Prevalence of Atrial Fibrillation in Korean Population

Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice and has been a major public health problem. The prevalence of AF globally has been reported to range from 0.4% to 2% in the adult population; however, the prevalence widely varies depending on the study population. Although AF prevalence in Asian population is about 1% lower than that in European and North American population, the number of AF patients in Asia is rapidly increasing concomitant with the increased aging of the population. However, previous studies that reported AF epidemiology in the Korean population are limited. According to a recent report based on the national health claims database, prevalence of AF in 2015 was 0.7% in the entire Korean adult population and showed a continuous increase with population aging. Additionally, among patients with AF, mean CHA2DS2-VASc score was significantly increased and the number of high thromboembolic risk patients has increased over time. Although oral anticoagulation (OAC) prescription in AF patients increased from 35% to 51%, especially after introduction of non-vitamin K antagonist anticoagulants, a substantial proportion of Korean patients with AF still remain undertreated. In this review, we aimed to summarize temporal changes in the prevalence and incidence of AF and to evaluate the thromboembolic risk in patients with AF. In addition, we also discussed the utilization of OAC therapy in patients with AF in Korean population.


Introduction
Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. 1 AF is a well-known independent risk factor for ischemic stroke, and globally, the prevalence of AF has continuously increased with the population aging; thus it has become a major public health problem. [2][3][4] The estimated prevalence of AF has been reported to range from 0.4% to 2% in the adult population; however, this varies widely depending on the study population. 5 Information on clinical epidemiology of AF has been derived from studies that have mainly included the population in Europe and the United States. Although Asian countries are known to have about 1% lower prevalence of AF than that in Europe and the United States, the number of Asian patients with AF is rapidly growing as the population ages. 6,7 Studies that reported AF epidemiology in Asian population are limited, but recently, corresponding to the increase in clinical research based on national health claim database, especially in Asian countries such as Taiwan and Korea, more accurate AF epidemiology data have been published. 8,9 While the global burden of AF has been increased over time, the management of AF has also greatly evolved. For stroke prevention in AF, the CHA2DS2-VASc score was introduced to assess thromboembolic risk and a non-vitamin K antagonist oral anticoagulant (NOAC) has become available as an effective and safe alternative to warfarin. [10][11][12] Although appropriate anticoagulation therapy could reduce the risk of stroke by 64% and mortality by 26% in patients with AF, many patients who need anticoagulation therapy for stroke prevention still remain untreated or undertreated. [13][14][15][16] Additionally, most of the studies reporting the utilization of oral anticoagulation (OAC) therapy in patients with AF are based on Western population. There are a few studies reporting the OAC prescription pattern therapy in Asian population. [16][17][18] Therefore, we aimed to summarize temporal changes in the prevalence and incidence of AF in Korean population.
Furthermore, we evaluated the thromboembolic risk in patients with AF and the utilization of OAC therapy for stroke prevention in Korean AF patients.

