Anticoagulation is very effective for primary and secondary prevention of thromboembolic events. However, questions persist about the risks and management of over-anticoagulation.
Major bleeding, which includes intracranial haemorrhage and bleeding leading to death or hospitalisation, has been reported in 1.2%–8.1% of patients during each year of long-term warfarin therapy.1,2 Despite these bleeding risks, warfarin use in Australia has increased between 6% and 9% per annum in the last 4 years, with current growth at about 9% per year.3 It is commonly used in the community setting for indications such as uncomplicated deep vein thrombosis and stroke prophylaxis in atrial fibrillation. By understanding the pharmacokinetics and pharmacodynamics of warfarin, and therefore the potential modifiers of warfarin’s effects, these bleeding risks can be minimised through preventive strategies with or without warfarin reversal.
These consensus guidelines offer advice on these preventive strategies and the principles of warfarin reversal, as well as bridging therapy in the face of different clinical settings. The recommendations draw on available evidence and the clinical experience of the panel of author practitioners.
Warfarin and other coumarin anticoagulants act by inhibiting the synthesis of functional vitamin K-dependent coagulation factors II, VII, IX and X.4 Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischaemic tissue damage. However, once thrombosis has occurred, anticoagulation therapy aims to prevent further clot progression and prevents secondary thromboembolic complications.4
The effective half-life of warfarin ranges from 20 to 60 hours, with a mean of about 40 hours. The duration of effect is 2–5 days.5 The drug is completely absorbed after oral administration, and peak concentrations occur within 4 hours. The elimination of warfarin is almost entirely by metabolism, with very little excreted unchanged in the urine and bile. Metabolism occurs mainly in the liver, involving the cytochrome P450, and in particular the CYP2C9, isoenzyme.4
Understanding the difference between the antithrombotic and anticoagulant effects of warfarin is useful in clinical practice. Initial increases in international normalised ratio (INR) are typically noted 24–36 hours after giving the first dose of warfarin. This early effect is related to the clearance of coagulation factor VII, which has a short half-life in vivo of 6 hours. However, the initial elevation of the INR is not thought to be associated with a clinically important antithrombotic effect, as warfarin is thought to exert its antithrombotic effect mostly through reductions in factor II (prothrombin) and factor X levels. If the ability of warfarin to curb existing clot growth and prevent further clot formation depends largely on the clearance of prothrombin with its half-life of 60–72 hours, then it should take a minimum of two prothrombin half-lives, or up to 5 days, to fully express the antithrombotic effect in patients.6 Because the effect of warfarin on the INR is dependent on the clearance of preformed coagulation factors, the maximum effect of a dose occurs up to 48 hours after administration, and the effect lasts for the next five days.2
These observations form the basis of the current recommendations that, unless there is reason to believe that the patient will be unusually sensitive, warfarin therapy is best initiated with a daily dose of 5 mg (about the usual maintenance dose) rather than by using a loading regimen. Much higher loading doses may expose patients to an increased risk of bleeding, and increase the required frequency of monitoring.6,7 Starting doses above 10 mg per day should be avoided.
Drug interactions can critically interfere with warfarin control. Common examples of drugs that can influence the absorption or metabolic clearance of warfarin include antibiotics, amiodarone, statins and anticonvulsants. Some herbal medications, such as St John’s wort, are recognised as important modifiers of the anticoagulant effects of warfarin, and patients should be carefully questioned about the use of these medications.8 Elderly patients can also exhibit an exaggerated response to warfarin, in part because they tend to store less vitamin K than younger people.9
The INR should be tested more frequently after starting, stopping or changing the dose of concomitant medication. It takes several days for enzyme induction or other drug effects to take place, so that an INR measured about one week after a change in medication should reflect clinically significant interactions.
