Dabigatran exposure may RE-LY on genetics

By Piriya Mahendra, medwireNews Reporter

Researchers have found that variants in the ABCB1 and CES1 genes are associated with increased dabigatran plasma levels in patients taking the oral anticoagulant.

Guillaume Pare (McMaster University, Ontario, Canada) reported the findings of the RE-LY Genetics trial at the European Society of Cardiology Congress in Munich, Germany. His team found that the ABCB1 single-nucleotide polymorphism (SNP) rs4148738 was associated with a 12% increase in peak dabigatran concentration per minor allele carried, while the CES1 SNP rs8192935 was associated with a significant decrease in peak dabigatran concentration per minor allele.

Pare told medwireNews: "Potentially, genetic information could be used to select the optimal safest dose of dabigatran. When we put things into perspective, there are a few risk factors for bleeding. Age and dabigatran dose are two of those risk factors.

"However, we do find a significant association with bleeds even after adjusting for these factors. Perhaps individuals known to have the protective genotype could safely use the highest dose of dabigatran which is known to reduce ischemic events further."

Two CES1 polymorphisms were associated with the trough concentration of plasma dabigatran. The lead polymorphism rs4580160 was linked to a 13% decrease in trough dabigatran levels per minor allele.

Further analysis showed many different polymorphisms were associated with dabigatran peak concentrations at the ABCB1 locus "confirming the presence of a strong genetic signal at this gene locus," said Pare. "Similar results were found for association of peak concentration at the CES1 locus and again for trough concentration at the CES1 locus."

When assessing the ABCB1 rs4148738, CES1 rs8192935, and CES1 rs2244613 polymorphisms for associations with events using logistic regression analysis, there was no significant association between the ABCB1 or CES1 polymorphisms and peak dabigatran concentration.

However, there was a significant association between the CES1 polymorphism rs2244613 and trough concentration and the risk for bleeding, at an odds ratio of 0.67 per minor allele carried. A consistent and statistically significant association was found with minor bleeding, at an odds ratio of 0.70, and a consistent but nonsignificant association was seen with major bleeding. However, no association was observed between the CES1 polymorphism rs2244613 and ischemic stroke or systemic embolism.

Pare said that more work is needed before genetic considerations can be considered a part of clinical decision making in patients undergoing dabigatran treatment.

"The first step will be to replicate these results in other populations so we can have a better idea of how we can implement this in the clinic. This is from a research point of view, and from a practice point of view there exist all the issues of how to implement genetic testing in clinical labs and clinical practices."

Pare says that another important point is that their study included only European Caucasian individuals. "I think it's very important to extend our findings to a more diverse population. It also warrants a discussion about how clinical trials should proceed to ensure a representative of our communities."

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