Underuse of Oral Anticoagulants in Atrial Fibrillation: A Systematic Review

CLINICAL RESEARCH STUDY Underuse of Oral Anticoagulants in Atrial Fibrillation: A Systematic Review Isla M. Ogilvie, PhD, a Nick Newton, PhD, a Sharon A. Welner, PhD, a Warren Cowell, MSc, b Gregory Y. H. Lip, MD c a BioMedCom Consultants Inc., Montréal, Canada; b Global Health Economics and Reimbursement, Bayer HealthCare, Uxbridge, England; c Haemostasis Thrombosis & Vascular Biology Unit, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK. ABSTRACT BACKGROUND: Atrial fibrillation is associated with substantial mortality and morbidity from stroke and thromboembolism. Despite an efficacious oral anticoagulation therapy (warfarin), atrial fibrillation patients at high risk for stroke are often under-treated. This systematic review compares current treatment practices for stroke prevention in atrial fibrillation with published guidelines. METHODS: Literature searches (1997-2008) identified 98 studies concerning current treatment practices for stroke prevention in atrial fibrillation. The percentage of patients eligible for oral anticoagulation due to elevated stroke risk was compared with the percentage treated. Under-treatment was defined as treatment of 7 of high-risk patients. RESULTS: Of 54 studies that reported stroke risk levels and the percentage of patients treated, most showed underuse of oral anticoagulants for high-risk patients. From 29 studies of patients with prior stroke/ transient ischemic attack who should all receive oral anticoagulation according to published guidelines, 25 studies reported under-treatment, with 21 of 29 studies reporting oral anticoagulation treatment levels below 6 (range 19%-81.3%). Subjects with a CHADS 2 (congestive heart failure, hypertension, age 75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score 2 also were suboptimally treated, with 7 of 9 studies reporting treatment levels below 7 (range 39%-92.3%). Studies (21 of 54) using other stroke risk stratification schemes differ in the criteria they use to designate patients as high risk, such that direct comparison is not possible. CONCLUSIONS: This systematic review demonstrates the underuse of oral anticoagulation therapy for real-world atrial fibrillation patients with an elevated risk of stroke, highlighting the need for improved therapies for stroke prevention in atrial fibrillation. 2010 Elsevier Inc. All rights reserved. The American Journal of Medicine (2010) 123, 638-645 KEYWORDS: Atrial fibrillation; Current treatment practices; Guidelines; Oral anticoagulant therapy; Stroke risk Atrial fibrillation, the most common significant cardiac rhythm disorder, is associated with substantial mortality and morbidity from stroke and thromboembolism. 1 Incidence of atrial fibrillation in the general population ranges from 0.85 to 4.1 per 1000 person-years, 2-4 and increases substantially with age. 2,5 Atrial fibrillation patients are at higher risk of stroke, and cardiovascular- and stroke-related death than the general population. 6-8 However, this elevated risk of stroke is not homogeneous and is increased by the presence of additional risk factors including prior stroke, transient ischemic attack, hypertension, increasing age, and diabetes. 9,10 Published guidelines for stroke prevention in atrial fibrillation patients recommend treatment with oral anticoagu- Funding: This study was funded by Bayer Healthcare, UK. Conflict of Interest: Dr. Gregory Y.H. Lip has acted as a consultant for Bayer Healthcare, AstraZeneca, Astellas, and Boehringer; and Warren Cowell is employed by Bayer Healthcare, UK. The other authors have no conflict of interest. Authorship: All authors had full access to data for this study and participated in writing and review of the manuscript. Poster was presented at the American College of Cardiology Annual Meeting 2009 in Orlando, Florida on March 29, 2009. Requests for reprints should be addressed to Isla Ogilvie, PhD, BioMedCom Consultants Inc., 1405 TransCanada, Suite 310, Montréal, QC H9P2V9, Canada. E-mail address: isla_ogilvie@biomedcom.org 0002-9343/$ -see front matter 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2009.11.025

Ogilvie et al Anticoagulant Underuse in High-risk Atrial Fibrillation 639 lants for patients at moderate or high risk of stroke, and aspirin or no antithrombotic therapy for patients at moderate or low risk. 11-15 Guidelines tend to differ over stroke risk stratification due to variations in the categorization of risk factors (Table 1, online). A recent review concluded that while all the schemes stratified stroke risk, the absolute stroke rates varied widely. 16 Observed stroke rates for those categorized as low risk ranged from to 2.3% per year while rates for those categorized as high risk ranged from 2.5% to 7.9% per year. 16 When applied to the same representative cohort, the percentage of patients categorized as low risk by the different schemes varied from 9% to 49%, and the percentage categorized as high risk varied from 11% to 77%. 