Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Emmerich, J.
Right arrow Articles by Connolly, S. J.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Emmerich, J.
Right arrow Articles by Connolly, S. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Indication for antithrombotic therapy for atrial fibrillation: reconciling the guidelines with clinical practice

Joseph Emmerich1,*, Jean-Yves Le Heuzey2, Philip M.W. Bath3 and Stuart J. Connolly4

1Department of Vascular Medicine and Hypertension and INSERM U428, Hôpital Européen Georges Pompidou, Médecine Vasculaire—HTA, University Paris V, 20 rue Leblanc, 75908 Paris Cedex 15, France
2Department of Cardiology, Hôpital Européen Georges Pompidou, University Paris V, Paris, France
3Institute of Neuroscience, University of Nottingham, Nottingham, UK
4Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada

* Corresponding author. Tel: +33 1 5609 3051; fax: +33 1 5609 3065. E-mail address: joseph.emmerich{at}egp.aphp.fr


   Abstract
Top
 Abstract
Introduction
 Review of antithrombotic...
 Treatment guidelines
 Conclusions
 Acknowledgements
 Conflicts of interest
 References
 
Cardioembolic stroke secondary to atrial fibrillation (AF) is an urgent public-health problem. On the basis of the data from several randomized controlled clinical trials and pooled analyses, several guidelines have been published to promote the use of anticoagulant treatment to prevent stroke in patients with AF. Current evidence-based guidelines recommend long-term anticoagulation for most patients with AF. However, only a small proportion of patients with AF whom best-practice guidelines identify as eligible for oral anticoagulant therapy actually receive it. One explanation for this low implementation is attributed to the high selection criteria of patients in randomized clinical studies, which often included patients with a lower risk of bleeding than those treated in clinical practice. Indeed, the fear of bleeding is a major consideration when implementing anticoagulation therapy as the risk of bleeding may be higher than the risk of stroke for some patients, which may explain why some physicians do not perceive the guidelines to be fully justified in clinical practice. Considering the complexities surrounding prescribing oral anticoagulation in patients with AF, new drugs with a better benefit/risk ratio are therefore required in the armamentarium for the prevention of thromboembolic events in patients with AF.

Key Words: Atrial fibrillation • Coagulation • Stroke • Treatment guidelines • Vitamin K antagonists • Warfarin


   Introduction
Top
 Abstract
 Introduction
Review of antithrombotic...
 Treatment guidelines
 Conclusions
 Acknowledgements
 Conflicts of interest
 References
 
Atrial fibrillation (AF) occurs in 1% of individuals <50 years of age, and it is particularly common in the elderly, reaching a prevalence of up to 10% in people >75 years of age.1,2 AF is a major contributor of stroke and other peripheral emboli and is responsible for 15–20% of all ischaemic strokes after 60 years of age.1,3,4 Non-valvular AF, the most common cause of arrhythmia, increases the risk of stroke by approximately five-fold and valvular AF up to 17-fold, in both men and women.5 Moreover, patients having a previous AF-related stroke appear to have a worse prognosis than those with a stroke unrelated to AF.6–8 Thus, with the ageing of the population, the number of patients with AF is expected to at least double by the year 2030, thus becoming a major public-health problem. Indeed, AF has been considered to be the epidemic of the new millennium.9,10

The use of anticoagulant treatment to prevent the occurrence of stroke in patients with AF is supported by several randomized controlled clinical trials, and by meta-analyses of these study data.11,12 On the basis of such studies, several guidelines have been published in order to promote evidence-based medicine in this field and to reduce inappropriate variations in clinical practice.2,13–16 However, despite the guidelines, there is still a large discrepancy between the recommendations and their implementation in clinical practice.17–19 This article aims to understand and reconcile the low implementation of the recommendations of current treatment guidelines in the primary prevention of AF into clinical practice, focusing particularly on an analysis of the patient selection criteria in randomized clinical trials, and risk stratification. Although a related topic, the issue of acute antithrombotic therapy in the acute phase of stroke associated with AF20,21 will not be discussed in this article.


