Introduction: Dabigatran is direct thrombin inhibitor approved in the prevention of stroke in patients with atrial fibrillation. It was shown in the RELY trial substudy that genetic variants could contribute to interindividual variability in concentrations of the active metabolite of dabigatran and influence the safety of treatment. Carriage of the CES1 rs2244613 minor allele was associated with lower exposure to active metabolite and with a lower bleeding risk compared to wild-type allele.
Aim: To determine the influence of gene CES1 polymorphism rs2244613 and through plasmatic concentration of dabigatran on occurrence of major bleeding in stroke patients.
Methods: Prospective observational monocentric study in consenting stroke patients initiated on dabigatran. Primary outcome was major bleeding defined using ISTH criteria. DNA analysis of CES1 polymorphism rs2244613 was done with RFLP analysis. Through concentration of dabigatran was measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS) at least 7 days after initiation.
Results: 110 patients after cardioembolic stroke, mean age 70,2 (SD 12.7), 56 (50.9%) women, were enrolled. Mean follow-up time was 19.9 months (total 182.2 patient years). 68 (61.8%) patients were wild-type, 37 (33.6%) were minor allele heterozygotes and 5 (4.5%) were homozygous minor allele carriers. Through dabigatran concentration were non-significantly lower in minor allele carriers: 132.8 (SD 98.7) ng/ml in wild-type patients, 112.2 (80.0) in heterozygotes and 95.6 (SD 88.1) in homozygotes. There were 6 episodes of major bleeding, all in patients with wild-type genotype. The patients with dabigatran level above 160 ng/ml (upper quartile) were more likely to have major bleeding, HR 5.74 (95% CI 1.05 - 31.42, p = 0.044). Age and renal function did not correlate with the bleeding.
Conclusion: Patients with higher dabigatran concentration had significantly higher major bleeding risk. Minor allele carriers had non-significant trend for having lower through dabigatran level. Personalized dabigatran dosing based on pharmacogenetics and monitoring plasmatic levels should be studied in future trials with the aim to increase the safety of treatment.