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Dabigatran Etexilate in Clinical Practice Confronting Challenges to Improve Safety and Effectiveness
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A number of novel anticoagulants are moving through various stages of drug development. Recently, the United States Food and Drug Administration approved the oral direct thrombin inhibitor dabigatran etexilate to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Although dabigatran offers a number of advantages over existing oral and parenteral anticoagulants, challenges exist for clinicians who must ensure its safe and effective use. Limited data are available on dabigatran use in patients with renal dysfunction and in obese patients, or in combination with other drugs. Clinical experience is lacking in populations for whom anticoagulants are routinely used, such as patients with a previous stroke, acute coronary syndromes, or pregnancy-associated thrombosis, or those requiring ablation therapy. More important, clinicians will be faced with incorporating dabigatran into hospital guidelines for transitioning between oral and parenteral anticoagulants, measuring anticoagulant intensity, managing anticoagulant-related hemorrhage, ensuring safe use around neuraxial anesthesia, and implementing computer-based alert or warning systems. Since anticoagulants are ubiquitously used in the prevention or treatment of venous and arterial thrombosis, both clinicians and patients must be provided structured education on dabigatran's benefits and limitations. In this article, our goal was to provide practical advice to enhance clinician understanding of dabigatran, identify clinical and operational challenges to its use, and offer system improvements that can ensure safe and effective use of dabigatran.
Introduction
Although thromboembolism is a common cause of mortality and morbidity, anticoagulants are effective and widely used for the prevention and treatment of thrombosis.[1, 2] Warfarin, a vitamin K antagonist, has been the primary oral anticoagulant used in the United States for the last 5 decades for stroke prevention in patients with atrial fibrillation.[3] Although it is an effective anticoagulant, warfarin is burdened with complexities surrounding its management. Systematic management models (i.e., anticoagulation management services and anticoagulation clinics) have emerged to ensure safe and effective warfarin use, with studies supporting their effectiveness compared with routine medical care.[4–7]
The quest for more convenient oral alternatives to warfarin has been under way for a number of years. The promising oral direct thrombin inhibitor ximelagatran failed in earlier years because of safety concerns related to drug-induced liver toxicity.[1, 3] More recently, dabigatran etexilate, a novel oral direct thrombin inhibitor, has been shown to surpass the standard of care with warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.[8] The primary outcome of stroke and systemic embolism was decreased by 34% (relative risk 0.66, 95% confidence interval [CI] 0.53–0.82, p<0.001) at a dabigatran dosage of 150 mg twice/day relative to warfarin, and an improved safety profile may also be achieved. Although there was no significant difference in major bleeding, hemorrhagic stroke was decreased 74% (relative risk 0.26, 95% CI 0.14–0.49, p<0.001), also at 150 mg twice/day versus warfarin.
In October 2010, the U.S. Food and Drug Administration (FDA) approved dabigatran etexilate for stroke prevention in patients with atrial fibrillation.[9] Several other oral anticoagulants are in clinical development or are used outside the United States. Their advantages over warfarin include a more predictable dose response with less interindividual variability; a wider therapeutic index (i.e., wider range of plasma levels without toxicity or loss of efficacy); fixed dosing, thus eliminating the need for routine coagulation testing and subsequent dosage adjustments; and fewer significant drug interactions.[10] Although the introduction of dabigatran has brought much anticipation and excitement, numerous challenges have also been raised regarding its safe and appropriate use in clinical practice. In this article, we identify current practice-based challenges to implementing safe and effective use of dabigatran and provide practical guidance for health systems and practitioners.
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