Advertisement

Management and dosing of warfarin therapy

      Abstract

      When initiating warfarin therapy, clinicians should avoid loading doses that can raise the International Normalized Ratio (INR) excessively; instead, warfarin should be initiated with a 5-mg dose (or 2 to 4 mg in the very elderly). With a 5-mg initial dose, the INR will not rise appreciably in the first 24 hours, except in rare patients who will ultimately require a very small daily dose (0.5 to 2.0 mg). Adjusting a steady-state warfarin dose depends on the measured INR values and clinical factors: the dose does not need to be adjusted for a single INR that is slightly out of range, and most changes should alter the total weekly dose by 5% to 20%. The INR should be monitored frequently (eg, 2 to 4 times per week) immediately after initiation of warfarin; subsequently, the interval between INR tests can be lengthened gradually (up to a maximum of 4 to 6 weeks) in patients with stable INR values. Patients who have an elevated INR will need more frequent testing and may also require vitamin K1. For example, a nonbleeding patient with an INR of 9 can be given low-dose vitamin K1 (eg, 2.5 mg phytonadione, by mouth). Patients who have an excessive INR with clinically important bleeding require clotting factors (eg, fresh-frozen plasma) as well as vitamin K1.
      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 The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. Top 200 brand-name drugs by prescriptions in 1999. Drug Topics. 2000:69–70. Available at: http://www.drugtopics.com/brand. html. Accessed March 7, 2000.

        • Hirsh J
        • Poller L
        The International Normalized Ratio.
        Arch Intern Med. 1994; 154: 282-288
        • Hirsh J
        • Dalen J.E
        • Anderson D.R
        • et al.
        Oral anticoagulants.
        Chest. 1998; 114: 445-469
        • Tait R.C
        • Sefcick A
        A warfarin induction regimen for out-patient anticoagulation in patients with atrial fibrillation.
        Br J Haematol. 1998; 101: 450-454
        • Vadher B.D
        • Patterson D.L
        • Leaning M.S
        Validation of an algorithm for oral anticoagulant dosing and appointment scheduling.
        Clin Lab Haematol. 1995; 17: 339-345
        • Doyle J.J
        • Koren G
        • Cheng M.Y
        • Blanchette V.S
        Anticoagulation with sodium warfarin in children.
        J Pediatr. 1988; 113: 1095-1097
        • James A.H
        • Britt R.P
        • Raskino C.L
        • Thompson S.G
        Factors affecting the maintenance dose of warfarin.
        J Clin Pathol. 1992; 45: 704-706
        • Bentley D.P
        • Backhouse G
        • Hutchings A
        • et al.
        Investigation of patients with abnormal response to warfarin.
        Br J Clin Pharmacol. 1986; 22: 37-41
        • Diab F
        • Feffer S
        Hereditary warfarin resistance.
        South Med J. 1994; 87: 407-409
        • O’Reilly R
        Vitamin K in hereditary resistance to oral anticoagulant drugs.
        Am J Physiol. 1971; 221: 1327-1330
        • Furuya H
        • Fernandez-Salguero P
        • Gregory W
        • et al.
        Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy.
        Pharmacogenetics. 1995; 5: 389-392
        • Crowther M.A
        • Harrison L
        • Hirsh J
        Warfarin.
        Ann Intern Med. 1997; 127: 333
        • Harrison L
        • Johnston M
        • Massicotte M.P
        • et al.
        Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy.
        Ann Intern Med. 1997; 126: 133-136
        • Crowther M.A
        • Ginsberg J.B
        • Kearon C
        • et al.
        A randomized trial comparing 5-mg and 10-mg warfarin loading doses.
        Arch Intern Med. 1999; 159: 46-48
        • Fennerty A
        • Dolben J
        • Thomas P
        • et al.
        Flexible induction dose regimen for warfarin and prediction of maintenance dose.
        BMJ (Clin Res Ed). 1984; 288: 1268-1270
        • Gedge J
        • Orme S
        • Hampton K.K
        • et al.
        A comparison of a low-dose warfarin induction regimen with the modified Fennerty regimen in elderly inpatients.
        Age Ageing. 2000; 29 ([see comments]): 31-34
        • Poller L
        • Wright D
        • Rowlands M
        Prospective comparative study of computer programs used for management of warfarin.
        J Clin Pathol. 1993; 46: 299-303
        • Vadher B
        • Patterson D.L
        • Leaning M
        Evaluation of a decision support system for initiation and control of oral anticoagulation in a randomised trial.
        BMJ. 1997; 314: 1252-1256
        • White R.H
        • Hong R
        • Venook A.P
        • et al.
        Initiation of warfarin therapy.
        J Gen Intern Med. 1987; 2: 141-148
        • Sun J
        • Chang M.W
        Initialization of warfarin dosages using computer modeling.
        Arch Phys Med Rehabil. 1995; 76: 453-456
        • Phillips W.S
        • Smith J
        • Greaves M
        • et al.
        An evaluation and improvement program for inpatient anticoagulant control.
        Thromb Haemost. 1997; 77: 283-288
        • Ellis R.F
        • Stephens M.A
        • Sharp G.B
        Evaluation of a pharmacy-managed warfarin-monitoring service to coordinate inpatient and outpatient therapy.
        Am J Hosp Pharm. 1992; 49: 387-394
        • Landefeld C.S
        • Anderson P.A
        Guideline-based consultation to prevent anticoagulant-related bleeding. A randomized, controlled trial in a teaching hospital.
        Ann Intern Med. 1992; 116: 829-837
        • Rospond R.M
        • Quandt C.M
        • Clark G.M
        • Bussey H.I
        Evaluation of factors associated with stability of anticoagulation therapy.
        Pharmacotherapy. 1989; 9: 207-213
        • Duxbury B.M
        Therapeutic quality control leading to further clinical assessment of oral anticoagulation.
        Acta Haematologica. 1986; 76: 65-67
        • Huber K.C
        • Gersh B.J
        • Bailey K.R
        • et al.
        Variability in anticoagulation control predicts thromboembolism after mechanical cardiac valve replacement.
        Mayo Clin Proc. 1997; 72: 1103-1110
        • McCurdy S.A
        • White R.H
        Accuracy and precision of a portable anticoagulation monitor in a clinical setting.
        Arch Intern Med. 1992; 152: 589-592
      2. Triplett DA. Current recommendations for warfarin therapy. Use and monitoring. Med Clin North Am. 1998;82:601–611.