Prevalence and incidence of atrial fibrillation in entire Korean population
In Western countries, the incidence and prevalence of AF has consistently increased over the past decades, with the current estimated prevalence of AF at approximately 2%. 1,19 The prevalence of AF increases with age, ranging from 0.1% among patients younger than 55 years to 9.0% among patients 80 years or older. 19 Studies reporting the AF epidemiology in Korean population are limited. From two different community-based cohort studies, the prevalence of AF reported in the early 2000s was 0.4% in population aged 40-69 years and 0.7% in those older than 40 years. 20,21 Based on a sample cohort study from the National Health Insurance Service database, the overall incidence of AF was reported to be 1.5 to 2.87 per 100 person-years and prevalence of AF was 1.38% in 2013. 22,23 Although previous reports provided insights into the AF epidemiology in Korean population, the sample sizes were relatively small; hence, there was no information on temporal trends of AF epidemiology and the association between population aging and the temporal change of AF epidemiology was not reported. Recently, we published temporal trends in the incidence and prevalence of AF in entire Korean population between 2008 and 2015 based on the national health claims database established by the National Health Insurance Service (NHIS) of Korea. 8 The definition of the incidence and prevalence of AF is as follows. The annual incidence of AF was calculated as the number of patients with newly diagnosed AF for each year divided by the total personyears at risk among all individuals of that year who did not have AF during the last 3-year period. 8 The annual prevalence of AF was calculated as the number of patients with AF divided by the total population of each year. 8 Briefly, AF incidence and prevalence gradually increased, and both significantly increased with older age. AF was defined as patients having at least one discharge diagnosis with AF or patients who were at least twice diagnosed with AF in an outpatient clinic. During the 8-years, the incidence of AF increased to >1.12-fold as follows: from 15.34 to 17.14 per 10,000 person-years (p<0.001) ( Figure 1A). The overall incidence rates per 10,000 person-years were 3.0, 6.0, 14.3, 33.7, and 67.4 per 10,000 person-years among those aged 30-39, 40-49, 50-59, 60-69, and 70-79 years, respectively. The AF incidence in those aged >80 years was 100.4 per 10,000 person-years. Recently, Korean population is aging faster than any other developed countries, which might be reflected in the gradual increase of AF incidence. Also, there are several possible explanations for increasing incidence of AF except for the natural increase of AF in Korea. The "AF awareness" in Korea has been increased, especially after introduction of NOAC, which could impact the incidence of AF. Compared to warfarin era, the risk of AF on stroke and the benefit of stroke prevention in high-risk population was more emphasized to general population and physicians due to the convenience and safety of NOAC. The strict reimbursement criteria of NOAC prescription, i.e. mandatory of AF diagnosis code, which made physicians not to omit the AF diagnosis code.
Lastly, the health-check up in Korea became more common, which could detect asymptomatic undiagnosed AF in general population.
Furthermore, the prevalence of AF consistently increased by 1.7-fold, from 0.40% in 2008 to 0.67 in 2015 ( Figure 1B). In 2015, 276,246 subjects (0.67% of the adult population aged ≥20 years) had AF. Men had a significantly higher prevalence of AF than women. AF prevalence increased with age, ranging from 0.03% among individuals aged ≥60 years in 2008 and 2.28% had AF in 2015. A linear increase in AF prevalence was observed from age 50-59 years to >80 years. The annual increase was more prominent in the older age group.
The prevalence of AF in the entire Korean population was 0.67%, lower than that in the Western population. 1,5,19 However, this prevalence is closer to that reported in China (0.8-0.9%), Japan (0.9%), and Taiwan (1.07%). 6,9,24,25 An important finding is that the increases in AF incidence and prevalence were primarily due to the increase in the elderly population. This result was in accordance with that of previous studies, which reported that the incidence and prevalence of AF have been increasing with population aging and the increasing prevalence of comorbidities. 1,[5][6][7]19

Prevalence of atrial fibrillation based on geographical distribution and socioeconomic status in Korean population
Considering the increasing burden of AF in Korea, appropriate anticoagulation therapy in AF patients is an important issue to improve clinical outcomes. However, many AF patients do not feel any need for stroke prevention because of absence of symptoms, and unfortunately, some of these patients present with stroke as an initial manifestation of AF. 26,27 It is very important to identify high-risk population using appropriate screening program for AF detection, and initiate adequate OAC therapy based on annual stroke risk. Regional and socioeconomic circumstance could influence the screening and management of AF. There are few population-based studies reporting the regional and socioeconomic differences in AF prevalence. Using 2015 National Health Insurance Service database, we performed a cross-sectional analysis of Korean adults to evaluate the AF epidemiology in different geographical location based on residence and income levels. 28 Overall prevalence of AF in suburban/rural regions was significantly higher than that observed in urban regions (0.72% vs.  The proportion of elderly people aged ≥ 75 years increased from 27.4% to 38.4% during the last 8 years (Figure 2A). Moreover, increasing prevalence of comorbidities, such as diabetes and heart failure, also led to an increase in high-risk population ( Figure 2B). showed a clear correlation with CHA 2 DS 2 -VASc score. The risk of stroke stratified by CHA 2DS2-VASc scores in Korean population was comparable to that reported in previous studies (Table 1). 10,11,32,[38][39][40][41][42] In particular, CHA2DS2-VASc score welldiscriminated the patients who were truly at low risk for stroke, and this was a meaningful finding. 38,39 In NOAC era, the efficacy and safety of OAC treatment improved and the threshold for OAC treatment in AF patients for stroke prevention has been lowered from an annual stroke rate of 1.7% with warfarin to 0.9% with NOACs. 12,43 Therefore, CHA2DS2-VASc score is useful tool for identifying patients at low risk for whom OAC treatment has no net clinical benefit in the Korean AF population. 38,39,44

