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Aspirin Resistance or Variable Response or Both?
Aspirin Resistance or Variable Response or Both? Xi Cheng, MD,a Wai-Hong Chen, MBBS,a,* and Daniel I. Simon, MDb Numerous clinical trials have demonstrated that aspirin is effective in secondary prevention and in high-risk primary prevention of adverse cardiovascular events. However, a constellation of clinical and laboratory evidence exists that demonstrates diminished or absent response to aspirin in some patients. This has led to the concept of “aspirin resistance,” which is a poorly defined, somewhat misleading term. The mechanism for aspirin resistance has not been fully established, but it is almost certainly due to a combination of clinical, biological, and genetic properties affecting platelet function. There are no criteria for distinguishing true resistance from treatment failure, and there is no consensus on whether the definition of aspirin resistance should be based on clinical outcomes, laboratory evidence, or both. Studies in large populations are needed to define antiplatelet resistance using consistent and reproducible assays and correlate the measurements with clinical outcomes. One such prospective randomized trial is completed, and 2 others are under way: the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial compared clopidogrel and aspirin with placebo and aspirin for high-risk primary or secondary prevention, and the Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial (ASCET) is evaluating whether switching to clopidogrel will be superior to continued aspirin therapy in improving clinical outcomes in aspirin-resistant patients with angiographically documented coronary artery disease. The Research Evaluation to Study Individuals Who Show Thromboxane or P2Y12 Receptor Resistance (RESISTOR) trial is investigating whether modifying antiplatelet regimens could prevent myonecrosis after percutaneous coronary intervention in patients with aspirin and clopidogrel resistance. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98[suppl]:11N–17N)
Aspirin is an effective antiplatelet agent with proven benefits in the prevention of atherothrombotic complications of cardiovascular disease. The antithrombotic effects of aspirin are essentially dependent on the interference with platelet aggregation. Aspirin exerts its antithrombotic effects by inhibiting the cyclooxygenase (COX) activity of prostaglandin H-synthase, which, in turn, blocks the metabolism of arachidonic acid to cyclic prostanoids such as thromboxane (TX) A2, prostacyclin, and other prostaglandins.1 Clinical trials have demonstrated that aspirin is effective in secondary prevention and in high-risk primary prevention of adverse cardiovascular events. Aspirin’s use in the secondary prevention of ischemic vascular events is well established. Numerous clinical studies have been conducted to prove the efficacy of aspirin in the secondary prevention of ischemic vascular events. Despite differences in study design, the demographics of the studied populations, the spectrum of baseline risk profiles, and treatment durations, all studies a Division of Cardiology, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China; and bDivision of Cardiology, Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. *Address for reprints: Wai-Hong Chen, MBBS, Room 1929C, Block K, Division of Cardiology, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China. E-mail address: [email protected].
0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.09.009
share the conclusion that the use of aspirin in patients with established ischemic heart disease reduces mortality and morbidity.2– 4 Aspirin Variability A recent meta-analysis including 287 studies enrolling ⬎200,000 patients reported that in patients at high risk for cardiovascular and cerebrovascular events, long-term treatment with aspirin decreased the risk for the composite end point of nonfatal myocardial infarction (MI), nonfatal ischemic stroke, and vascular death by approximately 25%. The risk reduction of any specific event was 34% for nonfatal MI, 25% for nonfatal stroke, and 18% for vascular mortality.5 Currently, aspirin is recommended by American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) guidelines as a first-line antiplatelet agent. Although the benefits of aspirin are widely accepted, there is still a proportion of patients who experience “breakthrough” events despite daily aspirin therapy. From clinical observation, recurrent ischemic events in patients regularly taking aspirin are not uncommon. It has been estimated that 55%– 60% of patients may experience thromboembolic events despite aspirin therapy,6 – 8 suggesting that the antiplatelet effects of aspirin may not be equivalent in all www.AJConline.org
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patients. In addition to these clinical observations, measurements of platelet aggregation, platelet activation, and bleeding time have indeed confirmed wide variability in patients’ responses to aspirin therapy.6,8 –10 It is based on this constellation of clinical and laboratory evidence of diminished or absent responses to aspirin treatment in some patients that the concept of “aspirin resistance” has emerged and has drawn the attention of professionals and the mass media.
Defining Aspirin Resistance Unfortunately, “aspirin resistance” remains a poorly defined term. There are conflicting reports on the incidence and clinical relevance of this phenomenon, because the term is being used to refer to a number of phenomena. These include the inability of aspirin to (1) protect patients from clinical arterial thrombotic complications, (2) cause a prolongation of bleeding time, (3) inhibit platelet TX biosynthesis, or (4) produce an anticipated effect on ⱖ1 in vitro tests of platelet function, mainly platelet aggregation.11,12 A clinical definition of aspirin resistance as the failure of the drug to prevent an atherothrombotic event despite the regular intake of appropriate doses is a relatively common problem, as demonstrated in the Platelet Glycoprotein IIb/ IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial,13 and also the most relevant for practicing physicians.12 Laboratory definitions of aspirin resistance have involved detecting either the failure of aspirin’s pharmacologic effect or the failure of aspirin to prevent the inhibition of platelet aggregation. Aspirin resistance, defined by its pharmacologic action, is the persistent production of TXA2 despite therapy, as measured by the presence of TXA2 metabolites in serum or urine. In contrast, persistent platelet aggregation despite aspirin treatment defines the failure of aspirin-mediated platelet inhibition, and this may occur via non–TX-mediated pathways of platelet activation. It has been suggested that “aspirin resistance” is a misleading term, because in some situations, aspirin successfully inhibits TX synthesis, even though platelet aggregation persists. The term “aspirin nonresponse” encompasses the failure of aspirin to inhibit TX synthesis and reduce platelet aggregation.14 In an attempt to clarify different patterns of aspirin resistance in patients, Weber and colleagues12 described 3 distinct groups, using simple biochemical tests and functional in vitro studies. Type 1 (the pharmacokinetic type) entails the inhibition of platelet TX formation in vitro but not in vivo. Type 2 (the pharmacodynamic type) is characterized by the inability of aspirin to inhibit platelet TX formation in vivo and in vitro. Type 3 (pseudoresistance) involves TX-independent platelet activation. This relatively complex definition attempts to classify objectively the difference between aspirin resistance and aspirin nonresponse but is limited to collagen agonist– based aggregometry as
