Asian Stroke Research Articles

Cerebrolysin for acute ischaemic stroke.

Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from pigs' brain tissue, which has potential neuroprotective and neurotrophic properties. It is widely used in the treatment of acute ischaemic stroke in Russia, China, and other Asian and post-Soviet countries. To assess the benefits and risks of Cerebrolysin for treating acute ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (October 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (November 2014), MEDLINE (1966 to November 2014), EMBASE (1974 to November 2014), Web of Science Core Collection, with Science Citation Index (1940 to November 2014), LILACS (1982 to December 2014), OpenGrey (1980 to December 2014), and a number of Russian Databases (1998 to December 2014). We also searched reference lists, ongoing trials registers and conference proceedings, and contacted the manufacturer of Cerebrolysin, EVER Neuro Pharma GmbH (formerly Ebewe Pharma). Randomised controlled trials comparing Cerebrolysin started within 48 hours of stroke onset and continued for at least two weeks with placebo or no treatment in people with acute ischaemic stroke. Two review authors independently applied inclusion criteria, assessed trial quality and risk of bias, and extracted data. We included one trial involving 146 participants. We evaluated risk of bias and judged it to be high for generation of allocation sequence, low for allocation concealment, high for incomplete outcome data (attrition bias), unclear for blinding, high for selective reporting and high for other sources of bias. The manufacturer of Cerebrolysin, pharmaceutical company Ebewe, provided Cerebrolysin and the placebo, as well as the randomisation codes. There was no difference in the number of deaths (6/78 in Cerebrolysin group versus 6/68 in placebo group; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.29 to 2.58) or in the total number of adverse events (16.4% versus 10.3%; RR 1.62, 95% CI 0.69 to 3.82) between the treatment and control groups. Routine administration of Cerebrolysin to people with acute ischaemic stroke cannot be supported by the available evidence from RCTs.

Association between orthostatic hypotension, mortality, and cardiovascular disease in Asians

BackgroundOrthostatic hypotension (OH) is a common condition encountered in the elderly. The present study aimed to examine the relationship between OH and adverse events in Asians. MethodsWe used the “National Health Insurance Research Database” in Taiwan. A total of 1226 patients with OH and without previous history of ischemic stroke and myocardial infarction were identified as the study group. For each study patient, ten age-, sex- and comorbidity-matched subjects without OH were selected to constitute the control group (n=12,260). The clinical endpoints were ischemic stroke, myocardial infarction and all-cause mortality. ResultsThe mean age of the study population was 54.8±19.0years and males accounted for 47% of the patients. During the follow-up of 4.5±2.9years, 704 (5.2%) patients developed ischemic stroke, 190 (1.4%) patients developed myocardial infarction, and 733 (5.4%) patients died. In the multivariable Cox regression analyses which were adjusted for age, gender and differences in medication usages, OH was significantly associated with an increased risk of ischemic stroke (hazard ratio [HR]=1.40, 95% confidence interval (CI)=1.09–1.81, p=0.009), all-cause mortality (HR=1.35; 95% CI=1.05–1.73, p=0.018) and adverse events (ischemic stroke, myocardial infarction or mortality) (HR=1.41; 95% CI=1.18–1.68, p<0.001). ConclusionOH is an independent factor associated with ischemic stroke and mortality in Asians. Whether aggressive managements for stroke prevention could improve the outcome for OH patients deserves further study.

Acute reperfusion therapy and stroke care in Asia after successful endovascular trials.

The current status of and prospects for acute stroke care in Asia in the situation where both intravenous thrombolysis and endovascular therapies have been recognized as established strategies for acute stroke are reviewed. Of 15 million people annually having stroke worldwide, ≈9 million are Asians. The burdens of both ischemic and hemorrhagic strokes are severe in Asia. The unique features of stroke in Asia include susceptibility to intracranial atherosclerosis, high prevalence of intracerebral hemorrhage, effects of dietary and lifestyle habits, and several disorders with genetic causes. These features affect acute stroke care, such as the dosage of alteplase for thrombolysis and consideration of bleeding complications during antithrombotic therapy. Acute endovascular thrombectomy, as well as intravenous thrombolysis, is relatively prevalent in East Asia, but most of the other Asian countries need to develop their human resources and fundamental medical infrastructure for stroke care. A limitation of endovascular therapy in East Asia is the high prevalence of intracranial atherosclerosis that can cause recanalization failure and require additional angioplasty or permanent stent insertion although intracranial stenting is not an established strategy. Multinational collaboration on stroke research among Asian countries is infrequent. Asians should collaborate to perform their own thrombolytic and endovascular trials and seek the optimal strategy for stroke care specific to Asia.

