Antiplatelet therapy with Plavix (clopidogrel) and aspirin is no better than aspirin alone for reducing stroke risk immediately following minor stroke or transient ischemic attack (TIA) in patients who are carriers of the CYP2C19 loss-of-function allele, researchers are reporting.
Their analysis of data from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Event (CHANCE) trial found that among patients with minor stroke or TIA, adding clopidogrel to aspirin therapy reduced the risk for new stroke only in patients who were not carriers of the allele.
The findings suggest that GYP2C19 genotyping could be a useful strategy for identifying patients with minor stroke or TIA who will benefit from the combination treatment, wrote Yong-Jun Wang, MD, of Capital Medical University in Beijing, China, and colleagues. The study was published online June 23 in the Journal of the American Medical Association.
The findings are particularly relevant for Asian patients, who have a higher prevalence of CYP2C19 loss-of-function alleles than other populations do. The frequency was 58.8% among the 2,933 CHANCE participants included in the newly reported analysis, which is similar to that reported in other East Asian populations, the researchers noted.
"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 team added that while clopidogrel is currently the only antiplatelet drug approved for use with aspirin to reduce future stroke risk immediately following minor stroke or TIA, new antiplatelet agents may prove to be more effective in carriers of the CYP2C19 loss-of-function alleles.
"Varying the dose of clopidogrel or shifting to new antiplatelet agents (e.g., prasugrel) based on genetic results may be alternatives but have not been adequately evaluated," Wang et al said.
Findings from the CHANCE study, which were originally published in July 2013, showed the combination of clopidogrel plus aspirin to be more effective than aspirin alone for reducing future stroke risk in patients with minor stroke or TIA treated within 24 hours of the onset of symptoms.
Polymorphisms of the CYP2C19 gene have been identified in past studies as predictors of lack of response to clopidogrel. In this new subanalysis of the CHANCE data, the researchers sought to determine if variations in the CYP2C19 gene modify responses to the drug in this patient population.
Among the 2,933 patients, 1,948 (66.4%) were men, with a mean age of 62.4. Overall, 1,207 patients (41.2%) were noncarriers of CYP2C19 loss-of-function alleles (*2, *3), and 1,726 (58.8%) were carriers.
The primary outcome was the development of new stroke events; secondary outcome was a composite of vascular events (ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death).
At 90-day follow-up, use of clopidogrel-aspirin reduced the rate of new stroke in the noncarriers but not in the carriers of the loss-of-function alleles.
Specifically:
- There were 41 events among noncarriers (6.7%) with use of clopidogrel-aspirin versus 74 events (12.4%) with aspirin -- HR, 0.51 (95% CI, 0.35-0.75);
- There were 80 events among carriers, (9.4%) with clopidogrel-aspirin versus 94 events (10.8%) with aspirin -- HR, 0.93 (95% CI, 0.69-1.26);
- Similar results were seen for the secondary composite efficacy outcome -- noncarriers: 41 (6.7%) with clopidogrel-aspirin versus 75 (12.5%) with aspirin; HR, 0.50 (95% CI, 0.34-0.74); carriers: 80 (9.4%) with clopidogrel-aspirin versus 95 (10.9%) with aspirin alone; HR, 0.92 (95% CI, 0.68-1.24); and
- The effect of treatment assignment on bleeding did not vary significantly between the carriers and the noncarriers of the loss-of-function alleles (2.3% among carriers and 2.5% among noncarriers in the clopidogrel-aspirin group versus 1.4% among carriers and 1.7% among noncarriers in the aspirin-only group).
The researchers noted that since the CHANCE study included only patients living in China, the findings may not be relevant to non-Asian populations. A trial similar to CHANCE, currently enrolling patients in North American and Europe, may shed some light on this: That study, the Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT) trial, which is sponsored by the National Institutes of Health, is designed to assess the benefits of 600 mg of clopidogrel within 12 hours of symptom onset in patients with minor stroke or TIA.
"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," Wang and colleagues wrote.
Funding for this research was provided by the Ministry of Science and Technology of People's Republic of China, the Beijing Biobank of Cerebral Vascular Disease, the Beijing Institute for Brain Disorders, and others.
The principal researchers reported no relevant relationships with industry.
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