Consensus guidelines for warfarin therapy

Recommendations from the Australasian Society of Thrombosis and Haemostasis

Abstract

• The anticoagulant effect of warfarin should be kept at an international normalised ratio (INR) of about 2.5 (desirable range, 2.0-3.0), although a higher level may be better in a few clinical conditions. The risk of bleeding increases exponentially with INR and becomes clinically unacceptable once the INR exceeds 5.0.

• Warfarin therapy should be continued for around six weeks for symptomatic calf vein thrombosis, and for 3-6 months after proximal deep vein thrombosis (DVT) that occurs after surgery or limited medical illness. Therapy for six months or longer could be considered for DVT occurring without an obvious precipitating factor, proven recurrent venous thromboembolism (VTE), or if there are continuing risk factors.

• Oral anticoagulants prevent ischaemic stroke in atrial fibrillation (AF). Maximum efficacy requires an INR > 2.0, but some benefit remains at an INR of 1.5-1.9. Patients aged over 75 years are at greatest risk of intracranial bleeding during warfarin therapy for AF, and the target INR may be reduced to 2.0-2.5, or perhaps as low as 1.5-2.0, in such patients. Warfarin should be withheld if it is more likely to cause major bleeding than to protect from stroke (eg, in young people with isolated AF where the annual baseline risk of stroke is < 1%). In patients with AF, aspirin is less effective than warfarin (much less effective after such patients have had a stroke or transient cerebral ischaemia).

• In people with prosthetic heart valves, an INR of 2.5-3.5 is probably sufficient for bileaflet or tilting disc valves, but a higher target INR is necessary for caged ball or caged disc valves. The addition of aspirin (100 mg/day) further decreases the risk of embolism but increases the risk of gastrointestinal bleeding.

Warfarin is used for preventing and treating venous or arterial thrombosis and embolism. It is a potentially hazardous drug, causing major bleeding in 1%-2% of people treated, and intracranial bleeding in about 0.1%-0.5% during each year of therapy. These risks are well recognised, but strong recent evidence that many otherwise healthy people with atrial fibrillation (AF) or venous thromboembolism (VTE) can benefit from long term warfarin therapy has led to a major increase in its use.

These consensus guidelines offer advice on the selection of patients for warfarin therapy and management of such patients. The recommendations draw on proceedings of the Fifth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy,¹ and are consistent with the most recent Guidelines on oral anticoagulation developed for the British Society for Haematology.²

Warfarin therapy and management of complications

The INR

The INR (international normalised ratio) is a good indicator of effectiveness and risk of bleeding during warfarin therapy and is best kept at about 2.5, with a target range of 2.0-3.0, for most clinical indications, although higher levels may be better for certain patients (Box 1). The lower limit of this target range recognises a threshold level for effectiveness, while the upper limit is set to minimise bleeding.

Starting and maintaining warfarin therapy

The daily maintenance dose of warfarin differs greatly between individuals, commonly between 0.5 mg/day and 15 mg/day, and often fluctuates over time. The average maintenance dose is about 4.5 mg/day, although this is lower in the elderly.

The drug is rapidly and completely absorbed and immediately blocks further hepatic synthesis of the functional vitamin K-dependent haemostasis factors (II, VII, IX, X, protein C, protein S). However, its impact on the INR is delayed until preformed coagulation factors are removed, so dose adjustment must allow for these delayed effects. The plasma half-life of warfarin is about 36 hours.³

In the past, it was customary to use a loading dose of 10 mg. However, for most situations, a reduced starting dose of 5 mg per day will achieve an INR of 2.0 in four to five days.⁴

INR is measured daily or every second day during the first week of treatment, with the dose of warfarin (taken in the evening) titrated against the morning's INR. It is then measured at increasing intervals depending on response. Many patients, once the dose is stable, can be well controlled with 4-6-weekly testing and dose adjustment, but others need more frequent assessment. An empirical approach to warfarin dosing can be smooth and effective but published dose-adjustment tables can help.² Old age, reduced body weight, and impaired cardiac or liver function all predict a smaller than average dose requirement. Multiple comorbidities and a need for many drugs increase the risk of an unstable anticoagulant response.

