An Examination of Stroke Risk and Burden in South Asians

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An Examination of Stroke Risk and Burden in South Asians Vineeta Singh, MD,* Shyam Prabhakaran, MD,† Seemant Chaturvedi, Aneesh Singhal, MD,§ and Jeyaraj Pandian, MD, DM‖

MD,‡

Background: South Asians (India, Pakistan, Sri Lanka, Bangladesh, Nepal, and Bhutan) are at a disproportionately higher risk of stroke and heart disease due to their cardiometabolic profile. Despite evidence for a strong association between diabetes and stroke, and growing stroke risk in this ethnic minority—notwithstanding reports of higher stroke mortality irrespective of country of residence—the explanation for the excess risk of stroke remains unknown. Methods: We have used extensive literature review, epidemiologic studies, morbidity and mortality records, and expert opinions to examine the burden of stroke among South Asians, and the risk factors identified thus far. Results: We summarize existing evidence and indicate gaps in current knowledge of stroke epidemiology among South Asian natives and immigrants. Conclusions: This research focuses attention on a looming epidemic of stroke mainly due to modifiable risk factors, but also new determinants that might aggravate the effect of vascular risk factors in South Asians causing more disabling strokes and death. Key Words: Stroke—race and ethnicity—immigrants—South Asians—special populations—epidemiology. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Introduction Immigrants from South Asia (India, Pakistan, Bangladesh, Bhutan, Nepal, and Sri Lanka) living in developed countries represent a unique and growing population with high prevalence of premature atherosclerosis.1-5 Comprising 25% of the world’s population, South Asians are a rapidly growing immigrant group in Northern America

From the *Department of Neurology, University of California San Francisco, San Francisco, California; †Department of Neurology, Northwestern University, Chicago, Illinois; ‡Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida; §Department of Neurology, Harvard Medical School, Boston, Massachusetts; and ‖Department of Neurology, Christian Medical College, Ludhiana, Punjab, India. Received January 19, 2017; revision received April 12, 2017; accepted April 29, 2017. Address correspondence to Vineeta Singh, MD, San Francisco General Hospital, University of California, San Francisco, Building 1, Room 101, 1001 Potrero Ave, San Francisco, CA 94110. E-mail: [email protected]. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.04.036

with current estimates of 4.8 million in the United States and 1.6 million in Canada.6 Many South Asians immigrated to developed countries between 1965 and 1985; these immigrants have now reached an age when stroke and dementia occurrence is a major health concern. For over 50 years, it has been known that native and immigrant South Asians are at increased risk for diabetes mellitus with major stroke risk at epidemic proportions. For natives, stroke mortality is high7 and not fully explained by poverty and low stroke awareness. For immigrants, stroke mortality is equally concerning; however, epidemiologic data pertaining to this particular population are scarce because South Asians are rarely distinguished from East Asians in most national health surveys and hospital-based stroke registries. In fact, current stroke treatment and prevention guidelines rely heavily on clinical trials that have enrolled too few South Asian immigrants for meaningful subgroup analyses. In order to adequately understand and serve this growing ethnic population in developed countries, there must be more and better data on stroke burden and risk in South Asian immigrants. The present article examines evidence from studies on stroke risk factors, burden, subtypes thus far, and ongoing investigations in South Asian immigrants.

Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■

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Stroke Epidemiology, Types, and Subtypes in South Asians There are few well-designed, population-based studies reporting stroke burden in South Asians. Most data come from India,8-12 with an annual incidence of 123-145 per 100,000 and the age-adjusted prevalence of 84-262 per 100,000 in rural and 334-424 per 100,000 in urban areas.11 In Pakistan, annual stroke incidence as derived from hospital-based studies, and thus likely a low estimate, is 250 per 100,000.13,14 The estimated prevalence of stroke in Sri Lanka is as high as 9 per 1000.15 The numbers from Bangladesh are similarly alarming, ranging from 3 to 10 per 1000 population.16-18 Data from other South Asian countries such as Afghanistan, Bhutan, and Nepal are not available. Therefore, although there may be high prevalence in these countries, we are unable to come to any conclusions about epidemiology due to lack of data. Ultimately, there is a critical lack of epidemiologic data on stroke in South Asian natives in addition to that in immigrants. Understanding the prevalence of different types of stroke (hemorrhagic versus ischemic) is necessary for appropriate risk modification. Community-based studies from India, Pakistan, and Bangladesh reported high rates (20%-46%) of hemorrhagic strokes compared with Western countries. Hemorrhagic stroke is known to be associated with a greater mortality rate despite being less prevalent than ischemic stroke. Similarly, although the prevalence of cerebral venous thrombosis (CVT) worldwide is lower than that of ischemic stroke, CVT prevalence in South Asia is the highest in the world.19-21 Moreover, CVT accounts for a large portion of stroke in young women in the region.9,22-28 Stroke remains to be the leading cause of death among South Asian women over age 6029 and is common during pregnancy and the postpartum period.30 The prevalence of various subtypes of ischemic stroke in South Asians versus Western natives suggests another area of necessary investigation. Extracranial atherosclerosis is common in the West; intracranial atherosclerosis in both anterior and posterior circulations appears to predominate among South Asians.2,31,32 However, differences in the extent of etiologic testing in South Asia versus developed nations may account for some of the reported differences in stroke mechanisms. Atrial fibrillation in this population may be infrequent, despite its role as one of the main risk factors of stroke in Caucasians.33-35 Lacunar stroke is the most common ischemic stroke subtype in South Asians living in the United States and attributes to a higher prevalence of diabetes in this group.3 South Asians with ischemic stroke are also more likely to have intracranial atherosclerotic stenosis (ICAS), as compared with whites,36 yet the predictors of ICAS other than reports of clustering of traditional stroke risk factors have not been fully examined. Compared with other ethnic groups, the pattern of ICAS described in South Asians is more diffuse and involves multiple cerebral arteries

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in addition to the symptomatic artery. Whether or not the presence of metabolic risk factors in South Asians exacerbates the effects of ICAS on cerebral vasculature and the brain parenchyma is yet to be determined. Ultimately, predictors of ICAS have yet to be fully examined. Silent cerebral ischemia, indicating stroke risk, and brain atrophy, indicating cognitive decline, in the symptomatic territory are frequently associated with ICAS.31 ICAS is thus a potential early marker of stroke risk and cognitive decline.34 According to a hospital-based neuroimaging study, ICAS occurs in 1 out of 3 asymptomatic Pakistanis with modifiable vascular risk factors. Longitudinal observational studies, such as this, are therefore needed to assess the natural history of ICAS in this racial/ethnic group.

Stroke Incidence and Mortality in South Asian Immigrants Indeed, South Asia is the biggest contributor of stroke deaths in the world.37,38 In this region, stroke mortality might be as high as that of coronary artery disease (CAD),39 and both stroke and CAD occur about a decade earlier in South Asia than in wealthy countries.12,40 The following several studies investigate the estimation of stroke incidence and stroke mortality in South Asian immigrants. In a population-based study, the incidence of stroke among South Asians living in the UK was estimated to be 111 per 100,000 persons, comparable with the incidence among Caucasians.41 Stroke mortality in South Asians living in the United Kingdom, however, was 1.5 times higher than the general population.42-44 The stroke risk profile, such as hyperlipidemia, has increased fivefold among South Asians, compared with Caucasians. For South Asian immigrants living in the United Kingdom, higher stroke mortality is consistent with reports of higher risk of CAD. In the United States, a small, community-based study determined stroke prevalence in South Asians to be 2.8% in 1991,1 which is similar to the age-adjusted stroke prevalence in other racial/ethnic groups. Stroke mortality among South Asian U.S. residents is 2-3 times higher than their Caucasian counterparts.45 South Asian immigrants living in America have the highest ischemic heart disease mortality rate among the top 6 racial/ethnic groups.46 There is no evidence to support such an assertion on the links between stroke and CAD among South Asians living in the United States. The SABRE (Southall and Brent Revisited) study is a longitudinal tri-ethnic, community-based cohort with a 20-year follow-up from London examining ethnic differences in cardiovascular disease (CVD) and stroke (see Table 1).47 Compared with Europeans, South Asians experienced more strokes (age- and sex-adjusted Standardized Hospitalization Ratio: 1.45 [95% confidence interval [CI]: 1.17 to 1.80, P = .001]), made worse by the presence of diabetes (age-adjusted Standardized Hospitalization Ratio: 1.97 [95% CI: 1.16 to 3.35, P = .038 for interaction]).47

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Longitudinal and cross-sectional

CVDNOR project

1990-2006 Rafnsson49

ICD-9 430-438, ICD-10 160-169 ICD-9 430-438, ICD-10 160-169 1994-2009 Rabanal48

Abbreviations: CVDNOR, The Cardiovascular Disease in Norway; EU, European Union; ICD, International Classification of Diseases; SA, South Asian.