16 In addition, the ability of commonly used risk stratification schemes to predict stroke in atrial fibrillation patients is limited. Gage and colleagues 17 reported that risk schemes had only fair discriminating ability (cstatistic: 0.56 to 0.62; ideal is 1), while Baruch et al 18 reported that only 3 schemes CHADS 2 (congestive heart failure, hypertension, CLINICAL SIGNIFICANCE age 75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score, 17,19 Stroke Prevention in Atrial Fibrillation, 20 and Framingham score 21 had greater predictive accuracy for stroke than chance. 18 Substantial, clinically relevant differences exist among published schemes that may lead to inconsistent stroke risk estimates for atrial fibrillation patients, resulting in confusion among clinicians and nonuniform use of anticoagulation therapy. 16 This study systematically reviews the literature concerning stroke prevention in high-risk atrial fibrillation patients to examine the use of oral anticoagulants in current practice with respect to guidelines for prophylaxis. PATIENTS AND METHODS Literature Search An extensive search of recent biomedical literature was performed using PubMed for studies pertaining to current treatment practices for stroke prevention for atrial fibrillation patients; the search was limited to studies on humans, published after May 1997. Combinations of the following search terms were used: practices, treatment, atrial fibrillation, stroke, antithrombotics, antiplatelets, oral anticoagulants, warfarin, and vitamin K antagonist. Studies were excluded if no stroke risk stratification was available for the whole patient population or if treatment details were not available for patients with prior stroke. Clinical trials were Underuse of oral anticoagulants for high-risk atrial fibrillation patients was found in most of the 54 studies (1998-2008) reporting both patient stroke risk and patients treated. Over two thirds of studies of atrial fibrillation patients with prior stroke or transient ischemic attack reported treatment levels of under 6 of eligible patients. Most studies based on CHADS 2 (congestive heart failure, hypertension, age 75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score reported oral anticoagulant treatment levels of high-risk subjects below 7. excluded because they contained no treatment data from real life clinical settings. English language articles were primarily reviewed, with promising articles in other languages as practical. Bibliographies of retrieved articles and abstracts returned as related articles from PubMed were screened to identify additional sources. All world regions were explored. Analyses were conducted by 2 independent investigators. Analysis of Current Treatment Practices for Stroke Prevention in High-risk Atrial Fibrillation Patients The following data were systematically extracted; patient population, study setting (general practice or hospital), risk stratification scheme or treatment guideline applied, relevant risk criteria, and proportion of patients treated with oral anticoagulation therapy or antiplatelet agents. Because the recommended treatment for atrial fibrillation is dependent on patient risk for stroke, only articles that reported treatment levels of atrial fibrillation patients at high risk of stroke were included. High-risk categories for this literature review include: atrial fibrillation patients with prior ischemic stroke or transient ischemic attack; patients with a CHADS 2 score of 2 or more; 17,22 and patients designated high risk by any other risk stratification scheme (American College of Cardiology/American Heart Association/European Society of Cardiology guidelines, and others). 23,24 Only patients at a high risk of stroke were included in the analysis. The following values were extracted or calculated from data presented in the literature selected. Firstly, the proportion of the study population with prior stroke/transient ischemic attack, who are all considered to be eligible for oral anticoagulation treatment according to all published guidelines, was captured. Secondly, the percentage of patients eligible for oral anticoagulation treatment according to the relevant risk stratification scheme or treatment guideline used to classify patients in that study was recorded. Thirdly, the percentage of patients actually treated with oral anticoagulation was noted. If data were available only for subpopulations (eg, men and women separately), an overall weighted average was calculated. Data on contraindications to oral anticoagulation therapy were captured if available. From values collected, we calculated the proportion of atrial fibrillation patients eligible for oral anticoagulation treatment due to either the presence of prior stroke/transient ischemic attack or a high risk designation from a risk strat-

