Yannie Soo

Risk vs benefit of anti-thrombotic therapy in ischaemic stroke patients with cerebral microbleeds

BackgroundRetrospective studies suggested that cerebral microbleeds (MB) on magnetic resonance images (MRI) increase risk of intracerebral haemorrhage (ICH).ObjectiveTo compare the benefit of anti-thrombotic agents in stroke prevention (absolute risk reduction 2.49 –6 %) versus risk of ICH in ischaemic stroke patients with MB.Materials and methodsWe prospectively studied patients admitted consecutively for acute ischaemic stroke between 1999 and 2004. MB on MRI were documented. Primary end points were subsequent ICH, recurrent cerebral infarct (CI) and mortality.ResultsA total of 908 patients were recruited. MB were identified in 252 (27.8 %) patients. Mean follow-up period was 26.6 ± 15.4 months. Risk of subsequent ICH increased significantly with quantity of MB: 0.6 % (no MB), 1.9 % (1 MB), 4.6 % (2–4 MB) and 7.6 % (≥ 5 MB) (p < 0.001). There was also a significant increase in mortality from ICH: 0.6 %, 0.9 %, 1.5 % and 3.8 % respectively (p = 0.054). Rate of recurrent CI was 9.6 %, 5.6 %, 21.5 % and 15.2 % respectively (p = 0.226). Mortality from CI and myocardial infarction did not increased with quantity of MB. Survival analyses showed that age, presence of MB, mixed cortical-subcortical distribution of MB were independent predictors of subsequent ICH.ConclusionRisk and mortality of ICH increased with quantity of MB. As tendency to recurrent CI exceed that of ICH, anti-thrombotic agents are still warranted. However, in patients with ≥ 5 MB, the high risk and mortality of ICH seem to outweigh the modest benefit of antithrombotic agents. Extra precautions should be taken to minimize risk of ICH. Further studies in patients on Coumadin and assessment of functional outcome are warranted to support these preliminary findings.

Prevalence and Outcomes of Symptomatic Intracranial Large Artery Stenoses and Occlusions in China The Chinese Intracranial Atherosclerosis (CICAS) Study

Background and Purpose— We aimed to establish the prevalence, characteristics, and outcomes of intracranial atherosclerosis (ICAS) in China by a large, prospective, multicenter study. Methods— We evaluated 2864 consecutive patients who experienced an acute cerebral ischemia <7 days after symptom onset in 22 Chinese hospitals. All patients underwent magnetic resonance angiography, with measurement of diameter of the main intracranial arteries. ICAS was defined as ≥50% diameter reduction on magnetic resonance angiography. Results— The prevalence of ICAS was 46.6% (1335 patients, including 261 patients with coexisting extracranial carotid stenosis). Patients with ICAS had more severe stroke at admission and stayed longer in hospitals compared with those without intracranial stenosis (median National Institutes of Health Stroke Scale score, 3 versus 5; median length of stay, 14 versus 16 days; both P<0.0001). After 12 months, recurrent stroke occurred in 3.27% of patients with no stenosis, in 3.82% for those with 50% to 69% stenosis, in 5.16% for those with 70% to 99% stenosis, and in 7.27% for those with total occlusion. Cox proportional hazards regression analyses showed that the degree of arterial stenosis, age, family history of stroke, history of cerebral ischemia or heart disease, complete circle of Willis, and National Institutes of Health Stroke Scale score at admission were independent predictors for recurrent stroke at 1 year. The highest rate of recurrence was observed in patients with occlusion with the presence of ≥3 additional risk factors. Conclusions— ICAS is the most common vascular lesion in patients with cerebrovascular disease in China. Recurrent stroke rate in our study was lower compared with those of previous clinical trials but remains unacceptably high in a subgroup of patients with severe stenosis.

Risk factors for incident dementia after stroke and transient ischemic attack

We hypothesized that chronic brain changes are important substrates for incident dementia after stroke and transient ischemic attack (TIA).

