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Keywords:

  • atrial fibrillation;
  • bleeding risk;
  • risk stratification;
  • stroke;
  • thromboprophylaxis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Atrial fibrillation and stroke – epidemiological insights
  5. Bleeding risk assessment
  6. Thromboprophylaxis in AF patients
  7. Future directions
  8. Disclosure of Conflict of Interests
  9. References

Summary.  Atrial fibrillation (AF) is the commonest sustained cardiac rhythm disorder, which is associated with a substantial risk of mortality and morbidity arising from stroke and thromboembolism. Extensive epidemiological evidence and robust data from clinical trials have shown that stroke and thromboembolism in AF can be prevented by oral anticoagulation (OAC). Despite this evidence and guidelines, appropriate thromboprophylaxis is still suboptimal, and this is partly due to the only OAC agent being available is the vitamin K antagonist class of drugs (e.g. warfarin) that has many limitations and disadvantages. With the availability of new OAC agents that avoid the disutility of the vitamin K antagonists, it is hoped that greater use of OAC would allow more effective thromboprophylaxis and have a great impact on preventing strokes related to AF. Additionally, stroke risk assessments need to evolve such that they are better at identifying the ‘truly low risk’ subjects who do not need antithrombotic therapy, whilst all other patients with ≥ 1 stroke risk factors can be considered for OAC. The availability of comprehensive stroke and bleeding risk assessments would enable us to make informed decisions in everyday clinical practice. The aim of the review article is to provide a state-of-the-art overview of the clinical epidemiology of stroke in AF, stroke (and bleeding) risk assessments and the current provision of thromboprophylaxis for patients with AF.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Atrial fibrillation and stroke – epidemiological insights
  5. Bleeding risk assessment
  6. Thromboprophylaxis in AF patients
  7. Future directions
  8. Disclosure of Conflict of Interests
  9. References

Atrial fibrillation (AF) is the commonest sustained cardiac rhythm disorder and is associated with a substantial risk of mortality and morbidity through stroke and thromboembolism [1].

Over the last few decades, there has been great interest into the clinical epidemiology of AF and stroke, as well as the assessment of stroke risk and provision of thromboprophylaxis [1,2]. Until recently, oral anticoagulation (OAC) was was provided by vitamin K antagonists (VKAs, e.g. warfarin). However, this has changed with the availability of new OACs, such as the oral direct thrombin inhibitors (e.g. dabigatran) and oral factor Xa inhibitors (e.g. rivaroxaban, apixaban) [3].

The aim of this review article is to provide a state-of-the-art overview of the clinical epidemiology of stroke in AF, stroke (and bleeding) risk assessments, and the provision of thromboprophylaxis for patients with AF.

Atrial fibrillation and stroke – epidemiological insights

  1. Top of page
  2. Abstract
  3. Introduction
  4. Atrial fibrillation and stroke – epidemiological insights
  5. Bleeding risk assessment
  6. Thromboprophylaxis in AF patients
  7. Future directions
  8. Disclosure of Conflict of Interests
  9. References

AF is the most common sustained cardiac arrhythmia, with an increasing prevalence and incidence with age [4–6]. Given the increasing mean age of the general population and the improvements in management of cardiovascular diseases, such as myocardial infarction and heart failure, the incidence of AF is increasing such that by 2050, 16 million Americans are predicted to have AF [6].

In AF-associated stroke, patients have a higher mortality and greater morbidity from longer hospital stays, greater disability and lower rates to discharge to their own home [7–10]. This epidemiological burden of AF translates to substantial health care costs related to AF, most of which pertain to hospitalisations [11,12].

Many patients with AF are asymptomatic, and AF may only be first detected during presentation with complications related to the arrhythmia, such as heart failure, stroke or thromboembolism. Indeed, only 1 in 12 paroxysms of AF are actually symptomatic, amongst patients with paroxysmal AF [13]. Other studies with pacemakers confirm that AF burden varies widely, and many paroxysms are asymptomatic [14,15].

