Warfarin: balancing the benefits and harms
Marija Borosak, Haematology Registrar, Pathology Department, Shin Choo, Senior Pharmacist, Department of Pharmacy, and Alison Street, Associate Professor and Head, Haematology Unit, The Alfred Hospital, Melbourne

Summary

The benefits of warfarin therapy are substantial in the prevention of arterial and venous thrombosis, and in the primary and secondary prevention of stroke related to non-rheumatic atrial fibrillation. The major risk of warfarin is bleeding, which can cause significant morbidity or mortality. If the bleeding risk is high then alternatives to therapeutic doses of warfarin may be considered, although their efficacy may be suboptimal and may not eliminate the risk of bleeding. Constantly review the patient's circumstances in order to weigh up the benefits and harms of treatment with warfarin.

Key words: anticoagulation, haemorrhage, thromboembolism.

Aust Prescr 2004;27:88-92

Introduction

Anticoagulation with warfarin significantly reduces the morbidity and mortality related to arterial and venous thromboembolism. For many patients the benefit is clear and the risk of harm is acceptable, so anticoagulation is indicated.

Almost 1.9 million out-of-hospital prescriptions for warfarin were dispensed in 2001.The cost to the Pharmaceutical Benefits Scheme (PBS) and Repatriation Pharmaceutical Benefits Scheme (RPBS) of warfarin for the same period was $8.3 million. From Health Insurance Commission statistics coagulation tests numbered 2.5 million in the same year at a cost of $29.4 million. Most of these tests are for routine monitoring of warfarin therapy. There are therefore many patients taking warfarin, but the decision to use the drug and accept the adverse effects requires constant review.

Indications for warfarin therapy

There are published recommendations, with supporting levels of evidence, for warfarin therapy.1,2 The major indications are for prophylaxis and treatment of venous thromboembolism and its extension, for example pulmonary embolism. Warfarin is also indicated for the prophylaxis of non-rheumatic atrial fibrillation in association with risk factors, particularly previous thromboembolism (transient ischaemic attack or ischaemic stroke), diabetes and hypertension. Warfarin is not indicated in patients with lone atrial fibrillation who are less than 60 years of age with no risk factors.

One of the most frequent indications for anticoagulation is reducing the risk of stroke associated with non-rheumatic atrial fibrillation, particularly in the elderly. The prevalence of atrial fibrillation approximately doubles with each advancing decade of age. Non-rheumatic atrial fibrillation is found in approximately 15% of all stroke patients.3,4 The average stroke rate among patients with atrial fibrillation is 5% per annum. With the ageing population stroke prevention in atrial fibrillation will continue to be a significant management issue.

Contraindications to warfarin therapy

Contraindications to warfarin are any localised or general physical condition or personal circumstance in which the hazard of haemorrhage might be greater than the potential clinical benefit of anticoagulation. These include:

  • haemorrhagic tendencies and blood dyscrasias
  • recent or contemplated surgery of the central nervous system or the eye
  • traumatic surgery resulting in large open surfaces.

Warfarin is contraindicated if the patient is unwilling or unable to comply with monitoring due to cognitive impairment, alcoholism, psychosis or problems with accessing services.

In the major interventional trials studying the efficacy of warfarin for stroke reduction in atrial fibrillation, patients considered at excessive risk of bleeding were excluded (Table 1).These exclusion criteria resulted in the recruitment of a fit group with only a very small sub-group of very elderly people, so there are inherent problems in extrapolating the study results into everyday practice.

Pregnancy

Warfarin is contraindicated during pregnancy, particularly during organogenesis (weeks 6-12).The risk of fetal bleeding remains throughout pregnancy due to the immature fetal liver.2 Warfarin is not normally prescribed at any stage during pregnancy in Australia.

Table 1

Exclusion criteria used in the major intervention trials of anticoagulation for patients with atrial fibrillation 13,19


Bleeding disorder or abnormal coagulation at baseline

Recent stroke or transient ischaemic attack (previous two years)

Uncontrolled hypertension (> 180/100 mmHg)

Active bleeding

Haemorrhagic retinopathy

History of intracranial haemorrhage

Use of non-steroidal anti-inflammatory drugs

Chronic alcohol abuse

Risk of gastrointestinal bleeding (active peptic ulcer disease, positive faecal occult blood testing, known oesophageal varices)

Planned surgery or invasive procedure

Pregnancy or breastfeeding

Psychiatric disorder or dementia

Expected poor compliance

Limited life expectancy

Significant renal dysfunction (creatinine > 0.25 mmol/L)

Platelet count < 100 x 109/L


Patients were also excluded if they refused to participate or if their doctor considered the risk of anticoagulation was too great.

