阿司匹林“抵抗”与肠溶包衣有关

一项纳入了400例健康成年人的研究表明，提示阿司匹林抵抗的指标只有在使用肠溶型阿司匹林时才表现明显，而使用速释型阿司匹林时则不会出现，所以这其实是阿司匹林“假抵抗”。

来自美国费城Perelman医学院转化医学与治疗学研究所的Tilo Grosser博士及其同事指出，阿司匹林抵抗的概念被用于解释患者为何会出现治疗失败，研究估计其发生率大约为5%~20%。

这项研究包括3个阶段，首先对年龄介于18~55岁的受试者进行筛查，评估其对于325 mg速释型或肠溶型阿司匹林单次给药的应答情况；然后在可能出现了阿司匹林抵抗的受试者中重复测试；最后再比较应答者和无应答者的应答情况。

研究者采用了多项指标来评估患者的应答情况，即反映阿司匹林分子靶点环氧化酶-1(COX-1)的活性，包括血小板聚集和血清血栓素形成，这可能提示阿司匹林抵抗的遗传学原因。

结果显示，服用了速释型阿司匹林的所有受试者均为应答者，但在服用肠溶型阿司匹林的受试者中有49%被视为无应答者。重复给药后，之前因服用肠溶型阿司匹林被归为无应答者的受试者在服用速释型阿司匹林后却表现出了应答证据。

研究者称：“我们没能找到任何一个人真正符合阿司匹林抵抗的标准。相反，因药物吸收延迟和减少而导致的假抵抗现象，在受试者服用肠溶型阿司匹林后十分常见。”

研究者总结道：“上述研究结果对采用单一床旁诊断方法来确诊阿司匹林抵抗的做法提出了质疑，支持肠溶型阿司匹林血小板抑制效果不一致的研究发现。”该研究已于12月4日在线发表于《循环》(Circulation)杂志上(2012 [doi: 10.1161/CIRCULATIONAHA.112.117283])。

美国哈佛大学医学教授/波士顿退伍军人健康保健院心脏科主任Deepak Bhatt博士在接受采访时说：“这项研究很好地证明了，至少在健康志愿者中，阿司匹林抵抗是不存在的。”医生和患者很关注的一个研究结果是，在可能出现了阿司匹林抵抗的受试者中，阿司匹林的肠溶包衣延迟并减少了药物的吸收，这与提示肠溶包衣可能影响阿司匹林吸收的既往研究数据相吻合。虽然之前也怀疑这可能解释了所谓的阿司匹林抵抗，但“这是首次有人对这个问题进行真正科学且客观的分析”。

Bhatt博士称，虽然研究结果仍需在真正患病(比如糖尿病或动脉粥样硬化)的患者中进行验证，但这一结果可能会影响到临床实践，目前只建议将速释型阿司匹林用于接受支架置入或者出现了心肌梗死的患者以使药物快速起效。但研究结果对于并没有真正患病的人长期服用阿司匹林提出了更多的疑问，如果他们服用肠溶型阿司匹林，那么会有多少人可能无法完全吸收阿司匹林？“如果有一部分患者不能完全获得阿司匹林的抗凝血效应……那这可能意味着数以百万计的正在服用肠溶型阿司匹林的患者可能并未获得期望的保护作用。”

Bhatt博士指出，还有一个没被大家公认的观点是，肠溶包衣能减少胃出血的说法“其实证据非常不足，有人甚至说这种作用根本就不存在”。虽然使用肠溶型阿司匹林的确能减轻胃部不适，用于预防消化道出血，“但如果患者没有在消化道方面受益，现在又可能引发假抵抗问题，就应该再仔细想想肠溶包衣到底有没有用。”

目前他对临床医生的建议是，在开具速释型阿司匹林时需确认所使用的是正确剂型，但不能随意停用肠溶型阿司匹林。

美国洛杉矶Burns and Allen研究所血管生理与血栓形成研究实验室主任Sanjay Kaul博士也建议道，鉴于这是一项在健康志愿者身上开展的研究，应谨慎将其结果外推至患有心脏病或慢性病的患者，因为这些疾病可能会影响阿司匹林在体内的作用。这项研究的目的并不是比较这两种剂型的相对临床疗效或安全性，所以他将其视为“一项反映阿司匹林应答差异药代学原因的机理研究”。

Kaul博士在接受采访时补充道，检测阿司匹林抵抗性的“意义尚不明确”，就如同氯吡格雷抵抗性一样，这个概念“在很大程度上是市场营销的一种手段”，也是为了开发评估阿司匹林应答水平的检测方法。

Kaul博士表示他会继续建议将速释型阿司匹林用于需要快速起效的情况，而长期使用则需改为肠溶型阿司匹林，尤其是对于既往有胃肠不耐受或副作用病史的患者。虽然目前还没有关于肠溶型阿司匹林在安全性方面优于速释型阿司匹林(比如消化道出血)的“确切证据”，但已有研究数据表明，肠溶型阿司匹林与内镜下胃黏膜糜烂发生率降低有关，尽管与胃黏膜糜烂的临床相关性尚不明确。

这项研究由美国国家心肺血液研究所、国家研究资源中心、美国心脏学会以及拜耳医药保健公司共同资助。作者之一、美国宾夕法尼亚大学的Garret FitzGerald博士声明接受了拜耳医药保健公司提供的研究经费。Grosser博士声明接受了PLx Pharma公司提供的咨询费。其余4名作者声明无潜在利益冲突。Bhatt博士声明担任了PLx Pharma公司的顾问，但没有接受其提供的酬金。Kaul博士声明无相关利益冲突。

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By: ELIZABETH MECHCATIE, Cardiology News Digital Network

In a study of 400 healthy adults, measurements indicating the presence of what has been thought to be aspirin resistance were evident only with enteric-coated aspirin, not immediate-release aspirin, which the authors have described as aspirin "pseudoresistance."

