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Warfarin and other VKAs: Dosing and adverse effects

Russell D Hull, MBBS, MSc
David A Garcia, MD
Sara R Vazquez, PharmD, BCPS, CACP
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Jennifer S Tirnauer, MD


Warfarin and other vitamin K antagonists (VKAs, also called coumarins; eg, acenocoumarol, phenprocoumon, fluindione) are used in a variety of clinical settings. Their use is challenging because their therapeutic range is narrow and dosing is affected by many factors including genetic variation, drug interactions, and diet. Time spent with a prothrombin time (PT)/international normalized ratio (INR) above the therapeutic range increases the risk of bleeding, and time spent below the therapeutic range increases the risk of thromboembolic complications, which these agents were administered to prevent. Nevertheless, these agents have a large body of clinical experience and are highly effective in reducing the risk of venous and arterial thromboemboli in many settings.

The general principles underlying the clinical use of VKAs, including their complications and laboratory monitoring, will be reviewed here.

Management of bleeding or supratherapeutic INR in patients receiving warfarin is discussed separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR" and "Reversal of anticoagulation in warfarin-associated intracerebral hemorrhage".)


Indications for vitamin K antagonists (VKAs) are presented in separate topic reviews:

Atrial fibrillation – (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization".)

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Literature review current through: Nov 2017. | This topic last updated: Oct 12, 2017.
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  1. Stergiopoulos K, Brown DL. Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials. JAMA Intern Med 2014; 174:1330.
  2. Belley-Cote EP, Hanif H, D'Aragon F, et al. Genotype-guided versus standard vitamin K antagonist dosing algorithms in patients initiating anticoagulation. A systematic review and meta-analysis. Thromb Haemost 2015; 114:768.
  3. Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013; 369:2294.
  4. Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013; 369:2283.
  5. Verhoef TI, Ragia G, de Boer A, et al. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med 2013; 369:2304.
  6. Gage BF, Bass AR, Lin H, et al. Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial. JAMA 2017; 318:1115.
  7. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e152S.
  8. Harrison L, Johnston M, Massicotte MP, et al. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997; 126:133.
  9. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5-mg and 10-mg warfarin loading doses. Arch Intern Med 1999; 159:46.
  10. Farahmand S, Saeedi M, Seyed Javadi HH, Khashayar P. High doses of warfarin are more beneficial than its low doses in patients with deep vein thrombosis. Am J Emerg Med 2011; 29:1222.
  11. Kovacs MJ, Rodger M, Anderson DR, et al. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Ann Intern Med 2003; 138:714.
  12. Cushman M, Booth SL, Possidente CJ, et al. The association of vitamin K status with warfarin sensitivity at the onset of treatment. Br J Haematol 2001; 112:572.
  13. Lubetsky A, Dekel-Stern E, Chetrit A, et al. Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thromb Haemost 1999; 81:396.
  14. Khan T, Wynne H, Wood P, et al. Dietary vitamin K influences intra-individual variability in anticoagulant response to warfarin. Br J Haematol 2004; 124:348.
  15. Franco V, Polanczyk CA, Clausell N, Rohde LE. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. Am J Med 2004; 116:651.
  16. Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009; 20:912.
  17. Keeling D, Baglin T, Tait C, et al. Guidelines on oral anticoagulation with warfarin - fourth edition. Br J Haematol 2011; 154:311.
  18. Garcia P, Ruiz W, Loza Munárriz C. Warfarin initiation nomograms for venous thromboembolism. Cochrane Database Syst Rev 2016; :CD007699.
  19. 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.
  20. Poller L, Keown M, Ibrahim S, et al. An international multicenter randomized study of computer-assisted oral anticoagulant dosage vs. medical staff dosage. J Thromb Haemost 2008; 6:935.
  21. Gage BF, Eby C, Johnson JA, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 2008; 84:326.
  22. Becker DM, Humphries JE, Walker FB 4th, et al. Standardizing the prothrombin time. Calibrating coagulation instruments as well as thromboplastin. Arch Pathol Lab Med 1993; 117:602.
  23. Gage BF, Fihn SD, White RH. Management and dosing of warfarin therapy. Am J Med 2000; 109:481.
