Disya Ratanakorn

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.

Prevalence and Association between Risk Factors, Stroke Subtypes, and Abnormal Ankle Brachial Index in Acute Ischemic Stroke

BACKGROUND Abnormal ankle brachial index (ABI) identifies a stroke subgroup with high risk of subsequent stroke and other vascular events. There are few data regarding the prevalence of abnormal ABI in ischemic stroke in Asian countries. METHODS We evaluated the prevalence of abnormal ABI in 747 Thai patients with ischemic stroke or transient ischemic attack and assessed the correlation of abnormal ABI with stroke risk factors and stroke subtypes. RESULTS The prevalence of abnormal ABI (≤0.9) in ischemic stroke patients was 18.1%. Abnormal ABI in ischemic stroke patients was significantly correlated with female gender (odds ratio [OR], 1.61; confidence interval [CI], 1.09-2.40; P = .017), age ≥ 60 years (OR, 3.54; CI, 2.14-5.85; P < .001), and previous ischemic events, including coronary artery disease (OR, 2.55; CI, 1.47-4.43; P = .001), cerebrovascular disease (OR, 2.15; CI, 1.37-3.55; P = .002), and atrial fibrillation (OR, 1.71; CI, 1.03-2.82; P = .036). There was a significant difference in the prevalence of abnormal ABI among stroke subtypes (P < .001), which tended to be more frequent in those with large artery disease (20.4%), cardioembolic stroke (29.2%), and undetermined etiology (20.6%). CONCLUSIONS An ABI examination should be considered in patients with ischemic stroke to facilitate the early detection and treatment of asymptomatic peripheral arterial disease and identification of excess risk for subsequent stroke or other vascular events.

Coexistent Extra- and Intracranial Stenosis, Cervical Atherosclerosis, and Abnormal Ankle Brachial Index in Acute Ischemic Stroke

BACKGROUND There are limited data regarding abnormal ankle brachial index (ABI) with coexistent extracranial carotid stenosis (ECS), intracranial stenosis (ICS), and nonstenotic cervical atherosclerosis (CAS) in stroke, especially in Asia. METHODS We studied the prevalence of ECS, ICS, CAS, and combined ECS and ICS in 756 Thai patients with acute ischemic stroke and correlated sites of atherosclerosis with stroke risk factors and abnormal ABI. RESULTS The prevalence of ECS was 8.8%, ICS 52.6%, CAS 36.0%, abnormal ABI 18.8%, combined ECS and ICS 4.6%, combined ECS and abnormal ABI 2.8%, combined ICS and abnormal ABI 10.6%, and combined ECS, ICS, and abnormal ABI 1.6%. The prevalence of ECS, CAS, and combined ECS and ICS was higher in abnormal ABI compared to normal ABI (14.8% v 7.5% [P = .006]; 46.5% v 33.5% [P = .004], and 8.4% v 3.7% [P = .016], respectively). ECS was significantly correlated with history of coronary artery disease (CAD) and abnormal ABI; ICS with male gender, no alcohol use, and no atrial fibrillation; CAS with age ≥ 60 years, history of CAD and abnormal ABI; and combined ECS and ICS with history of CAD. CONCLUSIONS The frequency of atherosclerosis, especially ICS, was high. Cervicocerebral atherosclerosis was higher in abnormal ABI. This suggests that ischemic stroke patients should be screened for ECS, CAS, ICS, and abnormal ABI, especially in specific subsets (age ≥ 60 years, male gender, and history of CAD). The improved identification of vascular lesions could allow for a more optimal choice of antithrombotics, neurointervention, and more aggressive control of risk factors, potentially improving prevention of disease progression and a decrease in recurrent vascular events.

Single oral loading dose of phenytoin: a pharmacokinetics study

In order to determine the optimal single oral loading dose of phenytoin in patients with seizures, a two part study of phenytoin pharmacokinetics was conducted. In the first part, 15 mg/kg of phenytoin was given orally as a single dose to 19 normal medical volunteers with informed consent. Serum concentrations of phenytoin reached the therapeutic level (10 micrograms/ml) with an average of 2.62 +/- 1.25 h. The peak concentrations at 7.26 +/- 4.77 h was 11.95 +/- 2.8 micrograms/ml. The oral loading doses, calculated from a model incorporating a first order of absorption and Michaelis-Menten elimination kinetics to yield the target phenytoin serum concentration of 15 micrograms/ml were 18.7 mg/kg in males and 24.8 mg/kg in females. The larger dose for females is probably required due to the higher total apparent volume of distribution in females than in males. In the second part, seven male and seven female patients with seizures with informed consent received these calculated dosage regimens. For these patients, a single oral loading dose of phenytoin rapidly produced therapeutic concentration (10 micrograms/ml) within an average of 2.04 +/- 0.44 h in males and 2.35 +/- 1.6 h in females with minimal side-effects. For males, the peak concentration at 9.71 +/- 5.94 h was 23.89 +/- 5.46 micrograms/ml and that for females was 21.46 +/- 5.08 micrograms/ml at 7.71 +/- 3.73 h, respectively. Oral loading dose of phenytoin is safe, effective and can be considered in patients who need prompt control of seizures within a few hours, particularly in those areas where medical facilities are limited. It may also replace the intravenous route of phenytoin when the intravenous route is contraindicated.