Genetics of cerebral small vessel disease.

Cerebral small vessel disease (SVD) is an important cause of stroke and cognitive impairment among the elderly and is a more frequent cause of stroke in Asia than in the US or Europe. Although traditional risk factors such as hypertension or diabetes mellitus are important in the development of cerebral SVD, the exact pathogenesis is still uncertain. Both, twin and family history studies suggest heritability of sporadic cerebral SVD, while the candidate gene study and the genome-wide association study (GWAS) are mainly used in genetic research. Robust associations between the candidate genes and occurrence of various features of sporadic cerebral SVD, such as lacunar infarction, intracerebral hemorrhage, or white matter hyperintensities, have not yet been elucidated. GWAS, a relatively new technique, overcomes several shortcomings of previous genetic techniques, enabling the detection of several important genetic loci associated with cerebral SVD. In addition to the more common, sporadic cerebral SVD, several single-gene disorders causing cerebral SVD have been identified. The number of reported cases is increasing as the clinical features become clear and diagnostic examinations are more readily available. These include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, COL4A1-related cerebral SVD, autosomal dominant retinal vasculopathy with cerebral leukodystrophy, and Fabry disease. These rare single-gene disorders are expected to play a crucial role in our understanding of cerebral SVD pathogenesis by providing animal models for the identification of cellular, molecular, and biochemical changes underlying cerebral small vessel damage.

Surprising Results of the EMPA-REG OUTCOME Study have brought a New Insight into Use of Sodium-Glucose Co-transporter 2 Inhibitors in Patients with Type 2 Diabetes

A surprising new study EMPA-REG OUTCOME has shown that empagliflozin, one of sodium-glucose cotransporter 2 (SGLT2) inhibitors, in addition to standard care had beneficial effects on cardiovascular morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular events. Subgroup analyses of the study revealed a better hazard ratio for the primary outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) in Asian than Caucasian and in patients with age ≥65 years, body-mass index <30, glycated hemoglobin <8.5% or higher cardiovascular risk than with the respective counterparts. Patients on diuretics also had the hazard ratio favoring empagliflozin, similar to that of patients not on diuretics. I infer that in poorlycontrolled diabetic patients, pre-existing osmotic diuresis is supposed to be augmented by the administration of SGLT2 inhibitors, possibly leading to an acceleration of their dehydration in spite of amelioration of hyperglycemia. Hypovolemia is inferred to be more likely to occur due to osmotic diuresis without an increase in blood glucose level to retain water. It may be recommended that use of SGLT2 inhibitors should be avoided in diabetic patients with glycated hemoglobin ≥8.5% at high risk for cardiovascular events. Because empagliflozin seems to have had no significant effect on nonfatal myocardial infarction or stroke, its ability to reduce cardiovascular mortality may be mediated through osmotic diuresis. SGLT2 inhibitors could be used as a new oral osmotic diuretic to excrete water with a little sodium into urine for non-diabetic patients with heart failure as well. Such action of SGLT2 inhibitors seems to be rather close to that of tolvaptan to promote water diuresis. Thus, the EMPA-REG OUTCOME study has brought a new insight into use of SGLT2 inhibitors in patients with type 2 diabetes.

