Effect of CES1 and ABCB1 genotypes on the pharmacokinetics and clinical outcomes of dabigatran etexilate in patients with atrial fibrillation and chronic kidney disease.

Background Despite the well-studied safety profile of dabigatran, its interactions with genetic polymorphism parameters are poorly understood, especially in patients with moderate chronic kidney disease (CKD). The study assessed whether genetic factors can contribute to CKD and alter dabigatran concentration. Methods Patients with atrial fibrillation (AF) and stage 3 CKD treated with dabigatran 110 or 150 mg have been included in the study. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the ABCB1 gene (rs1045642 and rs4148738) and CES1 gene (rs2244613). A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. Results A total of 96 patients aged 51-89 years (median age: 75 years) were evaluated. Patients on a reduced regimen of 110 mg twice a day were older (79.8 vs. 67.9, p < 0.0001) and had lower creatinine clearance (49.7 vs. 62.3 mL/min/1.73 m2, p = 0.015). Patients with the rs2244613 CC genotype had lower C/D values (70% reduction in the mean C/D vs. AA genotype, p = 0.001). Linear stepwise regression has shown the CKD epidemiology collaboration to be the only significant predictor of C/D among genetic factors and kidney function characteristics. During the median follow-up of 15 months, there were 15 bleedings in 13 patients. Conclusions Polymorphism of CES1 rs2244613 can contribute to the safety of dabigatran in patients with AF and CKD. There was no influence of the aforementioned polymorphisms of ABCB1 on dabigatran trough plasma concentrations and C/D. Kidney function is a mainstay of clinical decision-making on direct oral anticoagulant (DOAC) dose, and further knowledge should be accumulated on the role of genetic factors.

Factors Affecting Trough Plasma Dabigatran Concentrations in Patients with Atrial Fibrillation and Chronic Kidney Disease.

INTRODUCTION: Dabigatran is effective and widely used to prevent ischemic stroke and systemic embolism (SE) in patients with atrial fibrillation (AF). Chronic kidney disease (CKD) also has implications for choice of any medications, as it alters pharmacokinetic parameters of drugs. AIM: To evaluate trough plasma dabigatran concentration (DTPC) and to analyse potential factors affecting these values in patients with AF and CKD. METHODS: Patients with AF and stage 3 CKD were treated with dabigatran 110 mg or 150 mg have been included in the study and allocated into D110 or D150 group. DTPC was evaluated with high-performance liquid chromatography. A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. Factors affecting the DTPC were investigated. RESULTS: A total of 60 patients, aged 51-89 years, were evaluated. Compared with patients given 150 mg twice a day, those given 110 mg twice a day were older (79 vs 67.5, p < 0.0001) and had lower creatinine clearance (CrCl) (50.5 vs 60.5 mL/min/1.73 m2, p = 0.015). During the median follow up of 9.5 months there were 11 bleedings in 9 patients. The C/D ratio was higher in patients aged > 75 years (p = 0.024) and was also affected by CrCl (CrCl < 50 mL/min, p = 0.02). Individuals with CKD 3B had higher concentration of dabigatran were compared with those with 3A stage (488.7 vs 332 pg/ml: mg/day, p = 0.02). However, there was also negative correlation between C/D and CrCl (r = - 0.4, p = 0.0015). Co-prescribed medications did not influence DTPC. In addition, patients with bleeding events were additionally evaluated for C/D and no significant differences were found. CONCLUSION: Patients on dabigatran treatment showed highly variable trough plasma concentrations. C/D values were significantly higher in patients with CKD 3B stage and were influenced by elder age and comorbidities.

Impact of atrial fibrillation on the rate of mild cognitive impairment in the elderly.

Mild cognitive impairment (MCI) in patients with cardiovascular risks is a transitional state to vascular dementia but which still has a possibility of being managed. The objectives of this study were to assess the impact of atrial fibrillation (AF) on cognitive performances in the elderly in comparison with similar cardiovascular risks. One hundred unselected patients were included in AF+ and AF- groups. Patients with prodromal Alzheimer disease as shown by semantic cueing test, and those suffering from major cognitive decline according to DSM 5 criteria were evaluated separately from those patients analysed for vascular cognitive impairment. MCI was distinguished with the help of the Montreal cognitive assessment and the mood status was studied with the geriatric depression scale. AF+ patients predominantly had paroxysmal type of AF with a mean duration of 6.3 years, with 77% of the patients being on anticoagulation. AF- patients had arterial hypertension. Prevalence of MCI was significantly higher among AF- patients, possibly due to lower rates of BP control. These study results show less impact of AF itself on cognitive performances in comparison with uncontrolled hypertension.