the method of platelet function testing and is therefore encumbered by the limitations of this method. Definitions of aspirin resistance need to incorporate an understanding of pathophysiologic conditions with clinical outcomes. Defining aspirin resistance by assessing the inhibition of TXA2 production considers the pharmacologic action of aspirin but does not consider platelet aggregation, which is arguably a more clinically relevant outcome. Measurement of the metabolites of TXA2 in serum and urine, TXB2 and urinary 11-dehydro-TXB2, has been used to investigate aspirin resistance.14 However, urinary 11-dehydro-TXB2 levels can be influenced by recent acute thrombotic events such as MI or stroke, which may increase secretion and cause variation in the levels of this urinary marker.14 Altman and associates15 supported the view that aspirin resistance cannot be defined by the level of serum TX or its urinary metabolites, because these measurements do not correlate with the reduction of inhibition of platelet aggregation in response to multiple stimuli and because additional cellular origins are also a rich source of TXA2.16 –18
Dose Response Although much is currently known about the effects of aspirin on platelets, the mechanisms for aspirin resistance have not been fully established. Aspirin resistance is almost certainly multifactorial in origin; that is, it is likely due to a combination of clinical, biologic, and genetic properties affecting platelet function.1 The issue of whether higher aspirin doses might prevent resistance remains controversial. Although low-dose aspirin is demonstrated to inhibit COX-1 completely,19 –22 some patients may require higher doses to achieve the desired antiplatelet effect. This idea was explored in several cerebrovascular studies in the early 1990s that showed that resistance could be overcome by escalating the dose of aspirin (ie, daily doses of ⱖ500 mg, or even more).7,23–25 This suggests that there is a dose-response curve for aspirin’s ability to inhibit platelet function. In addition, Roller and associates26 found that the response to aspirin was improved in 20% of patients with aspirin resistance by increasing the dosage from 100 mg/day to 300 mg/day. However, other trials27–31 failed to confirm a dose response. Weksler and coworkers27 demonstrated that 3–7 days of treatment with aspirin 40 mg/day prevented platelet aggregation and TXA2 formation as effectively as higher doses in patients with previous cerebral ischemia. A comparative trial evaluated outcomes in patients who underwent carotid endarterectomy and were taking low-dose (81–325 mg/day) or high-dose (650 –1,300 mg/day) aspirin.28 The combined rate of stroke, MI, or death was less in the low-dose group than in the high-dose group at 30 days (5.4% vs 7.0%, p ⫽ 0.07) and 3 months (6.2% vs 8.4%, p ⫽ 0.03). A meta-analysis of 11 randomized, placebo-
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controlled trials found similar efficacy for secondary stroke prevention with aspirin doses ranging from 50 –1,500 mg/ day, suggesting a flat dose-response curve.29 Another metaanalysis, conducted by the Antiplatelet Trialists’ Collaboration,30 found similar prevention of vascular events with aspirin in daily doses of 75–325 mg compared with 500 – 1,500 mg, regardless of patients’ risk. The more recent meta-analysis by the same group also does not support the contention of escalating the aspirin dose to overcome its resistance.5 Although no optimal aspirin dose for the prevention of vascular events has been recommended, higher aspirin doses may not be practical in many patients because of dose-dependent side effects, such as gastrointestinal bleeding.11 In a randomized, double-blind, placebo-controlled study, 193 men failed to show resistance with aspirin 75 mg/day initiated within 72 hours after hospitalization for unstable coronary disease. Periodic platelet aggregation studies demonstrated consistently reduced platelet aggregation with no attenuation during 24 months of treatment.31 The investigators noted, however, that to achieve maximal platelet inhibition initially, a cumulative dose of ⬎300 mg/ day was necessary, suggesting the need for a loading dose, which might be problematic for those with gastrointestinal concerns.
Measuring Aspirin Resistance Because the antiplatelet effects of aspirin may not be uniform in all patients and over time, the exact prevalence of aspirin resistance remains uncertain. In most previous studies, it has been reported to range from 5%– 60% of the population. Variability in aspirin-mediated platelet inhibition was noted not only in patients with cerebrovascular disease, with coronary artery disease (CAD), or presenting for coronary artery bypass surgery, as well as in patients with some atherosclerosis-related conditions, but even in normal subjects.6 –9,32–34 The absence of standardized diagnostic criteria and a single validated method of identifying aspirin-resistant patients, as well as the lack of a precise understanding of biologic mechanisms at play in this phenomenon, has led to a wide range of population estimates. Techniques for measuring aspirin resistance: Techniques that have been used to measure aspirin resistance include bleeding time,9 optical platelet aggregometry10 and whole-blood aggregometry,35 the measurement of platelet aggregation ratios,36 the platelet reactivity index,37 TXA2 metabolites,14 flow cytometry,38 and the Platelet Function Analyzer 100 (PFA-100; Dade Behring Inc., Newark, DE)10,33 and VerifyNow (Accumetrics, San Diego, CA) rapid platelet function assay.39 Different methods have reported a wide range of estimates of aspirin resistance in selected populations, with poor concordance among those methods. Definitions of aspirin resistance or nonresponse,
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for example, vary according to the method of platelet function testing used. Also, different techniques define levels of platelet aggregation in units that cannot be directly compared. In addition, definitions of aspirin resistance within a particular technique are also subject to variation. Finally, the setting of criteria defining aspirin resistance is often arbitrary, and there is no standardized protocol in administering tests.