640 The American Journal of Medicine, Vol 123, No 7, July 2010 Figure 1 Literature search and study inclusion for oral anticoagulation treatment levels. CHADS 2 congestive heart failure, hypertension, age 75 years, diabetes mellitus, and prior stroke or transient ischemic attack. ification scheme that were actually treated with oral anticoagulation therapy. While the proportion of patients with contraindications against oral anticoagulation therapy was not specified or discussed for most study populations, previous studies found a prevalence of contraindications in around 15% of clinical atrial fibrillation patients. 25-28 Therefore a treatment level of below 7 of the eligible population was chosen for this analysis as the point at which a population was considered under-treated, to allow for the presence of patients with contraindications within these populations. RESULTS Current Treatment Practices In all, 54 studies were selected from a possible 98 that pertained to treatment of atrial fibrillation patients with oral anticoagulation therapy (Figure 1). The study populations were mostly elderly (over 65 years old). Of the 54 selected studies, 29 contained treatment data for atrial fibrillation patients with prior stroke or transient ischemic attack; these were used for the primary analysis. Additionally, 9 of the 54 studies presented treatment data for atrial fibrillation patients based on the CHADS 2 risk score data, while a further 21 studies used other risk stratification schemes to designate patients as being at high risk for stroke. There was some overlap between these studies and those containing treatment data for atrial fibrillation patients with prior stroke or transient ischemic attack. Forty-four studies were excluded from the analysis because they did not contain risk stratification data for atrial fibrillation patients, prior stroke data, or data from real life clinical settings. Details of the 29 studies containing treatment data for atrial fibrillation patients with prior stroke or transient ischemic attack included in this analysis are listed in Table 2 (online). Studies from 1997 to 2008 were captured. Study populations varied widely, from a minimum of 103 patients in a study from a single Italian stroke unit 29 to a maximum of 128,699 annual hospitalizations in a Canadian study of a national discharge database. 30 The mean age of study populations ranged from 63 to 82.5 years. The majority of the studies were based on patient chart review (20 studies), with only 9 studies making use of administrative databases. Figure 2 shows the percentage of treated and untreated atrial fibrillation patients from each study analyzed. Patients with prior stroke or transient ischemic attack, who should all receive oral anticoagulation therapy according to treatment guidelines, 11,12,14 were under-treated with oral anticoagulation therapy (treatment level 7 of high-risk patients) in all but 4 of the 29 studies. 28,31-33 Indeed, the majority of studies (21 of 29) reported that 6 of atrial fibrillation patients with prior stroke or transient ischemic attack were treated, and half of the analyzed studies (15 of 29) reported treatment levels of 5 of high-risk patients. The range of treatment levels across studies was large. In an Italian study set in a single teaching hospital, only 19% of atrial fibrillation patients with prior stroke or transient ischemic attack were treated, 34 while 81.3% of high-risk patients were treated in an intervention-based prospective study that used established guidelines. 31 Only 8 of 29 studies accounted for atrial fibrillation patients in their population who had contraindications to oral anticoagulation therapy. Table 3 (online) gives details of studies using CHADS 2 stroke risk stratification (9 of 54 studies) to designate atrial fibrillation patients as high risk for stroke. 22,35-42 Figure 3 shows the percentage of high-risk patients (CHADS 2 score 2) who received oral anticoagulation therapy and, where available, according to CHADS 2 score. Oral anticoagulation therapy treatment levels were suboptimal in all but 2 of the studies (below a threshold of 7 of high-risk patients). 35,39 In fact, the majority of studies (5 of 9) reported a high-risk patient treatment level of under 6. 36-38,41,42 Treatment level ranged from 39% of high-risk patients in a US study, set in the Veterans Affairs health care system in Boston, 42 to

Ogilvie et al Anticoagulant Underuse in High-risk Atrial Fibrillation 641 Figure 2 Patients with atrial fibrillation and prior stroke/transient ischemic attack: oral anticoagulation treatment levels as a proportion of patients eligible for oral anticoagulation therapy. *Contraindications taken into account. 92.3% in a study of 23 cardiology practices from Switzerland. 35 Oral anticoagulation treatment level rose according to CHADS 2 score in all studies, with 41% 37 to 35 of patients with a CHADS 2 score 4 receiving oral anticoagulation treatment. Studies (21 of 54; data not shown) used other stroke risk stratification schemes to designate patients at high risk such that direct comparison was not possible. In general, studies reported that patients at high risk for stroke were under-treated. Median treatment levels were 43.9%, ranging from 22.8% of high risk patients in an Italian study of general practices 43 to 81.9% in an Italian hospital study. 44 The relatively high treatment rate reported in the latter was due to implementation of hospital guidelines, before which, the treatment rate of high-risk patients was 57%. 