increased for patients who were diagnosed with arterial thrombosis during follow-up as compared with patients without venous or arterial thrombosis during follow-up.ConclusionPatients receiving ICPi have elevated risks of venous thrombosis and arterial thrombosis. Occurrence of venous thrombosis or arterial thrombosis during treatment with ICPi is associated with an increased mortality risk.背景 免疫检查点抑制剂（Immune Checkpoint Inhibitors, ICPi）已被证实存在促血栓形成与促动脉粥样硬化的倾向，可能会提升血栓发生风险。本研究旨在对比使用免疫检查点抑制剂的患者与普通人群的静脉血栓、动脉血栓（心肌梗死或缺血性脑卒中）发生率，并进一步探究静脉或动脉血栓发生与患者死亡率之间的关联。 方法 本研究纳入了2013年1月1日至2020年5月31日期间，在荷兰乌得勒支大学医学中心接受免疫检查点抑制剂治疗的患者。采用间接标准化法，对比使用免疫检查点抑制剂患者的静脉、动脉血栓发生率与普通人群按年龄、性别加权后的发生率。采用时变Cox比例风险回归模型计算风险比（Hazard Ratios, HRs）及其95%置信区间（Confidence Intervals, CIs），以探究免疫检查点抑制剂治疗后发生静脉或动脉血栓事件与患者死亡率之间的关联。 结果 相较于普通人群，663例接受免疫检查点抑制剂治疗的患者按年龄、性别加权后的血栓发生率显著升高：静脉血栓发生率为普通人群的22.7倍（95%CI 16.6–31.0），心肌梗死发生率为普通人群的3.0倍（95%CI 1.2–7.1），缺血性脑卒中发生率为普通人群的3.2倍（95%CI 1.6–5.7）。经校正后，随访期间确诊静脉血栓的患者全因死亡风险较随访期间未发生静脉或动脉血栓的患者升高2.3倍（95%CI 1.5–3.5）；随访期间确诊动脉血栓的患者全因死亡风险则升高2.2倍（95%CI 1.1–4.1）。 结论 接受免疫检查点抑制剂治疗的患者，其静脉血栓与动脉血栓发生风险均显著升高。在免疫检查点抑制剂治疗期间发生静脉或动脉血栓，与患者死亡率升高存在显著关联。