Jianhui Fu

Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): A randomised, open-label, blinded-endpoint trial

BACKGROUND Few randomised clinical trials have investigated the use of antithrombotic drugs for early secondary prevention of stroke or transient ischaemic attack in patients with intracranial atherosclerotic stenosis. Microembolic signals, detected by transcranial doppler, are a surrogate marker of future stroke risk and have been used to show treatment efficacy in patients with extracranial carotid stenosis. We aimed to investigate whether treatment with clopidogrel plus aspirin reduced the number of microembolic signals detected with transcranial doppler ultrasound compared with aspirin alone in patients with recent stroke. METHODS The clopidogrel plus aspirin for infarction reduction in acute stroke or transient ischaemic attack patients with large artery stenosis and microembolic signals (CLAIR) trial was a randomised, open-label, blinded-endpoint trial. Between Oct 28, 2003, and Nov 19, 2008, patients with acute ischaemic stroke or transient ischaemic attack who had symptomatic large artery stenosis in the cerebral or carotid arteries and in whom microembolic signals were present on transcranial doppler were randomly assigned within 7 days of symptom onset to receive clopidogrel (300 mg for the first day, then 75 mg daily) plus aspirin (75-160 mg daily) or aspirin alone (75-160 mg daily) for 7 days. Patients were randomly assigned in blocks of four or six by use of a randomisation website. Monitoring of microembolic signals on transcranial doppler was done on days 2 and 7. The primary endpoint was the proportion of patients who had microembolic signals on day 2. Analysis was by modified intention to treat. All analyses were done by an investigator masked to both patient identity and the day the recording was taken. This trial is registered with the Centre for Clinical Trials, Chinese University of Hong Kong, number CUHK_CCT00164. FINDINGS 100 patients were randomly assigned to clopidogrel plus aspirin (n=47) or aspirin monotherapy (n=53). 93 of 100 patients had symptomatic intracranial stenosis in either the intracranial internal carotid artery or the middle cerebral artery: 45 of 46 in the dual therapy group and 48 of 52 in the monotherapy group. At day 2, 14 of 45 patients in the dual therapy group and 27 of 50 patients in the monotherapy group for whom data were available had at least one microembolic signal on transcranial doppler (relative risk reduction 42.4%, 95% CI 4.6-65.2; p=0.025). Adverse events were similar in the two groups. No patients had intracranial or severe systemic haemorrhage, but two patients in the dual therapy group had minor haemorrhages. INTERPRETATION Combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing microembolic signals in patients with predominantly intracranial symptomatic stenosis. Clinical trials are now warranted to investigate whether this combination treatment also results in a reduction in stroke incidence.

Transcranial Doppler Ultrasound for Screening Cerebral Small Vessel Disease A Community Study

Background and Purpose— We explored the association between pulsatility index (PI) as derived from transcranial Doppler ultrasound with various measures of small vessel disease in the community. Methods— We performed transcranial Doppler and magnetic resonance imaging in 205 consecutive community-dwelling elderly subjects who were participants of the Shanghai Aging Study. We investigated the association between middle cerebral artery (MCA) PI with measures of white matter lesions (WML), lacunes, and microbleeds. Results— Multiple logistic regression found that MCA PI was associated with severe WML (odds ratio, 1.33 per 0.1 increase in PI; 95% confidence interval, 1.04–1.70; P=0.02). At optimal MCA PI cut-off, the area under curve, positive predictive value, and negative predictive value were 0.70 (95% confidence interval, 0.60–0.80), 34.9%, and 85.6%, respectively, for detection of severe WML. No association was found between MCA PI and measures of lacunes or microbleeds. Conclusions— PI correlates with WML severity. With a high negative predictive value, the chance of having severe WML with a normal PI is low. Transcranial Doppler may guide selective magnetic resonance imaging scanning for the detection of WML in the community.

