Prevention of Thromboembolism in Atrial Fibrillation Patients

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Abstract

Atrial fibrillation is the most common sustained cardiac arrhythmia and is associated with substantial morbidity and mortality, particularly due to thromboembolic complications. Antithrombotic therapy reduces the risk of stroke and other thromboembolic events, with the greatest benefit seen in individuals at the highest absolute risk of stroke. There is increasing recognition of the superiority of oral anticoagulation over antiplatelet therapy for stroke prevention in atrial fibrillation. Nevertheless, oral anticoagulation is underused, especially in elderly people, which may in part be explained by uncertainty in the assessment of both risk of stroke and bleeding in an individual patient. The new European Society of Cardiology (ESC) guidelines for the management of atrial fibrillation, which have recently been updated, recommend a risk-factor-based approach to thromboprophylaxis in patients with atrial fibrillation and provide practical tools for the assessment of individual risk. In this article we summarise strategies for prevention of thromboembolism in patients with atrial fibrillation as recommended by the ESC guidelines. New oral anticoagulants are also discussed.

Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Gregory YH Lip, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, B18 7QH, UK. E: g.y.h.lip@bham.ac.uk
Received date
19 November 2010
Accepted date
04 February 2011
Citation
European Cardiology - Volume 7 Issue 1;2011:7(1):37-43
Correspondence
Gregory YH Lip, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, B18 7QH, UK. E: g.y.h.lip@bham.ac.uk
DOI
http://dx.doi.org/10.15420/ecr.2011.7.1.37

Atrial fibrillation (AF) is the most common cardiac rhythm disorder in everyday clinical practice, affecting 1–2% of the general population. The prevalence of AF is strongly age-dependent, increasing from <1% in patients under 60 years of age to almost 10% in patients 80 years of age or older1 and 17.8% in those 85 years of age and above.2 Population-based studies have shown lifetime risks for the development of AF of 26% for men and 23% for women 40 years of age or older (North American epidemiological data) and 23.8% in men and 22.2% in women at 55 years of age in a European population.2,3 A rising prevalence of AF during the past two decades with a relative increase of 12.6% has been reported in the US population,4 and a two- to three-fold increase in hospitalisations for AF has been reported in Scotland.5 Thus, the projected number of people with AF in the US will exceed 10 million by 2050.4 We can perhaps expect a similar trend for the European population.
There is a near five-fold heightened risk of stroke in patients with non-valvular AF, which significantly increases with age, rising from 1.5% for those 50–59 years of age to 23.5% for those 80–89 years of age.6 AF satisfies all the components of Virchow’s triad for thrombogenesis: vessel wall abnormalities, abnormal blood flow (or stasis) and blood constituents.7 Vessel wall abnormalities are described as endothelial/endocardial damage, especially within the atrial appendages, and can be visualised at both macroscopic and microscopic levels, even in patients without valvular heart disease.7,8 Abnormal blood flow in AF manifests as stasis within the left atrium as a result of loss of atrial systole, and can be pictured using transoesophageal echocardiography as spontaneous echocontrast in the left atrium and reduced blood flow velocities in the left atrial appendage, which have been shown to predict thromboembolism in AF patients.9–11 Abnormal changes in coagulation, fibrinolysis and platelets, which may be associated with the indices of endothelial dysfunction and inflammation,7 complete the third part of Virchow’s triad, overall contributing to a prothrombotic and hypercoagulable state in AF patients.
Not surprisingly, thromboprophylaxis is the cornerstone of AF management.12 Strokes associated with AF are especially large and disabling; therefore, primary prevention is paramount.

Rhythm control does not seem to significantly reduce the stroke rate,13 and antithrombotic therapy is the mainstay for stroke prevention. Death rates are nearly doubled by AF, independent of other known predictors of mortality.14,15 Adjusted-dose oral anticoagulation (OAC) has been shown to reduce not only the frequency of ischaemic stroke but also its severity and the risk of death from stroke,16 and is associated with about 25% reduced all-cause mortality compared with no antithrombotic treatment.17

Antithrombotic Therapy
Warfarin

Pooled results from six large randomised controlled trials (five primary prevention and one secondary prevention, 2,900 participants) of warfarin versus placebo or no treatment have shown the superior efficacy of warfarin, which was consistent across studies, with an overall 64% (95% confidence interval [CI] 49–74%) reduction in the incidence of stroke and only small absolute increases (≤0.3% per year) in major extracranial haemorrhage.17 Warfarin was associated with similar relative risk reductions for disabling stroke and non-disabling stroke (60% for both). High-risk patients (particularly those with previous stroke or transient ischaemic attack [TIA]) have larger absolute reductions in stroke rate with anticoagulation therapy. The absolute risk reduction for all strokes was 2.7% per year (number of patients needed to treat [NNT] for one year to prevent one stroke was 37) for primary prevention, and 8.4% per year (NNT 12) for secondary prevention.17
Despite its strong evidence base, warfarin is often underused in high-risk AF patients, although this is associated with a worse cardiovascular prognosis.18–20 The use of warfarin in AF patients is limited mainly because of concerns about a higher bleeding risk associated with vitamin K antagonists (VKAs) and the necessity for frequent blood monitoring and dose adjustment, which make both patients and health practitioners reluctant to initiate the therapy in a substantial proportion of patients.

