The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy)

Author: Reilly, P.A.; Lehr, T.; Haertter, S.; Connolly, S.J.; Yusuf, S.; Eikelboom, J.W.; Ezekowitz, M.D.; Nehmiz, G.; Wang, S.; Wallentin, L.

Description: OBJECTIVES: The goal of this study was to analyze the impact of dabigatran plasma concentrations, patient demographics, and aspirin (ASA) use on frequencies of ischemic strokes/systemic emboli and major bleeds in atrial fibrillation patients.

BACKGROUND: The efficacy and safety of dabigatran etexilate were demonstrated in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, but a therapeutic concentration range has not been defined.

METHODS: In a pre-specified analysis of RE-LY, plasma concentrations of dabigatran were determined in patients treated with dabigatran etexilate 110 mg twice daily (bid) or 150 mg bid and correlated with the clinical outcomes of ischemic stroke/systemic embolism and major bleeding using univariate and multivariate logistic regression and Cox regression models. Patient demographics and ASA use were assessed descriptively and as covariates.

RESULTS: Plasma concentrations were obtained from 9,183 patients, with 112 ischemic strokes/systemic emboli (1.3%) and 323 major bleeds (3.8%) recorded. Dabigatran levels were dependent on renal function, age, weight, and female sex, but not ethnicity, geographic region, ASA use, or clopidogrel use. A multiple logistic regression model (c-statistic 0.657, 95% confidence interval [CI]: 0.61 to 0.71) showed that the risk of ischemic events was inversely related to trough dabigatran concentrations (p = 0.045), with age and previous stroke (both p < 0.0001) as significant covariates. Multiple logistic regression (c-statistic 0.715, 95% CI: 0.69 to 0.74) showed major bleeding risk increased with dabigatran exposure (p < 0.0001), age (p < 0.0001), ASA use (p < 0.0003), and diabetes (p = 0.018) as significant covariates.

CONCLUSIONS: Ischemic stroke and bleeding outcomes were correlated with dabigatran plasma concentrations. Age was the most important covariate. Individual benefit-risk might be improved by tailoring dabigatran dose after considering selected patient characteristics.

Subject headings: Age Factors; Aged; Antithrombins/administration & dosage/adverse effects/blood; Aspirin/therapeutic use; Atrial Fibrillation/blood/drug therapy; Benzimidazoles/administration & dosage/adverse effects/blood; Diabetes Mellitus/epidemiology; Embolism/prevention & control; Female; Hemorrhage/epidemiology; Humans; Male; Multivariate Analysis; Platelet Aggregation Inhibitors/therapeutic use; Pyridines/administration & dosage/adverse effects/blood; Risk Assessment; Stroke/epidemiology/prevention & control; Bleeding; Dabigatran

Publication year: 2014

Journal or book title: Journal of the American College of Cardiology

Volume: 63

Issue: 4

Pages: 321-328

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Type: Journal Article

Serial number: 1005