44 DISCUSSION This systematic review and analysis of available evidence has highlighted suboptimal treatment of high-risk atrial fibrillation patients. Patients with atrial fibrillation and prior stroke or transient ischemic attack were found to be undertreated with oral anticoagulation therapy in the majority of studies. Over two thirds of studies analyzed reported treatment levels of high-risk patients under 6. Similarly, high-risk subjects based on CHADS 2 stroke risk score also were suboptimally treated, with treatment levels ranging from 39% to 7, although treatment in one study reached 92.3% of high-risk patients. Reassuringly, the level of treatment with oral anticoagulation reported in this study rose according to CHADS 2 score. Although there is variability in stroke risk stratification, all guidelines recommend that atrial fibrillation patients at high risk for stroke should receive anticoagulation therapy. Indeed, atrial fibrillation predisposes patients to developing atrial thrombi and is associated with a 4- to 5-fold increase in risk of stroke from cardioembolism. 19 Up to 15% of all strokes, and 25% of strokes in those aged over 80 years, are attributable to atrial fibrillation. 45 However, despite availability of effective prophylaxis (warfarin), patients with atrial fibrillation at high risk for stroke are often undertreated. The recent Euro-Heart Survey, which examined stroke prevention in atrial fibrillation in 35 European countries, concluded that antithrombotic therapy in real life atrial fibrillation patients was not well tailored to the patient s stroke risk profile; 22 additionally, a US populationbased study reported that 41% of atrial fibrillation patients at high risk for stroke did not receive warfarin. 46 Underuse of oral anticoagulation therapy in the atrial fibrillation population may have many reasons. 29,47-49 These include low levels of therapy initiation, the narrow therapeutic margin (international normalized ratio 2-3 in nonvalvular atrial fibrillation) leading to the inconvenience of international normalized ratio monitoring, and patient compliance. 47 A longitudinal US cohort study reported that one

642 The American Journal of Medicine, Vol 123, No 7, July 2010 Figure 3 Patients with atrial fibrillation at high risk of stroke (CHADS 2 score): oral anticoagulant treatment levels as a proportion of patients eligible for therapy. *Includes patients treated with both oral anticoagulation therapy and antiplatelet therapy. Patients defined as having a CHADS 2 score of 1 and a bleeding score of 2 (the n value for this population was not available). CHADS 2 congestive heart failure, hypertension, age 75 years, diabetes mellitus, and prior stroke or transient ischemic attack. third of the atrial fibrillation population initially prescribed warfarin for stroke prevention had discontinued treatment after 30 months. 47 Similarly, a UK study reported a 3 attrition rate for warfarin use over 1 year. 29 Fear of catastrophic bleeding also might contribute to oral anticoagulation under-utilization for atrial fibrillation. In a survey of Australian family practitioners and another of senior UK hospital physicians, experience of bleeding events and fear of bleeding appeared to reduce prescription of oral anticoagulation therapy. 48,49 However, studies of the relationship between international normalized ratio intensity and stroke and bleeding risk have shown that an international normalized ratio of below 2.0 is associated with a greater increase in the risk of stroke than the increased bleeding risk associated with an international normalized ratio of more than 3.0. 50,51 It is probable that the underuse of oral anticoagulation therapy documented here leads to preventable thrombotic events in eligible atrial fibrillation patients who remain untreated. A retrospective chart review carried out in the US followed clinical event rates in 2 cohorts of atrial fibrillation patients. 52 The first cohort were atrial fibrillation patients on newly prescribed oral anticoagulants (warfarin treated); the second cohort were untreated patients who were eligible for warfarin according to American College of Cardiology/ American Heart Association/European Society of Cardiology guidelines from 2001 (warfarin candidates). The study reported an ischemic stroke rate of 2.25 events per 100 person-years in the warfarin treatment group versus 2.83 events per 100 person-years in the warfarin candidates group. After adjusting for age, sex, and additional risk factors for ischemic stroke, the relative risk of stroke was reduced by 22% with warfarin therapy (hazard ratio 0.78; 95% confidence interval, 0.65-0.93). 52 Conversely, underuse should result in lower bleeding rates, however, the study found no difference in bleeding rate between the 2 cohorts. 52 Consistent with Evans and Kalra (2001), 32 we observed little difference in major bleeding rates between the different study settings; however, the definition of major bleeding differed from study to study, limiting the validity of the comparison. Predictors for bleeding in anticoagulated patients are largely clinical factors and include uncontrolled hypertension, history of myocardial infarction or ischemic heart disease, cerebrovascular disease, anemia or a history of bleeding, and concomitant use of other drugs such as antiplatelet agents. 53 While some studies do not show an increase in bleeding with increasing age, 54,55 a recent metaanalysis by van Walraven et al clearly demonstrated that increasing age raises the risk of serious bleeding (adjusted hazard ratio per decade increase in age: 1.61; 95% confidence interval, 1.47-1.77). 56 In addition, the increased risk