        • Tiede D.J
        • Nishimura R.A
        • Gastineau D.A
        • et al.
        Modern management of prosthetic valve anticoagulation.
        Mayo Clin Proc. 1998; 73: 665-680
        • Brigden M.L
        • Kay C.L.A
        • Graydon C
        • McLeod B
        Audit of the frequency and clinical response to excessive oral anticoagulation in an out-patient population.
        Am J Hematol. 1998; 59: 22-27
        • Ryan P.J
        • Gilbert M
        • Rose P.E
        Computer control of anticoagulant dose for therapeutic management.
        BMJ. 1989; 299: 1207-1209
        • White R.H
        • Zhou H
        • Romano P
        • Mungall D
        Changes in plasma warfarin levels and variations in steady-state prothrombin times.
        Clin Pharmacol Ther. 1995; 58: 588-593
        • Britt R.P
        • James A.H
        • Raskino C.L
        • Thompson S.G
        Factors affecting the precision of warfarin treatment.
        J Clin Pathol. 1992; 45: 1003-1006
        • Fredriks D.A
        • Coleman R.W
        Nomogram for dosing warfarin at steady state.
        Clin Pharm. 1991; 10: 923-927
        • Ansell J.E
        • Patel N
        • Ostrovsky D
        • et al.
        Long-term patient self-management of oral anticoagulation.
        Arch Intern Med. 1995; 155: 2185-2189
        • Hathaway W.E
        • Goodnight S.H
        Disorders of Hemostasis and Thrombosis. McGraw-Hill Health Professions Division, New York1993
        • Ansell J.E
        • Buttaro M.L
        • Thomas O.V
        • Knowlton C.H
        Consensus guidelines for coordinated outpatient oral anticoagulation therapy management. Anticoagulation Guidelines Task Force.
        Ann Pharmacother. 1997; 31: 604-615
        • White R.H
        • Mungall D
        Outpatient management of warfarin therapy.
        Ther Drug Monit. 1991; 13: 46-50
        • Galloway M.J
        • Foggin J.J
        • Dixon S
        Introduction of computer assisted control of oral anticoagulation in general practice.
        J Clin Pathol. 1995; 48: 1144-1146
        • Wilson R
        • James A.H
        Computer assisted management of warfarin treatment.
        BMJ (Clin Res Ed). 1984; 289: 422-424
        • Poller L
        • Shiach C.R
        • MacCallum P.K
        • et al.
        Multicentre randomised study of computerised anticoagulant dosage.
        Lancet. 1998; 352: 1505-1509
        • Ageno W
        • Turpie A.G
        A randomized comparison of a computer-based dosing program with a manual system to monitor oral anticoagulant therapy.
        Thromb Res. 1998; 91: 237-240
        • Kubie A
        • James A.H
        • Timms J
        • Britt R.P
        Experience with a computer-assisted anticoagulant clinic.
        Clin Lab Haematol. 1989; 11: 385-391
        • Johnston M.E
        • Langton K.B
        • Haynes R.B
        • Mathieu A
        Effects of computer-based clinical decision support systems on clinician performance and patient outcome. A critical appraisal of research.
        Ann Intern Med. 1994; 120: 135-142
        • Fitzmaurice D.A
        • Hobbs F.D
        • Murray E.T
        • et al.
        Evaluation of computerized decision support for oral anticoagulation management based in primary care.
        Br J Gen Pract. 1996; 46: 533-535
        • Margolis A
        • Flores F
        • Kierszenbaum M
        • et al.
        Warfarin 2.0—a computer program for warfarin management. Design and clinical use.
        Proc Ann Sympos Comput Applic Med Care. 1994; 17: 846-850
        • Lee C
        • Coleman R.W
        • Mungall D.R
        Effect of using warfarin plasma concentrations in Bayesian forecasting of prothrombin-time response.
        Clin Pharm. 1987; 6: 406-412
        • Arnsten J.H
        • Gelfand J.M
        • Singer D.E
        Determinants of compliance with anticoagulation.
        Am J Med. 1997; 103: 11-17
        • Fairweather R.B
        • Ansell J
        • van den Besselaar A.M
        • et al.
        College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy.
        Arch Pathol Lab Med. 1998; 122: 768-781
        • Fihn S.D
        • McDonell M
        • Martin D
        • et al.
        Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group.
        Ann Intern Med. 1993; 118: 511-520
        • Landefeld C.S
        • Goldman L
        Major bleeding in outpatients with warfarin.
        Am J Med. 1989; 87: 144-152
        • Ezekowitz M.D
        • James K.E
        • Radford M.J
        • et al.
        Initiating and maintaining patients on warfarin anticoagulation.
