Fixed-dose unmonitored treatment with Dabigatran etexilate ( Pradaxa ) is effective and has a favorable safety profile in prevention of stroke in atrial fibrillation patients compared to Warfarin ( Coumadin ).

Researchers have hypothesized that genetic variants could contribute to inter-individual variability in blood concentrations of the active metabolite of Dabigatran etexilate, and influence the safety and efficacy of Dabigatran.

A genome-wide association study was conducted in 2,944 RE-LY participants. Single nucleotide polymorphisms ( SNP ) correlated with Dabigatran peak and trough concentrations were tested for an association with reported bleeding event ( n=587 ), major bleeding ( n=101 ) and ischemic events ( n=32 ).

The CES1 SNP rs2244613 was associated with trough concentrations, and the ABCB1 SNP rs4148738 and CES1 SNP rs8192935 were associated with peak concentrations at genome-wide significance ( P less than 9 x 10-8 ) with a gene-dose effect.

Each minor allele of the CES1 SNP rs2244613 was associated with lower trough concentrations ( 15% decrease per allele; P=1.2 x 10-8 ) and a lower risk of any bleeding ( odds ratio, OR=0.67; P=7 x 10-5 ) in Dabigatran-treated patients, with a consistent but non-significant lower risk of major bleeding ( OR=0.66 ).

The interaction between treatment ( Warfarin versus all Dabigatran ) and carrier status was statistically significant ( P=0.002 ) with carriers having less bleeding with Dabigatran than Warfarin ( hazard ratio, HR=0.59; P=5.2 x 10-5 ), in contrast to no difference in non-carriers ( HR=0.96; P=0.65 ).

There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events.

In conclusion, genome-wide association analysis has identified that carriage of CES1 rs2244613 minor allele occurred in 32.8% of patients in RELY and was associated with lower Dabigatran exposure.
The presence of the polymorphism was associated with a lower risk of bleeding.

Source: European Society of Cardiology ( ESC) Meeting, 2012

XagenaMedicine2012