Aspirin Resistance Outcomes It is obvious that aspirin resistance is arousing increasing concern in contemporary clinical practice, and growing evidence suggests that aspirin resistance is indeed clinically important. Several follow-up studies have explored the relation among platelet reactivity, aspirin therapy, and the risk for future vascular events. Cerebrovascular disease: Two cerebrovascular studies have attempted to correlate aspirin resistance with clinical outcomes. After reporting a 33% prevalence of aspirin resistance in 180 patients with stroke in 1991,37 Grotemeyer and colleagues evaluated the same poststroke cohort for 2 years. Importantly, they found that among 174 patients with complete follow-up, aspirin nonresponders had a 10-fold increase in the risk for recurrent ischemic vascular events compared with aspirin responders (40% vs 4.4%, p ⬍0.0001).6 More recently, through retrospective PFA-100 analysis, a cross-sectional study reported that in 53 patients treated with aspirin for the secondary prevention of transient ischemic attack or stroke, the rate of aspirin resistance was significantly higher (12 of 35; 34%) in those with recurrent cerebrovascular events compared with those without recurrence (0 of 18; 0%) (p ⫽ 0.0006).34 These results indicated that aspirin-resistant status may contribute to the failure of prophylactic aspirin therapy, but they were limited by the very small sample size and the arbitrary categorical method used for defining aspirin responsiveness. Peripheral vascular disease: Aspirin resistance has also been linked to poor long-term outcomes in patients with peripheral vascular disease. An Austrian study of 100 patients (70 men and 30 women taking aspirin 100 mg/day) who underwent peripheral arterial balloon angioplasty for intermittent claudication was able to associate clinical outcome with aspirin resistance.35 Platelet aggregation was tested with whole-blood aggregometry before the procedure and repeated at 4, 8, 26, and 52 weeks. Patients were evaluated for up to 18 months for complications. Although no reocclusions occurred in women, 8 reocclusions occurred in men for whom aggregometry had failed to prove aspirin’s prevention of aggregation induced by adenosine diphosphate or collagen. Overall, on the basis of the whole-blood aggregometry, 40% of patients were aspirin nonresponders, and 60% of men did not show the expected effects of aspirin. After an
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18-month follow-up period, the risk for arterial reocclusion in these aspirin-nonresponsive men was 87% higher than in the aspirin-responsive group (p ⫽ 0.0093). Cardiovascular disease: Recently, several published studies have correlated aspirin resistance with adverse clinical outcomes in larger cohorts of subjects with longer follow-up periods. First, in a nested case-control subgroup study of aspirin-treated patients from the Heart Outcomes Prevention Evaluation (HOPE) trial, Eikelboom et al14 reported that the risk for MI, stroke, or cardiovascular death was higher in patients showing aspirin resistance. Investigators measured baseline urinary concentration of 11-dehydro-TXB2, a marker of in vivo TX generation. The adjusted odds for the composite end point of MI, stroke, or vascular death increased with each increasing quartile of 11-dehydro-TXB2 levels. Patients in the highest quartile (indicating the incomplete inhibition of TXA2 synthesis and thereby aspirin resistance) had a 1.8-fold higher risk for the composite end point than those in the lowest quartile. Similarly, there was a 2-fold higher risk for MI and a 3.5-fold higher risk for cardiovascular death in the upper-quartile group compared with those in the lower quartile. This strong and graded association with adverse outcome, and laboratory evidence of aspirin resistance, was independent of conventional risk factors for atherothrombotic vascular diseases. Second, Gum and coworkers40 performed a 2-year follow-up study with a cohort of 326 stable cardiovascular patients receiving aspirin 325 mg/day who were observed in their previous prevalence study. In this prospective and blinded study, baseline aspirin resistance was determined by optical platelet aggregometry, the “gold standard” for assessing aspirin response. Follow-up was completed in 316 of the 326 patients (97%) included from 1997 to 1999, and the mean follow-up period was 679 ⫾ 185 days. Serious vascular events occurred in 34 patients (10%), including 4 of the 17 patients (23.5%; 95% confidence interval [CI], 6.8%– 49.9%) who were aspirin resistant and 30 of the 309 patients (9.7%; 95% CI, 6.6%–13.6%) who were not. Univariate analysis revealed that aspirin-resistant patients had a 3.1-fold increased hazard of meeting the composite end point of cardiac death, MI, or cerebrovascular accident compared with aspirin-sensitive patients (24% vs 10%; hazard ratio [HR], 3.1; 95% CI, 1.1– 8.9; p ⫽ 0.03). After adjusting for 12 potential prognostic factors, a multivariate analysis showed that aspirin resistance was associated with a 4.1-fold excess adjusted hazard of serious vascular events (HR, 4.1; 95% CI, 1.4 –12.1), independent of age, sex, and conventional vascular risk factors, suggesting that aspirin resistance is a significantly independent predictor of future major adverse outcomes. CAD: Similar adverse prognostic results have been observed in patients with CAD and aspirin resistance. In a 4-year retrospective cohort study of 129 post-MI patients, Andersen and colleagues33 noted a tendency toward a higher incidence of adverse vascular events in aspirin-resis-
tant patients than in aspirin-sensitive patients (36% vs 24%), although the difference did not reach statistical significance (p ⫽ 0.28). Chen and colleagues41 explored aspirin resistance in the setting of interventional cardiology. Using the VerifyNow Aspirin Assay, they categorized 151 patients with CAD who presented for nonurgent percutaneous coronary intervention into 2 groups, aspirin sensitive and aspirin resistant. They reported a 19.2% prevalence of aspirin resistance in this population. Despite adequate pretreatment with clopidogrel and procedural anticoagulation with heparin, aspirin-resistant patients had a 2.9-fold increased risk for creatine kinase–myocardial band (CK-MB) elevation compared with aspirin-sensitive patients. Troponin I elevations were in line with the findings on CK-MB. Thus, patients determined to be aspirin resistant with a bedside test were more likely to have postprocedural myonecrosis, including large CK-MB elevations. Using the same point-of-care assay to define aspirin resistance in 422 patients with stable CAD, the same group reported the results of a long-term follow-up study of this cohort.42 After a mean follow-up period of 379 ⫾ 200 days, patients with aspirin resistance were at increased risk for death, acute coronary syndromes, or stroke compared with patients who were aspirin sensitive (14.2% vs 5.2%; HR, 2.92; 95% CI, 1.50 –5.67; p ⫽ 0.002). Cox proportionalhazards regression modeling identified aspirin resistance, diabetes mellitus, previous MI, and a low hemoglobin level to be independently associated with major adverse longterm outcomes (HR for aspirin resistance, 2.71; 95% CI, 1.39 –5.28; p ⫽ 0.004). The results of prospective studies associating aspirin resistance with adverse clinical outcomes are summarized in Figure 1.
Conclusion Through this review of the literature we have a general understanding of aspirin and the resistance phenomenon in the field of cardiovascular disease. Aspirin is a traditional antiplatelet drug that is easy to give, is inexpensive, and has relatively few side effects at low doses. Furthermore, substantial evidence has proved that low-dose daily aspirin is an effective therapy for secondary prevention and high-risk primary prevention of atherothrombotic vascular events.30,43,44 Hence, in current clinical practice, aspirin is unlikely to ever be replaced as a firstline antiplatelet agent. However, the continuously incremental evidence presented in this review suggests that a substantial proportion of the population fails to show the anticipated response to daily aspirin intake; thus, the concept of aspirin resistance arises. However, some authorities take this phenomenon to represent only “treatment failure” rather than aspirin resistance, considering the lack of antiplatelet effect of aspirin in some patients to be a common phenomenon similar to other therapeutic drug failures (eg, lipid-lowering or antihypertensive drugs). Given the multifactorial nature of athero-
Cheng et al/Aspirin Resistance or Variable Response or Both?