        J Cardiovasc Pharmacol Ther. 1999; 4: 3-8
        • Oates A
        • Jackson P.R
        • Austin C.A
        • Channer K.S
        A new regimen for starting warfarin therapy in out-patients.
        Br J Clin Pharmacol. 1998; 46: 157-161
        • Fihn S.D
        • McDonell M.B
        • Vermes D
        • et al.
        A computerized intervention to improve timing of outpatient follow-up.
        J Gen Intern Med. 1994; 9: 131-139
        • Shah V.P
        • Yacobi A
        • Barr W.H
        • et al.
        Evaluation of orally administered highly variable drugs and drug formulations.
        Pharm Res. 1996; 13: 1590-1594
        • Kumar S
        • Haigh J.R
        • Rhodes L.E
        • et al.
        Poor compliance is a major factor in unstable outpatient control of anticoagulant therapy.
        Thromb Haemost. 1989; 62: 729-732
        • Sorano G.G
        • Biondi G
        • Conti M
        • et al.
        Controlled vitamin K content diet for improving the management of poorly controlled anticoagulated patients.
        Haemostasis. 1993; 23: 77-82
        • Michelson A.D
        • Bovill E
        • Monagle P
        • Andrew M
        Antithrombotic therapy in children.
        Chest. 1998; 114: 748-769
        • Horton J.D
        • Bushwick B.M
        Warfarin therapy.
        Am Fam Physician. 1999; 59: 635-646
        • Palareti G
        • Legnani C
        • Guazzaloca G
        • et al.
        Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants—a prospective study.
        Thromb Haemost. 1994; 72: 222-226
        • Hylek E.M
        • Singer D.E
        Risk factors for intracranial hemorrhage in outpatients taking warfarin.
        Ann Intern Med. 1994; 120: 897-902
        • Palareti G
        • Leali N
        • Coccheri S
        • et al.
        Bleeding complications of oral anticoagulant treatment.
        Lancet. 1996; 348: 423-428
        • Cannegieter S.C
        • Rosendaal F.R
        • Wintzen A.R
        • et al.
        Optimal oral anticoagulant therapy in patients with mechanical heart valves.
        N Engl J Med. 1995; 333: 11-17
        • 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: 5-10
        • Azar A.J
        • Cannegieter S.C
        • Deckers J.W
        • et al.
        Optimal intensity of oral anticoagulant therapy after myocardial infarction.
        J Am Coll Cardiol. 1996; 27: 1349-1355
        • van der Meer F.J.M
        • Rosendaal F.R
        • Vandenbroucke J.P
        • Brie E
        Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants.
        Thromb Haemostasis. 1996; 76: 12-16
        • Shetty H.G
        • Backhouse G
        • Bentley D.P
        • Routledge P.A
        Effective reversal of warfarin-induced excessive anticoagulation with low dose vitamin K1.
        Thromb Haemost. 1992; 67: 13-15
        • Weibert R.T
        • Le D.T
        • Kayser S.R
        • Rapaport S.I
        Correction of excessive anticoagulation with low-dose oral vitamin K1.
        Ann Intern Med. 1997; 126: 959-962
        • White R.H
        • McKittrick T
        • Hutchinson R
        • Twitchell J
        Temporary discontinuation of warfarin therapy.
        Ann Intern Med. 1995; 122: 40-42
        • Hylek E.M
        • Chang Y.C
        • Skates S.J
        • et al.
        Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation.
        Arch Intern Med. 2000; 160: 1612-1617
        • Taylor C.T
        • Chester E.A
        • Byrd D.C
        • Stephens M.A
        Vitamin K to reverse excessive anticoagulation.
        Pharmacotherapy. 1999; 19: 1415-1425
        • Brophy M.T
        • Fiore L.D
        • Deykin D
        Low-dose Vitamin K in excessively anticoagulated patients.
        J Thromb Thrombolysis. 1997; 4: 289-292
        • O’Reilly R.A
        • Kearns P
        Intravenous vitamin K1 injections.
        Arch Intern Med. 1995; 155: 2127
        • Lousberg T.R
        • Witt D.M
        • Beall D.G
        • et al.
        Evaluation of excessive anticoagulation in a group model health maintenance organization.
        Arch Intern Med. 1998; 158: 528-534
        • Poller L
        Guidelines on oral anticoagulation.
        British Society for Haematology; British Committee for Standards in Haematology. Haemostasis and Thrombosis Task Force. J Clin Pathol. 1990; 43: 177-183
        • Kasper C.K
        Thromboembolic complications.
        Thrombos Diathes Haemorrh. 1975; 33: 640-644
      3. Physicians’ Desk Reference. 48th ed. Montvale, NJ: Medical Economics; 1994:1404–5.