The effect of warfarin is subject to multiple interactions. These include the dietary content or extent of absorption of vitamin K, the absorption of warfarin and its effect on the liver (which are increased or decreased by many other drugs), and the clearance of blood-clotting factors.^1,3 Intercurrent illness, starting or stopping therapy with other drugs (especially antibiotics and amiodarone) and changes in diet or bowel function can all influence the INR. Rechecking the INR within a few days of any change in medication or clinical condition is prudent.

Bleeding is minimised by regular monitoring to avoid an excessive INR and by educating patients about how warfarin works, why their dose requirement may change, and the likely settings and symptoms of bleeding complications. Successful warfarin therapy requires a partnership with patients, who should be encouraged to have their INR checked soon after any change in their normal routine. Clinics should periodically audit their results with warfarin therapy and review exceptional cases. Between 50% and 75% of INRs are likely to fall into their designated therapeutic range.⁵

Two recent Australian case reports are reminders that bioequivalence has not been formally demonstrated for Coumadin and Marevan (both from Boots Healthcare Australia, Sydney, NSW), the two locally available formulations of warfarin.⁶

Warfarin and bleeding

Major bleeding has been reported in 1.1%-8.1% of patients during each year of long-term warfarin therapy (1.1%-2.7% by anticoagulant clinics managing patients with prosthetic heart valves,^7-9 1.3% in atrial fibrillation trials, and 2.8%-8.1% after a stroke or transient ischaemic attack^10-12). Risk factors include old age, serious illness (cerebral, cardiac, kidney or liver disease), cerebrovascular or peripheral vascular disease, and an unstable anticoagulant effect. Forgetfulness, non-steroidal anti-inflammatory drugs and alcohol abuse may also contribute.^7,9,13-15 Warfarin appears to be especially hazardous after a transient ischaemic attack or minor stroke; in one trial, 14 months of warfarin therapy with a relatively high target INR of 3.0-4.5 increased major bleeding from 0.9% to 8.1%, intracranial bleeding from 0.5% to 4.1%, and fatal intracranial bleeding from 0.2% to 2.6% (relative to low dose aspirin therapy).¹² Bleeding is most likely during the first three months of treatment, and often follows trauma or unmasks a previously unsuspected comorbidity.^8,13-15

Age alone is not a contraindication to warfarin therapy. Although one report showed that each decade above the age of 40 raised the risk of major bleeding by almost 50%, with a maximum effect above 70 years,⁷ others have found that age below 70 years has no influence.^8,15

The INR is the dominant determinant, whether bleeding is expressed as the absolute risk per annum (Box 2) or as relative risk. In a 1996 study, the bleeding rate was doubled as the INR increased from 2.0-2.9 to 3.0-4.4, quadrupled between 4.5-6.0, and was multiplied by five when the INR was above 7.0.¹⁵ There is a consistent increase in major bleeding (including intracranial bleeding¹⁶) when the INR exceeds 4.0-5.5.^7,11,14 A 1997 trial found that each increase in INR by 0.5 multiplied the risk of major bleeding (mostly intracranial) by 1.43.¹²

Managing an excessively prolonged INR or bleeding caused by warfarin therapy

An INR above 5.0 requires close monitoring and often needs intervention, as determined by the level of the INR and the presence or absence of bleeding (Box 3). The INR often remains elevated for some days, even if warfarin is withheld, but small amounts of vitamin K₁ quickly correct the INR to safer levels.

In most patients, 1-2.5 mg of oral vitamin K₁ reduces the INR from 5.0-9.0 to 2.0-5.0 within 24-48 hours; this intervention is usually sufficient in the absence of bleeding.^17,18 These small doses are obtained by withdrawing the desired amount from a 10 mg vial of injectable vitamin K₁ and giving this orally or parenterally. When the INR is > 9.0, then 5 mg vitamin K₁ may be more appropriate and can be given orally, subcutaneously or intravenously (very rarely, the last may cause a serious anaphylactoid reaction). In people with a massive accidental or self-inflicted warfarin overdose, the long half-life of warfarin means that the INR may rebound over several days as the effects of vitamin K₁ wear off. In any case, the response to vitamin K₁ needs to be monitored. Bleeding caused by a warfarin overdose is controlled with clotting factor replacement (Box 3), and this may also be indicated in the absence of bleeding when the risk is very high.¹⁹

Bleeding or an unstable dose-response should trigger a review of the need for warfarin. Continued treatment will require closer monitoring of the INR, both to detect the transient warfarin resistance caused by too much vitamin K₁, and to avoid further overanticoagulation. Heparin treatment may be required to cover a prolonged period of warfarin resistance.