Indeed, screening consecutive patients with ischaemic stroke with routine Holter monitoring will identify new onset AF/flutter in approximately one in 20 patients [16,17]. In the analysis by Jabaudon et al. [17], simply doing a 12 lead electrocardiogram (ECG) would detect AF in 6.7% of patients, but this prevalence would increase to 10.6% with a 24 h Holter and 15.6% with an 7 day event loop recorder.

Interest has also been directed towards the relation between AF burden and thromboembolism [18–21]. For example, Capucci et al. [18] first reported that monitored AF of 24 h or more was predictive of arterial embolic events in patients with antitachycardia pacemakers. There appears to be a dose-response relationship between AF burden and thromboembolism, which can be related to intrinsic stroke risk, as measured by the CHADS2 score [19]. AF burden seems to be additive to clinical criteria for stroke risk stratification [20].

Assessing stroke risk in AF

Whilst AF increases the risk of stroke by 5-fold, this risk is not homogeneous as the risk of stroke is altered by the presence of other stroke risk factors [1].

Two systematic reviews have investigated the impact of various risk factors on stroke, based on epidemiological cohorts and non-warfarin arms of clinical trial cohorts [21,22]. However, data from trial cohorts are limited depending on whether particular risk factors were systematically examined and/or recorded. An additional complication is that there have been inconsistencies in the definitions of certain risk factors between different trials.

The Stroke in AF Working Group [21] identified the following risk factors for stroke in AF: previous stroke/TIA [adjusted relative risk (RR) 2.5], age (RR 1.5/decade), hypertension (RR 2.0), diabetes (RR 1.8) and female gender (RR 1.6). History of heart failure was not significant (despite being the ‘C’ in the CHADS2 score that is commonly used for stroke risk stratification – see later), although the presence of moderate-systolic left ventricular dysfunction was still an independent predictor of thromboembolism upon multivariate analysis. The systematic review of stroke risk factors as part of the UK National Institute for Health and Clinical Evidence (NICE) guidelines identified history of stroke or TIA, increasing age, hypertension and structural heart disease (left-ventricular dysfunction or hypertrophy) to be good predictors of stroke risk in AF patients, whilst the evidence regarding diabetes mellitus, gender and other patient characteristics was less consistent [22].

These stroke risk factors have been used to formulate various stroke risk stratification schema [1]. Despite stroke risk in AF being a continuum, these schema have been used to ‘artificially’ categorise patients into low, moderate and high risk stroke strata, so that the patients at highest risk can be identified for warfarin therapy, given the disutility and limitations of the latter therapy that requires regular anticoagulation intensity monitoring and interactions with diet, drugs and alcohol [3].

Clearly, things have moved on with new information on stroke risk factors, and the availability of new OAC that are alternatives to warfarin. Thus, we need to be more inclusive (rather than exclusive) of common stroke risk factors, to get better at identifying the ‘truly low risk patients’ with AF [2,23]. This is relevant given that the latter category of patients can even be managed with no antithrombotic therapy, whilst those AF patients with ≥ 1 stroke risk factor could be treated with OAC, whether with well-controlled warfarin or the new agents, such as dabigatran [2,24].

Stroke risk stratification schema

The most common stroke risk stratification schema, given its simplicity, is the CHADS2 score [Congestive heart failure, Hypertension, Age ≥ 75, Diabetes mellitus, and prior Stroke or transient ischemic attack] [25] (see Table 1). The CHADS2 score was derived by amalgamation of the AF Investigators and SPAF-1 risk schema (both trial-based risk stratification schema) and validated in a hospitalised cohort of AF patients, the Non-Rheumatic AF cohort [25]. The limitations of the CHADS2 score have been discussed and debated [26], particularly since it does not include many common potential stroke risk factors. Based on its original validation study [25], it categorises a score of 0 as ‘low risk’, 1–2 as ‘moderate/intermediate risk’ and ≥ 3 as ‘high risk’. Thus, a patient with previous stroke or TIA alone as a risk factor would have a score of 2 and have been categorised as ‘moderate risk’ using the original categorisation, despite this sort of patient having the highest risk for subsequent stroke or thromboembolism. Nonetheless, current guidelines have partly remedied this, by defining a CHADS2 score ≥ 2 as ‘high risk’.

