Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial

Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
Circulation (Impact Factor: 14.43). 05/2011; 123(21):2363-72. DOI: 10.1161/CIRCULATIONAHA.110.004747
Source: PubMed


Dabigatran 150 and 110 mg twice a day and warfarin are effective for stroke prevention in atrial fibrillation. The purpose of this study was to compare their risks of bleeding in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial.
The RE-LY trial randomized 18 113 patients to receive dabigatran 110 or 150 mg twice a day or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0 for a median follow-up of 2.0 years. Compared with warfarin, dabigatran 110 mg twice a day was associated with a lower risk of major bleeding (2.87% versus 3.57%; P=0.002), whereas dabigatran 150 mg twice a day was associated with a similar risk of major bleeding (3.31% versus 3.57%; P=0.32). There was a significant treatment-by-age interaction, such that dabigatran 110 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in patients aged <75 years (1.89% versus 3.04%; P<0.001) and a similar risk in those aged ≥75 years (4.43% versus 4.37%; P=0.89; P for interaction <0.001), whereas dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in those aged <75 years (2.12% versus 3.04%; P<0.001) and a trend toward higher risk of major bleeding in those aged ≥75 years (5.10% versus 4.37%; P=0.07; P for interaction <0.001). The interaction with age was evident for extracranial bleeding, but not for intracranial bleeding, with the risk of the latter being consistently reduced with dabigatran compared with warfarin irrespective of age.
In patients with atrial fibrillation at risk for stroke, both doses of dabigatran compared with warfarin have lower risks of both intracranial and extracranial bleeding in patients aged <75 years. In those aged ≥75 years, intracranial bleeding risk is lower but extracranial bleeding risk is similar or higher with both doses of dabigatran compared with warfarin. Unique identifier: NCT00262600.