Antithrombotic therapy for stroke prevention in Korean patients with atrial fibrillation
Although there are clear benefits of OAC therapy for stroke prevention in high-risk AF patients, OAC is still underused in many patients with AF, particularly in the warfarin era. 12,[45][46][47] The narrow therapeutic range, needs of frequent monitoring/dose adjustments, and interactions with food or drug have made physicians and patients reluctant to use warfarin. 45 The landscape of stroke prevention in AF patients changed with the availability of NOACs. NOACs offer better efficacy, safety, and convenience, compared to warfarin. 12 Recently, we have reported the improved effectiveness and safety of NOAC over warfarin in Korean patients with AF. 48 Compared to warfarin, all three NOACs (dabigatran, rivaroxaban, and apixaban) showed similar risk of ischemic stroke and a lower risk of intracranial hemorrhage.
Furthermore, recent changes in AF guidelines, which favor NOAC use rather than warfarin use in high-risk AF patients and discourage aspirin prescription in low-risk AF patients, influenced the OAC prescription pattern in real world. 11,29,30 In 2016 European society of cardiology AF guidelines, OAC treatment is recommended for all male AF patients with a CHA 2DS2-VASc score ≥ 2 and all female patients with a CHA2DS2-VASc score ≥ 3. 30 Further, in male AF patients with a CHA2DS2-VASc score of 1 and female patients with CHA 2 DS 2 -VASc score of 2, OAC should be recommended considering individual characteristics and patient preferences. 30 Despite these major changes for stroke prevention in AF patients, little contemporary data is available about the changes of utilization of antithrombotic therapy patterns, particularly in Asian population. [14][15][16] We recently described temporal changes and the current state of antithrombotic therapy in Korean patients with AF, including the era of NOACs. 18  Compared to the European population, whether in the era of pre-or post-NOACs, a higher proportion of AF patients do not receive OAC treatment for stroke prevention in the Asian population. 16,17 In GLORIA-AF, OAC was prescribed in 55.2% of the total Asian population with AF, and about 50% of OAC users received NOACs. 16 Approximately 23.7% patients were prescribed aspirin, and 20% of patients did not receive any antithrombotic therapy. 16 The antithrombotic therapy distribution in 2015 for Korean AF population is similar to that of the Asian population in GLORIA-AF. 18 The decrease in aspirin use and increase in OAC prescription reflect major changes in the current guidelines in real world practice. 29,30,49 In keeping with the pivotal major trials and updated guidelines in other societies, the Korean guidelines recommended NOACs or warfarin in patients with CHA 2DS2-VASc score ≥ 1. 31 Although OAC is still underused in 2015, prescription patterns for stroke prevention in patients with AF has changed according to current guidelines. In the current era of NOACs, physicians might initiate OAC treatment earlier and more easily using NOACs without concern about frequent monitoring and dose adjustment. Nevertheless, the proportion of patients without any antithrombotic therapy has not changed over time despite the many changes in guidelines and introduction of NOACs.

Conclusion
In Korea, the prevalence and incidence of AF has increased gradually over the last several years. Although the CHA2DS2-VASc score has been validated in Korean patients with AF, there are still substantial numbers of patients who do not receive OAC therapy despite their high stroke risk. Therefore, a more comprehensive understanding of AF epidemiology is necessary to establish prevention and management strategies for AF and consequently improve clinical outcomes of AF patients in the current era.