Rates of stroke are elevated compared with Europeans and markedly so in people with diabetes in midlife. Norway 23301 Age-standardized SA had a higher risk of stroke stroke event rates during the study period. Cerebrovascular disease Six EU 60,296 (Denmark), 2,920,810 Cerebrovascular disease mortality mortality was higher among countries (England and Wales), 59,728 SA in Denmark, England and (France), 81,540 (Scotland), Wales, France, and Scotland. 44,967 (Sweden)

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Incidence rate, subhazard ratio

Prospective London, 1710 population-based United Kingdom 1988/1991-2008/2011 ICD-9 430-439, ICD-10 160-169 Tillin47

South Asians (n) Country Methods Stroke type/Diagnosis Year of study Author

Table 1. Stroke burden in South Asians living in developed countries

Epidemiologic indicator

Main findings

STROKE RISK IN SOUTH ASIANS

Although South Asians are known to be at a higher risk for all types of stroke and the majority of strokes are ischemic,50 this study, did not reliably differentiate stroke subtypes, which may well vary by ethnicity. Another study with a large sample size was the Cardiovascular Disease in Norway project,48 which provided information on stroke hospitalization from 1994 to 2009 for the entire Norwegian population and used country of birth to identify immigrants with at least one parent born abroad (see Table 1). South Asians had a higher stroke event rate in the age group of 35-64; for men, it was 242 and for women it was 199, compared with 194 and 116 in Norwegians per 100,000 person-years.48 The authors acknowledge that although large samples were available for analyses, a selection bias arising from the use of different healthcare services in immigrants could not be avoided. This study demonstrates yet another instance of a South Asian immigrant population with higher incidence of stroke than those native to the country. The next study used national death and population data from Denmark, England and Wales, France, the Netherlands, Scotland, and Sweden to examine inequalities in circulatory disease mortality constructed as mortality risk ratio (MRR) among immigrants compared with locals (see Table 1).49 South Asians in Denmark, England, Wales, and France experienced higher mortality (MRR = 1.37-1.91), whereas East Asians living in France, Scotland, and Sweden had lower mortality (MRR = .64-.50). Stroke mortality was 2-3 times higher for a few other immigrant groups, including South Asians, compared with Europeans. Higher stroke mortality in South Asians living in England and Wales corroborated findings of a previous study from the host country.44 Dutch data also showed high stroke mortality among those born in Suriname. Suriname is a former Dutch colony where 20%-30% of the population is of Indian ancestry. Additionally, South Asians living in Scotland are at a modestly greater risk of dying. This study confirms further instances of higher stroke mortality in South Asian immigrants compared with those native to that particular country. Although the above studies examined South Asian immigrants in various European countries, there are limited data on intergenerational differences in stroke risk and change in risk in South Asians with duration of residence in the host country. A Canadian immigrant study that links data from citizenship and immigration records to 9 population-based health databases found that the composite cardiovascular events, including Myocardial Infarction and stroke, were highest for South Asian immigrants compared with other ethnic groups.51 The overall incidence of major vascular event was 30% lower in immigrants compared with long-term residents. However, the agestandardized incidence rate varied fourfolds, with East Asian male and female immigrants at the lowest risk (2.4 and 1.1 per 1000 person-years) and South Asian male and female immigrants at the highest risk (8.9 and 3.6 per 1000 person-years). These differences raise concerns about

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the existence of factors other than environment and access to healthcare that might be responsible for the high cardiovascular risk among South Asians.51 These studies not only pointed to higher incidence of stroke among South Asian immigrants in several Western countries, but also demonstrated the need for more epidemiologic data. Particularly, the data presented came from either census reporting or immigrant registries in various Western countries. Such registries have not been used in the context of the United States. There is a dire need to better understand the burden of stroke as well as the prevalence and nature of types and subtypes of stroke.

