Warfarin Therapy Management

Effective Date: April 1, 2015

Recommendations and Topics

This guideline provides recommendations for the long-term management of warfarin therapy in patients aged ≥19 years in the primary care setting. The guideline describes: 1) warfarin initiation, 2) international normalized ratio (INR) monitoring with optimal ranges, and 3) warfarin dosage adjustment. This guideline assumes the physician has reviewed the indications for warfarin and the duration of therapy as these are not discussed in this guideline. Perioperative management of warfarin is covered in the BCGuidelines.ca - Warfarin Therapy – Management During Invasive Procedures and Surgery.

This guideline is part of the BCGuidelines.ca - Stroke and Atrial Fibrillation series. The series includes three other guidelines: Stroke and Transient Ischemic Attack – Acute and Long-Term Management; Atrial Fibrillation – Diagnosis and Management; and Use of Non-Vitamin K Antagonist Oral Anticoagulants (NOAC) in Non-Valvular Atrial Fibrillation.

Key Recommendations

  • Warfarin should be dosed to achieve the target therapeutic INR for the specific indication. Under- or over-anticoagulation is associated with high risks of thrombosis and bleeding.
  • Consider using a standard dosing nomogram or computerized decision-support software to maximize the time in therapeutic range.
  • Patients are advised to maintain a stable and consistent intake of vitamin K in their diet and not avoid vitamin K-containing foods.
  • Patient and caregiver education is necessary to promote compliance and stability of warfarin anticoagulation.

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Description

Warfarin therapy reduces the risk of thromboembolic events and has demonstrated effectiveness for the prevention of stroke in patients with atrial fibrillation (AF).1-3 Approximately 44,000, or 6%, of British Columbians > 65 years live with AF.4,5 Studies have shown that warfarin therapy could reduce the risk of stroke in these patients by about 66%.3  Approximately a third of the patients who would benefit from warfarin never receive it, and over half of those who do receive warfarin are managed suboptimally1,6 because of the complex pharmacology and numerous drug, disease, dietary and herbal interactions.

Warfarin is given orally and is absorbed rapidly and completely.6-8 Absorption is not impacted by food. It is almost fully bound to albumin in blood; thus hypoalbuminemic patients (e.g., malnourished, liver disorders, post-operative, etc.) need lower doses. An effect on the INR generally occurs within 24 hours after drug administration. However, the full anticoagulant effect may be delayed for 5-7 days due to the long half-life of prothrombin.6

The major challenge in warfarin therapy is its narrow therapeutic range. Over-anticoagulation may lead to hemorrhage while under-anticoagulation can result in thrombosis. Bleeding is the most serious complication of warfarin therapy.9-12 The average yearly bleeding rates vary widely depending on patient lifestyle, co-morbidities and the concomitant use of antiplatelet drugs. Estimated annual incidences are 0.6% for fatal bleeding, 3.0% for major bleeding, and 9.6% for minor bleeding.11-12 

A good warfarin management plan, including ongoing patient education, follow-up, dosing tools, and involved caregivers/other health professionals, can maximize the benefit to harm ratio. The time in therapeutic range (TTR) is an accepted measure of the quality of warfarin dosing and INR control. It represents the proportion of treatment time that a patient’s INR is within the therapeutic range. Most experts agree that the optimal or acceptable TTR is 65% or higher.

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Management

Warfarin management can be challenging. Dosing tools, ranging from paper-based nomograms to computerized decision-support software programs, are available and have been shown to improve the TTR (see Resources section). Patient and caregiver education is also essential to maximize compliance and maintain stability.

Initiation of Warfarin Therapy

Prior to initiating warfarin treatment:

  1. Consider the contraindications below in Table 1. All contraindications are relative to a patient’s risk for thrombosis weighed against the risk for bleeding (refer to Table 2 below) while on vitamin K antagonist anticoagulation therapy.13  
  2. Establish the baseline INR in every case and will guide further therapy.
  3. Discuss with the patient potential drug and diet interactions, the need for monitoring and signs of over- and under anticoagulation. For more information, refer to the Patient Education and Resources section below.

Table 1. Warfarin contraindications*

Pregnancy: If possible, warfarin therapy should be avoided during pregnancy.28 If warfarin therapy is essential, it should be avoided at least during the first trimester (because of teratogenicity) and from about 2 - 4 weeks before delivery to reduce risk of hemorrhagic complications. Unfractionated heparin or low molecular weight heparin could be substituted when appropriate because these agents do not cross the placenta and are considered the anticoagulant drugs of choice during pregnancy. Consider referral to hematologist and obstetrician.