  24. Barnes GD, Froehlich JB. Anticoagulation: a pathway to clinical effectiveness. Am J Med 2009; 122:126.
  25. Kim YK, Nieuwlaat R, Connolly SJ, et al. Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: a pilot study. J Thromb Haemost 2010; 8:101.
  26. Le Gal G, Carrier M, Tierney S, et al. Prediction of the warfarin maintenance dose after completion of the 10 mg initiation nomogram: do we really need genotyping? J Thromb Haemost 2010; 8:90.
  27. Borgman MP, Pendleton RC, McMillin GA, et al. Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation. Thromb Haemost 2012; 108:561.
  28. Van Spall HG, Wallentin L, Yusuf S, et al. Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries: an analysis of patients receiving warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Circulation 2012; 126:2309.
  29. Jones M, McEwan P, Morgan CL, et al. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 2005; 91:472.
  30. Wallentin L, Yusuf S, Ezekowitz MD, 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.
  31. Rose AJ, Ozonoff A, Berlowitz DR, et al. Warfarin dose management affects INR control. J Thromb Haemost 2009; 7:94.
  32. Rose AJ. Improving the management of warfarin may be easier than we think. Circulation 2012; 126:2277.
  33. Lefrère JJ, Guyon F, Horellou MH, et al. [Resistance to vitamin K antagonists. 6 cases]. Ann Med Interne (Paris) 1986; 137:384.
  34. Hallak HO, Wedlund PJ, Modi MW, et al. High clearance of (S)-warfarin in a warfarin-resistant subject. Br J Clin Pharmacol 1993; 35:327.
  35. Hulse ML. Warfarin resistance: diagnosis and therapeutic alternatives. Pharmacotherapy 1996; 16:1009.
  36. Limdi NA, Limdi MA, Cavallari L, et al. Warfarin dosing in patients with impaired kidney function. Am J Kidney Dis 2010; 56:823.
  37. Metlay JP, Hennessy S, Localio AR, et al. Patient reported receipt of medication instructions for warfarin is associated with reduced risk of serious bleeding events. J Gen Intern Med 2008; 23:1589.
  38. Anderson RJ. Cost analysis of a managed care decentralized outpatient pharmacy anticoagulation service. J Manag Care Pharm 2004; 10:159.
  39. Saokaew S, Permsuwan U, Chaiyakunapruk N, et al. Effectiveness of pharmacist-participated warfarin therapy management: a systematic review and meta-analysis. J Thromb Haemost 2010; 8:2418.
  40. Chiquette E, Amato MG, Bussey HI. Comparison of an anticoagulation clinic with usual medical care: anticoagulation control, patient outcomes, and health care costs. Arch Intern Med 1998; 158:1641.
  41. Gray DR, Garabedian-Ruffalo SM, Chretien SD. Cost-justification of a clinical pharmacist-managed anticoagulation clinic. Ann Pharmacother 2007; 41:496.
  42. Aziz F, Corder M, Wolffe J, Comerota AJ. Anticoagulation monitoring by an anticoagulation service is more cost-effective than routine physician care. J Vasc Surg 2011; 54:1404.
  43. Connock M, Stevens C, Fry-Smith A, et al. Clinical effectiveness and cost-effectiveness of different models of managing long-term oral anticoagulation therapy: a systematic review and economic modelling. Health Technol Assess 2007; 11:iii.
  44. Jowett S, Bryan S, Murray E, et al. Patient self-management of anticoagulation therapy: a trial-based cost-effectiveness analysis. Br J Haematol 2006; 134:632.
  45. Jennings I, Kitchen D, Keeling D, et al. Patient self-testing and self-management of oral anticoagulation with vitamin K antagonists: guidance from the British Committee for Standards in Haematology. Br J Haematol 2014; 167:600.
  46. McGuinn TL, Scherr S. Anticoagulation clinic versus a traditional warfarin management model. Nurse Pract 2014; 39:40.
  47. Manotti C, Moia M, Palareti G, et al. Effect of computer-aided management on the quality of treatment in anticoagulated patients: a prospective, randomized, multicenter trial of APROAT (Automated PRogram for Oral Anticoagulant Treatment). Haematologica 2001; 86:1060.
  48. Oake N, van Walraven C, Rodger MA, Forster AJ. Effect of an interactive voice response system on oral anticoagulant management. CMAJ 2009; 180:927.
  49. Louis KM, Martineau J, Rodrigues I, et al. Primary care practices and determinants of optimal anticoagulation management in a collaborative care model. Am Heart J 2010; 159:183.
  50. Fitzmaurice DA, Hobbs FD, Murray ET, et al. Oral anticoagulation management in primary care with the use of computerized decision support and near-patient testing: a randomized, controlled trial. Arch Intern Med 2000; 160:2343.
  51. Wilson SJ, Wells PS, Kovacs MJ, et al. Comparing the quality of oral anticoagulant management by anticoagulation clinics and by family physicians: a randomized controlled trial. CMAJ 2003; 169:293.
