Goli Rakesh R, Ibrahim Khalil, Shah Rohan, Kickler Thomas S, Clarke William A, Resar Jon R, Schulman Steven P, McEvoy John W
Saolta University Healthcare Group, University College Hospital Galway, Newcastle Rd, Galway, H91 YR71 Ireland.
J Invasive Cardiol. 2019 Sep;31(9):265-271.
In this secondary analysis of the PACIFY randomized trial, we assessed whether dose and timing of fentanyl have implications for the pharmacokinetics and pharmacodynamics of ticagrelor loading during percutaneous coronary intervention (PCI).
Among 212 patients undergoing clinically indicated coronary angiography, a total of 70 required PCI and received 180 mg oral ticagrelor. Of these, thirty-two patients received no fentanyl and 38 received fentanyl (with variability in the timing of administration and cumulative dose among those randomized to fentanyl, given that both were provided at the interventional cardiologist's discretion). A time-weighted cumulative fentanyl exposure variable was calculated based on total dose of fentanyl and proximity in time of fentanyl administrations to the ticagrelor load. Patients were stratified based on receiving above or below the median time-weighted cumulative dose. Outcomes included ticagrelor concentrations by mass spectrometry (24-hour area under the curve) and platelet function measured using both VerifyNow platelet reactivity units (PRU) and light-transmission aggregometry (LTA).
Unadjusted ticagrelor 24-hour area under the curve was significantly lower across the categories of increasing fentanyl exposure (P=.02). In adjusted regression models, this difference only remained when comparing the no-fentanyl group with the time-weighted cumulative dose above the median group (P=.04). Similarly, with the no-fentanyl group as the reference, adjusted models testing 2-hour PRU and LTA values demonstrated significant differences (with less platelet inhibition for both tests) only among those with time-weighted cumulative fentanyl exposures above the median value (5.1 μg/min).
We have previously shown that fentanyl slows absorption of oral ticagrelor, attenuating its effect on platelet inhibition. We now demonstrate this mechanism appears to be dose- and time-dependent.
在这项对PACIFY随机试验的二次分析中，我们评估了芬太尼的剂量和给药时间是否对经皮冠状动脉介入治疗（PCI）期间替格瑞洛负荷剂量的药代动力学和药效动力学有影响。
在212例接受临床指征冠状动脉造影的患者中，共有70例需要进行PCI并接受了180mg口服替格瑞洛。其中，32例患者未接受芬太尼，38例接受了芬太尼（在随机接受芬太尼的患者中，给药时间和累积剂量存在差异，因为两者均由介入心脏病专家酌情提供）。根据芬太尼的总剂量以及芬太尼给药时间与替格瑞洛负荷剂量的接近程度，计算了一个时间加权累积芬太尼暴露变量。患者根据接受的时间加权累积剂量高于或低于中位数进行分层。结果包括通过质谱法测定的替格瑞洛浓度（24小时曲线下面积）以及使用VerifyNow血小板反应单位（PRU）和光透射聚集法（LTA）测量的血小板功能。
在芬太尼暴露增加的类别中，未调整的替格瑞洛24小时曲线下面积显著降低（P = 0.02）。在调整后的回归模型中，只有在将无芬太尼组与时间加权累积剂量高于中位数的组进行比较时，这种差异才仍然存在（P = 0.04）。同样，以无芬太尼组为参照，对2小时PRU和LTA值进行测试的调整模型显示，仅在时间加权累积芬太尼暴露高于中位数（5.1μg/分钟）的患者中存在显著差异（两项测试的血小板抑制作用均较小）。
我们之前已经表明，芬太尼会减慢口服替格瑞洛的吸收，减弱其对血小板抑制的作用。我们现在证明这种机制似乎是剂量和时间依赖性的。