Table 2. Risk factors for bleeding complications of anticoagulation therapy6,9,13

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Initial Warfarin Dose

Initial dose of warfarin is typically 5 mg/day in most patients.14,15 A starting dose of < 5 mg may be considered for patients > 70 years of age, elevated baseline INR > 1.1, hypoalbuminemic patients (e.g., malnourished, liver disorders, post-operative), impaired nutrition (weight < 45 kg), heart failure, known to take medications that increase sensitivity of warfarin (Appendix A: Important Interactions with Warfarin), or previously documented increased sensitivity to warfarin.1,16 

Whenever feasible, a single strength warfarin tablet (highly recommend 1 mg only for safety and dose flexibility) should be prescribed such that doses are multiples of one tablet strength. Patients should take their warfarin once a day at the same time in the evening, and have their INR test performed in the morning. This limits diurnal variations and provides the physician with a same day window for dosage adjustment in the event of an unanticipated INR change.

Pharmacogenetics-based therapy has been suggested in the estimation of the therapeutic warfarin dose by genotyping patients for single nucleotide polymorphisms that affect warfarin metabolism or sensitivity. Although Health Canada has updated the label of warfarin to include information on pharmacogenetic testing, there is currently no evidence that genotyping will improve clinically relevant outcomes in individual patients.1,6,17,18

INR Target and Frequency of Monitoring

The optimal maintenance dose for warfarin varies from patient to patient and at different times in the same patient.6,19-21 There is no maximal or minimal dose to maintain a therapeutic range. The actual dose is not important and can range from 0.5 - 20 mg or higher daily. Asians tend to require lower doses while Blacks tend to use higher doses because of the differences in genetic polymorphisms in these populations.

Two therapeutic ranges are recommended, depending on the indication for anticoagulation.

Under-anticoagulation can result in stroke, recurrent venous or arterial thrombosis, while over-anticoagulation can produce minor or major hemorrhagic complications. The narrow therapeutic index and a high risk/benefit ratio necessitate close and long-term monitoring. During the first few days of treatment, the INR rises without concomitant clinical anticoagulant effect. Moreover, during the maintenance phase, dose changes may not be reflected in INR for 4 - 5 days. For these reasons, frequent dose changes are not recommended.

During the induction or initiation phase, it is recommended that INR be monitored every 2 - 4 days (initially daily if on therapeutic heparin) until the INR is in the patient’s target range for two consecutive values. Once the INR is stabilized within the patient’s target range, it can be monitored weekly. The interval can be gradually increased up to every 4 weeks if the INR remains stable and within the therapeutic range. Monitoring frequency of up to 12 weeks can be considered in patients with stable and therapeutic INRs whose doses have been unchanged for at least 3 months.23 For more information INR monitoring, refer to Figure 1 below. 

Figure 1. Recommended Frequency of INR Monitoring

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Dosage Adjustment & Maintenance Therapy

Dosage adjustment is not required for minor fluctuations of INR as long as the results remain within the patient’s target range. Fluctuations of INR beyond the patient’s target range should always prompt a direct communication with patient to determine cause. Consider causes such as a change in dosage of warfarin, patient adherence, medications including over-the-counter (OTCs), dietary changes, unusual alcohol consumption and intercurrent illness. For further dosage adjustment information, refer to Table 3 below.

The recent trend is to change the total weekly warfarin dose (TWD).15 For example, if the patient is taking 5 mg/day, the weekly dose is 35 mg. If the dose must be decreased by 10%, then the weekly dose should be 35 mg - 3.5 mg = 31.5 mg and the daily dose becomes 31.5 mg/7 = 4.5 mg.

Table 3. Dosage adjustments for patients on warfarin maintenance therapy (Target INR 2.0 – 3.0 or 2.5 or 3.5, No significant bleeding)

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Bleeding Complications

The most common sites of serious bleeding are gastrointestinal tract, genitourinary tract, and soft tissues including wounds.10 An underlying cause should always be sought, especially if the INR is within the therapeutic range or lower.

If patient’s clinical status is compromised due to bleeding, admit to an acute care facility for assessment and management. Bleeding with a high potential for complications (e.g., elderly, propensity to fall) requires clinical judgement to determine whether to manage within the office setting or to send to an acute care facility. The patient should be followed using the Associated Document: Warfarin Patient Record Sheet (or a similar log sheet) and encouraged to keep their own record.

If patient is to undergo an invasive procedure or surgery, refer to BCGuidelines.ca - Warfarin Therapy – Management During Invasive Procedures and Surgery.

