3.1 Atrial fibrillation and systemic thromboembolism

Most people in Scotland with atrial fibrillation (AF) do not have valvular heart disease (non-valvular atrial fibrillation). The prevalence of non-valvular AF increases with age, from about 0.5% at age 50-59 to about 9% at age 80-89. Compared to persons in sinus rhythm, persons with AF have a five-fold mean increase in risk of stroke, largely due to an increased risk of atrial thrombosis which may embolise to the brain (and less frequently to the limbs or other internal organs), although associated arterial disease (e.g. carotid stenosis) may also increase the risk of stroke due to arterial thromboembolism. Stroke mortality is also higher in patients with AF, compared to patients in sinus rhythm.^{77, 78}

The risk of stroke in non-valvular AF appears to be similar in men and in women, and in persons with continuous AF and in paroxysmal AF.¹⁰ The role of echocardiography in risk stratification in non-valvular AF remains unclear. Impaired left ventricular function or mitral valve calcification are risk predictors.⁷⁹ A consensus statement recommends that echocardiography (to determine whether or not valvular disease and left ventricular systolic dysfunction are present) is part of optimal assessment of AF.⁷⁹

3.2 Efficacy of warfarin and aspirin as antithrombotic prophylaxis

A prospective pooled analysis¹⁰ of five randomised controlled trials of warfarin in prophylaxis of systemic embolism (usually in patients with no history of previous embolism, i.e. primary prophylaxis), showed relative risk reductions for stroke of 68% (95% CI 50-79%) and for death of 33% (95% CI 9-51%). Evidence level Ia

The efficacy of warfarin was probably underestimated, because most strokes in patients in the 'warfarin groups' occurred when patients were not taking warfarin.^{10, 82} While the five trials used various target ranges of INR (between 1.5 and 4.5) the minimum risk of stroke appeared to occur in the INR range 2.0-3.0.^{10, 82} The annual risk of intracranial haemorrhage increased from 0.1% in controls to 0.3% in warfarin groups, (i.e. an excess of two intracranial bleeds per year per thousand patients treated) and was associated with an INR greater than 3.0 and with uncontrolled hypertension (there was also a non-significant association with increasing age).^{10, 82} (It should be noted that patients in these trials were selected to exclude those at increased risk of bleeding.) Lower intensity warfarin (INR 1.5-2.5) plus aspirin was less effective than standard intensity warfarin in high risk patients in the SPAF-3 study.⁸⁰ Evidence level Ia and Ib

Contraindications to warfarin include increased risk of bleeding due to co-existing medical conditions, and any tendency to falls or other exposure to trauma. Another consideration is the likelihood of poor concordance (compliance), which will be influenced not only be the patient's ability to manage medication but also by local facilities for control of the INR. Special care must be taken with other drugs that interact with warfarin, including amiodarone. Patient preference is important.⁷⁹

Aspirin has been evaluated as primary prophylaxis of systemic embolism in AF in two randomised controlled trials compared against 'no antithrombotic treatment^{7, 10, 11, 12, 18} and in one randomised controlled trial compared to warfarin.⁸¹ On-treatment analysis showed that aspirin was less effective than warfarin (20% risk reduction vs. 68%);^{11, 12, 18} however aspirin is simpler, less hazardous and less costly than warfarin. Evidence level Ib

Aspirin was significantly less effective than warfarin as secondary prophylaxis in patients with previous stroke or TIA.^{10, 17} Evidence level Ib

Warfarin and aspirin should only be given together in special circumstances⁷⁹ (see sections 4.4 and 8).

The absolute risk of stroke in persons with non-valvular AF (and hence the absolute benefits of aspirin or warfarin prophylaxis) varies greatly with the presence or absence of risk factors for thromboembolism.^{10, 82} Evidence level III

Meta-analyses of randomised controlled trials in primary prophylaxis^{6, 7, 10, 11, 12, 18, 19, 82} and one randomised controlled trial in secondary prophylaxis¹⁷ have shown that lower risk patients (annual stroke rate under 3%) require no antithrombotic prophylaxis, unless there are other indications for aspirin. In higher risk patients (annual stroke rate over 3%), warfarin (at a target INR of 2.5, range 2.0-3.0) is effective in prophylaxis of stroke, and significantly more effective than aspirin; however, it also carries a higher risk of bleeding. Evidence level Ia and Ib

In all patients with atrial fibrillation, risk factors for systemic thromboembolism should be assessed routinely.

Lower risk patients (annual stroke rate under 3%, as defined in section 3.4 below) should be given no antithrombotic prophylaxis , unless aspirin (75-300 mg/day) is given for other indications.

Higher risk patients (annual stroke rate over 3%, as defined in section 3.3 below) should be considered for warfarin at a target INR of 2.5, range 2.0-3.0. The balance of risks and benefits of warfarin should be assessed and discussed with the patient, and reassessed annually in individual higher risk patients: aspirin may be a safer alternative to warfarin in some of these patients.

Anticoagulant therapy after an acute cerebral ischaemic event should be delayed until most of the deficit has resolved or, in the case of more severe strokes, more than two weeks has elapsed.79 (See section 7.1.)

Having undertaken risk assessment, there are a variety of methods which may be used to stratify patients.^{79, 83} The following is one approach.