Table 1.   Assessment of stroke [CHA2DS2-VASc] and bleeding risk [HAS-BLED] in atrial fibrillation patients
CHA2DS2-VAScScoreHAS-BLEDScore
  1. CHA2DS2-VASc score of 0 recommend no antithrombotic therapy; CHA2DS2-VASc score = 1 recommend antithrombotic therapy with oral anticoagulation or antiplatelet therapy, but preferably oral anticoagulation; CHA2DS2-VASc score ≥ 2 recommend oral anticoagulation [24]. HAS-BLED score of ≥ 3 indicates that caution is warranted when predicting oral anticoagulation and regular clinical review is recommended [24]. INR, international normalised ratio; MI, myocardial infarction; PAD, peripheral artery disease; TE, thromboembolic; TIA, transient ischaemic attack.

Congestive heart failure1Hypertension (systolic blood pressure > 160 mmHg)1
Hypertension1Abnormal renal and liver function (1 point each)1 or 2
Aged ≥ 75 years2Stroke1
Diabetes mellitus1Bleeding tendency/predisposition1
Stroke/TIA/TE2Labile INRs (if on warfarin)1
Vascular disease (prior MI, PAD, or aortic plaque)1Elderly (e.g. age > 65)1
Aged 65–74 years1Drugs (e.g. NSAIDs, aspirin) or alcohol abuse (1 point for each category)1 or 2
Sex category (i.e. female gender)1  
Maximum score9Maximum score9

Furthermore, subsequent validation studies have shown a poor predictive value for the CHADS2 (and other) schema (c-statistics approximately 0.6). Furthermore, the CHADS2 score based on its original validation would categorise nearly 60%–65% of various AF populations into the ‘moderate/intermediate risk’ category, where older management guidelines would recommend ‘warfarin or aspirin’ as suitable treatments. This would give some uncertainty on what should one prescribe (warfarin or aspirin?) or some clinicians prescribing aspirin rather than warfarin, as ‘the guidelines allow it’. However, current guidelines would redefine ‘moderate/intermediate risk’ as those with a CHADS2 score = 1, and ‘warfarin or aspirin’ is recommended.

To complement the CHADS2 schema, the new European Society of Cardiology guidelines [24] de-emphasises the low, moderate and high risk categorisation and instead recommends a risk factor based approach with a new schema, the ‘CHA2DS2-VASc’ score to complement the CHADS2 scheme (see Table 1). The CHA2DS2-VASc schema places greater emphasis on what it terms ‘major risk factors’, that is, age ≥ 75 years and previous stroke/TIA, by allocating two points to each, with one point for the presence of each of the other ‘clinically relevant non-major’ risk factors (systolic heart failure, hypertension, diabetes, age 65–74, vascular disease and female gender), with total scores ranging from 0 to 9.

Of note, female gender, age 65–74, and vascular disease are not ‘new’ risk factors per se in AF, but rather, have considered as potential risk factors for stroke in AF in some guidelines. The ‘CHA2DS2-VASc’ scheme tries to formalise these risk factors in an attempt to become more inclusive of common stroke risk factors in AF. After all, any stroke risk factor confers ‘clinical risk’per se when AF is present, and the result may ultimately be a devastating stroke. Indeed, the CHA2DS2-VASc score is more inclusive of common stroke risk factors seen in most patients with non-valvular AF, so that it would at least be applicable most of the time, and easily implemented (informally, guidelines should be applicable for > 80% of the time, and in > 80% of patients). Thus, some less common risk factors associated with thromboembolism in AF (such as end-stage renal failure, amyloid heart disease, etc…) are not part of the CHA2DS2-VASc score as such risk factors have not been adequately studied in clinical trials, nor the balance between mortality, stroke and bleeding clearly defined.

The CHA2DS2-VASc score was first validated in a European cohort from the EuroHeart survey on AF [27]. This study concluded that the CHA2DS2-VASc was good at identifying ‘truly low risk’ patients with AF (≤ 1%/year, with a CHA2DS2-VASc score = 0), categorised the lowest proportion into the ‘moderate/intermediate risk’ strata and that the point estimate using the c-statistic was marginally better than the CHADS2 schema. However, the EuroHeart survey cohort had various limitations (including a proportion of patients lost to follow-up), and validation in other independent cohorts was necessary.