  52. Poller L, Keown M, Ibrahim S, et al. A multicentre randomised clinical endpoint study of PARMA 5 computer-assisted oral anticoagulant dosage. Br J Haematol 2008; 143:274.
  53. Wittkowsky AK, Nutescu EA, Blackburn J, et al. Outcomes of oral anticoagulant therapy managed by telephone vs in-office visits in an anticoagulation clinic setting. Chest 2006; 130:1385.
  54. Siebenhofer A, Berghold A, Sawicki PT. Systematic review of studies of self-management of oral anticoagulation. Thromb Haemost 2004; 91:225.
  55. Gardiner C, Williams K, Mackie IJ, et al. Patient self-testing is a reliable and acceptable alternative to laboratory INR monitoring. Br J Haematol 2005; 128:242.
  56. Fitzmaurice DA, Murray ET, McCahon D, et al. Self management of oral anticoagulation: randomised trial. BMJ 2005; 331:1057.
  57. Siebenhofer A, Rakovac I, Kleespies C, et al. Self-management of oral anticoagulation reduces major outcomes in the elderly. A randomized controlled trial. Thromb Haemost 2008; 100:1089.
  58. Ryan F, Byrne S, O'Shea S. Randomized controlled trial of supervised patient self-testing of warfarin therapy using an internet-based expert system. J Thromb Haemost 2009; 7:1284.
  59. Verret L, Couturier J, Rozon A, et al. Impact of a pharmacist-led warfarin self-management program on quality of life and anticoagulation control: a randomized trial. Pharmacotherapy 2012; 32:871.
  60. Nagler M, Raddatz-Müller P, Schmid P, et al. Accuracy of the point-of-care coagulometer CoaguChek XS in the hands of patients. J Thromb Haemost 2013; 11:197.
  61. Ward A, Tompson A, Fitzmaurice D, et al. Cohort study of Anticoagulation Self-Monitoring (CASM): a prospective study of its effectiveness in the community. Br J Gen Pract 2015; 65:e428.
  62. Heneghan C, Alonso-Coello P, Garcia-Alamino JM, et al. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet 2006; 367:404.
  63. Garcia-Alamino JM, Ward AM, Alonso-Coello P, et al. Self-monitoring and self-management of oral anticoagulation. Cochrane Database Syst Rev 2010; :CD003839.
  64. Bloomfield HE, Krause A, Greer N, et al. Meta-analysis: effect of patient self-testing and self-management of long-term anticoagulation on major clinical outcomes. Ann Intern Med 2011; 154:472.
  65. Heneghan CJ, Garcia-Alamino JM, Spencer EA, et al. Self-monitoring and self-management of oral anticoagulation. Cochrane Database Syst Rev 2016; 7:CD003839.
  66. Matchar DB, Jacobson A, Dolor R, et al. Effect of home testing of international normalized ratio on clinical events. N Engl J Med 2010; 363:1608.
  67. Ansell J, Jacobson A, Levy J, et al. Guidelines for implementation of patient self-testing and patient self-management of oral anticoagulation. International consensus guidelines prepared by International Self-Monitoring Association for Oral Anticoagulation. Int J Cardiol 2005; 99:37.
  68. Dolor RJ, Ruybalid RL, Uyeda L, et al. An evaluation of patient self-testing competency of prothrombin time for managing anticoagulation: pre-randomization results of VA Cooperative Study #481--The Home INR Study (THINRS). J Thromb Thrombolysis 2010; 30:263.
  69. Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med 1997; 127:177.
  70. Rose AJ, Ozonoff A, Berlowitz DR, et al. Reexamining the recommended follow-up interval after obtaining an in-range international normalized ratio value: results from the Veterans Affairs study to improve anticoagulation. Chest 2011; 140:359.
  71. Schulman S, Parpia S, Stewart C, et al. Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios: a randomized trial. Ann Intern Med 2011; 155:653.
  72. Fihn SD, McDonell MB, Vermes D, et al. A computerized intervention to improve timing of outpatient follow-up: a multicenter randomized trial in patients treated with warfarin. National Consortium of Anticoagulation Clinics. J Gen Intern Med 1994; 9:131.
  73. Pengo V, Barbero F, Biasiolo A, et al. A comparison between six- and four-week intervals in surveillance of oral anticoagulant treatment. Am J Clin Pathol 2003; 120:944.
  74. Kucher N, Connolly S, Beckman JA, et al. International normalized ratio increase before warfarin-associated hemorrhage: brief and subtle. Arch Intern Med 2004; 164:2176.
  75. European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995; 333:5.
  76. White HD, Gruber M, Feyzi J, et al. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V. Arch Intern Med 2007; 167:239.
  77. Oake N, Jennings A, Forster AJ, et al. Anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis. CMAJ 2008; 179:235.
  78. Lane DA, Lip GY. Maintaining therapeutic anticoagulation: the importance of keeping "within range". Chest 2007; 131:1277.