Dual antiplatelet therapy in stroke and ICAS Subgroup analysis of CHANCE

Objective: We aimed to investigate whether the efficacy and safety of clopidogrel plus aspirin vs aspirin alone were consistent between patients with and without intracranial arterial stenosis (ICAS), in the Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial. Methods: We assessed the interaction of the treatment effects of the 2 antiplatelet therapies among patients with and without ICAS, identified by magnetic resonance angiography (MRA) in CHANCE (ClinicalTrials.gov identifier NCT00979589). Results: Overall, 1,089 patients with MRA images available in CHANCE were included in this subanalysis, 608 patients (55.8%) with ICAS and 481 (44.2%) without. Patients with ICAS had higher rates of recurrent stroke (12.5% vs 5.4%; p < 0.0001) at 90 days than those without. But there was no statistically significant treatment by presence of ICAS interaction on either the primary outcome of any stroke (hazard ratio for clopidogrel plus aspirin vs aspirin alone: 0.79 [0.47–1.32] vs 1.12 [0.56–2.25]; interaction p = 0.522) or the safety outcome of any bleeding event (interaction p = 0.277). Conclusions: The results indicated higher rate of recurrent stroke in minor stroke or high-risk TIA patients with ICAS than in those without. However, there was no significant difference in the response to the 2 antiplatelet therapies between patients with and without ICAS in the CHANCE trial. Classification of evidence: This study provides Class II evidence that for patients with acute minor stroke or TIA with and without ICAS identified by MRA, clopidogrel plus aspirin is not significantly different than aspirin alone in preventing recurrent stroke.

Cerebral Microbleeds Is Antithrombotic Therapy Safe to Administer

Growing evidence suggests a link between cerebral microbleeds (CMBs) and increased risk of intracerebral hemorrhage (ICH), leading to concerns on the safety of administering antithrombotic drugs in patients with CMBs. This review summarized studies on the association among CMBs, ICH, and antithrombotic therapy (defined as antiplatelet and anticoagulant agents). Recommendations for future studies on this topic were also proposed. CMBs are small perivascular hemosiderin deposits (usually with macrophages) from leakage through cerebral small vessels, which can be visualized as small, rounded, homogeneous, and hypointense lesions on T2*-weighed gradient-recalled echo or susceptibility-weighted imaging MRI.1 CMBs indicate hemorrhage-prone pathological states, and studies have shown that the presence of CMBs is associated with increased risk of future ICH (odds ratio [OR], 8.52; 95% confidence interval [CI], 4.23–17.18),1 which is also the most feared complication associated with antithrombotic drugs. Thus, it is natural to wonder whether antithrombotic therapy should be averted in patients with CMBs. Different perspectives should be considered to address this question. In this review, we will seek to clarify this topic by answering the following questions: (1) What is the pathophysiology of CMBs? (2) Are CMBs common in populations who might require antithrombotic therapy? (3) Do patients taking antithrombotic therapy develop more CMBs? (4) Under antithrombotic therapy, do patients with CMBs have an increased risk of future ICH compared with patients without CMBs? (5) Does the increased risk of ICH outweigh the benefit of antithrombotic therapy in patients with CMBs? ### What Is the Pathophysiology of CMBs? Figure 1 illustrates our current understanding on the pathophysiology of CMBs. At least 2 pathological mechanisms may lead to CMBs: cerebral amyloid angiopathy (CAA) and hypertensive microangiopathy. CAA, characterized by amyloid-β deposition in vessel walls, is related to apolipoprotein E genotype.2 Amyloid-β, especially inflammatory amyloid, induces local inflammation ranging from mild changes to a granulomatous angiitis with apoptosis …

Patient-Specific Decision-Making for Warfarin Therapy in Nonvalvular Atrial Fibrillation: How Will Screening With Genetics and Imaging Help?

