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The Global Burden of Atrial Fibrillation and Stroke
CHEST
Original Research CARDIOVASCULAR DISEASE
The Global Burden of Atrial Fibrillation and Stroke A Systematic Review of the Epidemiology of Atrial Fibrillation in Regions Outside North America and Europe Gregory Y. H. Lip, MD; Carolyn M. Brechin, PhD; and Deirdre A. Lane, PhD
Background: Although atrial fibrillation (AF) is accepted as the most common sustained cardiac arrhythmia, most published epidemiologic studies focus on predominantly white populations in North America or Europe, and information on AF in nonwhite populations is scarce. The objective of this study was to undertake a systematic review of the published literature on the epidemiology of AF in other regions. Methods: Systematic literature searches (MEDLINE; 1990-2010) identified epidemiologic studies reporting on the prevalence or incidence of AF, stroke in AF, risk factors for AF, or the use of antithrombotic therapy in countries outside North America and Europe. This report presents a descriptive analysis of the data; no meta-analysis was planned. Results: Many of the 38 articles identified were from the Far East, although Australia, New Zealand, the Middle East, and South America were also represented. The reported prevalence of AF varied among countries, with different ranges in community- and hospital-based studies (0.1%-4% and 2.8%-14%, respectively). The use of anticoagulant therapy varied widely among countries and studies, as did the reported prevalence of stroke in patients with AF (2.8%-24.2%). Conclusions: High-quality epidemiologic studies are clearly required to improve understanding of the worldwide burden of AF and stroke in AF. Major improvements in the provision of thromboprophylaxis are also needed in many countries, given the high proportion of untreated patients who are, hence, at risk of stroke. CHEST 2012; 142(6):1489–1498 Abbreviations: AF 5 atrial fibrillation; INR 5 international normalized ratio
fibrillation (AF) has been described as the Atrial most common sustained cardiac arrhythmia, with
a prevalence of 1% to 2% in the general population in North America and Europe.1-3 The prevalence of AF increases with age, from 0.5% at age 50 to 59 years to almost 9% at age 80 to 89 years.4 More than 6 million Europeans and an estimated 2.3 million people in the United States have AF, and it is estimated that the prevalence will at least double in the next 50 years as the population ages and its size increases.1,2,5 AF may be present in 3% to 6% of acute medical admissions in the United Kingdom,6,7 and among patients with acute stroke, appropriate cardiac monitoring would detect AF in about one in 20 patients.8,9 AF is estimated to be associated with approximately 15% of all strokes.10 Increased use and improved methods of prolonged cardiac monitoring may increase the reported prevalence of AF among patients who have had a stroke.11
Most of the data on the clinical epidemiology of AF has been derived from published studies on predominantly white populations in North America or Europe, and information on AF in nonwhite populations is scarce. Furthermore, data based on hospital-centered attendances may give an inappropriate view of the For editorial comment see page 1368 clinical epidemiology of AF, because only one-third of patients with AF may have been admitted to hospital.12 For example, hospital-based surveys report ischemic heart disease and heart failure as the most common etiologic factors for AF,6 whereas community-based studies identify hypertension as the most common etiologic factor.12,13 In the UK-based West Birmingham AF Project, the prevalence of AF was 2.4% in two general practices,12
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and further extension of this project found that the prevalence of AF was lower among Indo-Asians, at 0.6%.14 Other studies have reported a lower incidence of AF in black populations compared with white populations.1,15,16 There are many risk factors for developing AF, and the main etiologic factors may differ among ethnic groups. In a multiethnic community within the United Kingdom, for example, the most common etiologic factor for AF among Afro-Caribbeans was hypertension, whereas among Indo-Asians, ischemic heart disease and diabetes were the most common.6 The aim of this study was to undertake a systematic review of the published literature on the epidemiology of AF in regions outside North America and Europe. Given the recognized differences between community-based and hospital-based epidemiologic studies, these were identified separately. No formal meta-analysis was intended or considered appropriate for this systematic review, owing to the apparent heterogeneity of the reported studies.
trials were excluded because they were considered unlikely to reflect community populations owing to restrictive eligibility criteria. Full-text articles, and English language translations as required, were obtained for all studies meeting the eligibility criteria based on review of abstracts. Articles meeting the eligibility criteria following review of the full text were selected for data extraction. When more than one report on the same cohort had been published, data were extracted from the most recent or main publication and earlier or secondary publications were excluded unless they provided additional relevant data. The following items were extracted from each article or calculated from the data presented: setting (including whether the study was community or hospital based); study population size and description (including any eligibility criteria); study design and dates; prevalence and incidence of AF; prevalence and incidence of stroke in patients with AF; prevalence of comorbidities or risk factors for AF among study participants with AF (prevalence of the comorbidities among participants without AF and results of any statistical analyses were extracted, if available); and the proportion of patients with AF receiving antithrombotic therapy (including a breakdown by type of agent, if provided).
Results Materials and Methods Comprehensive literature searches were performed using MEDLINE for studies published between January 1, 1990, and October 14, 2010, that reported on the epidemiology of AF, stroke in AF, risk factors for AF, or antithrombotic therapy use in AF, in populations outside North America and Europe. Search terms included “atrial fibrillation,” “epidemiology,” “prevalence,” “incidence,” “risk factors,” “stroke,” “thromboembolism,” “transient ischemic attack,” and names of countries and regions, excluding North America and Europe (Western and Eastern), based on world regions defined by the World Health Organization.17 See e-Appendix 1 for full search strings. The articles retrieved by the search were screened by title and selected for further review if they reported the prevalence or incidence of AF, stroke in AF, risk factors or comorbidities associated with AF, or the proportion of patients with AF receiving antithrombotic therapy, for a population in a country of interest. Both community- and hospital-based studies were included, and there were no language restrictions. Articles were excluded if data were presented for a North American or European population only or for a population of mixed nationalities including North Americans or Europeans, or if the country of study was not specified. Other exclusion criteria included study populations of , 750 people, epidemiologic studies focusing on specific patient populations or diseases other than AF, and clinical trials. Clinical Manuscript received November 11, 2011; revision accepted March 2, 2012. Affiliations: From the University of Birmingham Centre for Cardiovascular Sciences (Drs Lip and Lane), City Hospital, Birmingham; and the Research Evaluation Unit (Dr Brechin), Oxford PharmaGenesis Ltd, Oxford, England. Funding/Support: Funding for the systematic literature review was provided by Bayer Healthcare AG. Correspondence to: Gregory Y. H. Lip, MD, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, B18 7QH, England; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.11-2888
A total of 692 articles were retrieved by literature searches for reports on the epidemiology of AF in regions outside North America and Europe. Of these, 38 articles qualified for inclusion according to the prespecified eligibility criteria (Fig 1). Communitybased studies accounted for 23 of the included articles; the remaining 15 articles described hospital-based cohorts. The majority of the included studies were performed in Japan (14 articles) or China (eight articles). Other countries represented among the selected articles were Australia, Kuwait, India, Malaysia, New Zealand, Qatar, Singapore, South Korea (all one article each); Thailand and Brazil (two articles each); and Taiwan (four articles). Some articles that were excluded because of the small size of the study population reported on countries not represented among the eligible articles, including African countries (12 articles) and Middle Eastern countries (Iran, Jordan, Saudi Arabia; eight articles) as well as Chile and Mexico (five articles). Although some of these may have fulfilled other exclusion criteria, this observation suggests that epidemiologic research on AF may be taking place in other countries, but resources may not be available for larger studies. Incidence of AF Only six studies reported the incidence of newonset AF among their cohorts,18-23 three in communitybased cohorts18-20 and three in hospital-based cohorts.21-23 Dabdoob et al22 reported the overall annual incidence of AF in Qatar, although these data were derived from a hospital-based cohort and the methodology for extrapolating to the overall population was unclear.
