Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding

Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in the prevention of stroke in atrial fibrillation patients compared with warfarin. We hypothesized that genetic variants could contribute to interindividual variability in blood concentrations...

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Published in:Circulation (New York, N.Y.) N.Y.), 2013-04, Vol.127 (13), p.1404-1412
Main Authors: PARE, Guillaume, ERIKSSON, Niclas, SIEGBAHN, Agneta, SYVANEN, Ann-Christine, WADELIUS, Claes, WADELIUS, Mia, ZIMDAHL-GELLING, Heike, YUSUF, Salim, WALLENTIN, Lars, LEHR, Thorsten, CONNOLLY, Stuart, EIKELBOOM, John, EZEKOWITZ, Michael D, AXELSSON, Tomas, HAERTTER, Sebastian, OLDGREN, Jonas, REILLY, Paul
Format: Article
Language:English
Subjects:
Aged
Anticoagulants - adverse effects
Anticoagulants - blood
Antithrombin Proteins - adverse effects
Antithrombin Proteins - metabolism
Benzimidazoles - adverse effects
Benzimidazoles - blood
Biological and medical sciences
Blood and lymphatic vessels
Blood. Blood coagulation. Reticuloendothelial system
Cardiac dysrhythmias
Cardiology. Vascular system
Dabigatran
Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous
Female
Genome-Wide Association Study - methods
Heart
Hemorrhage - epidemiology
Hemorrhage - genetics
Humans
Male
Medical sciences
Neurology
Pharmacology. Drug treatments
Polymorphism, Single Nucleotide - genetics
Prodrugs - adverse effects
Prodrugs - metabolism
Pyridines - adverse effects
Pyridines - blood
Vascular diseases and vascular malformations of the nervous system
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Summary:Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in the prevention of stroke in atrial fibrillation patients compared with warfarin. We hypothesized that genetic variants could contribute to interindividual variability in blood concentrations of the active metabolite of dabigatran etexilate and influence the safety and efficacy of dabigatran. We successfully conducted a genome-wide association study in 2944 Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) participants. The CES1 single-nucleotide polymorphism rs2244613 was associated with trough concentrations, and the ABCB1 single-nucleotide polymorphism rs4148738 and the CES1 single-nucleotide polymorphism rs8192935 were associated with peak concentrations at genome-wide significance (P
ISSN:0009-7322
1524-4539
1524-4539
DOI:10.1161/CIRCULATIONAHA.112.001233