Long-Term Natural History of Intracranial Arterial Stenosis: An MRA Follow-Up Study

Background: Intracranial arterial stenosis (ICAS) is a major cause of ischemic stroke in Asians. Despite the clinical importance of ICAS, the literature on the natural history of ICAS has been less enlightening. The aims of our study were to evaluate a long-term natural course of symptomatic and asymptomatic ICAS. Methods: 102 subjects (37 symptomatic and 65 asymptomatic) underwent follow-up MR angiography (MRA) with a median time interval between initial and follow-up MRA of 5.7 years (range 3.6-8.5 years). For each patient, the extent of stenosis of five arteries (both middle cerebral arteries, both intracranial internal carotid arteries, and basilar artery) was classified according to five grades, by consensus: normal, mild (signal reduction <50%), moderate (signal reduction ≥50%), severe (focal signal loss with the presence of a distal signal), and occlusion. Because the sample size was too small to adjust for multiple confounders, we applied the propensity score. Results: Mean (Standard deviation) age at initial MRA was 63.5 (9.6) and 54% were men. The progression rate of ICAS differed significantly between symptomatic and asymptomatic patients (22 vs. 8%, p < 0.01), indicating a 3-fold risk of progression for symptomatic stenosis compared with asymptomatic stenosis [odds ratio (OR) 3.27, 95% confidence interval (CI) 1.08-9.95]. After adjustment for propensity score, the OR was 4.84 (95% CI, 1.40-16.7). In the matched cohort, the relative risk of stenosis progression was 5.20 for symptomatic stenosis (95% CI 1.00-27.23) compared with asymptomatic stenosis. Conclusion: We found a greater risk of progression for symptomatic stenosis compared with asymptomatic stenosis.

Increased risk for intracranial arterial stenosis in subjects with coronary artery calcification.

Intracranial arterial stenosis (ICAS) is considered an important cause of stroke in Asians. Coronary artery calcification (CAC) is a surrogate marker for subclinical atherosclerosis. We aimed to analyze the association of ICAS assessed by transcranial Doppler ultrasonography and CAC in middle-aged Korean population. This study included 10 550 participants (81.3% men, mean age 43 years) from a health screening program, in whom transcranial Doppler ultrasonography was used to detect >50% intracranial stenosis based on criteria modified from the stroke outcomes and neuroimaging of intracranial atherosclerosis trial. Multidetector computed tomography was used to assess coronary artery calcium score (CACS). CAC grade (0, 1-100, and >100) was defined by CACS. The subjects with CAC showed significantly higher proportion of subjects with ICAS compared with those without CAC (4.4% versus 2.8%; P<0.01). Conversely, the subjects with ICAS showed significantly higher proportion of subjects with CAC (24.8% versus 17.1%; P<0.01). When logistic regression analysis was performed with ICAS as the dependent variable, the presence of CAC showed significantly increased risk for ICAS after adjustment for confounding variables (odds ratio, 1.439; 95% confidence interval, 1.095-1.891). When CACS grade was included in the model, the odds ratio for ICAS was the highest in subjects with CACS >400 compared with those with CACS=0 (odds ratio, 2.754; 95% confidence interval, 1.205-2.936). The risk for ICAS was significantly increased in middle-aged Korean subjects with CAC compared with that in those without CAC. These findings suggest the possibility of a separate undetected atherosclerotic focus in subjects with 1 atherosclerotic event.

Mean arterial pressure is a stronger predictor of stroke in South Asian than European men, independent of other cardiometabolic risk factors; the SABRE study

Background: Stroke risk is greater in South Asians than Europeans. We sought to compare associations between blood pressure (BP) and stroke by ethnicity and determine how BP contributes to ethnic differences in disease. Methods: Population sample of 1510 European and 1195 South Asian men recruited between 1988-1991, mean age 52 7yrs. Incident fatal and nonfatal strokes were captured over 20 years of follow-up. Cox models demonstrated associations between mean arterial BP (MAP) and stroke. Results: South Asians had more incident strokes than Europeans (5.6 (4.7,6.7) versus 4.7 (4.0,5.6) per 1000 person years, age-adjusted hazard ratio:1.40 (1.08,1.76), pZ0.01) and higher MAPs than Europeans (97 12 versus 93 12mmHg, p<0.0001). MAP was more strongly associated with stroke in South Asians than Europeans, (HR (95% CI): 1.59(1.35,1.86) versus 1.19(1.00,1.43) respectively, ethnicity interaction pZ0.03), even accounting for receipt of anti-hypertensive medication (1.57(1.32,1.86 versus 1.10(0.91,1.32), interaction pZ0.03). The ethnic difference in impact of MAP diminished after further adjustment for smoking, waist circumference, HDL, fasting glucose, HOMA2IR, HbA1c and heart rate (1.40(1.12,1.75) versus 1.15(0.92,1.42), interaction pZ0.24). However, the greater effect of MAP on stroke in South Asians persisted when this latter model was restricted to people not receiving anti-hypertensive medications, (1.57(1.26,1.96) versus 1.08(0.85,1.37), interaction pZ0.02). Adjustment for MAP could not account for the excess stroke risk in South Asians (1.27 (1.00, 1.62) pZ0.05), nor could other risk factors. Conclusions: MAP had a greater impact on stroke risk in South Asians than Europeans, but could not account for their excess stroke risk, alone or in conjunction with additional risk factors.