Harm: benefit analysis in prescribing warfarin
(Fig. 1)

The risk of major bleeding in the atrial fibrillation intervention trials was 1-4% per year, with an intracranial bleeding rate of 0.2-0.5% per year. The fatality rate mirrored the intracranial bleeding rate.5 In observational studies of ambulatory patients the risk of major bleeding is 4-9% per annum.6,7

Major determinants of warfarin-induced bleeding include the intensity of anticoagulation, patient characteristics, the concomitant use of drugs that interfere with haemostasis, and the length of therapy.5 Before prescribing warfarin the risk of bleeding should be evaluated and discussed with each patient.8

Intensity of anticoagulation and duration of therapy

The risk of bleeding increases dramatically when the International Normalised Ratio (INR) exceeds 4.0.9,10 An INR greater than 4.0 is probably the most important risk factor for intracranial haemorrhage, independent of the indication for warfarin.5

The risk of major bleeding is greatest in the first month of therapy (3%) and decreases with time to 0.8% per month for the remainder of the first year and to 0.3% per month thereafter.7

Patient characteristics

Age

Atrial fibrillation is an increasingly important cause of stroke as patients get older. In the Framingham study the incidence of stroke due to atrial fibrillation increased from 1.5% for those aged 50-59 years to 23.5% for those aged 80-89 years.11 The prevalence of atrial fibrillation in those over 80 years old reaches approximately 10%.12

The results of studies conflict on whether age is an independent risk factor for bleeding. Advanced age is not itself a contraindication to warfarin. Studies in atrial fibrillation support the ongoing benefit of anticoagulation with increasing age. Warfarin therapy reduces the risk of ischaemic stroke in patients with non-rheumatic atrial fibrillation from 7.4% to 2.3% per year.13

Age is, however, a risk factor for more unstable prothrombin time results. For every 10-year increase in age there is a 15% increase in the risk of anticoagulation having to be suspended because of a raised INR.14

Comorbidities and medication

Conditions associated with an increased risk of bleeding during warfarin therapy include treated hypertension, cerebrovascular disease, serious heart disease, renal insufficiency and malignancy.5 Over time a person's comorbidities and medications accumulate. These increase the potential for interactions with warfarin.

The INR becomes unstable with the introduction, change in dose or suspension of many common drugs such as antibiotics. Warfarin and aspirin combinations are associated with a high frequency of bleeding, even when combined with 'low intensity' warfarin therapy.5

Some herbal preparations and large quantities of vitamin K-rich foods can also interfere with warfarin.15 Many such interactions are unpredictable so the INR should be checked within a few days of any change. Poor nutrition results in a relative deficiency of vitamin K and increased sensitivity to warfarin. A temporary dose reduction and increased monitoring are essential during an acute illness.

Falls

Patients should be assessed for their risk of falls and possible causes. Where a cause is identified and reversible, for example postural hypotension, and can be ameliorated by a change in medication, anticoagulation can be maintained although careful monitoring of the patient is essential. If the falls continue then the patient should be reviewed and alternatives to warfarin considered.

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A decision analysis model of the risks of central nervous system bleeding found that the propensity to fall is not a contraindication to the use of antithrombotic drugs (especially warfarin) in the elderly person with atrial fibrillation.16 However, approximately 1 in 10 falls causes major injury, including fractures, and people who fall are much more likely to suffer other serious morbidity. There is insufficient evidence to know whether those who fracture a bone while on warfarin suffer greater morbidity and mortality.

There are factors that contribute to the risk of falls that may also have an impact on the ability to adhere to warfarin therapy and monitoring. These include cognitive and sensory impairment as well as poor mobility due to gait, balance and foot problems. Often the general practitioner will be aware of other problems in addition to falls that preclude the safe and reliable use of anticoagulation.

Change in patient status

Each new diagnosis, treatment or major change in the patient's condition, particularly with concomitant poor diet, requires a further assessment of the risks and benefits of oral anticoagulation. The goals of therapy need constant review and possible revision, particularly when anticoagulation is used for long-term prophylaxis as, for example, in atrial fibrillation. An emphasis on 'perfect' primary prevention may be inappropriate when the patient only has a limited life expectancy.