Interrupting warfarin therapy for surgery

When there is a need for surgery, the risk of perioperative bleeding under continued warfarin therapy must be balanced against the risk of thromboembolism if warfarin therapy is stopped.²⁰

Most surgery, including hip or knee replacement and many thoracic or abdominal operations, can proceed under continued warfarin cover without undue bleeding (provided the INR during and soon after surgery is about 1.5-2.0). Warfarin therapy is a contraindication for regional anaesthesia (eg, spinal, epidural, brachial blocks) and is unacceptable where even minor bleeding might cause critical damage (as in neurosurgery and some plastic surgery). It is also unpopular with most surgeons.

However, the absolute daily risk of a serious thromboembolic event is small in most people with AF, previous systemic embolism or a prosthetic heart valve (the hazard is greatest from mitral and older-model prosthetic valves, and in patients with more than one prosthetic valve). Thus, it is safe to stop warfarin therapy for several days before and after surgery in such patients. High-dose heparin cover for these indications is rarely indicated as the risk of bleeding is usually prohibitive.²⁰ The risk of recurrence is greatest during the first four weeks after VTE, so warfarin therapy should not be interrupted during this time if at all possible. If anticoagulants must be stopped for surgery soon after VTE, a vena cava filter can be placed to minimise the risk of life-threatening pulmonary embolism.

Specific indications for warfarin therapy

Deep vein thrombosis and pulmonary embolism

Prevention: Heparins are now usually the preferred drugs for the prevention of perioperative VTE, but warfarin retains a limited role when the risk of thrombosis is very high. Its main role is in long-term therapy. Warfarin is no less effective than low molecular weight heparins after hip or knee replacement, and the risk of bleeding is similar or lower when therapy is started at about the time of surgery and continued at least until patients are fully mobile.²¹

Treatment: Anticoagulants prevent early thrombus extension and embolism and minimise late recurrence. Heparin treatment can be stopped after a minimum of five days when warfarin therapy is also being given, provided that the two drugs are overlapped for at least four days and the INR has exceeded 2.0 for two or more days.²²

Increasingly, deep vein thrombosis (DVT) is now managed at home -- an approach preferred by many patients and made possible by trials which found that initial treatment with low molecular weight heparins given in a fixed dose by subcutaneous injection is no less effective or safe after DVT than standard heparin therapy. Home heparin therapy requires close monitoring to ensure compliance and a safe and effective start for warfarin therapy.^23,24

Although warfarin is now usually given for 3-6 months after VTE, there is growing evidence that the optimal duration of treatment is determined by the patient's clinical presentation. Six to 12 weeks of warfarin therapy is probably enough when DVT follows surgery or transient immobilisation ("secondary" DVT), as recurrence is minimised by six weeks of treatment after symptomatic calf vein DVT,⁷ and by three months of treatment after proximal DVT.^25,26 However, warfarin therapy for longer than six months may be required after "idiopathic" DVT, recurrent VTE, or when there is a continuing cause like cancer or an inherited or acquired "hypercoagulable" state.^27-30 Whether, in these circumstances, warfarin should be given for 12 months, two years, or longer, remains under active investigation. For individuals, the choice will also be influenced greatly by risk of bleeding.

Controversies in the management of DVT and VTE

Calf vein thrombosis: Although calf vein DVT poses little immediate threat and is commonly believed to be clinically unimportant, it has the potential to extend and embolise. In a randomised comparison where 51 patients with symptomatic calf DVT were treated for five days with heparin only or with heparin followed by ongoing warfarin therapy, there was a recurrence during the next three months in eight of 28 patients from the first group (23%: seven clinically suspected and confirmed; five with proximal extension and one with embolism), but none in the second.³¹ Therefore, patients with calf vein thrombosis should be treated with warfarin unless there are contraindications.