Background and Purpose— Intracerebral hemorrhage (ICH) accounts for a majority of long-term morbidity and mortality associated with bleeding while on warfarin. Both ICH and warfarin-related ICH appear to have a genetic component. Furthermore, advanced neuroimaging using MRI can now identify individuals at increased risk of ICH. We explore whether screening strategies that include genetic profiling and neuroimaging might improve the safety of chronic anticoagulation for atrial fibrillation by identifying individuals from whom warfarin should be withheld. Methods— We used a Markov state transition decision model. Effectiveness was measured in quality-adjusted life-years. Data sources included the English language literature using MEDLINE searches and bibliographies from selected articles along with empirical data from our institutions. The base case was a 69-year-old man with newly diagnosed nonvalvular atrial fibrillation. Results— For patients at average risk for thromboembolic events and known to possess a hypothetical genetic profile increasing risk for warfarin ICH, anticoagulation remains the preferred strategy until the relative hazard of ICH exceeds 23.8. Genetic profiling would be favored for patients at low risk of thromboembolism (1.5% per year) if the hypothetical gene variant(s) conferred a relative risk of ICH >4.1. Screening strategies in which patients underwent genotyping and MRI before anticoagulation did not improve aggregate patient outcomes unless the predictive power of MRI exceeded current best guess estimates and patients were at low to moderate risk of thromboembolism. Conclusion— Currently identified genetic markers of bleeding risk do not confer a risk of ICH sufficiently high to warrant routine genetic testing for patients at average risk of thromboembolism. Even if patients undergo screening with MRI as well as genotyping, currently available data on the role of MRI on risk of ICH and warfarin ICH do not support use of these tests for withholding anticoagulation in patients with atrial fibrillation.

Geographic and Sex Difference in the Distribution of Intracranial Atherosclerosis in China

Background and Purpose— Geographic variation and sex difference in the distribution of intracranial atherosclerosis (ICAS) have not been fully discussed before in Chinese patients with cerebral ischemia. We performed this study with the aim to investigate geographic and sex difference in the distribution of ICAS in China. Methods— In this prospective multicenter study, we evaluated 2864 consecutive patients who experienced an acute cerebral ischemia within 7 days of symptom onset in 22 hospitals in China. All the inclusive patients underwent 3-dimensional time-of-flight MR angiography and duplex color Doppler ultrasound or contrast-enhanced MR angiography to document the presence of intracranial or extracranial stenosis. Intracranial large-artery atherosclerosis was defined as ≥50% diameter reduction on MR angiography. Results— The proportion of patients with ICAS was significantly higher in north China than in south China (50.22% versus 41.88%; P<0.0001). Patients in the north were likely to consume more alcohol and smoke more cigarettes and had significantly higher proportion of diabetes mellitus, family history of stroke, history of cerebral ischemia, heart disease, and higher body mass index. In patients aged >63 years, the percentage of ICAS in women was notably higher than in men (51.51% versus 45.40%; P=0.028). In elderly patients, women had higher proportion of diabetes mellitus, hypertension, hyperlipidemia, and heart disease than men. Conclusions— There exists geographic and sex difference in the distribution of symptomatic ICAS in China. Public health measures should strengthen improving social determinants of health and risk factor prevention/control in high-risk populations for decreasing stroke risk.

Validation of the ABCD2 Score to Identify the Patients With High Risk of Late Stroke After a Transient Ischemic Attack or Minor Ischemic Stroke

Background and Purpose— The ABCD2 score is able to predict the short-term risk of stroke after a transient ischemic attack/minor stroke. We aimed to explore its predictive value for long-term recurrent stroke. Methods— Consecutive patients with a transient ischemic attack/minor stroke, hospitalized during a 2-year period, were followed up to document any further stroke and death stratified by a 7-point ABCD2 score. Result— A total of 490 patients were followed for an average of 40.5 months (SD, 10.7 months). Further stroke were identified in 76 (15.5%) patients and 62 (12.7%) patients died during follow-up. Multivariate Cox regression analysis showed that an ABCD2 score >4 was found to be an independent risk factor for further stroke (hazard ratio, 2.27; 95% CI, 1.36 to 3.80) and for death (hazard ratio, 1.68; 95% CI, 0.99 to 2.85). Conclusions— In addition to predicting short-term stroke risk, ABCD2 score is a useful tool to predict long-term stroke risk after a transient ischemic attack or minor ischemic stroke.