Antiplatelet Therapy

To date, aspirin is the only treatment recommended for thromboprophylaxis in AF patients who are unsuitable for warfarin. However, aspirin demonstrates only very modest efficacy in stroke prevention compared with warfarin. Although antiplatelet therapy showed a significant reduction in the incidence of stroke (22%, 95% CI 6–35%) when all randomised data from all comparisons of antiplatelet agents and placebo or control groups were considered (eight trials, 4,876 participants), when aspirin alone was compared with placebo or no treatment in seven trials (3,990 participants), treatment with aspirin was associated with a non-significant reduction in the incidence of stroke: 19% (95% CI –1 to 35%).17 There was an absolute risk reduction of 0.8% per year (NNT 125) for primary prevention and 2.5% per year (NNT 40) for secondary prevention with aspirin.17 Much of the pooled benefit of aspirin was derived from the results of a single trial, the Stroke Prevention in Atrial Fibrillation I (SPAF-I) trial,21 which showed a significant reduction in the incidence of stroke associated with aspirin 325mg daily (relative risk reduction 42%, 95% CI 9–63%). In this trial, there was major heterogeneity in aspirin effect between anticoagulation-eligible and anticoagulation-ineligible patients, and aspirin did not prevent disabling or recurrent strokes or show any benefit in people over 75 years of age.21,22 The relative risk reduction of stroke with antiplatelet therapy shown in the meta-analysis by Hart et al. (22%) is very close to the 22% proportional reduction in non-fatal stroke produced by antiplatelet therapy in high-risk patients with vascular disease reported by the Antithrombotic Trialists’ Collaboration.23 Indeed, coronary artery disease is present in ≥20% of the AF population.24 Thoracic aortic plaque identified by transoesophageal echocardiography occurs in up to 57% of patients with AF, about 25% of whom have complex aortic plaques with thickness >4mm, ulceration, pedunculation or mobile elements.25 Indeed, the presence of complex plaque in the descending aorta is an independent risk factor for ischaemic stroke.26 Thus, the effect of aspirin on stroke reduction in patients with AF may reflect the effect of antiplatelet therapy on the prevention of occlusive thrombotic events in patients with atherosclerotic vascular disease. In the SPAF-I trial, aspirin reduced the occurrence of strokes categorised as non-cardioembolic to a significantly greater degree than strokes categorised as cardioembolic.27

Warfarin versus Antiplatelet Therapy

On the basis of 12 trials (12,963 participants) comparing adjusted-dose warfarin with antiplatelet therapy, adjusted-dose warfarin was substantially more efficacious than antiplatelet therapy (relative risk reduction for all strokes 39%, 95% CI 22–52%).17 Of note, intracranial haemorrhage was included with ischaemic stroke in all strokes; therefore, this most serious consequence of antithrombotic therapy was considered in the primary analysis. In the older trials, the risk of intracranial haemorrhage was doubled with adjusted-dose warfarin compared with aspirin, although the absolute risk increase was small (0.2% per year), and all-cause mortality was substantially reduced (26%, 95% CI 3–43%]) by adjusted-dose warfarin compared with control.17 The absolute risk of intracranial haemorrhage during warfarin therapy was much higher in the SPAF-II study (0.9% per year) than in the other studies included in this meta-analysis, which can probably be explained by the use of prothrombin time monitoring and a relatively high target intensity of anticoagulation in a very elderly cohort.28,29
The largest trial, Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE-W), enrolled 6,706 participants with AF plus one or more risk factor for stroke, who were allocated to receive adjusted-dose warfarin or aspirin plus clopidogrel for thromboprophylaxis. The study was stopped early because of clear evidence of superiority of OAC therapy.30 There were more events for each component of the primary outcome (stroke, non-central nervous system [CNS] systemic embolus, myocardial infarction [MI] or vascular death) with clopidogrel plus aspirin compared with OAC therapy. However, the main advantage of OAC therapy was seen in stroke (relative risk [RR] 1.72, 95% CI 1.24–2.37) and in non-CNS systemic embolism (RR 4.66, 95% CI 1.58–13.8). Rates of major haemorrhage were similar in the two groups. Still, minor bleeds and total bleeds were significantly more likely with clopidogrel plus aspirin than with OAC therapy. Intracranial bleeds (including subdural haematoma) were more common with OAC therapy than with clopidogrel plus aspirin (21 versus 11; p=0.08). Nevertheless, the net benefit (primary outcome event plus major haemorrhage) favoured OAC therapy (RR 1.41, 95% CI 1.19–1.67).30

