EXPRESS PUBLICATION: EDITORIAL COMMENT
Aspirin resistance: more than just a laboratory curiosity*
Deepak L. Bhatt, MD, FACC, FSCAI, FESC ,*
Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA
* Reprint requests and correspondence: Dr. Deepak L. Bhatt, Director, Interventional Cardiovascular Fellowship, Cleveland Clinic Foundation, Department of Cardiovascular Medicine, Desk F25, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
bhattd{at}ccf.org
It is remarkable that, even in 2004, new data regarding aspirin emerge (1). Among the most provocative pieces in the aspirin saga is the aspirin resistance story. In its broadest sense, clinical aspirin resistance refers to patients who have ischemic events despite receiving aspirin. Of course, aspirin resistance may appear to exist in patients who are not prescribed aspirin although they should have been, those who were prescribed aspirin but are not taking it, or those who are taking it but not absorbing it. Distressingly, even in the contemporary era, there are some physicians who appear to display aspirin resistance, that is, to resist the recommendation of guidelines and consensus panels to prescribe aspirin to appropriate patients, such as those with acute coronary syndromes or diabetes mellitus (2).
In a biochemical sense, aspirin resistance refers to patients who are taking aspirin but do not display an adequate degree of platelet inhibition (Fig. 1). The lack of standard definitions across studies of aspirin resistance has hampered the field. In part, the field has also been plagued by the desire to categorize aspirin resistance as a dichotomous response, when more likely it is a continuous variable, similar to blood pressure. Perhaps as a consequence, the range of aspirin resistance that is quoted varies widely, from 5% to 40%, depending on the assay and the population studied (3). Further complicating the issue is the uncertainty of how stable a parameter aspirin resistance may be over time in a single patient.
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Figure 1 Some of the possible mechanisms of apparent aspirin resistance. COX = cyclooxygenase; GP = glycoprotein; mRNA = messenger ribonucleic acid; vWF = von Willebrand factor.
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Aspirin works by acetylating the cyclooxygenase (COX)-1 enzyme irreversibly, leading to suppression of thromboxane A2 and related metabolites (4). Using patients who were taking aspirin from the Heart Outcomes Prevention Evaluation (HOPE) study, Eikelboom et al. (5) measured baseline urinary 11-dehydro thromboxane B2 levels, which serve as a marker of thromboxane generation. Levels were compared between those patients taking aspirin who sustained an ischemic event versus those who did not sustain an event. Those in the highest quartile of urinary thromboxane generation had twice the risk of a myocardial infarction than those in the lowest quartile. The researchers concluded that the incomplete suppression of thromboxane generation by aspirin—that is, aspirin resistance—was the cause of the increased risk. Investigators from the Cleveland Clinic Foundation (6) performed a prospective, blinded analysis of patients who were aspirin resistant as determined by optical platelet aggregometry, the gold standard for determining aspirin response. Of the 326 patients with stable cardiovascular disease who were followed, 17 (5.2%) patients were identified as aspirin-resistant and were found to have a three-fold risk for death, myocardial infarction, or stroke compared with the patients who were not deemed aspirin- resistant. Thus, two separate and well-conducted studies support an association between aspirin resistance and worse clinical outcome.
In this issue of the Journal, Chen et al. (7) bring aspirin resistance to the world of the clinician. Using the point-of-care Ultegra Rapid Platelet Function Assay (Accumetrics Inc., San Diego, California), patients were categorized as either aspirin-sensitive or -resistant, and the incidence of myonecrosis after elective percutaneous coronary intervention (PCI) was assessed. By this classification, 19.2% of patients were aspirin resistant. The incidence of any creatine kinase (CK)-MB elevation after PCI was twice as high in the aspirin-resistant (51.7%) versus aspirin-sensitive (24.6%) patients. Troponin elevation paralleled the findings with CK-MB. Thus, patients determined to be aspirin resistant with a bedside test were more likely to have peri-procedural myonecrosis, including large CK elevations.
Of note, the clopidogrel-loading regimen used in the study of Chen et al. (7), although the current standard of care, may in fact not be adequate. Also, patients in whom glycoprotein IIb/IIIa inhibitor use was planned were excluded from their study. Optimal durations and doses of clopidogrel pretreatment and/or intravenous glycoprotein IIb/IIIa inhibition may have diminished the clinical impact of patient differences in aspirin sensitivity. Certainly, the findings of Chen at al. (7) imply that if a patient about to undergo PCI is determined to be aspirin resistant, some attempt ought to be made to intensify antiplatelet therapy.
