Abstract

The use of non-vitamin K antagonist oral anticoagulants (NOACs) has become a breakthrough in anticoagulant treatment and it is expected to rise significantly in upcoming years. The use of conventional anticoagulants have several limitations: subcutaneous administration of heparin, or close monitoring of INR during application of vitamin K antagonists. In the last decade, target-specific oral anticoagulants (TSOAC) including dabigatran, rivaroxaban, apixaban, edoxaban have been marketed for prophylaxis and treatment. Therefore, it is crucial to understand the potential uses, side effects, and management of these agents in routine practice. NOACs have major pharmacologic advantages, including a rapid onset and offset of action, fewer drug interactions than conventional anticoagulants, and predictable pharmacokinetics. These agents are gaining popularity among both physicians and patients because of their easiness of administration and the eliminating the requirement for regular coagulation monitoring. In this review, we focus on discussing practical recommendations for the use of NOACs and the risks and benefits of incorporating them into routine practice.

References

• 1. Agnelli G., Buller H.R., Cohen A., Curto M., Gallus A.S., Johnson M.,Masiukiewicz U., Pak R., Thompson J., Raskob G.E., Weitz J.I., AMPLIFYInvestigators: Oral apixaban for the treatment of acute venous thromboembolism.N. Engl. J. Med., 2013; 369: 799-808
  Google Scholar
• 2. Agnelli G., Buller H.R., Cohen A., Curto M., Gallus A.S., Johnson M.,Porcari A., Raskob G.E., Weitz J.I., PLIFY-EXT Investigators: Apixabanfor extended treatment of venous thromboembolism. N. Engl. J. Med.,2013; 368: 699-708
  Google Scholar
• 3. Ahrens I., Peter K., Lip G.Y., Bode C.: Development and clinical applicationsof novel oral anticoagulants. Part II. Drugs under clinicalinvestigation. Discov. Med., 2012; 13: 445-450
  Google Scholar
• 4. Alexander J.H., Lopes R.D., James S., Kilaru R., He Y., Mohan P., BhattD.L., Goodman S., Verheugt F.W., Flather M., Huber K., Liaw D., HustedS.E., Lopez-Sendon J., De Caterina R. i wsp.: Apixaban with antiplatelettherapy after acute coronary syndrome. N. Engl. J. Med., 2011; 365:699-708
  Google Scholar
• 5. Cappato R., Ezekowitz M.D., Klein A.L., Camm A.J., Ma C.S., Le HeuzeyJ.Y., Talajic M., Scanavacca M., Vardas P.E., Kirchhof P., Hemmrich M.,Lanius V., Meng I.L., Wildgoose P., van Eickels M. i wsp.: Rivaroxaban vs.vitamin K antagonists for cardioversion in atrial fibrillation. Eur. HeartJ., 2014; 35: 3346-3355
  Google Scholar
• 6. Cavender M.A., Gibson C.M., Braunwald E., Wiviott S.D., Murphy S.A.,Toda Kato E., Plotnikov A.N., Amuchástegui M., Oude Ophuis T., vanHessen M., Mega J.L.: The effect of rivaroxaban on myocardial infarctionin the ATLAS ACS 2 – TIMI 51 trial. Eur. Heart J. Acute Cardiovasc.Care, 2015; 4: 468-474
  Google Scholar
• 7. Clot drug “could save thousands.” BBC, 2008. http://news.bbc.co-.uk/2/hi/health/7354818.stm (15.05.2015)
  Google Scholar
• 8. Cohen A.T., Spiro T.E., Büller H.R., Haskell L., Hu D., Hull R., MebazaaA., Merli G., Schellong S., Spyropoulos A.C., Tapson V., MAGELLAN Investigators:Rivaroxaban for thromboprophylaxis in acutely ill medicalpatients. N. Engl. J. Med., 2013; 368: 513-523