   Review of antithrombotic treatment guidelines in AF
Top
 Abstract
 Introduction
 Review of antithrombotic...
Treatment guidelines
 Conclusions
 Acknowledgements
 Conflicts of interest
 References
 
Summary of the evidence
The risk/benefit ratio of treatment with vitamin K antagonists, such as warfarin, vs. placebo or aspirin in patients with AF has been described previously in at least 16 studies.22–36 The total number of patients treated in such studies was almost 10 000 with a mean follow-up of 1.7 years. Meta-analyses of antithrombotic therapy in the prevention of stroke in patients with AF from a number of these studies allow a summary of the currently available trial data to be made.12

Oral anticoagulation has been compared with placebo or control in a meta-analysis of six trials involving 2900 patients.12 The mean international normalized ratio (INR) achieved ranged from 2.0 to 2.9, and the mean duration of follow-up per participant was 1.6 years. The rate of stroke among participants who did not receive anticoagulation was 4.6% per year in the five primary prevention trials and 12.3% per year in the sixth trial of secondary prevention. Four of the six trials were discontinued prematurely due to the efficacy of active treatment. A pooled analysis of the primary prevention trials demonstrated a 59% reduction in the relative risk of stroke. The relative risk reduction was 68% in the secondary prevention trial. The number needed to treat (NNT) to prevent one stroke over 1 year was 37 in primary prevention and 12 in secondary prevention. When only ischaemic stroke was considered, treatment with adjusted dose oral anticoagulant was associated with a relative risk reduction of stroke of 65%. The rate of intracranial haemorrhage was 0.3% per year in patients receiving anticoagulant therapy compared with 0.1% per year in placebo-treated patients. However, the increase in risk of extracranial bleeding does not overcome the important benefits of anticoagulation in the prevention of stroke. Indeed, all-cause of mortality is reduced by 26% in patients receiving warfarin.12

In this meta-analysis of six clinical trials, antiplatelet therapy with aspirin reduced the incidence of stroke by 22% when compared with placebo in more than 3300 patients.12 Whilst all individual trials showed a trend in favour of treatment with aspirin, only one study demonstrated a statistically significant benefit. The NNT for aspirin treatment was 67 during 1 year in primary prevention and 40 in secondary prevention, i.e. a lower benefit than that obtained with oral anticoagulant therapy. The superior efficacy of anticoagulant therapy compared with aspirin was confirmed by a direct comparison among five non-blinded randomized trials involving more than 2800 participants, in which adjusted dose warfarin reduced the overall risk of stroke by 36% relative to aspirin. However, warfarin was associated with a doubling in the risk of both intracranial and extracranial haemorrhage.12


   Treatment guidelines
Top
 Abstract
 Introduction
 Review of antithrombotic...
 Treatment guidelines
Conclusions
 Acknowledgements
 Conflicts of interest
 References
 
The two most recent international treatment guidelines, the ACC/AHA/ESC (American College of Cardiology/American Heart Association/European Society of Cardiology)13 and the ACCP (American College of Chest Physicians),2 differ in the categorization of the risk for antithrombotic therapy.5 This difference decreases with the recent publication of the seventh consensus of the ACCP, published in September 2004.14 In the ACCP consensus guidelines, oral anticoagulation is recommended for patients at high thromboembolic risk and antiplatelet therapy with aspirin is recommended for patients at low risk. Choice of antithrombotic therapy for patients judged to be at a defined intermediate risk is left to the physician (Table 1).14 In an attempt to prevent ambiguity in the indication for aspirin or oral anticoagulant, the risk of thromboembolism is more precisely defined in the ACC/AHA/ESC guidelines (Table 2).13 An additional discrepancy between these two guidelines concerns the recommended intensity of oral anticoagulation. The ACCP guidelines recommend a target INR of 2.5 (range 2.0–3.0) for all patients when oral anticoagulation is mandatory. However, the ACC/AHA/ESC guidelines suggest that a target INR of 2.5–3.5 may be appropriate for the highest risk patients, i.e. those with rheumatic heart disease, prior thromboembolism, or persistent atrial thrombus on transoesophageal echocardiography. A further difference is the option of combined treatment with both aspirin and oral anticoagulation in patients >65 years of age with AF and diabetes or coronary artery disease. However, both guidelines agree that the INR should not fall below 2.0, when the risk of stroke increases dramatically: a doubling in the risk of stroke occurs at an INR level of between 1.7 and 2.0, and doubles again at an INR of 1.4.37


View this table:
[in this window]
[in a new window]
  		Table 1 Recommendations for antithrombotic therapy in patients with AF in the seventh ACCP consensus
 

