Zidar David A, Al-Kindi Sadeer, Longenecker Chris T, Parikh Sahil A, Gillombardo Carl B, Funderburg Nicholas T, Juchnowski Steven, Huntington Lauren, Jenkins Trevor, Nmai Christopher, Osnard Michael, Shishebhor Mehdi, Filby Steven, Tatsuoka Curtis, Lederman Michael M, Blackstone Eugene, Attizzani Guilherme, Simon Daniel I
Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA.
Struct Heart. 2023 Apr 28;7(4):100182. doi: 10.1016/j.shj.2023.100182. eCollection 2023 Jul.
Inflammation and thrombosis are often linked mechanistically and are associated with adverse events after transcatheter aortic valve replacement (TAVR). High residual platelet reactivity (HRPR) is especially common when clopidogrel is used in this setting, but its relevance to immune activation is unknown. We sought to determine whether residual activity at the purinergic receptor P2Y12 (P2Y12) promotes prothrombotic immune activation in the setting of TAVR.
This was a randomized trial of 60 patients (enrolled July 2015 through December 2018) assigned to clopidogrel (300mg load, 75mg daily) or ticagrelor (180mg load, 90 mg twice daily) before and for 30 days following TAVR. Co-primary endpoints were P2Y12-dependent platelet activity (Platelet Reactivity Units; VerifyNow) and the proportion of inflammatory (cluster of differentiation [CD] 14+/CD16+) monocytes 1 day after TAVR.
Compared to clopidogrel, those randomized to ticagrelor had greater platelet inhibition (median Platelet Reactivity Unit [interquartile range]: (234 [170.0-282.3] vs. 128.5 [86.5-156.5], < 0.001), but similar inflammatory monocyte proportions (22.2% [18.0%-30.2%] vs. 25.1% [22.1%-31.0%], = 0.201) 1 day after TAVR. Circulating monocyte-platelet aggregates, soluble CD14 levels, interleukin 6 and 8 levels, and D-dimers were also similar across treatment groups. HRPR was observed in 63% of the clopidogrel arm and was associated with higher inflammatory monocyte proportions. Major bleeding events, pacemaker placement, and mortality did not differ by treatment assignment.
Residual P2Y12 activity after TAVR is common in those treated with clopidogrel but ticagrelor does not significantly alter biomarkers of prothrombotic immune activation. HRPR appears to be an indicator (not a cause) of innate immune activation in this setting.
炎症和血栓形成在机制上常常相互关联，并且与经导管主动脉瓣置换术（TAVR）后的不良事件相关。在这种情况下使用氯吡格雷时，高残余血小板反应性（HRPR）尤为常见，但其与免疫激活的相关性尚不清楚。我们试图确定嘌呤能受体P2Y12（P2Y12）的残余活性是否会在TAVR背景下促进血栓前免疫激活。
这是一项针对60例患者的随机试验（2015年7月至2018年12月入组），在TAVR前及术后30天给予氯吡格雷（负荷剂量300mg，每日75mg）或替格瑞洛（负荷剂量180mg，每日两次，每次90mg）。共同主要终点是TAVR术后1天P2Y12依赖性血小板活性（血小板反应单位；VerifyNow）和炎性（分化簇[CD]14+/CD16+）单核细胞比例。
与氯吡格雷相比，随机接受替格瑞洛治疗的患者血小板抑制作用更强（血小板反应单位中位数[四分位间距]：234[170.0 - 282.3]对128.5[86.5 - 156.5]，<0.001），但TAVR术后1天炎性单核细胞比例相似（22.2%[18.0% - 30.2%]对25.1%[22.1% - 31.0%]，P = 0.201）。各治疗组之间循环单核细胞 - 血小板聚集体、可溶性CD14水平、白细胞介素6和8水平以及D - 二聚体也相似。氯吡格雷组63%的患者观察到HRPR，且与更高的炎性单核细胞比例相关。主要出血事件、起搏器植入和死亡率在不同治疗组之间无差异。
TAVR后使用氯吡格雷治疗的患者中，P2Y12残余活性很常见，但替格瑞洛并未显著改变血栓前免疫激活的生物标志物。在这种情况下，HRPR似乎是先天免疫激活的一个指标（而非原因）。