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Figure 1. Prospective studies relating aspirin resistance to adverse clinical outcomes. ACS ⫽ acute coronary syndromes; CK-MB ⫽ creatine kinase– myocardial band; MI ⫽ myocardial infarction; PCI ⫽ percutaneous coronary intervention; PTA ⫽ percutaneous transluminal angioplasty.
thrombosis, it is not surprising that only a fraction (usually only 25%–33%) of all atherothrombotic complications can be prevented by any single preventive strategy.45 Although controversial, antithrombotic guidelines from the American College of Chest Physicians acknowledge the possibility of aspirin resistance.11 Moreover, it now appears that aspirin resistance is a clinically significant problem in the prevention of atherothrombotic complications. Several clinical trials demonstrating that aspirin resistance seems to be associated with poor clinical outcomes highlight this fact. Limitations of existing research: Despite our increasing understanding of aspirin resistance, the existing research presents a number of limitations. There is no consensus on a definition of aspirin resistance and on whether the definition should be based on clinical outcomes, laboratory evidence, or both, and there are no criteria for distinguishing true resistance from treatment failure. Numerous tests with varying methodologies, sensitivities, and specificities (and also their own limitations) have been used to assess platelet aggregation. Therefore, there is no accepted uniform measure for screening aspirin resistance in the clinical setting. The clearly elucidated biologic mechanisms for aspirin resistance are still unknown and probably multifactorial. Clinical outcome studies are limited by small sample sizes, varied definitions of aspirin resistance, and inadequate controlling of confounding variables by the study designs. The clinical application of aspirin resistance will require studies on larger populations that define antiplatelet resistance using consistent and reproducible assays and correlate the measurements with clinical outcomes that can be improved by alterations in antiplatelet strategy (eg, increasing the dose
of an antiplatelet agent, adding or substituting a second antiplatelet agent). New trials: Such prospective randomized trials are currently under way. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial compared clopidogrel and aspirin with placebo and aspirin for high-risk primary or secondary prevention. Urinary 11-dehydro-TXB2 levels were checked in a substudy, enabling the prospective assessment of the addition of clopidogrel to aspirin in reducing adverse events associated with aspirin resistance.46 The Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial (ASCET) is evaluating whether switching to clopidogrel will be superior to continued aspirin therapy in improving clinical outcomes in aspirin-resistant patients with angiographically documented CAD.47 The Research Evaluation to Study Individuals Who Show Thromboxane or P2Y12 Receptor Resistance (RESISTOR) trial will investigate whether modifying antiplatelet regimens could prevent myonecrosis after percutaneous coronary intervention in patients with aspirin and clopidogrel resistance. 1. Mason PJ, Freedman JE, Jacobs AK. Aspirin resistance: current concepts. Rev Cardiovasc Med 2004;5:156 –163. 2. Awtry EH, Loscalzo J. Aspirin. Circulation 2000;101:1206 –1218. 3. Cairns JA, Theroux P, Lewis HD, Ezekowitz M, Meade TW. Antithrombotic agents in coronary artery disease. Chest 2001;119:228S–252S. 4. Mehta P. Aspirin in the prophylaxis of coronary artery disease. Curr Opin Cardiol 2002;17:552–558. 5. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death,
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25. Chamorro A, Escolar G, Revilla M, Obach V, Vila N, Reverter JC, Ordinas A. Ex vivo response to aspirin differs in stroke patients with single or recurrent events: a pilot study. J Neurol Sci 1999;171:110 –114. 26. Roller RE, Dorr A, Ulrich S, Pilger E. Effect of aspirin treatment in patients with peripheral arterial disease monitored with the platelet function analyzer PFA-100. Blood Coagul Fibrinolysis 2002;13: 277–281. 27. Weksler BB, Kent JL, Rudolph D, Scherer PB, Levy DE. Effects of low dose aspirin on platelet function in patients with recent cerebral ischemia. Stroke 1985;16:5–9. 28. Taylor DW, Barnett HJ, Haynes RB, Ferguson GG, Sackett DL, Thorpe KE, Simard D, Silver SL, Hachinski V, Clagett GP, Barnes R, Spence JD, for the ASA and Carotid Endarterectomy (ACE) Trial Collaborators. Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. Lancet 1999;353:2179 –2184. 29. Johnson ES, Lanes SF, Wentworth CE, Satterfield MH, Abebe BL, Dicker LW. A metaregression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med 1999;159:1248 –1253. 30. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81–106. 31. Berglund U, Wallentin L. Persistent inhibition of platelet function during long-term treatment with 75 mg acetylsalicylic acid daily in men with unstable coronary artery disease. Eur Heart J 1991;12:428 – 433. 32. Macchi L, Christiaens L, Brabant S, Sorel N, Allal J, Mauco G, Brizard A. Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate. Thromb Res 2002; 107:45– 49. 33. Andersen K, Hurlen M, Arnesen H, Seljeflot I. Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease. Thromb Res 2002;108:37– 42. 34. Grundmann K, Jaschonek K, Kleine B, Dichgans J, Topka H. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks. J Neurol 2003;250:63– 66. 35. Mueller MR, Salat A, Stangl P, Murabito M, Pulaki S, Boehm D, Koppensteiner R, Ergun E, Mittlboeck M, Schreiner W, Losert U, Wolner E. Variable platelet response to low-dose ASA and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty. Thromb Haemost 1997;78:1003–1007. 36. Hurlen M, Seljeflot I, Arnesen H. The effect of different antithrombotic regimens on platelet aggregation after myocardial infarction. Scand Cardiovasc J 1998;32:233–237. 37. Grotemeyer KH. Effects of acetylsalicylic acid in stroke patients: evidence of nonresponders in a subpopulation of treated patients. Thromb Res 1991;63:587–593. 38. Zhao L, Bath P, Heptinstall S. Effects of combining three different antiplatelet agents on platelets and leukocytes in whole blood in vitro. Br J Pharmacol 2001;134:353–358. 39. Wang JC, Aucoin-Barry D, Manuelian D, Monbouquette R, Reisman M, Gray W, Block PC, Block EH, Ladenheim H, Simon DI. Incidence of aspirin nonresponsiveness using the Ultegra Rapid Platelet Function Assay-ASA. Am J Cardiol 2003;92:1492–1494. 40. Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003;41:961–965. 41. Chen WH, Lee PY, Ng W, Tse HF, Lau CP. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol 2004;43:1122–1126. 42. Chen WH, Cheng X, Lee PY, Ng W, Kwok YY, Lau CP. Prevalence, profile, predictors and natural history of aspirin resistance measured by the Ultegra Rapid Platelet Function Assay-ASA in
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46. Bhatt DL, Topol EJ. Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Am Heart J 2004;148:263–268. 47. Pettersen AA, Seljeflot I, Abdelnoor M, Arnesen H. Unstable angina, stroke, myocardial infarction and death in aspirin non-responders: a prospective, randomized trial. The ASCET (ASpirin non-responsiveness and Clopidogrel Endpoint Trial) design. Scand Cardiovasc J 2004;38:353–356.
