European Primary Care Cardiovascular Society (EPCCS) consensus guidance on stroke prevention in atrial fibrillation (SPAF) in primary care

Background: Atrial fibrillation affects 1-2% of the general population and 10% of those over 75, and is responsible for around a quarter of all strokes. These strokes are largely preventable by the use of anticoagulation therapy, although many eligible patients are not treated. Recent large clinical trials have added to the evidence base on stroke prevention and international clinical guidelines have been updated. Design: Consensus practical recommendations from primary care physicians with an interest in vascular disease and vascular specialists. Methods: A focussed all-day meeting, with presentation of summary evidence under each section of this guidance and review of European guidelines on stroke prevention in atrial fibrillation, was used to generate a draft document, which then underwent three cycles of revision and debate before all panel members agreed with the consensus statements. Results: Six areas were identified that included how to identify patients with atrial fibrillation, how to determine their stroke risk and whether to recommend modification of this risk, and what management options are available, with practical recommendations on maximising benefit and minimising risk if anticoagulation is recommended and the reasons why antiplatelet therapy is no longer recommended. The summary evidence is presented for each area and simple summary recommendations are highlighted, with areas of remaining uncertainty listed. Conclusions: Atrial fibrillation-related stroke is a major public health priority for most health systems. This practical guidance can assist generalist community physicians to translate the large evidence base for this cause of preventable stroke and implement this at a local level.

# Introduction
Atrial fibrillation (AF) is the most common cardiac arrhythmia, with about 1-2% of the general population estimated to be affected. [bib_ref] Guidelines for the management of atrial fibrillation: the Task Force for the..., Camm [/bib_ref] [bib_ref] 2012 focused update of the ESC Guidelines for the management of atrial..., Camm [/bib_ref] It is a particularly common disorder in the elderly, with over 5% of people over the age of 65 suffering from AF, and around 10% of people over the age of 75. [bib_ref] A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and..., Hobbs [/bib_ref] [bib_ref] Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study, Heeringa [/bib_ref] [bib_ref] ACCF/ AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the..., Fuster [/bib_ref] As a consequence of the ageing population, the prevalence of AF is predicted to rise. [bib_ref] Rising rates of hospital admissions for atrial fibrillation, Friberg [/bib_ref] Rising prevalence has also been attributed to better survival of patients following acute coronary events, and a greater awareness among healthcare professionals of the importance of diagnosing AF.

## Clinical picture of patients with atrial fibrillation
Patients with AF may have symptoms such as palpitations, lack of energy, dizziness, chest discomfort and shortness of breath, which may impair quality of life. [bib_ref] Health-related quality of life in atrial fibrillation patients over 65 years: a..., Zhang [/bib_ref] The degree of these symptoms varies considerably, from patients who are completely asymptomatic to those who are quite disabled by the arrhythmia. The use of rate and rhythm control to improve symptoms is beyond the scope of this guideline, which will focus exclusively on stroke prevention.
It is important to note that, for many patients with AF, the condition is often asymptomatic -or associated with minor symptoms that are ignored or unrecognised by patients -therefore, if the arrhythmia is to be identified in all, some type of AF screening is needed.
Perhaps the most important consequence of AF is the risk of embolic stroke. Patients with AF are at an almost fivefold higher risk of stroke compared with age-matched individuals with normal sinus rhythm, as shown in the Framingham study, [bib_ref] Atrial fibrillation as an independent risk factor for stroke: the Framingham Study, Wolf [/bib_ref] as well as at a twice as high risk of all-cause mortality and heart failure. About 20-25% of all ischaemic strokes are attributable to embolism as a result of AF. [bib_ref] Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on..., Albers [/bib_ref] Not only do patients with AF have more strokes, they also develop more recurrent strokes, both fatal and nonfatal. [bib_ref] Atrial fibrillation as an independent risk factor for stroke: the Framingham Study, Wolf [/bib_ref] In addition, strokes are likely to be more severe in patients with AF, than in patients who have a stroke not associated with AF, regardless of age. [bib_ref] Acute stroke with atrial fibrillation. The Copenhagen Stroke Study, Jorgensen [/bib_ref] Following a stroke, patients with AF are more likely to be left with long-term disability and may require long-term care. [bib_ref] Stroke severity in atrial fibrillation. The Framingham Study, Lin [/bib_ref] [bib_ref] Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe:..., Lamassa [/bib_ref] This disability is a major source of concern for patients and is associated with high costs for healthcare systems. Moreover, AF is often associated with other underlying pathology, such as cardiovascular comorbidity (coronary artery disease, heart failure, hypertension) and/or non-cardiovascular comorbidity (chronic obstructive pulmonary disease (COPD), renal failure, etc.). This is especially prevalent in the elderly, and highlights the role general Box 1.

