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).
OBJECTIVE
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).
Departments of Clinical Development and Clinical Biostatistics, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut. Electronic address: paul.reilly@boehringer-ingelheim.com.
Paul A
PA
Reilly
Departments of Translational Medicine and Biometry, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; Saarland University, Saarbrücken, Germany.
Thorsten
T
Lehr
Departments of Translational Medicine and Biometry, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Sebastian
S
Haertter
Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
Stuart J
SJ
Connolly
Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
Salim
S
Yusuf
Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
John W
JW
Eikelboom
Jefferson Medical College, Wynnewood, Pennsylvania.
Michael D
MD
Ezekowitz
Departments of Translational Medicine and Biometry, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Gerhard
G
Nehmiz
Departments of Clinical Development and Clinical Biostatistics, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
Susan
S
Wang
Uppsala Clinical Research Centre and Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Lars
L
Wallentin
D000367:Age Factors; D000368:Aged; D000991:Antithrombins / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D001241:Aspirin / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000097:blood / Q000188:drug therapy; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D000069604:Dabigatran; D003920:Diabetes Mellitus / Q000453:epidemiology; D004617:Embolism / Q000517:prevention & control; D005260:Female; D006470:Hemorrhage / Q000453:epidemiology*; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D018570:Risk Assessment; D020521:Stroke / Q000453:epidemiology* / Q000517:prevention & control
D000991:Antithrombins; D001562:Benzimidazoles; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D000069604:Dabigatran; D001241:Aspirin
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