Ogilvie et al Anticoagulant Underuse in High-risk Atrial Fibrillation 643 of serious hemorrhage due to oral anticoagulants was far smaller than the beneficial reduction in risk of stroke and other adverse vascular outcomes from this treatment for patients of all ages. 56 Of note, presence of diabetes mellitus, controlled hypertension, and sex were not identified as significant risk factors. Importantly, some risk factors for anticoagulation-related bleeding also are indications for the use of anticoagulants in atrial fibrillation patients. Our findings of overall under-treatment of high-risk atrial fibrillation patients with warfarin in clinical practice reflect the need for improvements in provision of thromboprophylaxis in atrial fibrillation. Current treatment practice does not appear to follow published treatment guidelines closely, which most likely results in elevated levels of preventable ischemic stroke in the atrial fibrillation population and, therefore, greater morbidity and overall cost to health care systems. While warfarin represents an efficacious and cost-effective therapy, adherence to treatment guidelines needs improvement. Additionally, there is an evident need for oral anticoagulant drugs with a wide therapeutic range, which do not require international normalized ratio monitoring, and have a safe bleeding profile. Limitations Our systematic review has identified limitations with current evidence that prevented more detailed comparisons between various published studies. For example, only a small proportion of the population of atrial fibrillation patients (those with prior stroke) was available for direct comparison of treatment levels from many studies, due to differences in the way stroke risk is categorized. Secondly, it was not possible to evaluate treatment levels for entire study populations unless risk stratification was available to determine how many patients should be treated with oral anticoagulation therapy, hence our focus on studies with treatment values for stroke patients and those designated at high risk. Further, only studies that used a common risk stratification scheme (CHADS 2 ) could be compared. Not many of the studies analyzed here accounted for the proportion of patients with contraindications against warfarin therapy within their populations, meaning that the undertreatment reported here may be over-estimated. 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The use of antithrombotics in patients presenting with stroke and atrial fibrillation. Ther Clin Risk Manag. 2007;3:491-498. 62. Deplanque D, Leys D, Parnetti L, et al. Secondary prevention of stroke in patients with atrial fibrillation: factors influencing the prescription of oral anticoagulation at discharge. Cerebrovasc Dis. 2006;21:372-379. 63. Burton C, Isles C, Norrie J, et al. The safety and adequacy of antithrombotic therapy for atrial fibrillation: a regional cohort study. Br J Gen Pract. 2006;56:697-702. 64. Touze E, Cambou JP, Ferrieres J, et al. Antithrombotic management after an ischemic stroke in French primary care practice: results from three pooled cross-sectional studies. Cerebrovasc Dis. 2005;20:78-84. 65. de Lusignan S, van Vlymen J, Hague N, et al. Preventing stroke in people with atrial fibrillation: a cross-sectional study. J Public Health (Oxf) 2005;27:85-92. 66. Bordin P, Mazzone C, Pandullo C, et al. Morbidity and mortality in 229 elderly patients with nonrheumatic atrial fibrillation. A five-year follow-up. Ital Heart J. 2003;4:537-543. 67. Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 2003;290:2685-2692. 68. Evans A, Perez I, Yu G, et al. Should stroke subtype influence anticoagulation decisions to prevent recurrence in stroke patients with atrial fibrillation? Stroke 2001;32:2828-2832. 69. Howard PA, Ellerbeck EF, Engelman KK, et al. Warfarin for stroke prevention in octogenarians with atrial fibrillation. Am J Geriatr Cardiol. 2001;10:139-144. 70. Cohen N, Almoznino-Sarafian D, Alon I, et al. Warfarin for stroke prevention still underused in atrial fibrillation: patterns of omission. Stroke 2000;31:1217-1222. 71. Tomita F, Kohya T, Sakurai M, et al. Prevalence and clinical characteristics of patients with atrial fibrillation: analysis of 20,000 cases in Japan. Jpn Circ J. 2000;64:653-658. 72. Gage BF, Boechler M, Doggette AL, et al. Adverse outcomes and predictors of underuse of antithrombotic therapy in medicare beneficiaries with chronic atrial fibrillation. Stroke 2000;31:822-827. 73. Caro JJ, Flegel KM, Orejuela ME, et al. Anticoagulant prophylaxis against stroke in atrial fibrillation: effectiveness in actual practice. CMAJ. 1999;161:493-497. 74. Deplanque D, Corea F, Arquizan C, et al. Stroke and atrial fibrillation: is stroke prevention treatment appropriate beforehand? SAFE I Study Investigators. Heart 1999;82:563-569. 75. White RH, McBurnie MA, Manolio T, et al. Oral anticoagulation in patients with atrial fibrillation: adherence with guidelines in an elderly cohort. Am J Med. 1999;106:165-171. 