Alcohol in small to moderate amounts probably has little effect on warfarin metabolism. In heavy drinkers, however, factors such as increased falls, alcohol-induced gastritis, poor diet and poor compliance increase the risk of bleeding.10
The amount of vitamin K in the diet partly determines the sensitivity to warfarin. This is important to consider in situations when diet changes, such as during illness, travel, fad diets, hospitalisation and postoperatively. Dark green vegetables such as spinach and broccoli are typically high in vitamin K. However, it takes a very large daily intake of “greens” to influence the INR. Rather than restricting vegetable intake, it is better to recommend a balanced and consistent diet.10
The most common complication of warfarin therapy is bleeding. A major determinant is the INR. In one study, the bleeding rate was doubled as the INR increased from 2.0–2.9 to 3.0–4.4, and quadrupled when the INR increased to 4.5–6.0.11 In another study, each increase in INR by 0.5 multiplied the absolute risk of major bleeding (mostly intracranial) by 1.43.12 Although the bleeding risk increases as the INR increases, 50% of bleeding episodes occur while the INR is less than 4.0.10
Observational studies suggest that the risk of bleeding is also related to age, history of past bleeding and specific comorbid conditions. Generally, elderly people have increased sensitivity to the anticoagulant effect of warfarin and require a lower mean daily dose than younger patients. One study showed a 46% increase in major bleeding for every 10-year increase above the age of 40.15 This increase is not necessarily linked to age itself, but may be related to comorbidity associated with age. Box 1 lists the patient-related risk factors.16,17
A patient’s risk of bleeding is greatest in the first three months after starting therapy. Bleeding during the early months of therapy, particularly from the gastrointestinal or renal tracts, often indicates an underlying lesion and should be thoroughly investigated.14
Many bleeding episodes are not clinically significant (although many patients are unlikely to view their bleeds in these terms). Such episodes include nosebleeds, bruising and excessive bleeding after minor injury, such as shaving. Patients should be made aware of these problems, and simultaneously reassured that, although common, they are not serious.13
Risk factors can be additive. Patients with two or three risk factors have a much higher incidence of warfarin-associated bleeding than those with none or one.9
Warfarin is a highly effective medication. Bleeding because of an excessive INR is minimised by therapeutic monitoring and when other precautionary measures are adopted.
Avoid high loading doses of warfarin, as they are not warranted and may result in bleeding episodes. An example would be the use of a 10 mg starting dose in a frail elderly individual. In general it is preferable to start treatment using an initial daily dose of 5 mg, or one that is closer to the usual maintenance dose of about 4–6 mg per day, as there is normally no immediate time constraint for achieving a target level of INR.7,9,18-21
Potential warfarin–drug interactions need to be considered.
Aim for an INR level that balances the therapeutic goal with the risk factors of bleeding on an individual basis. This will minimise haemorrhagic complications and maximise antithrombotic effect. The desirable target INR for most clinical indications is 2.5 (range, 2–3). The optimal INR for people with mechanical heart valves is still being debated, with the 2001 American College of Chest Physicians guidelines suggesting a reduced target of 2.5 for most recent-model prosthetic valves,22 while a recent meta-analysis suggests the target should remain above 3.0.23
A reduced target INR range (1.5–2.0) has not been proven to reduce bleeding risk, and is likely to lead to some reduction in effectiveness of therapy.24-26
Avoid frequent dose adjustments. A change in warfarin dose will take several days to influence the INR, so testing the INR within 24 or 48 hours of a dose change may not truly reflect the steady-state response to the dose adjustment.
Avoid excessive increases in dose when the INR drifts below the target INR range.
Effective patient education can minimise compliance problems. Box 2 lists the key components of patient education.
There is a close relationship between the INR and risk of bleeding. The risk of bleeding increases noticeably once the INR exceeds 4, and the risk rises sharply with values greater than 5. The management options for warfarin reversal are outlined in Box 3 and depend on the INR level and whether or not bleeding is present.27,28
In addition to stopping warfarin when the effect is excessive, vitamin K1 can be given, and coagulation factors replaced by infusing a prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP). The choice of approach is based largely on clinical judgement, because no randomised trials have compared these strategies in terms of clinical outcomes.9
Vitamin K1 is available as oral tablets or as ampoules for intravenous (IV) or oral administration. The ampoules are not recommended for intramuscular or subcutaneous use.29 Intramuscular vitamin K1 for reversal of warfarin is not recommended, as it exhibits depot characteristics that may interfere with recommencement of anticoagulation therapy. Furthermore, intramuscular injection in patients on anticoagulation therapy (particularly when over-anticoagulated) poses a significant risk of causing a haematoma to form.29 Studies have also shown that the response to intramuscular or subcutaneous vitamin K1 is unpredictable and sometimes delayed.30-33
Ideally, unless the patient is actively bleeding, vitamin K1 should be administered in a dose that will quickly lower the INR into a safe, but not subtherapeutic, range without causing resistance once warfarin is reinstated.9
Oral vitamin K1 is the treatment of choice unless very rapid reversal of anticoagulation is required.9 For most patients, 1.0–2.0 mg of oral vitamin K1 is sufficient. If the INR is particularly high, 5 mg orally may be required.2 The formulation of injectable vitamin K1 (Konakion MM, Roche Products Pty Ltd), while not approved for oral use by government regulatory agencies in Australia and New Zealand, is preferred for the reversal of anticoagulation because of its dosing flexibility.
