Genetic Testing to Guide Clopidogrel Treatment in Stroke/TIA?

July 05, 2016

Among patients with minor ischemic stroke or transient ischemic attack (TIA), clopidogrel does not appear to give additional benefit over aspirin in terms of reduced risk for new stroke in patients carrying the CYP2C19 loss-of-function genes, a new study shows.

"This study provided evidence supporting genetic testing that may allow clinicians to personalize antiplatelet therapy, especially in East Asian patient populations for whom the prevalence of CYP2C19 loss-of-function allele is high," the authors conclude.

The analysis, a substudy of the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial, was published online June 23 in JAMA.

The CHANCE trial was conducted in a Chinese population and study coauthor S. Claiborne Johnston, MD, University of Texas at Austin, told Medscape Medical News that the results probably need to be confirmed in other populations.

"I think the findings are highly suggestive, but I'd like to see the results confirmed in another population," he said.

Dr Johnson explained that the current testing takes too long to affect treatment decisions immediately after stroke/TIA but could still be useful for guiding longer-term therapy.

"At present it takes 3 days to get the results back, so many of the events that could have been prevented have already occurred. But for those taking long-term clopidogrel, I think it's quite reasonable to check for presence of these polymorphisms," he said.

In the JAMA paper, the authors, led by Yilong Wang, MD, Beijing Tiantan Hospital, China, note that clopidogrel, in combination with aspirin, has become a recommended treatment option for patients with TIA or acute minor stroke, following the results of the CHANCE trial. This showed that the combination of clopidogrel and aspirin, compared with aspirin alone, reduced the risk for stroke in patients treated within 24 hours after the onset of a TIA or minor stroke.

However, clopidogrel requires conversion to an active metabolite by hepatic cytochrome p450 (CYP) isoenzymes to exert an antiplatelet effect, and certain polymorphisms of the CYP2C19 gene have been identified as predictors of clopidogrel nonresponsiveness. There have been conflicting results on the association between CYP2C19 loss-of-function alleles and the clinical efficacy of clopidogrel.

Dr Wang and colleagues point out that very limited data are available addressing the effect of CYP2C19 variants on clopidogrel efficacy in stroke, especially in Asian populations, in which the rates of stroke incidence and mortality are higher than those in white populations. The prevalence of CYP2C19 loss-of-function variants is also high in Asian populations.

They add that in China, approximately 3 million new strokes Occur every year, and approximately 30% of them are minor ischemic strokes. TIA is even more common, with an estimated 24 million occurring each year.

"Understanding the relationship between CYP2C19 variants and clinical effect of clopidogrel is critically important to optimize treatment for patients with minor stroke or TIA," the authors write.

For the substudy, three CYP2C19 major alleles (*2, *3, and *17) were genotyped among 2933 Chinese patients who were enrolled in the CHANCE trial.

Results showed that 1726 patients (58.8%) were carriers of loss-of-function alleles (*2, *3).

At 90 days of follow-up, among noncarriers of the loss-of-function alleles the primary endpoint of new stroke had occurred in 6.7% of those receiving clopidogrel-aspirin vs 12.4% of those receiving aspirin alone, a hazard ratio of 0.51 (95% confidence interval [CI], 0.35 - 0.75).

But in carriers of the loss-of-function alleles, new stroke had occurred in 9.4% of those taking clopidogrel plus aspirin vs 10.8% of those on aspirin alone, a hazard ratio of 0.93 (95% CI, 0.69 - 1.26).

The interaction between the two groups of patients was statistically significant. (P = .02).

Results were similar for the secondary composite efficacy outcome (ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death).

There was no significant difference in bleeding between the carriers and the noncarriers of the loss-of-function alleles (2.3% for carriers and 2.5% for noncarriers in the combination group vs 1.4% for carriers and 1.7% for noncarriers in the aspirin-only group; P = .78 for interaction).

Dr Wang and coauthors suggest that these results support genetic testing to identify carriers of the clopidogrel loss-of-function alleles, especially in East Asian populations.

They point out that the frequency of CYP2C19 loss-of-function alleles in this study was high at 58.8%, but this is similar to other estimates in other East Asian populations. Other populations appear to have a lower frequency of these loss-of-function genes, with estimates ranging from 18% in Mexicans to 33% in African Americans.

They add that it will be important to compare the association of CYP2C19 variants with efficacy of clopidogrel in a different population before applying these results to non-Asian populations, particularly given the variability in results of cardiovascular studies.

They note that the question arises as to how to treat these patients because clopidogrel is the only approved antiplatelet agent adjunct to aspirin after stroke or TIA, "so there is no existing alternative in the acute period."

They suggest that varying the dose of clopidogrel or switching to one of the newer antiplatelet agents (eg, prasugrel) on the basis of genetic results may be alternatives, but these options have not been adequately evaluated.

They report that some additional information will come from the National Institutes of Health–sponsored POINT trial, which is assessing a higher loading dose of clopidogrel (600 mg) and a narrower time window (treatment within 12 hours after symptom onset).

The CHANCE study was supported by grants from the Ministry of Science and Technology of the People's Republic of China, the Beijing Biobank of Cerebral Vascular Disease, the Beijing Institute for Brain Disorders, the National Natural Science Foundation of China, the China Postdoctoral Science Foundation, the Natural Science Foundation of Fujian Province, the Beijing Municipal Science and Technology Commission, and the Shanghai Municipal Commission of Health and Family Planning. Dr Johnston reports receiving support from Sanofi and AstraZeneca. The other authors have disclosed no relevant financial relationships.

JAMA. Published online June 23, 2016. Abstract

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