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Figure 1. Literature search and review process.
The time period in which the incidence of AF was assessed was during the 1990s to the mid-2000s in the majority of studies,19-23 and the incidence of AF varied markedly among the cohorts. The lowest incidence of AF was in Taiwan, reported as 1.16 and 0.76 per 1,000 person-years in women, and 1.37 and 1.68 per 1,000 person-years in men, in a large-scale hospital-based study and a community-based study, respectively.20,23 The overall incidence of AF in Japan was 2.2 per 1,000 person-years in a large-scale community-based cohort,19 and incidences of higher than 7% per year were reported in smaller studies from China and Qatar.21,22 Prevalence of AF in Community-Based Studies The reported prevalence of AF varied among countries, ranging from 0.1% in India24 to 4% in Australia25 (Fig 2). Among the nine Japanese community-based cohorts,18,19,26-33 the prevalence of AF was consistent, ranging from 0.6% to 1.6%, and a similar prevalence
was reported in Taiwan (1.1%).20 The prevalence of AF was more variable among the Chinese and Thai community-based cohorts, ranging from 0.8% to 2.8%34-37 and 0.4% to 2.2%,38,39 respectively. In all the studies comparing the prevalence of risk factors for AF in patients with and without the disease, the prevalence of AF rose with increasing age and was usually higher in men than in women.19,20,26,27,30,31,35-37,40-42 In most studies, a large proportion of people with AF (57%-98%) were aged 60 years or older,20,26,35,37,42 although in one Thai study, the majority of people with AF were between the ages of 45 and 64 years.39 The distribution of AF by age was similar in the studies that reported it, with prevalences of 0.2% to 0.7% and 0.0% to 0.1% in men and women, respectively, aged 40 to 49 years, and up to 4.4% to 7.9% and 2.2% to 6.4% in men and women, respectively, aged over 80 years.27,31,40 Valvular heart disease was reported as a comorbidity in three community-based studies in Chinese or Japanese cohorts.18,30,36 Based on these reports, up to 22% of AF cases may be secondary
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Figure 2. Prevalence of atrial fibrillation reported in community-based studies from countries outside North America and Europe. The overall prevalence is presented where available; otherwise, the prevalence in men and women is presented separately.
to valvular heart disease in these populations. Hypertension was a common risk factor for AF in many countries19,20,26,27,30,35,36,41,42 (e-Appendix 1, e-Table 1), as were coexisting cardiac disease and diabetes mellitus in China, Japan, South Korea, and Taiwan.18,20,26,27,30,36,37,42 Prevalence of AF in Hospital-Based Studies
the use of antithrombotic therapy,21,43,45-50,53,54 although the proportion of patients receiving oral anticoagulant or antiplatelet therapy was highly variable (7%-60% and 17%-58%, respectively), with some patients (22%-47%) apparently not receiving any antithrombotic treatment.21,43,45,49,53,54 In the two studies that made the comparison, the use of oral anticoagulants increased between admission
The prevalence of AF was higher among the hospitalbased cohorts than in community studies, ranging widely from 2.8% in Malaysia to 14% in Japan (Fig 3).43-48 None of the Chinese studies reported the prevalence of AF among hospital-based cohorts, and the majority of hospital-based studies simply reported the prevalence of risk factors for AF in the cohort. Valvular heart disease and rheumatic heart disease were reported as comorbidities in 12% to 27%22,23,43,46,47,49,50 and 6% to 24%,21,48,51 respectively, of patients with AF. Few studies compared the prevalence of risk factors in patients with and without AF, although increasing age was associated with a greater prevalence of AF.43,51 Use of Antithrombotic Therapy Only five community-based studies reported the use of antithrombotic therapy in patients with AF.32,36,37,41,52 The use of warfarin was very low in China, reported at 0.5% and 2.7% in two separate studies,36,37 but high in Japan (70.1%).32 Acetylsalicylic acid was employed as antithrombotic therapy in about one-third or more of patients,32,36,37,52 and a small proportion of patients (approximately 5%-7%) received other antiplatelet drugs.32,52 Most of the hospital-based studies reported
Figure 3. Prevalence of atrial fibrillation reported in hospitalbased studies from countries outside Europe and North America.
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and discharge or a later follow-up visit.45,47 Older patient age was associated with lower prescribing of oral anticoagulants in the two studies that analyzed antithrombotic therapy by age.45,49 Incidence and Prevalence of Stroke in Patients With AF The incidence of stroke and embolic events was reported in only one community-based and three hospital-based studies.20,43,45,49 Among hospitalized patients, the incidence of embolic events (including stroke) ranged from 1.7% per year49 to 5.6% during a mean follow-up of 13.7 months.45 The prevalence of stroke among patients with AF in community-based cohorts (six studies) was similar in China,36,37 Japan,32 Singapore,41 and Taiwan52 at 13.0% to 15.4%, but much lower in South Korea at 2.8%.42 There was variability in the reported prevalence of stroke among patients with AF in hospital-based cohorts (eight studies), which ranged from 3.1% to 24.2%21,23,43,45,47,48,50,53,55 (e-Appendix 1, e-Table 1). The prevalence of stroke did not seem to be related to the level of warfarin use in different countries; the studies that reported the highest (70.1%) and lowest (2.7%) warfarin use observed a similar stroke prevalence (14.3% and 13.0%, respectively).32,37 Discussion This systematic review reveals marked variability in the reported prevalence of AF among countries outside North America and Europe, and clearly illustrates the differences in prevalence data derived from community- and hospital-based cohort studies. The use of antithrombotic therapy has been shown to vary widely among countries and among cohorts from the same country, and such variation is also shown in the reported prevalence of stroke. Differences in the availability of data from suitably sized populations were also apparent. The paucity of data was particularly striking for India: only one relatively small-scale study qualified for inclusion in this review. The searches retrieved few studies from South America and the Middle East, and no African studies met the eligibility criteria, although additional studies have been published since the original systematic searches were performed, including a hospital-based study from South Africa56 and a report on the design of a registry in the Middle East.57 There remains a clear need for additional high-quality epidemiologic studies in countries outside North America and Europe to provide a better definition of the burden of AF, and of stroke in AF, in these regions. In community-based studies, there was a higher prevalence of AF in Brazil (2.4%) and Australia (4%)25,40 than in Europe and North America (1%-2%),1-3
although this was based on only one study in each country. However, the prevalence in countries such as Japan,18,19,26,27,29-31 South Korea,42 Taiwan,20,58 and Singapore41 was similar to rates in North America and Europe. Compared with the other countries in the Far East, the reported prevalence of AF in China34-37 was of a similar magnitude but showed greater variability among studies. Interestingly, there was only one community study identified from India, which reported a prevalence of AF of 0.1%24; this study included younger participants (aged 15 years) from only one village in the Himalayas. Although based on a single small study, this low prevalence of AF among Indo-Asians is consistent with data from the West Birmingham AF Project and the E-Echocardiographic Heart of England Screening Study.14,59 Perhaps not surprisingly, the prevalence of AF in hospital-based studies was much higher than in community-based cohorts.43-48,50 This observation is consistent with data from Western countries6,7,12 and the recently published South African study in which 4.6% of new cardiac patients presented with AF during the 3-year study period.56 The differences seen here in the prevalence of AF and of stroke in AF across studies may reflect ethnic differences in the risk of developing AF, differences in age distribution among the study populations, and variability in assessments and study methodology. Few studies reported the incidence of AF,18-23 and the method of expressing incidence differed among them, making any comparison difficult. Large-scale population-based studies in North America and Europe have reported incidences of 3.68 and 9.9 per 1,000 patient-years, respectively, based on data from the year 2000 and 1990 to 1999.5,60 In the community studies in this systematic review, the prevalence of AF increased with increasing age and was generally higher in men than in women,19,20,26,27,30,31,35-37,40-42 consistent with data from North America and Europe.1,4,60 Hypertension was the most common risk factor for AF among the community-based cohorts,19,20,26,27,30,35,36,41,42 and cardiovascular disease and diabetes mellitus were also frequently associated with AF,18,20,26,27,30,36,37,42 in line with observations from North American and European populations.5,61,62 AF may be secondary to valvular heart disease in up to 22% of patients with the arrhythmia, according to community-based studies included in the present review.18,30,36 However, this may be an underestimate of the burden of AF secondary to valvular heart disease in regions outside North America and Europe, given the small number of studies that assessed this comorbidity and the lack of high-quality, relevant studies from less affluent countries. African countries, for example, may have a high prevalence of rheumatic fever and associated valvular heart disease.
