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Transcatheter Aortic Valve Replacement in Asia

Over the last decade, based on evidence from multiple randomized clinical trials, transcatheter aortic valve replacement (TAVR) has become the established treatment for patients with symptomatic severe aortic stenosis. Despite the overwhelming expansion of TAVR in Western countries, the initial uptake and widespread adoption of this procedure have been relatively delayed in Asian countries, owing to the high cost of devices; limited local health and reimbursement policies; and lack of specific training/proctoring program, specialized heart team, or dedicated infrastructure. Furthermore, it has not yet been determined whether there are substantial interracial and ethnic differences in the clinical characteristics, comorbidities, and anatomic features, as well as procedural and long-term outcomes, in patients receiving TAVR. In this review, we provide not only a comprehensive look at the current status and outcomes of TAVR in Asian populations compared with those of Western populations but also a perspective on the future of TAVR in Asia.

O ver the last 15 years, novel transcatheter therapies for valvular heart disease (VHD) have been rapidly developed and adopted worldwide (1). In Western countries, transcatheter aortic valve replacement (TAVR) was introduced earlier than it was in Asia, and since the inception of this procedure, it has been widely used for the treatment of severe aortic stenosis (AS). Among Asian countries, the first TAVR case was performed back in 2009 in Singapore (2), but the adoption of TAVR in Asia was slower than in the United States and Europe, mainly because of the lack of full reimbursement for TAVR and local regulations for new device approval (3).
Additionally, there are significant differences between Asian and Western patients in terms of physique, anatomy of the aortic complex, thrombogenicity, and hemorrhagic diathesis. In particular, reflecting the smaller body size, the aortic valvular dimension is smaller in Asian patients than in Western patients (4), which may affect the choice of device and valve size and eventually influence short-and long-term prognoses. Furthermore, compared with Western patients, Asian patients are more susceptible to bleeding events but are relatively resistant to thromboembolic events (5). Therefore, the optimal antithrombotic strategy post-TAVR for Asian patients may be different from that for Western patients. AS is the most common VHD worldwide, and its prevalence increases with age. Prior studies have suggested racial/ethnic differences in AS prevalence, but these were limited by potential selection bias (7). Although East Asian ethnic groups are among the most populous (>1.5 billion people), data from Asian populations with severe AS are limited, and the diagnosis of AS was less prevalent relative to that in Western populations. Based on a prior modeling study, the prevalence rate of AS was 12.4% in elderly individuals (>75 years), and AS is estimated to affect approximately 2.7 million and 4.9 million people in North America and Europe, respectively (8). Unfortunately, the disease prevalence of AS in elderly Asian individuals is still unknown. The established risk factors for the development and progression of AS include hypertension, advanced age, congenital bicuspid aortic valve (BAV), smoking, hyperlipidemia, renal insufficiency, diabetes mellitus, atherosclerosis, and congestive heart failure (9)(10)(11). However, few studies have examined the differences in the prevalence, contributory risk factors, management, and outcomes of severe AS in racially and ethnically diverse populations, especially East Asian populations (7).
A prior study using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample in the United States reported that Asian individuals might have a paradoxically lower prevalence or incidence of AS relative to White individuals, despite having a higher prevalence of traditional risk factors (12).
Similarly, results from MESA (the Multiethnic Study of Atherosclerosis) reported that Chinese participants had a lower prevalence of AS or aortic valve replacement than did White participants, without a difference in AS severity by race/ethnicity (13); however, the exact etiology and pathophysiologic mechanisms of these racial/ethnic disparities are unknown. Among the East Asian population, the most common cause of AS is degenerative calcific aortic valve disease, which shares many risk factors with atherosclerotic cardiovascular disease. AS can also be caused by congenital BAV and rheumatic VHD, which are more common in Asian countries. Although the prevalence of rheumatic VHD has steadily declined, this etiology is still substantially prevalent in Asia (4.54/1,000 in India, 1.86/1,000 in China, and 1.3/ 1,000 in Bangladesh) (14). However, TAVR is not usually an initial treatment because rheumatic AS progresses at a young age and is typically accompanied by mitral and tricuspid valve disease (15).
It has been widely reported that, compared to White patients, non-White patients (including Asian patients) possess higher rates of traditional AS risk factors, such as congestive heart failure, chronic kidney disease, smoking, hypertension, obesity, and diabetes mellitus (9)(10)(11)16,17). Given that comparative data on epidemiology and demographic characteristics of AS in East Asian populations and Western populations were not available, further research is required to elucidate the mechanism behind the socalled "AS paradox" in Asian populations (ie, more AS risk factors but a lower prevalence of AS) (7).