Aspirin is an effective antiplatelet agent with proven benefits in the prevention of atherothrombotic complications of cardiovascular disease. The antithrombotic effects of aspirin are essentially dependent on the interference with platelet aggregation. Aspirin exerts its antithrombotic effects by inhibiting the cyclooxygenase (COX) activity of prostaglandin H-synthase, which, in turn, blocks the metabolism of arachidonic acid to cyclic prostanoids such as thromboxane (TX) A2, prostacyclin, and other prostaglandins.1 Clinical trials have demonstrated that aspirin is effective in secondary prevention and in high-risk primary prevention of adverse cardiovascular events. Aspirin’s use in the secondary prevention of ischemic vascular events is well established. Numerous clinical studies have been conducted to prove the efficacy of aspirin in the secondary prevention of ischemic vascular events. Despite differences in study design, the demographics of the studied populations, the spectrum of baseline risk profiles, and treatment durations, all studies a Division of Cardiology, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China; and bDivision of Cardiology, Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. *Address for reprints: Wai-Hong Chen, MBBS, Room 1929C, Block K, Division of Cardiology, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China. E-mail address: [email protected].
0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.09.009
share the conclusion that the use of aspirin in patients with established ischemic heart disease reduces mortality and morbidity.2– 4 Aspirin Variability A recent meta-analysis including 287 studies enrolling ⬎200,000 patients reported that in patients at high risk for cardiovascular and cerebrovascular events, long-term treatment with aspirin decreased the risk for the composite end point of nonfatal myocardial infarction (MI), nonfatal ischemic stroke, and vascular death by approximately 25%. The risk reduction of any specific event was 34% for nonfatal MI, 25% for nonfatal stroke, and 18% for vascular mortality.5 Currently, aspirin is recommended by American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) guidelines as a first-line antiplatelet agent. Although the benefits of aspirin are widely accepted, there is still a proportion of patients who experience “breakthrough” events despite daily aspirin therapy. From clinical observation, recurrent ischemic events in patients regularly taking aspirin are not uncommon. It has been estimated that 55%– 60% of patients may experience thromboembolic events despite aspirin therapy,6 – 8 suggesting that the antiplatelet effects of aspirin may not be equivalent in all www.AJConline.org
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patients. In addition to these clinical observations, measurements of platelet aggregation, platelet activation, and bleeding time have indeed confirmed wide variability in patients’ responses to aspirin therapy.6,8 –10 It is based on this constellation of clinical and laboratory evidence of diminished or absent responses to aspirin treatment in some patients that the concept of “aspirin resistance” has emerged and has drawn the attention of professionals and the mass media.
Defining Aspirin Resistance Unfortunately, “aspirin resistance” remains a poorly defined term. There are conflicting reports on the incidence and clinical relevance of this phenomenon, because the term is being used to refer to a number of phenomena. These include the inability of aspirin to (1) protect patients from clinical arterial thrombotic complications, (2) cause a prolongation of bleeding time, (3) inhibit platelet TX biosynthesis, or (4) produce an anticipated effect on ⱖ1 in vitro tests of platelet function, mainly platelet aggregation.11,12 A clinical definition of aspirin resistance as the failure of the drug to prevent an atherothrombotic event despite the regular intake of appropriate doses is a relatively common problem, as demonstrated in the Platelet Glycoprotein IIb/ IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial,13 and also the most relevant for practicing physicians.12 Laboratory definitions of aspirin resistance have involved detecting either the failure of aspirin’s pharmacologic effect or the failure of aspirin to prevent the inhibition of platelet aggregation. Aspirin resistance, defined by its pharmacologic action, is the persistent production of TXA2 despite therapy, as measured by the presence of TXA2 metabolites in serum or urine. In contrast, persistent platelet aggregation despite aspirin treatment defines the failure of aspirin-mediated platelet inhibition, and this may occur via non–TX-mediated pathways of platelet activation. It has been suggested that “aspirin resistance” is a misleading term, because in some situations, aspirin successfully inhibits TX synthesis, even though platelet aggregation persists. The term “aspirin nonresponse” encompasses the failure of aspirin to inhibit TX synthesis and reduce platelet aggregation.14 In an attempt to clarify different patterns of aspirin resistance in patients, Weber and colleagues12 described 3 distinct groups, using simple biochemical tests and functional in vitro studies. Type 1 (the pharmacokinetic type) entails the inhibition of platelet TX formation in vitro but not in vivo. Type 2 (the pharmacodynamic type) is characterized by the inability of aspirin to inhibit platelet TX formation in vivo and in vitro. Type 3 (pseudoresistance) involves TX-independent platelet activation. This relatively complex definition attempts to classify objectively the difference between aspirin resistance and aspirin nonresponse but is limited to collagen agonist– based aggregometry as
the method of platelet function testing and is therefore encumbered by the limitations of this method. Definitions of aspirin resistance need to incorporate an understanding of pathophysiologic conditions with clinical outcomes. Defining aspirin resistance by assessing the inhibition of TXA2 production considers the pharmacologic action of aspirin but does not consider platelet aggregation, which is arguably a more clinically relevant outcome. Measurement of the metabolites of TXA2 in serum and urine, TXB2 and urinary 11-dehydro-TXB2, has been used to investigate aspirin resistance.14 However, urinary 11-dehydro-TXB2 levels can be influenced by recent acute thrombotic events such as MI or stroke, which may increase secretion and cause variation in the levels of this urinary marker.14 Altman and associates15 supported the view that aspirin resistance cannot be defined by the level of serum TX or its urinary metabolites, because these measurements do not correlate with the reduction of inhibition of platelet aggregation in response to multiple stimuli and because additional cellular origins are also a rich source of TXA2.16 –18