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This systematic review suggests that the use of antithrombotic therapy varies markedly among countries, and among patients managed in the community and those treated in hospital. The use of warfarin was very low in community-based cohorts in some countries, such as China (0.5%-2.7%),36,37 but high in Japan (70.1%),32 and acetylsalicylic acid was more commonly used than warfarin. Although warfarin use was, in general, greater among patients with AF in the hospitalbased cohorts than among those in community-based cohorts, many patients in both types of cohort did not receive any form of antithrombotic therapy. Indeed, the use of warfarin depends on local guidelines and access to the facilities for regular monitoring of international normalized ratio (INR); this, in turn, requires appropriate local and national infrastructure and resources. The combined costs of medication, trained personnel, and local facilities to monitor INR may be too high to provide anticoagulation services in some areas. Furthermore, awareness of the value of thromboprophylaxis in AF is also paramount to the uptake of available treatment options. It is important to note that oral anticoagulation also continues to be underused in North American and European populations; a recent systematic review reported that in the majority of studies retrieved (21 of 29), , 60% of patients with AF and prior stroke or transient ischemic attack received oral anticoagulation.63 The underuse of oral anticoagulation therapy in patients with AF at risk of stroke is likely due, in part, to concerns over the increased risk of bleeding associated with anticoagulation. The present systematic review did not set out to investigate the incidence of bleeding events, or risk factors for bleeding, in patients with AF outside Europe and North America, but these are clearly important areas for research. Given that many risk factors for anticoagulationrelated bleeding are also risk factors for stroke (and how bleeding risk is multifactorial),64-66 there is a clear need for a simple bleeding risk stratification scheme to aid clinical decision making on anticoagulation. The recent European Society of Cardiology guidelines2 recommend use of the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly [. 65], drugs/alcohol concomitantly) score, a bleeding risk stratification scheme that has now been validated in multiple independent cohorts.67,68 In combination with the stroke risk stratification schemes, such as CHA2DS2-VASc (congestive heart failure, hypertension, age 75 [doubled], diabetes, stroke [doubled], vascular disease, age 65-74, and sex category [female]),69 the HAS-BLED score can help decision making, balancing stroke against bleeding risk among patients with AF.67 These schemes could potentially provide
valuable clinical tools for the management of AF in regions outside Europe and North America, although validation in the relevant populations is probably needed to account for potential region-specific differences in risk factors. Although limitations in access to health care, availability of appropriate facilities, and physician awareness may all contribute to suboptimal anticoagulation, ethnic differences in patient perceptions and understanding of warfarin use in AF have also been reported.70 In the West Birmingham AF Project, only a minority of south Asians and Afro-Caribbeans with AF felt that their doctor had given them enough information about their warfarin therapy. Many patients from these ethnic groups reported that they were careless about taking their warfarin and had limited knowledge of AF and of the risks, actions, and benefits of warfarin.70 The prevalence of stroke among patients with AF varied among countries (2.8%-24.2%) and did not seem to be related to the reported level of warfarin use. Two community-based studies from China reported low warfarin use but a stroke prevalence (13%) similar to that reported in a Japanese cohort (14%) in which more than two-thirds of patients were receiving warfarin. These inconsistencies likely exist because most studies did not set out to assess the incidence of stroke in relation to warfarin use. Stroke prevalence was generally assessed from patient medical histories and therefore would not necessarily be expected to reflect current warfarin use, given that the provision of antithrombotic therapy may have changed over time. Underreporting, methodologic differences, and small sample sizes may also have contributed to the observed differences among studies. Recent clinical trials that have included large numbers of patients from nonNorth American or non-European countries have shown the beneficial effect of anticoagulation in preventing stroke.71-73 However, one of these studies showed that the quality of INR monitoring, as reflected by the average time in the therapeutic range, varied widely among countries, with low rates being evident in some countries in the Far East.74 Guideline-adherent management results in the best outcomes for stroke prevention,75,76 and several international guidelines for stroke prevention in AF are now available.2,77-80 However, guidelines need to be tailored to local clinical practice, taking into account how best to determine the risk of stroke and communicate the need for, as well as manage the provision of, anticoagulation monitoring. Although national AF guidelines are available in Japan,81 many Asian countries simply adopt American or European guidelines. With respect to risk stratification for stroke in AF, several schemes are in existence, with some clinically relevant differences among them; producing a clear,
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unified set of recommendations may also facilitate warfarin use in all patients who are eligible.82 New oral anticoagulants in development, which do not require routine monitoring,71-73 may have an impact on the management of AF. The studies in this systematic review demonstrate significant heterogeneity, and, thus, no formal metaanalysis was performed. There was wide variation in the sample size (ranging from 963 to 162,340 patients), study design (including community- vs hospital-based, retrospective chart reviews, registries, and formal epidemiologic screenings), sampling procedure, age of population, recording of risk factors, and verification of comorbidities and stroke/embolic events (eg, by imaging or objective verification). The method of AF diagnosis also varied (by a single ECG or with reference to patient medical history), meaning that some studies may have included patients with clinically silent AF, whereas others may have missed such patients, leading to underestimation of prevalence. The definition and reporting of stroke differed among studies; some gave a breakdown by type of stroke (eg, ischemic or hemorrhagic) or reported the prevalence or incidence of transient ischemic attack and other embolic events, whereas other studies did not provide these data. In addition, geographic differences, socioeconomic differences, and the quality of the conduct of the studies will all have had an impact on the observed prevalence of AF and stroke and the reported use of antithrombotic therapy. Indeed, health care in countries such as Australia or Japan would be comparable to North America and Europe, and the ethnic composition of, for example, Australia is probably closer to that of present-day United Kingdom than, for example, Thailand. Conclusions High-quality epidemiologic studies are needed to improve our understanding of the global burden of AF, along with greater efforts to improve the provision of thromboprophylaxis in many countries. The data presented here suggest that there is a highly variable prevalence of AF among countries, with low rates reported in an Indian study and several Chinese cohorts, and other studies from the Far East reporting values more in line with the prevalence in North America and Europe. In this analysis, the use of anticoagulant therapy varied widely, as did the reported prevalence of stroke in patients with AF. Given the population sizes of India and China, even if the prevalence of AF were relatively low in these countries, the number of patients with untreated AF, and hence at risk of stroke, may be great, and the impact on health-care resources therefore considerable.