Computational fluid dynamics modeling of symptomatic intracranial atherosclerosis may predict risk of stroke recurrence.

Background Patients with symptomatic intracranial atherosclerosis (ICAS) of ≥70% luminal stenosis are at high risk of stroke recurrence. We aimed to evaluate the relationships between hemodynamics of ICAS revealed by computational fluid dynamics (CFD) models and risk of stroke recurrence in this patient subset. Methods Patients with a symptomatic ICAS lesion of 70–99% luminal stenosis were screened and enrolled in this study. CFD models were reconstructed based on baseline computed tomographic angiography (CTA) source images, to reveal hemodynamics of the qualifying symptomatic ICAS lesions. Change of pressures across a lesion was represented by the ratio of post- and pre-stenotic pressures. Change of shear strain rates (SSR) across a lesion was represented by the ratio of SSRs at the stenotic throat and proximal normal vessel segment, similar for the change of flow velocities. Patients were followed up for 1 year. Results Overall, 32 patients (median age 65; 59.4% males) were recruited. The median pressure, SSR and velocity ratios for the ICAS lesions were 0.40 (−2.46–0.79), 4.5 (2.2–20.6), and 7.4 (5.2–12.5), respectively. SSR ratio (hazard ratio [HR] 1.027; 95% confidence interval [CI], 1.004–1.051; P = 0.023) and velocity ratio (HR 1.029; 95% CI, 1.002–1.056; P = 0.035) were significantly related to recurrent territorial ischemic stroke within 1 year by univariate Cox regression, respectively with the c-statistics of 0.776 (95% CI, 0.594–0.903; P = 0.014) and 0.776 (95% CI, 0.594–0.903; P = 0.002) in receiver operating characteristic analysis. Conclusions Hemodynamics of ICAS on CFD models reconstructed from routinely obtained CTA images may predict subsequent stroke recurrence in patients with a symptomatic ICAS lesion of 70–99% luminal stenosis.

Low-Molecular-Weight Heparin Versus Aspirin for Acute Ischemic Stroke With Large Artery Occlusive Disease Subgroup Analyses From the Fraxiparin in Stroke Study for the Treatment of Ischemic Stroke (FISS-tris) Study

Background and Purpose— The Fraxiparin in Stroke Study for the treatment of ischemic stroke (FISS-tris) study showed no superiority of low-molecular-weight heparin (LMWH) over aspirin for the primary end point (Barthel Index) in acute ischemic stroke due to large artery occlusive disease. This study aims to evaluate the efficacy of LMWH and aspirin in selected subgroups so as to generate hypotheses for further studies. Methods— The FISS-tris study was a multicenter, randomized trial to investigate the efficacy and safety of LMWH (nadroparin calcium 3800 antifactor Xa IU/0.4 mL subcutaneously twice daily) or aspirin (160 mg once daily) for the treatment of patients with acute ischemic stroke and large artery occlusive disease. The primary outcome was the Barthel Index score dichotomized at 85 6 months poststroke. Exploratory subgroup analysis was performed using different levels of baseline characteristics and the distribution of symptomatic arteries. Results— Compared with aspirin, LMWH improved outcome among older patients >68 years (P=0.043; OR, 1.86; 95% CI, 1.02–3.41) without ongoing antiplatelet treatment on admission (P=0.029; OR, 1.85; 95% CI, 1.06–3.21) and with symptomatic posterior circulation arterial disease (P=0.001; OR, 5.76; 95% CI, 2.00–16.56). Conclusions— Our findings suggest that LMWH may be of benefit in certain subgroups of patients with acute cerebral infarct and large artery occlusive disease. Hence, further investigation of LMWH may be justified in subgroups such as the elderly, nonusers of antiplatelet agents, and patients with posterior circulation stenosis. Clinical Trial Registration— URL: www.strokecenter.org/trials. Unique identifier: registration no. 493.