Several contemporary studies have prospectively compared the effectiveness of warfarin and aspirin in elderly people with AF, who are least likely to receive OAC therapy in real life, mainly because of a fear of increased risk for bleeding. The Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) study showed that adjusted-dose warfarin was superior to aspirin 75mg daily in reducing the primary end-point of fatal or disabling stroke (ischaemic or haemorrhagic), intracranial haemorrhage or clinically significant arterial embolism (RR 0.48, 95% CI 0.28–0.80), with no difference in the risk of major haemorrhage (or intracranial haemorrhage) between warfarin and aspirin.31 In addition, adjusted-dose warfarin was significantly better tolerated, with fewer adverse events (composite end-point of thromboembolism, major bleeding and death) than aspirin 300mg in AF patients >80 and <90 years of age in a small randomised clinical trial, Warfarin versus Aspirin for Stroke Prevention in Octogenarians with atrial fibrillation (WASPO).32
The study by Reitbrock and co-workers,33 conducted in a real-world setting (51,807 patients from the UK General Practice Research Database, over 30,000 participants 75 years of age and older), proved the beneficial effect of warfarin in reducing the stroke rate in patients with permanent AF (RR 0.62, 95% CI 0.54–0.71), whereas aspirin did not appear to have a major beneficial effect (RR 1.04, 95% CI 0.94–1.15). The magnitude of stroke reduction was greater in elderly warfarin users (by 45%) than in participants under 75 years of age (by 14%). The individual patient analysis by van Walraven et al.34 included 8,932 patients and 17,685 years of observation from 12 trials. Patient age increased the risk of ischaemic stroke (adjusted hazard ratio [HR] per decade increase 1.45, 95% CI 1.26–1.66), serious bleeding (HR 1.61, 95% CI 1.47–1.77) and cardiovascular events (HR 1.43, 95% CI 1.33–1.53). Compared with placebo, both OAC and antiplatelet therapy significantly reduced the risk of ischaemic stroke (OAC: HR 0.36, 95% CI 0.29–0.45; antipatelet therapy: HR 0.81, 95% CI 0.72–0.90) and cardiovascular outcomes (OAC: HR 0.59, 95% CI 0.52–0.66; antiplatelet therapy: HR 0.81, 95% CI 0.75–0.88), whereas OAC increased the risk of serious bleeding (HR 1.56, 95% CI 1.03–2.37). In this analysis, the relative benefit of OAC in preventing stroke was not significantly affected by increasing age, whereas the benefit of antiplatelet therapy decreased significantly as patients aged: at 77 years of age, the HR of antiplatelet treatment no longer excluded unity, and at 82 years of age, the HR of antiplatelet treatment exceeded 1. Thus, the authors concluded that because stroke risk increases with age, the absolute benefit of OAC increases as patients get older.34

In the aspirin arm of the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE A), in patients with AF for whom VKA therapy was unsuitable or where a VKA was declined, the addition of clopidogrel to aspirin was shown to reduce the risk of major vascular events, primarily due to a 28% relative reduction in the rate of stroke with combination therapy.35 However, the risk of major haemorrhage was significantly higher for combination therapy (RR 1.57, 95% CI 1.29–1.92), being broadly similar to that seen with warfarin therapy.

Combination of Oral Anticoagulation and Antiplatelet Therapy

Combined aspirin–OAC therapy has been shown to reduce the risk of arterial thromboembolism in patients with mechanical heart valves.36 However, in a subgroup of AF patients, the combination of OAC and aspirin did not demonstrate additional benefit for reducing arterial thromboembolism (odds ratio [OR] 0.99, 95% CI 0.47–2.07) compared with OAC therapy alone. The risk of bleeding was significantly higher in patients receiving combined therapy (OR 1.43, 95% CI 1.00–2.02).36,37 In a cohort study of 118,606 Danish patients surviving first-time hospitalisation for AF, it was demonstrated that patients receiving dual therapy with warfarin and clopidogrel and those receiving triple therapy with warfarin, aspirin and clopidogrel had a more than three-fold higher risk of bleeding than did patients treated solely with warfarin. The importance of this finding was highlighted by a significantly increased risk of death after a non-fatal bleeding episode and a non-beneficial effect in terms of preventing ischaemic stroke.38 Therefore, in patients with non-valvular AF and concomitant stable vascular disease without acute ischaemic events or percutaneous coronary (vascular) interventions/stent procedures in the preceding year, the addition of aspirin to VKA cannot be routinely recommended. Monotherapy with VKA is at least as effective as aspirin, but the addition of aspirin increases the bleeding risk significantly.39

Novel Oral Anticoagulants

The standard anticoagulation therapy for stroke prophylaxis in AF patients with warfarin reduces the risk of stroke by about two-thirds, but such treatment requires regular monitoring and dose adjustment, which limits its use, especially in elderly patients. Thus, there is a continuing search for safer, more practical antithrombotic agents that could be prescribed more widely, but so far attempts with dual platelet inhibition (aspirin plus clopidogrel) have been unsuccessful in terms of inferior efficacy and non-superior safety.

The two main anticoagulant drug classes under development interfere with pathways central for coagulation cascade, such as factor IIa (thrombin) and factor Xa.40 The first oral direct thrombin inhibitor that was approved for clinical use was ximelagatran. In a meta-analysis ximelagatran was as effective as adjusted-dose warfarin in the prevention of ischaemic strokes or systemic emboli with less risk of major bleeding;41 however, because of its liver toxicity ximelagatran was withdrawn from the market in February 2006.42
Dabigatran etexilate is another orally available direct thrombin inhibitor. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial43 of 18,113 patients with non-valvular AF randomised to dabigatran or warfarin, dabigatran 150mg twice daily was superior to warfarin with a similar risk of bleeding complications, while dabigatran 110mg twice daily was non-inferior to warfarin for the prevention of stroke or systemic embolism but superior to warfarin with respect to major bleeding. Apixaban, an oral direct factor Xa inhibitor, has been under clinical investigation for the prevention of stroke and systemic thromboembolism in AF patients in two ongoing phase III studies. The Apixaban for the Prevention of stroke in Subjects With Atrial Fibrillation (ARISTOTLE) trial is seeking to determine whether apixaban is as effective as warfarin in preventing stroke and systemic embolism in subjects with AF and risk factors for stroke.44
The Apixaban Versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) trial, designed to compare apixaban versus aspirin for the prevention of stroke or systemic embolism in high-risk AF patients unsuitable for treatment with warfarin, was terminated early after pre-defined interim analysis had shown clear evidence of a clinically important reduction in stroke and systematic embolism and an acceptable safety profile for apixaban compared with aspirin. The annual rate of stroke or systemic embolism (the primary outcome) was 4.0% per year on aspirin and 1.7% per year on apixaban (HR 0.43, 95% CI 0.30–0.62). The rate of major haemorrhage (1.2% per year on aspirin and 1.5% per year on apixaban) and the rate of haemorrhagic stroke (0.2% per year in both treatment groups) did not differ significantly. There was no evidence of hepatic toxicity or other major adverse events.45