A further large validation was performed in a cohort of 79884 AF patients aged ≥ 18 years in the UK General Practice Research Database, who were followed for an average of 4 years (average of 2.4 years up to the start of warfarin therapy) [28]. This analysis found that all 15 published AF stroke risk stratification schemes had modest discriminatory ability in AF patients, with c-statistics for predicting thromboembolism that ranged from 0.55 to 0.69 for strokes recorded by the general practitioner or in hospital, from 0.56 to 0.69 for stroke hospitalisations, and from 0.56 to 0.78 for death resulting from stroke as reported on death certificates. The proportion of patients assigned to individual risk categories also varied widely across the schemes, with the proportion categorised as moderate risk ranging from 12.7% (CHA2DS2-VASc) to 61.5% (modified CHADS2). Low-risk subjects were truly low risk (with annual stroke events < 0.5%) with the CHA2DS2-VASc schemes. Thus, the CHA2DS2-VASc schema was able to discriminate those at ‘truly low risk’ and minimised classification of subjects into the moderate/intermediate risk category.

A further cohort study used nationwide data on 73,538 hospitalised patients with AF who were not treated with VKAs in Denmark in the period 1997–2006 [29]. In ‘low risk’ subjects (score = 0), the rate of thromboembolism per 100 person-years was 1.67 (95% confidence interval 1.47–1.89) with CHADS2 and 0.78 (0.58–1.04) with CHA2DS2-VASc, at 1 year follow-up. In ‘moderate/intermediate risk’ subjects (score = 1), this rate was 4.75 (4.45–5.07) with CHADS2 and 2.01 (1.70–2.36) with CHA2DS2-VASc. When patients were categorised into low, intermediate, and high-risk strata, the c-statistics at 10 years follow-up were 0.812 (0.796–0.827) with CHADS2 and 0.888 (0.875–0.900) with CHA2DS2-VASc, respectively. In this huge cohort, therefore, the CHA2DS2-VASc scheme performed better than CHADS2 in predicting those at ‘high risk’, and those categorised as ‘low risk’ using CHA2DS2-VASc were ‘truly low risk’ for thromboembolism.

In a trial-based anticoagulated AF cohort (n = 7329 subjects) [30], c-statistics for stroke and thromboembolism were broadly similar among the contemporary risk stratification schema tested and varied between 0.575 (NICE 2006) and 0.647 (CHA2DS2-VASc). CHA2DS2-VASc classified 94.2% as being at high risk (after all, the patients needed to be at some risk of stroke to enter the trial), whereas most other schemes only categorised two-thirds as being at high risk. Of the 184 thromboembolic events, 181 (98.4%) occurred in patients identified as being at high risk by the CHA2DS2-VASc schema, which had the highest hazard ratio (3.75) among the tested schemes. The negative predictive value (i.e. the percent categorised as ‘not high risk’ actually being free from thromboembolism) for CHA2DS2-VASc was 99.5%. Of the contemporary stroke risk stratification schemes, the CHA2DS2-VASc scheme correctly identified the greatest proportion of AF patients at high risk, despite a similar predictive ability of most schemes as evidenced by the c-statistic.

In a ‘real world’ of 662 consecutive elderly anticoagulated AF patients [31], all stroke risk schema had modest discriminating ability, with c-statistics ranging from 0.54 (AF Investigators) to 0.72 (CHA2DS2-VASc). The CHADS2 and CHA2DS2-VASc schemes had the best c-statistics (0.717 and 0.724, respectively) with significant discriminating value between risk strata (both P < 0.001). The proportion of patients assigned to individual risk categories varied widely across the schema, with those categorised as ‘moderate-risk’ ranging from 5.3% (CHA2DS2-VASc) to 49.2% (CHADS2 classical).

A comparison of thromboembolism event rates with the CHADS2 and CHA2DS2-VASc score is shown in Table 2, using data from Olesen et al. [29].