# Strength of recommendations
The following colour coding will be used throughout the document, to indicate the strength of the individual recommendations.
Interventions that should (or should not) be used: a 'strong' recommendation 'Offer' (and similar words such as 'refer' or 'advise') indicates confidence that, for the vast majority of patients, an intervention will do more good than harm, and be cost-effective. Similar forms of words (for example, 'Do not offer. . .') are used when we are confident that an intervention will not be of benefit for most patients. Interventions that could be used 'Consider' indicates confidence that an intervention will do more good than harm for most patients, and be cost-effective, but other options may be similarly cost-effective. The choice of intervention, and whether or not to have the intervention at all, is more likely to depend on the patient's values and preferences than for a strong recommendation, and so the healthcare professional should spend more time considering and discussing the options with the patient.
Terminology used with permission from NICE.
practice should play in managing this multi-morbid disorder. AF has considerable impact on individuals and health systems. It is also associated with increased mortality, heart failure and high rates of hospitalisation because of stroke. Admission and readmission rates are the most important factors driving healthcare expenditure. [bib_ref] Increased atrial fibrillation mortality: United States, 1980-1998, Wattigney [/bib_ref] [bib_ref] Increasing trends in hospitalization for atrial fibrillation in the United States, 1985..., Wattigney [/bib_ref] [bib_ref] Heart disease and stroke statistics-2008 update: a report from the American Heart..., Rosamond [/bib_ref] Types of atrial fibrillation ESC guidelines distinguish various types of AF, mainly based on duration, for example paroxysmal (usually 48 hours), persistent (!7 days) and longstanding or permanent (>1 year). 1,2 These classifications are somewhat arbitrary and their use in clinical practice might be limited. They may, however, be relevant to determine how to treat the arrhythmia itself, rather than the stroke risk associated with AF. The risk of stroke is considered similar for all types of AF. [bib_ref] Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial..., Friberg [/bib_ref] It is also important to consider the distinction between valvular and non-valvular types of AF, as this affects management. In the ESC guidelines, 1,2 the term valvular AF is used to indicate that AF is related to rheumatic valvular disease (predominantly mitral stenosis) or prosthetic heart valves.
Atrial flutter, a different type of atrial arrhythmia, is sometimes considered along with AF. Patients with atrial flutter are often referred for consideration of curative management, but in the meantime stroke risk should be considered and managed in the same way as AF.
In summary, all types of AF, with the exception of clinically significant valvular AF as defined above, should be regarded as the same in terms of stroke risk. Defining the type of AF can provide a diagnostic label, which can be useful when considering rate or rhythm management, but stroke risk is similar. Importantly, re-establishing sinus rhythm will not remove the stroke risk. [bib_ref] Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies..., Carlsson [/bib_ref] [bib_ref] Impact of rate versus rhythm control on quality of life in patients..., Gronefeld [/bib_ref] [bib_ref] A comparison of rate control and rhythm control in patients with recurrent..., Van Gelder [/bib_ref] [bib_ref] A comparison of rate control and rhythm control in patients with atrial..., Wyse [/bib_ref] Role of the general practitioner in stroke prevention in atrial fibrillation AF often co-exists with other chronic diseases, and these comorbidities may have caused or exacerbated each other. Over extended periods of time, AF may cause substantial cardiac remodelling that can impact on the management of both conditions. A recent epidemiological study showed that 5% of over 65-yearolds had AF, and at least three other chronic conditions. [bib_ref] Epidemiology of multimorbidity and implications for health care, research, and medical education:..., Barnett [/bib_ref] This implies that the general practitioner can play a crucial, central role, as he or she is aware of and can manage different conditions.

