Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Circulation. 2013 Jan 22;127(3):377-85. doi: 10.1161/CIRCULATIONAHA.112.117283. Epub 2012 Dec 4.
Low dose aspirin reduces the secondary incidence of myocardial infarction and stroke. Drug resistance to aspirin might result in treatment failure. Despite this concern, no clear definition of aspirin resistance has emerged, and estimates of its incidence have varied remarkably. We aimed to determine the commonality of a mechanistically consistent, stable, and specific phenotype of true pharmacological resistance to aspirin-such as might be explained by genetic causes.
Healthy volunteers (n=400) were screened for their response to a single oral dose of 325-mg immediate release or enteric coated aspirin. Response parameters reflected the activity of the molecular target of aspirin, cyclooxygenase-1. Individuals who appeared aspirin resistant on 1 occasion underwent repeat testing, and if still resistant were exposed to low-dose enteric coated aspirin (81 mg) and clopidogrel (75 mg) for 1 week each. Variable absorption caused a high frequency of apparent resistance to a single dose of 325-mg enteric coated aspirin (up to 49%) but not to immediate release aspirin (0%). All individuals responded to aspirin on repeated exposure, extension of the postdosing interval, or addition of aspirin to their platelets ex vivo.
Pharmacological resistance to aspirin is rare; this study failed to identify a single case of true drug resistance. Pseudoresistance, reflecting delayed and reduced drug absorption, complicates enteric coated but not immediate release aspirin administration.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00948987.
小剂量阿司匹林可降低心肌梗死和中风的二次发病率。阿司匹林耐药可能导致治疗失败。尽管存在这种担忧，但尚未出现明确的阿司匹林耐药定义，其发生率的估计也存在显著差异。我们旨在确定一种与阿司匹林真正药理耐药机制一致、稳定且特异的表型的常见性，这种耐药可能由遗传原因引起。
健康志愿者（n=400）接受了单次口服 325 毫克速释或肠溶阿司匹林的反应筛选。反应参数反映了阿司匹林的分子靶标环氧化酶-1 的活性。在单次使用 325 毫克肠溶阿司匹林时出现阿司匹林耐药的个体接受了重复测试，如果仍然耐药，则接受低剂量肠溶阿司匹林（81 毫克）和氯吡格雷（75 毫克）各 1 周。可变吸收导致单次使用 325 毫克肠溶阿司匹林的明显耐药率很高（高达 49%），但对速释阿司匹林则没有（0%）。所有个体在重复暴露、延长给药后间隔或向血小板外添加阿司匹林时均对阿司匹林有反应。
阿司匹林的药理耐药性罕见；本研究未能确定一个真正耐药的病例。反映药物吸收延迟和减少的假性耐药使肠溶阿司匹林复杂化，但不影响速释阿司匹林的给药。