  Google Scholar
• 9. Cohen D.: Dabigatran: how the drug company withheld importantanalyses. BMJ, 2014; 349: g4670
  Google Scholar
• 10. Connolly S.J., Eikelboom J., Joyner C., Diener H.C., Hart R., GolitsynS., Flaker G., Avezum A., Hohnloser S.H., Diaz R., Talajic M., Zhu J., PaisP., Budaj A., Parkhomenko A. i wsp.: Apixaban in patients with atrialfibrillation. N. Engl. J. Med., 2011; 364: 806-817
  Google Scholar
• 11. Connolly S.J., Ezekowitz M.D., Yusuf S., Eikelboom J., Oldgren J., ParekhA., Pogue J., Reilly P.A., Themeles E., Varrone J., Wang S., Alings M.,Xavier D., Zhu J., Diaz R. i wsp.: Dabigatran versus warfarin in patientswith atrial fibrillation. N. Engl. J. Med., 2009; 361: 1139-1151
  Google Scholar
• 12. Diener H.C., Executive Steering Committee of the SPORTIFF III andV Investigators: Stroke prevention using the oral direct thrombin inhibitorximelagatran in patients with non-valvular atrial fibrillation.Pooled analysis from the SPORTIF III and V studies. Cerebrovasc. Dis.,2006; 21: 279-293
  Google Scholar
• 13. Eerenberg E.S., Kamphuisen P.W., Sijpkens M.K., Meijers J.C., BullerH.R., Levi M.: Reversal of rivaroxaban and dabigatran by prothrombincomplex concentrate: a randomized, placebo-controlled, crossover studyin healthy subjects. Circulation, 2011; 124: 1573-1579
  Google Scholar
• 14. EINSTEIN Investigators, Bauersachs R., Berkowitz S.D., Brenner B.,Buller H.R., Decousus H., Gallus A.S., Lensing A.W., Misselwitz F., PrinsM.H., Raskob G.E., Segers A., Verhamme P., Wells P., Agnelli G., BounameauxH. i wsp.: Oral rivaroxaban for symptomatic venous thromboembolism.N. Engl. J. Med., 2010; 363: 2499-2510
  Google Scholar
• 15. Eriksson B.I., Agnelli G., Cohen A.T., Dahl O.E., Mouret P., RosencherN., Eskilson C., Nylander I., Frison L., Ogren M., METHRO III Study Group:Direct thrombin inhibitor melagatran followed by oral ximelagatranin comparison with enoxaparin for prevention of venous thromboembolismafter total hip or knee replacement. Thromb. Haemost.,2003; 89: 288-296
  Google Scholar
• 16. Eriksson B.I., Dahl O.E., Rosencher N., Kurth A.A., van Dijk C.N.,Frostick S.P., Kälebo P., Christiansen A.V., Hantel S., Hettiarachchi R.,Schnee J., Büller H.R., RE-MODEL Study Group: Oral dabigatran etexilatevs. subcutaneous enoxaparin for the prevention of venous thromboembolismafter total knee replacement: the RE-MODEL randomized trial.J. Thromb. Haemost., 2007; 5: 2178-2185
  Google Scholar
• 17. Eriksson B.I., Dahl O.E., Rosencher N., Kurth A.A., van Dijk C.N., FrostickS.P., Prins M.H., Hettiarachchi R., Hantel S., Schnee J., Büller H.R.,RE-NOVATE Study Group: Dabigatran etexilate versus enoxaparin forprevention of venous thromboembolism after total hip replacement:a randomised, double-blind, non-inferiority trial. Lancet, 2007; 370:949–956
  Google Scholar
• 18. Eriksson B.I., Kakkar A.K., Turpie A.G., Gent M., Bandel T.J., HomeringM., Misselwitz F., Lassen M.R.: Oral rivaroxaban for the preventionof symptomatic venous thromboembolism after elective hip and kneereplacement. J. Bone Joint Surg. Br., 2009; 91: 636-644
  Google Scholar
