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RELY- Genetics: Genetic determinants of dabigatran plasma levels and their relation to clinical response

Cardiovascular Pharmacology and Pharmacotherapy


 

Presenter: Guillaume Pare | see Discussant report

 

Abstract:

 

Background
Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in prevention of stroke in atrial fibrillation patients compared to warfarin.  We 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.

Methods
We successfully conducted a genome-wide association study 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).

Results
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<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, 95%CI 10-19%; P=1•2 x 10-8) and a lower risk of any bleeding (OR=0•67, 95%CI 0.55-0•82; P=7 x 10-5) in dabigatran-treated participants, with a consistent but non-significant lower risk of major bleeding (OR=0•66, 95%CI 0•43-1•01). 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 (HR=0•59, 95%CI 0•46-0•76; P=5•2 x 10-5) in contrast to no difference in noncarriers (HR=0•96, 95%CI 0•81-1•14; P=0•65).  There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events.

Conclusions
Genome-wide association analysis 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.

Discussant: Jean-Philippe Collet | see Presenter abstract 

 

 

References


711001 - 711002

SessionTitle:

Clinical Trial & Registry Update III: Updates on Atrial Fibrillation and Valves

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.