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Available from: John Eikelboom, Dec 18, 2015
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    • "L'amiodarone a également montré dans des modèles pharmacologiques qu'elle augmentait la biodisponibilité du dabigatran. Cette interaction ne s'est pas traduite par des effets cliniques [22]. Cependant, notre étude présente plusieurs biais du fait de son caractère rétrospectif, monocentrique et observationnel avec un effectif réduit et donc probablement une puissance faible. "
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    ABSTRACT: Direct oral anticoagulants are a recent alternative to vitamin K antagonists but there is a lack of data regarding patients receiving these new types of treatment. The aim of the study was to identify and describe patients receiving direct oral anticoagulants admitted to an emergency unit. All the patients taking direct oral anticoagulants, admitted to the emergency room of the Clermont-Ferrand Hospital from January to August 2013, were included in this retrospective and descriptive study. Among the 73 patients included, 47.9 % were treated with dabigatran and 52.1 % with rivaroxaban. The indication was stroke prevention in 62 patients with atrial fibrillation whose average CHADS2 score was 2.6 [2.3-3](IC95 %). The average age was 76.4 years [73.7-79.1](IC95 %). Twenty-nine patients (39.7 %) had at least one drug association known for increasing the risk of bleeding. Average scores for bleeding risk were: HAS-BLED 3.1 [2.9-3.3](IC95 %) and Beyth 1.5 [1.3-1.6](IC95 %). Bleeding patients included a higher percentage of men (68.8 vs. 38.2 %, P=0.032). Creatinine clearance was lower in patients with major bleeding (45.2 % vs. 68.8mL/min, P=0.002). The Beyth score was highest in both sub-groups. In our study, we have found that the bleeding risk factors were: male gender, a high Beyth score, and a lowered creatinine clearance. Overall, patients treated with direct oral anticoagulants admitted to the emergency room were old with many co-morbidities, especially cardiovascular conditions; polymedication was frequent. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
    Full-text · Article · Jan 2015 · Journal des Maladies Vasculaires
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    • "This is an interesting finding because the lack of a monitoring assay and reversal agent for dabigatran therapy have been important safety concerns for clinicians; cases of bleeding events associated with dabigatran, especially in elderly patients with impaired renal function, have been published in the literature and have received recent regulatory attention in the US and elsewhere [24-28]. Compounded with the fact that dabigatran demonstrated an increased risk of intracranial bleeding among patients aged 75 years and older in a phase 3 study, it is not surprising that warfarin use was more frequent among those with a higher risk of bleeding [29]. While the Food and Drug Administration (FDA) is continuing to monitor new sources of drug surveillance data, they have concluded that bleeding rates associated with new dabigatran use do not appear to be greater than those associated with new warfarin use [28]. "
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    ABSTRACT: Background Dabigatran is one of the three newer oral anticoagulants (OACs) recently approved in the United States for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. The objective of this study was to identify patient, healthcare provider, and health plan factors associated with dabigatran versus warfarin use among NVAF patients. Methods Administrative claims data from patients with ≥2 NVAF medical claims in the HealthCore Integrated Research Database between 10/1/2009 and 10/31/2011 were analyzed. During the study intake period (10/1/2010 - 10/31/2011), dabigatran patients had ≥2 dabigatran prescriptions, warfarin patients had ≥2 warfarin and no dabigatran prescriptions, and the first oral anticoagulant (OAC) prescription date was the index date. Continuous enrollment for 12 months preceding (“pre-index”) and ≥ 6 months following the index date was required. Patients without pre-index warfarin use were assigned to the ‘OAC-naïve’ subgroup. Separate analyses were performed for ‘all-patient’ and ‘OAC-naïve’ cohorts. Multivariable logistic regression (LR) identified factors associated with dabigatran versus warfarin use. Results Of 20,320 patients (3,019 dabigatran and 17,301 warfarin) who met study criteria, 27% of dabigatran and 13% of warfarin patients were OAC-naïve. Among all-patients, dabigatran patients were younger (mean 67 versus 73 years, p < 0.001), predominantly male (71% versus 61%, p < 0.001), and more frequently had a cardiologist prescriber (51% versus 30%, p < 0.001) than warfarin patients. Warfarin patients had higher pre-index Elixhauser Comorbidity Index (mean: 4.3 versus 4.0, p < 0.001) and higher ATRIA bleeding risk score (mean: 3.0 versus 2.3, p < 0.001). LR results were generally consistent between all- and OAC-naïve patients. Among OAC-naïve patients, strongest factors associated with dabigatran use were prescriber specialty (OR = 3.59, 95% CI 2.68-4.81 for cardiologist; OR = 2.22, 95% CI 1.65-2.97 for other specialist), health plan type (OR = 1.47 95% CI 1.10-1.96 for preferred provider organization), and prior ischemic stroke (OR = 1.42, 95% CI 1.06-1.90). Older age decreased the probability of dabigatran use. Conclusions Beside patient characteristics, cardiology specialty of the prescribing physician and health plan type were the strongest factors associated with dabigatran use.
    Full-text · Article · Jul 2014 · BMC Health Services Research
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    • "The reasons for the lower rate of intracranial bleeding with either dose of dabigatran etexilate are not fully understood. It is speculated that dabigatran etexilate's single therapeutic target could preserve certain hemostatic mechanisms in the brain that may be protective against spontaneous CH [8]. However, ongoing registries will help clarify safety of dabigatran etexilate in routine clinical practice [21] [22]. "
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    ABSTRACT: Introduction: Our aim was to analyze our clinical experience with dabigatran etexilate in secondary stroke prevention. Methods: We retrospectively included patients starting dabigatran etexilate for secondary stroke prevention from March 2010 to December 2012. Efficacy and safety variables were registered. Results: 106 patients were included, median follow-up of 12 months (range 1-31). Fifty-six females (52.8%), mean age 76.4 (range 50-95, SD 9.8), median CHADS2 4 (range 2-6), CHA2DS2-VASc 5 (range 2-9), and HAS-BLED 2 (range 1-5). Indication for dabigatran etexilate was ischemic stroke in 101 patients and acute cerebral hemorrhage (CH) due to warfarin in 5 (4.7%). Dabigatran etexilate 110 mg bid was prescribed in 71 cases (67%) and 150 mg bid was prescribed in the remaining. Seventeen patients (16%) suffered 20 complications during follow-up. Ischemic complications (10) were 6 transient ischemic attacks (TIA), 3 ischemic strokes, and 1 acute coronary syndrome. Hemorrhagic complications (10) were CH (1), gastrointestinal bleeding (6), mild hematuria (2), and mild metrorrhagia (1), leading to dabigatran etexilate discontinuation in 3 patients. Patients with previous CH remained uneventful. Three patients died (pneumonia, congestive heart failure, and acute cholecystitis) and 9 were lost during follow-up. Conclusions: Dabigatran etexilate was safe and effective in secondary stroke prevention in clinical practice, including a small number of patients with previous history of CH.
    Full-text · Article · Jul 2014 · BioMed Research International
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