Options for stroke prevention
Evidence-based guidelines recommend the use of oral anticoagulant or antiplatelet therapy to reduce the incidence of stroke in patients with AF, regardless of the approach used to manage the arrhythmia [1, 6-8]. Pooled results from clinical trials show that warfarin reduces the risk of stroke in these patients by 64%, whilst aspirin, an antiplatelet agent, reduces this risk by 19% . Warfarin is also superior to dual antiplatelet therapy with aspirin and clopidogrel for the prevention of vascular events in patients with AF .
Although warfarin is clearly superior to antiplatelet agents, it has a relatively narrow therapeutic window and interacts with a variety of medications, foods and herbal products ; in addition, there are pharmacogenetic differences in response between patients . Due to these and other factors, responses to warfarin can vary widely between individuals, and therefore, routine monitoring and dose adjustment are required .
Even amongst patients who are eligible for warfarin therapy according to guidelines, the drug is under-used. In addition, those receiving warfarin spend a significant proportion of time with levels of anticoagulation too low or too high for optimal efficacy and safety. Variable INR values can lead to an excess of either stroke or bleeding events. Overall, whilst warfarin is superior to aspirin for stroke prevention, it is associated with a higher rate of the most significant types of bleeding, such as intracranial haemorrhage (ICH). Thus, the net benefit of warfarin relative to aspirin is reduced in patients with few additional risk factors for stroke. For this reason, guidelines for choosing aspirin rather than warfarin as antithrombotic therapy are based on risk stratification. It is interesting that in the era of new oral anticoagulants, this means that choosing aspirin becomes largely invalid, as discussed below.
Risk stratification for warfarin use, and the recent European Society of Cardiology guidelines
To assess an individual's risk of stroke, a risk stratification scheme is employed. The cardiac failure, hypertension, age, diabetes, stroke (doubled) (CHADS2) scheme  has been used primarily in recent years. However, with this scheme, a substantial proportion of subjects are categorized as having a ‘moderate risk’ of stroke (score of 1), for which there is no clear guidance on whether patients should receive a VKA (such as warfarin) or aspirin .
Refinements to this scheme have been made because evidence shows that some patients categorized as ‘moderate risk’ in the CHADS2 system clearly derive more benefit from an oral anticoagulant than from aspirin. For example, in patients with AF and a CHADS2 score of 1, warfarin was more effective than aspirin at reducing the incidence of ischaemic stroke without increasing the risk of major haemorrhage (although minor bleeding was more common with warfarin) . Similar results have been found in elderly (≥75 years) patients with AF at risk of stroke . Furthermore, the original CHADS2 scheme does not include additional known stroke risk factors, such as vascular disease.
The European Society of Cardiology 2010 guidelines for management of AF recommend use of the more comprehensive CHA2DS2-VASc scheme , which doubles the value assigned to older age as a risk factor and includes three additional moderate risk factors: vascular disease, age 65–74 years and sex category (female) (Table 1). For patients with a CHA2DS2-VASc score of ≥2, oral anticoagulant therapy with a VKA is recommended. For those with a CHA2DS2-VASc score of 1, oral anticoagulation with either a VKA or 75–325 mg aspirin daily is recommended; however, oral anticoagulant is preferred. For patients with no additional risk factors, 75–325 mg aspirin or no antithrombotic treatment is recommended; the latter is preferred (Table 2) . Provisional recommendations for the use of new oral anticoagulants are included in the guidelines; these are expected to evolve and are discussed below.
Table 1. Risk factors for stroke and thromboembolism in nonvalvular AF using the CHA2DS2-VASc scheme expressed as a point-based scoring system 
|Congestive heart failure or moderate to severe LV dysfunction (e.g. LVEF ≤ 40%)||1|
|Age ≥ 75 years||2|
|Age 65–74 years||1|
|Female sex category||1|
Table 2. Recommendations for thromboprophylaxis in patients with AF 
|Risk category||CHA2DS2-VASc score||Recommended antithrombotic therapy|
|One ‘major’ risk factor or ≥2 ‘clinically relevant nonmajor’ risk factors||≥2||Oral anticoagulanta|
|One ‘clinically relevant nonmajor’ risk factor||1|| |
Either oral anticoagulantb or aspirin 75–325 mg daily
Preferred: oral anticoagulant
|No risk factors||0|| |
Either aspirin 75 mg daily or no antithrombotic therapy
Preferred: no antithrombotic therapy
The CHA2DS2-VASc scheme helps to clarify treatment decisions as it results in a ‘low-risk’ category that is truly low risk, reduces the proportion of patients who were previously categorized as moderate risk and identifies the majority of patients who can expect a net benefit from oral anticoagulant therapy, as shown in Fig. 1 .
