Article

Stroke Prevention in Atrial Fibrillation - The Unmet Need and Morbidity Burden

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare: ReprintsWarehouse@springernature.com.

For permissions and non-commercial reprint enquiries, please visit Copyright.com to start a request.

For author reprints, please email rob.barclay@radcliffe-group.com.

  • Views: 1555

  • Likes: 0

  • Downloads: 10

  • Citations: 1

Average (ratings)
No ratings
Your rating

Abstract

Atrial fibrillation (AF) occurs in epidemic proportion and is now recognised to occur in about 2 % of the general population. Its prevalence is age-related – about 10 % of 80-year-olds have this arrhythmia with hypertension, valvular disease and heart failure being the most frequent underlying conditions. Up to 10 % of cases of AF may be idiopathic, although genetic, autonomic, inflammatory, infective and toxic causes may account for many of these. AF is associated with serious consequences of which death, sudden death, stroke, heart failure, pulmonary disease and hospitalisation are the most serious. Thromboembolic stroke occurs in about 5 % of AF patients each year, which is approximately five-fold the stroke rate in age and gender-matched patients without AF. AF-related thromboembolic stroke accounts for 15–20 % of all strokes. Risk factors for thromboembolic stroke include clinical factors (such as age, female gender, diabetes, heart failure, hypertension, renal failure and arterial disease), elevated levels of biomarkers (such as troponin, B-type natriuretic peptide, C-reactive protein and micro-albuminuria) and echocardiographic features (such as left ventricular systolic dysfunction, increased left atrial size, left atrial ‘smoke’ and thrombus). There are several clinical risk stratification schemes used to identify AF patients at high risk of thromboembolic stroke. The CHADS2 scheme is popular, but tends to group a high proportion of patients in low and intermediate risk categories. The recently introduced CHA2DS2-VASc scheme identifies truly low-risk patients and avoids placing more than a small proportion in a low or intermediate risk category where there is a guideline mandated choice between anticoagulant, antiplatelet or no therapy. This scheme, which is well validated, has been recommended by the European Society of Cardiology in anticipation of the introduction of new and safer oral anticoagulants. Although warfarin is an effective therapy for the prevention of thromboembolic complications of AF it is inadequately used because of fear of haemorrhagic complications and the difficulties associated with monitoring and maintenance of the correct level of anticoagulation. At present, as few as 20 % of patients who should be anticoagulated are effectively treated. New anticoagulant therapies, which are much easier to use, coupled with more attention to the indications for anticoagulation, should result in more effective anticoagulation and a major reduction in the thromboembolic complications associated with AF.

Keywords

Atrial fibrillation, antiplatelets, oral anticoagulants, risk stratification, stroke, thromboprophylaxis,

Disclosure:A John Camm has advised and spoken on behalf of Bayer, Boehringer Ingelheim, Pfizer, BMS and Daiichi.

Received:

Accepted:

DOI:https://doi.org/10.15420/ecr.2011.7.3.187

Support:The publication of this article, including writing and editorial assistance from Touch Medical Communications, was supported by BMS and Pfizer. BMS and Pfizer have had no involvement in the content of this article beyond review for factual accuracy and the views expressed are not necessarily those of Pfizer or BMS. The author was fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of the manuscript.

Correspondence Details:A John Camm, British Heart Foundation Professor of Clinical Cardiology, St George's University of London, Cranmer Terrace, London, SW17 0RE, UK. E: jcamm@sgul.ac.uk

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Atrial fibrillation (AF), a major cause of morbidity and mortality in the Western world, is considered to be a rising epidemic.1–3 In the US alone, approximately 2.7 million people are affected by AF4 and this figure is projected to increase to an estimated 16 million by 2050.5 The rising prevalence of AF is mainly attributable to the ageing population6 and survival from other cardiovascular disease. AF predominantly affects individuals over 80 years of age.4,7,8

AF is a strong independent risk factor for stroke and accounts for one in five strokes.9 Furthermore, stroke in AF has twice the mortality rate compared to other strokes,1 is a cause of severe disability compared to other strokes,10 more frequent hospital stays3 and is a major socioeconomic burden.11 Anticoagulation therapy with warfarin is recommended by evidence-based guidelines for stroke prevention in patients with AF and is widely regarded as the standard of care.12 However, warfarin therapy has severe limitations that make it difficult and inconvenient to use in clinical practice.13 Consequently, up to 50 % of AF patients at moderate to high risk of stroke do not receive appropriate anticoagulant treatment.14–19 Thus, there is an urgent need for improved antithrombotic therapy in AF management. This article aims to review the clinical consequences of stroke in AF and the recent improvements in risk stratification.12

Clinical Consequences of Atrial Fibrillation
Cardiovascular

AF is associated with palpitations, impaired exercise tolerance and symptoms from cardiac failure. Clinical deterioration may follow when AF complicates pre-existing cardiac disorders. In terms of cardiovascular events, women with a single electrocardiograph (ECG) recording showing AF have a five-fold increase in risk. The risk is increased two-fold in men with a single ECG of AF.2 Ten to 40 % of all elderly patients are asymptomatic.20 Additionally, in patients with either AF or congestive heart failure (HF) alone, development of the second condition as a concomitant disease carries a particularly poor prognosis. For example, in patients with AF, the subsequent development of congestive HF is associated with increased mortality (men: hazard ratio [HR] 2.7; 95 % confidence interval [CI], 1.9–3.7; women: HR 3.1; 95 % CI, 2.2–4.2).21

Stroke

Stroke and thromboembolic disease are considered the most important complications of AF and their occurrence is increased in both paroxysmal and chronic AF.22 In an analysis of the Framingham study, the impact of cardiovascular disease in 5,070 participants after 34 years of follow-up found that patients with AF had a nearly five-fold increased risk of stroke compared with age-matched individuals with normal sinus rhythm.23 Indeed, AF is thought to cause as many as one in five of the 700,000 strokes that occur each year in the US;24 in individuals over the age of 80, AF is linked to nearly one in every three strokes.6

A retrospective study examined whether AF was an independent prognostic factor in 3,849 patients with ischaemic stroke.25 The study found that AF was associated with a poor prognosis in patients with ischaemic stroke, including longer periods of hospitalisation (median 15 versus nine days), an increased risk of in-hospital medical complications (adjusted relative risk = 1.48, 95 % CI, 1.23–1.79) and recurrent stroke (adjusted HR = 1.30, 95 % CI: 0.93–1.82) when compared with patients without AF.