Stroke in Asia: a global disaster.

Although stroke is a world-wide problem, the burden of stroke is particularly serious in Asia; its mortality is higher than in Europe or North America. The situation in Asia is dichotomized. Stroke mortality and case fatality has been declining in northern-eastern countries such as Korea, Japan, Taiwan, and urbanized areas of China. This is attributed to both the risk factor control and stroke care improvement. However, declining stroke incidence is rarely observed, which is in part due to rapidly aging population. As a result, there is an increase in the number of stroke survivors who require long-term, costly care. The extremely low birth rate and relatively insecure social health system markedly increases the caregiver burden. The problem in southern Asian countries, such as India, Pakistan, Bangladesh, and Indonesia is more fundamental. With the improving control of infectious diseases, life expectancy is prolonged. However, risk factors such as hypertension, diabetes, obesity and cigarette smoking become prevalent, and are poorly controlled. Stroke neurologists, organized stroke centers, and diagnostic tools are insufficient, which has resulted in high stroke fatality and mortality. Throughout Asia, the most urgent priority should be the primary stroke prevention through promoting a healthy lifestyle, e.g. low salt intake, regular physical exercise, stopping smoking, government sectors should take a stronger initiative to accomplish this. The rapidly aging populations and stroke burden will shrink the economy and destabilize the society, not only in Asia but also globally unless appropriate efforts are promptly initiated, this may result in a global disaster.

Association between 12p13 SNP rs11833579 and ischemic stroke in Asian population: An updated meta-analysis

BackgroundA GWAS found that the single-nucleotide polymorphism rs11833579 near the NINJ2 gene on chromosome 12p13 was associated with an increased risk of ischemic stroke in Caucasians in 2009. Several studies have been carried out to explore the association between this SNP and ischemic stroke in Asians, but published results were contradictory. In the present study, we performed a meta-analysis to further evaluate this association in the Asian population. MethodsAll relevant articles were retrieved from the databases of PubMed, EMBASE, Chinese Biomedical Literature Database, CNKI, CQVIP, and WANFANG Database from the establishment date to February 2014. Statistical analyses were performed by using Stata 11. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of the association. Possible publication bias was checked by funnel plots, Begg's test and Egger's test. ResultsEleven studies were eligible for meta-analysis including 9358 cases and 8936 controls. Overall, there were no significant associations between rs11833579 and ischemic stroke under the allelic (OR=0.963, 95% CI: 0.850–1.092, p=0.559), dominant (OR=0.946, 95% CI: 0.778–1.150, p=0.580), recessive (OR=0.993, 95% CI: 0.914–1.078, p=0.868), and homozygote (OR=0.968, 95% CI: 0.796–1.177, p=0.744) genetic models in the Asian population. Further, we found no evidence of association of rs11833579 with large artery atherosclerosis (LAA) or small-artery occlusion (SAO) stroke in all genetic models. The results of the subgroup analysis for Chinese population and Japanese population were consistent with that of the overall study. ConclusionsOur meta-analysis shows that SNP rs11833579 is not related to ischemic stroke in the Asian population.

Orolingual angioedema after alteplase therapy of acute ischaemic stroke: incidence and risk of prior angiotensin-converting enzyme inhibitor use.

