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Background-The antiplatelet effect of aspirin is attributed to platelet cyclooxygenase-1 inhibition. Controversy exists on the prevalence of platelet resistance to aspirin in patients with coronary artery disease and effects of aspirin dose on inhibition. Our primary aim was to determine the degree of platelet aspirin responsiveness in patients, as measured by commonly used methods, and to study the relation of aspirin dose to platelet inhibition. Methods and Results-We prospectively studied the effect of aspirin dosing on platelet function in 125 stable outpatients with coronary artery disease randomized in a double-blind, double-crossover investigation (81, 162, and 325 mg/d for 4 weeks each over a 12-week period). At all doses of aspirin, platelet function was low as indicated by arachidonic acid (AA)-induced light transmittance aggregation, thrombelastography, and VerifyNow. At any 1 dose, resistance to aspirin was 0% to 6% in the overall group when AA was used as the agonist, whereas it was 1% to 27% by other methods [collagen and ADP-induced light transmittance aggregation, platelet function analyzer (PFA-100)]. Platelet response to aspirin as measured by collagen-induced light transmittance aggregation, ADP-induced light transmittance aggregation, PFA-100 (81 mg versus 162 mg, PՅ0.05), and urinary 11-dehydrothromboxane B 2 was dose-related (81 mg versus 325 mg, Pϭ0.003). No carryover effects were observed. Conclusions-The assessment of aspirin resistance is highly assay-dependent; aspirin is an effective blocker of AA-induced platelet function at all doses, whereas higher estimates of resistance were observed with methods that do not use AA as the stimulus. The observation of dose-dependent effects despite nearly complete inhibition of AA-induced aggregation suggests that aspirin may exert antiplatelet properties through non-cyclooxygenase-1 pathways and deserves further investigation. (Circulation. 2007;115:3156-3164.)

appears concerned about the uniform inhibition of arachidonic acid-induced aggregation observed in the AspirinInduced Platelet Effect (ASPECT) trial. We would like to reassure Dr Klein that the compliance of the patients in ASPECT was meticulously recorded and, as reported in the manuscript, was overall 98%. Dr Klein should also be aware of the significance of results determined by double crossover studies such as the ASPECT study and the robust statistical analyses performed. 1 Why were we not surprised by the results of the ASPECT study? In a previous study of 223 patients undergoing stenting who were treated with long-term aspirin therapy, only 1 compliant patient was resistant as determined by cyclooxygenase-1 (COX-1)-specific assays and arachidonic acid-induced aggregation in plasma and in whole blood. Interestingly, all of the noncompliant patients (3%) had high arachidonic acid-induced aggregation, suggesting the presence of "resistance," but exhibited low arachidonic acid-induced aggregation after in-hospital treatment. 2 Therefore, the message of the study Tantry et al 2 and of the ASPECT trial is that aspirin responsiveness is very high when assessed by arachidonic acidbased assays in compliant patients. Moreover, the ASPECT study demonstrates the uniformity of this property irrespective of the aspirin dose. Therefore, the our data are not "overshot." Rather, they demonstrate an important physiological effect of aspirin, that is, near uniform and potent inhibition of COX-1. A recent study by others has demonstrated concordant findings. 3 We agree that noncompliance is an important issue with any pharmacological therapy. On the basis of our data, arachidonic acid-induced platelet aggregation is a good barometer of patient compliance with aspirin and probably other drugs, as patients who are noncompliant with aspirin may also be more likely to be noncompliant with their other prescribed medications.The second important message from the ASPECT study relates to the potential antiplatelet effects of aspirin mediated by non-COX-1 pathways assessed by stimulating platelets with agonists other than arachidonic acid. We are glad that Dr Klein has also raised this issue. This is indeed a novel idea with potential clinical implications, as recent studies have demonstrated the association of adverse clinical events with "aspirin resistance" measured by a method that is not solely dependent on COX-1 activity. 4 In our article, we state that "The observation of dose-related effects despite near-complete inhibition of arachidonic acid-induced aggregation suggests that aspirin may also exert antiplatelet effects through non-COX-1 pathways" (p 3163). Clearly, we are hypothesizing a novel antiplatelet effect of aspirin that should be the focus of future research, especially in diabetic patients where the dose-dependent antiplatelet effects of aspirin may be more pronounced. 5 It took at least 70 years to determine that aspirin inhibits platelet function by acetylating COX-1 and that aspirin can be used as an effective a...

Pharmacological management of thrombotic complications is strongly influenced by antiplatelet treatment strategies. Recent clinical trials have clearly indicated that current antiplatelet strategies may not inhibit recurrent thrombotic events in selected patients and improvement is necessary. Recently, there has been a gradual modification in the guidelines for clopidogrel dosing. In addition, newly developed P2Y(12) receptor inhibitors and thrombin inhibitors are undergoing Phase II and III clinical trials. Moreover, research related to novel agents that interfere with other steps in coagulation and platelet adhesion, and platelet thromboxane and thrombin receptor blockers, show promise. An important future step will probably be the development of personalized therapy based on defining the individual patient's propensity for thrombosis through investigation of platelet-thrombin-fibrin interactions. Such an approach will enhance the targeting of specific therapy based on the pathophysiology of the individual patient.

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