Stroke Fast Track Reduces Time Delay to Neuroimaging and Increases Use of Thrombolysis in an Academic Medical Center in Thailand

Delays between hospital arrival and neuroimaging prevented patients from receiving thrombolysis. We report impact of Stroke Fast Track (SFT) on time to imaging, and rates of recombinant tissue plasminogen activator (rt‐PA) in eligible patients. Characteristics, time intervals, and rates of rt‐PA were evaluated in 464 patients with suspected acute stroke within 7 days (2005–2006). Complete time intervals were available on 380. Median times between emergency room arrival, brain computerized tomography (CT), and CT results were 25 and 45 minutes, respectively, for patients arriving <3 hours from onset, 40, and 65 minutes for those arriving >3 hours, and 35 and 60 minutes for all patients, which is significantly shorter than 2.5 hours to CT in 2004, prior to SFT (P < .0001). Although not different in time to first physician, patients arriving >3 hours had longer times to CT and CT results (P < .001). Overall, 5.5% of ischemic stroke patients received intravenous rt‐PA, including 27.1% of those arriving within 3 hours, which represented 100% of all eligible patients, compared with 0% in 2004. SFT reduced time delay in neuroimaging and increased use of rt‐PA in Thailand. Continuous quality improvement is needed to achieve best results in each setting, and to insure optimal care for acute stroke patients.

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.

Mirror-image artifact can affect transcranial Doppler interpretation.

Transcranial Doppler ultrasonography (TCD) allows evaluation of blood‐flow velocity in intracranial arteries detection and monitoring of vasospasm in patients with subarachnoid hemorrhage. Spectral Doppler artifacts can affect TCD data. A 1‐month series of TCD findings showed marked fluctuation in blood‐flow velocity values in both the middle and anterior cerebral arteries of a patient with subarachnoid hemorrhage. A mirror‐image artifact of the Doppler fast Fourier transform velocity spectrum resulted in erroneous interpretation of higher flow velocity in certain vessels. This artifact may cause misinterpretation of TCD flow‐velocity data and lead to improper diagnosis of the condition and treatment of patients.

Noninvasive ultrasound evaluation of the vertebral artery in hypertension.

Background and Purpose. Surgical decompression of the vascular loop of the vertebral artery (VA) at the left lateral medulla can reduce blood pressure (BP) in hypertension, and a larger diameter of the left VA has been found in hypertensive patients. Noninvasive evaluation of the VA in hypertension may assist selecting patients for more appropriate diagnosis and treatment. Duplex ultrasonography is used to study the relationship between VA diameter and BP. Methods. A retrospective review of VA duplex ultrasonography was performed in 112 consecutive patients who were sent to the neurovascular laboratory at the Wake Forest University School of Medicine during a 2‐month period. All measurements (BP, pulse rate, peak systolic velocity [PSV], end diastolic velocity [EDV], and diameters of both VAs) were determined according to standardized protocols. Left‐right comparisons of VA diameters, PSV, and EDV between hypertensives and normotensives were performed by the matched‐pairs analysis techniques. Results. Fifty‐five women and 57 men with a mean age of 64.8 years were studied. Hypertension was present in 65.2% of all patients. The age‐adjusted mean left VA diameter was significantly higher than that of the right VA with an age‐adjusted average differences of 0.2 mm (P= .03) for hypertensives compared to 0.04 mm (P= .75) for normotensives. No significant differences were observed in either PSV or EDV. Conclusions. Differences in left‐right VA diameter in hypertensive subjects may be a previously unrecognized component of the vascular disturbances associated with the disease and represent an additional criterion for identifying those who may benefit from surgical and medical management.

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.

Prevalence and predictors of carotid stenosis in Thai patients with ocular disorders

There are limited data on prevalence and predictors of carotid stenosis (CS) in Thai and Asian patients with ocular disorders. A total of 135 of 2849 patients enrolled in the Neurosonology Registry had an ocular indication (OI). Demographics, the nature of the OI, risk factors (RF), presence of CS >50% and non-stenotic carotid plaque (NSCP) were analyzed. The mean age of patients was 60.40 ± 14.02 years. The RF included hypertension (47.4%), hypercholesterolemia (34.07%), diabetes mellitus (DM) (31.11%) and current smoking (41.48%). NSCP was found in 20% of Thai patients with OD. CS was found in 11.11% (ipsilateral 10.37%). Predictors of CS were ocular ischemic syndrome (odds ratio [OR] 19.63, p = 0.000), retinal artery occlusion (OR 14.13, p = 0.000), anterior ischemic optic neuropathy (OR 9.75, p = 0.002), neovascularized glaucoma (OR 8.15, p = 0.018), and DM (OR 2.53, p = 0.037). The presence of CS (11.11%), and CS or NSCP (31%) are markers of atherosclerotic risk. The nature of the OI predicted carotid findings. Carotid ultrasound helps to identify the risk for cardiovascular events and should be considered in patients with OI.