Novel oral anticoagulants in gastroenterology practice

      Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with a 5-fold increase in the risk of ischemic stroke, and AF-related strokes have worse outcomes than those not associated with AF.
      • Rosamond W.
      • Flegal K.
      • Furie K.
      • et al.
      Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
      • Wolf P.A.
      • D'Agostino R.B.
      • Belanger A.J.
      • et al.
      Probability of stroke: a risk profile from the Framingham Study.
      Warfarin reduces the risk of stroke in patients with AF by approximately two-thirds and is more effective than aspirin or dual antiplatelet therapy with aspirin and clopidogrel.
      • Hart R.G.
      • Benavente O.
      • McBride R.
      • et al.
      Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.
      Although effective, warfarin has limitations that complicate its use. These include unpredictable pharmacokinetics and pharmacodynamics related to genetic polymorphisms and to variations in dietary vitamin K intake and numerous drug-drug interactions. Therefore, frequent monitoring is needed to attempt to keep the international normalized ratio (INR) within the therapeutic range. Such monitoring is inconvenient for patients and physicians and costly for the healthcare system. The limitations of warfarin contribute to its underuse in eligible patients with AF, and even when warfarin is given, the INR is frequently outside the therapeutic range.

      Abbreviations:

      AF (atrial fibrillation), aPTT (activated partial thromboplastin time), ARISTOTLE (apixaban for reduction in stroke and thromboembolic events in atrial fibrillation), ASGE (American Society for Gastrointestinal Endoscopy), INR (international normalized ratio), NOAC (novel oral anticoagulant), NSAID (nonsteroidal anti-inflammatory drug), PCC (prothrombin complex concentrate), PPI (proton pump inhibitor), PT (prothrombin time), RE-LY (randomized evaluation of long term anticoagulant therapy), ROCKET-AF (rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation), RR (relative risk)
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      References

        • Rosamond W.
        • Flegal K.
        • Furie K.
        • et al.
        Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
        Circulation. 2008; 117 (e25-146)
        • Wolf P.A.
        • D'Agostino R.B.
        • Belanger A.J.
        • et al.
        Probability of stroke: a risk profile from the Framingham Study.
        Stroke. 1991; 22: 312-318
        • Hart R.G.
        • Benavente O.
        • McBride R.
        • et al.
        Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.
        Ann Int Med. 1999; 131: 492-501
        • Blech S.
        • Ebner T.
        • Ludwig-Schwellinger E.
        • et al.
        The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans.
        Drug Metab Disposit. 2008; 36: 386-399
        • Potpara T.S.
        • Lip G.Y.H.
        • Apostolakis S.
        New anticoagulant treatments to protect against stroke in atrial fibrillation.
        Heart (British Cardiac Society). 2012; 98: 1341-1347
        • Ganetsky M.
        • Babu K.M.
        • Salhanick S.D.
        • et al.
        Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant.
        J Med Toxicol. 2011; 7: 281-287
        • Kreutz R.
        Pharmacodynamic and pharmacokinetic basics of rivaroxaban.
        Fund Clin Pharmacol. 2012; 26: 27-32
        • Kubitza D.
        • Becka M.
        • Roth A.
        • et al.
        Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects.
        Current medical research and opinion. 2008; 24: 2757-2765
        • Weinz C.
        • Schwarz T.
        • Kubitza D.
        • et al.
        Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans.
        Drug Metabol Disposit. 2009; 37: 1056-1064
        • Moore K.T.
        • Plotnikov A.N.
        • Thyssen A.
        • et al.
        Effect of multiple doses of omeprazole on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban.
        J Cardiovasc Pharmacol. 2011; 58: 581-588
        • Raghavan N.
        • Frost C.E.
        • Yu Z.
        • et al.
        Apixaban metabolism and pharmacokinetics after oral administration to humans.
        Amer Soc Pharm Exp Thera. 2009; 37: 74-81
        • Frost C.
        • Wang J.
        • Schuster A.
        • et al.
        Apixaban, an oral, direct factor Xa inhibitor: single-dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects.
        Br J Clin Pharmacol. 2013; 75: 476-487
      1. Eliquis 2.5 mg film-coated tablets—Summary of Product Characteristics (SPC)—(eMC) [Internet]. 2012. Accessed Dec 15, 2012. Available from: http://www.medicines.org.uk/EMC/medicine/24988/SPC/Eliquis+2.5+mg+film-coated+tablets.

