doi: 10.1161/CIRCULATIONAHA.107.740928
(Circulation. 2008;117:e22.)
© 2008 American Heart Association, Inc.
Correspondence |
Response to the Letter Regarding Article, "Evaluation of Dose-Related Effects of Aspirin on Platelet Function: Results From the Aspirin-Induced Platelet Effect (ASPECT) Study"
Sinai Center for Thrombosis Research, Baltimore, Md
Department of Mathematics and Statistics, University of Maryland Baltimore County, Baltimore, Md
Dr Klein appears concerned about the uniform inhibition of arachidonic acid–induced aggregation observed in the Aspirin-Induced 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 al2 and of the ASPECT trial is that aspirin responsiveness is very high when assessed by arachidonic acid–based 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 antithrombotic agent. However, we must ask ourselves whether the evidence supports COX-1 inhibition as the sole mechanism to explain the antiplatelet effect of aspirin. Hopefully, it will take less than 70 years to answer this important question and others related to aspirin dosing, as well as to elucidate the clinical relevance of measuring platelet function in the individual patient.
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Disclosures
Dr Gurbel has received research grants and honoraria from Hemoscope, AstraZeneca, Schering-Plough, Medtronic, Lilly/Sankyo, Sanofi, Boston-Scientific, and Bayer. The remaining authors report no conflicts.
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 Top References |
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1. Gurbel PA, Bliden KP, DiChiara J, Newcomer J, Weng W, Neerchal NK, Gesheff T, Chaganti SK, Etherington A, Tantry US. Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation. 2007; 115: 3156–3164.
2. Tantry US, Bliden KP, Gurbel PA. Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol. 2005; 46: 1705–1709.
3. Lordkipanidze M, Pharand C, Schampaert E, Turgeon J, Palisaitis DA, Diodati JG. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J. 2007; 28: 1702–1708.
4. Marcucci R, Paniccia R, Antonucci E, Gori AM, Fedi S, Giglioli C, Valente S, Prisco D, Abbate R, Gensini GF. Usefulness of aspirin resistance after percutaneous coronary intervention for acute myocardial infarction in predicting one-year major adverse coronary events. Am J Cardiol. 2006; 98: 1156–1159.[CrossRef][Medline] [Order article via Infotrieve]
5. DiChiara J, Bliden KP, Tantry US, Hamed MS, Antonino MJ, Suarez TA, Bailon O, Singla A, Gurbel PA. The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients: an analysis from the Aspirin-Induced Platelet Effect (ASPECT) study. Diabetes. 2007; 56: 3014–3019.[CrossRef][Medline] [Order article via Infotrieve]
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