Figure 1. The proportion of patients in the Euro Heart Survey assigned to different stroke risk categories by CHADS2 (revised) score compared with CHA2DS2-VASc score amongst those who did not receive anticoagulation at baseline, and the corresponding incidence of thromboembolic events (TE; i.e. stroke, pulmonary embolism or peripheral embolism)  and treatment recommendations . OAC, oral anticoagulant.
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A large, registry-based cohort study evaluating the individual risk factors comprising the CHADS2 and CHA2DS2-VASc scores in patients admitted to hospital with AF and not treated with VKAs has supported the original validation of CHA2DS2-VASc.
It confirmed that the CHA2DS2-VASc performed better than CHADS2 in stratifying stroke risk. The rate of thromboembolism at 1-year follow-up was 1.67 per 100 person-years in patients with a CHADS2 score of 0, compared to only 0.78 per 100 person-years in those with a CHA2DS2-VASc score of 0; in intermediate-risk patients with CHADS2 versus CHA2DS2-VASc scores of 1, the rates were 4.75 vs. 2.01 per 100 person-years, respectively. In general, similar rates of events persisted at 5- and 10-year follow-ups .
Nevertheless, the importance of some individual risk factors has been debated. The 2006 American College of Cardiology/American Heart Association/European Society of Cardiology guidelines for the management of patients with AF  included age 65–74 years, coronary artery disease, female gender and thyrotoxicosis as less well validated or weaker risk factors. By contrast, in the development of the CHA2DS2-VASc scheme based on patients in the Euro Heart Survey on Atrial Fibrillation , the first three of these were found to be significant risk factors. However, in the large cohort study mentioned above, female sex alone (CHA2DS2-VASc score = 1) was a statistically significant risk factor for hospitalization or death due to thromboembolism at 1-year follow-up (1.24 events per 100 person-years) but was not significant at 5 and 10 years. On the other hand, women with hypertension had a higher stroke risk. If female sex is considered equivalent to a score of 0, appropriate treatment would be no therapy or aspirin; by contrast, female sex plus hypertension would provide a clear indication for oral anticoagulant therapy, corresponding to a score of 2 (of note, either an oral anticoagulant or aspirin would be recommended if these factors represented a score of 1).
Future trials may further refine these schemes. There is current interest in the role of biomarkers that can easily be tested as indicators of stroke risk. For example, in a large clinical trial population of patients with AF randomly assigned to warfarin or dabigatran etexilate, elevated cardiac troponin I levels were associated with an increased risk of stroke and systemic embolism as well as death . Furthermore, elevated levels of N-terminal pro-B-type natriuretic peptide were related to increased risks of stroke, cardiovascular death and major bleeding, even after the adjustment for CHADS2 risk factors .
Of note, use of stroke risk schemes to guide therapy needs to be balanced by a full appreciation of the bleeding risk. The European Society of Cardiology 2010 guidelines state that the recently introduced hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly (age > 65 years), drugs/alcohol concomitantly (HAS-BLED) scheme  is appropriate for assessing bleeding risk in patients with AF receiving a VKA . HAS-BLED produces similar results to an older scheme, HEMORR(2)HAGES, but is easier to use in everyday practice . A five-factor risk score based on patients taking warfarin in the ATRIA study has also recently been published incorporating anaemia, severe renal disease (three points each), age ≥ 75 years (two points), prior bleeding and hypertension (one point each) .
The concept of net clinical benefit (ischaemic stroke versus ICH) has been used to compare VKA therapy or aspirin alone, VKA therapy plus aspirin and no treatment. Patients with AF in a large real-world cohort were evaluated for stroke and bleeding risks using CHADS2, CHA2DS2-VASc and HAS-BLED. VKA treatment consistently lowered the risk of thromboembolism compared with aspirin or no treatment, whereas VKA plus aspirin provided no additional benefit. The risk of bleeding was higher in all risk groups compared with no treatment, but overall, there was a positive net clinical benefit of VKAs alone in patients with CHADS2 score ≥1 or CHA2DS2-VASc score ≥2 and a neutral or positive net clinical benefit in patients with CHADS2 score ≥0 or CHA2DS2-VASc score ≥1 .