RE-LY: Dabigatran Bleeding-Related Gene Variant Could Herald Personalized Dosing

September 04, 2012

September 3, 2012 (Munich, Germany) — 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 [1].

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 Randomized 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 randomized 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 personalizing the use of dabigatran in our population."

RE-LY investigators performed a genomewide association analysis of > 550 000 genetic markers and their influence on dabigatran peak and trough concentrations in the trial's 1490 patients who were genotyped and had dabigatran peak and trough levels measured.

The rs2244613 variant was associated with "a consistent and significant association" with any bleeding and, separately, with minor bleeds, independent of randomized treatment in the trial. It showed only a trend of an association with major bleeds.

Odds ratio* per minor allele for clinical outcomes associated with rs2244613 in RE-LY

End point OR (95% CI) p
Ischemic stroke or systemic embolism 0.70 (0.33–1.47) 0.34
Any bleeding 0.67 (0.55–0.82) 0.00007
Major bleeding 0.66 (0.43–1.01) 0.06
Minor bleeding 0.70 (0.57–0.85) 0.0004

*Adjusted for dabigatran dose, age, sex, CHADS2 score, aspirin use, creatinine clearance.

The rs2244613 SNP was also associated with survival free of bleeding among those who received dabigatran but not among those getting warfarin. The hazard ratio (HR) for bleeding among those getting the newer antithrombin was 0.70 (95% CI 0.58–0.84, p=0.00016). Among warfarin recipients it was 1.13 (95% CI 0.90-1.41, p=0.29). The interaction between rs2244613 carrier status and randomized treatment group was significant at p=0.0015.

Collet said in order to apply these findings to personalized medicine, "we need a point-of-care assay that can be used in outpatients."

According to Paré, the RE-LY trial was supported by Boehringer Ingelheim, from which the authors of the genetic analysis have received consulting fees; four of the cited coauthors are employees of Boehringer Ingelheim. Collet reported no conflicts of interest.