A retrospective study of 1,061 patients with acute ischaemic stroke demonstrated that patients with AF had an increased stroke severity that was independent of advanced age and other stroke risk factors.26 The degree of disability from acute ischaemic stroke was significantly different in patients with AF versus those without AF in the 65–74 and 75–84 age groups.26 Patients with AF are also more likely to have both cerebral lesions and diminished functional status compared with patients without AF.26,27

Mortality

The mortality rate of patients with AF is double that of patients in sinus rhythm and linked to the severity of underlying heart disease.1,28,29 In the Studies of left ventricular dysfunction (SOLVD), mortality was 34 % for those with AF compared with 23 % for patients in sinus rhythm (p<0.001). This difference was attributed to an increased risk of death due to HF rather than to thromboembolism.30 Indeed, AF has been found to be an independent risk factor for HF2 and is associated with poor outcomes in patients with chronic HF.31

Population-based data indicate that subjects with AF have markedly reduced survival compared with subjects without AF, with risk factor-adjusted odds ratios (OR) for death of 1.5 and 1.9 in men and women, respectively.1 The current treatments used for AF present additional challenges, which may further increase morbidity and mortality, including the potential to cause fatal proarrhythmia by the inappropriate use of antiarrhythmic drugs.28,32

Quality of Life

AF is associated with reduced quality of life (QoL).28 In the symptomatic patient, the spectrum of symptoms associated with AF range from palpitations and light-headedness to exacerbation of HF and chest pain, all of which negatively affect QoL.28,33 Furthermore, in patients with paroxysmal AF (PAF), QoL, as measured by a generic scale Medical Outcomes Study Short Form 36 (SF-36) has been found to be comparable to that of post-myocardial infarction patients and when compared with healthy subjects (n=47) patients with PAF (n=152) had significantly lower health-related QoL scores (p<0.001).34 Although impact on QoL can be mostly attributed to physical symptoms of AF, QoL is also influenced by patient factors.35 Even patients with an apparently clinically silent, asymptomatic AF do not have a typical QoL. Moreover, some patients initially deny that they have any symptoms but when the arrhythmia is ultimately treated, subsequently admit that their QoL was severely restricted. Others appear genuinely asymptomatic, with typical activity scores, although their QoL is evidently low.36 Consequently, relief of symptoms and improving QoL are often primary goals of therapeutic management of rhythm control interventions.33

A recent study has shown that control of symptomatic PAF patients has a positive beneficial impact on QoL.37 However, there is no gold standard for measuring QoL in AF patients and most questionnaires are cumbersome and time-consuming to complete. To address these limitations, a patient-guided AF-specific QoL questionnaire (Atrial Fibrillation Effect on Quality-of-life [AFEQT]) was recently developed and validated in a large prospective observational study. The 20-item self-administered AFEQT questionnaire assesses the impact of AF on patients QoL and evaluates patients’ perceptions of their symptoms, functional impairment, treatment concerns and satisfaction with treatment.

Thus, this tool may serve as an important QoL outcome measure in different clinical settings including clinical research, survey studies, or clinical practice.38 A simple, objective bedside measurement, such as the Canadian Cardiovascular Society Severity in AF scale or disease-specific AF QoL measure, may also be useful in determining the impact of symptoms on QoL.37,39,40

Economic and Healthcare System Costs of Atrial Fibrillation

AF represents a costly threat to the financial stability of healthcare systems. A prevalence-based analysis of the economic burden of AF in the UK estimated the direct cost of AF to be 0.62 % (￡244 million) of the total National Health Service (NHS) expenditure in 1995 and this was projected to account for 0.97  % (￡459 million) of the NHSbudget in 2000 − reflecting a predicted doubling in only a five-year time span.3 Yet, this study indicated that these costs were probably an underestimate. Factoring in the costs of stroke care and length of stay when AF complicates another illness would further increase the expenditure.

In the US, the total annual cost (2005 US dollars) for the treatment of AF was estimated at US$6.65 billion, including US$2.93 billion for hospitalisations.41 In the Cost of Care in AF (COCAF) survey of 671 AF patients from across France, the annual cost per patient was estimated at €3,209.42 Furthermore, the Euro Heart Survey on AF (2003−2004) reported that the total annual cost of AF amounted to €272 million in Greece, €3,286 million in Italy, €526 million in Poland, €1,545 million in Spain and €554 million in the Netherlands.43

The number of hospitalisations due to AF is also increasing.44,45 In the UK alone, AF accounts for 3 to 6 % of acute hospital admissions.46,47 The Euro Heart Survey on AF suggested that inpatient care and interventional procedures account for more than 70 % of total annual costs for AF in five European countries.43 A national costing report on AF by the National Institute for Health and Clinical Excellence (NICE) in 2006 estimated the unit cost of anticoagulation services to be an average of ￡565.8 per year per person and the annual cost per case of stroke was estimated to be ￡7,800. This report estimated the annual cost saving through stroke reduction to be ￡54.33 million, producing a net resource impact of ￡21.86 million.48 However, this may be an underestimation because it does not include the associated comorbidities that would require proactive management in AF.