Orolingual angioedema (OA) is an uncommon but potentially life-threatening complication of treatment with recombinant tissue plasminogen activator (rt-PA; alteplase) during acute ischaemic stroke. This study aimed to determine the incidence of rt-PA-related OA in an Asian stroke population and the risk of pre-stroke anti-hypertensive drug use for development of this complication. A multi-center stroke registry was used to identify the pre-stroke medications of acute ischaemic stroke patients receiving intravenous rt-PA from January 2002 to December 2013. The clinical manifestations of rt-PA-related OA were recorded and the incidence of this complication was determined. The risks of pre-stroke use of different anti-hypertensive agents for the occurrence of rt-PA-related OA were determined from this study and from a meta-analysis. A total of 559 patients received intravenous rt-PA over a 12-year period. Five patients (two males) developed OA after rt-PA administration. The incidence of OA amongst these patients was 0.89% (95% confidence interval 0.29%-2.09%), which was lower than that obtained by meta-analysis (1.9%). Amongst pre-stroke anti-hypertensive medications, angiotensin-converting enzyme (ACE) inhibitors were found in this study to have the highest relative risk for rt-PA-related OA (17.1; 95% confidence interval 3.0-96.9). Meta-analysis also revealed that pre-stroke use of ACE inhibitors was associated with a high relative risk of OA after intravenous rt-PA (12.9; 95% confidence interval 4.5-37.0). The incidence of rt-PA-related OA in the Asian population is lower than that in the Caucasian population. Pre-stroke use of ACE inhibitors significantly increases the risk of this complication.

Efficacy and Safety of Apixaban Compared with Warfarin for Stroke Prevention in Patients with Atrial Fibrillation from East Asia: A Subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial

The perceived risk of serious bleeding is an obstacle to the use of oral anticoagulation in East Asia. The efficacy and safety of apixaban in East Asian patients with atrial fibrillation are unknown. ARISTOTLE included 18,201 patients with nonvalvular atrial fibrillation randomized to apixaban 5mg twice daily or warfarin. The efficacy and safety of apixaban and warfarin among patients recruited from East Asia (n = 1,993) were compared with those recruited from outside East Asia (n = 16,208). Compared with warfarin, apixaban resulted in a consistent reduction in stroke or systemic embolism in East Asian (hazard ratio [HR] 0.74, 95% CI 0.50-1.10) and non-East Asian (HR 0.81, 95% CI 0.66-0.99) patients (interaction P = .70). Consistent benefits of apixaban over warfarin were also seen for major bleeding in East Asian (HR 0.53, 95% CI 0.35-0.80) and non-East Asian (HR 0.72, 95% CI 0.62-0.83) patients (interaction P = .17). There was a greater reduction in major or clinically relevant nonmajor bleeding with apixaban compared with warfarin in East Asian (HR 0.49, 95% CI 0.35-0.67) than in non-East Asian (HR 0.71, 95% CI 0.63-0.79) patients (interaction P = .03). Numerically higher rates of intracranial bleeding were seen in East Asian patients with warfarin but not with apixaban. Apixaban resulted in similar reductions in stroke or systemic embolism and major bleeding and greater reductions in major or clinically relevant nonmajor bleeding in patients from East Asia. Warfarin is associated with more intracranial bleeding, particularly in patients from East Asia.

Does Digoxin Increase the Risk of Ischemic Stroke and Mortality in Atrial Fibrillation? A Nationwide Population-Based Cohort Study

BackgroundDigoxin and related cardiac glycosides have been used for almost 100 years in atrial fibrillation (AF). However, 2 recent analyses of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial showed inconsistent results regarding the risk of mortality associated with digoxin use. The goal of the present study was to investigate the relationship between digoxin and the risk of ischemic stroke and mortality in Asians. MethodsThis study used the National Health Insurance Research Database (NHIRD) in Taiwan. A total of 4781 patients with AF who did not receive any antithrombotic therapy were selected as the study population. Among the study population, 829 participants (17.3%) received the digoxin treatment. The risk of ischemic stroke and mortality in patients who received digoxin and those who did not was compared. ResultsThe use of digoxin was associated with an increased risk of clinical events, with an adjusted hazard ratio of 1.41 (95% confidence interval [CI], 1.17-1.70) for ischemic stroke and 1.21 (95% CI, 1.01-1.44) for all-cause mortality. In the subgroup analysis based on coexistence with heart failure or not, digoxin was a risk factor for adverse events in patients without heart failure but not in those with heart failure (interaction P < 0.001 for either end point). Among patients with AF without heart failure, the use of β-blockers was associated with better survival, with an adjusted hazard ratio of 0.48 (95% CI, 0.34-0.68). ConclusionsDigoxin should be avoided for patients with AF without heart failure because it was associated with an increased risk of clinical events. β-Blockers may be a better choice for controlling ventricular rate in these patients.