The Effectiveness of Dual Antiplatelet Treatment in Acute Ischemic Stroke Patients with Intracranial Arterial Stenosis: A Subgroup Analysis of CLAIR Study:

Background Dual antiplatelet therapy with clopidogrel and aspirin reduces the presence and number of microembolic signals in patients with large artery disease. However, whether it is effective in patients with intracranial disease alone remains uncertain. We performed a subgroup analysis of the The CLopidogrel plus Aspirin for Infarction Reduction (CLAIR in acute stroke or transient ischemic attack patients with large artery stenosis and microembolic signals) study of only patients with intracranial occlusive disease, excluding those with extra cranial disease. Methods CLAIR was a randomized-controlled, open-label, multicenter clinical trial with blinded outcome evaluation, which recruited patients with symptoms of ischemic stroke or transient ischemic attack within seven-days of onset, with large artery stenosis verified by transcranial Doppler and carotid ultrasound, and with microembolic signals detected by transcranial Doppler recording. All patients were randomized to receive clopidogrel plus aspirin daily for seven-days (dual treatment), or aspirin alone for seven-days (monotherapy). Repeated transcranial Doppler recordings for microembolic signals were made on day one, two, and seven. This subgroup study only analyzed the patients with purely intracranial large artery disease and excluded those with extra cranial stenosis. Results There were 70 patients recruited with purely intracranial stenosis, 34 in the dual treatment group and 36 in the monotherapy group. The proportion of the patients with positive emboli at day seven in the dual treatment group was significantly lower than that in the monotherapy group (relative risk reduction 56·5%, 95% confidence interval 2·5–80·6; P = 0·029). The number of emboli in the dual treatment group decreased significantly at day two (P = 0·043) and day seven (P = 0·018) compared with the monotherapy group. After adjustment for the number of emboli at day one, the effect of dual treatment was still significant for the reduction of presence (relative risk reduction 56·0%; 95% confidence interval 5·4–79·6; P = 0·036) and number (adjusted mean difference −0·9; 95% confidence interval −1·5 to −0·3; P = 0·004) of positive emboli at day seven. Conclusions Dual treatment with clopidogrel and aspirin for seven-days is more effective than aspirin alone to reduce microembolic signals in patients with intracranial arterial stenosis.

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.

Effects of Statins on Progression of Subclinical Brain Infarct

Background: Subclinical brain infarct (SBI) is associated with subsequent stroke and cognitive decline. A longitudinal epidemiological study suggests that statins may prevent development of SBI. We investigated the effects of statins upon development of brain infarct by performing a post-hoc analysis of the Regression of Cerebral Artery Stenosis (ROCAS) study. Methods: The ROCAS study is a randomized, double-blind, placebo-controlled study evaluating the effects of simvastatin 20 mg daily upon progression of asymptomatic middle cerebral artery stenosis among stroke-free individuals over 2 years. A total of 227 subjects were randomized to either placebo (n = 114) or simvastatin 20 mg daily (n = 113). The number of brain infarcts as detected by MRI was recorded at baseline and at the end of the study. The primary outcome measure was the number of new brain infarcts at the end of the study. Results: Among the 227 randomized subjects, 33 (14.5%) had SBI at baseline. At the end of the study, significantly fewer subjects in the active group (n = 1) had new brain infarcts compared with the placebo group (n = 8; p = 0.018). The new brain infarcts of subjects in the active group were subclinical. Among the placebo group, the new brain infarcts of 3 subjects were symptomatic while those of the remaining 5 subjects were subclinical. Among putative variables, multivariate regression analysis showed that only the baseline number of SBIs (OR = 6.27, 95% CI 2.4–16.5) and simvastatin treatment (OR = 0.09, 95% CI 0.01–0.82) independently predicted the development of new brain infarcts. Conclusions: Consistent with findings of the epidemiological study, our study suggests that statins may prevent the development of a new brain infarct.

Dual antiplatelets reduce microembolic signals in patients with transient ischemic attack and minor stroke: subgroup analysis of CLAIR study

Background Short course of dual antiplatelet therapy for early secondary prevention is a promising treatment for patients with minor stroke or transient ischemic attack at high risk of recurrence. Methods We examined the efficacy and safety of dual antiplatelets in patients with transient ischemic attack or minor stroke, defined as National Institute of Health Stroke Scale scores 0–3, in a subgroup analysis of Clopidogrel plus aspirin versus Aspirin alone for Reducing embolization in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR) study. Microembolic signals on transcranial Doppler monitoring was used as surrogate marker for recurrent stroke risk. Patients with ≥1 microembolic signals at baseline were randomized to receive dual therapy (aspirin 75–160 mg daily and clopidogrel 300 mg day 1 then 75 mg daily) or monotherapy (aspirin 75–160 mg daily) for seven-days. Results Sixty-five of 100 patients recruited had transient ischemic attack or minor stroke: 30 received dual therapy and 35 received monotherapy. Mean onset-to-randomization was 2·3 days in dual therapy group and 3·2 days in monotherapy group (P = 0·03). At day 7, the proportion of patients with ≥1 microembolic signals was 9 of 29 patients in dual therapy group and 18 of 34 patients in monotherapy group (adjusted relative risk reduction 41·4%, 95% CI 29·8–51·1, P < 0·001). The median number of microembolic signals on day 7 was 0 in dual therapy group and 1·0 in monotherapy group (P = 0·046). No patients had intracranial or severe systemic hemorrhage. Conclusions Early dual therapy with clopidogrel and aspirin reduces microembolic signals in patients with minor ischemic stroke or transient ischemic attack, without causing significant bleeding complications.