## Practical recommendations
Based on current evidence and experience, we recommend the following in a primary care setting:
. All patients with AF, regardless of AF type, are at increased risk of stroke as they age or develop certain comorbid conditions and therefore all AF patients should be offered assessment of their stroke risk (see How to decide whether to treat stroke risk in atrial fibrillation?). . Patients who are treated for AF and returned to sinus rhythm should be risk assessed as if they were still in AF and should remain on their stroke prevention therapy if it was indicated prior to rhythm control. If a decision is taken to stop anticoagulation in these patients, it should be a specialist decision.
How is atrial fibrillation detected? Should we screen for atrial fibrillation? Rationale for opportunistic case-finding AF is one of the most important causes of preventable stroke, is associated with more severe strokes and is therefore a major health risk to modify in patients and an important disease target for health systems. AF meets all the Wilson-Jungner criteria to be a condition worth screening for. Patients with AF may present with symptoms, and AF should be considered in anyone complaining of palpitations (fluttering or irregular heart beat), dizziness or fainting spells, chest discomfort, shortness of breath and/or reduced exercise tolerance. However, not all patients with AF will have symptoms and may, therefore, be unaware they have an arrhythmia. The observation that even short episodes of silent AF (as measured with implanted devices and by Holter electrocardiograms (ECGs)) convey an increased risk of stroke 22,23 offers the rationale for opportunistic screening.
Opportunistic screening by pulse palpation in general practice detected a large number of patients with previously undiagnosed AF compared with usual care (1.64% per year by screening vs. 1.04% per year with care as usual), yielding a feasible number of 169 needed to screen. [bib_ref] Screening versus routine practice in detection of atrial fibrillation in patients aged..., Fitzmaurice [/bib_ref] These data suggest that active screening for AF in patients of 65 years and older can identify patients eligible for anticoagulation treatment according to CHADS 2 criteria. [bib_ref] Is screening for AF worthwhile? Stroke risk in a screened population from..., Fitzmaurice [/bib_ref] New technologies, such as modified sphygmomanometers capable of detecting an irregular pulse, may also improve pickup rates.

## Confirming the diagnosis in suspected atrial fibrillation
In patients with suspected AF, an ECG, preferably 12lead ECG, can confirm the diagnosis. Loss of P-waves and completely irregular R-R distances are characteristic features of AF on ECG; however, ECG changes may be subtle, so judgement by a competent ECGreader is required to confidently diagnose AF. [bib_ref] ACCF/ AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the..., Fuster [/bib_ref] Adequate interpretation of a single-lead ECG may be considered as convincing as a 12-lead ECG for detection or exclusion of AF. [bib_ref] Validation and clinical use of a novel diagnostic device for screening of..., Tieleman [/bib_ref] Conventionally, an ECG should contain a total of 30 seconds of AF to confirm the diagnosis, but this criterion is consensus not evidence-based, and was developed for considering which patients to offer cardioversion or pacing. Therefore, a standard 12-lead ECG of 10 seconds is perhaps sufficient in practice settings.

## Practical recommendations
Based on current evidence and experiences, we recommend the following case finding efforts in a primary care setting:
Interventions that should be used . Opportunistic case finding should be carried out for timely detection of AF in all patients over 65 years of age, and in anyone who receives routine cardiovascular follow-up: Pulse palpation, at least once a year could be incorporated into already existing medical visits, for instance during an annual cardiac disease review, and/or at flu vaccinations or pharmacy visits. . In the case of a positive pulse palpation:
12-lead ECG follow-up should be performed shortly after pulse assessment. 12-lead ECG follow-up should be done by a practitioner who is competent in ECG interpretation.

## Alternative approach
. Modified sphygmomanometers or other devices using single-lead ECG registrations to detect an irregular pulse may be used instead of pulse palpation, but only where they have been subject to independent validation with a 12lead ECG.
. If not enough expertise is available in the primary care setting to confidently read a 12-lead ECG, it should be reviewed by a specialist. 12-lead ECG may also provide other useful information on cardiac functioning.
Additional work recommended in this area/gaps in the evidence:
. See web version How to decide whether to treat stroke risk in atrial fibrillation? Risk assessment for stroke prevention in atrial fibrillation When giving antithrombotic agents to reduce stroke risk in AF, both thromboembolic risk and bleeding risk need to be considered. 'Whom not to treat?' is a question at least as important to ask as 'whom to treat?', as each form of antithrombotic therapy has an inherent, and possibly severe, bleeding risk.
The CHADS 2 score is a valuable tool that has been used for some time to assess stroke risk in patients with AF, 27,28 but observational data highlighted the need for a more robust stroke risk score. The CHA 2 DS 2 -VASc score has since been developed, which includes additional risk factors and gives a maximum score of 9 compared with a maximum of 6 in the CHADS 2 score (see [fig_ref] Table 1: CHADS 2 and CHA 2 DS 2 -VASc risk score components [/fig_ref] for components of the CHA 2 DS 2 -VASc score). Age can contribute 2 points, rather than 1, if the patient is !75 years old. Vascular disease and female sex also add an extra point, 1,2 the latter only contributing a score, however, if other stroke risk factors are present (i.e. if the only 'risk' factor is being female, the CHA 2 DS 2 -VASc score is 0). The improved risk stratification with CHA 2 DS 2 -VASc as opposed to CHADS 2 score has been validated in several studies, [bib_ref] Validation of risk stratification schemes for predicting stroke and thromboembolism in patients..., Olesen [/bib_ref] [bib_ref] Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation..., Lip [/bib_ref] [bib_ref] Reliable identification of ''truly low'' thromboembolic risk in patients initially diagnosed with..., Potpara [/bib_ref] [bib_ref] A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation..., Van Staa [/bib_ref] [bib_ref] Comparison of the reliability and validity of four contemporary risk stratification schemes..., Abu-Assi [/bib_ref] and CHA 2 DS 2 -VASc is the recommended score for assessment of stroke risk in the ESC guidelines. [bib_ref] 2012 focused update of the ESC Guidelines for the management of atrial..., Camm [/bib_ref] Event rates of hospital admission and death caused by thromboembolism (including peripheral artery embolism, ischaemic stroke, and pulmonary embolism) for each CHADS 2 and CHA 2 DS 2 -VASc category are shown in [fig_ref] Table 2: Event rates per CHADS 2 and CHA 2 DS 2 -VASc category [/fig_ref].