Is Calcification of Intracranial Arteries Important and How?

Intracranial atherosclerosis is a well-recognized and common cause of stroke in Asian, black, and Hispanic individuals.1,2 Recent studies showed that intracranial occlusive disease is also a more common cause of stroke in white individuals than previously thought.3 In this issue of JAMA Neurology, Bos and colleagues4 provide evidence that intracranial carotid artery calcification is an important risk factor for stroke in an elderly white Dutch population. As part of the prospective, population-based Rotterdam study, the authors followed up 2323 individuals to determine the incidence of stroke (parenchymal brain hemorrhage or ischemic) after they had nonenhanced computed tomography (CT) scanning that imaged the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries. The authors used calcification volume in these arteries as an indicator of atherosclerosis and correlated this with the risk for all stroke and ischemic stroke. They found that larger intracranial carotid calcification volume was independently associated with all stroke and that intracranial carotid calcification was a more important risk factor for stroke than aortic arch calcification or extracranial carotid calcification. The apparent discrepancy between the importance of intracranial carotid calcification as a major risk factor for stroke in this study and the low frequency of stroke caused by intracranial atherosclerosis in most studies of white patients is largely explained by the different design of these studies. Prior studies identified consecutive patients with stroke and determined the frequency of proximal intracranial atherosclerotic arterial stenosis. In the current study, intracranial carotid calcification (not stenosis) was measured and correlated with subsequent stroke regardless of the territory of the stroke. Data on the size, location (cortical or subcortical), and vascular territory of brain infarcts were not collected. While the current study suggests that intracranial carotid artery calcification is an important, previously seldom considered, risk factor for subsequent stroke in any vascular territory in white patients, the study did not show that the intracranial vascular lesions were the cause of the strokes. Many of the ischemic strokes in this study were almost surely not caused by intracranial carotid atherosclerosis because the strokes were either in a different vascular territory or were caused by other vascular diseases (eg, coexisting penetrating artery disease,5 a cardiac source of embolism). Moreover, at least 11% of the strokes in the study were hemorrhagic and no causal relationship has been established between intracranial arterial calcification and parenchymal brain hemorrhage. Recent interest in calcification of arteries has been spurred on by the strong association between coronary calcification detected by cardiac CT and the risk for future cardiac events.6 The situation appears to be different in relation to carotid artery disease in the neck where the presence of heavy calcification on spiral CT has been correlated with stable, noninflammatory, asymptomatic plaques.7 Whether intracranial arterial calcification is also associated with stable plaque that is unlikely to cause a distal stroke is unknown. What is known is that severe stenosis of an intracranial artery is strongly associated with a high risk for stroke distal to the stenosis in patients presenting with a transient ischemic attack or stroke.8 If the presence of severe intracranial carotid calcification implied coexistent severe arterial stenosis of the artery, that would provide some evidence of a potential causal link between calcification and risk for stroke attributable to the affected artery. However, the relationship between calcification of the intracranial carotid artery and coexistent stenosis is unsettled. Older pathological studies found that heavy calcification of the carotid siphon did not necessarily indicate stenosis of the lumen9; however, a more recent neuroimaging study showed that the positive predictive value of severe carotid siphon calcification on CT for a stenosis of greater than 50% on angiography was 86% using bone window measurements.10 It is also possible that intracranial carotid calcification may cause stroke without the presence of coexistent stenosis if calcification is associated with unstable plaque features that predispose to distal embolism. This study by Bos and colleagues4 raises important questions about the role of calcification in the pathophysiology of intracranial atherosclerosis and should reawaken interest in intracranial atherosclerosis as a cause of stroke inwhite individuals. The study indicates that intracranial carotidcalcification isamajor risk factor for stroke inwhite individuals but does not establish a pathophysiologic causal relationshipbetweenthe two.Establishing thatwill require further prospective studies that correlate the association between intracranial arterial calcification and stenosis more clearly, identifyatheroscleroticplaque featuresassociatedwith calcification thatmay be associatedwith a high risk for distal embolism, and classify ischemic strokes that occur in patientswith intracranial carotid calcification according to size, location (cortical or subcortical), vascular territory, and thecoexistenceofotherpotential causesof stroke.Muchworkneeds to be done. Related article page 405 Opinion

Concurrent stenoses: A common etiology of stroke in Asians.