The curative effect comparison of two kinds of therapeutic regimens on decreasing the relative intensity of microembolic signal in CLAIR trial

BACKGROUND Microembolic signals (MESs) are direct markers of unstable large artery atherosclerotic plaques. In a previous study, we found that the number of MESs is associated with stroke recurrence and that clopidogrel plus aspirin more effectively reduce the number of MESs than does aspirin alone. Stroke recurrence is associated with not only the number of MESs but also the size of the MES, which can theoretically be estimated by monitoring the MES intensity via transcranial doppler (TCD). Thus, we compared the effects of clopidogrel and aspirin with aspirin alone on MES intensity using TCD. METHODS We recruited 100 patients who experienced acute ischemic stroke or transient ischemic attack (TIA) within 7days of symptom onset. All patients also had large artery stenosis in the cerebral or carotid arteries and the presence of MES as revealed by TCD. The patients were randomized to receive either aspirin or clopidogrel and aspirin for 7days. MES monitoring was performed on days 2 and 7. RESULTS Intent-to-treat (ITT) analysis (46 patients in the dual therapy group, 52 patients in the monotherapy group) and per-protocol (PP) analysis (25 patients in the dual therapy group, 31 patients in the monotherapy group) were performed on 98 patients. The primary finding was that the MES intensity was dramatically reduced in the dual therapy group. ITT analysis of the dual therapy group revealed that the MES intensity was 8.04 (0-16) dB before treatment, 0.00 (0-17) dB on day 2, and 0.00 (0-12) dB on day 7 (P=0.000). In the monotherapy group, the MES intensity was 9.00 (0-20) dB before treatment, 8.25 (0-17) dB on day 2, and 7.0 (0-18) dB on day 7 (P=0.577). PP analysis revealed similar results. No severe hemorrhagic complications were detected. The two patients in this study who experienced stroke recurrence were in the monotherapy group. CONCLUSIONS Clopidogrel and aspirin more effectively decrease the MES intensity than aspirin alone in patients with large artery stenotic minor stroke or TIA.

Adding computed tomography and transcranial Doppler findings to the ABCD2 score to predict long‐term risk of stroke after transient ischaemic attack or minor stroke

The ABCD2 score can predict the early risk of stroke after transient ischaemic attack or minor stroke. However, there is no simple and practical assessment method for the long‐term risks. Computed tomography (CT) and transcranial Doppler (TCD) findings were added to the ABCD2 score to build an ABCD2L2 score and whether the new scoring system could improve the predictive value of the ABCD2 score for the long‐term risk of stroke was determined.

Mapping the contribution and strategic distribution patterns of neuroimaging features of small vessel disease in poststroke cognitive impairment

Objectives Individual neuroimaging features of small vessel disease (SVD) have been reported to influence poststroke cognition. This study aimed to investigate the joint contribution and strategic distribution patterns of multiple types of SVD imaging features in poststroke cognitive impairment. Methods We studied 145 first-ever ischaemic stroke patients with MRI and Montreal Cognitive Assessment (MoCA) examined at baseline. The local burdens of acute ischaemic lesion (AIL), white matter hyperintensity, lacune, enlarged perivascular space and cross-sectional atrophy were quantified and entered into support vector regression (SVR) models to associate with the global and domain scores of MoCA. The SVR models were optimised with feature selection through 10-fold cross-validations. The contribution of SVD features to MoCA scores was measured by the prediction accuracy in the corresponding SVR model after optimisation. Results The combination of the neuroimaging features of SVD contributed much more to the MoCA deficits on top of AILs compared with individual SVD features, and the cognitive impact of different individual SVD features was generally similar. As identified by the optimal SVR models, the important SVD-affected regions were mainly located in the basal ganglia and white matter around it, although the specific regions varied for MoCA and its domains. Conclusions Multiple types of SVD neuroimaging features jointly had a significant impact on global and domain cognitive functionings after stroke on top of AILs. The map of strategic cognitive-relevant regions of SVD features may help clinicians to understand their complementary impact on poststroke cognition.