## Risk assessment for bleeding risks from anticoagulation
Bleeding is an important, potentially serious, side effect of anticoagulation and should be considered for all patients prior to treatment initiation.
Bleeding risk can be assessed with the HAS-BLED score, as introduced in the 2010 ESC Guidelines (see [fig_ref] Table 3: HAS-BLED risk score components [/fig_ref] for components of the HAS-BLED score). [bib_ref] Guidelines for the management of atrial fibrillation: the Task Force for the..., Camm [/bib_ref] [bib_ref] A novel userfriendly score (HAS-BLED) to assess 1-year risk of major bleeding..., Pisters [/bib_ref] The score takes into account nine risk factors for bleeding that should be considered before starting antithrombotic treatment. The most important factor determining both stroke and bleeding risk appears to be age, 2,35-38 which justifies its double weight in the [bib_ref] Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation..., Lip [/bib_ref] tools to assess stroke risk in patients with AF. These risk assessment tools help to determine who should and who should not receive anticoagulation. CHA 2 DS 2 -VASc improves risk stratification in patients with CHADS 2 140 or 1, and allows for identification of patients at truly low risk.
CHA 2 DS 2 -VASc score. An observational retrospective study has confirmed increased bleeding rates in incremental HAS-BLED scores. [bib_ref] Bleeding risk in 'real world' patients with atrial fibrillation: comparison of two..., Olesen [/bib_ref] shows the incidence of major bleeding per HAS-BLED category as seen in non-selected patients receiving anticoagulation. HAS-BLED should guide the patient and clinician to reduce modifiable bleeding risks (namely high blood pressure, liver and kidney function, INR control and use of interacting medications or alcohol), but not determine whether to offer anticoagulation or notthat decision is based on stroke risk estimation.
Falls are sometimes given as an argument not to anticoagulate a frail patient, yet evidence suggests that patients with low impact falls need to fall a great number of times before it actually increases the bleeding risk. Patient preferences should determine treatment; some patients are willing to endure many bleeds to avoid one stroke and its consequences, whereas others may accept stroke risk rather than the inconvenience of taking anticoagulants. [bib_ref] Differences between perspectives of physicians and patients on anticoagulation in patients with..., Devereaux [/bib_ref] In general, it should be noted that with an area under the curve below 70, 38,40,41 these risk scores remain less than perfect predictors of individual risk.

