CYP2C19 gene variants undermine clopidogrel stroke prevention

By Eleanor McDermid

The first look at CYP2C19 mutations in the context of a randomised controlled trial has confirmed suspicions that they affect the efficacy of clopidogrel in patients with acute stroke.

As reported in JAMA, the preplanned secondary analysis of patients from the CHANCE trial shows that carriers of the two loss-of-function alleles derived no benefit from the addition of clopidogrel to aspirin during the 90 days following an ischaemic stroke or transient ischaemic attack (TIA).

The 1207 patients with the CYP2C19*17 allele benefited from clopidogrel, with a recurrent stroke rate of 6.7% versus 12.4% among those taking aspirin only. But the 1726 carriers of the loss-of-function *2 or *3 alleles gained no benefit, with stroke rates of 9.4% among those taking clopidogrel plus aspirin and 10.8% among those taking aspirin alone.

The findings were the same for the composite endpoint, which also included haemorrhagic stroke, myocardial infarction and vascular death. Bleeding risk with dual-antiplatelet treatment was unaffected by CYP2C19 genotype.

The CHANCE trial participants were all Chinese, and were randomly assigned to receive aspirin with or without clopidogrel within 24 hours of stroke or TIA. CYP2C19*2 was the most common allele in this population, occurring in 52.5% of the patients, and 9.0% carried the CYP2C19*3 allele.

This overall frequency of 58.8% (a few patients carried both alleles) is in line with that previously reported in East Asian populations, say Yongjun Wang (Beijing Tiantan Hospital, China) and co-researchers, and substantially higher than the frequencies reported for other ethnicities, which range from 18% to 33%.

The high prevalence of these loss-of-function alleles did not completely obscure the benefits of clopidogrel, with stroke risk reduced by 29% in the overall population. But the reduction was markedly greater in patients without the alleles, at 48% compared with a nonsignificant 7% to 16% in those with the alleles.

"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", say the researchers.

However, they note that "clopidogrel is currently the only approved antiplatelet agent adjunct to aspirin after stroke or TIA, so there is no existing alternative in the acute period."

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