Risk Stratification for Stroke

Risk stratification for stroke is critical in the management of patients with AF to ensure that patients receive appropriate anticoagulant therapy.12

Risk Stratification Schemes

The risk factors for stroke included in current stroke risk stratification schemes are mainly derived from analyses of clinical trials cohorts.21,49–51

The Framingham Stroke Risk Profile was one of the first risk stratification schemes for stroke to be developed. This scheme is gender-specific and includes AF, age, use of antihypertensive therapy, prior cardiovascular disease, cigarette smoking, diabetes mellitus, left ventricular hypertrophy by electrocardiogram and systolic blood pressure.51 Currently, the CHADS2 (one point each for congestive heart failure, hypertension, age ≥75 years and diabetes, and two points for a previous history of stroke, thromboembolism or transient ischemic attack) scheme is the most frequently used stroke risk stratification scheme (see Table 1).52,53 Risk factors included in the CHADS2 scheme were selected from those that independently predicted the risk of stroke in AF during clinical trials.52 However, many risk stratification models have been found to only have a modest predictive value in identifying patients with high thromboembolic risk.54,55 In fact, a large proportion of patients are classified into the moderate/intermediate-risk category, causing uncertainty amongst clinicians as to the appropriate treatment strategy.56,57

Recently, additional risk factors such as female sex, age 65−74 years and vascular disease have been demonstrated to influence the risk of stroke and thromboembolism in AF patients. Consequently, the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke, thromboembolism or transient ischaemic attack, vascular disease, age 65–74 years, female sex category; age ≥75 years and previous stroke, thromboembolism or transient ischemic attack carry doubled risk weight) scheme was developed to complement the CHADS2 scoring systems (see Table 1).50

The performance of the CHADS2 scheme was compared to the CHA2DS2- VASc risk scheme by applying both scoring systems to a large nationwide registry of patients admitted to hospital with AF in Denmark.58 Although the c-statistics – a measure of the predictive value of a risk scoring scheme – were similar when the two risk schemes were tested as continuous point scales, CHA2DS2-VASc had unusually high c-statistics when applied using the traditional categories of low- (CHADS2 score of 0), intermediate- (CHADS2 score of 1–2) and high-risk groups (CHADS2 score of ≥3), which suggests that the new scheme provides improvements in predicting stroke risk over the CHADS2 scheme. The annual rate of thromboembolism including peripheral artery embolism, ischaemic stroke and pulmonary embolism in the CHA2DS2-VASc low risk group was 0.78 per 100 person years, compared with 1.67 per 100 person years in the CHADS2 low risk group.

Only 8.7 % of the study population met the low risk CHA2DS2-VASc criteria, compared with 22.3 % when using the CHADS2 criteria (see Figure 1).58 This finding is similar to other assessments, including a UK study in which only 8.6 % of patients with AF in general practice were considered low risk by CHA2DS2-VASc.59 In the Danish study, the CHA2DS2-VASc scheme performed better than CHADS2 in predicting patients at high risk; 80 % of the patients were considered high risk using CHA2DS2-VASc, however fewer than half would have met high-risk criteria if CHADS2 were used.58 The study also found that the rate for patients in the intermediate risk group was 4.75 with CHADS2 compared with 2.01 with CHA2DS2-VASc. Thus, the newer stratification methods such as CHA2DS2-VASc appear to offer improved risk stratification, reduce the number of people classified into the intermediate-risk group, which is the category that can cause ambiguity regarding whether to treat with warfarin or aspirin.50,55 Moreover, a recent study assessed the risk of stroke according to specific risk stratification schemes, in a cohort of 662 elderly AF patients treated with warfarin.

The results indicated that the CHADS2 and CHA2DS2-VASc schemes had the best c-statistics (0.717 and 0.724, respectively) for predicting the residual thromboembolic risk despite warfarin treatment and that other risk schemes had some limitations in this setting.55

Other Risk Factors, Risk Modifiers and the Role of Biomarkers

In addition to the risk factors included in current risk stratification schemes, several other risk factors have been recognised. These include a family history of stroke,60 the presence of chronic kidney disease, atrial high-rate episodes (AHRE) and atrial tachyarrhythmia (AT)/AF burden.61–65

Chronic kidney disease is a major cardiovascular risk factor, which is particularly common among elderly people.61 However, whether it does in fact independently raise the risk for ischaemic stroke is poorly understood. Among 13,535 adults with AF, chronic kidney disease raised the risk of thromboembolism in AF independently of other known risk factors.61 The presence of proteinuria has also been shown to reflect an increased thromboembolic risk in patients with normal or moderately impaired renal function.61

The duration of AF was previously not considered as a risk factor for stroke in AF patients due to the ambiguity of clinical symptoms.65 However, the diagnostic features of atrial-based pacemakers are now sufficiently advanced to supply information on the presence and duration of atrial arrhythmias.65 Three key studies have assessed the consequences related to these arrhythmias. In a study to evaluate the relationship between daily AT burden from implantable device diagnostics and stroke risk (The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk [TRENDS]), the overall rate of ischaemic events was low in this cohort of more than 2,400 patients (1.3 % per year). Patients with atrial rate >175 bpm, lasting >20 seconds, for <5.5 hours on a single day during a 30-day period experienced a clinical thromboembolism rate of 1.1 % per year, while the event rate among those with a high AT/AF burden was 2.4 % per year. After statistical adjustment for stroke risk factors and antithrombotic therapy, a high AT/AF burden <5.5 hours per day over 30 days was associated with a risk of thromboembolism similar to that of patients entirely free of AT/AF, while the risk doubled among patients with AT/AF during >5.5 hours per day. However, compared with zero burden, the difference in HR for the groups with low and high AT/AF burdens was not statistically significant.65

In preliminary results presented at the American Heart Association Scientific Sessions 2010 of the Asymptomatic atrial fibrillation and stroke evaluation in pacemaker patients and the atrial fibrillation reduction atrial pacing trial (ASSERT), episodes of device-detected atrial tachycardia greater than six minutes were found in 261 of 2,580 pacemaker patients, with hypertension but no history of AF over almost three years of follow-up. These arrhythmias were associated with a 2.5-fold increase in risk of ischaemic stroke and systemic embolism. Among the patients with a CHADS2 score of ≥2, device-detected ATs increased the absolute risk of stroke to 2.1 % per year. Among pacemaker patients without any prior history of atrial arrhythmias, 35 % of all strokes and systemic emboli were preceded by device-detected ATs.63,64

A study contributing further information comparing the duration of AF with the risk of stroke found that in patients without atrial arrhythmias, the risk of stroke was 1.2 % per year. If at least five minutes of atrial arrhythmias were detected, the event rate remained low at 1.7 % per year. If 24 hours or more of atrial arrhythmias were detected, the event rate was 4 % per year. However, by adding the patient’s CHADS2 score to the duration of atrial arrhythmia, groups at low risk (0.8 % per year) and at high risk (5 % per year) for thromboembolic events could be better identified.62 This is still an uncertain area, however there are several ongoing registries and trials that will report in the next several years and lead to a clarification.