Although IV injection produces a more rapid response, it may be associated with anaphylactic reactions. There is no evidence that this rare, but serious, complication can be avoided by using low doses.9 In Australia and New Zealand, vitamin K1 is a mixed micelle-based formulation, and may not carry the same risk of allergies, including anaphylaxis, as earlier formulations.
The optimal IV dose of vitamin K1 for partial reversal of over-anticoagulation with warfarin is 0.5–1.0 mg. If correction of the INR (rather than just return to the usual therapeutic range) is desired, larger doses of vitamin K1 are needed (see Box 3). The INR can usually be normalised within 24 hours with an IV dose of 5–10 mg of vitamin K1.34
Large doses of vitamin K1 may produce some resistance to re-anticoagulation with warfarin, and this can be avoided by giving smaller doses. Larger doses are appropriate if a clinical decision has been made to discontinue further warfarin treatment.27
Box 4 presents the recommended dose ranges of vitamin K1 preparations available in Australasia for anticoagulation reversal.
The full effect of vitamin K1 in reducing the INR takes up to 24 hours to develop, even when given in larger doses with the intention of complete reversal. For immediate reversal of clinically significant bleeding, the combination of prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP) covers the period before vitamin K1 has reached its full effect.
Vitamin K1 is essential for sustaining the reversal achieved by a PCC and FFP.27
Prothrombinex-HT is the only PCC approved in Australia and New Zealand for warfarin reversal. It is a three-factor concentrate, containing factors II, IX and X, but only low levels of factor VII. Therefore, the adjunctive use of FFP should be considered as a source of factor VII.27
Box 5 provides a summary of the characteristics of Prothrombinex-HT and FFP.35,36
The overall management of over-anticoagulation depends on:
the risk of bleeding,
the clinical significance of the bleed, and
the level of INR.
Box 3 summarises the consensus reached on the management of an elevated INR in different clinical settings. Note, however, that expert advice on management should be sought whenever there is bleeding in patients taking warfarin who have a high risk of a disabling thromboembolic event in the absence of anticoagulation therapy (as with prosthetic heart valves or a recent pulmonary embolism or extensive venous thrombosis).
Opinion varies about how to manage anticoagulation in patients who have been taking warfarin long-term and who need to undergo surgery, as the evidence is mainly anecdotal.
For most patients, warfarin can be withheld 5 days before elective surgery; the INR usually falls to below 1.5 in this time, and surgery can be conducted safely.
There are some procedures, however, which entail a low risk of bleeding, and so do not require interruption to warfarin therapy if the INR is within the therapeutic range. Examples include simple dental procedures, periodontal therapy, and minor dermatological procedures where pressure can be applied if required.
If withholding warfarin preoperatively is necessary, a number of issues need to be considered. These include:
Prolonged immobility during surgery and afterward increases the risk of venous thromboembolism.
The potential risk of thrombosis should be assessed. The need for bridging therapy is very much dependent on the risk of the thrombosis recurring during the period that patients are not receiving anticoagulation therapy.
Unfractionated heparin offers some advantages as an anticoagulant in the 24 hours preceding surgery because of its faster onset and offset of action. There is significant disagreement about who should and should not receive such bridging therapy, principally because there is a lack of randomised controlled trial data.
In some situations, clinical experience suggests that bridging anticoagulation is not required. Patients who take anticoagulants because of atrial fibrillation, or in whom the index event requiring anticoagulation occurred more than 3 months ago, can be safely managed without bridging anticoagulation. These patients are at relatively low risk of thromboembolism. Box 6 lists an appropriate approach for these patients.
Patients with prosthetic valves and those who have suffered an acute thrombosis within the preceding 3 months should receive bridging anticoagulation in the perioperative and postoperative period. This should be done in consultation with the relevant experts in this area. Box 6 lists the recommended plan of management for these patients who are at relatively high risk of thromboembolism.