Gastrointestinal bleeding

A similar analytical model has also been used to balance the risk of stroke and gastrointestinal bleeding in older patients with atrial fibrillation.17 For those with a significant risk of upper gastrointestinal bleeding or lower risks of stroke, warfarin is not clearly the optimal antithrombotic therapy. An 80-year-old with a baseline risk of stroke of 4.3% per year, who is concurrently taking a non-steroidal anti-inflammatory drug, has no difference in predicted outcomes with warfarin, aspirin or no treatment (quality-adjusted life-years of 7.44 for warfarin, 7.39 for aspirin and 7.21 for no treatment).17

What are the alternatives to oral anticoagulation?

If the target INR carries too high a risk of bleeding with the usual doses of warfarin, consider if the patient will benefit from other strategies.

Aspirin

When warfarin is contraindicated in patients with atrial fibrillation, aspirin should be given as it confers a 42% risk reduction compared to placebo.13 This is inferior to warfarin and still increases the risk of bleeding (major bleeding rate of 1.4% per year13).

Reduced intensity regimens

Moderately sub-therapeutic levels of anticoagulation (INR 1.6-1.9) may still reduce the risk of stroke in patients with non-rheumatic atrial fibrillation18 although a minimum INR of 2.0 is required if there is a history of prior stroke or recent transient ischaemic attack.19 However, there is conflicting evidence about the efficacy and safety of reduced intensity regimens.

Previous studies of fixed low doses of warfarin showed low rates of major bleeding.5 A more recent study of long-term, low intensity treatment with warfarin (INR target 1.5-2.0) for the prevention of recurrent thromboembolism also found low rates of major haemorrhage6, while other research reported no difference in bleeding risk.20 Another study has found that reduced intensity regimens result in more frequent strokes, that are more severe and lead to greater mortality, than regimens which aim for an INR greater than 2.0.This study found the stroke rate was no better than with aspirin and the bleeding complications were greater.21 These findings suggest that the target INR should be at least 2.0.

Low molecular weight heparin

An alternative to warfarin is the extended use of low molecular weight heparin for venous thromboembolism. If there are problems with compliance or with recurrent wild fluctuations in the INR, low molecular weight heparin can be administered under supervision. It is important to measure renal function as accumulation occurs with renal impairment, particularly when the creatinine clearance falls below 30 mL/min.

Discontinuation of warfarin

Warfarin therapy should be discontinued when the risk of bleeding outweighs the potential benefit. Any decision to discontinue warfarin should only be made after discussion with the patient or carer. Once the decision is made the relevant clinical carers should be informed, and the reasoning and the harm: benefit analysis should be clearly identified and documented. This decision should be subsequently reviewed if clinical or social circumstances alter.

Future directions

New oral anticoagulants, particularly the oral direct thrombin inhibitors, appear promising. They are currently being evaluated for a variety of thrombotic disorders including atrial fibrillation.

Note

See the two case studies below

References

1. Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: mechanism of action, clinical effectiveness and optimal therapeutic range. Chest 1998;114(5 Suppl):445S-69S.

2. Haemostasis and thrombosis task force for the British committee for standards in haematology. Guidelines on oral anticoagulation: third edition. Br J Haematol 1998;101:374-87.

3. Wolf PA, Dawber TR,Thomas HE Jr, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurology 1978;28: 973-7.

4. Sherman DG, Hart RG, Easton JD. The secondary prevention of stroke in patients with atrial fibrillation. Arch Neurol 1986;43:68-70.

5. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 2001;119 (1 Suppl):108S-21S.

6. Ridker PM, Goldhaber SZ, Danielson E, RosenbergY, Eby CS, Deitcher SR, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425-34.

7. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med 1989;87:144-52.

8. Campbell P, Roberts G, Eaton V, Coghlan D, Gallus A. Managing warfarin therapy in the community. Aust Prescr 2001;24:86-9.

9. van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briet E. Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Thromb Haemost 1996;76:12-6.

10. Palareti G, Hirsh J, Legnani C, Manotti C, D'Angelo A, Pengo V, et al. Oral anticoagulation treatment in the elderly: a nested, prospective, case-control study. Arch Intern Med 2000;160:470-8.

11. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke 1991;22:983-8.

12. Laupacis A, Albers G, Dalen J, Dunn MI, Jacobson AK, Singer DE. Antithrombotic therapy in atrial fibrillation. Chest 1998;114(5 Suppl):579S-89S.

13. Stroke prevention in atrial fibrillation study. Final results. Circulation 1991;84:527-39.

14. Froom P, Miron E, Barak M. Oral anticoagulants in the elderly. Br J Haematol 2003;120:526-8.

15. Myers SP. Interactions between complementary medicines and warfarin. Aust Prescr 2002;25:54-6.

16. Man-Son-Hing M, Nichol G, Lau A, Laupacis A. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med 1999;159:677-85.

