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B.C. Home » Ministry of Health » BC Guidelines & Protocols » Warfarin Therapy Management

Warfarin Therapy Management

Effective Date: October 1, 2010

Summary | Flow Sheet | Patient Guide | Full Guideline in PDF

Recommendations and Topics

Scope

This guideline applies to long term management of warfarin therapy in adults, 19 years and over, within the office 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 BC Guideline Warfarin Therapy - Management During Invasive Procedures and Surgery.

Initiation of Warfarin

1) Consider Contraindications - Prior to initiating warfarin treatment consider the contraindications below. All contraindications are relative to a patient's risk for thrombosis weighed against the risk for bleeding (Table 2) while on vitamin K antagonist anticoagulation therapy.¹ For a complete list of contraindications, refer to the product monograph.

Absolute Contraindications	Some Relative Contraindications
The presence of a severe or active bleeding diathesis Non-adherence to medication and INR monitoring Pregnancy2 (avoided at least during the first trimester and from about 2 to 4 weeks before delivery) Allergy or intolerance to warfarin (consider warfarin alternative - Nicoumalone)	Uncontrolled hypertension (greater than 180/100 mm Hg) Severe liver disease Recent surgery and procedures involving the nervous system, spine or eye

2) Establish baseline INR - Should be done in every case and will guide further therapy.

3) Initial Dose - Initial dose of warfarin is typically 5 mg/day in most patients.^3,4 A starting dose of less than 5 mg may be considered for patients greater than 70 years of age, elevated baseline INR greater than 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), or previously documented increased sensitivity to warfarin.^5,6

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.^6-9

4) INR Target and Frequency of Monitoring - The optimal maintenance dose for warfarin to enable a therapeutic INR varies from patient to patient and at different times in the same patient.^9-12 There is no maximal or minimal dose to maintain a therapeutic range. Two therapeutic ranges are recommended, depending on the indication for anticoagulation.

Under-anticoagulation can result in 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. Below is a flowchart outlining the recommended INR testing interval.

Recommended INR Testing Interval

5) 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 compliance, medications including OTCs, dietary changes, unusual alcohol consumption, or intercurrent illness.

The recent trend is to change the total weekly warfarin dose (TWD).¹⁵ For example, if the patient is taking 5mg/day, the weekly dose is 35mg. 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 1: Dosage Adjustments for Patients on Warfarin Maintenance Therapy (Target INR 2.0 - 3.0 or 2.5 - 3.5, No Significant Bleeding)
INR	Intervention (Refer to flowchart above for timing of next INR)
≤ 1.5	Give one time top-up equal to 20% of weekly dose and increase weekly dose by 10-20%
1.5 < INR < therapeutic range	No change in dose If two consecutive INRs are low, increase weekly dose by 10-20%
INR in therapeutic range	No change
INR > therapeutic range but < 5.0	Lower weekly dose (10-20%) or consider omitting one single dose Increase the frequency of INR monitoring and resume therapy at 10-20% lower weekly dose when INR therapeutic Note: If the INR is only minimally elevated (0.1 - 0.4 above upper limit of the therapeutic range), dose reduction may not be necessary14
INR 5.0 – 9.0*	Omit 1 to 2 doses then recheck INR Increase the frequency of INR monitoring and resume therapy at 10-20% lower weekly dose when INR therapeutic If the patient is at high risk of serious bleeding, consider administering vitamin K** 1 to 2 mg orally
>9.0; no bleeding	Discontinue warfarin temporarily, consider administering vitamin K 2-5 mg orally then recheck INR*** Increase the frequency of INR monitoring and resume therapy at 20% lower weekly dose when INR therapeutic Give additional vitamin K if INR is not substantially reduced by 24 hrs***

Notes:

• 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 Warfarin Record Sheet (attached) 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.

Table 2: Risk Factors for Bleeding Complications of Anticoagulation Therapy1,9,18
Risk Factor Category	Specific Risk Factors
Age Time Period Cardiac Gastrointestinal Hematologic/Oncologic Neurologic Renal Trauma Alcohol Medications	> 70 years Within first year of warfarin treatment Uncontrolled hypertension, heart failure History of gastrointestinal haemorrhage, active peptic ulcer,hepatic insufficiency Thrombocytopenia, platelet dysfunction, coagulation defect,underlying malignancy History of stroke, cognitive or psychological impairment Renal insufficiency Recent trauma, history of falls Excessive alcohol intake Use of aspirin or other NSAIDs; Discontinuing medications that reduce INR; See Medication Interaction Table

Adapted from: Warfarin Reversal Position Statement, Australasian Society of Thrombosis & Hematosis¹⁹

The most common sites of serious bleeding are gastrointestinal tract, genitourinary tract, and soft tissues including wounds.²⁰ An underlying cause should always be sought, especially if the INR is within the therapeutic range or lower.

6) 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. The effect of warfarin may be inhibited by very high dietary or supplemental vitamin K intake. It is generally recommended that patients on warfarin try to consume the adequate intake for vitamin K (90-120 μg),²¹ while avoiding large fluctuations in vitamin K intake that might interfere with the adjustment of their anticoagulant dose . A separate resource guide, including resources with patient information sheets, is available with these guidelines and should be discussed with the patient.