Trials of two other oral direct inhibitors of factor Xa are in progress. Rivaroxaban has being investigated in the phase III Rivaroxaban Once daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) clinical trial.46 Preliminary data presented at the American Heart Association meeting in November 2010 found rivaroxaban to be non-inferior to warfarin; on an intention-to-treat analysis, rivaroxaban was not superior to warfarin, although an on-treatment analysis did suggest superiority of rivaroxaban. Major bleeding rates were comparable between rivaroxaban and warfarin.
The Global Study to Assess the Safety and Effectiveness of DU-176b versus Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (ENGAGE AF-TIMI48) is a phase III comparison of two exposure strategies of edoxaban to warfarin for the prevention of thromboembolism in patients with AF.47 In the Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation (AMADEUS) trial of idraparinux, a synthetic pentasaccharide that specifically inhibits factor Xa and that can be given in fixed weekly doses by subcutaneous injection without the need for coagulation monitoring, patients were randomised to receive either idraparinux subcutaneously (2.5mg weekly) or adjusted-dose VKA. The primary efficacy outcome (all strokes and non-CNS systemic embolism rates) satisfied the criteria for non-inferiority (idraparinux 0.9 versus warfarin 1.3 per 100 patient-years; HR 0.71, 95% CI 0.39–1.30), but the trial was stopped after randomisation of 4,576 patients and a mean follow-up of 10.7 months because of excess clinically relevant bleeding with idraparinux, particularly increased in elderly patients and those with renal impairment.48 The Evaluation of Weekly Subcutaneous Biotinylated Idraparinux Versus Oral Adjusted-dose Warfarin to Prevent Stroke and Systemic Thromboembolic Events in Patients With Atrial Fibrillation (BOREALIS-AF) trial (ClinicalTrials.gov identifier NCT00580216) will compare biotinylated idraparinux, dose-adjusted according to age and renal function, with warfarin in AF patients.

Risk Assessment in Patients with Atrial Fibrillation and Antithrombotic Therapy

The choice of antithrombotic strategy in AF patients must be guided by an assessment of individual risk of thromboembolism and bleeding. Accurate risk stratification for both thromboembolism and haemorrhage before starting the treatment and during therapy should be considered in patients with AF who are at increased risk of both thromboembolism and bleeding.49

The new European Society of Cardiology (ESC) guidelines for the management of AF, which were recently updated, provide practical tools to evaluate individual risk in ‘real-world’ AF patients, supporting clinicians in their decision-making regarding antithrombotic therapy.50 The absolute stroke rates vary widely among patients with non-valvular AF. Systematic reviews of risk factors for stroke and thromboembolism in AF patients identified four clinical features (prior stroke/TIA, advancing age, hypertension, diabetes) to be consistent independent risk factors for stroke in AF patients.51,52 Prior stroke/TIA was the most powerful risk factor and reliably conferred a high stroke risk (>5% per year, averaging 10% per year).51
Based on stroke risk factors, many risk stratification schemes have been developed with a different number of risk factors included, similar predictive ability and markedly varied proportions of patients classified as low, intermediate and high risk,53,54 which has caused inconsistency in recommendations for antithrombotic therapy depending on which scheme is applied.
The new ESC guidelines encourage an objective risk-factor-based approach to risk stratification for stroke and thromboembolism in AF patients, given the cumulative nature of risk factors where a combination of risk factors would confer a greater risk than any one factor alone. Acknowledging that the congestive heart failure, hypertension, age ≥75 years, diabetes, stroke (doubled [CHADS2]) score55 is simple and in common clinical use, the new ESC guidelines recommend the CHADS2 score as an initial, rapid and easy-to-remember means of assessing stroke risk (see Tables 1 and 2). In patients with a CHADS2 score ≥2, chronic OAC with a VKA is recommended in an adjusted-dose approach with a target international normalised ratio (INR) of 2.5 (2.0–3.0) unless this is contraindicated. Other new anticoagulants (if approved) may be alternatives to VKAs in the future.
Given the limitations of the CHADS2 score,56 for patients with a CHADS2 score of 0–1 and for a more detailed stroke risk assessment, the new ESC guidelines recommend a risk-factor-based approach with consideration of additional stroke risk factors or ‘stroke risk modifiers’. The guidelines place a greater emphasis on ‘major risk factors’, which are previous stroke/TIA or thromboembolism and age ≥75 years, by allocating two points for each, and define congestive heart failure, hypertension, diabetes, age 65–74 years, vascular disease and female gender as ‘clinically relevant non-major risk factors’, with one point allocated for the presence of each (see Tables 1 and 3).