Acknowledgments Author contributions: Dr Lip: contributed to the idea for the article and wrote the first draft of the text and subsequent revisions. Dr Brechin: contributed to the systematic review, formulated the evidence tables, and contributed manuscript revisions. Dr Lane: contributed to the drafting of the text and manuscript revisions. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Lip has served as a consultant for Bayer; Astellas Pharma US, Inc; Merck & Co, Inc; AstraZeneca; Sanofi-Aventis; Bristol-Myers Squibb/Pfizer, Inc; and Boehringher Ingelheim GmbH and has been on the speakers bureau for Bayer; Sanofi-Aventis; Bristol-Myers Squibb/Pfizer, Inc; and Boehringher Ingelheim GmbH. Dr Brechin is an employee of Oxford PharmaGenesis Limited, which has received project funding from Bayer HealthCare AG. Dr Lane has received funding for research from Bayer and has been on the speakers’ bureau for Bayer; Bristol-Myers Squibb/Pfizer, Inc; and Boehringer Ingelheim GmbH. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript. Other contributions: Editorial assistance was provided by Oxford Pharmagenesis Ltd. Additional information: The e-Appendix and e-Table can be found in the “Supplemental Materials” area of the online article.
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measurement for heart disease screening in a Japanese population. Heart. 2002;87(2):131-135. Ohsawa M, Okayama A, Sakata K, et al. Rapid increase in estimated number of persons with atrial fibrillation in Japan: an analysis from national surveys on cardiovascular diseases in 1980, 1990 and 2000. J Epidemiol. 2005;15(5):194-196. Ohsawa M, Okayama A, Okamura T, et al. Mortality risk attributable to atrial fibrillation in middle-aged and elderly people in the Japanese general population: nineteen-year follow-up in NIPPON DATA80. Circ J. 2007;71(6):814-819. Ohsawa M, Itai K, Tanno K, et al. Cardiovascular risk factors in the Japanese northeastern rural population. Int J Cardiol. 2009;137(3):226-235. Uchiyama S, Shibata Y, Hirabayashi T, et al; J-TRACE Investigators. Risk factor profiles of stroke, myocardial infarction, and atrial fibrillation: a Japanese Multicenter Cooperative Registry. J Stroke Cerebrovasc Dis. 2010;19(3):190-197. Watanabe H, Tanabe N, Watanabe T, et al. Metabolic syndrome and risk of development of atrial fibrillation: the Niigata preventive medicine study. Circulation. 2008;117(10): 1255-1260. Mu HY, Qiu P, Lu WH, et al. Electrocardiogram Minnesota codings from 30 000 adult cases with Kazakh ethnicity in Xinjiang, China [in Chinese]. Zhonghua Liu Xing Bing Xue Za Zhi. 2010;31(4):451-454. Long MJ, Jiang CQ, Lam TH, et al. Atrial fibrillation and obesity among older Chinese: the Guangzhou Biobank Cohort Study. Int J Cardiol. 2011;148(1):48-52. Zhang X, Zhang S, Li Y, et al. Association of obesity and atrial fibrillation among middle-aged and elderly Chinese. Int J Obes (Lond). 2009;33(11):1318-1325. Zhou Z, Hu D. An epidemiological study on the prevalence of atrial fibrillation in the Chinese population of mainland China. J Epidemiol. 2008;18(5):209-216. Assantachai P, Panchavinnin P, Pisalsarakij D. An electrocardiographic survey of elderly Thai people in the rural community. J Med Assoc Thai. 2002;85(12):1273-1279. Kiatchoosakun S, Pachirat O, Chirawatkul A, Choprapawan C, Tatsanavivat P. Prevalence of cardiac arrhythmias in Thai community. J Med Assoc Thai. 1999;82(7):727-733. Kawabata-Yoshihara LA, Benseñor IM, Kawabata VS, Menezes PR, Skazufca M, Lotufo PA. Prevalence of electrocardiographic findings in elderly individuals: the Sao Paulo aging & health study. Arq Bras Cardiol. 2009;93(6):602-607, 651-656. Yap KB, Ng TP, Ong HY. Low prevalence of atrial fibrillation in community-dwelling Chinese aged 55 years or older in Singapore: a population-based study. J Electrocardiol. 2008;41(2):94-98. Jeong JH. Prevalence of and risk factors for atrial fibrillation in Korean adults older than 40 years. J Korean Med Sci. 2005;20(1):26-30. Tomita F, Kohya T, Sakurai M, et al; Hokkaido Atrial Fibrillation Study Group. Prevalence and clinical characteristics of patients with atrial fibrillation: analysis of 20,000 cases in Japan. Jpn Circ J. 2000;64(9):653-658. Suzuki S, Yamashita T, Ohtsuka T, et al. Body size and atrial fibrillation in Japanese outpatients. Circ J. 2010;74(1):66-70. Fornari LS, Calderaro D, Nassar IB, et al. Misuse of antithrombotic therapy in atrial fibrillation patients: frequent, pervasive and persistent. J Thromb Thrombolysis. 2007;23(1):65-71. Freestone B, Rajaratnam R, Hussain N, Lip GY. Admissions with atrial fibrillation in a multiracial population in Kuala Lumpur, Malaysia. Int J Cardiol. 2003;91(2-3):233-238. Stewart FM, Singh Y, Persson S, Gamble GD, Braatvedt GD. Atrial fibrillation: prevalence and management in an acute general medical unit. Aust N Z J Med. 1999;29(1):51-58.
