HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD 21204, USA.
Am Heart J. 2009 Dec;158(6):925-32. doi: 10.1016/j.ahj.2009.10.012.
Noncompliance is probably the major cause of clopidogrel "resistance." However, noncompliance is difficult to prove without confirming that the drug has been administered. Therefore, detection of plasma clopidogrel and/or metabolite(s) as the reliable objective method to confirm compliance is important.
We sought to correlate the inhibition of platelet aggregation (IPA) with plasma levels of unchanged clopidogrel (UC), active thiol metabolite (ATM), and inactive carboxyl metabolite (ICM) in a large cohort of patients with coronary artery disease and ischemic stroke treated with clopidogrel. We conducted secondary post-hoc analyses of IPA and plasma UC, ATM, and ICM in a dataset consisting of presumably compliant patients with coronary disease (n = 422) and post-stroke (n = 209).
Overall noncompliance rate was 22% (n = 138), while such risks were significantly higher in stroke survivors (n = 79, or 38%) when compared to patients with coronary disease (14%; n = 59; P = .001). Only ICM (19,154 +/- 7,228 ng/ml) was suitable for detecting compliance, while UC (15.2 +/- 9.4 ng/ml), and ATM (8.1 +/- 3.7 ng/ml) in most cases are barely detectable, and diminish over time in the stored samples. The best correlation with IPA (r2 = 0.847) was observed for active metabolite, followed by unchanged clopidogrel (r2 = 0.602), and finally inactive metabolite (r2 = 0.529). The predictive value for noncompliance was also high for inactive metabolite (c-statistic = 0.911).
Therapy with clopidogrel is associated with double-digit underestimated risks for noncompliance, especially in stroke survivors, supporting the hypothesis that lack of IPA, and clopidogrel "resistance" are attributed to hidden noncompliance. Plasma ICM, but not UC, or ATM is a useful marker to monitor compliance to clopidogrel in registries and clinical trials.
不遵医嘱可能是氯吡格雷“抵抗”的主要原因。但是，在没有确认药物已被使用的情况下，很难证明不遵医嘱。因此，检测未改变的氯吡格雷（UC）、活性硫醇代谢物（ATM）和无活性羧酸代谢物（ICM）等血浆药物作为可靠的客观方法来确认依从性非常重要。
我们旨在通过对接受氯吡格雷治疗的大量冠心病和缺血性卒中患者的血小板聚集抑制率（IPA）与血浆中未改变的氯吡格雷（UC）、活性硫醇代谢物（ATM）和无活性羧酸代谢物（ICM）水平进行相关性研究。我们对假定患有冠心病（n=422）和卒中后（n=209）的依从性患者数据集进行了 IPA 和血浆 UC、ATM 和 ICM 的二次事后分析。
总体不遵医嘱率为 22%（n=138），而在卒中幸存者（n=79，或 38%）中这种风险显著更高，与冠心病患者（14%；n=59；P=.001）相比。只有 ICM（19,154±7,228ng/ml）适合检测依从性，而在大多数情况下 UC（15.2±9.4ng/ml）和 ATM（8.1±3.7ng/ml）几乎无法检测到，并且在储存样本中随时间推移而减少。与 IPA 相关性最好的是活性代谢物（r2=0.847），其次是未改变的氯吡格雷（r2=0.602），最后是无活性代谢物（r2=0.529）。无活性代谢物的不依从预测值也很高（c 统计量=0.911）。
氯吡格雷治疗与双位数的低估不遵医嘱风险相关，尤其是在卒中幸存者中，这支持了 IPA 缺乏和氯吡格雷“抵抗”归因于隐匿性不遵医嘱的假说。在登记处和临床试验中，血浆 ICM，但不是 UC 或 ATM，是监测氯吡格雷依从性的有用标志物。
