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VKA- Overview

Warfarin has been the mainstay of treatment for the prevention of stroke in AF for decades. Compared with no therapy, warfarin reduces the risk of stroke by approximately 64%.1 Warfarin achieves its anticoagulant effect by preventing the gamma-carboxylation of the vitamin-dependent coagulation factors II, VII, IX, and X. Warfarin achieves this therapeutic effect by maintaining the anticoagulation intensity, as measured by the international normalized ratio (INR), between 2.0 and 3.0.2 The risk of ischemic stroke increases with INR levels less than 2, and the risk of major hemorrhage increases with INR levels greater than 4.0.

The narrow therapeutic range of warfarin and the variability of its dose response mandate frequent monitoring of the INR to ensure maintenance of a therapeutic level and avoidance of supertherapeutic anticoagulation. Because its action involves the vitamin K cycle, dietary sources of vitamin K can interfere with its anticoagulant effect. Warfarin is metabolized by the liver, principally by the CYP enzyme 2C9, which renders it susceptible to interference by other drugs competing for these same pathways. Compared with men, women require lower doses of warfarin to achieve the same therapeutic levels. Warfarin dose requirements also decrease with older age.3 The delayed onset of action of warfarin (72 to 96 hours) may necessitate bridging with parenteral anticoagulant therapy for those patients at highest risk of stroke. The long half-life of warfarin (40 hours) also complicates its management, particularly in the event of acute hemorrhage or urgent need for surgery.

The need for frequent monitoring and challenge of maintaining a therapeutic level are among the reasons most often cited for the under use of warfarin in clinical practice. Recent data from the Global Anticoagulation Registry in the FIELD (GARFIELD) demonstrate the persistence of this trend with approximately 40% of individuals receiving either aspirin or no therapy at all.4 Among 138,319 individuals with AF receiving warfarin in the United States, the mean time in therapeutic range was 53.7%, which increased to 57.5% after six months of therapy.5

These data highlight that although warfarin and other VKAs have been available for stroke prevention for over 60 years, many eligible AF patients remain untreated or have difficulty maintaining a consistently effective and safe level of anticoagulation. The development of NOACs as alternatives to VKAs helps to address this unmet need.




1.         Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.Ann Intern Med.2007;146(12):857-867.

2.         Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest.2012;141(2 Suppl):e44S-88S.

3.         Garcia D, Regan S, Crowther M, Hughes RA, Hylek EM. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population.Chest.2005;127(6):2049-2056.

4.         Kakkar AK, Mueller I, Bassand JP, et al. Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry.PLoS One.2013;8(5):e63479.

5.         Dlott JS, George RA, Huang X, et al. National assessment of warfarin anticoagulation therapy for stroke prevention in atrial fibrillation.Circulation.2014;129(13):1407-1414.




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