Echocardiography is valuable to define the origin of AF and may add useful information in predicting the risk of stroke. Among high-risk patients, impaired left ventricular systolic function on transthoracic echocardiography, thrombus, dense spontaneous echo contrast or reduced velocity of blood flow in the left atrium appendage and complex atheromatous plaque in the thoracic aorta on transoesophageal echocardiography have been associated with increased thromboembolic risk.28

There has been increased interest in the role of biomarkers for improving stroke risk prediction models. C-reactive protein, D-dimer, fibrinogen, gamma glutamyl transferase, plasminogen-activator inhibitor type 1 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are some examples.66–71 Sub-study analyses of the 18,113- patient Randomisation evaluation of long-term anticoagulation therapy (RE-LY) trial,72 involving the new oral anticoagulant (OAC) dabigatran assessed the prognostic value of the biomarkers D-dimer and NT-proBNP for predicting cardiovascular events in patients with non-valvular AF.70,71

D-dimer concentration at initiation of treatment with warfarin or dabigatran was strongly associated with the risk of stroke, mortality and bleeding independently of CHADS2 risk factors and baseline anticoagulant treatment.70 In AF patients with risk factors for stroke, the NT-proBNP level was significantly raised compared with healthy subjects of similar age. A raised NT-proBNP level was associated with an elevated risk of stroke, major haemorrhage and death even after adjustment for the CHADS2 risk factors and study drug.71

The assessment of the contribution to improved risk prediction by considering of new risk factors and biomarkers has stimulated examination of optimal statistical techniques for these evaluations.73 However, the added value of these markers to current risk stratification schemes is yet to be determined.

Challenges and Unmet Needs in Antithrombotic Therapy for Stroke Prevention

Warfarin has long been established as the standard of care for prevention of stroke and thromboembolism in patients with AF. Several studies have evaluated the efficacy of antiplatelet therapy for the prevention of stroke in AF.74,75 In a meta-analysis of antithrombotic therapy to prevent stroke in patients with AF, antiplatelet therapy (eight trials, totalling 4,876 participants) reduced stroke by 22 % (CI, 6 to 35 %) compared to control. In contrast, adjusted-dose warfarin (six trials, totalling 2,900 participants) reduced stroke by 64 % (95 % CI, 49 to 74 %).74 Thus, the low efficacy of aspirin compared with warfarin is a severe limitation.

However, effective warfarin therapy depends on inter- and intra-individual variability in maintaining the international normalised ratio (INR), which is driven by a number of genetic and environmental factors.76,105–111 For effective thromboprophylaxis with warfarin, the target intensity of anticoagulation involves a balance between stroke prevention and avoidance of haemorrhage, particularly intracranial haemorrhage (see Figure 2).28,77–80 Maintaining the narrow therapeutic range of warfarin requires close and frequent monitoring of the patient’s INR, highlighting the benefit of monitoring in a designated anticoagulation clinic setting rather than community practice, although self-management can be effective in anticoagulation therapy.79,81

The greater the proportion of time spent in the therapeutic range of warfarin the more effective the anticoagulation. By contrast, increased time spent outside the therapeutic range is associated with an increased risk of mortality, ischaemic stroke or other thromboembolic event, myocardial infarction and major bleeding.10,74,82–89 Due to the risk of major bleeding, particularly intracranial haemorrhage, warfarin may not be recommended in patients at significant risk of bleeding.12,28 The risk of major bleeding is greater in elderly patients ≥80 years of age,90 who make up a large proportion of patients with AF.4,7

In antithrombotic therapy for stroke prevention in AF, the beneficial effect of antiplatelet therapy on ischaemic stroke appears to decrease with age compared with treatment with warfarin.12 In a meta-analysis, aspirin was associated with a lower rate of intracranial haemorrhage included in major bleeding event rates91 and extracranial haemorrhage compared with warfarin.74 These findings were not supported in a study comparing warfarin and aspirin treatment in an elderly population (mean age = 81.5 years), which observed similar rates of major bleeding, including intra- or extracranial haemorrhage, in the two treatment groups.92 Indeed, increasing age has a deleterious effect on the efficacy of aspirin, with little or no reduction in the risk of stroke in patients aged >75 years.93

The consequences of inadequate thromboprophylaxis were highlighted in a study examining the effect of pre-admission antithrombotic therapy on stroke severity in 1,938 patients with acute brain ischemia; 329 out of the 1,938 patients included had AF (17 %).94 Fewer severe strokes were seen in patients treated with warfarin to INR ≥2.0 (38 %) (p=0.01) compared to patients treated with warfarin to INR <2.0 (59 %), patients treated with antiplatelet therapy (55 %) or patients receiving no treatment (70 %). Moreover, adequate adjusted-dose warfarin therapy was associated with better rates of survival (p=0.004).94

Despite the demonstrated efficacy of warfarin for stroke prevention in AF, the perceived limitations of current therapeutic options have resulted in substantial underuse of antithrombotic therapy (see Table 2).95–98,107 This underuse has also been shown to result in increased risk for the combined endpoint of cardiovascular death, thromboembolism, or major bleeding.98 Underuse of vitamin K agonists (VKAs) may be due to a number of physician and patient related factors (see Table 3).14,17,18,99–101