Table 2.   Event rates (95% CI) of hospital admission and death due to thromboembolism per 100 person years, based on the CHADS2 and CHA2DS2-VASc scores
Score/risk category1 year’s follow-up
  1. Data from Olesen et al. [29]

CHADS2
 01.67 (1.47–1.89)
 14.75 (4.45–5.07)
 27.34 (6.88–7.82)
 315.47 (14.62–16.36)
 421.55 (20.03–23.18)
 519.71 (16.93–22.93)
 622.36 (14.58–34.30)
CHADS2
 Low risk (0)1.67 (1.47–1.89)
 Intermediate risk (1)4.75 (4.45–5.07)
 High risk (2–6)12.27 (11.84–12.71)
CHA2DS2-VASc
 00.78 (0.58–1.04)
 12.01 (1.70–2.36)
 23.71 (3.36–4.09)
 35.92 (5.53–6.34)
 49.27 (8.71–9.86)
 515.26 (14.35–16.24)
 619.74 (18.21–21.41)
 721.50 (18.75–24.64)
 822.38 (16.29–30.76)
 923.64 (10.62–52.61)
CHA2DS2-VASc
 Low risk (0)0.78 (0.58–1.04)
 Intermediate risk (1)2.01 (1.70–2.36)
 High risk (2–9)8.82 (8.55–9.09)

Bleeding risk assessment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Atrial fibrillation and stroke – epidemiological insights
  5. Bleeding risk assessment
  6. Thromboprophylaxis in AF patients
  7. Future directions
  8. Disclosure of Conflict of Interests
  9. References

The approach to thromboprophylaxis in AF requires not only assessment of stroke risk, but also the risk of bleeding. The systematic review as part of the NICE guidelines [32] reported that the following AF patient characteristics had supporting evidence for being risk factors for anticoagulation-related bleeding complications: advanced age, uncontrolled hypertension, history of myocardial infarction or ischaemic heart disease, cerebrovascular disease, anaemia or a history of bleeding, and the concomitant use of other drugs such as antiplatelet agents. The presence of diabetes mellitus, controlled hypertension and gender were not identified as significant risk factors. Some of the risk factors for anticoagulation-related bleeding were also indications for the use of anticoagulants in AF patients [33].

Various models for prediction of bleeding have been proposed, although few have been derived and validated in AF populations [33]. Until recently, none of these were in widespread use in AF management nor recommended in older AF guidelines as many were not user-friendly and required complex mathematical formulae and/or including risk factors that are not routinely measured in clinical practice (e.g. genetic factors) [34].

More recently, a new bleeding scoring system has been proposed with the acronym HAS-BLED [35] (uncontrolled Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly> 65 years, Drugs/alcohol concomitantly). One point is given for each risk factor with a maximums score of 9. A score of ≥ 3 suggests a high risk of bleeding that merits some caution and/or regular clinical review of the patient [24].

The HAS-BLED score has also been validated in a large anticoagulated clinical trial cohort [36], where it outperformed other published schema, with a stepwise increase in rates of major bleeding with increasing HAS-BLED score [P(trend) < 0.0001]. The c-statistic for bleeding varied between 0.50 and 0.67 in the entire cohort and 0.68 among patients who were naive to warfarin at baseline. In this cohort, significant predictors of bleeding by multivariate analyses were concurrent aspirin use, renal impairment, age > 75 years, diabetes and heart failure or left ventricular dysfunction.

Indeed, the HAS-BLED score was a potential practical tool in clinical decision making, as recommended in recent guidelines [24,37]. After all, the HAS-BLED score is simple to use, and makes clinicians think about addressing any correctable bleeding risk factors (e.g. uncontrolled hypertension, co-administration of NSAIDs or aspirin, etc.).

Thromboprophylaxis in AF patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Atrial fibrillation and stroke – epidemiological insights
  5. Bleeding risk assessment
  6. Thromboprophylaxis in AF patients
  7. Future directions
  8. Disclosure of Conflict of Interests
  9. References

In general, older management guidelines recommended that ‘high risk’ patients be treated with OAC, whist moderate/low risk AF patients be treated with ‘OAC or aspirin’ and low risk AF patients be treated with aspirin [1].

