Advertisement

Dabigatran in Clinical Practice

      Abstract

      Background

      Stroke and systemic thromboembolism remain critical causes of mortality and morbidity in patients with paroxysmal or persistent atrial fibrillation. Dabigatran etexilate is a novel oral direct thrombin inhibitor, which provides stroke risk reduction for patients with nonvalvular atrial fibrillation. Randomized clinical data demonstrate dabigatran to be an alternative oral anticoagulant with an improved efficacy profile compared with oral warfarin dose adjusted to an INR (international normalized ratio) target of 2.0 to 3.0.

      Objectives

      Our aim was to review the pharmacology, mechanism of action, drug metabolism, and clinical trial data supporting dabigatran use.

      Methods

      We reviewed all the major published clinical studies of dabigatran and analyzed data regarding practical applications in selected clinical scenarios.

      Results

      This review provides recommendations for clinicians regarding dosing during invasive surgical procedures, transitioning off alternative anticoagulants, and a discussion of storage and handling of the drug.

      Conclusions

      Our effort should facilitate the safe and effective use of dabigatran in atrial fibrillation.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Menke J.
        • Luthje L.
        • Kastrup A.
        • Larsen J.
        Thromboembolism in atrial fibrillation.
        Am J Cardiol. 2010; 105: 502-510
        • Go A.S.
        • Hylek E.M.
        • Phillips K.A.
        • 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
        • Connolly S.J.
        • Pogue J.
        • Hart R.G.
        • et al.
        Effect of clopidogrel added to aspirin in patients with atrial fibrillation.
        N Engl J Med. 2009; 360: 2066-2078
      1. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study.
        Lancet. 1994; 343: 687-691
      2. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation.
        Arch Intern Med. 1994; 154: 1449-1457
        • Fuster V.
        • Ryden L.E.
        • Cannom D.S.
        • et al.
        2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.
        J Am Coll Cardiol. 2011; 57: e101-e198
        • Wann L.S.
        • Curtis A.B.
        • January C.T.
        • et al.
        2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
        J Am Coll Cardiol. 2011; 57: 223-242
        • Weitz J.I.
        • Eikelboom J.W.
        • Samama M.M.
        New anticoagulant drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical; practice guidelines.
        Chest. 2012; 141: e120S-e151S
      3. Pradaxa (dabigatran etexilate mesylate) capsules.
        ([prescribing information]) Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT2012
        • Wood S.
        • O'Riordan M.
        FDA approves dabigatran for stroke prevention, embolism, in AF patients.
        (Accessed February 6, 2012)
        • 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.
        Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate.
        Clin Pharmacokinet. 2008; 47: 285-295
        • Di Nisio M.
        • Middeldorp S.
        • Buller H.R.
        Direct thrombin inhibitors.
        N Engl J Med. 2005; 353: 1028-1040
        • Stangier J.
        • Rathgen K.
        • Stahle H.
        • Mazur D.
        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
        • 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
        • Ezekowitz M.D.
        • Reilly P.A.
        • 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
        • Ezekowitz M.D.
        • 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 (810.e1–e2): 805-810
        • Connolly S.J.
        • Ezekowitz M.D.
        • Yusuf S.
        • et al.
        Dabigatran versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2009; 361: 1139-1151
        • Connolly S.J.
        • Ezekowitz M.D.
        • Yusuf S.
        • et al.
        Newly identified events in the RE-LY trial.
        N Engl J Med. 2010; 363: 1875-1876
        • Hankey G.J.
        • Eikelboom J.W.
        Dabigatran etexilate: a new oral thrombin inhibitor.
        Circulation. 2011; 123: 1436-1450
        • Eikelboom J.W.
        • Wallentin L.
        • Connolly S.J.
        • et al.
        Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.
        Circulation. 2011; 123: 2363-2372
        • Diener H.C.