        • 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
        • FDA Briefing Document for the Cardiovascular and Renal Drugs Advisory Committee (CRDAC)
        Rivaroxaban.
        Janssen Pharmaceuticals, Inc., 2012
        • Hohnloser S.H.
        • Hijazi Z.
        • Thomas L.
        • et al.
        Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial.
        Eur Heart J. 2012; 33: 2821-2830
        • Strate L.L.
        Lower GI bleeding: epidemiology and diagnosis.
        Gastroenterology Clin N Am. 2005; 34: 643-664
        • Coleman C.I.
        • Sobieraj D.M.
        • Winkler S.
        • et al.
        Effect of pharmacological therapies for stroke prevention on major gastrointestinal bleeding in patients with atrial fibrillation.
        Int J Clin Pract. 2012; 66: 53-63
        • Marmo R.
        • Koch M.
        • Cipolletta L.
        • et al.
        Predictive factors of mortality from nonvariceal upper gastrointestinal hemorrhage: a multicenter study.
        Am J Gastroenterol. 2008; 103: 1639-1647
        • Radaelli F.
        • Paggi S.
        • Terruzzi V.
        • et al.
        Management of warfarin-associated coagulopathy in patients with acute gastrointestinal bleeding: a cross-sectional physician survey of current practice.
        Dig Liver Dis. 2011; 43: 444-447
        • Choudari C.P.
        • Rajgopal C.
        • Palmer K.R.
        Acute gastrointestinal haemorrhage in anticoagulated patients: diagnoses and response to endoscopic treatment.
        Gut. 1994; 35: 464-466
        • Wilcox C.M.
        • Truss C.D.
        Gastrointestinal bleeding in patients receiving long-term anticoagulant therapy.
        Am J Med. 1988; 84: 683-690
        • Rubin T.A.
        • Murdoch M.
        • Nelson D.B.
        Acute GI bleeding in the setting of supratherapeutic international normalized ratio in patients taking warfarin: endoscopic diagnosis, clinical management, and outcomes.
        Gastrointest Endosc. 2003; 58: 369-373
        • Hashash J.G.
        • Shamseddeen W.
        • Skoury A.
        • et al.
        Gross lower gastrointestinal bleeding in patients on anticoagulant and/or antiplatelet therapy: endoscopic findings, management, and clinical outcomes.
        Journal of clinical gastroenterology. 2009; 43: 36-42
      2. FDA Advisory Committee Briefing Document. Boehringer Ingelheim. Dabigatran etexilate. 2010;1-168.

        • Patel M.
        • Mahaffey K.
        • Garg J.
        • et al.
        Rivaroxaban versus Warfarin in nonvavular atrial fibrillation.
        New Engl J Med. 2011; 365: 883-891
        • Nessel C.
        • Mahaffey K.
        • Piccini J.
        • et al.
        Incidence and outcomes of gastrointestinal hemorrhage in patients with atrial fibrillation treated with rivaroxaban or warfarin: results from the ROCKET AF trial.
        Chest J [Internet]. 2012; (Accessed Dec 4, 2012;142(4_MeetingAbstracts):84A)
        • Flaker G.C.
        • Eikelboom J.W.
        • Shestakovska O.
        • et al.
        Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: the apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K.
        Stroke. 2012; 43: 3291-3297
      3. Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. New Engl J Med. Epub 2013 March 13.

      4. European Medicines Agency—Human medicines—European Medicines Agency updates patient and prescriber information for Pradaxa [Internet]. Accessed March 16, 2013. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/public_health_alerts/2012/05/human_pha_detail_000061.jsp&mid=WC0b01ac058001d126.