Current Guidelines on Stroke Prevention

Risk factors can be incorporated either formally in a scoring system as has been suggested by the European Society of Cardiology (ESC) or in an informal fashion as recommended in the 2006 American College of Cardiology Foundation/American Heart Association/ESC guidelines.12,28,78 The current ESC guidelines have been framed with an emphasis on a risk factor-based approach and less emphasis on the use of the artificial low-/moderate-/high-risk strata due to the latter’s poor predictive value. The concept of stroke risk as a continuum has been adopted within the latest ESC guidelines, thus emphasising the cumulative effect of various risk factors.12

In relation to stroke prevention, the ESC recommendations for assessing antithrombotic therapy requirements utilise this risk factor-based approach. The CHADS2 scoring system is recommended for an initial rapid assessment of risk in non-valvular AF. For a more comprehensive assessment of risk, the CHA2DS2- VASc scheme, which considers ‘major’ and ‘clinically relevant non-major’ stroke risk factors, should be used.12 The antithrombotic strategy should be based on CHADS2/CHA2DS2-VASc scores (see Figure 3 and Table 4).12

The ESC guidelines also suggest the use of a new scoring system to evaluate the risk of bleeding, HAS-BLED (uncontrolled hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly e.g. >65 years, drugs/alcohol concomitantly) (see Table 5).12 Each factor scores one point, with a maximum score of nine. A score of three or more suggests high risk for bleeding. The predictive accuracy for one-year bleeding risk was consistent in different subgroups. This score is simple and provides a potentially practical tool in clinical decision-making.102 A regular review of those patients with a HAS-BLED score ≥3 upon initiation of antithrombotic therapy is highly recommended.12

Discussion

Clinicians should consider whether risk stratification to identify patients at risk of stroke will be the best approach in the future. It may be more appropriate, as recommended in the ESC guidelines, to consider which patients should not be anticoagulated and to assume that all AF patients should receive treatment unless they are younger than 65 years with no heart disease. Certainly, if the CHA2DS2-VASc criteria were adopted, most people with AF would be offered anticoagulation.

It is not certain whether all women with AF should be deemed to be at least at intermediate risk and therefore be considered for anticoagulation. Gender has an inconsistent association with stroke, some observational studies have found higher rates of AF related stroke in women,103 while others have not. Although female gender may not prove powerful enough in itself to justify anticoagulation, when added to other risk factors such as hypertension or age 65 to 74 it raises the thromboembolic risk and substantially strengthens the case for anticoagulation.

CHA2DS2-VASc is certainly better than CHADS2 at identifying those individuals who are at very low risk. This is clinically important, particularly since many individuals with a CHADS2 score of zero or one are, in fact, at relatively high risk of thromboembolism (consider for example, a patient with widespread vascular disease aged 65 to 74 years).

Although the risk factors for stroke in AF are well recognised and there have been strong treatment recommendations for some time, neither physicians nor patients appear able to accept the guidance. This may be attributable to the problems associated with warfarin and has resulted in many patients at the highest risk for stroke, the elderly, not receiving anticoagulation therapy.

The decision-making of clinicians must consider the strong evidence base for antithrombotic prophylaxis, whilst at the same time considering the individual patient, comorbidities, patient values and preferences.

The development of new treatments for stroke prevention in AF might potentially address unmet needs in current therapeutic options and could persuade clinicians to lower the threshold at which they prescribe anticoagulants. Indeed, new OACs probably have demonstrated better safety profiles and may improve the ease of use compared with VKAs.104 Furthermore, OACs have also shown to have less drug and food interactions, and less haemorrhagic complications, particularly intracranial bleeding.104

The recent or imminent introduction into clinical practice of dabigatran, an example of a new OAC, has resulted in a shift of the guidelines towards identifying more patients at potential risk for stroke of less than 2 % per year, compared to the 3 % per year risk that was necessary with older anticoagulants. New OACs could affect the general status of anticoagulation and how clinicians decide who should be anticoagulated.

In this developing situation, where new therapeutic options for antithrombotic prophylaxis are being tested and validated as tools for prevention of stroke, the future challenge for physicians will be to make appropriate and timely clinical decisions based on the increasingly strong evidence base, after assessment of the individual patient’s clinical profile.

