Dabigatran for stroke prevention in atrial fibrillation: from RE-LY to daily clinical practice
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AbstractObjective — The RE-LY trial has shown that the oral direct thrombin inhibitor dabigatran etexilate is a valid replacement for oral anticoagulation with vitamin K antagonists (VKA) in patients with atrial fibrillation at thromboembolic risk. After a decade of failures, these results signify a breakthrough in anticoagulation management. This article summarizes the available evidence from the perspective of the practicing clinician: do the results apply to all patients with AF? And what considerations should we make when prescribing this new oral anticoagulant?Methods and results — We review the trials searching for oral alternatives to VKA therapy, with emphasis on the RE-LY data.We have integrated available interaction data, and data on how to deal with side effects and (bleeding) complications with the direct thrombin inhibitor dabigatran etexilate.Conclusions — Dabigatran etexilate is a viable alternative to VKA, improving efficacy and safety in many respects, for many patients, and likely preferred by most patients themselves. Choosing the dose should be based on patient-specific factors. These include the presence of coronary artery disease (with potential requirement of concomitant aspirin ± clopidogrel), decreased renal function, age, low body weight, administration of other AF drugs or P-glycoprotein inhibitors, a history of gastro-intestinal bleeding, and patient compliance.Key Words: Atrial fibrillationstrokeanticoagulationdabigatranwarfarinKeywords:
Direct thrombin inhibitor
Stroke
Gastrointestinal bleeding
Concomitant
As the only oral anticoagulation option available in the United States, warfarin use remains widespread. However, concerns of safety remain a substantial issue. Additional anticoagulation options include unfractionated heparin, low‐molecular‐weight heparins (e.g., enoxaparin, dalteparin, and tinzaparin), and the indirect‐acting factor Xa inhibitor, fondaparinux. Direct thrombin inhibitors represent a newer class of anticoagulants used primarily in the treatment of heparin‐induced thrombocytopenia and percutaneous coronary interventions. Three intravenous agents are currently available—lepirudin, bivalirudin, and argatroban—with an oral agent, dabigatran etexilate, undergoing clinical investigation. Dabigatran etexilate offers a rapid onset of action after oral administration, reaching peak plasma concentrations and onset of anticoagulant effect within 0.5–2 hours after administration. Studies have demonstrated linear pharmacokinetics, a linear relationship between ecarin clotting time and international normalized ratio, and no known clinically significant drug or food interactions. Dabigatran etexilate has been studied in clinical trials as prophylaxis for venous thromboembolism in patients undergoing total knee replacement or total hip replacement surgeries, as well as for stroke prevention in patients with atrial fibrillation. Dabigatran etexilate has demonstrated superiority and noninferiority to enoxaparin as prophylaxis for venous thromboembolism in patients undergoing orthopedic surgery, with the most frequent adverse effects being gastrointestinal complaints. Elevations in alanine aminotransferase concentrations were noted in small percentages of patients in both the dabigatran etexilate and enoxaparin groups, with no observed dose association. The overall rates of major bleeding were low, with minor bleeding commonly noted, often at surgical sites. Clinical trials of dabigatran etexilate in patients with atrial fibrillation are ongoing. Results of short‐term efficacy and safety appear promising. Further research is needed regarding long‐term safety and efficacy for other anticoagulation indications.
Direct thrombin inhibitor
Lepirudin
Fondaparinux
Bivalirudin
Ximelagatran
Activated clotting time
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<b><i>Background:</i></b> The novel direct oral anticoagulants (NOA), dabigatran (a thrombin inhibitor), rivaroxaban and apixaban (factor Xa inhibitors) have shown at least noninferiority compared to warfarin concerning the prevention of stroke and systemic embolism as well as the risk of hemorrhagic complications in large phase III trials in patients with atrial fibrillation (AF). These results have been obtained under regular monitoring of side effects and reinforcement of medication adherence in carefully controlled clinical trials. To what extent they translate into clinical practice is a matter of ongoing research. While postmarketing registers, most prominently the GLORIA-AF registry, are currently recruiting and will not report data for several years, we aimed at extracting risk factors for hemorrhagic complications under NOA from all available case reports and single case series published to date. <b><i>Methods:</i></b> To identify risk factors which increase the risk of hemorrhage under NOA, we performed a PubMed search for both dabigatran and rivaroxaban, as well as three search terms for hemorrhagic complications. The cases of hemorrhagic complications were analyzed for the presence of the following four factors: ‘prescriber errors', ‘unfavorable comedications', ‘renal impairment' and ‘prescription of NOA in the frail elderly'. <b><i>Results and Discussion:</i></b> We found a discrepancy in the frequency of case reports on hemorrhagic complications to the disadvantage of dabigatran which can hardly be attributed to the earlier marketing time of dabigatran alone. As risk factors, we identified prescriber errors, impaired renal function, comedication with antiplatelet drugs or p-glycoprotein inhibitors, old age and low body weight. Strikingly, the majority of the bleeding complications reported in this compilation of case reports showed at least one and in most cases several risk factors. <b><i>Conclusions:</i></b> We should, therefore, carefully select our patients for treatment with the NOA with an emphasis on age, body weight, renal function and comedications and follow them faithfully concerning their medication adherence and eventual side effects.
