Definitions for the strength of the recommendations (1A-2C) are provided at the end of the "Major Recommendations" field.
Indications
Venous Thromboembolic (VTE) Disease
Warfarin therapy should be continued for 6 weeks for patients with symptomatic calf vein thrombosis. Patients with proximal vein thrombosis with a precipitating cause such as surgery or immobilization should receive anticoagulation therapy for 3 to 6 months. Patients with idiopathic proximal vein thrombosis and or pulmonary embolism should receive anticoagulation therapy for at least 6 months (Grade 1A).
Indefinite anticoagulant therapy is indicated for patients with more than one episode of idiopathic proximal vein thrombosis or for those with continuing prothrombotic risk factors (Grade 1A) (Ansell et al., 2004; Institute for Clinical Systems Improvement, 2003; Wittkowsky, 1995; Warfarin [drug evaluation monograph]; Hirsch et al., 2003; "Guidelines on oral anticoagulation," 1998)
Atrial Fibrillation
Indefinite anticoagulation therapy is required for prevention of thromboembolic stroke and events (Grade 1A). The benefits must be weighed against the risks. An alternative less effective option with lower risk is the use of anti-platelet drugs. (Ansell et al., 2004; Institute for Clinical Systems Improvement, 2003; Wittkowsky, 1995; Warfarin [drug evaluation monograph]; Hirsch et. al., 2003; "Guidelines on oral anticoagulation," 1998)
Prosthetic Heart Valves
Indefinite anticoagulation therapy is required for prevention of thromboembolic stroke and events (Grade 1C+). (Ansell et al., 2004; Institute for Clinical Systems Improvement, 2003; Wittkowsky, 1995; Warfarin [drug evaluation monograph]; Hirsch et. al., 2003; "Guidelines on oral anticoagulation," 1998)
Tissue Heart Valves
Patients with newly replaced tissue heart valves should receive anticoagulation therapy for 3 months (Grade 1C).
Patients with bioprostheses and atrial fibrillation (AF), previous embolism or severe left ventricular (LV) dysfunction should receive anticoagulants indefinitely (Grade 1C+). (Ansell et al., 2004)
Myocardial Infarction
Lifelong anticoagulation therapy is indicated for:
- Post-myocardial infarction (MI) patients in persistent AF, lifetime (Grade 1A). The benefits must be weighed against the risks.
- Patients with LV thrombus should receive warfarin for at least 3 months (Grade 2A).
(Ansell et al., 2004)
Dosing and Monitoring
General Principles of Warfarin Dosing
- Loading dose for rapid induction of warfarin should be avoided. Warfarin (irrespective of international normalised ratio [INR]) is not fully effective in the first several days of therapy because of a delayed decrease in several circulating clotting factors. Loading doses can increase a patient's risk of supra-therapeutic INR and make it more difficult to determine a steady-state dose.
- The target INR for most conditions is 2 to 3. However, this range should be adjusted according to the bleeding and thrombotic risks of each individual.
- While there is a significant increase in thromboembolism as INR values decrease below 1.7, the bleeding risk increases substantially at INR above 5. Clinical risk and past medical history should be considered in all dosing decisions.
- Prescription and over-the-counter medications can adversely affect the INR response to warfarin. Herbal or natural remedies can change the INR response to warfarin and/or increase a patient's risk of bleeding. In these instances, additional monitoring may be needed. Please refer to table 7.1 and 7.2 in the original guideline document for the drug-drug and drug-herb interactions respectively.
- Food that contains moderate amounts of vitamin K can decrease the INR response to warfarin. Patients should maintain a consistent diet. Please refer to table 7.3 in the original guideline document for the vitamin K content in common foods.
Initiation and Maintenance of Warfarin Therapy
- For patients with ongoing thrombosis, warfarin should be started concomitantly with low molecular weight heparin or standard heparin. Patients without active thrombosis but who require warfarin for prophylactic indications, e.g., atrial fibrillation, can be initiated on warfarin alone.
- Patients receiving warfarin for the first time should begin with 2 mg to 5 mg daily.
- Lower warfarin doses should be considered for patients with any of the following factors:
- Age greater than 75 years
- Multiple co-morbid conditions
- Low albumin levels and poor nutritional status
- Impaired liver function, cardiac function and thyroid function
(Please refer to table 7.4 in the original guideline document for endogenous interactions with warfarin)
- A baseline INR value should be drawn to rule out any underlying coagulopathy.
- Monitoring of INR can be done at inpatient or outpatient settings.
- During the first week, INR should be measured daily or every other day and warfarin dosage adjusted accordingly. It is then measured at increasing intervals, depending on the INR response.
- Once the warfarin dose is stable, many patients can be well controlled with 4 to 8 weekly INR testing and warfarin dose adjustments. Steady-state INR values will not be realized for up to 3 weeks following a dose adjustment.
- Patients with INR values outside target INR range should be considered for more frequent monitoring. Those with INR less than 1.5 or above 4 should have their INR repeated within seven days following dose adjustments.
- Warfarin maintenance dose is usually in the range of 2 mg to 10 mg orally once a day.
- Warfarin dosing is affected by numerous factors. These are tabulated in table 7.5 in the original guideline document. An assessment of clinical variables known to affect the INR should be made with each dose adjustment.