View this table:
[in this window]
[in a new window]
  		Table 2 Recommendations for antithrombotic therapy in patients with AF in the ACC/AHA/ESC consensus
 
The clinical practice guidelines from the American Academy of Family Physicians (AAFP) and the American College of Physicians (ACP)16 also recommend that patients with AF should receive chronic anticoagulation with adjusted dose warfarin, unless they are at low risk of stroke or have a particular contraindication to the use of warfarin (thrombocytopaenia, recent trauma or surgery, or alcoholism). Their prediction of risk is based on the CHADS2 score (discussed subsequently).38 Other regional guidelines exist, as reviewed for example in the UK, which conclude that widespread non-systematic production of guidelines leads to confusion in clinical decision making and are likely to be variable in content and impact.39

Implementing the guidelines in clinical practice
Several reports have demonstrated that patients with AF do not receive appropriate anticoagulation therapy according to the published guidelines. Surveys have reported an implementation rate of anticoagulation therapy of between 20 and 40%.40–42 Most of these surveys were undertaken before the publication of the ACC/AHA/ESC and ACCP guidelines in 2001. More recent surveys suggest that the rate of patients receiving appropriate anticoagulation is increasing, with 63% in the Cost of Care in Atrial Fibrillation (COCAF) study conducted in France during 200243 and 71% in the FALSTAF study.44 This increase in the per cent of patients with AF being prescribed long-term oral anticoagulation therapy is probably a result of the dissemination of treatment guidelines. Nevertheless, a reluctance of general practitioners, and even cardiologists, to implement the guideline recommendations remains, particularly in patients >80 years of age.19 Poor mobility, impaired cognitive function, frailty, and risk of falls associated with frequent polymedication are undoubtedly risk factors of bleeding in this population, who were excluded from the large randomized clinical trials. However, the intensity of oral anticoagulation plays a major role in the prevention of stroke and mortality, especially in these patients.45

Evidence-based data influencing guideline implementation
One explanation for the low implementation of the guidelines is attributed to the high selection criteria of patients in the randomized clinical studies, which often included patients with a lower risk of bleeding than those treated in clinical practice.46 For example, only 7% of the initial 7982 patients with AF screened were finally included in the SPINAF study: 3206 patients had a contraindication to anticoagulation; and 2304 had chronic alcoholism or a psychological, social, or general condition rendering them unsuitable for anticoagulation.31 In the AFASAK study, of the 2546 patients who were invited to take part in the study, 1539 patients were excluded: 835 refused to take part, and 505 had contraindications to anticoagulation.26 In the SPAF-I trial 17 046 patients were screened, but only 1330 (8%) were entered into the study.33

This suggests that patients included in the trials were highly selected, motivated, and had a better compliance to the treatment and its follow-up when compared with the general population. Owing to this high selection of patients in trials, it is therefore plausible that a higher per cent of real-life patients starting oral anticoagulants are not able to comply and have a higher risk of bleeding complications and may also explain why some physicians do not perceive the guidelines to be fully justified in clinical practice. Indeed, the reluctance of physicians to prescribe oral anticoagulants is often underestimated in the implementation of guidelines.

Despite the relatively short-term duration of treatment in the trials, a significant number of patients withdrew from the studies. A withdrawal rate ~10% was observed in SPINAF,31 BAATAF,22 and SPAF-I,33 and 38% of patients withdrew from the AFASAK study.26 Although a similar withdrawal rate was observed in the placebo group of the SPINAF trial, a much lower rate of withdrawal was observed in patients who received either aspirin or placebo in the SPAF-I and AFASAK studies.

In addition, despite the high selectivity in these trials of patients with AF, the total number of deaths was greater than the number of strokes, reflecting the advanced age of the population studied. This high mortality rate is also linked to the frequent association of AF with atherosclerotic vascular disease, metabolic syndrome, hypertension, and/or diastolic dysfunction in this population.47 Additional approaches to decreasing cardiovascular mortality in this high-risk patient population, such as the co-prescription of angiotensin-converting enzyme inhibitors, ß-blockers, or statins, requires further trials.