Thus, extra weighting is given to ‘age ≥75 years’ as a single risk factor, and other risk factors not included in the CHADS2 score (e.g. age 65–74 years, female gender and vascular disease) are considered.57–60 These additional ‘clinically relevant non-major’ risk factors can be expressed as the congestive heart failure/LV dysfunction, hypertension, age ≥75 years, diabetes, stroke, vascular disease (prior MI, peripheral arterial disease or aortic plaque), age 65–74 years, sex category (i.e. female gender [CHA2DS2-VASc]) score.57 Patients with one ‘major’ or ≥2 ‘clinically relevant non-major’ risk factors (that is, a CHA2DS2-VASc score ≥2) clearly merit OAC (see Table 4).
For patients with one ‘clinically relevant non-major’ risk factor (that is, a CHA2DS2-VASc score of 1), thromboprophylaxsis with antithrombotic therapy is recommended; given the available evidence,61,62 OAC is preferred over aspirin, especially if the patient’s risk of stroke outweighs the potential risk of bleeding. For patients at truly low risk (that is, a CHA2DS2-VASc score of 0), either aspirin 75–325mg daily or no antithrombotic therapy is recommended, although no antithrombotic therapy is preferred given the limited data on the benefit of aspirin in this group and the potential harm from bleeding.63
Importantly, the stroke and thromboembolic risk in paroxysmal AF is not different from that in persistent or permanent AF.64 Therefore, patients with paroxysmal AF should receive their thromboprophylaxis according to their risk score.
Crucial to both stroke and bleeding prevention is the quality of INR control. High anticoagulation intensity and intraindividual variation in INR are risk factors for haemorrhage, with an INR ≥3.5 associated with a nearly five-fold increased risk of major haemorrhage, especially among the elderly.65 At the same time, an INR <2.0, which is suggested for the elderly who were previously at increased risk of bleeding, is not associated with a lower rate of intracranial haemorrhage than standard INR targets in the elderly65,66 and is not recommended, given the increased risk of thromboembolic events at suboptimal INR levels.67 The time in therapeutic range of INR is also an important point. Recent studies have demonstrated that the time in therapeutic range needs to be at minimum 58% to derive benefit from OAC.68

Many risk factors for stroke are also risk factors for bleeding.69,70 Different bleeding risk stratification schemes have been proposed, but many are neither user-friendly nor well-validated in prospective cohorts of AF patients. Using a ‘real-world’ cohort of 3,978 European subjects with AF, a new bleeding risk score (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly [>65 years of age], drugs/alcohol concomitantly [HAS-BLED]) has been proposed (see Table 5), which has demonstrated consistent predictive accuracy in the overall population when applied in several subgroups (c-statistic 0.72), and even higher in patients receiving antiplatelet agents alone or no antithrombotic therapy (c-statistic 0.91 and 0.85, respectively).71
Given its good predictive accuracy, user-friendliness and ease of clinical application, the HAS-BLED score has been introduced in the new ESC guidelines to unify and support the assessment of bleeding risk in AF patients in all healthcare settings. In this scheme, one point is allocated for the presence of each risk factor (see Table 5), and a HAS-BLED score ≥3 indicates a high risk of bleeding, which means that some caution and regular review of patients is needed following the initiation of antithrombotic therapy, whether with a VKA or aspirin. In the future, patients at high risk of bleeding may be considered as candidates for the lower dose of dabigatran (if approved) or for a left atrial appendage occlusion device.72

Special Situations
Ischaemic Heart Disease

The addition of aspirin to OAC for stable vascular disease associated with AF is not recommended.39 The strategy is quite different for AF patients presenting with an acute coronary syndrome and/or requiring percutaneous coronary intervention with or without stenting.
The new ESC guidelines based their recommendations on a systematic review and consensus document from the ESC Working Group on Thrombosis, endorsed by the European Heart Rhythm Association (EHRA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI), whereby drug-eluting stents should be avoided and triple therapy (VKA, aspirin and clopidogrel) used in the short term (two to four weeks, depending on haemorrhagic risk and clinical setting), followed by longer therapy (up to 12 months) with VKA plus a single antiplatelet agent (aspirin or clopidogrel).50,73

Acute Stroke

Within the first two weeks of cardioembolic stroke, patients are at risk of recurrent stroke, intracranial haemorrhage or haemorrhagic transformation of the cerebral infarct.74 Uncontrolled hypertension should be appropriately managed and cerebral imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) should be performed to exclude haemorrhage before antithrombotic therapy is started. In the absence of haemorrhage, anticoagulation therapy should begin after two weeks;50 however, it may be delayed in the presence of a large cerebral infarction.74 In patients with AF and acute TIA, anticoagulation treatment should begin as soon as possible, provided that the cerebral infarction or haemorrhage has been excluded by CT or MRI.50

Patients Unsuitable for Vitamin K Antagonist Therapy or Declining Warfarin

In the new ESC guidelines, the majority of patients with AF should receive OAC. The HAS-BLED score, as introduced in the new ESC guidelines, will help to overcome physician uncertainty about what to consider as true risk factors for bleeding and help them feel more confident in prescribing OAC where appropriate. Dual antiplatelet therapy may be an alternative to OAC in patients who refuse to take VKA or are unable to safely sustain adjusted chronic anticoagulation, but not in patients with a high bleeding risk.50 Such an approach has been debated,75,76 and will probably change after the new oral anticoagulants that do not require regular monitoring and perhaps have a better safety profile are approved for clinical use. Encouraging data from RE-LY and AVERROES raise hopes that all patients eligible for OAC will receive it in the future.