Atherosclerosis of cerebral vessels is a common cause of stroke. Racial differences in the distribution of cerebrovascular occlusive disease are well documented. Extracranial stenosis is more common in Caucasians, while intracranial stenosis is more common in Asians, Hispanics and African-Americans. Concurrent atherosclerosis of extracranial and intracranial vessels is common in Asians. The incidence of concurrent stenoses ranges from 10% to 48% in patients with symptomatic cerebrovascular disease. The long-term prognosis of these patients is poor and they are at high risk of further vascular events or death. The purpose of this review is to examine the epidemiology, risk factors, stroke mechanism and genetics of concurrent stenoses and to discuss strategies for treatment.

New oral anticoagulants may be particularly useful for asian stroke patients.

Atrial fibrillation (AF) is an emerging epidemic in both high-income and low-income countries, mainly because of global population aging. Stroke is a major complication of AF, and AF-related ischemic stroke is more disabling and more fatal than other types of ischemic stroke. However, because of concerns about bleeding complications, particularly intracranial hemorrhage, and the limitations of a narrow therapeutic window, warfarin is underused. Four large phase III randomized controlled trials in patients with non-valvular AF (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48) demonstrated that new oral anticoagulants (NOACs) are superior or non-inferior to warfarin as regards their efficacy in preventing ischemic stroke and systemic embolism, and superior to warfarin in terms of intracranial hemorrhage. Among AF patients receiving warfarin, Asians compared to non-Asians are at higher risk of stroke or systemic embolism and are also more prone to develop major bleeding complications, including intracranial hemorrhage. The extra benefit offered by NOACs over warfarin appears to be greater in Asians than in non-Asians. In addition, Asians are less compliant, partly because of the frequent use of herbal remedies. Therefore, NOACs compared to warfarin may be safer and more useful in Asians than in non-Asians, especially in stroke patients. Although the use of NOACs in AF patients is rapidly increasing, guidelines for the insurance reimbursement of NOACs have not been resolved, partly because of insufficient understanding of the benefit of NOACs and partly because of cost concerns. The cost-effectiveness of NOACs has been well demonstrated in the healthcare settings of developed countries, and its magnitude would vary depending on population characteristics as well as treatment cost. Therefore, academic societies and regulatory authorities should work together to formulate a scientific healthcare policy that will effectively reduce the burden of AF-related stroke in this rapidly aging society.

The primary goal of anticoagulation in atrial fibrillation to prevent stroke and not to offer the apparently cheapest treatment.

Patients with atrial fibrillation (AF) have a particular high risk of cardio-embolic stroke. Cardio-embolic strokes have a high mortality (20%) and >50% of patients remain permanently disabled. Oral anticoagulation with warfarin is highly effective in preventing strokes as long as warfarin is taken. Unfortunately many patients with atrial fibrillation refuse to take warfarin because they are afraid of major bleeding complications in particular intracranial bleeds. In addition long term compliance and adherence with warfarin is terrible due to the need of regular international normalized ratio (INR) monitoring and the many interactions with food and drugs in elderly patients with polypharmacy. Anticoagulation is most effective in old patients who have difficulties to get to a physicians' office or an anticoagulation clinic to get the INR monitored. Just imagine the 86 years old lady with unsteady gate and a walker needing to get to a doctor in winter with ice and freezing temperatures outside. Data from Canadian and German stroke units on admission of patients with AF and a new stroke display shocking facts.1,2 One third of patients with AF and without contraindications for anticoagulation are untreated at the time of stroke. Thirty percent are treated with aspirin which is not effective in secondary stroke prevention in AF.3 Another 30% are treated with warfarin but the INR was <2.0 at the time of stroke. Only 10% of patients were on warfarin and the INR was between 2.0 and 3.0. Reimbursement bodies, however, will consider only the last 10% of patients, namely patients with AF well controlled on warfarin. This does not reflect clinical reality. The most restrictions for the use of novel anticoagulants (NOACs) instead of warfarin prevent the patients in highest need of stroke prevention from a drug that is superior to warfarin and has fewer intracranial bleeds, namely the elderly. In this issue, Bang et al.4 summarized pieces of evidence that NOACs may be particularly helpful for Asian stroke patients. Indeed, Asians are at particular high risk of major bleeds on warfarin. This risk is much lower with novel anticoagulants. Therefore it is not rational to restrict the use of NOACs in Asian patients with AF. My policy would be to offer all patients who had a transient ischemic attack or ischemic stroke and AF a NOAC, because these patients have a particular high risk of a recurrent stroke. In primary prevention I would offer NOACs to untreated patients, patients on aspirin and patients poorly controlled on warfarin. I see no reason to switch well controlled patients on warfarin to NOACs. In summary putting high hurdles on the prescription of NOACs will lead to many strokes with severe disability and tremendous costs for a national health care system.