17. Man-Son-Hing M, Laupacis A. Balancing the risks of stroke and upper gastrointestinal tract bleeding in older patients with atrial fibrillation. Arch Intern Med 2002;162:541-50.

18. 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;335:540-6.

19. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet 1993;342:1255-62.

20. Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, Julian JA, et al. Comparison of low-intensity warfarin therapy with conventional-intensity therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003;349:631-9.

21. Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019-26.

Conflict of interest: none declared

Self-test questions

The following statements are either true or false (click here for the answers)

1. Old age is a contraindication to warfarin therapy.

2. The risk of bleeding increases dramatically with INR values above 4.0.


Case study 1

Secondary prophylaxis

Mrs A is an 82-year-old woman with atrial fibrillation and a history of stroke. She does not have rheumatic valvular disease, but has congestive cardiac failure and diabetes. Mrs A lives on her own and her family live interstate. Her medications include metformin, enalapril, amiloride/hydrochlorothiazide and temazepam.

Question: Is anticoagulation indicated?

Answer: Yes. Her risk factors for stroke are atrial fibrillation, previous stroke, congestive cardiac failure, diabetes and old age. Her risk of stroke due to atrial fibrillation is approximately 45% over five years which will be reduced to 14% with warfarin therapy.22 She would therefore benefit considerably from stroke prevention with warfarin anticoagulation.

Question: Is there an excessive risk of bleeding or a contraindication identified?

Answer: No. Her annual risk of bleeding on warfarin is 8-19% for minor bleeding10 and 1-4% per year major bleeding rate including intracranial haemorrhage with a mortality rate of 0.2-0.5%.5

The appropriate target range is an INR of 2-3. Education, supported with written information is vital. Careful monitoring is required in the first three months when bleeding risk is greatest. Avoidance of over anticoagulation especially an INR greater than 4.0 ensures the bleeding risk is acceptable.

At a later appointment, Mrs A says she has begun to fall, and has had three falls recently.

Question: What may be contributing to these falls and what are the implications for her anticoagulation?

Answer: Diuretics, antihypertensives and sedatives may be contributing factors to postural instability and the risk of falls. Recurrent falls, age and polypharmacy increase her bleeding risk.

Question: How would you manage the patient?

Answer: The safety of warfarin should be reconsidered. The falls should be investigated for reversible factors and these managed. If the falls risk abates then warfarin can be continued. The propensity to fall may not be a contraindication to the use of warfarin in elderly patients with atrial fibrillation.16

Question: Are there satisfactory alternatives to warfarin?

Answer: Consideration should be given to the warfarin control and the intensity of anticoagulation. Adjustment to target INR values closer to 2-2.7 may be more reasonable than having frequent readings of 3.0 or above. Lower target INR and aspirin do not have the same efficacy and should be considered as the last resort.

This is a good opportunity to review her other medications. The decision and reasons to continue or discontinue anticoagulation should be documented and communicated to relevant carers (other medical practitioners, hospital, family). Review of the risks and benefits of anticoagulation should occur regularly.

Case study 2

Poor compliance

Mr B is a 45-year-old man with a recent deep venous thrombosis above his left knee. He lives alone, is unemployed and regularly binge drinks despite medical advice. Mr B has had a course of low molecular weight heparin for seven days and is stabilised on warfarin. He presents after a delay of a week for his INR check and is found to have an INR of 8.0.

Question: Should anticoagulation be continued?

Answer: Yes. There is a clear indication for continuing antithrombotic treatment in this man, without which the risks of recurrence are deemed too great (50% in the absence of anticoagulation in the first three months). In the setting of a reversible predisposing factor four weeks of anticoagulation may be adequate, however in the setting of idiopathic venous thromboembolism at least three months for the first episode is advisable23 and longer periods may be needed. Sometimes the presence of additional identifiable risk factors can assist with this decision e.g, combined heritable risk factors or antiphospholipid antibodies.

Question: Is there an excessive risk of bleeding or a contraindication identified?

Answer: Yes. Poor compliance due to alcoholism is a recognised contraindication to anticoagulation with warfarin.

Question: Are there satisfactory alternatives?

Answer: Management of the alcohol problem with close monitoring and re-education about the importance of warfarin may allow for therapy with warfarin to continue safely. If adherence to recommendations is neglected and wild fluctuations of INR occur then consideration of low molecular weight heparin with supervised administration may be an alternative.


First published online: August - 2004