References

  1. Benjamin EJ, Wolf PA, D'Agostino RB, et al., Impact of atrial fibrillation on the risk of death: the Framingham Heart Study, Circulation, 1998;98:946–52.
    Crossref | PubMed
  2. Stewart S, Hart CL, Hole DJ, et al., 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
  3. Stewart S, Murphy NF, Walker A, et al., Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK, Heart, 2004;90:286–92.
    Crossref | PubMed
  4. 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 study, JAMA, 2001;285:2370–5.
    Crossref | PubMed
  5. 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;114:9–25.
    Crossref | PubMed
  6. Wolf PA, Abbott RD, Kannel WB, Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study, Arch Intern Med, 1987;147:1561–4.
    Crossref | PubMed
  7. 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
  8. Murphy NF, Simpson CR, Jhund PS, et al., A national survey of the prevalence, incidence, primary care burden and treatment of atrial fibrillation in Scotland, Heart, 2007;93:606–12.
    Crossref | PubMed
  9. Marini C, De Santis F, Sacco S, et al., Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study, Stroke, 2005;36:1115–9.
    Crossref | PubMed
  10. 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
  11. Levi M, Hobbs FD, Jacobson AK, et al., Improving antithrombotic management in patients with atrial fibrillation: current status and perspectives, Semin Thromb Hemost, 2009;35:527–42.
    Crossref | PubMed
  12. Camm AJ, Kirchhof P, Lip GY, 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), Eur Heart J, 2010;31:2369–429.
    Crossref | PubMed
  13. Hirsh J, Dalen JE, Deykin D, et al., Oral anticoagulants. Mechanism of action, clinical effectiveness, and optimal therapeutic range, Chest, 1995;108:231S–46S.
    Crossref | PubMed
  14. Bungard TJ, Ghali WA, Teo KK, et al., Why do patients with atrial fibrillation not receive warfarin?, Arch Intern Med, 2000;160:41–6.
    Crossref | PubMed
  15. Connolly SJ, Eikelboom J, O'Donnell M, et al., Challenges of establishing new antithrombotic therapies in atrial fibrillation, Circulation, 2007;116:449–55.
    Crossref | PubMed
  16. Waldo AL, Becker RC, Tapson VF, et al., Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation, J Am Coll Cardiol, 2005;46:1729–36.
    Crossref | PubMed
  17. Hylek EM, D'Antonio J, Evans-Molina C, et al., Translating the results of randomized trials into clinical practice: the challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation, Stroke, 2006;37:1075–80.
    Crossref | PubMed
  18. Nieuwlaat R, Capucci A, Lip GY, et al., Antithrombotic treatment in real-life atrial fibrillation patients: a report from the Euro Heart Survey on Atrial Fibrillation, Eur Heart J, 2006;27:3018–26.
    Crossref | PubMed
  19. Go AS, Hylek EM, Borowsky LH, et al., Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study, Ann Intern Med, 1999;131:927–34.
    Crossref | PubMed
  20. Rho RW, Page RL, Asymptomatic atrial fibrillation, Prog Cardiovasc Dis, 2005;48:79–87.
    Crossref | PubMed
  21. Wang TJ, Larson MG, Levy D, et al., Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study, Circulation, 2003;107:2920–5.
    Crossref | PubMed
  22. Narayan SM, Cain ME, Smith JM, Atrial fibrillation, Lancet, 1997;350:943–50.
    Crossref | PubMed
  23. 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
  24. Caro JJ, An economic model of stroke in atrial fibrillation: the cost of suboptimal oral anticoagulation, Am J Manag Care, 2004;10:S451–58; discussion S8–61.
    PubMed
  25. Thygesen SK, Frost L, Eagle KA, et al., Atrial fibrillation in patients with ischemic stroke: A population-based study, Clin Epidemiol, 2009;1:55–65.
    Crossref | PubMed
  26. Dulli DA, Stanko H, Levine RL, Atrial fibrillation is associated with severe acute ischemic stroke, Neuroepidemiology, 2003;22:118–23.
    Crossref | PubMed
  27. Karatas M, Dilek A, Erkan H, et al., Functional outcome in stroke patients with atrial fibrillation, Arch Phys Med Rehabil, 2000;81:1025–9.
    Crossref | PubMed
  28. Fuster V, Ryden LE, Cannom DS, et al., 2011 ACCF/AHA/HRS Focused Updates Incorporated Into the ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society, J Am Coll Cardiol, 2011;57:e101–98.
    Crossref | PubMed
  29. Krahn AD, Manfreda J, Tate RB, et al., The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study, Am J Med, 1995;98:476–84.
    Crossref | PubMed
  30. Dries DL, Exner DV, Gersh BJ, et al., Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction, J Am Coll Cardiol, 1998;32:695–703.
    Crossref | PubMed
  31. Maggioni AP, Latini R, Carson PE, et al., Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT), Am Heart J, 2005;149:548–57.
    Crossref | PubMed
  32. Hersi A, Wyse DG, Management of atrial fibrillation, Curr Probl Cardiol, 2005;30:175–233.
    Crossref | PubMed
  33. Reynolds MR, Lavelle T, Essebag V, et al., Influence of age, sex, and atrial fibrillation recurrence on quality of life outcomes in a population of patients with new-onset atrial fibrillation: the Fibrillation Registry Assessing Costs, Therapies, Adverse events and Lifestyle (FRACTAL) study, Am Heart J, 2006;152:1097–103.
    Crossref | PubMed
  34. Dorian P, Jung W, Newman D, et al., The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy, J Am Coll Cardiol, 2000;36:1303–9.
    Crossref | PubMed
  35. Paquette M, Roy D, Talajic M, et al., Role of gender and personality on quality-of-life impairment in intermittent atrial fibrillation, Am J Cardiol, 2000;86:764–8.
    Crossref | PubMed
  36. Savelieva I, Paquette M, Dorian P, et al., Quality of life in patients with silent atrial fibrillation, Heart, 2001;85:216–7.
    Crossref | PubMed
  37. Guedon-Moreau L, Capucci A, Denjoy I, et al., Impact of the control of symptomatic paroxysmal atrial fibrillation on health-related quality of life, Europace, 2010;12:634–42.
    Crossref | PubMed
  38. Spertus J, Dorian P, Bubien R, et al., Development and validation of the Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) Questionnaire in patients with atrial fibrillation, Circ Arrhythm Electrophysiol, 2011;4:15–25.
    Crossref | PubMed