Dose Response Although much is currently known about the effects of aspirin on platelets, the mechanisms for aspirin resistance have not been fully established. Aspirin resistance is almost certainly multifactorial in origin; that is, it is likely due to a combination of clinical, biologic, and genetic properties affecting platelet function.1 The issue of whether higher aspirin doses might prevent resistance remains controversial. Although low-dose aspirin is demonstrated to inhibit COX-1 completely,19 –22 some patients may require higher doses to achieve the desired antiplatelet effect. This idea was explored in several cerebrovascular studies in the early 1990s that showed that resistance could be overcome by escalating the dose of aspirin (ie, daily doses of ⱖ500 mg, or even more).7,23–25 This suggests that there is a dose-response curve for aspirin’s ability to inhibit platelet function. In addition, Roller and associates26 found that the response to aspirin was improved in 20% of patients with aspirin resistance by increasing the dosage from 100 mg/day to 300 mg/day. However, other trials27–31 failed to confirm a dose response. Weksler and coworkers27 demonstrated that 3–7 days of treatment with aspirin 40 mg/day prevented platelet aggregation and TXA2 formation as effectively as higher doses in patients with previous cerebral ischemia. A comparative trial evaluated outcomes in patients who underwent carotid endarterectomy and were taking low-dose (81–325 mg/day) or high-dose (650 –1,300 mg/day) aspirin.28 The combined rate of stroke, MI, or death was less in the low-dose group than in the high-dose group at 30 days (5.4% vs 7.0%, p ⫽ 0.07) and 3 months (6.2% vs 8.4%, p ⫽ 0.03). A meta-analysis of 11 randomized, placebo-
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controlled trials found similar efficacy for secondary stroke prevention with aspirin doses ranging from 50 –1,500 mg/ day, suggesting a flat dose-response curve.29 Another metaanalysis, conducted by the Antiplatelet Trialists’ Collaboration,30 found similar prevention of vascular events with aspirin in daily doses of 75–325 mg compared with 500 – 1,500 mg, regardless of patients’ risk. The more recent meta-analysis by the same group also does not support the contention of escalating the aspirin dose to overcome its resistance.5 Although no optimal aspirin dose for the prevention of vascular events has been recommended, higher aspirin doses may not be practical in many patients because of dose-dependent side effects, such as gastrointestinal bleeding.11 In a randomized, double-blind, placebo-controlled study, 193 men failed to show resistance with aspirin 75 mg/day initiated within 72 hours after hospitalization for unstable coronary disease. Periodic platelet aggregation studies demonstrated consistently reduced platelet aggregation with no attenuation during 24 months of treatment.31 The investigators noted, however, that to achieve maximal platelet inhibition initially, a cumulative dose of ⬎300 mg/ day was necessary, suggesting the need for a loading dose, which might be problematic for those with gastrointestinal concerns.
Measuring Aspirin Resistance Because the antiplatelet effects of aspirin may not be uniform in all patients and over time, the exact prevalence of aspirin resistance remains uncertain. In most previous studies, it has been reported to range from 5%– 60% of the population. Variability in aspirin-mediated platelet inhibition was noted not only in patients with cerebrovascular disease, with coronary artery disease (CAD), or presenting for coronary artery bypass surgery, as well as in patients with some atherosclerosis-related conditions, but even in normal subjects.6 –9,32–34 The absence of standardized diagnostic criteria and a single validated method of identifying aspirin-resistant patients, as well as the lack of a precise understanding of biologic mechanisms at play in this phenomenon, has led to a wide range of population estimates. Techniques for measuring aspirin resistance: Techniques that have been used to measure aspirin resistance include bleeding time,9 optical platelet aggregometry10 and whole-blood aggregometry,35 the measurement of platelet aggregation ratios,36 the platelet reactivity index,37 TXA2 metabolites,14 flow cytometry,38 and the Platelet Function Analyzer 100 (PFA-100; Dade Behring Inc., Newark, DE)10,33 and VerifyNow (Accumetrics, San Diego, CA) rapid platelet function assay.39 Different methods have reported a wide range of estimates of aspirin resistance in selected populations, with poor concordance among those methods. Definitions of aspirin resistance or nonresponse,
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for example, vary according to the method of platelet function testing used. Also, different techniques define levels of platelet aggregation in units that cannot be directly compared. In addition, definitions of aspirin resistance within a particular technique are also subject to variation. Finally, the setting of criteria defining aspirin resistance is often arbitrary, and there is no standardized protocol in administering tests.
Aspirin Resistance Outcomes It is obvious that aspirin resistance is arousing increasing concern in contemporary clinical practice, and growing evidence suggests that aspirin resistance is indeed clinically important. Several follow-up studies have explored the relation among platelet reactivity, aspirin therapy, and the risk for future vascular events. Cerebrovascular disease: Two cerebrovascular studies have attempted to correlate aspirin resistance with clinical outcomes. After reporting a 33% prevalence of aspirin resistance in 180 patients with stroke in 1991,37 Grotemeyer and colleagues evaluated the same poststroke cohort for 2 years. Importantly, they found that among 174 patients with complete follow-up, aspirin nonresponders had a 10-fold increase in the risk for recurrent ischemic vascular events compared with aspirin responders (40% vs 4.4%, p ⬍0.0001).6 More recently, through retrospective PFA-100 analysis, a cross-sectional study reported that in 53 patients treated with aspirin for the secondary prevention of transient ischemic attack or stroke, the rate of aspirin resistance was significantly higher (12 of 35; 34%) in those with recurrent cerebrovascular events compared with those without recurrence (0 of 18; 0%) (p ⫽ 0.0006).34 These results indicated that aspirin-resistant status may contribute to the failure of prophylactic aspirin therapy, but they were limited by the very small sample size and the arbitrary categorical method used for defining aspirin responsiveness. Peripheral vascular disease: Aspirin resistance has also been linked to poor long-term outcomes in patients with peripheral vascular disease. An Austrian study of 100 patients (70 men and 30 women taking aspirin 100 mg/day) who underwent peripheral arterial balloon angioplasty for intermittent claudication was able to associate clinical outcome with aspirin resistance.35 Platelet aggregation was tested with whole-blood aggregometry before the procedure and repeated at 4, 8, 26, and 52 weeks. Patients were evaluated for up to 18 months for complications. Although no reocclusions occurred in women, 8 reocclusions occurred in men for whom aggregometry had failed to prove aspirin’s prevention of aggregation induced by adenosine diphosphate or collagen. Overall, on the basis of the whole-blood aggregometry, 40% of patients were aspirin nonresponders, and 60% of men did not show the expected effects of aspirin. After an