Apixaban
Stroke
Direct thrombin inhibitor
Postmarketing surveillance
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Direct thrombin inhibitor
Chromogenic
Clotting time
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BACKGROUND Direct Thrombin Inhibitors (DTIs) represent a new and promising class of anticoagulants. Unlike heparin, they directly interact with thrombin and block fibrinogen binding. Dabigatran etexilate is becoming the most representative of the DTIs administered orally. AIM OF THE REVIEW This review aims at analysing efficacy and safety of the dabigatran in the prevention of venous and arterial thromboembolism. It analyses the pharmacokinetic and pharmacodynamic profile of dabigatran by underlying both advantages and disadvantages as compared to heparin and warfarin. It further analyses both phase 2 and phase 3 studies already completed and published and others still in progress, in terms of efficacy and clinical safety when compared with low molecular weight heparin and warfarin. The drug has been employed in different clinical settings such as the prevention of venous thromboembolism in patients undergoing major orthopedic surgery, the treatment of acute thromboembolism, the prevention of arterial thromboembolism (stroke and systemic embolism) in patients with chronic atrial fibrillation. CONCLUSIONS The results from clinical trials have shown an efficacy comparable to that of low molecular weight heparin and warfarin. Some doubts are still remaining about clinical safety, especially as concerning liver toxicity in long-term treatments.
Direct thrombin inhibitor
Pharmacodynamics
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Novel Oral Anticoagulants (NOACs) such as Dabigatran, Rivaroxaban, Apixaban and Edoxaban are becoming increasingly popular choices for anticoagulation in place of oral Vitamin K Antagonists in various clinical settings. However, they are thought to be associated with an increased risk of gastrointestinal bleeding. Moreover, no specific antidote is available which can rapidly reverse the anti-coagulant action of NOACs raising concern that gastrointestinal bleeding with NOACs could carry a worse prognosis than that associated with conventional agents. In this review, we describe a case of gastrointestinal bleeding in the setting of NOAC use, followed by a brief overview of the pivotal trials involving NOACs. Clinical issues such as pathophysiology, diagnosis and management of NOAC induced GI bleeding have been described. Future trials will help elucidate the true incidence, risk factors and preventive strategies for NOAC associated gastrointestinal bleeding.
Edoxaban
Apixaban
Gastrointestinal bleeding
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Abstract Introduction Several specific assays are commercially available to determine dabigatran anticoagulant activity. Aims of this multicenter and multiplatform study were to compare five methods for dabigatran measurement and investigate their performances in the low concentration range. Methods Dabigatran levels were analyzed in 295 plasma samples from patients enrolled in the START ‐Laboratory Register by the following methods using dedicated calibrators and controls: STA ‐ ECA II (Diagnostica Stago), standard and low range Hemoclot Thrombin Inhibitors (Hyphen BioMed), Direct Thrombin Inhibitor Assay (Instrumentation Laboratory), Direct Thrombin Inhibitor Assay (Siemens), Technoclot DTI (Technoclone). Results Methods showed variable agreement with the Hemoclot Thrombin Inhibitors assay used as reference test, with modest under‐ or overestimations (Bland‐Altman bias from −17.3 to 4.0 ng/mL). Limits of detection and quantification varied depending on the assay (4‐52 and 7‐82 ng/mL, respectively). Between‐run precision and accuracy were good for all methods for both quality control levels. Assay's repeatability assessed at very low dabigatran concentrations (from 10 to 60 ng/mL) was also acceptable, variability generally increased at lower drug levels. Conclusion The five dabigatran‐specific assays evaluated in this study provided reliable assessment of dabigatran plasma levels, although showing different performances.
Direct thrombin inhibitor
Repeatability
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New anticoagulants, like the orally available direct thrombin inhibitor (DTI) dabigatran etexilate, have recently been introduced into the market for venous thromboembolic prophylaxis and for stroke prevention in atrial fibrillation. While dabigatran has been approved for use without the need for routine therapeutic monitoring, there are clinical scenarios in which monitoring can help guide clinical management. We report herein the application of a recently described plasma-diluted thrombin time (DTI assay) used to monitor intravenous DTI as a useful and easily implemented method to monitor oral DTIs.
Direct thrombin inhibitor
Thrombin time
Stroke
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Apixaban
Edoxaban
Direct thrombin inhibitor
Thrombin time
Thromboplastin
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