Reversing Anticoagulant Effects of Warfarin in Patients Going for Surgery
- For elective procedures, warfarin should be stopped 3 to 5 days prior to surgery.
- Patients with INRs of between 2 to 2.5 should achieve an INR of less than 1.5 after stopping warfarin for 3 days. Patients with INRs of between 2.5 to 3.5 generally require discontinuation of warfarin for 4 days before their INRs will drop to less than 1.5.
- INR should be checked just before surgery to ensure adequate haemostatic function.
- Warfarin may be restarted 24 hours after surgery if there is no bleeding risk.
- The need to use heparin or low molecular weight heparin during the perioperative period should be considered based on the bleeding risk from the surgery as well as the thrombotic risk arising from the surgery and the duration that the patient has to come off warfarin. This should be reviewed by the physician in charge.
Managing Bleeding and Excessive Anticoagulation
The Risk of Bleeding and INR
Bleeding risk increases significantly when INR exceeds 5. An INR above 5 requires close monitoring. Intervention is required based on the INR reading, the presence of bleeding and the patient's underlying condition, as outlined.
The Recommendation for Management if There is No Significant Bleeding and Patient has Low Bleeding Risks
| INR |
Recommendation |
| 4.0 to 5.0 |
Reduce dose or omit 1 to 2 doses. Monitor international normalised ratio (INR) more frequently and resume therapy at a lower dose when INR is within therapeutic range. |
| 5.0 to 9.0 |
Check for bleeding/headache/anaemia. Admit if any suspicion of bleeding or if patient is unwell. If not for admission, advise patient of risk of bleeding and to go to accident and emergency (A & E) if there is any suspicion of bleeding or if patient is unwell. Omit 2 to 3 doses. Monitor INR more frequently and resume therapy at a lower dose when INR is within therapeutic range. Alternatively, omit 1 dose and administer 1 mg to 3 mg of oral vitamin K. Check INR in 24 hours. If INR remains high, administer additional 1 mg to 2 mg of oral vitamin K. Resume therapy at a lower dose when INR is within therapeutic range. |
| Above 9.0 |
Admit. Check for bleeding/headache/anaemia. Omit warfarin and administer 3 mg to 5 mg of oral vitamin K. Check INR in 24 hours. Administer additional vitamin K if necessary. Resume therapy at a lower dose when INR is within therapeutic range. |
The Recommendation for Management if There is Serious Bleeding and INR is Elevated
Hold warfarin therapy and administer 10 mg vitamin K by slow intravenous (IV) infusion, supplemented with fresh plasma or prothrombin complex concentrate 50 IU/kg, depending on the urgency of the situation. Vitamin K administration can be repeated every 12 hours.
For life-threatening bleed, hold warfarin therapy and administer prothrombin complex concentrate 50 IU/kg, supplemented with 10 mg vitamin K by slow IV infusion. Check INR every 6 hours and repeat the procedure if necessary, depending on the INR.
Oral vitamin K is given for outpatients. The oral preparation is prepared from KONAKION MM® preparation. IV Konakion® has oral bioavailability of 50% (Roche company data).
Considerations for Vitamin K
The dose of vitamin K used to reverse over-anticoagulation depends on the INR. Ideally, vitamin K should be administered in a dose that will quickly lower INR into a safe but not sub-therapeutic range. For most patients, 1 mg to 3 mg of vitamin K is sufficient in the absence of bleeding. These small doses are obtained by dilutions from a 10 mg vial of injectable vitamin K and this is administered via oral or parental route.
High doses of vitamin K (10 mg) are very effective but will lower the INR to sub-therapeutic range and lead to warfarin resistance for up to a week.
Due to near complete absorption, oral vitamin K has shown to be convenient and effective.
Intravenous injection produces a rapid response but anaphylactic reaction is a rare complication. This is reserved for patients who require very rapid reversal of anticoagulation; and can be administered by slow intravenous infusion (10 mg over 30 minutes in 50 mL dextrose 5%).
Warfarin Counselling
See the original guideline document for Frequently Asked Questions during Warfarin Counselling.
Definitions:
| Grade of Recommendation |
Clarity of Risk/Benefit |
Methodological Strength of Support Evidence |
Implications |
| 1A |
Clear |
Randomized clinical trials) RCTs without important limitations |
Strong recommendation; can apply to most patients in most circumstances without reservation |
| 1B |
Clear |
RCTs with important limitations (inconsistent results, methodological flaws) |
Strong recommendation; likely to apply to most patients |
| 1C+ |
Clear |
No RCTs but strong RCT results can be unequivocally extrapolated, or overwhelming evidence from observational studies |
Strong recommendation; can apply to most patients in most circumstances |
| 1C |
Clear |
Observational studies |
Intermediate-strength recommendation; may change when stronger evidence is available |
| 2A |
Unclear |
RCTs without important limitations |
Intermediate-strength recommendation; best action may differ depending on circumstances or patients' or societal values |
| 2B |
Unclear |
RCTs with important limitations (inconsistent results, methodological flaws) |
Weak recommendation; alternative approaches likely to be better for some patients under circumstances |
| 2C+ |
Unclear |
No RCTs but strong RCT results can be unequivocally extrapolated, or overwhelming evidence from observational studies |
Weak recommendation; best action may differ depending on circumstances or patients' or societal values |
| 2C |
Unclear |
Observational studies |
Very weak recommendations; other alternatives may be equally reasonable |