• 19. FDA Grants Priority Review to Boehringer Ingelheim’s BiologicsLicense Application for Idarucizumab. FierceBiotech. http://www.fiercebiotech.com/press-releases/fda-grants-priority-review-boehringeringelheims-biologics-license-applicat (15.05.2015)
  Google Scholar
• 20. Fiessinger J.N., Huisman M.V., Davidson B.L., Bounameaux H., FrancisC.W., Eriksson H., Lundström T., Berkowitz S.D., Nyström P., ThorsénM., Ginsberg J.S., THRIVE Treatment Study Investigators: Ximelagatranvs low-molecular-weight heparin and warfarin for the treatment ofdeep vein thrombosis: a randomized trial. JAMA, 2005; 293: 681-689
  Google Scholar
• 21. Food and Drug Administration. FDA Drug Safety Communication:FDA study of Medicare patients finds risks lower for stroke and deathbut higher for gastrointestinal bleeding with Pradaxa (dabigatran) comparedto warfarin. http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm (15.05.2015)
  Google Scholar
• 22. Friedman R.J., Dahl O.E., Rosencher N., Caprini J.A., Kurth A.A.,Francis C.W., Clemens A., Hantel S., Schnee J.M., Eriksson B.I., RE-MOBILIZE,RE-MODEL, RE-NOVATE Steering Committees: Dabigatran versusenoxaparin for prevention of venous thromboembolism after hipor knee arthroplasty: a pooled analysis of three trials. Thromb. Res., 2010; 126: 175-182
  Google Scholar
• 23. Fuji T., Fujita S., Tachibana S., Kawai Y., Koretsune Y., Yamashita T.,Nakamura M.: Efficacy and safety of edoxaban versus enoxaparin forthe prevention of venous thromboembolism following total hip arth-roplasty: STARS J-V. trial. Blood, 2010; 116: 1360
  Google Scholar
• 24. Fuji T., Wang C.J., Fujita S., Kawai Y., Nakamura M., Kimura T., IbusukiK., Ushida H., Abe K., Tachibana S.: Safety and efficacy of edoxaban,an oral factor Xa inhibitor, versus enoxaparin for thromboprophylaxisafter total knee arthroplasty: the STARS E-3 trial. Thromb. Res., 2014;134: 1198-1204
  Google Scholar
• 25. Giugliano R.P., Ruff C.T., Braunwald E., Murphy S.A., Wiviott S.D.,Halperin J.L., Waldo A.L., Ezekowitz M.D., Weitz J.I., Špinar J., RuzylloW., Ruda M., Koretsune Y., Betcher J., Shi M. i wsp.: Edoxaban versuswarfarin in patients with atrial fibrillation. N. Engl. J. Med., 2013; 369:2093-2104
  Google Scholar
• 26. Go A.S., Hylek E.M., Chang Y., Phillips K.A., Henault L.E., Capra A.M.,Jensvold N.G., Selby J.V., Singer D.E.: Anticoagulation therapy for strokeprevention in atrial fibrillation: how well do randomized trials translateinto clinical practice? JAMA, 2003; 290: 2685-2692
  Google Scholar
• 27. Granger C.B., Alexander J.H., McMurray J.J., Lopes R.D., Hylek E.M.,Hanna M., Al-Khalidi H.R., Ansell J., Atar D., Avezum A., Bahit M.C., DiazR., Easton J.D., Ezekowitz J.A., Flaker G. i wsp.: Apixaban versus warfarinin patients with atrial fibrillation. N. Engl. J. Med., 2011; 365: 981-992
  Google Scholar
• 28. Greinacher A., Thiele T., Selleng K.: Reversal of anticoagulants:an overview of current developments. Thromb. Haemost., 2015; 113:931-942
  Google Scholar
• 29. Hart R.G., Pearce L.A., Aguilar M.I.: Meta-analysis: antithrombotictherapy to prevent stroke in patients who have nonvalvular atrial fibrillation.Ann. Intern. Med., 2007; 146: 857-867
  Google Scholar