## Practical recommendations
Based on current evidence and experiences, we recommend the following stroke and bleeding risk assessment strategy in primary care in patients who have been diagnosed with AF:
Stroke and bleeding risk interventions that should be used . CHA 2 DS 2 -VASc score is superior to CHADS 2 score for assessing stroke risk in AF, notably in identifying those that should not receive anticoagulation. . Alternatively, as CHADS 2 is simpler to use, patients' risk of stroke can be initially assessed using CHADS 2 but if their score is 1 or less, then a CHA 2 DS 2 -VASC score should be performed to identify those patients who do not require anticoagulation. . Patients with a CHA 2 DS 2 -VASc score of 0 should not be offered antiplatelet or anticoagulation therapy. . Patients with a CHA 2 DS 2 -VASc score of 2 or above should be offered anticoagulation. In patients with a CHA 2 DS 2 -VASc score of 1, consider anticoagulation and base any decision to treat or not treat on patient preference after balancing the benefits with risks of treatment. . As a second step, HAS-BLED should be used to assess bleeding risk, with the aim of modifying this risk through addressing individual risk factors that can be altered. . HAS-BLED should not be used to decide whether to offer anticoagulation in someone with a CHA 2 DS 2 -VASc score of 2 or above, but consider its use to balance the benefits of anticoagulation in patients with a CHA 2 DS 2 -VASc score of 1. . On a regular basis, and at least once a year, the risk status of patients with AF should be re-evaluated depending on change in risk factors (change of age category, new hypertension, etc).
These scoring tools are available on the EPCCS website at: www.epccs.eu.
Alternative risk assessment approaches that may be used:
. A more pragmatic strong risk application might simply be to consider age, as women over 65 with AF and an additional risk factor qualify for anticoagulation according to CHA 2 DS 2 -VASc stroke risk stratification, and so do men over 75. . People under 65 with no additional risk factor to their AF, in contrast, do not need anticoagulation. . Risk assessment should also be done in patients younger than 65 years of age who have multiple risk factors.
Additional work recommended in this area/gaps in the evidence:
. See web version.
What are the management options to treat stroke risk in atrial fibrillation? What is the evidence for anticoagulation in patients with atrial fibrillation in primary care?
Different antithrombotic strategies to prevent stroke in AF have been investigated over time. Early studies suggested that antiplatelet agents were effective in reducing stroke risk with one meta-analysis showing that acetyl salicylic acid (ASA) reduced the stroke rate by 22%, [bib_ref] Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial..., Hart [/bib_ref] and addition of clopidogrel led to a risk reduction of 28%. [bib_ref] Effect of clopidogrel added to aspirin in patients with atrial fibrillation, Connolly [/bib_ref] Vitamin K antagonists show risk reductions of 66%. [bib_ref] Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial..., Connolly [/bib_ref] [bib_ref] Newer oral anticoagulants should be used as first-line agents to prevent thromboembolism..., Granger [/bib_ref] The BAFTA study specifically studied an elderly (!75 years old) primary care population, and compared warfarin with ASA in a randomised controlled trial, showing that warfarin was much more effective than ASA at reducing stroke (see [fig_ref] Table 5: Nature of primary events with warfarin or aspirin in an elderly community... [/fig_ref]. Strokes occurring in the elderly are more likely to be embolic strokes. [bib_ref] Warfarin versus aspirin for stroke prevention in an elderly community population with..., Mant [/bib_ref] The BAFTA data are supported by the individual patient data (IPD) meta-analysis of the totality of available warfarin and aspirin data in preventing AF stroke by age, which showed that aspirin became less effective and more likely to cause bleeding with increasing age, with no benefits observed beyond age 75. [bib_ref] Effect of age on stroke prevention therapy in patients with atrial fibrillation:..., Van Walraven [/bib_ref] 

## Comorbidity in atrial fibrillation
Patients with AF often have other chronic conditions, which may be a cause or consequence of the arrhythmia Stroke risk management in atrial fibrillation patients with rate or rhythm control strategies
In symptomatic AF patients, it is important to optimise and control heart rate and it may also be appropriate to try to re-establish and maintain sinus-rhythm. Now that all guidelines advocate consideration of the use of antithrombotic therapy in all patients based on risk calculation, it is important to consider that control of rate and rhythm should only be attempted alongside controlling for the stroke risk. Importantly, antithrombotic therapy should be continued, even if rhythm control is obtained. [bib_ref] Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies..., Carlsson [/bib_ref] [bib_ref] Impact of rate versus rhythm control on quality of life in patients..., Gronefeld [/bib_ref] [bib_ref] A comparison of rate control and rhythm control in patients with recurrent..., Van Gelder [/bib_ref] [bib_ref] A comparison of rate control and rhythm control in patients with atrial..., Wyse [/bib_ref] Practical recommendations
Based on current evidence and experiences, we recommend the following stroke risk reduction management in primary care patients who have been diagnosed with AF: Management strategies that should be used . Patients with a CHA 2 DS 2 -VASc score of 2 or above should be offered anticoagulation.

## Management strategies that should not be used
. Patients assessed as low risk on the CHA 2 DS 2 -VASc score (0) should not be offered antiplatelet or anticoagulation therapy, but may be offered standard advice regarding improving vascular risk factors (smoking cessation, BP and cholesterol control). . Patients with a CHA 2 DS 2 -VASc score of 1, should not be offered single antiplatelet therapy. . Patients at high stroke risk, with a CHA 2 DS 2 -VASc score of 2 or more, should not be offered single or dual antiplatelet therapy.

