Letter by Dong et al Regarding Article, “CYP2C19 Polymorphisms and Antiplatelet Effects of Clopidogrel in Acute Ischemic Stroke in China”
To the Editor:
With interest we read the article by Jia et al1 in which they investigated the CYP2C19 polymorphisms and antiplatelet effects of clopidogrel in acute ischemic stroke in China. They revealed the correlation between CYP2C19 genotype and neurological function of stroke patients. The authors proposed that patients with none had better outcomes than patients with CYP2C19 loss-of-function alleles, as demonstrated by the National Institute of Health Stroke Scale and the modified Rankin scale scores after treatment.
As was known, clopidogrel therapy can prevent stroke patients from recurrent ischemic strokes by inhibiting ADP. Recently, nonresponsiveness is widely recognized and is related to raising rates of recurrent ischemic events and all causes of death.2,3 Cayla et al3 identified CYP2C19 polymorphisms and its loading dose were independently associated with early stent thrombosis. Furthermore, patients with the CYP2C19*2 variant were more likely to have an ischemic event or death during 1 year of follow-up.2 Mega et al4 published a meta-analysis of 9 studies evaluating CYP2C19 genotype and cardiovascular outcomes in 9685 patients treated with clopidogrel. There was a trend toward increased risk of nonfatal ischemic stroke associated with carriers of ≥1 reduced-function allele; however, because of the low rate of recurrent stroke events in the study cohort, this was not statically significant. Studies revealed that the CYP2C19*2 genotype was associated with diminished clopidogrel response2–4; however, whether the diminished response in stroke patients was correlated with more recurrent ischemic events was unknown.
In our ongoing study, we recorded both uninhibited baseline platelet functional response to ADP and inhibited response after clopidogrel treatment using recurrent vascular events, such as ischemic stroke, transient ischemic attack, myocardial infarction, and other vascular disease as primary end points. However, Jia et al1 used National Institute of Health Stroke Scale and modified Rankin scale scores to evaluate the effect of clopidogrel treatment, which we think is inappropriate. The scores could well demonstrate the improvement of neurological function but is hardly correlated with the effect of clopidogrel treatment. We assume that because of the small number of patients recruited and short time of follow-up, Jia et al1 might be unable to find significant differences in stroke recurrence among different CYP2C19 polymorphisms.
We agree with idea of Bennett and Yan5 that an underlying cause for suboptimal platelet inhibition is varying response to clopidogrel, which is linked to polymorphisms in the CYP2C19 gene responsible for the metabolism and activation of clopidogrel. So far, there were no significant differences in the average uninhibited baseline platelet functional response to ADP between responders and nonresponders, and no significant correlation among clinical variables was found with nonresponder status. Currently, there is no definitive evidence linking ex vivo platelet aggregation measurements to clinical outcomes. Furthermore, it is unclear how patients should be managed based on these test results. Our ongoing study is investigating the clinical outcomes of CYP2C19 genotyping to inform decision making in secondary stroke prevention.
Yi Dong, MD
XinCheng, MD, PhD
QiangDong, MD, PhD
Department of Neurology
All authors have made substantial contributions in the article. We appreciated Dr Ding Hongyan, who took part in designing on ongoing clinical trial and given some suggestion to authors.
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- © 2013 American Heart Association, Inc.
- Jia DM,
- Chen ZB,
- Zhang MJ,
- Yang WJ,
- Jin JL,
- Xia YQ,
- et al
- Bennett D,
- Yan B