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48. Ridha M, Al-Sayed Amin A, Saleh SA, et al. The prevalence of atrial fibrillation among acute medical admissions in Kuwait. Med Princ Pract. 2005;14(3):136-139. 49. Research Group for Antiarrhythmic Drug Therapy. Survey of atrial fibrillation and thromboembolism in the elderly: a multicenter cooperative study [in Japanese]. J Cardiol. 1999; 33(1):27-35. 50. Suzuki S, Yamashita T, Ohtsuka T, et al. Prevalence and prognosis of patients with atrial fibrillation in Japan: a prospective cohort of Shinken Database 2004. Circ J. 2008;72(6): 914-920. 51. Liu Y, Liu H, Dong L, Chen J, Guo J. Prevalence of atrial fibrillation in hospitalized patients over 40 years old: ten-year data from the People’s Hospital of Peking University. Acta Cardiol. 2010;65(2):221-224. 52. Lin LJ, Cheng MH, Lee CH, Wung DC, Cheng CL, Kao Yang YH. Compliance with antithrombotic prescribing guidelines for patients with atrial fibrillation—a nationwide descriptive study in Taiwan. Clin Ther. 2008;30(9): 1726-1736. 53. Sun Y, Hu D, Li K, Zhou Z. Predictors of stroke risk in native Chinese with nonrheumatic atrial fibrillation: retrospective investigation of hospitalized patients. Clin Cardiol. 2009;32(2):76-81. 54. Hsieh FI, Lien LM, Chen ST, et al; Taiwan Stroke Registry Investigators. Get With the Guidelines-Stroke performance indicators: surveillance of stroke care in the Taiwan Stroke Registry: Get With the Guidelines-Stroke in Taiwan. Circulation. 2010;122(11):1116-1123. 55. Hu DY, Sun YH, Zhou ZQ, et al. Risk factors for stroke in Chinese with non valvular atrial fibrillation: a case-control study [in Chinese]. Zhonghua Nei Ke Za Zhe. 2003;42(3): 157-161. 56. Sliwa K, Carrington MJ, Klug E, et al. Predisposing factors and incidence of newly diagnosed atrial fibrillation in an urban African community: insights from the Heart of Soweto Study. Heart. 2010;96(23):1878-1882. 57. Zubaid M, Rashed WA, Alsheikh-Ali AA, et al; Gulf Survey of Atrial Fibrillation Events (Gulf SAFE) Investigators. Gulf Survey of Atrial Fibrillation Events (Gulf SAFE): design and baseline characteristics of patients with atrial fibrillation in the Arab Middle East. Circ Cardiovasc Qual Outcomes. 2011;4(4):477-482. 58. Wang TD, Chen WJ, Su SS, et al. Increased levels of tissue plasminogen activator antigen and factor VIII activity in non valvular atrial fibrillation: relation to predictors of thromboembolism. J Cardiovasc Electrophysiol. 2001;12(8): 877-884. 59. Gill PS, Calvert M, Davis R, et al. The prevalence of left ventricular systolic dysfunction and AF in 5354 South Asian and African Caribbean subjects: results from the EthnicEchocardiographic Heart of England (E-ECHOES) study. Abstract presented at European Society of Cardiology Congress 2010, Stockholm, Sweden, 28 August-September 1, 2010. Eur Heart J. 2010;31(suppl 1):599. 60. 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(8):949-953. 61. Nabauer M, Gerth A, Limbourg T, et al. The Registry of the German Competence NETwork on Atrial Fibrillation: patient characteristics and initial management. Europace. 2009;11(4):423-434. 62. Nieuwlaat R, Capucci A, Camm AJ, et al; European Heart Survey Investigators. Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J. 2005;26(22): 2422-2434.
63. Ogilvie IM, Newton N, Welner SA, Cowell W, Lip GY. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med. 2010;123(7):638-645. 64. Lip GY, Andreotti F, Fauchier L, et al; European Heart Rhythm Association. Bleeding risk assessment and management in atrial fibrillation patients. Executive summary of a position document from the European Heart Rhythm Association [EHRA], endorsed by the European Society of Cardiology [ESC] Working Group on Thrombosis. Thromb Haemost. 2011;106(6):997-1011. 65. Garcia DA, Lopes RD, Hylek EM. New-onset atrial fibrillation and warfarin initiation: high risk periods and implications for new antithrombotic drugs. Thromb Haemost. 2010;104(6):1099-1105. 66. Naganuma M, Shiga T, Sato K, et al. Clinical outcome in Japanese elderly patients with non-valvular atrial fibrillation taking warfarin: a single-center observational study. Thromb Res. 2011. 67. Olesen JB, Lip GY, Lindhardsen J, et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: a net clinical benefit analysis using a ‘real world’ nationwide cohort study. Thromb Haemost. 2011;106(4):739-749. 68. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. 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(5):1093-1100. 69. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. 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(2):263-272. 70. Lip GYH, Kamath S, Jafri M, Mohammed A, Bareford D. Ethnic differences in patient perceptions of atrial fibrillation and anticoagulation therapy: the West Birmingham Atrial Fibrillation Project. Stroke. 2002;33(1):238-242. 71. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361(12):1139-1151. 72. Connolly SJ, Eikelboom J, Joyner C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-817. 73. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. 74. Wallentin L, Yusuf S, Ezekowitz MD, et al; RE-LY investigators. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010;376(9745):975-983. 75. Nieuwlaat R, Olsson SB, Lip GY, et al; Euro Heart Survey Investigators; The Euro Heart Survey on Atrial Fibrillation. Guideline-adherent antithrombotic treatment is associated with improved outcomes compared with undertreatment in high-risk patients with atrial fibrillation. Am Heart J. 2007; 153(6):1006-1012. 76. Gorin L, Fauchier L, Nonin E, Charbonnier B, Babuty D, Lip GY. Prognosis and guideline-adherent antithrombotic treatment in patients with atrial fibrillation and atrial flutter: implications of undertreatment and overtreatment in real-life clinical practice; the Loire Valley Atrial Fibrillation Project. Chest. 2011;140(4):911-917. 77. Fuster V, Rydén LE, Cannom DS, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006
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Guidelines for the Management of Patients with Atrial Fibrillation: 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): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114(7):e257-e354. 78. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(suppl 6):546S2592S. 79. National Collaborating Centre for Chronic Conditions. Atrial Fibrillation: National Clinical Guideline for Management
in Primary and Secondary Care. London, England: Royal College of Physicians; 2006. 80. Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M; CCS Atrial Fibrillation Guidelines Committee. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol. 2011;27(1): 74-90. 81. JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2008): digest version. Circ J. 2010; 74(11):2479-2500. 82. Stroke Risk in Atrial Fibrillation Working Group. Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial fibrillation. Stroke. 2008;39(6): 1901-1910.
