Education and debate

How To Do It: Commentary: Caution needed in introducing warfarin treatment

^a St Leonard's Medical Practice, Exeter EX1 1SF

Correspondence to: Dr Sweeney.

We welcome the cautious interpretation of the recent trials of warfarin in atrial fibrillation provided by the authors of this article and concur with their concerns about the generalisability of the results of this group of trials. We congratulate them on introducing the concept of packages of care in this context--packages that include not just the prescribing of drugs but rigorous selection of patients and meticulous monitoring and follow up.

The authors' analysis of the trials highlights the huge exclusion rates of patients initially considered eligible and, correctly in our view, links these stringent exclusion criteria and the intensity of follow up of patients to the uniformly low bleeding rates that were found in all the trials. We would go further and point out that for quite large periods of time in all but one of the trials patients were in fact underanticoagulated according to the individual trial's acceptable range of anticoagulation (table). We also argue that the minor bleeding rates in these trials were not given enough consideration in the reviews that summarised their results.⁷ There was no agreed definition of minor bleeding among the trials, and in one, the Boston area anticoagulation trials for atrial fibrillation,² minor bleed was held to include any bleeding event that required transfusion of up to four units of blood. There is evidence that minor bleeding has a substantial impact on patients receiving warfarin,⁸ and, as general practitioners, we recognise the impact of these events on the workload of the primary health care team. Even clinically innocuous complaints like menorrhagia or epistaxis require prompt assessment, often at home, if they occur in patients taking warfarin.

Percentage of days where anticoagulant control fell outside stated range
------------------------------------------------------------------------------------------------------------------------
Trial                                                            Below lower limit (%)          Above higher limit (%)
------------------------------------------------------------------------------------------------------------------------
Atrial fibrillation, aspirin, anticoagulation1                        26.0                        0.6
Boston area anticoagulation trial for atrial fibrillation2             9.0                        8.0
Stroke prevention in atrial fibrillation3                             23.0                        5.0
Canadian atrial fibrillation anticoagulation4                         39.6                       16.6
Stroke prevention in nonrheumatic atrial fibrillation5                29.0                       15.0
European atrial fibrillation trial6                                   32.0                        9.0

Finally, we welcome the authors' assessment of the cost implications of treating patients with warfarin. Up to now cost analyses in this context have focused on a narrow health service perspective when the wider cost may well be greater.

View larger version (44K): [in this window] [in a new window]   FIG 2--Spontaneous haemorrhage is a danger of warfarin treatment

What, then, is the best way forward? The results in the trial populations certainly show that warfarin protects against stroke in patients with atrial fibrillation. After the publication of the stroke prevention in atrial fibrillation II trial, and the analysis of the pooled data, doctors are now in a better position to stratify risk in patients with atrial fibrillation.^{9 10} The former confirmed the usefulness of considering clinical predictors of thromboembolism--hypertension, recent congestive heart failure, and previous thromboembolism--when choosing between aspirin and warfarin for treating patients with atrial fibrillation. Evidence also shows that patients with lone atrial fibrillation may not need prophylaxis. In one retrospective study their annual incidence of stroke was 0.5%.¹¹ On the basis of the present evidence all other patients who have atrial fibrillation should be considered for anticoagulants if there are no contraindications.

We agree with Sudlow et al that this may well result in increased referrals for echocardiography, as this also may influence the choice of aspirin against warfarin. We also support the authors' concern that factors beyond the firm contraindications for warfarin may influence general practitioners' decision to give anticoagulants. Advising patients about their warfarin dose over the telephone may not be prudent if patients are developing a visual impairment and may not be able to read the label on their bottle or if they are becoming forgetful and cannot remember taking their tablets at the usual time. Such important but ill defined circumstances will influence decisions to start warfarin treatment and will have to be re-evaluated regularly as the treatment continues.

Finally, patients' autonomy will be the final factor that influences the acceptance or rejection of doctors' advice about treatment. While some argue that patients are overwhelmingly driven by a fear of stroke (A Laupacis, personal communication), that is not our experience in general practice. Concerns about bleeding, the inconvenience of frequent blood tests, and worries about taking other drugs all play a part, rightly or wrongly, in patients' decisions when they are offered warfarin treatment. We certainly support these authors' call for evidence based guidelines for patient selection and treatment; we suggest that these should include advice about stopping treatment when other developing conditions render it unsafe to continue. This issue has highlighted the need for primary care researchers to evaluate new evidence which will have a substantial impact on their sector of health care.

1. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B, for the Copenhagen AFASAK study. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. Lancet 1989;1:175-9. [Medline]
2. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990;323:1505-11. [Abstract]
3. Stroke Prevention in Atrial Fibrillation Investigators. Stroke prevention in atrial fibrillation study. Final results. Circulation 1991;84:527-39. [Abstract/Free Full Text]
4. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C, for the CAFA Study Coinvestigators. Canadian atrial fibrillation anticoagulation (CAFA) study. J Am Coll Cardiol 1991;18:349-55. [Abstract]
5. Ezekowitz MD, Bridgers SL, James KE, Carliner NH, Colling CL, Gornick CC, et al, for the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. N Engl J Med 1992;327:1406-12. [Abstract]
6. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993;342:1255-62. [Medline]
7. Lowe GDO. Antithrombotic and atrial fibrillation. BMJ 1992;305:1445-6.
8. Lancaster TR, Singer DE, Sheehan MA, Oertel LB, Maraventano SW, Hughes RA, et al, for the BATAF investigators. The impact of long term warfarin therapy on quality of life. Arch Intern Med 1991;151:1944-9. [Abstract]
9. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for the prevention of thrombo-embolism in atrial fibrillation. Stroke prevention in atrial fibrillation II study. Lancet 1994;343:687-91. [Medline]
10. Risk factors for stroke and efficacy of anti-thrombotic therapy in atrial fibrillation. Analysis of pooled data from 5 randomised controlled trials. Arch Intern Med 1994;154:1449-57. [Abstract]
11. Kopecky SL, Gersh BJ, McGoon MD, Whisnant JP, Holmes DR, Ilstrup MS, et al. The natural history of lone atrial fibrillation: A population based study over 3 decades. N Engl J Med 1987;317:669-74. [Abstract]