Finally, the fear of bleeding is higher than the risk of stroke for some patients. This problem was perhaps best demonstrated in an observational study of patients based on a decision analysis model.48 It appears that some patients who are willing and able to participate in shared decision-making are more averse to the risk of anticoagulation than to the risks associated with AF.48–50 The physician's attitude is also important and often underestimated in the implementation of guidelines. The likelihood of prescribing oral anticoagulants in clinical practice is dictated by the physician's approach to translating a perceived balance associated between the benefits of treatment against the bleeding risk, especially in older patients.21

Risk stratification in AF
The aforementioned potential shortcomings of anticoagulation therapy clearly justify the need to stratify the risk of treatment for the primary prevention of stroke and peripheral embolism in patients with AF. Several trials have clearly identified the risk factors of thromboembolic events in AF. In a collaborative multivariate analysis, the relative risks of stroke were 2.5 for previous stroke or transient ischaemic attack, 1.6 for history of hypertension, 1.4 for congestive heart failure, 1.7 for diabetes, and 1.5 for coronary artery disease.11 The relative risk of stroke per decade of increasing age was 1.4.

The CHADS2 score has been proposed to evaluate the risk of stroke in AF patients.38 In this score, a value of 1 point is allocated to the following risk factors: a recent episode of heart failure, a history of hypertension, an age >75 years, and diabetes. A history of stroke or transient ischaemic attack is considered as a higher risk factor and is thus allocated 2 points. According to this score, the annual incidence of ischaemic stroke for a 100 patients progressively increases from 1.2 (score 0) to 2.8 (score 1), 3.6 (score 2), 6.4 (score 3), 8.0 (score 4), 7.7 (score 5), and 44 (score 6).

The AFFIRM trial compared rhythm vs. rate control in patients with AF with one or more risk factors of stroke and/or death as follows: age >65 years, hypertension, diabetes, congestive heart failure, history of stroke, transient ischaemic attack or systemic embolism, enlarged left atrium >50 mm at echocardiography, shortening ejection fraction of <25% at echocardiography, and/or left ventricular ejection fraction <40%.51 The main conclusion of the trial, even though the primary endpoint of a difference between the efficacies of the two strategies may not have been met, is that continuous oral anticoagulation therapy is clearly justified in patients with such risk factors and a poor prognosis of stroke and/or death. Thus, it is argued that rate control could be chosen as a primary therapeutic strategy and not only if the rhythm control strategy fails. Furthermore, if rhythm control is chosen, it is mandatory to continue anticoagulation after restoration of sinus rhythm if risk factors of stroke and/or death are evident. Indeed, the rate of recurrence of stroke and/or death in the first 2 years remains high in these patients, at ~60%.


   Conclusions
Top
 Abstract
 Introduction
 Review of antithrombotic...
 Treatment guidelines
 Conclusions
Acknowledgements
 Conflicts of interest
 References
 
AF is the most common cause of cardioembolic stroke and is increasing in prevalence on an epidemic scale. However, AF-related stroke is preventable by implementation of evidence-based treatment guidelines and oral anticoagulant therapy. Such guidelines provide physicians with systematic overviews of the randomized-trial findings relevant to making decisions on antithrombotic therapy in AF. Yet, in spite of the proven efficacy of anticoagulant therapy, its utilization has increased only gradually over the past decade, and approximately half of eligible patients remain untreated. The narrow therapeutic index of warfarin and its non-selective inhibition of multiple coagulation factors have led to a new generation of rationally targeted anticoagulant agents, each of which targets a single prothrombotic mediator. Thus, and considering the complexities surrounding prescribing oral anticoagulation in patients with AF, new drugs with a better benefit/risk ratio are required in the armamentarium for the prevention of thromboembolic events in patients with AF.


   Acknowledgements
Top
 Abstract
 Introduction
 Review of antithrombotic...
 Treatment guidelines
 Conclusions
 Acknowledgements
Conflicts of interest
 References
 
Thrombosis Quorum is supported by an educational grant from AstraZeneca. This supplement has been developed as part of the Thrombosis Quorum initiative, under the direction of the Thrombosis Quorum Steering Group [G. Agnelli (Chairman), P. Bath, J. Emmerich, B. Gersh, M. Ögren, S. Schulman, and J. Weitz].


   Conflicts of interest
Top
 Abstract
 Introduction
 Review of antithrombotic...
 Treatment guidelines
 Conclusions
 Acknowledgements
 Conflicts of interest
References
 
P. Bath has consulted for AstraZeneca and given lectures at sponsored symposia. S. Connolly is a consultant to and has received research funding from AstraZeneca, Sanofi-Aventis, BMS, and EV3.