Accuracy of diagnostic tests for DVT: Venous ultrasonography has now replaced venography as the first-line diagnostic test for clinically suspected DVT. Despite its limited sensitivity to small calf vein DVTs, a negative ultrasound result almost excludes thrombosis when there is a low pretest clinical probability for DVT (a DVT score of zero on a checklist of clinical features obtained before ultrasonography, such as active cancer, immobilisation, major surgery, entire leg swelling, localised tenderness, calf swelling, pitting oedema and collateral superficial veins).³² However, for patients in whom the pretest clinical probability is moderate (DVT score of 1-2) or high (score, > 3), a negative ultrasound result does not exclude a small DVT, and they should have either early venography or further ultrasonography once or twice within the next seven days in case there is proximal extension of an undetected calf thrombus. This approach is validated by extensive clinical follow-up.³³

Recurrent or idiopathic DVT or VTE: In a randomised trial of patients presenting with recurrent DVT, oral anticoagulant therapy for six months was followed by a recurrence in 21% during four years of follow-up, compared with 3% when treatment was continued. However, ongoing warfarin therapy increased the rate of major bleeding during the four years from 2.7% to 8.6%, while mortality remained unchanged.²⁷ Similarly, in a separate trial of management after a first "idiopathic" VTE, warfarin therapy for three months was followed by recurrence in 16 of 77 patients during 10 months of follow-up, compared with only one of 76 patients in whom warfarin therapy was continued.³⁰ However, the use of warfarin increased the annual risk of major bleeding from zero to 4%.³⁰ These high rates of bleeding reinforce the need for careful risk assessment when considering patients for long term anticoagulant therapy after VTE.

The results of these trials suggest that warfarin therapy should be continued for one year after an "idiopathic" or recurrent VTE if the risk of bleeding is acceptable, and that treatment should be extended to two years if warfarin control is straightforward and the bleeding risk remains low.

Atrial fibrillation

Warfarin is now widely used to prevent systemic embolism in otherwise healthy patients with atrial fibrillation (AF). In clinical trials, warfarin consistently reduced the annual risk of a first ischaemic stroke (including stroke with a residual functional deficit) by almost 70% (from 7% to 3% per annum) and mortality by 33%, at the cost of a small increase in serious bleeding (from 1.0% to 1.3% per annum).^10,34,35

The prevalence of AF rises from about 3% at 65 years to more than 10% by 85 years, and AF accounts for about 1.5% of all strokes in people aged 50-59 years, and almost 25% of strokes in people aged 80-89 years. Age is therefore an important determinant of ischaemic stroke in AF (the relative risk [RR] of stroke in AF rises by 1.4 with each decade).³⁵ Previous stroke or transient ischaemic attack (RR, 2.5), diabetes (RR, 1.7), and treated hypertension (RR, 1.6) also contribute, as do heart failure, ischaemic heart disease, a large left atrium, and left ventricular dysfunction.¹⁰ Stroke is unlikely in isolated AF but becomes more likely as additional risk factors accumulate (Box 4). This makes warfarin therapy inappropriate for young people with AF alone and no other cardiac risk factor (isolated AF), as their annual risk of stroke (< 1%) is low enough to ensure that risk of bleeding always equals or exceeds any likelihood of gain.

Because of the risk of bleeding, these reports raise important questions about the best target level of INR, and about which patients with AF should be offered long-term warfarin therapy. The incidence of stroke is minimised by an INR > 2.0 and increases exponentially below this level, but some benefit remains while the INR is 1.5-1.9. When considering warfarin therapy for AF, each candidate requires a formal estimate of the relative risks of stroke (Box 4) and bleeding (Box 2).