Conclusion

AF is associated with an increased risk of thromboembolic complications. The growing prevalence of AF in the world population makes optimal thromboprophylaxis in AF patients of paramount importance. To date, the superior efficacy of OAC therapy in stroke prevention has been well documented in clinical trials and has been shown to be safe when administered considering the individual risk of thromboembolism and bleeding and controlled appropriately. The new ESC guidelines confirm OAC as the treatment of choice for thromboprophylaxis in AF patients with one or more risk factor for stroke. Providing useful tools for individual risk assessment, the new ESC guidelines will help clinicians to be more confident in their decision-making regarding antithrombotic therapy in all patients and in identifying subjects who may benefit from new oral anticoagulants should they receive regulatory approval.

References
  1. Go AS, Hylek EM, Phillips KA, et al., Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study, JAMA, 2001;285:2370–5.
    Crossref | PubMed
  2. Heeringa J, van der Kuip DA, Hofman A, et al., Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study, Eur Heart J, 2006;27:949–53.
    Crossref | PubMed
  3. Lloyd-Jones DM, Wang TJ, et al., Lifetime risk for development of atrial fibrillation: the Framingham Heart Study, Circulation, 2004;110:1042–6.
    Crossref | PubMed
  4. Miyasaka Y, Barnes ME, Gersh BJ, et al., Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence, Circulation, 2006;114:119–25.
    Crossref | PubMed
  5. Stewart S, MacIntyre K, MacLeod MM, et al., Trends in hospital activity, morbidity and case fatality related to atrial fibrillation in Scotland, 1986–1996, Eur Heart J, 2001;22:693–701.
    Crossref | PubMed
  6. Wolf PA, Abbott RD, Kannel WB, Atrial fibrillation as an independent risk factor for stroke: the Framingham Study, Stroke, 1991;22:983–8.
    Crossref | PubMed
  7. Watson T, Shantsila E, Lip GY, Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited, Lancet, 2009;373:155–66.
    Crossref | PubMed
  8. Boldt A, Wetzel U, Lauschke J, et al., Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease, Heart, 2004;90:400–5.
    Crossref | PubMed
  9. Wysokinski WE, Ammash N, Sobande F, et al., Predicting left atrial thrombi in atrial fibrillation, Am Heart J, 2010;159:665–71.
    Crossref | PubMed
  10. Miyazaki S, Ito T, Suwa M, et al., Role of transesophageal echocardiography in the prediction of thromboembolism in patients with chronic nonvalvular atrial fibrillation, Jpn Circ J, 2001;65:874–8.
    Crossref | PubMed
  11. Kamp O, Verhorst PM, Welling RC, Visser CA, Importance of left atrial appendage flow as a predictor of thromboembolic events in patients with atrial fibrillation, Eur Heart J, 1999;20:979–85.
    Crossref | PubMed
  12. Tay KH, Lip GY, Lane DA, Atrial fibrillation and stroke risk prevention in real-life clinical practice, Thromb Haemost, 2009;101:415–6.
    Crossref | PubMed
  13. Sherman DG, Stroke prevention in atrial fibrillation: pharmacological rate versus rhythm control, Stroke, 2007;38:615–7.
    Crossref | PubMed
  14. Stewart S, Hart CL, Hole DJ, McMurray JJ, A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study, Am J Med, 2002;113:359–64.
    Crossref | PubMed
  15. Vidaillet H, Granada JF, Chyou PH, et al., A population-based study of mortality among patients with atrial fibrillation or flutter, Am J Med, 2002;113:365–70.
    Crossref | PubMed
  16. Hylek 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;349:1019–26.
    Crossref | PubMed
  17. Hart RG, Pearce LA, Aguilar MI, Meta-analysis: antithrombotic therapy to prevent stroke in patients who have non-valvular atrial fibrillation, Ann Intern Med, 2007;146:857–67.
    Crossref | PubMed
  18. Nieuwlaat R, Olsson SB, Lip GY, et al., Euro Heart Survey Investigators, Guideline-adherent antithrombotic treatment is associated with improved outcomes compared with undertreatment in high-risk patients with atrial fibrillation. The Euro Heart Survey on Atrial Fibrillation, Am Heart J, 2007;153:1006–12.
    Crossref | PubMed
  19. Ogilvie IM, Newton N, Welner SA, et al., Underuse of oral anticoagulants in atrial fibrillation: a systematic review, Am J Med, 2010;123:638–45.e4.
    Crossref | PubMed
  20. Pisters R, van Oostenbrugge RJ, Knottnerus IL, et al., The likelihood of decreasing strokes in atrial fibrillation patients by strict application of guidelines, Europace, 2010;12:779–84.
    Crossref | PubMed
  21. Stroke Prevention in Atrial Fibrillation Investigators, Stroke Prevention in Atrial Fibrillation Study. Final results, Circulation, 1991;84:527–39.
    Crossref | PubMed
  22. Stroke Prevention in Atrial Fibrillation Investigators, Preliminary report of the Stroke Prevention in Atrial Fibrillation Study, N Engl J Med, 1990;322:863–8.
    Crossref | PubMed
  23. Antithrombotic Trialists’ Collaboration, Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients, BMJ, 2002;324:71–86.
    Crossref | PubMed
  24. Nieuwlaat R, Capucci A, Camm AJ, et al., European Heart Survey Investigators, Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation, Eur Heart J, 2005;26:2422–34.
    Crossref | PubMed
  25. Blackshear JL, Pearce LA, Hart RG, et al., Aortic plaque in atrial fibrillation: prevalence, predictors, and thromboembolic implications, Stroke, 1999;30:834–40.