Risk Factors for Stroke in South Asians There are several stroke risk factors that are common among the general population and unique to South Asians. The prevalence of hypertension, diabetes, and dyslipidemia is similar among the various South Asian countries.16,52-54 Hypertension is the largest contributor to the overall societal burden of stroke. It is estimated that about 40% of first-time strokes among individuals in their 50s and 60s are attributable to hypertension.55 Hypertension is one of the most important risk factors for ischemic stroke for both sexes and across ages in Indians.56 Similarly, hypertension remains a principal stroke risk factor in Pakistan, Bangladesh, and Sri Lanka.17,24,25,53,57-61 South Asians in the United Kingdom are at an increased risk of hypertension.62-64 The prevalence of hypertension in this ethnic minority has been estimated to be 30%, which is higher compared with whites in the United Kingdom.62 The most compelling data on stroke risk among South Asians come from a population-based study from 22 countries, namely the INTERSTROKE study, which found that 5 risk factors (hypertension, current smoking, abdominal obesity, diet, and physical activity) explained 80% of the risk attributed to stroke worldwide.60 Several studies have shown a strong association between diabetes and stroke in South Asians. Compared with 4 other ethnic groups (white, Asians, African–American, and Latinos), South Asians are at a disproportionately higher risk of developing diabetes due to biological and lifestyle factors.65 Notably, in South Asians, the increased prevalence of diabetes mellitus has been associated with incident stroke, particularly small artery or lacunar stroke, stroke recurrence, and stroke mortality.3,66-69 A recent study conducted in the United States found that diabetes is more prevalent (23%) in South Asians than in Hispanics (17%), African–Americans (18%), Chinese Americans (13%), and whites (6%).65 In a recent meta-analysis comparing South Asians living in Canada with white Canadians, the former group had a higher prevalence and incidence of CVD, higher prevalence of diabetes (odds ratio: 2.25, 95% CI: 1.81 to 2.80, P < .001) and hypertension (odds ratio: 1.11, 95% CI: 1.02 to 1.22, P = .02), and lower high-density lipoprotein (HDL) levels (mean difference: −.19 mmol/L,

95% CI: −.25 to −.13 mmol/L, P < .001). Furthermore, South Asians had a higher percentage of body fat and were also found to be less active and consume more carbohydrate and less tobacco than white Canadians. Finally, several studies have shown a strong association between diabetes and stroke in South Asians.36,50,70 Hyperlipidemia is a common vascular risk factor and is present in more than one quarter of South Asians with stroke. South Asians have an atherogenic profile with disproportionately higher levels of triglycerides,69 low HDL,71 and elevated lipoprotein.72,73 Two studies of South Asian stroke patients reported that more than half of stroke patients had elevated cholesterol levels.74,75 Of note, low HDL in South Asians is a more significant risk factor than higher cholesterol level.76 The current epidemic of stroke in India has been attributed to changes in demographics (increased life expectancy), lifestyle (more food consumption and less physical activity), and socioeconomic status, particularly rising living standards and adopting Western lifestyles can be attributed. Higher socioeconomic status in Indians has been associated with higher rates of CVD.77 However, no such data exist for stroke. In a community-based survey by Kamal et al, 68% of Indian stroke patients and up to 75% of Pakistani stroke patients were obese.14 In a global attempt to identify stroke risk factors, the INTERSTROKE study showed that hypertension, tobacco exposure—in cigarettes, beedis, paan, and other forms78—abdominal obesity,54,79 diet, and physical activity explained 80% of the risk attributed to stroke.60 Carotid intimal medial thickness (CIMT) is an established marker of atherosclerosis80 and a predictor of morbidity and mortality from stroke and heart disease. Even after controlling for age, sex, blood pressure, body mass index (BMI), smoking, diabetes, low-density lipoprotein-cholesterol, and triglycerides, South Asians had higher CIMT compared with other ethnic groups.80,81 Elevated serum homocysteine levels have been implicated in the development of subclinical atherosclerosis via inflammatory changes.82 The methyltetrahydrofolate reductase (MTHFR) gene is involved in homocysteine metabolism, and C667T mutation in MTHFR gene has been associated with increased homocysteine levels in SA.82 The frequency of MTHFR mutation in South Asians is similar to those in Caucasians, but there is a much higher homocysteine level than in other ethnicities. It is quite likely that this differential effect on homocysteine results from vitamin deficiency in South Asians due to their strict vegetarian diet and cooking practices that deplete folate at higher temperatures.82 A study from the United Kingdom showed that glycemic index was independently associated with impaired endothelial function and increased vessel wall stiffness.83 Both glycemia and homocysteine mechanisms seem to be affected in diabetes.82,83 A higher glycemic state causes a drop in production of nitric oxide, causing a drop in vascular smooth muscle relaxation and 5

