Genetic variation in young heart attack patients makes anti-clotting drug clopidogrel less effective

December 22, 2008

If a young heart attack patient (under 45 years of age) has a certain genetic variation, the anticlotting drug clopidogrel is less effective in that person and they are much more likely to die, have another heart attack, require urgent repeat coronary intervention or have stent thrombosis. These are the conclusions of authors of an Article published Online first and in an upcoming edition of The Lancet, written by Dr Gilles Montalescot, Hôpital Pitié-Salpêtrière, Paris, France, and colleagues.

Clopidogrel and low-dose aspirin have become the mainstay oral treatments to prevent recurrent blood vessel blockages in patients who have suffered heart attacks and/or had stents implanted. Variability in the gene encoding the cytochrome P450 2C19 enzyme is thought to contribute to the effectiveness of clopidogrel as an anticlotting (antiplatelet) agent. This enzyme is vital in a biochemical pathway which converts clopidogrel from its original form to an active metabolite. The authors investigated whether variation in this gene affected long-term prognosis of young heart attack patients (aged <45 years) who were chronically treated with clopidogrel.

Between 1996 and 2008, 259 patients who survived a first heart attack and were exposed to clopidogrel treatment for a least a month had their genetic status with respect to the above gene investigated. 73 (28%) of the patients were carriers of the gene variation, the 186 were non-carriers -- the authors say this is typical of western populations, while in Asia an even higher proportion of patients carry the variation. Median clopidogrel exposure was just over a year, and patients were then followed-up every six months. Carriers of a particular variation at position 681 on the gene (where adenine replaced guanine on the DNA) were more than three-and-a-half times more likely to either die, have another heart attack or need urgent repeat coronary intervention. When looked at alone, stent blockage (thrombosis) was six times more likely to occur in patients with the variation. The detrimental effect of the variation also persisted from the initiation of clopidogrel treatment until the end of follow-up, up to eight years later. Furthermore, after a statistical analysis in which all possible variables were accounted for, the carrying of this genetic variation was the only independent predictor of cardiovascular events, with carriers four times more likely to experience an event than non-carriers.

The authors conclude: "Our study shows a strong relation between the presence of the CYP2C19*2 allelic variant and recurrent thrombotic coronary events in clopidogrel-treated patients predominantly of European ancestry who survived a heart attack before 45 years of age. Whether the prognostic information associated with the CYP2C19*2 genotype can also be used to guide management of these patients needs to be investigated further. These findings need to be independently replicated...before being extrapolated to older patients or those of non-European ancestry."

In an accompanying Comment, Dr Robert F Storey, Cardiovascular Research Unit, University of Sheffield School of Medicine, UK, says: "Although the fascinating observations of Montalescot and co-workers focus attention on the importance of factors that influence the response to clopidogrel, genotyping of patients with acute coronary syndrome is not necessarily the appropriate solution without further work to validate such an approach."
Dr Gilles Montalescot, Hôpital Pitié-Salpêtrière, Paris, France T) + 33 6 12 59 23 26 E)

Dr Robert F Storey, Cardiovascular Research Unit, University of Sheffield School of Medicine, UK T) +44 (0) 114 2713964 E)

Full Article and Comment: :


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