Use of Vitamin K

If required, oral vitamin K therapy is a safe, effective and convenient treatment for overcoagulation.29,30  Subcutaneous vitamin K should be avoided as it may be absorbed unpredictably. Likewise, intramuscular vitamin K should be avoided as it promotes intramuscular haemorrhage. Intravenous vitamin K is the most predictable30 but can cause facial flushing, diaphoresis, chest pain, hypotension, dyspnea, and, rarely, anaphylaxis, and should be given only in emergency situations and by slow infusion.

Some effect of oral vitamin K therapy on INR is usually observed within 24 hours and with intravenous vitamin K in 6-8 hours.29,30 Patients who have received vitamin K, particularly parenteral doses above 5-10 mg, may be difficult to reanticoagulate. Accordingly, doses of vitamin K should be kept as low as feasible. An oral formulation of vitamin K is no longer available in Canada; most pharmacies administer oral doses of the parenteral preparation in juice or water. Oral vitamin K therapy may not be appropriate for patients with disorders that may affect the absorption of vitamin K such as biliary obstruction, liver insufficiency or other malabsorptive syndromes.

If emergency reversal of warfarin is required for life and limb threatening haemorrhage, plasma or prothrombin complex concentrate (Octaplex®) may be used in consultation with a specialist. For further information on the use of vitamin K in the perioperative period, see BCGuidelines.ca - Warfarin Therapy – Management During Invasive Procedures and Surgery.

Alternatives to Warfarin

Nicoumalone (Sintrom®) is a vitamin K antagonist available for patients allergic to warfarin. Several new orally administered alternatives to warfarin are approved for use in Canada for thromboprophylaxis during joint replacement or for stroke prevention in atrial fibrillation or treatment of thrombosis. The use of non-Vitamin K antagonist oral anticoagulants (NOAC; formally known as novel oral anticoagulant) in the prevention of stroke and systemic embolism in patients, aged ≥ 19 years, with non-valvular atrial fibrillation is discussed within the BCGuidelines.ca - Use of Non-Vitamin K Antagonist Oral Anticoagulants (NOAC) in Non-Valvular Atrial Fibrillation.

Patient Education

Warfarin is more likely to be used safely by a patient who is aware of the potential for drug and diet interactions, understands the need for monitoring, and can recognize the signs of over- and under- anticoagulation. For patient resources, refer to the Resources section below.

The effect of warfarin may be inhibited by very high dietary or supplemental vitamin K intake. However, it is not necessary to advise patients to avoid or limit vitamin K intake. It is generally recommended that patients on warfarin try to consume the adequate intake for vitamin K (90-120 mg),31 while avoiding large fluctuations in vitamin K intake that might interfere with the adjustment of their anticoagulant dose.

At the initiation of warfarin therapy, it is recommended to discuss the following with the patient and/or other care providers:

  • The reason for prescribing warfarin and duration of treatment.
  • The need to adhere with recommended warfarin dosage.
  • The importance of monitoring and the patient’s target INR.
  • The need to take warfarin once a day → Recommend a routine of taking warfarin at the same time in the evening, and test INR in the morning, along with the use of a daily pill box to assist with improving compliance with warfarin therapy.
  • Side effects, signs of bleeding and potential need for blood products → Set-up an agreed upon system of communication when side effects or changes occur.
  • When to call the doctor or seek urgent attention at an emergency facility → Encourage wearing a MedicAlert® bracelet or necklace to assist with care in an emergency.
  • The need for caution when initiating or stopping other medications (including ASA), herbs or supplements → Review of current medications (prescription & non-prescription), herbal supplements and diet for potential interactions.
  • The importance of consistent vitamin K content in the diet.
  • The need to avoid heavy or variable alcohol consumption.
  • Influence of intercurrent illness.
  • The importance of avoiding pregnancy while taking warfarin (if applicable).
  • The importance of not changing brands of warfarin.
  • The need to avoid intramuscular injections → For flu shots, recommend that a firm, prolonged pressure is applied for several minutes after a deltoid injection.