Controversies about the use of warfarin or aspirin to prevent stroke in atrial fibrillation

Stroke and the INR: The risk of stroke during warfarin therapy for AF is dictated by the INR. Below 2.0, the relative risk doubles at 1.7, triples at 1.5, sextuples at 1.3, and reaches 18 times once the INR is normal, but nothing is gained by increasing the INR beyond its therapeutic threshold of 2.0.³⁶ Results were similar when warfarin was given for secondary stroke prevention in patients with AF who had already developed a stroke or transient cerebral ischaemia.¹¹ Again, in a randomised trial in which patients with AF plus at least one other risk factor for stroke were given either warfarin in a dose to prolong their INR (INR, 2.0-3.0; median, 2.4) or aspirin combined with a low dose of warfarin (0.5-3.0 mg/day; INR, 1.2-1.5; median, 1.3), the dose aiming for the higher INR was clearly superior.³⁷

Aspirin or warfarin for AF? The 30% risk reduction in stroke from aspirin treatment is well below the 70% achieved with warfarin therapy.¹⁰ In a blinded analysis of clinical outcomes when the two drugs were compared, warfarin was better at preventing cardioembolic strokes and strokes of uncertain cause.³⁸ This is consistent with the small effect observed with aspirin for secondary stroke prevention in patients with AF and who have had a stroke or TIA -- warfarin reduced the risk of recurrence by 62%, compared with only 16% for aspirin.³⁹ It may be a useful compromise to reserve aspirin for patients with uncomplicated AF whose baseline risk of embolism is low.

Warfarin, INR and aspirin in elderly patients with AF: Age above 75 years and a high INR both increase the hazard from intracranial and other major bleeding during warfarin therapy. Because there is some residual benefit at an INR of 1.5-1.9, this reduced target range may offer an acceptable exchange of safety for benefit in some elderly patients. Where the risk of bleeding is high, aspirin is less effective, but safer than warfarin.

Cardioembolic stroke prevention in conditions other than AF

There is evidence that cardioversion to correct a recent cardiac arrhythmia should be delayed until after three weeks of anticoagulant cover to prevent systemic embolism.³⁵ Warfarin prevents embolic stroke and other arterial embolism, as well as VTE, after myocardial infarction (MI), and is often given for 3-6 months when MI is followed by intraventricular thrombus formation (risk factors include transmural anterior infarction and ventricular dysfunction).⁴⁰ A good case also exists for long term warfarin therapy in some patients with ongoing left ventricular dysfunction.^41,42

Prosthetic heart valves

Improved design has greatly reduced the thrombogenicity of mechanical prosthetic heart valves, but the need for effective, lifelong warfarin therapy remains because systemic embolism is still the main source of late mortality and morbidity. The risk is determined by the type of valve and its position (higher for mitral than aortic valves, greatest when both are replaced). Tissue valves, by contrast, are almost free of thromboembolic complications, except during the first three months.⁴³

The American College of Chest Physicians recommends an INR of 2.0-3.0 for recent-model bileaflet or tilting disc valves, and 2.5-3.5 for older and more thrombogenic valves that have a caged ball or disc; patients with a newly placed bioprosthetic (tissue) valve require three months of warfarin and an INR of 2.0-3.0.⁴³ However, in our view, because the evidence is incomplete, it remains prudent to retain a target range of 2.5-3.5 for most ("low-risk") prosthetic valves while aiming higher (3.0-4.5) for older and more thrombogenic models, provided there is no contraindication (Box 1). This view is consistent with recent recommendations from the British Society for Haematology.²

Antiplatelet drugs alone are ineffective, but combining dipyridamole or aspirin (100 mg/day) with warfarin reduces the risk of systemic embolism. Meta-analysis suggests that the penalty for adding aspirin is a 2.5-times increase in major gastrointestinal bleeding,⁴⁴ so the combination is perhaps best avoided, except in patients considered to be at unusually high risk of systemic thromboembolism (more than one mechanical valve, previous embolism, associated AF).⁴³