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Original Research CARDIOVASCULAR DISEASE
The Global Burden of Atrial Fibrillation and Stroke A Systematic Review of the Epidemiology of Atrial Fibrillation in Regions Outside North America and Europe Gregory Y. H. Lip, MD; Carolyn M. Brechin, PhD; and Deirdre A. Lane, PhD
Background: Although atrial fibrillation (AF) is accepted as the most common sustained cardiac arrhythmia, most published epidemiologic studies focus on predominantly white populations in North America or Europe, and information on AF in nonwhite populations is scarce. The objective of this study was to undertake a systematic review of the published literature on the epidemiology of AF in other regions. Methods: Systematic literature searches (MEDLINE; 1990-2010) identified epidemiologic studies reporting on the prevalence or incidence of AF, stroke in AF, risk factors for AF, or the use of antithrombotic therapy in countries outside North America and Europe. This report presents a descriptive analysis of the data; no meta-analysis was planned. Results: Many of the 38 articles identified were from the Far East, although Australia, New Zealand, the Middle East, and South America were also represented. The reported prevalence of AF varied among countries, with different ranges in community- and hospital-based studies (0.1%-4% and 2.8%-14%, respectively). The use of anticoagulant therapy varied widely among countries and studies, as did the reported prevalence of stroke in patients with AF (2.8%-24.2%). Conclusions: High-quality epidemiologic studies are clearly required to improve understanding of the worldwide burden of AF and stroke in AF. Major improvements in the provision of thromboprophylaxis are also needed in many countries, given the high proportion of untreated patients who are, hence, at risk of stroke. CHEST 2012; 142(6):1489–1498 Abbreviations: AF 5 atrial fibrillation; INR 5 international normalized ratio
fibrillation (AF) has been described as the Atrial most common sustained cardiac arrhythmia, with
a prevalence of 1% to 2% in the general population in North America and Europe.1-3 The prevalence of AF increases with age, from 0.5% at age 50 to 59 years to almost 9% at age 80 to 89 years.4 More than 6 million Europeans and an estimated 2.3 million people in the United States have AF, and it is estimated that the prevalence will at least double in the next 50 years as the population ages and its size increases.1,2,5 AF may be present in 3% to 6% of acute medical admissions in the United Kingdom,6,7 and among patients with acute stroke, appropriate cardiac monitoring would detect AF in about one in 20 patients.8,9 AF is estimated to be associated with approximately 15% of all strokes.10 Increased use and improved methods of prolonged cardiac monitoring may increase the reported prevalence of AF among patients who have had a stroke.11
Most of the data on the clinical epidemiology of AF has been derived from published studies on predominantly white populations in North America or Europe, and information on AF in nonwhite populations is scarce. Furthermore, data based on hospital-centered attendances may give an inappropriate view of the For editorial comment see page 1368 clinical epidemiology of AF, because only one-third of patients with AF may have been admitted to hospital.12 For example, hospital-based surveys report ischemic heart disease and heart failure as the most common etiologic factors for AF,6 whereas community-based studies identify hypertension as the most common etiologic factor.12,13 In the UK-based West Birmingham AF Project, the prevalence of AF was 2.4% in two general practices,12
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and further extension of this project found that the prevalence of AF was lower among Indo-Asians, at 0.6%.14 Other studies have reported a lower incidence of AF in black populations compared with white populations.1,15,16 There are many risk factors for developing AF, and the main etiologic factors may differ among ethnic groups. In a multiethnic community within the United Kingdom, for example, the most common etiologic factor for AF among Afro-Caribbeans was hypertension, whereas among Indo-Asians, ischemic heart disease and diabetes were the most common.6 The aim of this study was to undertake a systematic review of the published literature on the epidemiology of AF in regions outside North America and Europe. Given the recognized differences between community-based and hospital-based epidemiologic studies, these were identified separately. No formal meta-analysis was intended or considered appropriate for this systematic review, owing to the apparent heterogeneity of the reported studies.
trials were excluded because they were considered unlikely to reflect community populations owing to restrictive eligibility criteria. Full-text articles, and English language translations as required, were obtained for all studies meeting the eligibility criteria based on review of abstracts. Articles meeting the eligibility criteria following review of the full text were selected for data extraction. When more than one report on the same cohort had been published, data were extracted from the most recent or main publication and earlier or secondary publications were excluded unless they provided additional relevant data. The following items were extracted from each article or calculated from the data presented: setting (including whether the study was community or hospital based); study population size and description (including any eligibility criteria); study design and dates; prevalence and incidence of AF; prevalence and incidence of stroke in patients with AF; prevalence of comorbidities or risk factors for AF among study participants with AF (prevalence of the comorbidities among participants without AF and results of any statistical analyses were extracted, if available); and the proportion of patients with AF receiving antithrombotic therapy (including a breakdown by type of agent, if provided).
Results Materials and Methods Comprehensive literature searches were performed using MEDLINE for studies published between January 1, 1990, and October 14, 2010, that reported on the epidemiology of AF, stroke in AF, risk factors for AF, or antithrombotic therapy use in AF, in populations outside North America and Europe. Search terms included “atrial fibrillation,” “epidemiology,” “prevalence,” “incidence,” “risk factors,” “stroke,” “thromboembolism,” “transient ischemic attack,” and names of countries and regions, excluding North America and Europe (Western and Eastern), based on world regions defined by the World Health Organization.17 See e-Appendix 1 for full search strings. The articles retrieved by the search were screened by title and selected for further review if they reported the prevalence or incidence of AF, stroke in AF, risk factors or comorbidities associated with AF, or the proportion of patients with AF receiving antithrombotic therapy, for a population in a country of interest. Both community- and hospital-based studies were included, and there were no language restrictions. Articles were excluded if data were presented for a North American or European population only or for a population of mixed nationalities including North Americans or Europeans, or if the country of study was not specified. Other exclusion criteria included study populations of , 750 people, epidemiologic studies focusing on specific patient populations or diseases other than AF, and clinical trials. Clinical Manuscript received November 11, 2011; revision accepted March 2, 2012. Affiliations: From the University of Birmingham Centre for Cardiovascular Sciences (Drs Lip and Lane), City Hospital, Birmingham; and the Research Evaluation Unit (Dr Brechin), Oxford PharmaGenesis Ltd, Oxford, England. Funding/Support: Funding for the systematic literature review was provided by Bayer Healthcare AG. Correspondence to: Gregory Y. H. Lip, MD, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, B18 7QH, England; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.11-2888
A total of 692 articles were retrieved by literature searches for reports on the epidemiology of AF in regions outside North America and Europe. Of these, 38 articles qualified for inclusion according to the prespecified eligibility criteria (Fig 1). Communitybased studies accounted for 23 of the included articles; the remaining 15 articles described hospital-based cohorts. The majority of the included studies were performed in Japan (14 articles) or China (eight articles). Other countries represented among the selected articles were Australia, Kuwait, India, Malaysia, New Zealand, Qatar, Singapore, South Korea (all one article each); Thailand and Brazil (two articles each); and Taiwan (four articles). Some articles that were excluded because of the small size of the study population reported on countries not represented among the eligible articles, including African countries (12 articles) and Middle Eastern countries (Iran, Jordan, Saudi Arabia; eight articles) as well as Chile and Mexico (five articles). Although some of these may have fulfilled other exclusion criteria, this observation suggests that epidemiologic research on AF may be taking place in other countries, but resources may not be available for larger studies. Incidence of AF Only six studies reported the incidence of newonset AF among their cohorts,18-23 three in communitybased cohorts18-20 and three in hospital-based cohorts.21-23 Dabdoob et al22 reported the overall annual incidence of AF in Qatar, although these data were derived from a hospital-based cohort and the methodology for extrapolating to the overall population was unclear.
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Figure 1. Literature search and review process.
The time period in which the incidence of AF was assessed was during the 1990s to the mid-2000s in the majority of studies,19-23 and the incidence of AF varied markedly among the cohorts. The lowest incidence of AF was in Taiwan, reported as 1.16 and 0.76 per 1,000 person-years in women, and 1.37 and 1.68 per 1,000 person-years in men, in a large-scale hospital-based study and a community-based study, respectively.20,23 The overall incidence of AF in Japan was 2.2 per 1,000 person-years in a large-scale community-based cohort,19 and incidences of higher than 7% per year were reported in smaller studies from China and Qatar.21,22 Prevalence of AF in Community-Based Studies The reported prevalence of AF varied among countries, ranging from 0.1% in India24 to 4% in Australia25 (Fig 2). Among the nine Japanese community-based cohorts,18,19,26-33 the prevalence of AF was consistent, ranging from 0.6% to 1.6%, and a similar prevalence
was reported in Taiwan (1.1%).20 The prevalence of AF was more variable among the Chinese and Thai community-based cohorts, ranging from 0.8% to 2.8%34-37 and 0.4% to 2.2%,38,39 respectively. In all the studies comparing the prevalence of risk factors for AF in patients with and without the disease, the prevalence of AF rose with increasing age and was usually higher in men than in women.19,20,26,27,30,31,35-37,40-42 In most studies, a large proportion of people with AF (57%-98%) were aged 60 years or older,20,26,35,37,42 although in one Thai study, the majority of people with AF were between the ages of 45 and 64 years.39 The distribution of AF by age was similar in the studies that reported it, with prevalences of 0.2% to 0.7% and 0.0% to 0.1% in men and women, respectively, aged 40 to 49 years, and up to 4.4% to 7.9% and 2.2% to 6.4% in men and women, respectively, aged over 80 years.27,31,40 Valvular heart disease was reported as a comorbidity in three community-based studies in Chinese or Japanese cohorts.18,30,36 Based on these reports, up to 22% of AF cases may be secondary
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Figure 2. Prevalence of atrial fibrillation reported in community-based studies from countries outside North America and Europe. The overall prevalence is presented where available; otherwise, the prevalence in men and women is presented separately.