1 Risk factors for bleeding complications of anticoagulation therapy
Risk factor category |
Specific risk factors |
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Age16,17 |
> 65 years |
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Cardiac16,17 |
Uncontrolled hypertension |
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Gastrointestinal16,17 |
History of gastrointestinal haemorrhage, active peptic ulcer, hepatic insufficiency |
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Haematologic/oncologic16,17 |
Thrombocytopenia (platelet count, < 50 × 109/L), platelet dysfunction, coagulation defect, underlying malignancy |
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Neurologic16,17 |
History of stroke, cognitive or psychological impairment |
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Renal16,17 |
Renal insufficiency |
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Trauma16,17 |
Recent trauma, history of falls (> 3 per within previous treatment year, or recurrent, injurious falls) |
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Alcohol16,17 |
Excessive alcohol intake |
||||||||||||||
Medications*16,17 |
Aspirin, COX-I-specific non-steroidal anti-inflammatory drugs (COX-II inhibitors do not impair platelet function, but can influence warfarin effect), “natural remedies” that interfere with haemostasis. |
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* Careful monitoring of warfarin effect is critical to minimise risk in patients taking multiple medications. |
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2 Key patient education components17
Explain the
Reason for treatment
Mechanism of action of warfarin
Time of day to take warfarin (same time of day)
The INR, target range and need for regular testing
Signs and symptoms of bleeding
Effect of illness, injury or any changes in physical status
Potential effect of invasive procedure, surgery or dental work
The effects of common over-the-counter (OTC) medication interactions
The need for consistent intake of vitamin K-rich foods
Effects of alcohol intake
Appropriate action if diarrhoea or vomiting occurs
Some patients may consider the use of a Medic Alert bracelet/necklace and warfarin identification card.
3 Guidelines for the management of an elevated international normalised ratio (INR) in adult patients with or without bleeding
Clinical setting |
Action |
||||||||||||||
INR higher than the therapeutic range but < 5.0; bleeding absent |
|
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INR 5.0–9.0;* bleeding absent |
|
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INR > 9.0; bleeding absent |
|
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Any clinically significant bleeding where warfarin-induced coagulopathy is considered a contributing factor |
OR
OR
|
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* Bleeding risk increases exponentially from INR 5 to 9;13 INR ≥ 6 should be monitored closely. † Vitamin K effect on INR can be expected within 6–12 hours. ‡ Examples of patients in whom the bleeding risk would be expected to be high include those with active gastrointestinal disorders (such as peptic ulcer or inflammatory bowel disease), those receiving concomitant antiplatelet therapy, those who underwent a major surgical procedure within the preceding two weeks, and those with a low platelet count. See Box 1 for a list of bleeding risk factors. § In all situations carefully reassess the need for ongoing warfarin therapy. |
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4 Recommended dose range for vitamin K1 preparations available in Australia and New Zealand for reversing anticoagulation*
Dosage route |
Oral† |
Intravenous† |
|||||||||||||
Usual dose for anticoagulation reversal |
1.0–2.0 mg |
0.5–10.0 mg |
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* These recommendations may not be consistent with the approved product indications29 of Konakion in Australia and New Zealand. † Konakion injectable paediatric or adult formulation; Roche Products Pty Ltd. |
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5 Summary of characteristics of Prothrombinex-HT* and fresh frozen plasma (FFP)
|
Prothrombinex-HT† |
Fresh frozen plasma† |
|||||||||||||
Description |
Prepared from plasma collected from voluntary donors. Sterile freeze-dried powder containing coagulation factors II, IX and X and low levels of factor VII. |
Separated and frozen within 18 hours of collection from volunteer donors. Contains all coagulation factors. |
|||||||||||||
Contraindications |
Patients showing signs of thrombosis or disseminated intravascular coagulation. |
Do not use when coagulopathy can be corrected more effectively with specific therapy, such as vitamin K, cryoprecipitate or other specific factor concentrates. |
|||||||||||||
Specifications |
Available in vials containing 500 IU of factor IX, II and X to be reconstituted in 20 mL of water for injections. Each vial also contains 25 IU of antithrombin and 200 IU of heparin. |
