Johns Hopkins University, Osler Medical Building, 7600 Osler Drive, Suite 307, Towson, Maryland, 21204, USA.
Thromb Haemost. 2010 Feb;103(2):415-8. doi: 10.1160/TH09-09-0631. Epub 2009 Nov 13.
Impaired response to clopidogrel, or "resistance" is a cornerstone concept for justification of more aggressive antiplatelet regimens, and development of new more potent drugs. There are over 1,000 citations (although predominantly reviews, or case reports) in MEDLINE related to clopidogrel "resistance", while about 100 of them attempted to link low response to adverse clinical outcomes. However, most of these studies are woefully small, and not randomised. The TRITON trial assessed head-to-head novel antiplatelet agent prasugrel versus clopidogrel in patients with acute coronary syndromes. This study was the first in a decade to challenge clopidogrel monopoly, and to indirectly test the "resistance" hypothesis. The primary endpoint was the rate of cardiovascular death, non-fatal myocardial infarction, or stroke, and occurred in 12.1% of patients treated with clopidogrel, and 9.9% of patients randomised to prasugrel, suggesting impressive vascular outcome benefit of prasugrel over clopidogrel. However, the Food and Drug Administration (FDA) presented more balanced, and realistic outlook on TRITON. While very early periprocedural benefit exists, long-term prasugrel therapy yielded identical to clopidogrel vascular outcomes among 13,608 TRITON patients challenging the postulate that clopidogrel "resistance" phenomenon is clinically relevant. Despite the fact that prasugrel 10 mg/daily cause 2.5 times more potent platelet inhibition than conventional clopidogrel 75 mg/daily, with fewer patients exhibiting broad response variability, and/or antiplatelet "resistance", the vascular benefit beyond acute phase was identical. Keeping in mind growing over time bleeding, cancer, and mortality risks associated with chronic prasugrel use, small observational studies should be judged with skepticism as hypothesis-generating, pending confirmation in randomised trials.
对氯吡格雷反应受损，或“抵抗”，是为更积极的抗血小板治疗方案和新的更有效的药物开发提供理由的基石概念。在 MEDLINE 中有超过 1000 篇与氯吡格雷“抵抗”相关的文献（尽管主要是综述或病例报告），其中约 100 篇试图将低反应与不良临床结局联系起来。然而，这些研究大多数规模较小，且非随机。TRITON 试验评估了新型抗血小板药物普拉格雷与氯吡格雷在急性冠脉综合征患者中的头对头比较。这项研究是十年来首次挑战氯吡格雷的垄断地位，并间接检验了“抵抗”假说。主要终点是心血管死亡、非致死性心肌梗死或中风的发生率，接受氯吡格雷治疗的患者中有 12.1%，随机接受普拉格雷的患者中有 9.9%发生上述事件，表明普拉格雷在血管结局方面优于氯吡格雷。然而，食品和药物管理局（FDA）对 TRITON 提出了更平衡、更现实的看法。尽管存在非常早期的围手术期获益，但在 TRITON 的 13608 名患者中，长期普拉格雷治疗与氯吡格雷的血管结局相同，这挑战了氯吡格雷“抵抗”现象具有临床相关性的假设。尽管每天 10 毫克的普拉格雷比每天 75 毫克的常规氯吡格雷引起的血小板抑制作用强 2.5 倍，且较少患者表现出广泛的反应变异性和/或抗血小板“抵抗”，但急性阶段以外的血管获益是相同的。考虑到随着时间的推移，长期使用普拉格雷与出血、癌症和死亡风险增加有关，对于小型观察性研究，应该持怀疑态度，将其视为产生假说的研究，等待随机试验的证实。
