Abstract
Atrial fibrillation (AF) is well known as one of the leading causes of stroke and systemic embolism. Anticoagulation therapy is recommended in all patients at moderate-to-high risk of stroke. The vitamin K antagonist warfarin has traditionally been used in these patients but presents challenges in dosing and monitoring in these patients. The oral direct thrombin inhibitor dabigatran etexilate (Pradaxa®; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA) was recently approved for use in the US for preventing stroke and systemic embolism in patients with nonvalvular AF. Clinical trials have shown it to reduce the risk of stroke and systemic embolism when compared with warfarin (goal international normalized ratio [INR] 2–3) with a similar risk for severe bleeding. It can be given twice daily, with the dose adjusted for renal function. It does not have any dietary restrictions, has few drug interactions (except involving permeability [P]-glycoprotein [P-gp] agents), and does not require routine laboratory monitoring. Patients may experience significant dyspepsia with its use. Compared with warfarin there is increased risk for gastrointestinal bleeding and perhaps myocardial infarction. Currently, no reversal agent exists for use in situations of overdose or severe bleeding although some strategies have been suggested. Despite its high acquisition cost compared with warfarin, analysis using theoretical models has shown it to be cost-effective. Dabigatran offers a unique alternative to warfarin in patients with nonvalvular AF and can be beneficial in patients requiring anticoagulation therapy.
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References
Go AS, Hylek EM, Phillips JA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention; the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285:2370–2375.
Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133:546S–592S.
Feinberg WM, Blackshear JL, Laupacis A, et al. Prevalence, age distribution, and gender of patients with atrial fibrillation: analysis and implications. Arch Intern Med. 1995;155:468–473.
Lakshminarayan K, Solid CA, Collins AJ, et al. Atrial fibrillation and stroke in the general Medicare population: a 10-year perspective (1992 to 2002). Stroke. 2006;37:1969–1974.
Glazer NL, Dublin S, Smith NL, et al. Newly detected atrial fibrillation and compliance with antithrombotic guidelines. Arch Intern Med. 2007;167:246–252.
[No authors listed.] Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154:1449–1457.
Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists. Chest. 2008;133:160S–198S.
Hirsh J, O’Donnell M, Eikelboon JW. Beyond unfractionated heparin and warfarin: current and future advances. Circulation. 2007;116:552–560.
Baetz BE, SA Spinler. Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases. Pharmacotherapy. 2008;28:1354–1373.
Dager WE, Branch JM, King JH, et al. Optimization of inpatient warfarin therapy: impact of daily consultation by a pharmacist-managed anticoagulation service. Ann Pharmacother. 2000;34:567–572.
Bond CA, Raehl CL. Pharmacist-provided anticoagulation management in United States hospitals: death rates, length of stay, Medicare charges, bleeding complications, and transfusions. Pharmacotherapy. 2004;24:953–963.
Baker WL, Cios DA, Sander SD, et al. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Managed Care Pharm. 2009;15:245–253.
Boehringer Ingelheim Pharmaceuticals, Inc. Pradaxa Medication Guide. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA.
Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost. 2009;15:9S–16S.
European Medicines Agency (EMEA). Committee for Medicinal Products for Human Use (CHMP) assessment report for Pradaxa. 2008. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf. Accessed April 14, 2011.
Wienen W, Stassen JM, Priepke H, et al. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost. 2007;98:155–162.
Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47:285–295.
Di Nisio M, Middeldrorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028–1040.
Sanford M, Plosker GL. Dabigatran etexilate. Drugs. 2008;68:1699–1709.
Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics, and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64:292–303.
Stangier J, Stahle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet. 2008;47:103–111.
Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol. 2005;45:555–563.
Siddiqui FM, Qureshi AI. Dabigatran etexilate, a new oral direct thrombin inhibitor, for stroke prevention in patients with atrial fibrillation. Expert Opin Pharmacother. 2010;11:1403–1411.
Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 2008;36:386–399.
Stangier J, Rathgen K, Stahle H, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate. An open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49:259–268.
Stangier J, Stahle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol. 2008;48:1411–1419.
Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol. 2007;100:1419–1426.
Nagarakanti R, Ezekowitz MD, Parcham-Azad K, et al. Long-term open label extension of the Prevention of Embolic and Thrombotic Events on Dabigatran in Atrial Fibrillation (PETRO-Ex) study. Circulation. 2008;118:S_922. Abstract # 4629.
Ezekowitz MD, Connolly S, Parekh A, et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J. 2009;157:805–810.e2.
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151.
Deinher HC, Executive Steering Committee of the SPORTIFF III and V Investigators. Stroke prevention using the oral direct thrombin inhibitor ximelagatran in patients with non-valvular atrial fibrillation: pooled analysis from the SPORTIF III and V studies. Cerebrovasc Dis. 2006;21:279–293.
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875–1876.
Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran). J Am Coll Cardiol. 2011;57:1330–1337.
European Atrial Fibrillation Trial (EAFT) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke. Lancet. 1993;342:1255–1262.
Diener HC, Connolly SJ, Ezekowitz MD, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack of stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol. 2010;9:1157–1111.
Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. Circulation. 2011;123:e269–e367.
Weinberg DM, Mancini J. Anticoagulation for conversion of atrial fibrillation. Am J Cardiol. 189;63:745–746.
Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation. An analysis of patients undergoing cardioversion. Circulation. 2011;123:131–136.
Albers GW, Diener HC, Grind M, et al. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomized controlled trial. Lancet. 2003;362:1691–1698.
Albers GW, diener HC, Frison L, et al. Ximelagatran vs. warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. JAMA. 2005;293:690–698.
Ezekowitz MD, Wallentin L, Connolly SJ, et al. Dabigatran and warfarin in vitamin K antagonist-naïve and -experienced cohorts with atrial fibrillation. Circulation. 2010;122:2246–2253.
Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalized ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010;376:975–983.
Clemens A, Yamamura N, Rathgen, et al. Switching from enoxaparin to dabigatran etexilate: effects on safety, pharmacokinetics and pharmacodynamics. Pharm World Sci. 2010;32:285. Abstract #PK-06.
Van Ryn J, Sieger P, Kink-eiband M, et al. Adsorption of dabigatran etexilate in water or dabigatran in pooled human plasma by activated charcoal in vitro. Blood. 2009;114. Abstract# 1065.
Van Ryn J, Ruehl D, Priepke H, et al. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant factor VIIa or activated prothrombin complex concentrate. Haematologica. 2008;93:148s. Abstract # 0370.
Van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate — a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116–1127.
Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis. 2011;31:326–343.
Stangier J, Stahle H, Rathgen K, et al. No interaction of the oral direct thrombin inhibitor dabigatran etexilate and digoxin. Thromb Haemost. 2007;5. Abstract#P-W_672.
Stangier J, Rathgen K, Stahle H, et al. Coadministration of dabigatran etexilate and atorvastatin. Assessment of potential impact on pharmacokinetics and pharmacodynamics. Am J Cardiovasc Drugs. 2009;9:59–68.
Freeman JV, Ruo PZ, Owens DK, et al. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med. 2011;154:1–11.
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Bendel, S.D., Bona, R. & Baker, W.L. Dabigatran: an oral direct thrombin inhibitor for use in atrial fibrillation. Adv Therapy 28, 460–472 (2011). https://doi.org/10.1007/s12325-011-0025-1
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DOI: https://doi.org/10.1007/s12325-011-0025-1