76. Brass LM, Krumholz HM, Scinto JD, et al. 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Table 1 Study Fuster et al, 2001 23 International Fuster et al, 2006 11 International Singer et al, 2004 12 US National Institute for Health and Clinical Excellence, 2006 14 UK Goldstein et al, 2006 13 US Stroke Risk Stratification Criteria for Stroke Prevention in Atrial Fibrillation and the Corresponding Treatment Recommendations from Published Guidelines Guideline Name American College of Cardiology; American Heart Association; European Society of Cardiology Guidelines for the Management of Patients with Atrial Fibrillation, 2001 American College of Cardiology; American Heart Association; European Society of Cardiology Guidelines for the Management of Patients with Atrial Fibrillation, 2006 The Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic therapy, Antithrombotic therapy in atrial fibrillation: National institute for Health and Clinical Excellence, 2004 Atrial fibrillation: the management of atrial fibrillation American Heart Association and American Stroke Association; Primary prevention of Ischaemic stroke Clinical Guidelines Patient Risk Designation High risk: Age 60 years with diabetes mellitus or coronary artery disease, age 75 years (especially women), heart failure, LV ejection fraction 0.35, thyrotoxicosis, hypertension, prior thromboembolism, or persistent atrial thrombus on transesophageal echocardiography Low risk: Age 60 years, no risk factors, or age 60 years, heart disease but no risk factors Lowest risk: Age 60 years, no heart disease (lone AF) High risk: Any high-risk factor or 1 moderate risk factor High risk factors: Previous stroke, TIA or embolism, mitral stenosis. prosthetic heart valve Moderate risk: One moderate-risk factor Moderate-risk factors: Age 75 years, hypertension, heart failure, LV ejection fraction 35% Low risk: One or more weaker risk factors Less validated or weaker risk factors: Diabetes mellitus, female sex, age 65-75 years, coronary artery disease, thyrotoxicosis Lowest risk: No risk factors or has contraindications for OAC High risk: Previous TIA or stroke, systemic embolism, age 75 years, moderate/severely impaired LV function, congestive heart failure history of hypertension or diabetes, mitral stenosis, prosthetic heart valves Recommended Treatment Oral anticoagulation (INR 2.0-3.0) (Plus aspirin, 81-162 mg daily optional) Aspirin (325 mg daily) Aspirin (325 mg daily) or no therapy Warfarin (INR 2.0-3.0, target 2.5) Warfarin (INR 2.0-3.0, target 2.5) or aspirin 81 to 325 mg daily Warfarin (INR 2.0-3.0, target 2.5) or aspirin 81-325 mg daily Aspirin, 81-325 mg daily Oral anticoagulation such as warfarin (target INR 2.5; range 2.0-3.0) Moderate risk: Age 65-75 years Oral anticoagulation (target INR 2.5; range 2.0-3.0) or aspirin (325 mg/day) Low risk: Age 65 years old with no other risk factors Aspirin (325 mg/day) High risk: Previous ischemic stroke/tia or thromboembolic event; age 75 with Warfarin target INR 2.5 (range 2.0-3.0), If hypertension, diabetes or vascular disease; clinical evidence of valve disease, heart contraindications to warfarin consider aspirin failure, or impaired LV function on echocardiography 75-300 mg/day Moderate risk: Age 65 years with no high risk factors; age 75 with hypertension, Warfarin target INR 2.5 (range 2.0-3.0), or diabetes or vascular disease aspirin 75-300 mg/day Low risk: Age 65 years with no moderate/high risk factors Aspirin 75-300 mg/day CHADS 2 risk criteria score: Congestive heart failure Hypertension Age 75 years Diabetes Prior stroke or transient ischemic attack Low risk: CHADS 2 score 0 Stroke rate 1./year Low-moderate risk: CHADS 2 score 1 Strokerate 1.5%/year Moderate risk: CHADS 2 score 2 Stroke rate 2.5%/year High risk: CHADS 2 score 3 Stroke rate 5./year Very high risk: CHADS 2 score 4 Stroke rate 7%/year 1 point 1 point 1 point 1 point 2 points Aspirin (75-325 mg/day) Warfarin INR 2.0-3.0 or aspirin (75-325 mg/day) Warfarin INR 2.0-3.0 Warfarin INR 2.0-3.0 Warfarin INR 2.0-3.0 AF atrial fibrillation; CHADS 2 congestive heart failure, hypertension, age 75 years, diabetes mellitus, and prior stroke or transient ischemic attack; INR international normalized ratio; LV left ventricular; OAC oral anticoagulation; TIA transient ischemic attack. 645.e1 The American Journal of Medicine, Vol 123, No 7, July 2010

Table 2 Anticoagulation Use in Atrial Fibrillation Patients with Prior Stroke/Transient Ischemic Attack Study/Country Population Risk Measure Lock Hansen, 2008 57 Denmark Gandolfo et al, 2008 29 Italy Leoo, 2008 58 Sweden Srivastava et al, 2008 37 US Fornari, 2007 59 Brazil Andersen, 2007 60 Denmark Burgess, 2007 61 New Zealand Rowan et al, 2007 31 US Deplanque, 2006 62 Europe Burton, 2006 63 UK Touze, 2005 64 France de Lusignan, 2005 65 UK Humphries et al, 2004 30 Canada Bordin, 2003 66 Italy Go, 2003 67 US 108,791 patients discharged following first-time atrial fibrillation; Danish National Hospital Register; 1995-2004; aged 50-99 years; contraindications data not available 103 acute stroke patients with atrial fibrillation; 22 new-onset AF patients; Italian stroke unit; 2003-2005; 23.81% of patients not receiving oral anticoagulation had contraindications 889 adult patients with recurrent stroke; The Recurrent Stroke Quality and Epidemiology (RESQUE) study. 