Special circumstances for anticoagulation

Antiphospholipid antibody syndrome and factor V Leiden: Two retrospective surveys of clinical outcomes in patients with antiphospholipid antibody syndrome and venous and/or arterial thrombosis suggest that warfarin therapy fails to prevent recurrent thromboses unless the INR is prolonged above 3.0.^45,46 This contrasts with a more recent report of few recurrences while the INR was 2.0-3.5.⁴⁷ Without better information, and until randomised trials are complete, it is not possible to make a firm recommendation about the optimal target range for this condition. The effect of aspirin alone in preventing thrombosis in the antiphospholipid antibody syndrome is unclear.^45-47 There is no current evidence to suggest that patients with factor V Leiden-heterozygous abnormality should require more intense anticoagulation. It is still uncertain whether the duration of therapy should be increased in these patients, as evidence from reports about the risk of recurrent VTE is conflicting.^28,29,48

Oral anticoagulants in pregnancy: Oral anticoagulants cross the placenta and should be avoided throughout pregnancy, especially during the first and third trimesters.⁴⁹ Treatment at 6-12 weeks' gestation causes calcified epiphyses (chondrodysplasia punctata) and a characteristic nasal hypoplasia in offspring,⁵⁰ while later exposure is associated with central nervous system abnormalities, including microcephaly.⁵¹ In one report, almost 30% of children (10 of 35) born to mothers with a prosthetic heart valve were malformed if acenocoumarol was taken through 6-12 weeks' gestation, but none of 19 developed a malformation when this drug was replaced with heparin before the sixth week.⁵² Continuing warfarin therapy until term also exposes infants to the risk of intracranial and other major bleeding during birth. Heparins do not cross the placenta and do not cause these problems.^53-55 It is safe to breastfeed during warfarin therapy as there is minimal excretion into breast milk.⁵⁶