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18-month follow-up period, the risk for arterial reocclusion in these aspirin-nonresponsive men was 87% higher than in the aspirin-responsive group (p ⫽ 0.0093). Cardiovascular disease: Recently, several published studies have correlated aspirin resistance with adverse clinical outcomes in larger cohorts of subjects with longer follow-up periods. First, in a nested case-control subgroup study of aspirin-treated patients from the Heart Outcomes Prevention Evaluation (HOPE) trial, Eikelboom et al14 reported that the risk for MI, stroke, or cardiovascular death was higher in patients showing aspirin resistance. Investigators measured baseline urinary concentration of 11-dehydro-TXB2, a marker of in vivo TX generation. The adjusted odds for the composite end point of MI, stroke, or vascular death increased with each increasing quartile of 11-dehydro-TXB2 levels. Patients in the highest quartile (indicating the incomplete inhibition of TXA2 synthesis and thereby aspirin resistance) had a 1.8-fold higher risk for the composite end point than those in the lowest quartile. Similarly, there was a 2-fold higher risk for MI and a 3.5-fold higher risk for cardiovascular death in the upper-quartile group compared with those in the lower quartile. This strong and graded association with adverse outcome, and laboratory evidence of aspirin resistance, was independent of conventional risk factors for atherothrombotic vascular diseases. Second, Gum and coworkers40 performed a 2-year follow-up study with a cohort of 326 stable cardiovascular patients receiving aspirin 325 mg/day who were observed in their previous prevalence study. In this prospective and blinded study, baseline aspirin resistance was determined by optical platelet aggregometry, the “gold standard” for assessing aspirin response. Follow-up was completed in 316 of the 326 patients (97%) included from 1997 to 1999, and the mean follow-up period was 679 ⫾ 185 days. Serious vascular events occurred in 34 patients (10%), including 4 of the 17 patients (23.5%; 95% confidence interval [CI], 6.8%– 49.9%) who were aspirin resistant and 30 of the 309 patients (9.7%; 95% CI, 6.6%–13.6%) who were not. Univariate analysis revealed that aspirin-resistant patients had a 3.1-fold increased hazard of meeting the composite end point of cardiac death, MI, or cerebrovascular accident compared with aspirin-sensitive patients (24% vs 10%; hazard ratio [HR], 3.1; 95% CI, 1.1– 8.9; p ⫽ 0.03). After adjusting for 12 potential prognostic factors, a multivariate analysis showed that aspirin resistance was associated with a 4.1-fold excess adjusted hazard of serious vascular events (HR, 4.1; 95% CI, 1.4 –12.1), independent of age, sex, and conventional vascular risk factors, suggesting that aspirin resistance is a significantly independent predictor of future major adverse outcomes. CAD: Similar adverse prognostic results have been observed in patients with CAD and aspirin resistance. In a 4-year retrospective cohort study of 129 post-MI patients, Andersen and colleagues33 noted a tendency toward a higher incidence of adverse vascular events in aspirin-resis-
tant patients than in aspirin-sensitive patients (36% vs 24%), although the difference did not reach statistical significance (p ⫽ 0.28). Chen and colleagues41 explored aspirin resistance in the setting of interventional cardiology. Using the VerifyNow Aspirin Assay, they categorized 151 patients with CAD who presented for nonurgent percutaneous coronary intervention into 2 groups, aspirin sensitive and aspirin resistant. They reported a 19.2% prevalence of aspirin resistance in this population. Despite adequate pretreatment with clopidogrel and procedural anticoagulation with heparin, aspirin-resistant patients had a 2.9-fold increased risk for creatine kinase–myocardial band (CK-MB) elevation compared with aspirin-sensitive patients. Troponin I elevations were in line with the findings on CK-MB. Thus, patients determined to be aspirin resistant with a bedside test were more likely to have postprocedural myonecrosis, including large CK-MB elevations. Using the same point-of-care assay to define aspirin resistance in 422 patients with stable CAD, the same group reported the results of a long-term follow-up study of this cohort.42 After a mean follow-up period of 379 ⫾ 200 days, patients with aspirin resistance were at increased risk for death, acute coronary syndromes, or stroke compared with patients who were aspirin sensitive (14.2% vs 5.2%; HR, 2.92; 95% CI, 1.50 –5.67; p ⫽ 0.002). Cox proportionalhazards regression modeling identified aspirin resistance, diabetes mellitus, previous MI, and a low hemoglobin level to be independently associated with major adverse longterm outcomes (HR for aspirin resistance, 2.71; 95% CI, 1.39 –5.28; p ⫽ 0.004). The results of prospective studies associating aspirin resistance with adverse clinical outcomes are summarized in Figure 1.
Conclusion Through this review of the literature we have a general understanding of aspirin and the resistance phenomenon in the field of cardiovascular disease. Aspirin is a traditional antiplatelet drug that is easy to give, is inexpensive, and has relatively few side effects at low doses. Furthermore, substantial evidence has proved that low-dose daily aspirin is an effective therapy for secondary prevention and high-risk primary prevention of atherothrombotic vascular events.30,43,44 Hence, in current clinical practice, aspirin is unlikely to ever be replaced as a firstline antiplatelet agent. However, the continuously incremental evidence presented in this review suggests that a substantial proportion of the population fails to show the anticipated response to daily aspirin intake; thus, the concept of aspirin resistance arises. However, some authorities take this phenomenon to represent only “treatment failure” rather than aspirin resistance, considering the lack of antiplatelet effect of aspirin in some patients to be a common phenomenon similar to other therapeutic drug failures (eg, lipid-lowering or antihypertensive drugs). Given the multifactorial nature of athero-
Cheng et al/Aspirin Resistance or Variable Response or Both?