23 Swedish stroke centers; Nov 2004 to Jul 2006; mean age 77 years; 29% of patients had AF 364 consecutive atrial fibrillation patients single hospital; Retrospective chart review; 2003-2003; 1 year follow-up; 29.5% of patients had documented reasons (real or perceived) for not prescribing oral anticoagulation 3764 patients treated on 5 separate days; 2002 Brazilian University Heart Hospital; cross-sectional study; 301 with atrial fibrillation; 17.6% had prior stroke; 1 year follow-up 3670 stroke patients with atrial fibrillation; nationwide registry all hospitalized stroke patients in Denmark; 1909 had no contraindication to oral anticoagulation 219 patients with stroke and atrial fibrillation admitted to a single hospital; Retrospective case study; 1999-2001; n 150 had known atrial fibrillation before admission 40.5 million patient visits with a diagnosis of atrial fibrillation; National Ambulatory Medical Care Survey database; 1994-2003 320 patients admitted for ischemic stroke or transient ischemic attack with known prior atrial fibrillation; Stroke and Atrial Fibrillation Ensemble II study; 40 centers in 5 European countries 601 patients with atrial fibrillation, retrospective review of regional cohort; General practice; mean age: 77 years (at recruitment); 2002-2003 4322 stroke patients; with 765 patients with atrial fibrillation; three French cross-sectional primary care-based studies 944 patients with atrial fibrillation UK 8 general practices; 81,811 total population (2004) 128,699 annual hospitalizations for atrial fibrillation Canadian Institute for Health Information Discharge Abstract and Morbidity databases; 1997-2000 229 patients, with atrial fibrillation; Trieste Cardiovascular Center; aged 65 years; 5-year follow-up 11,409 atrial fibrillation patients with no contra-indications to oral anticoagulation, HMO,1996-1997 High-risk Patients n (%) High-risk Criteria High-risk Patients (%) All guidelines n 13,034 (12%) Prior stroke/tia 38.8% Actual Treatment (% of Atrial Fibrillation Patients) OAC Alone OAC AP AP Alone None All guidelines n 81 (78.6%) Prior stroke/tia 22% 39.5% 37% All guidelines n 258 with AF (29%) Prior stroke 26% N/A 67% N/A All guidelines n 90 (24.7%) Prior stroke/tia 52.2% 47.8% AHA/ACC/ESC n 85 (2.2%) Prior stroke at * 49% N/A 17% 34% 2001 first visit Prior stroke at follow-up * 60.4% N/A 17% 22.6% All guidelines n 1909 (52%) Prior stroke * 60.2% N/A N/A 39.8% All guidelines n 150 (69.4%) Prior stroke/tia 25% 1.3% 37.3% 36% All guidelines n 1,236,976 patient Prior stroke/tia 70.4% N/A N/A N/A visits (3.1%) All guidelines n 320 () Prior stroke/tia 81.3%* 58% N/A 36.9% 2.1% All guidelines n 133 (22.1%) Prior stroke/tia 49% N/A 38% 14% All guidelines n 765 () Prior stroke 43.5% N/A 54.4% 2.1% SIGN/PRODIGY n 167 (17.7%) Prior stroke/tia * 42.5% N/A 33.5% 24. based All guidelines n 2362 (1.8%) Prior stroke/tia 47.3% N/A N/A N/A All guidelines n 62 (27%) Prior embolism 88.7% 41.9% N/A 45% 14.5% (88.7% CNS) All guidelines n 896 (7.85%) Prior stroke/tia * 55% N/A N/A 45% Ogilvie et al Anticoagulant Underuse in High-risk Atrial Fibrillation 645.e2

Table 2 Continued Study/Country Population Risk Measure Ageno et al, 2001 34 Italy Evans, 2001 68 UK Howard, 2001 69 US Leckey et al, 2000 33 Canada Cohen, 2000 70 Israel Tomita, 2000 71 Japan Gage, 2000 72 US Caro, 1999 73 Canada Deplanque, 1999 74 Europe White, 1999 75 US Go et al, 1999 28 US Brass, 1998 76 US Brass, 1997 77 US Gurwitz, 1997 78 US and Canada 3121 patients at single center 224 patients had atrial fibrillation 1 year follow-up (1999) 386 atrial fibrillation patients with acute stroke; secondary prevention intervention study; district general hospital; 32% had contra-indications to warfarin 283 atrial fibrillation patients; Medicare beneficiaries, Kansas hospital discharge; 142 patients 65-79 years of age; 141 patients 80 years old 722 patients with acute ischemic stroke; tertiary teaching hospital; 92 had atrial fibrillation; 68 survived 9% and all patients had contraindications 1027 patients discharged with chronic or persistent atrial fibrillation; 510 patients in main study group 19,825 patients who visited cardiovascular clinics of 13 hospitals; Hokkaido, Japan, 1995; 2457 atrial fibrillation patients; 1998 NVAF 597 Medicare beneficiaries; chart reviews from all Missouri hospitals; Medicare claims data; 1993-1996. 221 patients with atrial fibrillation; outpatients at 2 hospital cardiology practices; Montreal; 1990-1993 213 patients admitted for ischemic stroke/transient ischemic attack with known prior atrial fibrillation; Stroke and Atrial Fibrillation Ensemble I study; 3 centers in 3 European countries 172 (4.1%) participants with atrial fibrillation; subgroup of participants in the Cardiovascular Health Study; 1993-1995. 