European Heart Journal Advance Access published online on February 8, 2007
European Heart Journal, doi:10.1093/eurheartj/ehl500
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Variability in response to clopidogrel: where is the threshold for ‘low response’?: reply
Medizinische Klinik III
Department of Cardiology
University Hospital Tuebingen
Tuebingen
Germany
E-mail address: tobias.geisler{at}email.de
Medizinische Klinik III
Department of Cardiology
University Hospital Tuebingen
Tuebingen
Germany
We appreciate to read Dr Komócsís comments to our article entitled ‘Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation’.
He critically remarked the mortality rate in our study. Indeed, we found an all-cause mortality of 5.2% within 3 months (cardiovascular mortality: 3.9%). However, it is worthy to note that we investigated an unselected patient collective with moderate- to high-risk patients. In this context, around 45% of the initially enrolled patients were admitted with acute coronary syndromes and 21% had a STEMI.
The quoted meta-analysis of randomized stent trials by Nordmann et al. that was recently published in European Heart Journal provides a systematic overview mainly over trials that excluded patients with acute myocardial infarction like the RAVEL-trial.1 In fact, in studies describing a strictly elective setting the mortality is lower. To our opinion the mortality-rate observed in our patient cohort lies within the range reported in previous multicentre PCI studies including a similar risk collective. In trials with acute interventions, the mortality is comparable with or even higher than the mortality in our patient cohort. In PCI-CURE, 2658 patients with NSTEMI-ACS were enrolled, 4.5% had suffered a cardiovascular death after 30 days (all-cause mortality was even higher) and 6.0% at the end of follow-up (mean follow-up period 8 months).2 In ISAR-REACT II of 2022 patients with NSTEMI-ACS, around 1.4% of the patients (1.6% in the placebo group) had died after 30 days.3 Given the heterogeneity of the setting of our study including an important number of high-risk patients, and considering the follow-up period of 3 months, the mortality we reported is therefore reasonable and to our opinion in agreement with the literature. Besides, in many studies, the adoption of rigid criteria for randomization resulted in the exclusion of many patients at high risk of adverse events.
In addition, Dr Komócsi remarked the possible bias of acute coronary syndromes on the worse cardiovascular outcome of low responders to clopidogrel in our study. Concerning the prognostic influence of acute coronary syndrome in the low-responder group, we cannot neglect that patients with ACS show an increased a priori risk for recurrent cardiovascular events. However, when compared with other relevant factors in multivariable Cox regression analysis, low response and left ventricular dysfunction were independently associated with composite events within 3 months. Future trials will have to show that response to antiplatelet therapy has an essential impact on the prognosis of ACS patients. In this context, Cuisset et al.4 observed a significantly higher rate of cardiovascular events in NSTEMI-ACS patients who had a residual platelet aggregation of > 70%. Furthermore, the author of the letter raised the question concerning the proper cut-off value. In the past, multiple definitions on the basis of different methods have been adopted to characterize response to antiplatelet therapy with clopidogrel (difference of pre- and post-treatment platelet activity < 10%, platelet aggregation in the upper quartile, residual platelet activity > 70%).4–6 However, there is a growing agreement that independently from definition, a high degree of remaining platelet activity has a relevant impact on cardiovascular outcome of coronary stent patients. Since we learn more and more about the importance of antiplatelet drug response, it should be the aim to develop a consensual method that on the one hand is practicable in clinical routine and on the other hand helps to identify patients at increased risk for cardiovascular events. Our aim was to evaluate the risk in patients with very high residual platelet aggregation (late ADP 20 µmol/L induced platelet aggregation > 70%). It might be for the patients' sake to lower this cut-off value (median) to segregate low responders from responders. However, if around half of the patients are not optimally treated and therefore might benefit from an intensified antiplatelet therapy in terms of better clinical prognosis has to be critically evaluated.
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