   References
Top
 Abstract
 Introduction
 Review of antithrombotic...
 Treatment guidelines
 Conclusions
 Acknowledgements
 Conflicts of interest
 References
 

  1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–988.[Abstract/Free Full Text]
  2. Albers GW, Dalen JE, Laupacis A et al. Antithrombotic therapy in atrial fibrillation. Chest 2001;119(Suppl. 1):194S–206S.[Free Full Text]
  3. 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;98:476–484.[CrossRef][Web of Science][Medline]
  4. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study. Arch Intern Med 1987;147:1561–1564.[Abstract/Free Full Text]
  5. Rockson SG, Albers GW. Comparing the guidelines: anticoagulation therapy to optimize stroke prevention in patients with atrial fibrillation. J Am Coll Cardiol 2004;43:929–935.[Abstract/Free Full Text]
  6. Lin HJ, Wolf PA, Kelly-Hayes M et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27:1760–1764.[Abstract/Free Full Text]
  7. Jorgensen HS, Nakayama H, Reith J et al. Acute stroke with atrial fibrillation. The Copenhagen Stroke Study. Stroke 1996;27:1765–1769.[Abstract/Free Full Text]
  8. Lamassa M, Di Carlo A, Pracucci G et al. Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (The European Community Stroke Project). Stroke 2001;32:392–398.[Abstract/Free Full Text]
  9. Go AS, Hylek EM, Phillips KA et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370–2375.[Abstract/Free Full Text]
  10. Ezekowitz MD. Atrial fibrillation: the epidemic of the new millennium. Ann Intern Med 1999;131:537–538.[Free Full Text]
  11. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449–1457.[Abstract/Free Full Text]
  12. Hart RG, Benavente O, McBride R et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131:492–501.[Abstract/Free Full Text]
  13. Fuster V, Ryden LE, Asinger RW et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. Eur Heart J 2001;22:1852–1923.[Free Full Text]
  14. Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(Suppl. 3):429S–456S.[Abstract/Free Full Text]
  15. Thomson R, Parkin D, Eccles M et al. Decision analysis and guidelines for anticoagulant therapy to prevent stroke in patients with atrial fibrillation. Lancet 2000;355:956–962.[CrossRef][Web of Science][Medline]
  16. Snow V, Weiss KB, LeFevre M et al. Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med 2003;139:1009–1017.[Abstract/Free Full Text]
  17. Connolly SJ. Anticoagulation for patients with atrial fibrillation and risk factors for stroke. Warfarin reduces the risk by two thirds, but doctors still aren't prescribing it enough. BMJ 2000;320:1219–1220.[Free Full Text]
  18. York M, Agarwal A, Ezekowitz M. Physicians' attitudes and the use of oral anticoagulants: surveying the present and envisioning future. J Thromb Thrombolysis 2003;16:33–37.[CrossRef][Web of Science][Medline]
  19. Dubhghaill CT, Moonen L, O'Loughlin A et al. Implementation of anticoagulation guidelines in general practice: a practice report. Ir Med J 2003;96:296–299.[Medline]
  20. Hart RG, Palacio S, Pearce LA. Atrial fibrillation, stroke, and acute antithrombotic therapy: analysis of randomized clinical trials. Stroke 2002;33:2722–2727.[Abstract/Free Full Text]
  21. Hack W, Kaste M, Bogousslavsky J et al. European Stroke Initiative Recommendations for Stroke Management-update 2003. Cerebrovasc Dis 2003;16:311–337.[CrossRef][Web of Science][Medline]
  22. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990;323:1505–1511.[Abstract]
  23. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993;342:1255–1262.[Web of Science][Medline]
  24. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994;343:687–691.[CrossRef][Web of Science][Medline]
  25. Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996;348:633–688.[CrossRef][Web of Science][Medline]
  26. Petersen P, Boysen G, Godtfredsen J et al. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet 1989;1:175–179.[Web of Science][Medline]
  27. Pengo V, Zasso A, Barbero F et al. Effectiveness of fixed minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation. Am J Cardiol 1998;82:433–437.[CrossRef][Web of Science][Medline]
  28. Gullov AL, Koefoed BG, Petersen P et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998;158:1513–1521.[Abstract/Free Full Text]