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arterial stiffening. There is also evidence for clustering of thrombotic factors (tissue plasminogen factor, plasminogen activator inhibitor 1, and fibrinogen) in South Asians with insulin resistance.84 In a small hospitalbased study of South Asians,85 high CIMT was more prevalent in ischemic stroke patients compared with ageand sex-matched controls, and also related to C-reactive Protein and fibrinogen levels. Because individuals with a higher CIMT are at a four- to fivefold greater risk of heart attack and stroke, this marker may have utility in vascular risk stratification of asymptomatic patients and primary stroke prevention. The C-reactive protein, lipoprotein (a), and microalbuminuria are the most frequently reported nontraditional vascular risk factors among healthy individuals of South Asian descent.86-88 The ApoE gene polymorphism has been shown to produce dyslipidemia and excess stroke risk.89-94 In a hospital-based study, patients with an e4 allele had fourfold higher odds of developing stroke.93 For the most part, metabolic syndrome and premature atherosclerosis are the most important contributors, even among younger stroke patients.32,35 However, infections and less common stroke risk factors such as hypercoagulable states,95,96 hyperhomocysteinemia,97 and elevated lipoproteins98 have also been reported.

A study of South Asian immigrants in United Kingdom found that unconventional risk factors such as elevated lipoprotein (a), high C-reactive protein, and hyperhomocysteinemia further potentiated the risk of CVDs. Furthermore, a U.K. study reporting on secular trends in risk profile of South Asian stroke patients compared with African Caribbeans showed a significant increase in hypertension in all ethnicities, and in particular a sharp increase in the prevalence of hyperlipidemia in South Asians.99 Additionally, compared with ethnically matched healthy controls, South Asian stroke survivors had elevated lipoprotein (a) levels and apolipoprotein B to AI ratios.100 Taken together, there is evidence to believe that novel risk factors are not simply associations but possibly play some role in imparting excess stroke risk in South Asians.

Stroke Risk and Subtypes in South Asian Immigrants Living in Developed Countries Few studies have reported higher rates of vascular risk factors in South Asian immigrants who, compared with other ethnic groups, suffer their first stroke at much younger ages3,4,33,101,102 (see Table 2). Gezmu et al found that South Asian stroke patients were likely to have the highest glycosylated hemoglobin

Table 2. Risk factors and stroke subtypes in South Asians living in developed countries

Country/Author

Singapore/ De Silva33

United Kingdom/ Banerjee101

Patients Type of study

186 72 Hospital-based Hospital-based registry registry (2003-2006) (2003-2007)

Comparison group

None

Age (years) Risk factors (%) Hypertension Diabetes mellitus Dyslipidemia Smoking Atrial fibrillation TOAST stroke classification Small v stroke (%) Large v stroke (%) Cardioembolic OCSP stroke classification Total anterior circulation Partial anterior circulation Posterior circulation Lacunar

White

Canada/Khan4

United States/ Gezmu3

United States/ Moussouttas36

210 273 99 Prospective, Retrospective study Retrospective hospital-based (1997-2005) study, Canadian (2006-2011) Stroke Network (2003-2008) White, East Asians White, African– European-American American, Hispanic 69 (72, 72) 65 (73, 65, 64) 66 (70)

64

65 (73)

78 61 75 35 4

87 (64) 54 (15) 70 (45) 15 (33) 12 (23)

75 (68, 72) 42 (24, 26) 42 (31, 34) 8 (19, 12) 9 (17, 13)