to valvular heart disease in these populations. Hypertension was a common risk factor for AF in many countries19,20,26,27,30,35,36,41,42 (e-Appendix 1, e-Table 1), as were coexisting cardiac disease and diabetes mellitus in China, Japan, South Korea, and Taiwan.18,20,26,27,30,36,37,42 Prevalence of AF in Hospital-Based Studies
the use of antithrombotic therapy,21,43,45-50,53,54 although the proportion of patients receiving oral anticoagulant or antiplatelet therapy was highly variable (7%-60% and 17%-58%, respectively), with some patients (22%-47%) apparently not receiving any antithrombotic treatment.21,43,45,49,53,54 In the two studies that made the comparison, the use of oral anticoagulants increased between admission
The prevalence of AF was higher among the hospitalbased cohorts than in community studies, ranging widely from 2.8% in Malaysia to 14% in Japan (Fig 3).43-48 None of the Chinese studies reported the prevalence of AF among hospital-based cohorts, and the majority of hospital-based studies simply reported the prevalence of risk factors for AF in the cohort. Valvular heart disease and rheumatic heart disease were reported as comorbidities in 12% to 27%22,23,43,46,47,49,50 and 6% to 24%,21,48,51 respectively, of patients with AF. Few studies compared the prevalence of risk factors in patients with and without AF, although increasing age was associated with a greater prevalence of AF.43,51 Use of Antithrombotic Therapy Only five community-based studies reported the use of antithrombotic therapy in patients with AF.32,36,37,41,52 The use of warfarin was very low in China, reported at 0.5% and 2.7% in two separate studies,36,37 but high in Japan (70.1%).32 Acetylsalicylic acid was employed as antithrombotic therapy in about one-third or more of patients,32,36,37,52 and a small proportion of patients (approximately 5%-7%) received other antiplatelet drugs.32,52 Most of the hospital-based studies reported
Figure 3. Prevalence of atrial fibrillation reported in hospitalbased studies from countries outside Europe and North America.
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and discharge or a later follow-up visit.45,47 Older patient age was associated with lower prescribing of oral anticoagulants in the two studies that analyzed antithrombotic therapy by age.45,49 Incidence and Prevalence of Stroke in Patients With AF The incidence of stroke and embolic events was reported in only one community-based and three hospital-based studies.20,43,45,49 Among hospitalized patients, the incidence of embolic events (including stroke) ranged from 1.7% per year49 to 5.6% during a mean follow-up of 13.7 months.45 The prevalence of stroke among patients with AF in community-based cohorts (six studies) was similar in China,36,37 Japan,32 Singapore,41 and Taiwan52 at 13.0% to 15.4%, but much lower in South Korea at 2.8%.42 There was variability in the reported prevalence of stroke among patients with AF in hospital-based cohorts (eight studies), which ranged from 3.1% to 24.2%21,23,43,45,47,48,50,53,55 (e-Appendix 1, e-Table 1). The prevalence of stroke did not seem to be related to the level of warfarin use in different countries; the studies that reported the highest (70.1%) and lowest (2.7%) warfarin use observed a similar stroke prevalence (14.3% and 13.0%, respectively).32,37 Discussion This systematic review reveals marked variability in the reported prevalence of AF among countries outside North America and Europe, and clearly illustrates the differences in prevalence data derived from community- and hospital-based cohort studies. The use of antithrombotic therapy has been shown to vary widely among countries and among cohorts from the same country, and such variation is also shown in the reported prevalence of stroke. Differences in the availability of data from suitably sized populations were also apparent. The paucity of data was particularly striking for India: only one relatively small-scale study qualified for inclusion in this review. The searches retrieved few studies from South America and the Middle East, and no African studies met the eligibility criteria, although additional studies have been published since the original systematic searches were performed, including a hospital-based study from South Africa56 and a report on the design of a registry in the Middle East.57 There remains a clear need for additional high-quality epidemiologic studies in countries outside North America and Europe to provide a better definition of the burden of AF, and of stroke in AF, in these regions. In community-based studies, there was a higher prevalence of AF in Brazil (2.4%) and Australia (4%)25,40 than in Europe and North America (1%-2%),1-3
although this was based on only one study in each country. However, the prevalence in countries such as Japan,18,19,26,27,29-31 South Korea,42 Taiwan,20,58 and Singapore41 was similar to rates in North America and Europe. Compared with the other countries in the Far East, the reported prevalence of AF in China34-37 was of a similar magnitude but showed greater variability among studies. Interestingly, there was only one community study identified from India, which reported a prevalence of AF of 0.1%24; this study included younger participants (aged 15 years) from only one village in the Himalayas. Although based on a single small study, this low prevalence of AF among Indo-Asians is consistent with data from the West Birmingham AF Project and the E-Echocardiographic Heart of England Screening Study.14,59 Perhaps not surprisingly, the prevalence of AF in hospital-based studies was much higher than in community-based cohorts.43-48,50 This observation is consistent with data from Western countries6,7,12 and the recently published South African study in which 4.6% of new cardiac patients presented with AF during the 3-year study period.56 The differences seen here in the prevalence of AF and of stroke in AF across studies may reflect ethnic differences in the risk of developing AF, differences in age distribution among the study populations, and variability in assessments and study methodology. Few studies reported the incidence of AF,18-23 and the method of expressing incidence differed among them, making any comparison difficult. Large-scale population-based studies in North America and Europe have reported incidences of 3.68 and 9.9 per 1,000 patient-years, respectively, based on data from the year 2000 and 1990 to 1999.5,60 In the community studies in this systematic review, the prevalence of AF increased with increasing age and was generally higher in men than in women,19,20,26,27,30,31,35-37,40-42 consistent with data from North America and Europe.1,4,60 Hypertension was the most common risk factor for AF among the community-based cohorts,19,20,26,27,30,35,36,41,42 and cardiovascular disease and diabetes mellitus were also frequently associated with AF,18,20,26,27,30,36,37,42 in line with observations from North American and European populations.5,61,62 AF may be secondary to valvular heart disease in up to 22% of patients with the arrhythmia, according to community-based studies included in the present review.18,30,36 However, this may be an underestimate of the burden of AF secondary to valvular heart disease in regions outside North America and Europe, given the small number of studies that assessed this comorbidity and the lack of high-quality, relevant studies from less affluent countries. African countries, for example, may have a high prevalence of rheumatic fever and associated valvular heart disease.