3.3 Higher risk groups

3.3.1

People with non-valvular AF and previous ischaemic stroke or TIA had a high annual risk of stroke in a meta-analysis of randomised trials of warfarin: 11.7% in controls and 5.1% in warfarin groups.¹⁰ These results are similar to those in a randomised trial of secondary prophylaxis with warfarin in patients with a previous stroke or TIA: 12% in controls and 4% in warfarin groups.¹⁷ In contrast, the relative risk reduction with aspirin was only 19%,¹¹ which is similar to that seen for secondary prevention of stroke in patients in sinus rhythm.⁷ Detailed sensitivity analyses have suggested that these estimates may be overoptimistic when applied in routine clinical practice.^{79, 83} Evidence level Ia and Ib

Warfarin (target INR 2.5, range 2.0-3.0) should be considered for antithrombotic prophylaxis in patients with non-valvular atrial fibrillation and a history of previous ischaemic stroke or TIA.

If warfarin is declined, or contraindicated by increased risk of bleeding, aspirin (75-300 mg/day) should be considered, but is less effective than warfarin.

3.3.2

People with non-valvular AF who are aged over 65 and also have at least one other risk factors for stroke (history of hypertension, diabetes, heart failure, or left ventricular dysfunction) also have a high annual risk of stroke (5-8%) which is significantly reduced by warfarin.^{10, 12, 82} Such patients should also be considered for warfarin, which reduces this risk below 5%. Warfarin is also cost-effective in these patients.¹² However, the incidence of intracranial haemorrhage also increases with age and blood pressure. Warfarin sensitivity also increases with age and in heart failure. Poor compliance, difficulty in attending clinics for monitoring, warfarin interactions with multiple diseases and drugs, and tendency to falls with head injury may each increase the risk of intracranial haemorrhage, especially in older patients (age over 75 years). Aspirin (75-300 mg/day) is a less effective, but safer, alternative antithrombotic drug in this group.¹¹ Evidence level Ia

People with non-valvular AF who are aged over 65 years without other risk factors, or who are aged under 65 and have at least one other risk factor for stroke (history of hypertension, diabetes, heart failure, or left ventricular dysfunction) also have a significant increased annual risk of stroke (3-5%) which is significantly reduced by warfarin. Such patients should also be considered for warfarin.^{10, 12, 82} Warfarin is cost-effective in such patients.¹² Aspirin is again a less effective alternative antithrombotic drug in this group.¹¹ Evidence level Ia

Warfarin (target INR 2.5, range 2.0-3.0) should be considered for antithrombotic prophylaxis in patients with non-valvular atrial fibrillation and other risk factors for stroke (age over 65 years, history of hypertension, diabetes, heart failure, or left ventricular dysfunction ). In pateints over 75 years, the relative balance of risks and benefits of warfarin should be carefully assessed

Warfarin (target INR 2.5, range 2.0-3.0) should also be considered for antithrombotic prophylaxis in patients with non-valvular atrial fibrillation who are aged under 65 and have a history of hypertension, diabetes, heart failure, or left ventricular dysfunction.

If warfarin is declined, or contraindicated by increased risk of bleeding, aspirin (75-300 mg/day) should be considered but is less effective than warfarin.

3.3.3

Observational studies suggest an increased risk of systemic embolism in patients with AF associated with heart valve disease or prosthesis (see section 4.3), thyrotoxicosis, intracardiac thrombus, or non-cerebral thromboembolism.^{84, 85, 86} Evidence level III

Warfarin prophylaxis should be considered in patients with atrial fibrillation and heart valve disease or prosthesis, thyrotoxicosis, intracardiac thrombus, or non-cerebral thromboembolism.

3.3.4

The annual risk of major bleeding (up to 2% in randomised trials^{10, 81}) should be considered when deciding the level of risk which merits use of warfarin.

To minimise the risk of intracranial bleeding from prophylactic warfarin in patients with AF, hypertension should be adequately controlled, compliance assessed, and the risks and benefits of warfarin reviewed annually, especially in patients aged over 75 years.

3.4 Lower risk groups

People with non-valvular AF who are aged under 65 and have none of the above risk factors for stroke, have a low annual risk of stroke (about 1%) which is not significantly reduced by either warfarin or aspirin.^{10, 11, 12} Warfarin is not indicated (and is not cost-effective) in such patients.¹² Aspirin may be considered if there are other indications, e.g. ischaemic heart disease or peripheral arterial disease.

The annual risk of stroke for patients with atrial fibrillation and number needed to treat with warfarin instead of aspirin for one year to prevent one stroke are summarised in Table 5.

3.5 Cardioversion

Restoration of sinus rhythm may avoid the need for long term warfarin. Cardioversion, however, carries a moderate risk of systemic thromboembolism in patients who have been in AF for more than two days. ^{79, 82, 86, 87} Evidence level III and IV

A consensus statement⁷⁹ recommends that:

Cardioversion of AF should be considered in selected patients.

Patients with very recent onset AF require immediate assessment and treatment with heparin.

If it is certain that AF has been present for two days or less, cardioversion should be attempted electrically or pharmacologically. Warfarin therapy is not required in these patients if cardioversion is successful.

If AF has been present for more than two days, warfarin should be given to reduce the risk of thromboembolism* for three weeks before cardioversion and continued for at least four weeks after cardioversion.

* The SIGN guideline development group recommended a target INR of 2.5, range 2.0-3.0.

With the latter strategy, the risk of thromboembolism early after the procedure is reduced from 5-7% to 1-2%. Whether warfarin should be given beyond four weeks is uncertain, but this treatment may be considered in patients with a continuing high risk of recurrence of AF (large left atrium, poor left ventricular function, hypertension) or previously symptomatic AF.⁷⁹

Table 5

Annual risk of stroke on no treatment, aspirin, or warfarin in high, moderate and low risk patients with non-valvular atrial fibrillation

* Number needed to treat with warfarin instead of aspirin for one year to prevent one stroke

(Adapted from the Royal College of Physicians of Edinburgh Atrial Fibrillation Consensus Statement⁷⁹)