      5. Drug Safety and Availability—FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran) [Internet]. Accessed March 16, 2013. Center for Drug Evaluation and Research; Available from: http://www.fda.gov/Drugs/DrugSafety/ucm326580.htm.

        • Kernan L.
        • Ito S.
        • Shirazi F.
        • et al.
        Fatal gastrointestinal hemorrhage after a single dose of dabigatran.
        Clin Tox. 2012; 50: 571-573
        • Fellows S.E.
        • Rosini J.M.
        • Curtis J.A.
        • et al.
        Hemorrhagic gastritis with dabigatran in a patient with renal insufficiency.
        J Em Med. 2012; 44: e221-e225
        • Wychowski M.K.
        • Kouides P.A.
        Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment.
        Ann Pharmacother. 2012; 46: e10
        • Cryer B.
        • Feldman M.
        Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans.
        Gastroenterology. 1999; 117: 17-25
        • Pisters R.
        • Lane D.A.
        • Nieuwlaat R.
        • et al.
        A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
        Chest. 2010; 138: 1093-1100
        • Ansell J.
        • Hirsh J.
        • Hylek E.
        • et al.
        Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
        Chest. 2008; 133: 160S-198S
        • Anderson M.A.
        • Ben-Menachem T.
        • Gan S.I.
        • et al.
        Management of antithrombotic agents for endoscopic procedures.
        Gastrointest Endosc. 2009; 70: 1060-1070
        • Garcia D.
        • Barrett Y.C.
        • Ramacciotti E.
        • et al.
        Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants.
        J Thromb Haemost. 2013; 11: 245-252
      6. Product information for Pradaxa. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877. December 2012.

      7. Product information for Xarelto. Janssen Pharmaceuticals, Inc. Titusville, NJ 08560. November 2012.

      8. Prescribing information for Eliquis. Pfizer, Inc. New York, NY 10017. December 2012.

        • Miyares M.A.
        • Davis K.
        Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient.
        AJHP. 2012; 69: 1473-1484
        • Hirsh J.
        • Guyatt G.
        • Albers G.W.
        • et al.
        Executive summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
        Chest. 2008; 133: 71S-109S
        • Fuster V.
        • Rydén L.E.
        • Cannom D.S.
        • et al.
        ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences.
        Europace. 2006; 8: 651-745
        • Garcia D.A.
        • Granger C.B.
        Anticoagulation, novel agents, and procedures: Can we pardon the interruption?.
        Circulation. 2012; 126: 255-257
        • 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 Haemostasis. 2010; 103: 1116-1127
        • 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
        • Dumkow L.E.
        • Voss J.R.
        • Peters M.
        • et al.
        Reversal of dabigatran-induced bleeding with a prothrombin complex concentrate and fresh frozen plasma.
        Am J Health-system Pharm. 2012; 69: 1646-1650
        • Pragst I.
        • Zeitler S.H.
        • Doerr B.
        • et al.
        Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model.
        J Thrombosis Haemostasis. 2012; 10: 1841-1848
        • Van Ryn J.
        • Litzenburger T.
        • Schurer J.
        Reversal of anticoagulant activity of dabigatran and dabigatran-induced bleeding in rats by a specific antidote (antibody fragment).
        Circulation [Internet]. 2012; (Accessed Jan 2, 2013. Available from:)
        • Lu G.
        • Deguzman F.R.
        • Hollenbach S.J.
        • et al.
        A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa.
        Nature Med [Internet]. Mar 3, 2013; (Accessed Mar 11, 2013; Available from:)
        • Stangier J.
        • Rathgen K.
        • Stähle H.
        • et al.
        Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study.
        Clinical Pharmacokinetics. 2010; 49: 259-268
        • Warkentin T.E.
        • Margetts P.
        • Connolly S.J.
        • et al.
        Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding.
        Blood. 2012; 119: 2172-2174
        • Wolf A.T.
        • Wasan S.K.
        • Saltzman J.R.
        Impact of anticoagulation on rebleeding following endoscopic therapy for nonvariceal upper gastrointestinal hemorrhage.
        Am J Gastroenterol. 2007; 102: 290-296
        • Hwang J.H.
        • Fisher D.A.
        • Ben-Menachem T.
        • et al.
        The role of endoscopy in the management of acute non-variceal upper GI bleeding.
        Gastrointest Endosc. 2012; 75: 1132-1138
        • Connolly S.
        • Ezekowitz M.
        • Salim Y.
        • et al.
        Dabigatran versus warfarin in patients with atrial fibrillation.
        New Engl J Med. 2009; 361: 1139-1151
        • Douketis J.D.
        • Spyropoulos A.C.
        • Spencer F.A.
        • et al.
        Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
        Chest. 2012; 141: e326S-e350S
      9. Product monograph for Pradaxa. Boehringer Inhelheim Canada Ltd. Burlington, ON L7L 5H4. December 2012.