        • Connolly S.J.
        • Ezekowitz M.D.
        • et al.
        Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial.
        Lancet Neurol. 2010; 9: 1157-1163
        • Oldgren J.
        • Alings M.
        • Darius H.
        • et al.
        Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: a subgroup analysis of the RE-LY trial.
        Ann Intern Med. 2011; 155 (W204): 660-667
        • Nagarakanti R.
        • Ezekowitz M.D.
        • Oldgren J.
        • et al.
        Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion.
        Circulation. 2011; 123: 131-136
        • Wallentin L.
        • Yusuf S.
        • Ezekowitz M.D.
        • et al.
        Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial.
        Lancet. 2010; 376: 975-983
        • 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 ([abstract 0370]): 148
        • van Ryn J.
        • Dorr B.
        • Kaspereit F.
        • et al.
        Beriplex P/N reverses bleeding in an acute renal injury model after dabigatran overdose in rabbits.
        Pathophysiol Haemost Thromb. 2010; 37 ([abstract P486]): A94
        • Eerenberg E.S.
        • Kamphuisen P.W.
        • Sijpkens M.K.
        • et al.
        Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.
        Circulation. 2011; 124: 1573-1579
        • Zhou W.
        • Schwarting S.
        • Illanes S.
        • et al.
        Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran.
        Stroke. 2011; 42: 3594-3599
        • Matute M.C.
        • Guillan M.
        • Garcia-Caldentey J.
        • et al.
        Thrombolysis treatment for acute ischaemic stroke in a patient on treatment with dabigatran.
        Thromb Haemost. 2011; 106: 178-179
        • De Smedt A.
        • De Raedt S.
        • Nieboer K.
        • et al.
        Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with dabigatran.
        Cerebrovasc Dis. 2010; 30: 533-534
        • Baruch L.
        • Sherman O.
        Potential inaccuracy of point-of-care INR in dabigatran-treated patients.
        Ann Pharmacother. 2011; 45: e40
        • Winkle R.A.
        • Mead R.H.
        • Engel G.
        • et al.
        The use of dabigatran immediately after atrial fibrillation ablation.
        J Cardiovasc Electrophysiol. 2012; 23: 264-268
        • Serebruany V.L.
        • Steinhubl S.R.
        • Berger P.B.
        • et al.
        Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials.
        Am J Cardiol. 2005; 95: 1218-1222
        • Roederer M.W.
        Cytochrome P450 enzymes and genotype-guided drug therapy.
        Curr Opin Mol Ther. 2009; 11: 632-640
        • 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
        • Brunet A.
        • Hermabessiere S.
        • Benain X.
        Pharmacokinetic and pharmacodynamic interaction of dronedarone and dabigatran in healthy subjects (abstract P3566).
        Eur Heart J. 2011; 32: 618-619
        • van Ryn J.
        • Baruch L.
        • Clemens A.
        Interpretation of point-of-care INR results in patients treated with dabigatran.
        Am J Med. 2012; 125: 417-420
        • Stangier J.
        • Feuring M.
        Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran.
        Blood Coagul Fibrinolysis. 2012; 23: 138-143
        • van Ryn J.
        • Litzenburger T.
        • Waterman A.
        • et al.
        Dabigatran anticoagulant activity is neutralized by an antibody selective to dabigatran in in vitro and in vivo models.
        J Am Coll Cardiol. 2011; 57 (abstract 1142-367): 1130
        • Alberts M.J.
        • Bernstein R.A.
        • Naccarelli G.V.
        • Garcia D.A.
        Using dabigatran in patients with stroke: a practical guide for clinicians.
        Stroke. 2011; 43: 271-279
      4. FDA Drug Safety Communication: Special storage and handling requirements must be followed for Pradaxa (dabigatran etexilate mesylate) capsules. Safety announcement.
        (Accessed February 9, 2012)
        • Freeman J.V.
        • Zhu R.P.
        • Owens D.K.
        • et al.
        Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation.
        Ann Intern Med. 2011; 154: 1-11
        • Kamel H.
        • Johnston S.C.
        • Easton J.D.
        • Kim A.S.
        Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in patients with atrial fibrillation and prior stroke or transient ischemic attack.
        Stroke. 2012; 43: 881-883