        • Fetrow C.W
        • Overlock T
        • Leff L
        Antagonism of warfarin-induced hypoprothrombinemia with use of low-dose subcutaneous vitamin K1.
        J Clin Pharmacol. 1997; 37: 751-757
        • van der Meer J
        • Hemker H.C
        • Loeliger E.A
        Pharmacological aspects of Vitamin K1.
        Thrombos Diathes Haemorrh. 1968; 29: 1-96
        • Whitling A.M
        • Bussey H.I
        • Lyons R.M
        Comparing different routes and doses of phytonadione for reversing excessive anticoagulation.
        Arch Intern Med. 1998; 158: 2136-2140
        • Raj G
        • Kumar R
        • McKinney W.P
        Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione.
        Arch Intern Med. 1999; 159: 2721-2724
        • Byars T.D
        • Greene C.E
        • Kemp D.T
        Antidotal effect of vitamin K1 against warfarin-induced anticoagulation in horses.
        Am J Vet Res. 1986; 47: 2309-2312
        • Crowther M.A
        • Donovan D
        • Harrison L
        • McGinnis J
        • Ginsberg J
        Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin.
        Thromb Haemost. 1998; 79: 1116-1118
        • Pengo V
        • Banzato A
        • Garelli E
        • et al.
        Reversal of excessive effect of regular anticoagulation.
        Blood Coagul Fibrinolysis. 1993; 4: 739-741
        • Schirger A
        • Spittel J.A
        • Ragen P.A
        Small doses of vitamin K1 for correction of reduced prothrombin activity.
        Proc Mayo Clinic. 1959; 34: 453-458
        • Cosgriff S.W
        The effectiveness of an oral vitamin K1 in controlling excessive hypoprothrombinemia during anticoagulant therapy.
        Ann Intern Med. 1956; 45: 14-22
        • Harrell C.C
        • Kline S.S
        Oral vitamin K1.
        Ann Pharmacother. 1995; 29: 1228-1232
        • Makris M
        • Greaves M
        • Phillips W.S
        • et al.
        Emergency oral anticoagulant reversal.
        Thromb Haemost. 1997; 77: 477-480
        • Development Task Force of the College of American Pathologists
        Practice parameter for the use of fresh-frozen plasma, cryoprecipitate, and platelets.
        JAMA. 1994; 271: 777-781
        • Cohen H
        Avoiding the misuse of fresh frozen plasma.
        BMJ. 1993; 307: 395-396
        • Madura J.A
        • Rookstool M
        • Wease G
        The management of patients on chronic Coumadin therapy undergoing subsequent surgical procedures.
        Am Surg. 1994; 60: 542-547
        • Nee R
        • Doppenschmidt D
        • Donovan D.J
        • Andrews T.C
        Intravenous versus subcutaneous vitamin K1 in reversing excessive oral anticoagulation.
        Am J Cardiol. 1999; 83: 286-288
        • Shearer M.J
        • McBurney A
        • Barkhan P
        Studies on the absorption and metabolism of phylloquinone (vitamin K1) in man.
        Vitam Horm. 1974; 32: 513-542
      4. Bjornsson TD, Blaschke TF. Vitamin K1 disposition and therapy of warfarin overdose. Lancet. 1978;2:846–847. Letter.