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

• 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 their warfarin once a day, preferably at the same time in the evening, and to have their INR test performed in the morning
• 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
• strongly encourage to wear Medic Alert bracelets or necklaces to assist with care in an emergency
• review of current medications (prescription & non-prescription), herbal supplements and diet for potential interactions
• the need for caution when initiating or stopping other medications (including ASA), herbs or supplements
• the use of a daily pill box to assist with improving patient compliance with warfarin therapy
• 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 - physicians are recommended to apply firm, prolonged pressure for several minutes after a deltoid injection)

Rationale

Warfarin therapy reduces the risk of thromboembolic events. There has been an extraordinary increase in the use of warfarin over the past decade, mainly because of aging of the population, and the demonstration of its benefit in atrial fibrillation.^6,22,23 Studies have shown that warfarin therapy could reduce these patients risk of stroke by about 66%.²³ Unfortunately, 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 suboptimally because of the complex pharmacology and numerous drug, disease, dietary and herbal interactions.^6,9

Warfarin is given orally and is absorbed rapidly and completely.^9,26,27 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 to 7 days due to the half-life of prothrombin.⁹

The major challenge in warfarin therapy is its narrow therapeutic range. Even a mild degree of over-anticoagulation may lead to haemorrhage. Bleeding is the most serious complication of warfarin therapy.^18,20,24,25 The average yearly bleeding rates vary widely depending on study design. Estimated annual incidences are 0.6% for fatal bleeding, 3.0% for major bleeding, and 9.6% for minor bleeding.^24,25 A good warfarin management plan can reduce bleeding risk.

Pregnancy: If possible, warfarin therapy should be avoided during pregnancy.² If warfarin therapy is essential, it should be avoided at least during the first trimester (because of teratogenicity) and from about 2 to 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.

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 predictable,³⁰ but can cause facial flushing, diaphoresis, chest pain, hypotension, dyspnea, anaphylaxis and cerebral thrombosis, 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 the 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 either in clinical trial or approved for limited use in Canada for thromboprophylaxis during joint replacement or for stroke prevention in atrial fibrillation or treatment of thrombosis. It is not within the scope of this guideline on warfarin management to discuss the relative risks and benefits of these agents. Physicians are encouraged to stay abreast of new evidence but exercise caution when using new medications.

References

1. Burnett B, et al. Institute for Clinical Systems Improvement. Health Care Guideline Supplement. Anticoagulation Therapy Supplement 2009. Available at: www.icsi.org (accessed June 2009).
2. Abadi S, Einarson A, Koren G. Use of warfarin during pregnancy. Canadian Family Physician 2002;48(4):695-697.
3. 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.
4. 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.
5. 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.
6. Garcia D, Regan S, Crowther M, et al, Warfarin maintenance dosing patterns in clinical practice. Chest 2005;127:2049-2056.
7. 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.
8. Gage BF, Eby C, Johnson JA, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Nature 2008;84(3):326-331.
9. 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 Edition). Chest 2008;133:123S-131S.
10. Baglin TP, Keeling DM, Watson HG. Guidelines on oral anticoagulation (warfarin): third edition -2005 update, British Society for Haematology 2005;132:277-285.
11. Gage BF, Fihn SD, White RH. Management and dosing of warfarin therapy. Am J Med. 2000;109(6):481-488.
12. Hylek EM. Oral anticoagulants. Pharmacologic issues for use in the elderly. Clin Geriatr Med. 2001;17(1):1-13.
13. 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 Edition), Chest 2008;133;593S-629S.
14. 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.
15. Goodnight SH, Hathaway WE, editors. Disorders of hemostasis and thrombosis: a clinical guide. 2nd ed. New York: McGraw Hill; 2001.
16. Fitzmaurice D, Blann A, Lip GYH. Bleeding risks of antithrombotic therapy. BMJ. 2002;325:828-831.
17. Fihn SD, Callahan CM, Martin DC, et al. The risk for and severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med. 1996;124:970-979.
18. Schulman S, Beyth RJ, Kearon C, et al. Hemorrhagic complications of anticoagulant treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:257S-298S.
19. 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.
20. Beyth RJ. Hemorrhagic complications of oral anticoagulant therapy. Clin Geriatr Med. 2001;17(1): 49-56.
21. Health Canada. Dietary reference intakes: Reference values for vitamins. Available from:URL: www.hc-sc.gc.ca/fn-an/nutrition/reference/table/ref_vitam_tbl-eng.php (accessed July 2009).
22. 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. Thrombosis Journal 2008;6:6.
23. 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.
24. 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.
25. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. AM J Med. 1993;95:315-28
26. Brigden ML. Oral anticoagulant therapy: practical aspects of management. Postgrad Med. 1996;99(6):81-84,87-89,93-94 passim.
27. Hirsh J, Dalen J, Anderson DR et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119:8S-21S.
28. Bristol-Myers Squibb Pharma Company. Coumadin product monograph. Available from:URL:www.coumadin.com (accessed October 7, 2009).
29. Pendry K, Bhavnani M, Shwe K. The use of oral vitamin K for reversal of over-warfarinization. Br J Haematol. 2001;113(3):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(1):145-149.

Resources

For local information contact a hematologist at your closest referral centre/ major hospital, or call the following anticoagulation/thrombosis clinics:

• Vancouver Coastal Health - Vancouver General Thrombosis Clinic, Vancouver (604) 875-4111 ext. 69275
• Vancouver Island Health - Royal Jubilee Hospital, Victoria (250) 370-8776
• Fraser Health - Outpatient Anticoagulation Program, Burnaby Hospital, Burnaby (604) 412-6288

List of Abbreviations

INR	international normalized ratio
OTC	over the counter medications
TWD	total weekly warfarin dose

Appendices

Appendix A: Important Interactions with warfarin: medications, foods, herbs and supplements

Associated Documents

• Warfarin Record Sheet
• Warfarin: A Guide for Patients
• Warfarin and Food: Guide for Patients (including Vitamin K Content of Selected Foods and Resource Guide: Information Sources for Patients)

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

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

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 problems.  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.

A mobile version of this and other guidelines is also available at www.BCGuidelines.ca

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