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Resources

References

  1. Garcia D, Regan S, Crowther M, et al. Warfarin maintenance dosing patterns in clinical practice. Chest 2005;127:2049-2056.
  2. Srivastava A, Hudson M, Hamoud I, et al. Examining warfarin underutilization rates in patients with atrial fibrillation: Detailed chart review essential to capture contraindications to warfarin therapy. Thromb J. 2008;6:6.
  3. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867.
  4. Sacco RL, Benjamin EJ, Broderick JP, et al. Risk Factors Panel. Stroke 1997;28:1507-1517.
  5. BC Stats [Internet]. Victoria: Government of British Columbia; 2014 [cited 2014 Jan 23].
  6. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the Vitamin K antagonist: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th ed. Chest 2008;133:123S-131S.
  7. Brigden ML. Oral anticoagulant therapy: Practical aspects of management. Postgrad Med. 1996;99:81-84,87-89,93-94 passim.
  8. Hirsh J, Dalen J, Anderson DR et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119:8S-21S.
  9. Schulman S, Beyth RJ, Kearon C, et al. Hemorrhagic complications of anticoagulant treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th ed. Chest 2008;133:257S-298S.
  10. Beyth RJ. Hemorrhagic complications of oral anticoagulant therapy. Clin Geriatr Med. 2001;17:49-56.
  11. Dahri K, Loewen P. The risk of bleeding with warfarin: A systematic review and performance analysis of clinical prediction rules. Thromb Haemost. 2007;98:980-987.
  12. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. AM J Med. 1993;95:315-28.
  13. Maddali S, Biring T, Bluhm J, et al. Institute for Clinical Systems Improvement. Antithrombotic Therapy Supplement. Updated February 2013 Available at: www.icsi.org (accessed October 2014).
  14. 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;126:133-136.
  15. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5mg and 10 mg warfarin loading doses. Arch Intern Med. 1999;159:46-48.
  16. Ageno W, Steidl L, Ultori C, et al. The initial phase of oral anticoagulation with warfarin in outpatients with deep venous thrombosis. Blood Coagul Fibrinolysis. 2003;14:11-14.
  17. Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007;116:2563–2570.
  18. Gage BF, Eby C, Johnson JA, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Nature 2008;84:326-331.
  19. Keeling DM, Baglin TP, Watson HG, et al. Guidelines on oral anticoagulation with warfarin - fourth edition, Br J Haematol. 2011;154:311-324.
  20. Gage BF, Fihn SD, White RH. Management and dosing of warfarin therapy. Am J Med. 2000;109:481-488.
  21. Hylek EM. Oral anticoagulants. Pharmacologic issues for use in the elderly. Clin Geriatr Med. 2001;17:1-13.
  22. Salem DN, O’Gara PT, Madias C, et al. Valvular and Structural Heart Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th ed. Chest 2008;133;593S-629S.
  23. 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(Suppl):e152S–e184S.
  24. Goodnight SH, Hathaway WE, editors. Disorders of hemostasis and thrombosis: a clinical guide. 2nd ed. New York: McGraw Hill; 2001.
  25. Banet GA, Waterman AD, Milligan PE, et al. Warfarin dose reduction vs watchful waiting for mild elevations in the International Normalized Ratio. Chest 2003;123;499-503.
  26. Fitzmaurice D, Blann A, Lip GYH. Bleeding risks of antithrombotic therapy. BMJ. 2002;325:828-831.
  27. Baker RI, Coughlin PB, Gallus AS, et al. Warfarin reversal: Consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis, Medical Journal Australia 2004;181:492-497.
  28. Abadi S, Einarson A, Koren G. Use of warfarin during pregnancy. Can Fam Physician. 2002;48:695-697.
  29. Pendry K, Bhavnani M, Shwe K. The use of oral vitamin K for reversal of over-warfarinization. Br J Haematol. 2001;113:839-840.
  30. Watson HG, Baglin T, Laidlaw SL, et al. A comparison of the efficacy and rate of response to oral and intravenous vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol. 2001;115:145-149.
  31. Health Canada. [Internet]. Ottawa: Dietary reference intakes: Reference values for vitamins; 2010 [cited 2014 Dec 19].

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Resources

  • Thrombosis Canada, thrombosiscanada.ca, for patient information and dosing tools (paper-based nomograms and computerized decision-support software programs).
  • Coumadin, www.coumadin.com, for patient information.
  • HealthLink BC, www.healthlinkbc.ca, for more information on warfarin and vitamin K.

Appendices

Associated Documents

The following documents accompany this guideline:

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This guideline is based on scientific evidence current as of the Effective Date.

This guideline was developed by the Guidelines and Protocols Advisory Committee, approved by the British Columbia Medical Association, and adopted by the Medical Services Commission.

The principles of the Guidelines and Protocols Advisory Committee are to:

  • encourage appropriate responses to common medical situations
  • recommend actions that are sufficient and efficient, neither excessive nor deficient
  • permit exceptions when justified by clinical circumstances.

Contact Information

Guidelines and Protocols Advisory Committee
PO Box 9642 STN PROV GOVT
Victoria BC V8W 9P1

E-mail: hlth.guidelines@gov.bc.ca

Web site: www.BCGuidelines.ca

 


Disclaimer

The Clinical Practice Guidelines (the “Guidelines”) have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.