  39. Dorian P, Guerra PG, Kerr CR, et al., Validation of a new simple scale to measure symptoms in atrial fibrillation: the Canadian Cardiovascular Society Severity in Atrial Fibrillation scale, Circ Arrhythm Electrophysiol, 2009;2:218–24.
    Crossref | PubMed
  40. Harden M, Nystrom B, Kulich K, et al., Validity and reliability of a new, short symptom rating scale in patients with persistent atrial fibrillation, Health Qual Life Outcomes, 2009;7:65.
    Crossref | PubMed
  41. Coyne KS, Paramore C, Grandy S, et al., Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States, Value Health, 2006;9:348–56.
    Crossref | PubMed
  42. Le Heuzey JY, Paziaud O, Piot O, et al., Cost of care distribution in atrial fibrillation patients: the COCAF study, Am Heart J, 2004;147:121–6.
    Crossref | PubMed
  43. Ringborg A, Nieuwlaat R, Lindgren P, et al., Costs of atrial fibrillation in five European countries: results from the Euro Heart Survey on atrial fibrillation, Europace, 2008;10:403–11.
    Crossref | PubMed
  44. Friberg J, Buch P, Scharling H, et al., Rising rates of hospital admissions for atrial fibrillation, Epidemiology, 2003;14:666–72.
    Crossref | PubMed
  45. Wattigney WA, Mensah GA, Croft JB, Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention, Circulation, 2003;108:711–6.
    Crossref | PubMed
  46. Lip GY, Tean KN, Dunn FG, Treatment of atrial fibrillation in a district general hospital, Br Heart J, 1994;71:92–5.
    Crossref | PubMed
  47. Zarifis J, Beevers G, Lip GY, Acute admissions with atrial fibrillation in a British multiracial hospital population, Br J Clin Pract, 1997;51:91–6.
    PubMed
  48. NICE, National cost impact report to accompany Atrial fibrillation: the management of atrial fibrillation, Clinical guideline 36, 2006;1–39.
  49. Hughes M, Lip GY, 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
  50. 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
  51. Wolf PA, D'Agostino RB, Belanger AJ, et al., Probability of stroke: a risk profile from the Framingham Study, Stroke, 1991;22:312–8.
    Crossref | PubMed
  52. 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
  53. Gaita F, Blandino A, Atrial fibrillation. Left atrial fibrosis--a promising stroke risk factor?, Nat Rev Cardiol, 2011;8:307–8.
    Crossref | PubMed
  54. Fang MC, Go AS, Chang Y, et al., 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. Poli D, Lip GY, Antonucci E, et al., Stroke risk stratification in a "real-world" elderly anticoagulated atrial fibrillation population, J Cardiovasc Electrophysiol, 2011;22:25–30.
    Crossref | PubMed
  56. 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
  57. Velu S, Lip GY, What is the role of the cardiologist in future management of stroke prevention in atrial fibrillation?, Adv Ther, 2010;28:1–12.
    Crossref | PubMed
  58. Olesen JB, Lip GY, Hansen ML, et al., Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study, BMJ, 2011;342:d124.
    Crossref | PubMed
  59. Van Staa TP, Setakis E, Di Tanna GL, et al., A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice, J Thromb Haemost, 2011;9:39–48.
    Crossref | PubMed
  60. Morrison AC, Bare LA, Chambless LE, et al., Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study, Am J Epidemiol, 2007;166:28–35.
    Crossref | PubMed
  61. Go AS, Fang MC, Udaltsova N, et al., Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study, Circulation, 2009;119:1363–9.
    Crossref | PubMed
  62. Botto GL, Padeletti L, Santini M, et al., Presence and duration of atrial fibrillation detected by continuous monitoring: crucial implications for the risk of thromboembolic events, J Cardiovasc Electrophysiol, 2009;20:241–8.
    Crossref | PubMed
  63. Healey JS, ASymptomatic atrial fibrillation and Stroke Evaluation in pacemaker patients and the atrial fibrillation Reduction atrial pacing Trial (ASSERT). Presentation slides, American Heart Association Scientific Sessions. Available at: http://my.americanheart.org/idc/groups/ahamahpublic/@wcm/@sop/@scon/docu... (accessed 29 July 2011).
  64. Healey JS, 2010 Clinical Trial/Clinical Science Abstracts, Circulation, 2010;122:2215–26.
    Crossref
  65. Glotzer TV, Daoud EG, Wyse DG, et al., The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk: the TRENDS study, Circ Arrhythm Electrophysiol, 2009;2:474–80.
    Crossref | PubMed
  66. Di Napoli M, Papa F, Bocola V, C-reactive protein in ischemic stroke: an independent prognostic factor, Stroke, 2001;32:917–24.
    Crossref | PubMed
  67. Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, et al., Fibrinogen as a risk factor for stroke and myocardial infarction, N Engl J Med, 1984;311:501–5.
    Crossref | PubMed
  68. Bots ML, Salonen JT, Elwood PC, et al., Gammaglutamyltransferase and risk of stroke: the EUROSTROKE project, J Epidemiol Community Health, 2002;56 (Suppl. 1):i25–9.
    Crossref | PubMed
  69. Lindgren A, Lindoff C, Norrving B, et al., Tissue plasminogen activator and plasminogen activator inhibitor-1 in stroke patients, Stroke, 1996;27:1066–71.
    Crossref | PubMed
  70. Eikelboom J, Hijazi Z, Oldgren J, et al., Abstract 18321: Ddimer is Prognostic for Stroke, Major Bleeding and Death During Anticoagulation of Atrial Fibrillation - a RELY Substudy, Circulation, 2010;122:A18321.
  71. Hijazi Z, Oldgren J, Andersson U, et al., Abstract 13472: NTproBNP is Prognostic for Stroke and Death in Atrial Fibrillation - a RELY Substudy, Circulation, 2010;122:A13472.
  72. Ezekowitz MD, Connolly S, Parekh A, et al., Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran, Am Heart J, 2009;157:805–10.e2.
    Crossref | PubMed
  73. Pencina MJ, D'Agostino RB, Sr., D'Agostino RB, Jr., et al., Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond, Stat Med, 2008;27:157–72; discussion 207–12.
    Crossref | PubMed
  74. Hart RG, Pearce LA, Aguilar MI, Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation, Ann Intern Med, 2007;146:857–67.
    Crossref | PubMed
  75. Connolly SJ, Pogue J, Hart RG, et al., Effect of clopidogrel added to aspirin in patients with atrial fibrillation, N Engl J Med, 2009;360:2066–78.
    Crossref | PubMed
