European Heart Journal Advance Access originally published online on February 22, 2007
European Heart Journal 2007 28(5):641-642; doi:10.1093/eurheartj/ehl522
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Acute coronary syndromes, response to clopidogrel, and worsened cardiovascular outcomes: the hen and the egg dilemma: reply
Medizinische Klinik III
Department of Cardiology
University Hospital Tuebingen
Tuebingen
Germany
Medizinische Klinik III
Department of Cardiology
University Hospital Tuebingen
Tuebingen
Germany
E-mail address: meinrad.gawaz{at}medl.med.tu-muenchen.de
We thank Dr Serebruany for his interest and careful reading of our article entitled "Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation".
He critically remarked the influence of acute coronary syndromes (ACS) on response to clopidogrel in our patient cohort. We agree with Dr Serebruany that acute coronary events may have substantial influence on measured platelet activity and, of course, also influence cardiovascular outcome. The very justified comment is supported by previous clinical studies.1,2
Our aim of the present manuscript was to provide data on platelet response after administration of 600 mg loading dose of clopidogrel in an unselected consecutive patient cohort undergoing coronary stenting and to investigate its association on cardiovascular outcome. The measurement was done in a clinically practical way by a single measurement. We found that patients identified as low responders showed an increased incidence of cardiovascular events within 3 months. In univariate analysis we found ACS to be significantly associated with low response to clopidogrel. We agree that the lower response of platelet inhibition in ACS may be related to a higher degree of platelet activation. However, multivariate analysis of potential variables that may influence cardiovascular outcome including ACS shows that low response to clopidogrel and severe left ventricular dysfunction was independently associated with adverse cardiovascular events.
We are absolutely aware that multiple factors may have an impact on response to clopidogrel, which were not regarded in this study and that low response cannot be considered as a sole risk factor for cardiovascular events. However, the published data suggest that residual platelet activity after administration of 600 mg clopidogrel loading dose represents an additional risk factor for recurrent cardiovascular events and that point-of-care testing of platelet function detects patients at risk for upcoming cardiovascular events. Besides, the data fit well to previously published data on the clinical relevance of response to clopidogrel measured by platelet function tests.3 In the study by Matetzky et al.4 high-risk patients with acute myocardial infarction who received eptifibatide for 14 ± 2 h, clopidogrel-resistant patients expected an increased risk of atherothrombotic events despite intensive antithrombotic treatment by GPIIb-IIIa antagonists.
Importantly, the aim of the presented study was not to question the benefits of a dual antiplatelet therapy in cardiovascular risk patients as already proved by several studies including the CURE trial and the quoted COMMIT trial. As demonstrated by the relatively small proportion of low responders in our patient cohort, our results do not stand in contradiction to the previous data showing the effectiveness of clopidogrel therapy. An additional critical point mentioned is the random time-point chosen for measurement. In real clinical practice it is not practical to assess platelet function at a specific point of time ± few hours. Therefore, we chose a time-point when maximum platelet inhibition is achieved (>2 h) after the first administration of a loading dose of 600 mg clopidogrel.5 After this time-point we (Figure 1) and others6 did not reveal further attenuation of clopidogrel-dependent platelet inhibition. This is not only true for the total patient cohort but also for the subgroup of patients with ACS. In summary, on behalf of the present and previously published data we think that a single post-treatment platelet function test can be of help to identify risk patients independently from ACS.7 Therefore, assessment of post-treatment platelet activity may help to further improve post-interventional antiplatelet therapy and may point to the necessity of individualized antiplatelet therapy. This has to be verified, however, in clinical trials.
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References
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[Abstract/Free Full Text] - Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. (2004) Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 109:3171–3175.
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[Free Full Text] - Hochholzer W, Trenk D, Frundi D, Blanke P, Fischer B, Andris K, Bestehorn HP, Buttner HJ, Neumann FJ. (2005) Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 111:2560–2564.
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