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Figure 1. Prospective studies relating aspirin resistance to adverse clinical outcomes. ACS ⫽ acute coronary syndromes; CK-MB ⫽ creatine kinase– myocardial band; MI ⫽ myocardial infarction; PCI ⫽ percutaneous coronary intervention; PTA ⫽ percutaneous transluminal angioplasty.
thrombosis, it is not surprising that only a fraction (usually only 25%–33%) of all atherothrombotic complications can be prevented by any single preventive strategy.45 Although controversial, antithrombotic guidelines from the American College of Chest Physicians acknowledge the possibility of aspirin resistance.11 Moreover, it now appears that aspirin resistance is a clinically significant problem in the prevention of atherothrombotic complications. Several clinical trials demonstrating that aspirin resistance seems to be associated with poor clinical outcomes highlight this fact. Limitations of existing research: Despite our increasing understanding of aspirin resistance, the existing research presents a number of limitations. There is no consensus on a definition of aspirin resistance and on whether the definition should be based on clinical outcomes, laboratory evidence, or both, and there are no criteria for distinguishing true resistance from treatment failure. Numerous tests with varying methodologies, sensitivities, and specificities (and also their own limitations) have been used to assess platelet aggregation. Therefore, there is no accepted uniform measure for screening aspirin resistance in the clinical setting. The clearly elucidated biologic mechanisms for aspirin resistance are still unknown and probably multifactorial. Clinical outcome studies are limited by small sample sizes, varied definitions of aspirin resistance, and inadequate controlling of confounding variables by the study designs. The clinical application of aspirin resistance will require studies on larger populations that define antiplatelet resistance using consistent and reproducible assays and correlate the measurements with clinical outcomes that can be improved by alterations in antiplatelet strategy (eg, increasing the dose
of an antiplatelet agent, adding or substituting a second antiplatelet agent). New trials: Such prospective randomized trials are currently under way. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial compared clopidogrel and aspirin with placebo and aspirin for high-risk primary or secondary prevention. Urinary 11-dehydro-TXB2 levels were checked in a substudy, enabling the prospective assessment of the addition of clopidogrel to aspirin in reducing adverse events associated with aspirin resistance.46 The Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial (ASCET) is evaluating whether switching to clopidogrel will be superior to continued aspirin therapy in improving clinical outcomes in aspirin-resistant patients with angiographically documented CAD.47 The Research Evaluation to Study Individuals Who Show Thromboxane or P2Y12 Receptor Resistance (RESISTOR) trial will investigate whether modifying antiplatelet regimens could prevent myonecrosis after percutaneous coronary intervention in patients with aspirin and clopidogrel resistance. 1. Mason PJ, Freedman JE, Jacobs AK. Aspirin resistance: current concepts. Rev Cardiovasc Med 2004;5:156 –163. 2. Awtry EH, Loscalzo J. Aspirin. Circulation 2000;101:1206 –1218. 3. Cairns JA, Theroux P, Lewis HD, Ezekowitz M, Meade TW. Antithrombotic agents in coronary artery disease. Chest 2001;119:228S–252S. 4. Mehta P. Aspirin in the prophylaxis of coronary artery disease. Curr Opin Cardiol 2002;17:552–558. 5. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death,
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25. Chamorro A, Escolar G, Revilla M, Obach V, Vila N, Reverter JC, Ordinas A. Ex vivo response to aspirin differs in stroke patients with single or recurrent events: a pilot study. J Neurol Sci 1999;171:110 –114. 26. Roller RE, Dorr A, Ulrich S, Pilger E. Effect of aspirin treatment in patients with peripheral arterial disease monitored with the platelet function analyzer PFA-100. Blood Coagul Fibrinolysis 2002;13: 277–281. 27. Weksler BB, Kent JL, Rudolph D, Scherer PB, Levy DE. Effects of low dose aspirin on platelet function in patients with recent cerebral ischemia. Stroke 1985;16:5–9. 28. Taylor DW, Barnett HJ, Haynes RB, Ferguson GG, Sackett DL, Thorpe KE, Simard D, Silver SL, Hachinski V, Clagett GP, Barnes R, Spence JD, for the ASA and Carotid Endarterectomy (ACE) Trial Collaborators. Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. Lancet 1999;353:2179 –2184. 29. Johnson ES, Lanes SF, Wentworth CE, Satterfield MH, Abebe BL, Dicker LW. A metaregression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med 1999;159:1248 –1253. 30. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81–106. 31. Berglund U, Wallentin L. Persistent inhibition of platelet function during long-term treatment with 75 mg acetylsalicylic acid daily in men with unstable coronary artery disease. Eur Heart J 1991;12:428 – 433. 32. Macchi L, Christiaens L, Brabant S, Sorel N, Allal J, Mauco G, Brizard A. Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate. Thromb Res 2002; 107:45– 49. 33. Andersen K, Hurlen M, Arnesen H, Seljeflot I. Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease. Thromb Res 2002;108:37– 42. 34. Grundmann K, Jaschonek K, Kleine B, Dichgans J, Topka H. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks. J Neurol 2003;250:63– 66. 35. Mueller MR, Salat A, Stangl P, Murabito M, Pulaki S, Boehm D, Koppensteiner R, Ergun E, Mittlboeck M, Schreiner W, Losert U, Wolner E. Variable platelet response to low-dose ASA and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty. Thromb Haemost 1997;78:1003–1007. 36. Hurlen M, Seljeflot I, Arnesen H. The effect of different antithrombotic regimens on platelet aggregation after myocardial infarction. Scand Cardiovasc J 1998;32:233–237. 37. Grotemeyer KH. Effects of acetylsalicylic acid in stroke patients: evidence of nonresponders in a subpopulation of treated patients. Thromb Res 1991;63:587–593. 38. Zhao L, Bath P, Heptinstall S. Effects of combining three different antiplatelet agents on platelets and leukocytes in whole blood in vitro. Br J Pharmacol 2001;134:353–358. 39. Wang JC, Aucoin-Barry D, Manuelian D, Monbouquette R, Reisman M, Gray W, Block PC, Block EH, Ladenheim H, Simon DI. Incidence of aspirin nonresponsiveness using the Ultegra Rapid Platelet Function Assay-ASA. Am J Cardiol 2003;92:1492–1494. 40. Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003;41:961–965. 41. Chen WH, Lee PY, Ng W, Tse HF, Lau CP. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol 2004;43:1122–1126. 42. Chen WH, Cheng X, Lee PY, Ng W, Kwok YY, Lau CP. Prevalence, profile, predictors and natural history of aspirin resistance measured by the Ultegra Rapid Platelet Function Assay-ASA in
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46. Bhatt DL, Topol EJ. Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Am Heart J 2004;148:263–268. 47. Pettersen AA, Seljeflot I, Abdelnoor M, Arnesen H. Unstable angina, stroke, myocardial infarction and death in aspirin non-responders: a prospective, randomized trial. The ASCET (ASpirin non-responsiveness and Clopidogrel Endpoint Trial) design. Scand Cardiovasc J 2004;38:353–356.