A follow-up subanalysis of the most influential atrial-fibrillation (AF) trial of dabigatran etexilate (Pradaxa, Boehringer Ingelheim), an oral antithrombin alternative to warfarin, identified a common gene variant that seems to influence the bleeding risk associated with the drug but not its antithrombotic efficacy .
About 33% of Europeans are carriers of the variant, the CES1 gene single-nucleotide polymorphism (SNP) rs2244613, which blunts the biotransformation of the drug’s oral etexilate form to active dabigatran and thereby accentuates its trough serum concentrations, according to investigators from the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.
Each minor allele of the SNP was associated with a 15% drop in dabigatran trough levels in RE-LY patients who received the drug, which corresponded to a 27% decrease in their adjusted relative risk of bleeding, reported Dr Guillaume Paré (McMaster University, Hamilton, ON) last week at the European Society of Cardiology (ESC) 2012 Congress.
Their associated risk of major or minor bleeding, the trial’s primary safety end point, was significantly lower than for both rs2244613 noncarriers and patients in the cohort who had been randomised to warfarin.
The finding potentially explains observed variation in serum dabigatran levels among people who have received the etexilate prodrug, according to Paré. The variant, he said, had no apparent association with the trial’s primary efficacy end point, ischemic stroke or systemic embolism.
Dr Jean-Philippe Collet (Groupe Hospitalier la Pitié-Salpêtrière, Paris, France), the featured discussant following Paré’s presentation of the analysis, brought up the potential of a test to identify carriers of such SNPs for possible tailoring of their dabigatran etexilate dosing. One task ahead, he said, might be to perform “an interventional trial . . . to figure out whether we can improve clinical outcomes by personalising the use of dabigatran in our population.”
- Paré G, Erikkson N, Lehr T, et al. RE-LY-Genetics: Genetic determinants of dabigatran plasma levels and their relation to clinical response. European Society of Cardiology 2012 Congress; August 29, 2012, Munich, Germany.