        • Sawicki P.T
        • Working Group for the Study of Patient Self-Management of Oral Anticoagulation
        A structured teaching and self-management program for patients receiving oral anticoagulation.
        JAMA. 1999; 281: 145-150
      5. Doggette AL, Banet GA, Milligan P, Frazier A, Verzino E, Walton B, Gage BF. Patient and physician satisfaction with a telephone-based anticoagulation service. J Gen Intern Med. 2000. In press.

      6. Beyth RJ, Quinn L, Landefeld CS. A multi-component intervention to prevent major bleeding complications in older patients on warfarin: A randomized controlled trial. Ann Intern Med 2000. In press.

        • Garabedian-Ruffalo S.M
        • Gray D.R
        • Sax M.J
        • Ruffalo R
        Retrospective evaluation of a pharmacist-managed warfarin anticoagulation clinic.
        Am J Hosp Pharm. 1985; 42: 304-308
        • Cortelazzo S
        • Finazzi G
        • Viero P
        • et al.
        Thrombotic and hemorrhagic complications in patients with mechanical heart valve prosthesis attending an anticoagulation clinic.
        Thromb Haemostas. 1993; 69: 316-320
        • Wilt V.M
        • Gums J.G
        • Ahmed O.I
        • Moore L.M
        Outcome analysis of a pharmacist-managed anticoagulation service.
        Pharmacotherapy. 1995; 15: 732-739
        • Chiquette E
        • Amato M.G
        • Bussey H.I
        Comparison of an anticoagulation clinic with usual medical care.
        Arch Intern Med. 1998; 158: 1641-1647
        • White R.H
        • McCurdy S.A
        • von Marensdorff H
        • et al.
        Home prothrombin time monitoring after the initiation of warfarin therapy. A randomized, prospective study.
        Ann Intern Med. 1989; 111: 730-737
        • Anderson D.R
        • Harrison L
        • Hirsh J
        Evaluation of a portable prothrombin time monitor for home use by patients who require long-term oral anticoagulant therapy.
        Arch Intern Med. 1993; 153: 1441-1447
        • Wells P.S
        • Holbrook A.M
        • Crowther N.R
        • Hirsh J
        Interactions of warfarin with drugs and food.
        Ann Intern Med. 1994; 121: 676-683
      7. Drug Interaction Facts. 1.0 ed. St. Louis: Facts and Comparisons; 1998.