• 30. Heidbuchel H., Verhamme P., Alings M., Antz M., Hacke W., OldgrenJ., Sinnaeve P., Camm A.J., Kirchhof P., European Heart Rhythm Association:European Heart Rhythm Association Practical Guide on the use ofnew oral anticoagulants in patients with non-valvular atrial fibrillation.Europace, 2013; 15: 625-651
  Google Scholar
• 31. Hokusai-VTE Investigators, Büller H.R., Décousus H., Grosso M.A.,Mercuri M., Middeldorp S., Prins M.H., Raskob G.E., Schellong S.M.,Schwocho L., Segers A., Shi M., Verhamme P., Wells P.: Edoxaban versuswarfarin for the treatment of symptomatic venous thromboembolism.N. Engl. J. Med., 2013; 369: 1406-1415
  Google Scholar
• 32. Kwiatkowska W., Knysz B., Gąsiorowski J., Witkiewicz W.: Deep veinthrombosis of the lower limbs in intravenous drug users. Postępy Hig.Med. Dośw., 2015; 69: 510-520
  Google Scholar
• 33. Lassen M.R., Gallus A., Raskob G.E., Pineo G., Chen D., Ramirez L.M.,ADVANCE-3 Investigators: Apixaban versus enoxaparin for thromboprophylaxisafter hip replacement. N. Engl. J. Med., 2010; 363: 2487-2498
  Google Scholar
• 34. Lassen M.R., Raskob G.E., Gallus A., Pineo G., Chen D., Hornick P.,ADVANCE-2 investigators: Apixaban versus enoxaparin for thromboprophylaxisafter knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet, 2010; 375: 807-815
  Google Scholar
• 35. Lindahl T.L., Wallstedt M., Gustafsson K.M., Persson E., Hillarp A.:More efficient reversal of dabigatran inhibition of coagulation by activatedprothrombin complex concentrate or recombinant factor VIIathan by four-factor prothrombin complex concentrate. Thromb. Res.,2015; 135: 544-547
  Google Scholar
• 36. Lip G.Y., Merino J., Ezekowitz M., Ellenbogen K., Zamoryakhin D.,Lanz H., Jin J., Al-Saadi N., Mercuri M., Goette A.: A prospective evaluationof edoxaban compared to warfarin in subjects undergoing cardioversionof atrial fibrillation: the EdoxabaN vs. warfarin in subjectSUndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) study.Am. Heart J., 2015; 169: 597-604
  Google Scholar
• 37. Mega J.L., Braunwald E., Murphy S.A., Plotnikov A.N., Burton P., KissR.G., Parkhomenko A., Tendera M., Widimsky P., Gibson C.M.: Rivaroxabanin patients stabilized after a ST-segment elevation myocardialinfarction: results from the ATLAS ACS-2-TIMI-51 trial (Anti-Xa Therapyto Lower Cardiovascular Events in Addition to Standard Therapy inSubjects with Acute Coronary Syndrome-Thrombolysis In MyocardialInfarction-51). J. Am. Coll. Cardiol., 2013; 61: 1853-1859
  Google Scholar
• 38. Mendell J., Tachibana M., Shi M., Kunitada S.: Effects of food on thepharmacokinetics of edoxaban, an oral direct factor Xa inhibitor, in healthyvolunteers. J. Clin. Pharmacol., 2011; 51: 687-694
  Google Scholar
• 39. Patel M.R., Mahaffey K.W., Garg J., Pan G., Singer D.E., Hacke W., BreithardtG., Halperin J.L., Hankey G.J., Piccini J.P., Becker R.C., Nessel C.C.,Paolini J.F., Berkowitz S.D., Fox K.A. i wsp.: Rivaroxaban versus warfarinin nonvalvular atrial fibrillation. N. Engl. J. Med., 2011; 365: 883-891
  Google Scholar
• 40. Prandoni P.: Anticoagulant treatment of pulmonary embolism:impact and implications of the EINSTEIN PE study. Eur. J. Haematol.,2012; 89: 281-287
  Google Scholar
