Dabigatran and Postmarketing Reports of Bleeding

From the Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD.
New England Journal of Medicine (Impact Factor: 55.87). 03/2013; 368(14). DOI: 10.1056/NEJMp1302834
Source: PubMed


In the months following the approval of the oral anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) in October 2010, the Food and Drug Administration (FDA) received through the FDA Adverse Event Reporting System (FAERS) many reports of serious and fatal bleeding events associated with use of the drug. Because dabigatran is an anticoagulant, reports of bleeding were anticipated, but the rate of reported incidents was unusually high and was greater than the concurrent rate of reported bleeding incidents with warfarin, which had been the anticoagulant of choice for nearly 60 years before dabigatran was approved. In contrast, the controlled trial that supported . . .

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    • "This controversy lead to a FDA initiative through Mini-Sentinel, a pilot post-marketing surveillance system. A preliminary report[FDA, 2012]and a publication showed that bleeding risk with dabigatran was actually lower than with warfarin both for intracranial and gastrointestinal hemorrhage, attributing the large number of reported bleeding events as a 'a salient example of stimulated reporting'[Southworth et al. 2013]. Controversy persisted[Institute for Safe Medication Practices, 2013]and so did postmarketing surveillance with Mini-Sentinel. "
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    ABSTRACT: Dabigatran is increasingly being used in clinical practice for the thromboprophylaxis in atrial fibrillation as a convenient therapy that needs no drug level monitoring. However, analysis of the data of the same clinical trial that led to the adoption of dabigatran in fixed-dosing regimens has indicated a small subgroup of patients that could be either over-treated, risking bleeding, or under-treated, risking embolism. Additional post-marketing data lends support to the favorable therapeutic profile of dabigatran but at the same time raises doubts about patient characteristics such as weight, age, renal function and their pharmacokinetic effects that, in some cases, could be serious enough to expose a minority of patients to risk. We will present a clinical case of a patient with an ischemic stroke while on dabigatran that was found with low dabigatran plasma levels and we will discuss the currently available data on the effects of inherent patient characteristics on dabigatran pharmacokinetics, the clinical impact of dabigatran plasma levels on safety and efficacy as well as the possibility of improving the risk-benefit profile of this agent by tailoring the dose for selected patient groups.
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    • "A subgroup analysis in secondary stroke prevention with 3,623 patients showed a nonsignificant trend in favor of dabigatran etexilate having greater efficacy, with a significantly lower rate of CH [10]. Dabigatran etexilate has also been shown in postmarketing surveillance studies to be both safe [11] and cost-effective [12]. Clinical guidelines recommend the use of dabigatran etexilate over VKA in "
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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.
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    • "Few data exist regarding the safety of NOACs in clinical practice, and the available information reflects the limitations of post-authorization studies, such as reporting bias. Recent evidence provides contradiction to earlier safety reports that suggested that the major bleeding rates in patients receiving NOACs in clinical practice did not exceed the rates reported in the pivotal trials [21] [33]. "
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    ABSTRACT: Dabigatran etexilate (DE), rivaroxaban, and apixaban are nonvitamin K antagonist oral anticoagulants (NOACs) that have been compared in clinical trials with existing anticoagulants (warfarin and enoxaparin) in several indications for the prevention and treatment of thrombotic events. All NOACs presented bleeding events despite a careful selection and control of patients. Compared with warfarin, NOACs had a decreased risk of intracranial hemorrhage, and apixaban and DE (110 mg BID) had a decreased risk of major bleeding from any site. Rivaroxaban and DE showed an increased risk of major gastrointestinal bleeding compared with warfarin. Developing strategies to minimize the risk of bleeding is essential, as major bleedings are reported in clinical practice and specific antidotes are currently not available. In this paper, the following preventive approaches are reviewed: improvement of appropriate prescription, identification of modifiable bleeding risk factors, tailoring NOAC’s dose, dealing with a missed dose as well as adhesion to switching, bridging and anesthetic procedures.
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