## Management strategies that may be used
. In patients with a CHA 2 DS 2 -VASc score of 1, consider anticoagulation and base any decision to treat or not to treat on patient preference after balancing the benefits with risks of treatment. In this situation, the decision to treat with anticoagulation or not should be based on patient preferences of their primary desire to reduce their stroke risk or to avoid bleeding risk. As their stroke risk is moderate rather than high, it is also very important to attempt to modify any bleeding risk factors. . Only in those intolerant of, or declining, anticoagulation may a combination of antiplatelets be considered (although the bleeding risk of this strategy will approach that of anticoagulation).
What are the therapeutic options to treat stroke risk in atrial fibrillation?
Although vitamin K antagonists (VKAs), and to a lesser extent other antithrombotic agents, importantly reduce the risk of stroke in patients with AF, they have several drawbacks, and a lot of effort has been dedicated to developing new anticoagulant agents. VKAs require intensive monitoring of international normalised ratio (INR) to ensure the drug is effective yet safe by maintaining figures within a therapeutic range (INR target 2.5, range 2-3 for NVAF). Moreover, it is important to achieve INR control above 65% time in therapeutic range (TTR), as shown in [fig_ref] Figure 1: Percent of patients free from stroke over time, stratified by time spent... [/fig_ref]. Four new oral anticoagulants (NOACs) are now available, namely dabigatran etexilate, a direct thrombin inhibitor, [bib_ref] Efficacy and safety of dabigatran compared with warfarin at different levels of..., Wallentin [/bib_ref] [bib_ref] Dabigatran versus warfarin in patients with atrial fibrillation, Connolly [/bib_ref] and the direct factor Xa inhibitors apixaban, [bib_ref] Apixaban versus warfarin in patients with atrial fibrillation, Granger [/bib_ref] rivaroxaban, [bib_ref] Rivaroxaban versus warfarin in nonvalvular atrial fibrillation, Patel [/bib_ref] and edoxaban. [bib_ref] Rivaroxaban versus warfarin in nonvalvular atrial fibrillation, Patel [/bib_ref] [bib_ref] Edoxaban versus warfarin in patients with atrial fibrillation, Giugliano [/bib_ref] These newer agents offer additional options to current treatments for SPAF, as outlined below.

## Efficacy of noacs versus warfarin in non-valvular af
In recent years, new classes of anticoagulants have been developed and tested. Data of large trials on their efficacy and safety have been evaluated extensively, including 'real life' follow-up data. In several, large randomised controlled trials (RCTs) of AF patients without severe valve disease or mechanical valves, NOACs have been shown to be effective at reducing stroke risk. [bib_ref] Efficacy and safety of dabigatran compared with warfarin at different levels of..., Wallentin [/bib_ref] [bib_ref] Dabigatran versus warfarin in patients with atrial fibrillation, Connolly [/bib_ref] [bib_ref] Apixaban versus warfarin in patients with atrial fibrillation, Granger [/bib_ref] [bib_ref] Rivaroxaban versus warfarin in nonvalvular atrial fibrillation, Patel [/bib_ref] [bib_ref] Edoxaban versus warfarin in patients with atrial fibrillation, Giugliano [/bib_ref] These RCTs were designed as noninferiority studies; thus powered to show that NOACs are at least as good as warfarin in the prevention of stroke in AF. Fuller study details are available in the web version of this paper. A systematic review 53 that evaluated the results of the NOAC versus warfarin trials (RE-LY, ROCKET-AF and ARISTOTLE) concluded that overall mortality was decreased in patients with AF taking NOACs (risk difference estimated to be 8 [95% fewer deaths per 1000 patients, RR 0.88, 95% CI 0.82-0.96). In the meta-analysis that also included ENGAGE AF-TIMI, all-cause mortality was also significantly reduced

## Safety of noacs versus warfarin
Anticoagulation comes with an inherent bleeding risk, thus bleeding events were closely monitored and documented in the NOAC trials. When combining all data of the first three large trials, namely RELY, ROCKET-AF and ARISTOTLE, on direct thrombin inhibitors and Factor Xa inhibitors, fatal bleeds were found to be significantly reduced in comparison with anticoagulation with warfarin (RR 0.60, 95% CI 0.46-0.77, estimated risk difference is 1 fewer death per 1000 patients). Reduction in major bleeds did not reach statistical significance (RR 0.80, 95% CI 0.63-1.01), [bib_ref] Newer oral anticoagulants should be used as first-line agents to prevent thromboembolism..., Granger [/bib_ref] [bib_ref] Edoxaban versus warfarin in patients with atrial fibrillation, Giugliano [/bib_ref] [bib_ref] Comparison of the efficacy and safety of new oral anticoagulants with warfarin..., Ruff [/bib_ref] The data of individual trials are summarised in in the web version of this paper.
The meta-analysis of all NOAC RCTs also showed that NOACs were associated with a higher rate of GI bleeds (751 events in 29287 [2.6%] patients on NOACs vs. 591 events in 29211 [2.0%] warfarin-treated patients, RR 1.25, 95% CI 1.01-1.55, p140.0430). [bib_ref] Edoxaban versus warfarin in patients with atrial fibrillation, Giugliano [/bib_ref] Meta-analyses of the NOAC trials did not find a difference in the rate of MI with NOACs versus warfarin on combined data of all trials evaluated (RR 0.95, 95% CI 0.81-1.11, 53 and RR 0.97, 95% CI 0.78-1.20 [bib_ref] Edoxaban versus warfarin in patients with atrial fibrillation, Giugliano [/bib_ref].

