Influence of proton pump inhibitors on blood dabigatran concentrations in Japanese patients with non‐valvular atrial fibrillation
Tasuku KuwayamaHiroyuki OsanaiMasayoshi AjiokaKotaro TokudaHirofumi OhashiAkihiro TobeTsutomu YoshidaTomohiro MasutomiTakahiro KambaraYosuke InoueYoshihito NakashimaHiroshi AsanoKazuyoshi Sakai
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Abstract:
Dabigatran is a direct thrombin inhibitor used to decrease the risk of ischemic stroke in patients with non-valvular atrial fibrillation (NVAF). Its prodrug, dabigatran etexilate (DE) is often co-administrated with a proton pump inhibitor (PPI) because of its adverse effects on the gastrointestinal tract. Drug-drug interactions between DE and PPIs in daily clinical practice have not been fully elucidated.Changes in blood dabigatran concentration (DC) were investigated using the dilute thrombin time test in a randomized, open-label, two-period crossover study including 34 Japanese patients with NVAF receiving dabigatran therapy with or without PPI.The average trough DC was significantly higher without PPI than with PPI (83 ± 42.3 vs. 55.5 ± 24.6 ng/mL, respectively; P < 0.001). Similarly, the average peak DC was significantly higher without PPI than with PPI (184.1 ± 107.7 vs. 124 ± 59.2 ng/mL, respectively; P = 0.0029). The average ratio of DC change at the trough and peak levels did not differ significantly among the three PPI types.PPI administration significantly decreased the trough and peak DCs in patients with NVAF. Therefore, when prescribing PPIs for patients with NVAF in a clinical setting, the possibility that the bioavailability of dabigatran may decrease should be considered.Keywords:
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: Atrial fibrillation is the most common arrhythmia in over-midlife patients. In addition to systolic heart failure, cerebral thromboembolism represents the most dramatic complication of this rhythm disorder, contributing to morbidity and mortality. Traditionally, anticoagulation has been considered the main strategy in preventing stroke and systemic embolism in atrial fibrillation patients and vitamin K-dependent antagonists have been widely used in clinical practice. Recently, the development of direct oral anticoagulants has certainly improved the management of this disease, providing, for the first time, the opportunity to go beyond vitamin K-dependent antagonists limits. In the RE-LY trial, dabigatran 150 mg twice daily was superior to warfarin in the prevention of stroke or systemic embolism and dabigatran 110 mg twice daily was noninferior. Both doses greatly reduced hemorrhagic stroke, and dabigatran 110 mg twice daily significantly reduced major bleeding compared with warfarin. Based on these results, dabigatran, a direct thrombin inhibitor, was the first direct oral anticoagulant to receive the regulatory approval for nonvalvular atrial fibrillation patients. To date, a specific reversal agent has just been approved as an antidote for this molecule. This review provides a summary of randomized trials, postmarket registries and specific clinical-settings summary on dabigatran in nonvalvular atrial fibrillation.
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Dabigatran, a direct thrombin inhibitor, is the first oral alternative to warfarin for stroke prevention in atrial fibrillation. Dabigatran offers several potential advantages over warfarin including ease of dosing, fewer drug interactions, and the lack of required coagulation monitoring. However, its overall effectiveness and safety will depend upon appropriate patient selection. This article discusses factors that should be taken into account when considering dabigatran for patients with atrial fibrillation.
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The presence of atrial fibrillation (AF) increases the risk of stroke, especially in patients with risk factors as outlined by the CHADS2 and CHA2DS2-VASc scoring systems. Although warfarin can reduce stroke rates by over 65%, only 55% of patients, in the USA, who should be on warfarin for AF and stroke prevention are taking the drug due to the need of INR monitoring, difficulties in maintaining a therapeutic INR in the therapeutic range and dietary and drug interactions. Dabigatran, an oral direct thrombin inhibitor and rivaroxaban and apixaban, factor Xa inhibitors, have demonstrated efficacy in reducing stroke in large clinical trials. These novel anticoagulants will change the therapeutic landscape since patients will be able to prevent stroke with a lower risk of intracranial hemorrhage and without the need for INR monitoring and less drug-dietary interactions.
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In 2010, dabigatran etexilate, a direct thrombin inhibitor, was the first new oral anticoagulant to be approved for thromboembolic prophylaxis in atrial fibrillation in over 50 years. Dabigatran, unlike warfarin, has a short half-life with a rapid onset of anticoagulant effect, does not require dose adjustment or monitoring, and does not interact with food. The RE-LY trial compared two doses of dabigatran (110 and 150 mg twice daily) with adjusted dose warfarin in patients with non-valvular atrial fibrillation and at least 1 stroke risk factor. Compared with warfarin, dabigatran 150 mg twice daily was superior in reducing the risk of stroke or systemic embolism and was associated with a similar rate of major bleeding, while dabigatran 110 mg twice daily was equally effective in reducing stroke or systemic embolism and was associated with less major bleeding. Despite these favorable results, there remains disagreement regarding the optimal dose and overall safety of dabigatran in certain patient populations including the elderly and those with renal dysfunction.
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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 fibrillationstrokeanticoagulationdabigatranwarfarin
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Patients with atrial fibrillation are at an increased risk for stroke. Anticoagulation therapy has been shown to significantly reduce the risk for stroke in these patients. Warfarin therapy is effective at reducing the risk for thromboembolic events, but requires frequent monitoring of its anticoagulation effect using the international normalized ratio and significantly increases the risk for hemorrhagic events, including intracranial hemorrhage. Novel oral anticoagulants provide simpler, effective stroke prophylaxis in patients with atrial fibrillation. These drugs include dabigatran (a direct thrombin inhibitor) as well as rivaroxaban and apixaban (factor Xa inhibitors). The new anticoagulants have rapid onset of effect; their anticoagulatory effect is stable, predictable, and dose related; and they do not require monitoring of anticoagulation effect using the international normalized ratio. The pharmacology, clinical efficacy, and potential adverse effects of these drugs in patients with atrial fibrillation are reviewed herein.
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