The researchers used several measurements to evaluate responses reflecting the activity of cyclooxygenase-1 (COX-1), the molecular target of aspirin, including platelet aggregation and serum thromboxane formation, which could indicate a genetic cause of aspirin resistance. Still, "we failed to find a single person who satisfied" the criteria for true aspirin resistance, reported Dr. Tilo Grosser, of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine in Philadelphia, and his associates. "By contrast, pseudoresistance, due to delayed and reduced drug absorption, was common after ingestion of enteric-coated aspirin," they said.

"These observations question the value of seeking to diagnose aspirin resistance with single point-of-care diagnostic approaches and support the finding of inconsistent platelet inhibition following enteric-coated preparations of aspirin," they concluded. The study appeared in Circulation online Dec. 4 (2012 [doi: 10.1161/CIRCULATIONAHA.112.117283]).

The concept of aspirin resistance has been used to explain treatment failures occurring in patients, with estimates of incidence ranging from 5% to 20% in studies, they noted.

The study had several phases, which included screening the study participants, aged 18-55 years, for their response to a single 325-mg dose of immediate-release or enteric-coated aspirin, repeating testing among those who appeared to be resistant to aspirin, and comparing responses in responders and nonresponders.

Among the specific findings: All of the individuals who received a dose of immediate-release aspirin were responders, but up to 49% of those who received enteric aspirin were considered nonresponders. With repeated exposure, individuals categorized as nonresponders when given enteric-coated aspirin showed evidence of responses when administered immediate-release aspirin.

"What they have shown in an extremely elegant way is that aspirin resistance, at least in healthy volunteers, doesn’t exist," Dr. Deepak Bhatt said in an interview.

Of great interest to physicians and patients is the finding that in the individuals who appeared to be aspirin resistant, enteric coating on aspirin was delaying and reducing absorption, which is consistent with old data that indicate enteric coating can interfere with aspirin absorption, he said. While this may have been suspected as an explanation for so-called aspirin resistance, "this is the first time someone has really nailed it down in a scientifically unassailable way," said Dr. Bhatt, professor of medicine at Harvard University, Boston, and chief of cardiology at VA Boston Healthcare System.

Although the results need to be replicated in patients with actual disease, such as diabetes or atherosclerosis, he said the results will potentially impact practice, although immediate-release aspirin is recommended for patients who are being stented or are having a myocardial infarction, for the rapid pharmacologic effect.

But the results raise further questions about more chronic administration of aspirin in patients who are not acutely ill and how many of these patients may not be fully absorbing aspirin if they are taking an enteric-coated formulation. "If there is a proportion of patients who are not getting the full anticlotting effect of aspirin ... that means potentially millions of patients are taking enteric-coated aspirin and not getting the protection they or their doctors are assuming they are getting," he said.

Another consideration, which he said is not widely appreciated, is that evidence that enteric coating reduces stomach bleeding "is quite scant, some might even say nonexistent." While enteric coated aspirin does reduce stomach upset, it is used for GI bleeding protection, "but if you’re not getting the GI benefit, and now potentially there is this issue of pseudoresistance these authors are raising, you’ve got to think twice about whether enteric coating is doing anything useful or good."

Dr. Bhatt’s recommendation to clinicians, which predates the publication of this study, is to make sure that patients who are prescribed the immediate-release aspirin get the correct formulation, and not end up with an enteric-coated formulation unintentionally.

Dr. Sanjay Kaul, director of the vascular physiology and thrombosis research laboratory at the Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, also advised caution about extrapolating the results of a study of healthy volunteers to patients with heart disease or chronic illnesses that may affect how aspirin works in the body. The study was not designed to address comparative clinical efficacy or safety between the two formulations, and he views it as "a mechanistic study demonstrating a pharmacokinetic reason for variability in aspirin responsiveness."

In an interview, he added that testing for aspirin resistance is "of dubious value," and the concept, like resistance to clopidogrel, "is driven to a large extent by marketing considerations," and the development of tests to assess aspirin responsiveness.

Dr. Kaul said he will continue to recommend immediate-release formulation for rapid onset of action and switch to enteric-coated aspirin for chronic use, especially in patients with a history of gastric intolerance or side effects. Although "unequivocal evidence" of safety advantages over immediate-release aspirin, such as GI bleeding, is lacking, data have shown reduced rates of gastric erosions on endoscopy associated with enteric-coated aspirin, although the clinical relevance of the erosions is unclear, he said.

The study was funded by the National Heart, Lung, and Blood Institute; the National Center for Research Resources; the American Heart Association; and Bayer HealthCare. Coauthor Dr. Garret FitzGerald of the University of Pennsylvania, Philadelphia, received research funding from Bayer HealthCare to support partial funding of this study, and Dr. Grosser received consultancy fees from PLx Pharma. The four remaining coauthors had no potential conflicts of interest to disclose.

Dr. Bhatt said his disclosures include being an unpaid consultant to PLx Pharma. Dr. Kaul said he had no relevant disclosures.