## Noacs and mechanical valves (without af)
The recent RE-ALIGN study reported that dabigatran should not be used in patients with mechanical heart valves, as more thromboembolic and bleeding events were observed in patients on dabigatran than in the warfarin-treated patients (to a higher target INR than in NVAF). The same contraindication is currently extended to all NOACs in this 'high flow' setting.

## Potential barriers to noac use
Reversibility of the anticoagulant effect. Although there are no specific antidotes yet for NOACs, nonspecific reversal strategies, such as administration of prothrombin complex or recombinant factor VII, may be applied.
A large advantage of NOACs in comparison with VKAs is that NOACs have a much shorter half-life. Thus, the duration of the effect is much shorter, thereby decreasing the need for an antidote. Clinical impact of major bleeds, as seen by, for instance, mortality, or the need for hospitalisation or intensive care unit stay, indeed appears to be less with the new oral anticoagulants than with VKAs, despite the fact that an antidote exists for the latter. [bib_ref] Management and outcomes of major bleeding during treatment with dabigatran or warfarin, Majeed [/bib_ref] Specific antidotes are currently under development, such as an antibody against dabigatran 56 and recombinant factor Xa. [bib_ref] A specific antidote for reversal of anticoagulation by direct and indirect inhibitors..., Lu [/bib_ref] Renal impairment. Severe chronic kidney disease, defined as an eGFR<30 ml/min or <15 ml/min depending on type of NOAC, is a contraindication to NOAC use. There are limited trial data for VKA and NOACs in frail elderly patients.
Costs. Although NOACs may still be more expensive than VKA, INR monitoring is also expensive. Logistics and available resources may vary between countries or by region and will determine specific cost-effect balances. Cost-effectiveness of AF-related stroke prevention strategies is being explored, and efforts are dedicated to determine the impact of NOACs on health economics. Available evidence suggests that NOACs are cost-effective alternatives to warfarin with regard to efficacy and safety, although the final balance will depend on individual healthcare settings. [bib_ref] Cost effectiveness of treatments for stroke prevention in atrial fibrillation: focus on..., Kasmeridis [/bib_ref] Comparisons between NOACs are emerging, but are based on indirect comparisons.
Treatment adherence. Because of the shorter half-life of NOACs compared with VKAs, compliance is very important. It is therefore vital for physicians to emphasise the need for daily treatment adherence.
An advantage of NOACs may lie in their fixed dose, compared with VKA doses that need to be adjusted based on INR measurements. However, this lack of need for monitoring drug levels reinforces the importance of stressing drug adherence with patients. It should not be underestimated that although the new agents are more convenient, they are still powerful anticoagulants. A dosage box with all medications to dispense may facilitate compliance (although not for dabigatran which requires original packaging). Rivaroxaban needs to be taken with food as taking it on an empty stomach may reduce therapeutic drug levels by up to 40%.
Real-life data. Observational studies comparing the actual impact of NOAC use in daily clinical care are now emerging; some show similar and comparable results on the efficacy and safety of NOAC use. From a primary care perspective, such observational studies will help show efficacy and safety of NOAC use in frail elderly patients not included in the large trials.
In summary, NOACs are at least as safe as VKA. Barriers for implementation still exist but these may improve with the growing body of trial data on safety and subgroup analyses. Moreover, generalisability may expand as a result of having more registries. In addition, growing confidence in reversal strategies should facilitate implementation.

## Practical recommendations
Based on current evidence and experiences, we recommend the following anticoagulation treatment strategy in a primary care setting:

## Management strategies that may be used
. ASA alone has no role in SPAF.
. In patients at all ages who are unable or unwilling to take VKAs or NOACs, ASA may be used in combination with clopidogrel as antiplatelet therapy to prevent stroke.
Additional work recommended in this area/gaps in the evidence . See web version.

## Practical considerations for atrial fibrillation stroke prevention in primary care
A large evidence base on the effectiveness of warfarin regimes, the limitations of antiplatelets, and the licensing of several new anticoagulants, has meant that traditional management strategies of SPAF have been challenged in recent years. The practicalities of screening, diagnosis, stroke risk assessment, treatment initiation, monitoring and, where appropriate, cessation of therapy will need to be determined at a local level according to the structure of the healthcare system and expertise of the team. The full web version of this paper provides a list of practical guidance on: Finding the patient with atrial fibrillation; Making the diagnosis of atrial fibrillation; Risk assessment; Preferable anticoagulant; NOAC use with impaired renal function; and initiating and monitoring treatment.