The value of OAC for stroke prevention is well established [1,38,39]. When compared with placebo, adjusted dose VKA reduced stroke risk by 64% (95% CI, 49%–74%), with an absolute reduction of 2.7% (NNT- to prevent 1 stroke in 1 year = 37) in primary prevention and 8.4% (NNT 12) for secondary prevention [40]. In a cohort of Medicare patients, the use of warfarin increased between 1992 and 2002, and this had a great impact on the incidence of ischaemic stroke, which was markedly reduced over that decade and with no appreciable change in the rate of haemorrhagic strokes [38]. Nonetheless, VKA has significant inter-patient and intra-patient variability in INR (as a measure of anticoagulation efficacy, given that patients need to keep within a narrow therapeutic range of 2.0–3.0) as well as being influenced by diet, drugs and alcohol. There is good evidence that good anticoagulation control is associated with lower rates of ischaemic stroke and bleeding events [41].

Our approach to provision of thromboprophylaxis has recently been altered by the availability of new OAC drugs that do not require monitoring [3]. Of the various new agents, the oral direct thrombin inhibitor, dabigatran etexilate has recently received approval in USA, Canada and Japan for stroke prevention in AF. The pivotal trial with dabigatran compared this drug (two doses, 150 and 110 mg bid) to warfarin: dabigatran 150 mg was superior to warfarin for the reduction of stroke, with a similar rate of major haemorrhage and less intracranial haemorrhage, whilst dabigatran 110 mg was non-inferior to warfarin for efficacy, with significantly less major bleeding [42]. Both doses of dabigatran had significantly less intracranial haemorrhage compared to warfarin.

A recent network meta-analysis indirectly compared dabigatran etexilate with antiplatelet therapy and placebo using statistical indirect comparison methodology [43]. This found that, compared to placebo, dabigatran 150 mg BID was estimated to significantly reduce the risk of any stroke (ischaemic and haemorrhagic) by 75%, ischaemic stroke by 77%, systemic embolism by 83% and mortality by 36%. Dabigatran 150 mg BID was estimated to significantly reduce the risk of any stroke compared with aspirin monotherapy by 63% and aspirin plus clopidogrel by 61%. There was no significant increase in intracranial or extracranial haemorrhage with dabigatran compared to antiplatelet therapy.

The value of aspirin in AF has been subject to much debate. In the meta-analysis by Hart et al. [40], antiplatelet therapy compared to control reduced strokes by 22% (95%CI 6%–35%), but when confined to aspirin-only trials, aspirin showed a non-significant 19% (95% CI, −1% to 35%) reduction in the incidence of stroke. OAC was associated with 39% (95% CI, 22%–50%) risk reduction compared with antiplatelet therapy. Even the effect size of aspirin therapy (−19% stroke risk reduction) was driven by one single positive trial, the SPAF-1 trial, which showed a 42% stroke risk reduction with aspirin 325 mg daily, compared to placebo – with great heterogeneity between the anticoagulation-eligible and anticoagulation-ineligible arms of the trial (94% vs. 8% stroke risk reduction, respectively), and aspirin was ineffective in those aged ≥ 75 and did not prevent severe strokes [44].

In the individual patient meta-analysis by the AF Investigators [45], the risk of stroke (and vascular events) rose with increasing age, from age 65, but as patients got older, the absolute benefit of OAC increased markedly whereas the effect of aspirin declined appreciably. Serious bleeding showed a small increase with increasing age, with no marked difference between OAC and aspirin, consistent with recent trials [46–48]. In low risk AF patients, there was no difference between aspirin and control for the primary endpoint of thromboembolism-related complications, with a trend towards more major bleeding (and intracranial haemorrhage) in aspirin treated patients [49]. In the Birmingham Atrial Fibrillation Treatment in the Aged (BAFTA) trial [46], the rate of major haemorrhage (and intracranial haemorrhage) was not significantly different between warfarin and aspirin treated patients.