However, the most important question remains unanswered. In patients in whom aspirin resistance has been identified, what exactly should physicians do to decrease patient risk, especially over the long haul? There is no good evidence that increasing aspirin dose would be useful (8). Indeed, the data thus far suggest that higher aspirin doses increase bleeding and gastrointestinal complications, but do not lead to better efficacy. Data from both the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) and Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) studies support this premise (9,10).
Another option for patients who display aspirin resistance would be to add or substitute alternative antithrombotic therapy. The antiplatelet agent clopidogrel would be a logical choice, because, unlike aspirin, it blocks the adenosine diphosphate receptor. Data from Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study show modest superiority of clopidogrel monotherapy over aspirin monotherapy, with an amplification of benefit in high-risk subgroups (11,12). Both the CURE and Clopidogrel for the Reduction of Events During Observation (CREDO) studies support the superiority of dual antiplatelet therapy over aspirin monotherapy. Interestingly, a study did find that patients who were aspirin-resistant had platelets that were more sensitive to adenosine diphosphate (13).
Various additional factors may affect response to antiplatelet therapy, and bedside testing may not detect the impact of all these factors. Acute coronary syndromes have been associated with increased degrees of platelet activation, as has congestive heart failure more recently (14). Body mass index and insulin resistance may affect the level of platelet activity and blunt aspirin's effect. Hyperglycemia and hypercholesterolemia, by means of producing reactive oxidant species, may diminish the response to antiplatelet therapy (15,16). Even exercise with its adrenergic surge may affect platelet responsiveness, as may the catecholamine excess associated with stress (17). Thus, the categorization of a patient as either aspirin-resistant or -sensitive may change depending on the presence of a number of other factors. Furthermore, characterization of aspirin sensitivity based solely on measures of platelet inhibition would not capture any potential anti-inflammatory benefit of anti-platelet therapy (1,18–20). Although it remains unclear whether cardiac doses of aspirin have a clinically significant effect on arterial inflammation, with data on both sides of the fence, such an effect might still be of clinical benefit in a patient who is characterized as aspirin-resistant (20).
Several mechanisms of aspirin resistance have been proposed. Naturally, if a patient is noncompliant with aspirin, the patient will appear to derive no effect or benefit from aspirin therapy. Measurement of salicylate levels will address this possibility. Another mechanism is drug interaction. The most plausible interaction described pertains to ibuprofen. It appears that ibuprofen is able to bind to the COX-1 binding site of aspirin, and via steric hindrance may prevent aspirin from binding and exerting its antiplatelet effect (21). Whether enteric coating might contribute to aspirin resistance is something that, surprisingly, has been sparsely studied. Inadequate inhibition of platelet COX-1 is a popular hypothesis to explain aspirin resistance. Aspirin resistance has also been attributed to COX-2 expression by platelets and endothelial cells, but this remains controversial because of conflicting data (22,23). Generation of F2-isoprostane 8-iso-PGF2 by free radical catalyzed arachidonate peroxidation may lead to aspirin resistance by binding to thromboxane receptors. Polymorphisms of platelet membrane glycoproteins such as the Pl (A1/A2) have been associated with a diminished response to aspirin (24,25). A number of other polymorphisms such as of the von Willebrand Factor (vWF) or the collagen receptor gene have been speculated to cause aspirin resistance (26,27). Functional single nucleotide polymorphisms of the COX-1 gene that might affect response to aspirin have already been identified (28).
Although bedside measures of platelet function are a significant advance compared with the prior gold standard of cumbersome platelet aggregometry, the future may lie also in determination of individual genetic profiles. Potentially, then, a number of different polymorphisms may account for some degree of aspirin resistance. However, before this future is realized, large studies need to be performed of patients receiving antiplatelet therapy who undergo platelet function assays before and after initiation of therapy, with assessment of clinical end points and concomitant analyses of single nucleotide polymorphisms and haplotypes to determine how genetic variation modulates the connection between aspirin resistance and clinical outcomes, especially within the context of established risk factors.
The study by Chen et al. (7) provides an impetus for further study of how to modify the risk associated with aspirin resistance once it is identified, and potentially a template for future studies. Aspirin remains the most commonly prescribed cardiovascular medication; thus, it behooves us as physicians to determine the optimal strategy for using this life-saving medication. Beyond that, the concept of tailoring antiplatelet therapy in general is one that is prime for testing, although this would best be studied with adequately powered trials having long-term follow-up. Such studies will permit us to move aspirin resistance from a laboratory curiosity into mainstream medical practice. More importantly, the results of such investigation might allow us to take the first steps toward truly personalized medicine.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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