    Crossref | PubMed
  26. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography, Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation, Ann Intern Med, 1998;128:639–47.
    Crossref | PubMed
  27. Miller VT, Rothrock JF, Pearce LA, et al., Ischemic stroke in patients with atrial fibrillation: effect of aspirin according to stroke mechanism. Stroke Prevention in Atrial Fibrillation Investigators, Neurology, 1993;43:32–6.
    Crossref | PubMed
  28. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation:Stroke Prevention in Atrial Fibrillation II Study, Lancet, 1994;343:687–91.
    PubMed
  29. Hart RG, Halperin JL, Pearce LA, et al., Stroke Prevention in Atrial Fibrillation Investigators, Lessons from the Stroke Prevention in Atrial Fibrillation trials, Ann Intern Med, 2003;138:831–8.
    Crossref | PubMed
  30. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, et al., Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial, Lancet, 2006;367:1903–12.
    Crossref | PubMed
  31. Mant J, Hobbs FD, Fletcher K, et al., BAFTA investigators; Midland Research Practices Network (MidReC), Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial, Lancet, 2007;370:493–503.
    Crossref | PubMed
  32. Rash A, Downes T, Portner R, et al., A randomised controlled trial of warfarin versus aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO), Age Ageing, 2007;36:151–6.
    Crossref | PubMed
  33. Rietbrock S, Plumb JM, Gallagher AM, van Staa TP, How effective are dose-adjusted warfarin and aspirin for the prevention of stroke in patients with chronic atrial fibrillation? An analysis of the UK General Practice Research Database, Thromb Haemost, 2009;101:527–34.
    Crossref | PubMed
  34. van Walraven C, Hart RG, Connolly S, et al., Effect of age on stroke prevention therapy in patients with atrial fibrillation: the atrial fibrillation investigators, Stroke, 2009;40:1410–6.
    Crossref | PubMed
  35. ACTIVE Investigators, Connolly SJ, Pogue J, Hart RG, et al., Effect of clopidogrel added to aspirin in patients with atrial fibrillation, N Engl J Med, 2009;360:2066–7.
    Crossref | PubMed
  36. Dentali F, Douketis JD, Lim W, Crowther M, Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials, Arch Intern Med, 2007;167:117–24.
    Crossref | PubMed
  37. Lechat P, Lardoux H, Mallet A, et al., FFAACS (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontané) Investigators, Anticoagulant (fluindione)-aspirin combination in patients with high-risk atrial fibrillation. A randomized trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontané; FFAACS), Cerebrovasc Dis, 2001;12:245–52.
    Crossref | PubMed
  38. Hansen ML, Sørensen R, Clausen MT, et al., Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation, Arch Intern Med, 2010;170:1433–41.
    Crossref | PubMed
  39. Lip GY, Don’t add aspirin for associated stable vascular disease in a patient with atrial fibrillation receiving anticoagulation, BMJ, 2008;336:614–5.
    Crossref | PubMed
  40. Ahrens I, Lip GY, Peter K, New oral anticoagulant drugs in cardiovascular disease, Thromb Haemost, 2010;104:49–60.
    Crossref | PubMed
  41. Lip GY, Edwards SJ, Stroke prevention with aspirin, warfarin and ximelagatran in patients with non-valvular atrial fibrillation: a systematic review and meta-analysis, Thromb Res, 2006;118:321–33.
    Crossref | PubMed
  42. Agnelli G, Eriksson BI, Cohen AT, et al., EXTEND Study Group, Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran, Thromb Res, 2009;123:488–97.
    Crossref | PubMed
  43. Connolly SJ, Ezekowitz MD, Yusuf S, et al., RE-LY Steering Committee and Investigators, Dabigatran versus warfarin in patients with atrial fibrillation, N Engl J Med, 2009;361:1139–51.
    Crossref | PubMed
  44. Lopes RD, Alexander JH, Al-Khatib SM, et al., ARISTOTLE Investigators, Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale, Am Heart J, 2010;159:331–9.
    Crossref | PubMed
  45. www.escardio.org/congresses/esc-2010/ congress-reports/Pages/708-3-AVERROES.aspx
  46. ROCKET AF Study Investigators, Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study, Am Heart J, 2010;159:340–47.e1.
    Crossref | PubMed
  47. Ruff CT, Giugliano RP, Antman EM, et al., Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48), Am Heart J, 2010;160:635–41.
    Crossref | PubMed
  48. Amadeus Investigators, Bousser MG, Bouthier J, Büller HR, et al., Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial, Lancet, 2008;371:315–21.
    Crossref | PubMed
  49. Guo Y, Wu Q, Zhang L, Yet al., Antithrombotic therapy in very elderly patients with atrial fibrillation: is it enough to assess thromboembolic risk?, Clin Interv Aging, 2010;5:157–62.
    Crossref | PubMed
  50. Authors/Task Force Members, Camm AJ, Kirchhof P, Lip GY, et al., ESC Committee for Practice Guidelines (CPG), Vahanian A, Auricchio A, Bax J, et al., Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Developed with the special contribution of the European Heart Rhythm Association (EHRA); Endorsed by the European Association for Cardio-Thoracic Surgery (EACTS), Eur Heart J, 2010; in press.
  51. Stroke Risk in Atrial Fibrillation Working Group, Independent predictors of stroke in patients with atrial fibrillation: a systematic review, Neurology, 2007;69:546–54.