75 (77, 82, 70) 45 (31, 42, 32) 33 (35, 31, 32) 9 (17, 15, 8) N/A

76 (73) 48 (33) 29 (45) 18 (42) 4 (9)

35 41 10

N/A N/A N/A

N/A N/A N/A

29 (22, 23, 24) 26 (23, 20, 30) 8 (20, 12, 15)

16 (8) 29 (24) 7 (23)

8 16 14 62

3 (12) 22 (31) 26 (20) 45 (32)

9 (11, 13) 40 (39, 35) 20 (23, 21) 19 (16, 24)

N/A N/A N/A N/A

N/A N/A N/A N/A

Abbreviations: N/A, not applicable; OCSP, Oxfordshire Community Stroke Project; TOAST, Trial of Org 10172 in Stroke; v, vessel. Comparison groups ( ).

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levels and a much higher proportion of diabetes overall than Caucasians, Hispanics, and African–Americans.3 Furthermore, atrial fibrillation was less frequent among South Asians compared with Caucasian stroke patients. The HDL levels were lower in South Asians with high total cholesterol : HDL ratio a predictor of cardiovascular morbidity. The relatively smaller diameter of coronary arteries has been considered to play a negative role in disease progression among South Asians. A multivessel disease pattern is also more common in South Asians, and it is possible, although unproven, that the same may be true for cerebral arteries.103 For a given BMI compared with Caucasians, South Asians are reported to have more generalized obesity, subcutaneous fat, and visceral fat, not always apparent by their non-fat BMI. 104,105 Based on robust epidemiologic data, in 2015 the American Diabetes Association appropriately recommended a lower BMI cutoff point of 23 kg/m2 for Asian Americans to be considered for diabetes screening and early intervention to improve outcomes in this ethnic group.41 Similarly, ethnicspecific cutoff points may be appropriate for South Asians to delineate the burden of obesity and associated comorbidities in this population. Among South Asian patients in the United States, small vessel occlusive disease was the most common stroke mechanism, followed by large artery atherothrombosis and other etiologies.3,36 Only 8% of South Asians had an ischemic stroke subtype diagnosis of cardioembolic etiology as compared with 20% of Caucasian patients.3 Another U.S. study found that South Asians with stroke were threefold more likely to have ICAS and had a higher prevalence of diabetes compared with European Americans.36

Future Directions Future epidemiologic studies involving immigrant ethnic groups should include data on lifestyle changes and acculturation after immigration and their impact on stroke risk. Underestimation of stroke events is also possible in studies involving immigrants due to the well-described “healthy immigrant” effect,106,107 which implies that immigrants are usually healthier than native-born individuals. Using country of birth as a proxy for ethnicity could have led to underestimation of stroke risk among South Asians in younger age groups. Ongoing efforts such as the Indo-US Collaborative Stroke Project, jointly funded by the U.S. National Institutes of Health and the Indian Government’s Department of Biotechnology, and the National Institutes of HealthNational Heart, Lung, and Blood Institute-funded INSPIRE (INdian Stroke ProspectIve REgistry) will soon provide more information on the risk factors for stroke in India. An expansion of these efforts to other South Asian countries would provide more comprehensive and precise data regarding stroke risk across the region. The Mediators of

Atherosclerosis in South Asians Living in America study is an ongoing population-based longitudinal study of South Asian men and women investigating the predictors and outcomes associated with subclinical CVDs.108 The participants in this study are predicted to have a high lifetime risk of CVD.109 Long-term follow-up of this cohort will help elucidate the relationship between risk assessment scores and incident CVD events, including TIA, stroke, and mortality, in South Asians living in the United States. With an expected rise in the diabetic epidemic in South Asians over the next several years, the alarmingly high rates of stroke could only get worse. Given the potential economic and physical impact of stroke in South Asians, the focus should be on risk assessment and prevention strategies. It remains to be answered which genetic and environmental stroke risk factors explain differences in stroke subtype and mechanism in South Asians compared with other ethnic groups. Further studies elucidating risk factors, causative mechanisms, identifying subclinical disease, and quantifying stroke and vascular cognitive impairment in this vulnerable immigrant population should be prioritized to address these gaps in our knowledge and decrease the enormous burden of stroke for South Asians worldwide.

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