Dataset Information

Influence of ABCB1 and CYP3A5 gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke.

ABSTRACT: Introduction:Difficulties in non-vitamin K anticoagulant (NOAC) administration in acute stroke can be associated with changes in pharmacokinetic parameters of NOAC such as biotransformation, distribution, and excretion. Therefore, obtaining data on pharmacokinetics of NOAC and factors that affect it may help develop algorithms for personalized use of this drug class in patients with acute cardioembolic stroke. Patients and methods:Pharmacokinetics of apixaban in patients with acute stroke was studied earlier by Kryukov et al. The present study enrolled 17 patients with cardioembolic stroke, who received 5 mg of apixaban. In order to evaluate the pharmacokinetic parameters of apixaban, venous blood samples were collected before taking 5 mg of apixaban (point 0) and 1, 2, 3, 4, 10, and 12 hours after drug intake. Blood samples were centrifuged at 3000 rpm for 15 minutes. Separate plasma was aliquoted in Eppendorf tubes and frozen at -70°C until analysis. High-performance liquid chromatography mass spectrometry analysis was used to determine apixaban plasma concentration. Genotyping was performed by real-time polymerase chain reaction. CYP3A isoenzyme group activity was evaluated by determining urinary concentration of endogenous substrate of the enzyme and its metabolite (6-?-hydroxycortisol to cortisol ratio). Statistical analysis was performed using SPSS Statistics version 20.0. The protocol of this study was reviewed and approved by the ethics committee; patients or their representatives signed an informed consent. Results:ABCB1 (rs1045642 and rs4148738) gene polymorphisms do not affect the pharmacokinetics of apixaban as well as CYP3A5 (rs776746) gene polymorphisms. Apixaban pharmacokinetics in groups with different genotypes did not differ statistically significantly. Correlation analysis showed no statistically significant relationship between pharmacokinetic parameters of apixaban and the metabolic activity of CYP3A. Conclusion:Questions such as depending on genotyping results for apixaban dosing and implementation of express genotyping in clinical practice remain open for NOACs. Large population studies are required to clarify the clinical significance of genotyping for this drug class.

SUBMITTER: Kryukov AV

PROVIDER: S-EPMC5868588 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Influence of <i>ABCB1</i> and <i>CYP3A5</i> gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke.

Kryukov Alexander Valerevich AV Sychev Dmitry Alekseevich DA Andreev Denis Anatolevich DA Ryzhikova Kristina Anatolievna KA Grishina Elena Anatolievna EA Ryabova Anastasia Vladislavovna AV Loskutnikov Mark Alekseevich MA Smirnov Valeriy Valerevich VV Konova Olga Dmitrievna OD Matsneva Irina Andreevna IA Bochkov Pavel Olegovich PO

Pharmacogenomics and personalized medicine 20180322

<h4>Introduction</h4>Difficulties in non-vitamin K anticoagulant (NOAC) administration in acute stroke can be associated with changes in pharmacokinetic parameters of NOAC such as biotransformation, distribution, and excretion. Therefore, obtaining data on pharmacokinetics of NOAC and factors that affect it may help develop algorithms for personalized use of this drug class in patients with acute cardioembolic stroke.<h4>Patients and methods</h4>Pharmacokinetics of apixaban in patients with acut ...[more]

PMID: 29606886

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Project description:BackgroundA previous FDA study reported a favorable benefit risk for apixaban compared with warfarin for stroke prevention in older non-valvular atrial fibrillation (NVAF) patients (≥ 65 years). However, it remains unclear whether this favorable benefit risk persists in other populations including younger users. We examined if a similar benefit risk was observed in the Sentinel System and if it varied by age group.ObjectiveTo examine the risk of ischemic stroke, gastrointestinal (GI) bleeding, and intracranial hemorrhage (ICH) in apixaban users compared with warfarin users in Sentinel Distributed Database (SDD).Design and participantsA retrospective new user cohort study was conducted among patients, 21 years and older initiating apixaban and warfarin for NVAF, between December 28, 2012, and June 30, 2018, in the SDD.Main measuresCox proportional hazard regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (95% CI) for each outcome (ischemic stroke, GI bleeding, and ICH) in propensity score matched apixaban users compared with the warfarin users. Subgroup analyses by age (21-64, 65-74, and 75+ years) were conducted.Key resultsAfter matching, 55.3% and 58.4% (n = 55,038) of the apixaban and warfarin users were included in the main analysis. GI bleeding was the most common outcome. The HR (95% CI) for GI bleeding, ICH, and ischemic stroke in apixaban users compared with warfarin users were 0.57 (0.50-0.66), 0.53 (0.40-0.70), and 0.56 (0.45-0.71) respectively. The reduced risk of these outcomes in apixaban compared with warfarin users persisted across age groups.ConclusionIn NVAF patients of all ages initiating either apixaban or warfarin for stroke prevention in the Sentinel System, apixaban was associated with a decreased risk of GI bleeding, ICH, and ischemic stroke compared with warfarin. Among patients less than 65 years of age, apixaban use was associated with a decreased risk of GI bleeding and ischemic stroke.