      10. Product monograph for Xarelto. Bayer, Inc. Toronto, ON M9W 1G6. July 2012.

      11. Product monograph for Eliquis. Pfizer Canada, Inc. Kirkland, QC H9J 2M5. November 2012.

        • Weitz J.I.
        • Quinlan D.J.
        • Eikelboom J.W.
        Periprocedural management and approach to bleeding in patients taking dabigatran.
        Circulation. 2012; 126: 2428-2432
      12. Advisory Committee Briefing Document. Dabigatran. B. Ingelheim. 2010.

        • Healey J.S.
        • Eikelboom J.
        • Douketis J.
        • et al.
        Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial.
        Circulation. 2012; 126: 343-348
        • Komocsi A.
        • Vorobcsuk A.
        • Kehl D.
        • et al.
        Use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an acute coronary syndrome.
        Arch Int Med. 2013; 172: 1537-1545
        • Andreotti F.
        • Testa L.
        • Biondi-Zoccai G.G.L.
        • et al.
        Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients.
        Eur Heart J. 2006; 27: 519-526
        • Wallentin L.
        • Wilcox R.G.
        • Weaver W.D.
        • et al.
        Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial.
        Lancet. 2003; 362: 789-797
        • Oldgren J.
        • Budaj A.
        • Granger C.B.
        • et al.
        Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.
        Eur Heart J. 2011; 32: 2781-2789
        • Steg P.G.
        • Mehta S.R.
        • Jukema J.W.
        • et al.
        RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome.
        Eur Heart J. 2011; 32: 2541-2554
        • Alexander J.H.
        • Lopes R.D.
        • James S.
        • et al.
        Apixaban with antiplatelet therapy after acute coronary syndrome.
        New Eng J Med. 2011; 365: 699-708
        • Mega J.L.
        • Braunwald E.
        • Mohanavelu S.
        • et al.
        Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.
        Lancet. 2009; 374: 29-38
        • Mega J.L.
        • Braunwald E.
        • Wiviott S.
        • et al.
        Rivaroxaban in patients with a recent acute coronary syndrome.
        New Eng J Med. 2012; 366: 9-19
        • Alexander J.H.
        • Becker R.C.
        • Bhatt D.L.
        • et al.
        Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the apixaban for prevention of acute ischemic and safety events (APPRAISE) trial.
        Circulation. 2009; 119: 2877-2885
        • Abraham N.
        Novel oral anticoagulants and gastrointestinal bleeding: a case for cardiogastroenterology.
        Clin Gastroenterol Hepatol. 2013; 11 (Epub 2013 Jan 21): 324-328
        • Bytzer P.
        • Connolly S.J.
        • Yang S.
        • et al.
        Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial.
        Clin Gastroenterol Hepatol. 2013; 11: 246-252
        • Hoffman A.
        • Galle P.R.
        Gastrointestinal disorders and dabigatran.
        Scand J Gastroenterol. 2012; 48: 9-16
        • Lip G.Y.H.
        • Andreotti F.
        • Fauchier L.
        • et al.
        Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis.
        Europace. 2011; 13: 723-746