The new 2010 ESC guidelines [24] (see Fig. 1) addressed the recognised caveats discussed above by de-emphasising the artificial categorisation into low-/moderate-/high-risk strata (given the poor predictive value of such a categorisation) and recommends a risk factor based approach for more detailed stroke risk assessment. As discussed above, the ESC guidelines define ‘major risk factors’ as prior stroke or TIA, or thromboembolism, and older age (≥ 75 years); and ‘clinically relevant non-major’ risk factors as heart failure [especially moderate to severe systolic LV dysfunction, defined arbitrarily as left ventricular ejection fraction (LVEF) ≤ 40%], hypertension, or diabetes, as well as female sex, age 65–74 years, and vascular disease (more specifically, myocardial infarction, complex aortic plaque and PAD).

image

Figure 1.  Algorithm for thromboprophylaxis in AF, from the 2010 European Society of Cardiology guidelines [24].

Download figure to PowerPoint

The guidelines also emphasise the importance of the cumulative effects of risk factors. In the ESC guideline, therefore, the CHADS2 score is recommended as an initial simple risk assessment to identify the high-risk patients (CHADS2 score of ≥ 2) who clearly need OAC. In those with a CHADS2 score of 0–1, a more detailed comprehensive risk assessment is called for, with the CHA2DS2-VASc risk score.

Future directions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Atrial fibrillation and stroke – epidemiological insights
  5. Bleeding risk assessment
  6. Thromboprophylaxis in AF patients
  7. Future directions
  8. Disclosure of Conflict of Interests
  9. References

Stroke is a common and devastating complication of AF, the commonest sustained cardiac rhythm disorder. Extensive epidemiological evidence and robust data from clinical trials has shown that stroke and thromboembolism in AF can be prevented by OAC. Despite this evidence and guidelines, appropriate thromboprophylaxis is suboptimal, and this is partly due to the only OAC agent being available being the VKA class of drugs (e.g. warfarin) that have many limitations and disadvantages. With the availability of new OAC agents that avoid the disutility of the VKAs, it is hoped that greater use of OAC will allow more effective thromboprophylaxis and have a great impact on preventing strokes related to AF. Additionally, stroke risk assessments need to evolve to enable better identification of the ‘truly low risk’ subjects who do not need antithrombotic therapy, whilst all other patients with ≥ 1 stroke risk factors can be considered for OAC. The availability of comprehensive stroke and bleeding risk assessments would enable us to make informed decisions – rather than guessing or ‘gut feeling’ decisions – in everyday clinical practice, especially since bleeding concerns remain a real concern during initiation of OAC therapy [50,51].

Clearly, many of the clinical risk factors for thromboembolism derived from trial cohorts would need validation in ‘real world’ registries [52]. This is important since many trial cohorts only include a proportion of subjects screened (e.g. in the historical trials, < 10% of those screened were randomised [1]), and many stroke risk factors are inconsistently recorded or defined. As discussed above, the limitations of the CHADS2 score have been debated [26], and the importance of risk factors, such as female gender and vascular disease, have been recognised [2,53,54].

Future refinements of stroke risk stratification may also include biomarkers, given the prothrombotic state associated with AF, and the potential for various indices, such as plasma von Willebrand factor [55], fibrin D-dimer [56] and C-reactive protein [57], to complement clinical risk factors in predicting stroke and mortality. The complex problem of renal failure as a risk factor also merits attention as such patients are at great risk of stroke, death, myocardial infarction and bleeding [58,59]. These patients have not been well studied in clinical trials, and recent large trials with the new OAC drugs have essentially excluded patients with severe renal impairment. Indeed, the balance between thromboembolism and bleeding amongst AF patients with severe renal impairment remains a fine one.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Atrial fibrillation and stroke – epidemiological insights
  5. Bleeding risk assessment
  6. Thromboprophylaxis in AF patients
  7. Future directions
  8. Disclosure of Conflict of Interests
  9. References

Professor Lip has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi, BMS/Pfizer, and Boehringer and has been on the speakers bureau for Bayer, BMS/Pfizer, Boehringer, and Sanofi.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Atrial fibrillation and stroke – epidemiological insights
  5. Bleeding risk assessment
  6. Thromboprophylaxis in AF patients
  7. Future directions
  8. Disclosure of Conflict of Interests
  9. References
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