Available in 150–300 mL sizes. May be stored in blood refrigerator at 2–6oC for up to 5 days once thawed, and relabelled “thawed plasma”. Thawed plasma has levels of factors II, VII, IX and X adequate for warfarin reversal. |
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Availability |
From relevant blood service or hospital blood bank. No need to consider ABO group. |
Available in all ABO groups and should be ABO-group compatible with patient’s red cells (or use AB plasma). |
|||||||||||||
Considerations for use |
Known allergies to prothrombin complex concentrates. Predisposition to venous thrombosis, disseminated intravascular coagulation and myocardial infarction.‡ |
Most common adverse events — allergic reactions and volume overload. Potential for transmission of infections, transfusion-related acute lung injury and other transfusion reactions. |
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* CSL Limited. † For more comprehensive information on these products, refer to Prothrombinex-HT Australian35 and New Zealand37 approved product information, the Australian Red Cross Blood Service Circular of information 2003,36 the Australian Red Cross Blood Service Transfusion medicine manual 200327 and the New Zealand Blood Service Transfusion medicine handbook 2003.38 ‡ From its date of issue in 1992 to date there have been no instances reported to CSL Bioplasma of thrombotic episodes with Prothrombinex-HT. |
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6 Managing oral anticoagulation during invasive procedures according to risk of thromboembolism
Time |
Patients at relatively low risk |
Patients at relatively high risk |
|||||||||||||
Before surgery |
|
|
|||||||||||||
After surgery |
|
|
|||||||||||||
INR = international normalised ratio. APTT = activated partial thromboplastin time. * Exercise caution in patients with impaired renal function (calculated creatinine clearance rate, < 30 mL/hour). LMWH can accumulate and contribute to bleeding. |
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Background and evidence basis of recommendations
These consensus guidelines for warfarin reversal were produced by the Warfarin Reversal Consensus Group on behalf of the Australasian Society of Thrombosis and Haemostasis. The writing committee consisted of Hatem Salem (Chair), Ross Baker, Paul Coughlin, Alex Gallus and Paul Harper. The guidelines were developed after extensive consultation, including several workshops and teleconferences. The guidelines draw on review of all available evidence from published studies and from clinical experience. The aim of the Warfarin Reversal Consensus Group is to provide an Australian and New Zealand perspective on the safe and effective management of bleeding risks resulting from warfarin therapy.
- Ross I Baker1
- Paul B Coughlin2
- Hatem H Salem3
- Alex S Gallus4
- Paul L Harper5
- Erica M Wood6
- 1 Thrombosis and Haemophilia Service, Royal Perth Hospital, Perth, WA.
- 2 Monash University, Box Hill Hospital, Box Hill, VIC.
- 3 SouthPath, Flinders Medical Centre, Bedford Park, SA.
- 4 Auckland City Hospital, Auckland, New Zealand.
- 5 Australian Red Cross Blood Service, Southbank, VIC.
The Warfarin Reversal Consensus Group thanks Lucy Race and Kim Magner, of Discovery International Australia, for their assistance in the writing of the manuscript.
An unrestricted educational grant from CSL Bioplasma enabled the Warfarin Reversal Consensus Group (WRCG) to meet, develop and write these guidelines. As part of this grant, a number of members of the WRCG received paid honoraria. In addition, CSL Bioplasma and the Australian Red Cross Blood Service were consulted for technical information relating to Prothrombinex-HT and fresh frozen plasma.
- 1. Levine MN, Raskob G, Landefeld S, et al. Hemorrhagic complications of anticoagulant therapy. Chest 1998; 114: 511S-523S.
- 2. Gallus AS, Baker RI, Chong BH, et al. Consensus guidelines for warfarin therapy. Med J Aust 2002; 172: 600-605. <MJA full text>
- 3. Australian pharmaceutical index. Sydney: IMS Health, January 2004.
- 4. Boots Healthcare Australia. Coumadin. Australian product information. Sydney: Boots Healthcare Australia Pty Ltd, 26 July 2000.
- 5. Majerus PW, Broze GJ, Miletich JP, et al. Anticoagulant thrombolytic, and antiplatelet drugs. In: Hardman JG, Limbird LE, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 1347-351.
- 6. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119: 8S-21S.
- 7. 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.
- 8. Fugh-Berman A. Herb-drug interactions. Lancet 2000; 355: 134-138.
- 9. Hirsh J, Fuster V, Ansell J, et al. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003; 107: 1692-1711.
- 10. Campbell P, Roberts G, Eaton V, et al. Managing warfarin therapy in the community. Aust Prescriber 2001; 24: 86-89.
- 11. Palareti G, Leali N, Coccheri S, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996; 348: 423-428.
- 12. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomised trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997; 42: 857-865.