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References

1. Hirsh J, Dalen JE, Anderson D, et al. Oral Anticoagulants. Mechanism of action, clinical effectiveness and optimal therapeutic range. Chest 1998; 114 Suppl: 445S-469S.
2. Walker ID, Machin S, Baglin TP, et al. Guidelines on oral anticoagulation. 3rd ed. Br J Haematol 1998; 101: 374-387.
3. Holbrook AM, Wells PS, Crowther NR. Pharmacokinetics and drug interactions with warfarin. In: Poller L, Hirsh J, editors. Oral anticoagulants. Sydney: Arnold, 1996: 30-48.
4. 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.
5. Rose P. Audit of anticoagulant therapy. J Clin Pathol 1996; 49: 5-9.
6. Coumadin and Marevan are not interchangeable. Aust Adverse Drug React (ADRAC) Bull 1999; 18: 6.
7. van der Meer FJM, Rosendaal FR, Vandenbroucke JP, Briet E. Bleeding complications in oral anticoagulant therapy: an analysis of risk factors. Arch Intern Med 1993; 153: 1557-1562.
8. Cannegieter SC, Rosendaal FR, Wintzen AR, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333: 11-17.
9. Levine M, Raskob GE, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 1998; 114 Suppl: 511S-523S.
10. Laupacis A, Boysen G, Connolly S, et al. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449-1457.
11. The 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.
12. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997; 42: 857-865.
13. Landefeld S, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction and prevention. Am J Med 1993; 95: 315-328.
14. Fihn SD, McDonnell M, Martin D, et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Ann Intern Med 1993; 118: 511-520.
15. 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.
16. Hylek EM, Singer D. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120: 897-902.
17. Weibert RT, Le DT, Kayser SR, Rapaport SI. Correction of excessive anticoagulation with low-dose oral vitamin K₁. Ann Intern Med 1997; 125: 959-962.
18. Crowther M, Donovan D, Harrison L, et al. Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin. Thromb Haemost 1998; 79: 1116-1118.
19. Makris M, Greaves M, Philips W, et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1996; 77: 477-480.
20. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336: 1506-1511.
21. Clagett GP, Anderson FA, Geerts WH, et al. Prevention of venous thromboembolism. Chest 1998; 114 Suppl: 531S-560S.
22. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 1998; 114 Suppl: 561S-578S.
23. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334: 682-687.
24. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677-681.
25. Schulman S, Rhedin A-S, Lindmarker P, et al. Comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995; 332: 1661-1665.
26. Levine MN, Hirsh J, Gent M, et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal DVT. Thromb Haemost 1995; 74: 606-611.
27. Schulman S, Granqvist S, Holmstrom M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997; 336: 393-398.
28. van den Belt AGM, Sanson B-J, Simioni P, et al. Recurrence of venous thromboembolism in patients with familial thrombophilia. Arch Intern Med 1997; 157: 2227-2232.
29. Simioni P, Prandoni P, Lensing AWA, et al. The risk of recurrent venous thromboembolism in patients with an Arg⁵⁰⁶ to Gln mutation in the gene for factor V (Factor V Leiden). N Engl J Med 1997; 336: 399-403.
30. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 901-907.
31. Lagerstedt CI, Olsson C-G, Fagher BO, et al. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet 1985; 2: 515-518.
32. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350: 1795-1798.
33. Heijboer H, Buller HR, Lensing AW, et al. A comparison of real-time compression ultrasonography with impedance plethysmography for the diagnosis of deep-vein thrombosis in symptomatic outpatients. N Engl J Med 1993; 329: 1365-1369.
34. Singer DE. Overview of the randomized trials to prevent stroke in atrial fibrillation. Ann Epidemiol 1993; 3: 563-567.
35. Laupacis A, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation. Chest 1998; 114 Suppl: 579S-589S.
36. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335: 540-546.
37. Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-638.
38. Miller VT, Pearce LA, Feinberg WM, et al. Differential effect of aspirin versus warfarin on clinical stroke types in patients with atrial fibrillation. Neurology 1996; 46: 238-240.
39. European Atrial Fibrillation Trial Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342: 1255-1262.
40. Cairns JA, Theroux P, Lewis HD Jr, et al. Antithrombotic agents in coronary artery disease. Chest 1998; 114 Suppl: 611S-633S.
41. Fuster V, Gersh BJ, Giuliani ER, et al. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981; 47: 525-531.
42. Al-Khadra AS, Salem DN, Rabd WR, et al. Warfarin anticoagulation and survival: a cohort analysis from the studies of left ventricular dysfunction. J Am Coll Cardiol 1998; 31: 749-753.
43. Stein PD, Alpert JS, Dalen JE, et al. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1998; 114 Suppl: 602S-610S.
44. Cappelleri JC, Fiore LD, Brophy MT, et al. Efficacy and safety of combined anticoagulant and antiplatelet therapy versus anticoagulant monotherapy after mechanical heart-valve replacement: a metaanalysis. Am Heart J 1995; 130: 547-552.
45. Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992; 117: 303-308.
46. Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332: 993-997.
47. Krnic-Barrie S, O'Connor CR, Looney SW, et al. A retrospective review of 61 patients with antiphospholipid syndrome: analysis of factors influencing recurrent thrombosis. Arch Intern Med 1997; 157: 2101-2108.
48. Eichinger S, Pabinger I, Stumpflen, et al. The risk of recurrent venous thromboembolism in patients with and without Factor V Leiden. Thromb Haemost 1997; 77: 624-628.
49. Ginsberg J, Barron W. Pregnancy and prosthetic heart valves. Lancet 1994; 344: 1170-1172.
50. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998; 338: 1128-1137.
51. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68: 122-140.
52. Iturbe-Alessio I, del Carmen Fonseca M, Mutchinik O, et al. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 1986; 315: 1390-1393.
53. Ginsberg JS, Kowalchuk G, Hirsh J, et al. Heparin therapy during pregnancy. Risks to the fetus and mother. Arch Intern Med 1989; 149: 2233-2236.
54. Fejgin MD, Lourwood DL. Low molecular weight heparins and their use in obstetrics and gynecology. Obstet Gynecol Surv 1994; 49: 424-431.
55. Sanson B-J, Lensing AWA, Prins MH, et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-672.
56. Orme ML, Lewis PJ, de Swiet M, et al. May mothers given warfarin breast-feed their infants? BMJ 1977; 1: 1564-1565.