Project description:Non-vitamin K antagonist oral anticoagulants (NOACs) are widely used for prevention of stroke secondary to nonvalvular atrial fibrillation (NVAF). Increased use of NOACs is partially a result of simplified regimens compared with warfarin, which has been associated with poor adherence and persistence to therapy. Few studies have assessed adherence to NOACs, especially using contemporary data now that multiple NOACs are available.To evaluate adherence to NOACs in a cohort of newly diagnosed NVAF patients who are commercially insured.Incident, treatment-naïve NVAF patients were identified in 2013 from a large claims database. Patients were included who initiated rivaroxaban, dabigatran, or apixaban within 30 days after diagnosis. Subjects were required to have 12 months of pre-index information to assess demographic and clinical characteristics (comorbidities, CHA2 DS2-VASc, and HAS-BLED scores). Adherence to the index medication and adherence to any oral anticoagulant was assessed using proportion of days covered (PDC) at 3, 6, and 9 months. The number of switches and gaps in therapy were also evaluated. Analyses were stratified by stroke risk scores, and a logistic regression model was used to control for factors that may predict high adherence (PDC ? 0.80).A total of 3,455 rivaroxaban, 1,264 dabigatran, and 504 apixaban users were included with no major clinical or demographic differences between groups. At 3, 6, and 9 months of follow-up, dabigatran had lower adherence (PDC = 0.77, 0.67, and 0.62) compared with rivaroxaban (PDC = 0.84, 0.75, and 0.70; P < 0.001) and apixaban (PDC = 0.82, 0.75, and 0.71; P < 0.001), as well as nearly twice the number of switches to either other anticoagulants or antiplatelet therapy. At 9 months, 55.0% of rivaroxaban initiators had PDC ? 0.80, which was comparable with 56.8% for apixaban and significantly greater than 46.7% for dabigatran (P < 0.001). Adherence was higher overall as stroke risk increased and showed dabigatran had consistently lower adherence compared with the other NOACs. Overall adherence to any oral anticoagulants, allowing for switches to another NOAC or warfarin, was not dependent on the index medication (9-month PDC = 0.74, 0.71, and 0.74 for rivaroxaban, dabigatran, and apixaban initiators). Adjusted analyses showed that increasing age and comorbid hypertension and diabetes were associated with higher adherence. Compared with rivaroxaban, dabigatran initiators had nearly 30% lower odds of being adherent to their index medication, and no differences were observed between apixaban and rivaroxaban. At 9 months, there were no differences between NOACs for overall adherence to oral anticoagulants.In this real-world analysis of adherence to NOACs, rivaroxaban and apixaban had favorable profiles compared with dabigatran, and rivaroxaban appeared to have higher overall adherence among the NOACs. Clinicians and managed care organizations should consider the implications of lower adherence on clinical outcomes as well as quality assessment.The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1TR000117. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Brown reports receiving a training fellowship from Human and Pfizer. Study concept and design were contributed by Brown and Shewale. Talbert took the lead in data collection, along with Brown, and data interpretation was primarily performed by Brown, along with Shewale. The manuscript was written primarily by Brown, along with Shewale, and revised by all the authors.

Project description:AimsApproximately 20% of ischaemic stroke patients exhibit spontaneous arterial recanalization, attributable to endogenous fibrinolysis, which strongly relates to improved functional outcome. The impact of oral anticoagulants on endogenous fibrinolysis is unknown. Our aim was to test the hypothesis that apixaban enhances endogenous fibrinolysis in non-valvular atrial fibrillation (NVAF).Methods and resultsIn a prospective cross-sectional analysis, we compared endogenous fibrinolysis in NVAF patients (n = 180) taking aspirin, warfarin, or apixaban. In a prospective longitudinal study, patients were tested before and after apixaban (n = 80). Endogenous fibrinolysis was assessed using the Global Thrombosis Test (GTT) and thromboelastography (TEG). Endogenous fibrinolysis [measured by GTT lysis time (LT)] was shorter on apixaban compared with warfarin or aspirin [median 1850 (IQR 1591-2300) vs. 2758 (2014-3502) vs. 2135 (1752-2463) s, P < 0.0001]. Among TEG indices, a small but significant difference in clot lysis time (CLT) was observed [apixaban 60.0 (45.0-61.0) vs. warfarin 61.0 (57.0-62.0) vs. aspirin 61.0 (59.0-61.0) min, P = 0.036]. Apixaban improved endogenous fibrinolysis measured using the GTT [LT pre-treatment 2204 (1779-2738) vs. on-treatment 1882 (1607-2374) s, P = 0.0003], but not by using TEG. Change in LT (ΔLT) with apixaban correlated with baseline LT (r = 0.77, P < 0.0001). There was weak correlation between ΔLT and ΔCLT in response to apixaban (r = 0.28, P = 0.02) and between on-apixaban LT and CLT (r = 0.25, P = 0.022).ConclusionApixaban enhances endogenous fibrinolysis, with maximal effect in those with impaired fibrinolysis pre-treatment. Apixaban-treated patients exhibit more favourable fibrinolysis profiles than those taking warfarin or aspirin. Whether apixaban may confer additional thrombotic risk reduction in NVAF patients with impaired fibrinolysis, compared to warfarin, merits further study.

Dataset Information

Influence of ABCB1 and CYP3A5 gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke.

Publications

Influence of <i>ABCB1</i> and <i>CYP3A5</i> gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke.

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