  79. Oake N, Fergusson DA, Forster AJ, van Walraven C. Frequency of adverse events in patients with poor anticoagulation: a meta-analysis. CMAJ 2007; 176:1589.
  80. Kaatz S. Determinants and measures of quality in oral anticoagulation therapy. J Thromb Thrombolysis 2008; 25:61.
  81. Phillips KW, Ansell J. Outpatient management of oral vitamin K antagonist therapy: defining and measuring high-quality management. Expert Rev Cardiovasc Ther 2008; 6:57.
  82. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367:1903.
  83. van Walraven C, Jennings A, Oake N, et al. Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest 2006; 129:1155.
  84. Mahtani KR, Heneghan CJ, Nunan D, Roberts NW. Vitamin K for improved anticoagulation control in patients receiving warfarin. Cochrane Database Syst Rev 2014; :CD009917.
  85. Dentali F, Crowther M, Galli M, et al. Effect of Vitamin K Intake on the Stability of Treatment with Vitamin K Antagonists: A Systematic Review of the Literature. Semin Thromb Hemost 2016; 42:671.
  86. Sconce E, Avery P, Wynne H, Kamali F. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2007; 109:2419.
  87. Reese AM, Farnett LE, Lyons RM, et al. Low-dose vitamin K to augment anticoagulation control. Pharmacotherapy 2005; 25:1746.
  88. http://www.gnc.com/product/index.jsp?productId=2133377 (Accessed on May 24, 2010).
  89. Cairns JA, Weitz JI. Transition from apixaban to warfarin--addressing excess stroke, systemic embolism, and major bleeding. Am Heart J 2015; 169:1.
  90. Granger CB, Lopes RD, Hanna M, et al. Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Am Heart J 2015; 169:25.
  91. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e44S.
  92. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf (Accessed on April 30, 2015).
  93. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022406s004lbl.pdf (Accessed on June 02, 2015).
  94. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf (Accessed on June 02, 2015).
  95. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf (Accessed on April 30, 2015).
  96. http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf (Accessed on April 30, 2015).
  97. http://packageinserts.bms.com/pi/pi_eliquis.pdf (Accessed on April 30, 2015).
  98. Halkin H, Shapiro J, Kurnik D, et al. Increased warfarin doses and decreased international normalized ratio response after nationwide generic switching. Clin Pharmacol Ther 2003; 74:215.
  99. Milligan PE, Banet GA, Waterman AD, et al. Substitution of generic warfarin for Coumadin in an HMO setting. Ann Pharmacother 2002; 36:764.
  100. Witt DM, Tillman DJ, Evans CM, et al. Evaluation of the clinical and economic impact of a brand name-to-generic warfarin sodium conversion program. Pharmacotherapy 2003; 23:360.
  101. Meyering C, Howard T. Hypercoagulability in athletes. Curr Sports Med Rep 2004; 3:77.
  102. Mellwig KP, van Buuren F, Gohlke-Baerwolf C, Bjørnstad HH. Recommendations for the management of individuals with acquired valvular heart diseases who are involved in leisure-time physical activities or competitive sports. Eur J Cardiovasc Prev Rehabil 2008; 15:95.
  103. Bauer KA. Coumarin-induced skin necrosis. Arch Dermatol 1993; 129:766.
  104. Teepe RG, Broekmans AW, Vermeer BJ, et al. Recurrent coumarin-induced skin necrosis in a patient with an acquired functional protein C deficiency. Arch Dermatol 1986; 122:1408.
  105. Haran MZ, Lichman I, Berebbi A, et al. Unbalanced protein S deficiency due to warfarin treatment as a possible cause for thrombosis. Br J Haematol 2007; 139:310.
  106. Bols A, Nevelsteen A, Verhaeghe R. Atheromatous embolization precipitated by oral anticoagulants. Int Angiol 1994; 13:271.
  107. Rauh G, Spengel FA. Blue toe syndrome after initiation of low-dose oral anticoagulation. Eur J Med Res 1998; 3:278.
  108. Hyman BT, Landas SK, Ashman RF, et al. Warfarin-related purple toes syndrome and cholesterol microembolization. Am J Med 1987; 82:1233.
  109. Koos R, Mahnken AH, Mühlenbruch G, et al. Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography. Am J Cardiol 2005; 96:747.
  110. Koos R, Krueger T, Westenfeld R, et al. Relation of circulating Matrix Gla-Protein and anticoagulation status in patients with aortic valve calcification. Thromb Haemost 2009; 101:706.
  111. Rennenberg RJ, van Varik BJ, Schurgers LJ, et al. Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans. Blood 2010; 115:5121.
  112. Weijs B, Blaauw Y, Rennenberg RJ, et al. Patients using vitamin K antagonists show increased levels of coronary calcification: an observational study in low-risk atrial fibrillation patients. Eur Heart J 2011; 32:2555.
  113. Kruis-de Vries MH, Stricker BH, Coenraads PJ, Nater JP. Maculopapular rash due to coumarin derivatives. Dermatologica 1989; 178:109.