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J Am Coll Cardiol. 2014 Feb 4;63(4):321-8. doi: 10.1016/j.jacc.2013.07.104. Epub 2013 Sep 27.

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 information

1
Departments of Clinical Development and Clinical Biostatistics, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut. Electronic address: paul.reilly@boehringer-ingelheim.com.
2
Departments of Translational Medicine and Biometry, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; Saarland University, Saarbrücken, Germany.
3
Departments of Translational Medicine and Biometry, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
4
Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
5
Jefferson Medical College, Wynnewood, Pennsylvania.
6
Departments of Clinical Development and Clinical Biostatistics, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
7
Uppsala Clinical Research Centre and Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Abstract

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. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600).

KEYWORDS:

AF; ASA; CAD; CI; CrCl; DE; DE 110; DE 150; PK; SEE; aspirin; atrial fibrillation; bid; bleeding; confidence interval; coronary artery disease; creatinine clearance; dabigatran; dabigatran etexilate; dabigatran etexilate 110 mg twice daily; dabigatran etexilate 150 mg twice daily; pharmacokinetic(s); pharmacokinetics; stroke; systemic embolic event(s); twice daily

PMID:
24076487
DOI:
10.1016/j.jacc.2013.07.104
[Indexed for MEDLINE]
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