13,428 patients with a confirmed ambulatory diagnosis of NVAF and known warfarin status; 11,082 with no contraindications; HMO; 1996-1997 278 patients with atrial fibrillation and stroke;168 no contraindications; chart review; hospitalized Medicare patients, aged 65 years; 1994 488 patients with prior atrial fibrillation; chart review of hospitalized Medicare patients, aged 65 years in 1994; use of warfarin before admission 413 patients with atrial fibrillation from 5500 long-term residents; 30 long-term care facilities in New England (n 16), Quebec (n 12), and Ontario (n 2). High-risk Patients n (%) High-risk Criteria High-risk Patients (%) Actual Treatment (% of Atrial Fibrillation Patients) OAC Alone OAC AP AP Alone None All guidelines n 40 (17.9%) Prior stroke/tia 19% N/A 33.3% 47.7% All guidelines n 386 () Prior stroke/tia * 81.3% 18.7% All guidelines n 85 (3) Prior stroke/tia 54% All guidelines n 68 (9.4%) Prior stroke/tia 74% 19% 7% All guidelines n 79 (15.5%) Prior stroke/tia 68% All Guidelines n 484 (18%) Prior stroke/tia 46% 22.2% 10.4% All guidelines n 151 (25.3%) Prior stroke/tia 41% 23% 38% All guidelines n 26 (11.8%) Prior stroke/tia 69% 27% 3.8% All guidelines n 51 (24%) Prior stroke/tia Admission 15.7% 38% 46.3% n 213 () Prior stroke/tia Discharge 41.6% 44.9% 13.5 All guidelines n 22 (12.8%) Prior stroke/tia 45% All guidelines n 1249 (9.3%) Prior stroke/tia * 70.3% 28.9% All guidelines n 168 (6) Prior stroke/tia 6 15% 25% All guidelines n 131 (26.8%) Prior stroke/tia 42% 25% 33% All guidelines n 139 (34%) Prior stroke/tia 41.7% 58.9% ACC American College of Cardiology; AF atrial fibrillation; AHA American Heart Association; AB Alberta; AP antiplatelet; BC British Columbia; CNS central nervous system; ESC European Society of Cardiology; GP general practitioner; HMO health management organisation; N/A not available; NS Nova Scotia; OAC oral anticoagulation; ON Ontario; SIGN Scottish intercollegiate guidelines network; TIA transient ischemic attack. *Contraindications taken into account. 23.81% of patients not receiving OAC had contraindications. 9% of patients receiving aspirin had contraindications. All patients had contraindications. 645.e3 The American Journal of Medicine, Vol 123, No 7, July 2010

Table 3 Study/Country Meiltz et al, 2008 35 Switzerland Suzuki et al, 2008 36 Japan Srivastava et al, 2008 37 US Partington et al, 2007 38 Canada Nieuwlaat et al, 2006 22 Euro Heart survey Boulanger et al, 2006 39 US Birman-Deych et al, 2006 40 US Inoue et al, 2006 41 Japan Brophy et al, 2004 42 US Anticoagulation Use in High-risk Atrial Fibrillation Patients Stratified by CHADS 2 Score Population 622 patients aged 18 years; prospective study; January 2005 to December 2005; 23 cardiologists. Contraindications present in 4% of the population 286 patients with atrial fibrillation; single hospital database; prospective cohort study, 11 months; mean age 64.1 years 364 consecutive atrial fibrillation patients single hospital; retrospective chart review; 2003-2003; 1-year follow-up; 29.5% of patients had documented reasons (real or perceived) for not prescribing warfarin 196 patients admitted with a primary diagnosis of ischemic stroke and atrial fibrillation; retrospective chart review; Hamilton General Hospital; 1999-2004 5333 hospitalized and ambulant patients 2381patients for whom CHADS 2 score and treatment was known; 35 countries; ESC survey; high proportion university hospitals; figures estimated from Figure 2c 13,709 outpatients with chronic NVAF, US database 17,272 (hospitalized population with atrial fibrillation), US, Medicare population (bleeding score 2) 509 patients including 309 with chronic atrial fibrillation and 200 with paroxysmal atrial fibrillation, 5 university hospitals Prospective observational study; Sept 1999; follow-up: 2.0 0.4 years 2217 patients with nonvalvular atrial fibrillation Retrospective cohort study of in the Veterans Affairs Boston Healthcare System: 1997-2001; 28% (n 621) excluded due to contraindications # High-risk Patients (% of Total) n 273 (43.9%) n 78 (27.2%) n 227 (62%) n 106 (54%); excluded 18 with contraindications to oral anticoagulation n 1352 (57%) n 5539 (4) CHADS 2 Score 2 2 3 4 5 6 2 2 3 4 5 3 3 4 5 6 High-risk Patients (%) 62% 22% 11% 4.4% 0.7% 72% 23% 3.7% 1.1% * 51.5% 26.4% 16.3% 5.7% Actual Treatment (% of Atrial Fibrillation Patients) OAC Alone OAC AP AP Alone None 71.4% 46.7% 16.1% 5.1% 2.9% 0.3% 55% 36% 14% 3.7% 1.1% 48.9% 26% 14.1% 6.6% 2.2% 20.9% 10.3% 3.3% 5.5% 1.5% 0.4% 6.6% 4. 2.2% 0.4% 1.1% 1.1% 51.1% 25.6% 12.3% 9.7% 3.5% 1 * 54% N/A N/A N/A 2 2 3 4 5 6 2 2-3 4 53% 27% 12.7% 5.3% 1.1% 82.9% 17.1% 56.9% 30.7% 15.9% 6.5% 3.1% 0.7% 50.9% 41.9% 8.2% 3.8% 0.6% 1.4% 1.3% 0.3% 0.2% 20.9% 16.2% 4.7% 32.2% 17.5% 8.1% 4.6% 1.8% 0.2% 10.7% 9.3% 1.4% N/A 1 * 64.6% N/A N/A N/A n 98 (19.2%) n 1179 (73.9% of those with no contraindications) 3 4 5 2 2 3 4 5 6 * 36.6% 30.7% 17.8% 10.9% 3.9% 56% 72% 92% 38.8% 12.4% 11. 8.4% 5.1% 1.8% N/A 34% 23% 8% 6.4% 4.2% 1.6% 0.4% 0.2% 0. 18.9% 16.2% 2.7% 1 5% N/A N/A N/A AF atrial fibrillation; AP antiplatelet; CHADS 2 congestive heart failure, hypertension, age 75 years, diabetes mellitus, and prior stroke or transient ischemic attack; GP general practitioner; HMO health management organisation; N/A not available; NVAF nonvalvular atrial fibrillation; OAC oral anticoagulation; TIA transient ischemic attack. *Contraindications taken into account. Ogilvie et al Anticoagulant Underuse in High-risk Atrial Fibrillation 645.e4