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This systematic review suggests that the use of antithrombotic therapy varies markedly among countries, and among patients managed in the community and those treated in hospital. The use of warfarin was very low in community-based cohorts in some countries, such as China (0.5%-2.7%),36,37 but high in Japan (70.1%),32 and acetylsalicylic acid was more commonly used than warfarin. Although warfarin use was, in general, greater among patients with AF in the hospitalbased cohorts than among those in community-based cohorts, many patients in both types of cohort did not receive any form of antithrombotic therapy. Indeed, the use of warfarin depends on local guidelines and access to the facilities for regular monitoring of international normalized ratio (INR); this, in turn, requires appropriate local and national infrastructure and resources. The combined costs of medication, trained personnel, and local facilities to monitor INR may be too high to provide anticoagulation services in some areas. Furthermore, awareness of the value of thromboprophylaxis in AF is also paramount to the uptake of available treatment options. It is important to note that oral anticoagulation also continues to be underused in North American and European populations; a recent systematic review reported that in the majority of studies retrieved (21 of 29), , 60% of patients with AF and prior stroke or transient ischemic attack received oral anticoagulation.63 The underuse of oral anticoagulation therapy in patients with AF at risk of stroke is likely due, in part, to concerns over the increased risk of bleeding associated with anticoagulation. The present systematic review did not set out to investigate the incidence of bleeding events, or risk factors for bleeding, in patients with AF outside Europe and North America, but these are clearly important areas for research. Given that many risk factors for anticoagulationrelated bleeding are also risk factors for stroke (and how bleeding risk is multifactorial),64-66 there is a clear need for a simple bleeding risk stratification scheme to aid clinical decision making on anticoagulation. The recent European Society of Cardiology guidelines2 recommend use of the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly [. 65], drugs/alcohol concomitantly) score, a bleeding risk stratification scheme that has now been validated in multiple independent cohorts.67,68 In combination with the stroke risk stratification schemes, such as CHA2DS2-VASc (congestive heart failure, hypertension, age 75 [doubled], diabetes, stroke [doubled], vascular disease, age 65-74, and sex category [female]),69 the HAS-BLED score can help decision making, balancing stroke against bleeding risk among patients with AF.67 These schemes could potentially provide
valuable clinical tools for the management of AF in regions outside Europe and North America, although validation in the relevant populations is probably needed to account for potential region-specific differences in risk factors. Although limitations in access to health care, availability of appropriate facilities, and physician awareness may all contribute to suboptimal anticoagulation, ethnic differences in patient perceptions and understanding of warfarin use in AF have also been reported.70 In the West Birmingham AF Project, only a minority of south Asians and Afro-Caribbeans with AF felt that their doctor had given them enough information about their warfarin therapy. Many patients from these ethnic groups reported that they were careless about taking their warfarin and had limited knowledge of AF and of the risks, actions, and benefits of warfarin.70 The prevalence of stroke among patients with AF varied among countries (2.8%-24.2%) and did not seem to be related to the reported level of warfarin use. Two community-based studies from China reported low warfarin use but a stroke prevalence (13%) similar to that reported in a Japanese cohort (14%) in which more than two-thirds of patients were receiving warfarin. These inconsistencies likely exist because most studies did not set out to assess the incidence of stroke in relation to warfarin use. Stroke prevalence was generally assessed from patient medical histories and therefore would not necessarily be expected to reflect current warfarin use, given that the provision of antithrombotic therapy may have changed over time. Underreporting, methodologic differences, and small sample sizes may also have contributed to the observed differences among studies. Recent clinical trials that have included large numbers of patients from nonNorth American or non-European countries have shown the beneficial effect of anticoagulation in preventing stroke.71-73 However, one of these studies showed that the quality of INR monitoring, as reflected by the average time in the therapeutic range, varied widely among countries, with low rates being evident in some countries in the Far East.74 Guideline-adherent management results in the best outcomes for stroke prevention,75,76 and several international guidelines for stroke prevention in AF are now available.2,77-80 However, guidelines need to be tailored to local clinical practice, taking into account how best to determine the risk of stroke and communicate the need for, as well as manage the provision of, anticoagulation monitoring. Although national AF guidelines are available in Japan,81 many Asian countries simply adopt American or European guidelines. With respect to risk stratification for stroke in AF, several schemes are in existence, with some clinically relevant differences among them; producing a clear,
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unified set of recommendations may also facilitate warfarin use in all patients who are eligible.82 New oral anticoagulants in development, which do not require routine monitoring,71-73 may have an impact on the management of AF. The studies in this systematic review demonstrate significant heterogeneity, and, thus, no formal metaanalysis was performed. There was wide variation in the sample size (ranging from 963 to 162,340 patients), study design (including community- vs hospital-based, retrospective chart reviews, registries, and formal epidemiologic screenings), sampling procedure, age of population, recording of risk factors, and verification of comorbidities and stroke/embolic events (eg, by imaging or objective verification). The method of AF diagnosis also varied (by a single ECG or with reference to patient medical history), meaning that some studies may have included patients with clinically silent AF, whereas others may have missed such patients, leading to underestimation of prevalence. The definition and reporting of stroke differed among studies; some gave a breakdown by type of stroke (eg, ischemic or hemorrhagic) or reported the prevalence or incidence of transient ischemic attack and other embolic events, whereas other studies did not provide these data. In addition, geographic differences, socioeconomic differences, and the quality of the conduct of the studies will all have had an impact on the observed prevalence of AF and stroke and the reported use of antithrombotic therapy. Indeed, health care in countries such as Australia or Japan would be comparable to North America and Europe, and the ethnic composition of, for example, Australia is probably closer to that of present-day United Kingdom than, for example, Thailand. Conclusions High-quality epidemiologic studies are needed to improve our understanding of the global burden of AF, along with greater efforts to improve the provision of thromboprophylaxis in many countries. The data presented here suggest that there is a highly variable prevalence of AF among countries, with low rates reported in an Indian study and several Chinese cohorts, and other studies from the Far East reporting values more in line with the prevalence in North America and Europe. In this analysis, the use of anticoagulant therapy varied widely, as did the reported prevalence of stroke in patients with AF. Given the population sizes of India and China, even if the prevalence of AF were relatively low in these countries, the number of patients with untreated AF, and hence at risk of stroke, may be great, and the impact on health-care resources therefore considerable.
Acknowledgments Author contributions: Dr Lip: contributed to the idea for the article and wrote the first draft of the text and subsequent revisions. Dr Brechin: contributed to the systematic review, formulated the evidence tables, and contributed manuscript revisions. Dr Lane: contributed to the drafting of the text and manuscript revisions. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Lip has served as a consultant for Bayer; Astellas Pharma US, Inc; Merck & Co, Inc; AstraZeneca; Sanofi-Aventis; Bristol-Myers Squibb/Pfizer, Inc; and Boehringher Ingelheim GmbH and has been on the speakers bureau for Bayer; Sanofi-Aventis; Bristol-Myers Squibb/Pfizer, Inc; and Boehringher Ingelheim GmbH. Dr Brechin is an employee of Oxford PharmaGenesis Limited, which has received project funding from Bayer HealthCare AG. Dr Lane has received funding for research from Bayer and has been on the speakers’ bureau for Bayer; Bristol-Myers Squibb/Pfizer, Inc; and Boehringer Ingelheim GmbH. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript. Other contributions: Editorial assistance was provided by Oxford Pharmagenesis Ltd. Additional information: The e-Appendix and e-Table can be found in the “Supplemental Materials” area of the online article.
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