  76. Merli GJ, Tzanis G, Warfarin: what are the clinical implications of an out-of-range-therapeutic international normalized ratio?, J Thromb Thrombolysis, 2009;27:293–9.
    Crossref | PubMed
  77. Ezekowitz MD, Falk RH, The increasing need for anticoagulant therapy to prevent stroke in patients with atrial fibrillation, Mayo Clin Proc, 2004;79:904–13.
    Crossref | PubMed
  78. Fuster V, Ryden LE, Cannom DS, et al., ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation), J Am Coll Cardiol, 2006;48:854–906.
    Crossref
  79. Baker WL, Cios DA, Sander SD, et al., Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States, J Manag Care Pharm, 2009;15:244–52.
    PubMed
  80. Connolly SJ, Pogue J, Eikelboom J, et al., 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
  81. van Walraven C, Jennings A, Oake N, et al., Effect of study setting on anticoagulation control: a systematic review and metaregression, Chest, 2006;129:1155–66.
    Crossref | PubMed
  82. Chiquette E, Amato MG, Bussey HI, Comparison of an anticoagulation clinic with usual medical care, Arch Intern Med, 1998;158:1641–7.
    Crossref | PubMed
  83. 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
  84. Fang MC, Go AS, Chang Y, et al., Death and disability from warfarin-associated intracranial and extracranial hemorrhages, Am J Med, 2007;120:700–5.
    Crossref | PubMed
  85. Hart RG, Tonarelli SB, Pearce LA, Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas, Stroke, 2005;36:1588–93.
    Crossref | PubMed
  86. Jones M, McEwan P, Morgan CL, et al., Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population, Heart, 2005;91:472–7.
    Crossref | PubMed
  87. Morgan CL, McEwan P, Tukiendorf A, et al., Warfarin treatment in patients with atrial fibrillation: observing outcomes associated with varying levels of INR control, Thromb Res, 2009;124:37–41.
    Crossref | PubMed
  88. Sarawate C, Sikirica MV, Willey VJ, et al., Monitoring anticoagulation in atrial fibrillation, J Thromb Thrombolysis, 2006;21:191–8.
    Crossref | PubMed
  89. White HD, Gruber M, Feyzi J, et al., Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control. Results from SPORTIF III and V, Arch Intern Med, 2007;167:239–45.
    Crossref | PubMed
  90. Hylek EM, Evans-Molina C, Shea C, et al., Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation, Circulation, 2007;115:2689–96.
    Crossref | PubMed
  91. van Walraven C, Hart RG, Singer DE, et al., Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis, JAMA, 2002;288:2441–8.
    Crossref | PubMed
  92. Mant J, Hobbs R, Fletcher K, et al., 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
  93. 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
  94. Schwammenthal Y, Bornstein N, Schwammenthal E, et al., Relation of effective anticoagulation in patients with atrial fibrillation to stroke severity and survival (from the National Acute Stroke Israeli Survey [NASIS]), Am J Cardiol, 2010;105:411–6.
    Crossref | PubMed
  95. Steger C, Pratter A, Martinek-Bregel M, et al., Stroke patients with atrial fibrillation have a worse prognosis than patients without: data from the Austrian Stroke registry, Eur Heart J, 2004;25:1734–40.
    Crossref | PubMed
  96. Glazer NL, Dublin S, Smith NL, et al., Newly detected atrial fibrillation and compliance with antithrombotic guidelines, Arch Intern Med, 2007;167:246–52.
    Crossref | PubMed
  97. Rosenman M, Simon T, Teal E, et al., Tuesday, 1 September 2009. Atrial fibrillation, warfarin, and contraindications – an electronic medical record system study of real-world practice: http://eurheartj.oxfordjournals.org/content/30/suppl_1/587. short, Eur Heart J, 2009;30:587–843.
    Crossref
  98. Nieuwlaat R, Olsson SB, Lip GY, et al., 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
  99. Gattellari M, Worthington J, Zwar N, et al., Barriers to the use of anticoagulation for nonvalvular atrial fibrillation: a representative survey of Australian family physicians, Stroke, 2008;39:227–30.
    Crossref | PubMed
  100. Lane DA, Lip GY, Barriers to anticoagulation in patients with atrial fibrillation: changing physician-related factors, Stroke, 2008;39:7–9.
    Crossref | PubMed
  101. Partington SL, Abid S, Teo K, et al., Pre-admission warfarin use in patients with acute ischemic stroke and atrial fibrillation: The appropriate use and barriers to oral anticoagulant therapy, Thromb Res, 2007;120:663–9.
    Crossref | PubMed
  102. Pisters R, Lane DA, Nieuwlaat R, et al., A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey, Chest, 2010;138:1093–100.
    Crossref | PubMed
  103. Fang MC, Singer DE, Chang Y, et al., Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study, Circulation, 2005;112:1687–91.
    Crossref | PubMed
  104. Paikin JS, Haroun MJ, Eikelboom JW, Dabigatran for stroke prevention in atrial fibrillation: the RE-LY trial, Expert Rev Cardiovasc Ther, 2011;9:279–86.
    Crossref | PubMed
  105. Caldwell MD, Berg RL, Zhang KQ, et al., Evaluation of genetic factors for warfarin dose prediction, Clin Med Res, 2007;5:8–16.
    Crossref | PubMed
  106. Coumadin package insert, 2010. Available at: http://packageinserts.bms.com/pi/pi_coumadin.pdf (accessed 28 July 2011).
  107. Gallagher AM, Rietbrock S, Plumb J, et al., Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis?, J Thromb Haemost, 2008;6:1500–6.
    Crossref | PubMed
  108. Moyer TP, O'Kane DJ, Baudhuin LM, et al., Warfarin sensitivity genotyping: a review of the literature and summary of patient experience, Mayo Clin Proc, 2009;84:1079–94.
    Crossref | PubMed
  109. Sanderson S, Emery J, Higgins J, CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnetTM systematic review and meta-analysis, Genet Med, 2005;7:97–104.
    Crossref | PubMed
  110. Waterman AD, Milligan PE, Bayer L, et al., Effect of warfarin nonadherence on control of the International Normalized Ratio, Am J Health-Syst Pharm, 2004;61:1258–64.
    PubMed
  111. Lip GY, Agnelli G, Thach AA, et al., Oral anticoagulation in atrial fibrillation: A pan-European patient survey, Eur J Intern Med, 2007;18:202–8.
    Crossref | PubMed
Previous Volume Article Next Volume Article