Genetic polymorphism of β-fibrinogen gene-455G/A can contribute to the risk of ischemic stroke

Many studies have investigated the association between the β-fibrinogen gene-455G/A (FGβ-455G/A) polymorphism and the risk of ischemic stroke. However, these evidences were inadequate to provide stronger conclusions because most studies were generally small. To shed light on these inconclusive findings, we conducted a large sample size meta-analysis of studies relating to the FGβ-455G/A polymorphism and the risk of ischemic stroke. Odds ratios with a 95 % confidence interval were used to investigate the association between FGβ-455G/A polymorphism and ischemic stroke. Publication bias was tested by Egger's test and funnel plot. Inconsistency index and Cochran's Q statistic were used to check heterogeneity. Cumulative and recursive cumulative meta-analyses were performed to provide a framework for updating a genetic effect from all of the included studies. Twenty-six independent publications with 4,070 cases and 4,649 controls were included in this meta-analysis. Results showed that the β-fibrinogen-455G/A polymorphism was significantly associated with the risk of ischemic stroke. The FGβ-455G/A polymorphism was found to be a risk factor for ischemic stroke in Asians and adults, while association was not observed for Caucasians and juveniles based on the small size and it may be necessary to conduct larger studies on them to investigate the association in the future. The cumulative meta-analysis indicated a decline from 1998 to 2003, and the results remained stable during the period 2004-2012. The results indicate that FGβ-455G/A polymorphism may be a susceptible predictor of ischemic stroke. More studies are needed to elucidate the relationship further.

Gender Differences in the Age-Stratified Prevalence of Risk Factors in Korean Ischemic Stroke Patients: A Nationwide Stroke Registry-Based Cross-Sectional Study

Although ethnic or cultural differences affect prevalence of cardiovascular risk factors, limited information is available about the age- and gender-stratified prevalence of the risk factors in Asian stroke population. We assessed gender- and age-stratified prevalences of major risk factors in Korean stroke patients, and assumed that the gender differences are attenuated by adjustment with lifestyle factors. Using the nationwide hospital-based stroke registry, we identified 9417 ischemic stroke patients admitted between April 2008 and January 2011. Prevalence of hypertension, diabetes, hyperlipidemia, atrial fibrillation, prior stroke, and coronary heart disease was assessed in both genders by age groups. We analyzed gender differences of the prevalence among the age groups by calculating prevalence ratio, and further explored the influence of lifestyle factors on the gender difference in multivariable analyses. Hypertension and hyperlipidemia were more common in men until middle age, but after that more common in women, whereas diabetes was more common in women after 65 years of age. Atrial fibrillation increased steadily with age in both genders but was more common in women through all age groups. Prior stroke and coronary heart disease showed inconsistent gender differences. Gender differences in hypertension and diabetes among the age groups were attenuated by adjustment with accompanying risk factors including lifestyle factors. Korean women with stroke had more hypertension and hyperlipidemia after middle age, more diabetes after 65 years, and more atrial fibrillation throughout all ages. Strategies to control risk factors in women at risk for stroke are eagerly needed.

Association between body mass index and cardiovascular disease mortality in east Asians and south Asians: pooled analysis of prospective data from the Asia Cohort Consortium

Objective To evaluate the association between body mass index and mortality from overall cardiovascular disease and specific subtypes of cardiovascular disease in east and south Asians.Design Pooled analyses of 20...