Background and evidence basis of recommendations

The Australasian Society of Thrombosis and Haemostasis Consensus Guidelines for Warfarin Therapy were written on behalf of the Australasian Society of Thrombosis and Haemostasis (ASTH). The writing committee was commissioned by council and consisted of Associate Professor A S Gallus (Chairman), Dr R I Baker, Professor B H Chong, Dr P A Ockelford and Associate Professor A M Street. The guidelines were developed after extensive consultation with the membership of the ASTH, including several workshops and teleconferences. The draft recommendations were open for comment and discussion at the 1998 annual scientific meeting of the ASTH in Sydney. They draw upon review of all available evidence from published studies and from clinical experience. The aim is to provide an Australian perspective on the evidence to guide all practitioners in the safe and effective use of oral anticoagulants in hospital and the community. We are grateful for the help of Dr K McGrath, Dr M Herzberg (Quality Assurance Program in Haematology, Royal College of Pathologists of Australasia), Dr P Montanaro (Royal Australian College of General Practitioners), Dr P Steele (Australia and New Zealand Cardiac Society) and Professor J Fletcher (International Union of Angiology).

Authors' details

Australasian Society of Thrombosis and Haemostasis, Perth, WA.
Alex S Gallus, FRACP, FRCPA, Chairman;
Ross I Baker, FRACP, FRCPA;
Beng H Chong, FRACP, FRCPA;
Paul A Ockelford, FRACP, FRCPA;
Alison M Street, FRACP, FRCPA.

Reprints will not be available from the authors.
Correspondence: Professor A S Gallus, Director, SouthPath, C/- Flinders Medical Centre, Bedford Park, SA 5042.

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1: Range of international normalised ratio (INR) recommended for specific applications of warfarin therapy*
Condition	INR range
Preventing DVT (high risk patients, like those who have had hip replacement)	2.0-3.0
Therapy after DVT or pulmonary embolism	2.0-3.0
Preventing systemic embolism Atrial fibrillation Valvular heart disease After myocardial infarction Tissue heart valves (first 3 months)	2.0-3.0 2.0-3.0 2.0-3.0 2.0-3.0
Bileaflet mechanical heart valve (aortic)	2.5-3.5
Mechanical prosthetic heart valve (high risk)	3.0-4.5
Preventing recurrence of myocardial infarction	3.0-4.5
Thrombosis in antiphospholipid antibody syndrome	3.0-4.5
DVT=deep vein thrombosis . *Based largely on the 5th American College of Chest Physicians Consensus Conference1 and consistent with current recommendations of the British Society for Haematology.2

2: Risk of major bleeding (% per annum) and international normalised ratio (INR) - findings of two studies23,30
INR	Study 130	Study 223
< 2.0 2.0-2.9 3.0-3.9 4.0-4.9 5.0-5.9 ≥ 6	3% 2%-3% 2%-3% 4% 5% 5%-13%	0 1% 3% 4% 50%

3: Managing overdose and bleeding during warfarin therapy*
Clinical setting	Action
INR >5.0 but < 9.0 (no bleeding)	Stop warfarin, give 1-2.5mg vitamin K1, measure INR in 6-12 hours, restart warfarin at reduced dose once INR is < 5
INR ≥9.0 (no bleeding)	Stop warfarin, give 5mg vitamin K1, measure INR in 6-12 hours, restart warfarin at reduced dose once INR is < 5, clotting factor replacement? if high risk of bleeding
Major bleeding (any level of INR)	Stop warfarin, give 5mg vitamin K1, clotting factor replacement, measure INR as required, assess need to restart warfarin
INR=international normalised ratio. *Based on Makris et al, 1996.19 ?Blood products available in Australia for clotting factor replacement after warfarin overdose include fresh frozen plasma and Prothrombinex-HT (CSL Limited), a factor II, IX and X concentrate.

4: Risk of ischaemic stroke in patients with atrial fibrillation (AF), grouped by age and other risk factors* (derived from Laupacis et al10)
Risk categories	Patients affected per annum
Lone atrial fibrillation† Age < 60 years Age 60-69 years Age 70-79 years Age ≥80 years	0 1.6% 2.1% 3.0%
Age < 65 years No risk factors One or more risk factors	1.0% 4.9%
Age 65-75 years No risk factors One or more risk factors	4.3% 5.7%
Age >75 years No risk factors One or more risk factors	3.5% 8.1%
*Hypertension, diabetes, previous stroke or transient ischaemic attack. †Atrial fibrillation without transient ischaemic attack or stroke, myocardial infarction, hypertension or heart failure.