  29. Morocutti C, Amabile G, Fattapposta F et al. Indobufen versus warfarin in the secondary prevention of major vascular events in nonrheumatic atrial fibrillation. SIFA (Studio Italiano Fibrillazione Atriale) Investigators. Stroke 1997;28:1015–1021.[Abstract/Free Full Text]
  30. Harenberg J, Weuster B, Pfitzer M et al. Prophylaxis of embolic events in patients with atrial fibrillation using low molecular weight heparin. Semin Thromb Hemost 1993;19(Suppl. 1):116–121.
  31. Ezekowitz MD, Bridgers SL, James KE et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med 1992;327:1406–1412.[Abstract]
  32. Connolly SJ, Laupacis A, Gent M et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991;18:349–355.[Abstract]
  33. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84:527–539.[Abstract/Free Full Text]
  34. Hellemons BS, Langenberg M, Lodder J et al. Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. BMJ 1999;319:958–964.[Abstract/Free Full Text]
  35. Posada IS, Barriales V. Alternate-day dosing of aspirin in atrial fibrillation. LASAF Pilot Study Group. Am Heart J 1999;138:137–143.[CrossRef][Web of Science][Medline]
  36. Yamaguchi T. Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation: a multicenter, prospective, randomized trial. Japanese Nonvalvular Atrial Fibrillation-Embolism Secondary Prevention Cooperative Study Group. Stroke 2000;31:817–821.[Abstract/Free Full Text]
  37. Hylek EM, Skates SJ, Sheehan MA et al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996;335:540–546.[Abstract/Free Full Text]
  38. 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;285:2864–2870.[Abstract/Free Full Text]
  39. Thomson R, McElroy H, Sudlow M. Guidelines on anticoagulant treatment in atrial fibrillation in Great Britain: variation in content and implications for treatment. BMJ 1998;316:509–513.[Abstract/Free Full Text]
  40. Lip GY, Golding DJ, Nazir M et al. A survey of atrial fibrillation in general practice: the West Birmingham Atrial Fibrillation Project. Br J Gen Pract 1997;47:285–289.[Web of Science][Medline]
  41. Sudlow M, Thomson R, Kenny RA et al. A community survey of patients with atrial fibrillation: associated disabilities and treatment preferences. Br J Gen Pract 1998;48:1775–1778.[Web of Science][Medline]
  42. Levy S, Maarek M, Coumel P et al. Characterization of different subsets of atrial fibrillation in general practice in France: the ALFA study. The College of French Cardiologists. Circulation 1999;99:3028–3035.[Abstract/Free Full Text]
  43. Le Heuzey JY, Paziaud O, Piot O et al. Cost of care distribution in atrial fibrillation patients: the COCAF study. Am Heart J 2004;147:121–126.[CrossRef][Web of Science][Medline]
  44. Leizorovicz A, Guenoun M, Le Heuzey JY et al. The FALSTAF study group. How dose age influence the prescribing of antithrombotic therapy for ambulatory patients with permanent atrial fibrillation? J Am Coll Cardiol 2004;43(Suppl. 1):A135–A136.
  45. 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;349:1019–1026.[Abstract/Free Full Text]
  46. Lip GY. Thromboprophylaxis for atrial fibrillation. Lancet 1999;353:1620–1621.[CrossRef][Web of Science][Medline]
  47. Wyse DG, Gersh BJ. Atrial fibrillation: a perspective: thinking inside and outside the box. Circulation 2004;109:3089–3095.[Free Full Text]
  48. Protheroe J, Fahey T, Montgomery AA et al. The impact of patients' preferences on the treatment of atrial fibrillation: observational study of patient based decision analysis. BMJ 2000;320:1380–1384.[Abstract/Free Full Text]
  49. Howitt A, Armstrong D. Implementing evidence based medicine in general practice: audit and qualitative study of antithrombotic treatment for atrial fibrillation. BMJ 1999;318:1324–1327.[Abstract/Free Full Text]
  50. Devereaux PJ, Anderson DR, Gardner MJ et al. Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study. BMJ 2001;323:1218–1222.[Abstract/Free Full Text]
  51. Wyse DG, Waldo AL, DiMarco JP et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–1833.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Emmerich, J.
Right arrow Articles by Connolly, S. J.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Emmerich, J.
Right arrow Articles by Connolly, S. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?