• 41. Prins M.H., Lensing A.W., Bauersachs R., van Bellen B., BounameauxH., Brighton T.A., Cohen A.T., Davidson B.L., Decousus H., RaskobG.E., Berkowitz S.D., Wells P.S., EINSTEIN Investigators: Oral rivaroxabanversus standard therapy for the treatment of symptomatic venousthromboembolism: a pooled analysis of the EINSTEIN-DVT and PErandomized studies. Thromb. J., 2013; 11: 21
  Google Scholar
• 42. Reilly P.A., Lehr T., Haertter S., Connolly S.J., Yusuf S., Eikelboom J.W.,Ezekowitz M.D., Nehmiz G., Wang S., Wallentin L., RE-LY Investigators:The effect of dabigatran plasma concentrations and patient characteristicson the frequency of ischemic stroke and major bleeding in atrialfibrillation patients: the RE-LY Trial (Randomized Evaluation of Long–Term Anticoagulation Therapy). J. Am. Coll. Cardiol., 2014; 63: 321-328
  Google Scholar
• 43. RE-MOBILIZE Writing Committee, Ginsberg J.S., Davidson B.L.,Comp P.C., Francis C.W., Friedman R.J., Huo M.H., Lieberman J.R., MuntzJ.E., Raskob G.E., Clements M.L., Hantel S., Schnee J.M., Caprini J.A.: Oralthrombin inhibitor dabigatran etexilate vs North American enoxaparinregimen for prevention of venous thromboembolism after knee arthroplastysurgery. J. Arthroplasty, 2009; 24: 1-9
  Google Scholar
• 44. Romualdi E., Donadini M.P., Ageno W.: Oral rivaroxaban after symptomaticvenous thromboembolism: the continued treatment study (EINSTEIN-extension study). Expert Rev. Cardiovasc. Ther., 2011; 9: 841-844
  Google Scholar
• 45. Schulman S.: Treatment of venous thromboembolism with dabigatran.Curr. Opin. Pulm. Med., 2012; 18: 410-415
  Google Scholar
• 46. Schulman S., Crowther M.A.: How I treat with anticoagulants in2012: new and old anticoagulants, and when and how to switch. Blood,2012; 119: 3016-3023
  Google Scholar
• 47. Schulman S., Kearon C., Kakkar A.K., Mismetti P., Schellong S., ErikssonH., Baanstra D., Schnee J., Goldhaber S.Z., RE-COVER Study Group:Dabigatran versus warfarin in the treatment of acute venous thromboembolism.N. Engl. J. Med., 2009; 361: 2342-2352
  Google Scholar
• 48. Schulman S., Kearon C., Kakkar A.K., Schellong S., Eriksson H., BaanstraD., Kvamme A.M., Friedman J., Mismetti P., Goldhaber S.Z., RE–MEDY Trial Investigators, RE-SONATE Trial Investigators: Extendeduse of dabigatran, warfarin, or placebo in venous thromboembolism.N. Engl. J. Med., 2013; 368: 709-718
  Google Scholar
• 49. Schulman S., Wåhlander K., Lundström T., Clason S.B., Eriksson H.,THRIVE III Investigators: Secondary prevention of venous thromboembolismwith the oral direct thrombin inhibitor ximelagatran. N. Engl. J.Med., 2003; 349: 1713-1721
  Google Scholar
• 50. Undas A., Pasierski T., Windyga J., Crowther M.: Practical aspects ofnew oral anticoagulant use in atrial fibrillation. Pol. Arch. Med. Wewn.,2014; 124: 124-135
  Google Scholar
• 51. Van Montfoort M.L., Meijers J.C.: Recent insights into the role ofthe contact pathway in thrombo-inflammatory disorders. HematologyAm. Soc. Hematol. Educ. Program, 2014; 2014: 60-65
  Google Scholar
• 52. Zahir H., Brown K.S., Vandell A.G., Desai M., Maa J.F., Dishy V., LomeliB., Feussner A., Feng W., He L., Grosso M.A., Lanz H.J., AntmanE.M.: Edoxaban effects on bleeding following punch biopsy and reversalby a 4-factor prothrombin complex concentrate. Circulation,2015; 131: 82-90
  Google Scholar

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