- 13. Fitzmaurice D, Blann A, Lip GYH. Bleeding risks of antithrombotic therapy. BMJ 2002; 325: 828-831.
- 14. Landefeld S, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction and prevention. Am J Med 1993; 95: 315-328.
- 15. van der Meer FJM, Rosendaal FR, Vanderbroucke JP, et al. Bleeding complications in oral anticoagulant therapy: an analysis of risk factors. Arch Intern Med 1993; 153: 1557-1562.
- 16. Levine MN, Raskob G, Landefeld S, et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: 108S-121S.
- 17. Institute for Clinical Systems Improvement. Health Care Guideline Supplement. Anticoagulation therapy supplement 2003. Available at: www.icsi.org (accessed Feb 2004).
- 18. Hirsh J, Dalen JE, Deykin D, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1995; 108: 231S-246S.
- 19. 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. Ann Intern Med 2003; 138: 714-719.
- 20. Tait RC, Sefcick A. A warfarin induction regimen for out-patient anticoagulation in patients with atrial fibrillation. Br J Haematol 1998; 101: 450-454.
- 21. 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: 46-48.
- 22. Stein PD, Alpert JS, Bussey HI, et al. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 2001; 119: 2205-2275.
- 23. Vink R, Kraaijenhagen RA, Hutten BA, et al. The optimal intensity of vitamin K antagonists in patients with mechanical heart valves: a meta-analysis. J Am Coll Cardiol 2003; 42: 2042-2048.
- 24. Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003; 349: 631-639.
- 25. Hyleck EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349: 1019-1026.
- 26. Perret-Guillaume C, Wahl DG. Low-dose warfarin in atrial fibrillation leads to more thromboembolic events without reducing major bleeding when compared with adjusted dose. A meta-analysis. Thromb Haemost 2004; 91: 394-402.
- 27. Australian Red Cross Blood Service. Transfusion medicine manual 2003. Available at: http://www.arcbs.redcross.org.au/Clinical/ResourceLibrary/resource_tmm.asp (accessed Feb 2004).
- 28. Ansell J, Dalen J, Bussey H, et al. Managing oral anticoagulant therapy. Chest 2001; 119: 22S-38S.
- 29. Roche Products. Konakion. Australian product information. Sydney: Roch Products Pty Ltd, 12 February 1998 (tablets and MM ampoules); 18 October 2000 (MM Paediatric).
- 30. Soedirman JR, De Bruijn EA, Maes RA, et al. Pharmacokinetics and tolerance of intravenous and intramuscular phylloquinone (Vitamin K1) mixed micelles formulation. Br J Clin Pharmacol 1996; 41: 517-523.
- 31. Raj G, Kumar R, McKinney WP. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Arch Intern Med 1999; 159: 2721-2724.
- 32. Whitling AM, Bussey HI, Lyons RM. Comparing different routes and doses of phytonadione for reversing excessive anticoagulation. Arch Intern Med 1998; 158: 2136-2140.
- 33. Crowther MA, Douketic JD, Schnurr T, et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy: a randomized controlled trial. Ann Intern Med 2002; 137: 251-254.
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Abstract
For most warfarin indications, the target maintenance international normalised ratio (INR) is 2–3.
Risk factors for bleeding complications with warfarin use include age, history of past bleeding and specific comorbid conditions.
To reverse the effects of warfarin, vitamin K1 can be given. Immediate reversal is achieved with a prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP). Vitamin K1 is essential for sustaining the reversal achieved by PCC and FFP.
When oral vitamin K1 is used for warfarin reversal, the injectable formulation of vitamin K1 is preferable to tablets because of its flexible dosing; this formulation can be given orally or injected.
To temporarily reverse the effect of warfarin when there is a need to continue warfarin therapy, vitamin K1 should be given in a dose that will quickly lower the INR to a safe, but not subtherapeutic, range and will not cause resistance once warfarin is reinstated.
Prothrombinex-HT is the only PCC approved in Australia and New Zealand for warfarin reversal. It contains factors II, IX and X, and low levels of factor VII. FFP should be added to Prothrombinex-HT as a source of factor VII when used for warfarin reversal.
Simple dental or dermatological procedures may not require interruption to warfarin therapy.
If necessary, warfarin therapy can be withheld 5 days before elective surgery, when the INR usually falls to below 1.5 and surgery can be conducted safely.
Bridging anticoagulation therapy for patients at high risk for thromboembolism should be undertaken in consultation with the relevant experts.