RACIAL DIFFERENCES IN PREVALENCE AND ANATOMY
OF BAV. Compared to AS in a tricuspid aortic valve, the combination of AS in BAV is frequently found in patients with younger age and involves severely calcified valves, larger dimensions of the ascending aorta, and combined aortopathy. The prevalence of BAV in Asian populations is thought to be higher than that in Western populations, although comparative clinical data are still scant. Li et al (18) reported that the incidence of BAV was 0.4% in a West China Hospital cohort, and 87% of cases were complicated by various degree of AS or aortic regurgitation (AR). In a health screening study of 23,291 Korean patients, a BAV prevalence of 0.16% was reported (19). In contrast, the prevalence of BAV was 7.9% in a community-based, cross-sectional study including 14,530 Chinese children (20). More comparative data are required to determine true racial differences in BAV incidence.
Few studies have reported potential racial differences in BAV disease between Asian and Western populations. Kong et al (21) reported BAV morphology and function using data from 2 large cohorts of European and Asian patients with BAV. Key findings were that: 1) Asians had a higher prevalence of type 1 BAV, with more fusion of the right and noncoronary cusps, than did Europeans (Europeans vs Asians: 14% vs 20%), whereas Europeans had a higher prevalence of type 0 BAV than did Asians (15% vs 7%, respectively); 2) functionally, AS is common in both Asian and Europeans, but the prevalence of moderate and severe AR was higher in Europeans than in Asians (44% vs 27%); and 3) the indexed sizes of the annulus, sinus of Valsalva, sinotubular junction, and ascending aorta were significantly larger among Asians than among Europeans. However, in some Chinese registries, the prevalence of type 0 BAV was reported to be as high as 54.4% (22); thus, to clarify this discrepancy, further large-scale studies are needed to determine the distribution of BAV morphology types in Asian countries. The small aortic size and peripheral vessels in Asian patients are of significant concern to physicians because of an increased risk for complications.
between the 2 populations ( Figure 2). Particularly, the   ( Figure 3). Several studies have proposed that racial and ethnic disparities exist in the performance and outcomes of TAVR (26,52,53 the "high-cost medical expense benefit" is also applied, which means that a ceiling amount is predetermined (57). Given the coverage of public health insurance, Japan has had the largest number of TAVR implants to date in Asia (6,810 cases in 2018) (58). Currently, the local Asian companies manufacturing devices are trying to increase the potential market of TAVR by lowering prices, which may increase market competition and eventually contribute to device cost reduction.
Each country has its own regulatory pathway. In     TAVR IN BAV. The prevalence of BAV in patients undergoing TAVR was 2.7% in the OCEAN-TAVI registry (63); 5.8% in the Asian-TAVR Registry (26); and 3% to 3.5% in the TVT registry (64,65). BAV is reported to be very common in Chinese patients, with a prevalence near 50% in patients with severe AS undergoing TAVR (22). The high prevalence of BAV in the Asian-TAVR Registry may be due to a truly high incidence or the enrollment of low-risk or young patients (22,26,63  rehospitalization rates at 1 year. In contrast, a recent report on the OCEAN-TAVI registry revealed that the incidence of moderate to severe PPM was 9.6% (moderate: 8.9%; severe: 0.7%), but the presence of PPM was not associated with an increased risk of mortality (85). In this Japanese cohort, independent predictors for PPM were young age, large BSA, small aortic valve area, small annulus area, no balloon postdilatation, and use of the Edwards Sapien 3.
With regard to the race-specific differential incidence of PPM, the annular area on preprocedure computed tomography is small in Asians, but BSA is substantially smaller in Asian than in White individuals (84)(85)(86). Thus, the incidence of PPM was not

CONCLUSIONS
Until recently, few comparative studies existed regarding differential clinical, anatomic, and procedural characteristics and outcomes of TAVR between Asian and Western populations. Although the association between racial disparities and adverse clinical events among TAVR patients has been a major topic of study, the contributing factors are still poorly understood. Given that the elderly population is rapidly increasing in Asian countries, a substantial number of potential candidates for TAVR is expected, with more affordable device prices and, thus, broader TAVR use.
Further racial and ethnic-based comparative studies will provide a better understanding of the observed racial differences in the clinical and anatomic characteristics and outcomes of TAVR recipients between Asian and Western populations, which may facilitate risk stratification and the development of race-based novel approaches for TAVR procedures.

HIGHLIGHTS
Given increased life expectancy in the Asia Pacific, the field of TAVR is rapidly expanding.
There were substantial interracial differences in clinical, anatomic, and procedural characteristics in TAVR patients.
There were specific population-and health care system-related challenges to TAVR use in Asia.
Future research into racial/ethnic disparities can help optimize TAVR procedures in Asia Pacific countries.