    Crossref | PubMed
  52. Hughes M, Lip GY, Guideline Development Group, National Clinical Guideline for Management of Atrial Fibrillation in Primary and Secondary Care, National Institute for Health and Clinical Excellence, Stroke and thromboembolism in atrial fibrillation: a systematic review of stroke risk factors, risk stratification schema and cost effectiveness data, Thromb Haemost, 2008;99:295–304.
    Crossref | PubMed
  53. Stroke Risk in Atrial Fibrillation Working Group. Collaborators: Hart RG, Pearce LA, Halperin JL, et al., Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial fibrillation, Stroke, 2008;39:1901–10.
    Crossref | PubMed
  54. Fang MC, Go AS, Chang Y, et al., ATRIA Study Group, Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation, J Am Coll Cardiol, 2008;51:810–5.
    Crossref | PubMed
  55. Gage BF, Waterman AD, Shannon W, et al., Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation, JAMA, 2001;285:2864–70.
    Crossref | PubMed
  56. Karthikeyan G, Eikelboom JW, The CHADS2 score for stroke risk stratification in atrial fibrillation—friend or foe?, Thromb Haemost, 2010;104:45–8.
    Crossref | PubMed
  57. Lip GY, Nieuwlaat R, Pisters R, et al., Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation, Chest, 2010;137:263–72.
    Crossref | PubMed
  58. Lane DA, Lip GY, Female gender is a risk factor for stroke and thromboembolism in atrial fibrillation patients, Thromb Haemost, 2009;101:802–5.
    Crossref | PubMed
  59. Conway DS, Lip GY, Comparison of outcomes of patients with symptomatic peripheral artery disease with and without atrial fibrillation (the West Birmingham Atrial Fibrillation Project), Am J Cardiol, 2004;93:1422–5, A10.
    Crossref | PubMed
  60. Marinigh R, Lip GY, Fiotti N, et al., Age as a risk factor for stroke in atrial fibrillation patients implications for thromboprophylaxis, J Am Coll Cardiol, 2010;56:827–37.
    Crossref | PubMed
  61. Gorin L, Fauchier L, Nonin E, et al., Antithrombotic treatment and the risk of death and stroke in patients with atrial fibrillation and a CHADS2 score=1, Thromb Haemost, 2010;103:833–40.
    Crossref | PubMed
  62. Lip GY, Anticoagulation therapy and the risk of stroke in patients with atrial fibrillation at ‘moderate risk’ [CHADS2 score=1]: simplifying stroke risk assessment and thromboprophylaxis in real-life clinical practice, Thromb Haemost, 2010;103:683–5.
    Crossref | PubMed
  63. Sato H, Ishikawa K, Kitabatake A, et al., Japan Atrial Fibrillation Stroke Trial Group. Low-dose aspirin for prevention of stroke in low-risk patients with atrial fibrillation: Japan Atrial Fibrillation Stroke Trial, Stroke, 2006;37:447–51.
    Crossref | PubMed
  64. Friberg L, Hammar N, Rosenqvist M, Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial Fibrillation, Eur Heart J, 2010;31:967–75.
    Crossref | PubMed
  65. Fang MC, Chang Y, Hylek EM, et al., Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation, Ann Intern Med, 2004;141:745–52.
    Crossref | PubMed
  66. Pengo V, Cucchini U, Denas G, et al., Lower versus standard intensity oral anticoagulant therapy (OAT) in elderly warfarin-experienced patients with non-valvular atrial fibrillation, Thromb Haemost, 2010;103:442–9.
    Crossref | PubMed
  67. Singer DE, Chang Y, Fang MC, et al., Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?: the ATRIA study, Circ Cardiovasc Qual Outcomes, 2009;2:297–304.
    Crossref | PubMed
  68. Connolly SJ, Pogue J, Eikelboom J, et al., ACTIVE W Investigators, Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range, Circulation, 2008;118:2029–37.
    Crossref | PubMed
  69. Hughes M, Lip GY, Guideline Development Group for the NICE national clinical guideline for management of atrial fibrillation in primary and secondary care, Risk factors for anticoagulation-related bleeding complications in patients with atrial fibrillation: a systematic review, QJM, 2007;100:599–607.
    Crossref | PubMed
  70. Palareti G, Cosmi B, Bleeding with anticoagulation therapy – who is at risk, and how best to identify such patients, Thromb Haemost, 2009;102:268–78.
    Crossref | PubMed
  71. Pisters R, Lane DA, Nieuwlaat R, et al., A novel user-friendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillation patients: The Euro Heart Survey, Chest, 2010 Mar 18 [Epub ahead of print].
  72. Holmes DR, Reddy VY, Turi ZG, et al., PROTECT AF Investigators, Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial, Lancet, 2009;374:534–42.
    Crossref | PubMed
  73. Lip GY, Huber K, Andreotti F, et al., European Society of Cardiology Working Group on Thrombosis, Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/ stenting, Thromb Haemost, 2010;103:13–28.
    Crossref | PubMed
  74. Kalra L, Lip GY, Guideline Development Group for the NICE clinical guideline for the management of atrial fibrillation. Antithrombotic treatment in atrial fibrillation, Heart, 2007;93:39–44.
    Crossref | PubMed
  75. Apostolakis S, Shantsila E, Lip GY, Lane DA, Contra: “Anti-platelet therapy is an alternative to oral anticoagulation for atrial fibrillation”, Thromb Haemost, 2009;102:914–15.
    Crossref | PubMed
  76. Healey JS, Pro: “Anti-platelet therapy is an alternative to oral anticoagulation for atrial fibrillation”, Thromb Haemost, 2009;102:912–3.
    Crossref | PubMed