## Practical guidance on the use of noacs
The European Heart Rhythm Association (EHRA) has assembled an excellent practical guide on the use of NOACs, to help physicians use NOACs in specific clinical situations. [bib_ref] European Heart Rhythm Association Practical Guide on the use of new oral..., Heidbuchel [/bib_ref] The different clinical scenarios as outlined in the EHRA practical guide, which are useful for both physician and patients to learn how to use these new agents safely and effectively, are summarised in the web version. All recommendations given in this consensus document are summarised in the flow chart in [fig_ref] Figure 2: Flow chart of recommendations [/fig_ref] for easy reference.

# Conclusions
Atrial fibrillation is a common disorder, especially in those aged over 75, and is a major cause of preventable embolic stroke. Anticoagulation therapy, available for 50 years as vitamin K antagonist derivatives like warfarin, can reduce this risk by up to two-thirds, but its use has been complicated by major food and drug interactions, significant bleeding risks, a narrow therapeutic range and the need to monitor. As a consequence, in most countries, only around half of those eligible for anticoagulation are on treatment and many of those treated are poorly controlled. The evidence base for atrial fibrillation stroke risk is considerable and growing, resulting in recent major changes to clinical guidance internationally. This guidance has particular implications for primary care with many new recommendations on better AF diagnosis, more reliable methods of determining stroke risk to guide treatment choice for patients and bleeding risks to manage the risk factors better, and revised treatment options, with the exclusion of low-dose aspirin as an option for most patients, the importance of good therapeutic control if warfarin is used, and the availability of a range of new rapid-onset, short-acting, anticoagulants with few interactions and no monitoring requirements.

## Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The idea, rationale, and methods in generating the guidance originated with the EPCCS. All preparation, presentations, document drafting and printing was done by the EPCCS and its Secretariat. The EPCCS approached the sponsors. The sponsors had no input or role in producing or commenting on the guidance. A full list of competing interests is available in the web version.

# Funding
The costs of producing this document were met by the EPCCS which itself received an unrestricted educational grant from Bayer, Boehringer Ingelheim and Pfizer/BMS to support these costs. FDR Hobbs is supported by NIHR BRC and CLAHRC.
[fig] Figure 1: Percent of patients free from stroke over time, stratified by time spent in therapeutic range (INR 2.0-3.0). Adapted from Gallagher et al., Thromb and Haem 2011. 60 [/fig]
[fig] Figure 2: Flow chart of recommendations. Management of stroke prevention in atrial fibrillation as recommended in this document. Strength of recommendations is indicated by colour, with recommendations that should be used in green, and interventions that may be considered in blue. See text for explanation of HAS-BLED and CHA 2 DS 2 -VASc scores. AF: atrial fibrillation; OACs: oral anticoagulants; NOACs: novel oral anticoagulants; ASA: acetyl salicylic acid; VKA: vitamin K antagonists. [/fig]
[table] Table 2: Event rates per CHADS 2 and CHA 2 DS 2 -VASc category. Event rates (95% CI) of hospital admission and death caused by thromboembolism (including peripheral artery embolism, ischaemic stroke and pulmonary embolism) per 100 person years, for each CHADS 2 and CHA 2 DS 2 -VASc category. Risk profiles are largely similar with different lengths of follow-up. Adapted from Olesen et al., BMJ 2011 29 . [/table]
[table] Table 1: CHADS 2 and CHA 2 DS 2 -VASc risk score components. This table shows the components of the CHADS 2 (Gage et al., JAMA 2001) 28 and CHA 2 DS 2 -VASc scores (Lip et al., Chest 2010) [/table]
[table] Table 3: HAS-BLED risk score components (Camm et al., Eur Heart J 2010 1 and Pisters et al., Chest 2010 34 ) used to assess bleeding risk. [/table]
[table] Table 5: Nature of primary events with warfarin or aspirin in an elderly community population with atrial fibrillation. [/table]
[table] MONITORING TREATMENT: OPPORTUNISTIC CASE-FINDINGPulse Palpitation In all patients over 65 years old and anyone routinely receiving cardiovascular follow-up DIAGNOSIS 12-lead ECG : confirm or rule out AF Referral to cardiologist (if symptomatic AF/complications) RISK ASSESSMENT CHA 2 DS 2 -VASc score: assess stroke risk HAS-BLED score: identify modifiable risk factors to minimise bleeding risk ANTICOAGULATION THERAPY NOACs VKA  Counselling on risk and benefits of anticoagulation  Emphasise importance of treatment adherence CHA 2 DS 2 -VASc=0 [/table]