Jose C. Navarro

The Accuracy of Transcranial Doppler in the Diagnosis of Middle Cerebral Artery Stenosis

Background and Purpose: It was the aim of this study to systematically review available literature on the accuracy of transcranial Doppler (TCD) compared with angiography for the diagnosis of ≧50% middle cerebral artery stenosis in patients with transient ischemic attack or ischemic stroke. Methods: We performed a systematic review that included original articles published on TCD accuracy from 1982 until the end of December 2005 using angiography as the gold standard. The following measures of diagnostic accuracy were obtained from each primary study: sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Weighted mean averages were then calculated from individual results for different velocity cutoffs. Results: Six papers met our selection criteria. Using laboratory-specific variable mean flow velocity cutoffs, self-reported best accuracy results yield a mean weighted average sensitivity of 92%, specificity of 92%, PPV of 88% and NPV of 98% for 80 cm/s cutoff. For 100 cm/s cutoff, the sensitivities were 100%, specificity 97%, PPV 88% and NPV 100%. Conclusions: Although limited to few reports, this analysis demonstrates fair TCD performance against angiography. Since increasing velocity cutoffs do not yield decreasing sensitivity and increasing specificity, further studies are required to determine optimal velocity values and possibly other criteria such as velocity ratios to develop a screening test with balanced performance parameters.

A Double-Blind, Placebo-Controlled, Randomized, Multicenter Study to Investigate Chinese Medicine Neuroaid Efficacy on Stroke Recovery (CHIMES Study):

Rationale Traditional Chinese Medications (TCM) have been reported to have beneficial effects in stroke patients, but were not rigorously evaluated by GCP standards. Aim This study tests the hypothesis that Neuroaid, a TCM widely used in China post-stroke, is superior to placebo in reducing neurological deficit and improving functional outcome in patients with acute cerebral infarction of an intermediate severity. Design This is a multicenter, randomised, double-blind, placebo-controlled study of Neuroaid in ischemic stroke patients with National Institute of Health Stroke Scale (NIHSS) 6–14 treated within 48 h of stroke onset. Neuroaid or placebo is taken (4 capsules) 3 times daily for 3 months. Treatments are assigned using block randomization, stratified for centers, via a central web-randomization system. With a power of 90% and two-sided test of 5% type I error, a sample size is 874. Allowing for a drop-out rate of up to 20%, 1100 individuals should be enrolled in this study. Study Outcomes The primary efficacy endpoint is the modified Rankin Scale (mRS) grades at 3 months. Secondary efficacy endpoints are the NIHSS score at 3 months; difference of NIHSS scores between baseline and 10 days, and between baseline and 3 months; difference of NIHSS sub-scores between baseline and 10 days, and between baseline and 3 months; mRS at 10 days, 1 month, and 3 months; Barthel index at 3 months; Mini Mental State Examination at 10 days and 3 months. Safety outcomes include complete blood count, renal and liver panels, and electrocardiogram. Study registration: ClinicalTrials.gov identifier: NCT00554723.

Chinese Medicine Neuroaid Efficacy on Stroke Recovery A Double-Blind, Placebo-Controlled, Randomized Study

Background and Purpose— Previous clinical studies suggested benefit for poststroke recovery when MLC601 was administered between 2 weeks and 6 months of stroke onset. The Chinese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study tested the hypothesis that MLC601 is superior to placebo in acute, moderately severe ischemic stroke within a 72-hour time window. Methods— This multicenter, double-blind, placebo-controlled trial randomized 1100 patients with a National Institutes of Health Stroke Scale score 6 to 14, within 72 hours of onset, to trial medications for 3 months. The primary outcome was a shift in the modified Rankin Scale. Secondary outcomes were modified Rankin Scale dichotomy, National Institutes of Health Stroke Scale improvement, difference in National Institutes of Health Stroke Scale total and motor scores, Barthel index, and mini-mental state examination. Planned subgroup analyses were performed according to age, sex, time to first dose, baseline National Institutes of Health Stroke Scale, presence of cortical signs, and antiplatelet use. Results— The modified Rankin Scale shift analysis–adjusted odds ratio was 1.09 (95% confidence interval, 0.86–1.32). Statistical difference was not detected between the treatment groups for any of the secondary outcomes. Subgroup analyses showed no statistical heterogeneity for the primary outcome; however, a trend toward benefit in the subgroup receiving treatment beyond 48 hours from stroke onset was noted. Serious and nonserious adverse events rates were similar between the 2 groups. Conclusions— MLC601 is statistically no better than placebo in improving outcomes at 3 months when used among patients with acute ischemic stroke of intermediate severity. Longer treatment duration and follow-up of participants with treatment initiated after 48 hours may be considered in future studies. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00554723.

Effects of MLC601 on Early Vascular Events in Patients After Stroke The CHIMES Study

Background and Purpose— Early vascular events are an important cause of morbidity and mortality in the first 3 months after a stroke. We aimed to investigate the effects of MLC601 on the occurrence of early vascular events within 3 months of stroke onset. Methods— Post hoc analysis was performed on data from subjects included in the CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study, a randomized, placebo-controlled, double-blinded trial that compared MLC601 with placebo in 1099 subjects with ischemic stroke of intermediate severity in the preceding 72 hours. Early vascular events were defined as a composite of recurrent stroke, acute coronary syndrome, and vascular death occurring within 3 months of stroke onset. Results— The frequency of early vascular events during the 3-month follow-up was significantly less in the MLC601 group than in the placebo group (16 [2.9%] versus 31 events [5.6%]; risk difference=−2.7%; 95% confidence interval, −5.1% to −0.4%; P=0.025) without an increase in nonvascular deaths. Kaplan–Meier survival analysis showed a difference in the risk of vascular outcomes between the 2 groups as early as the first month after stroke (Log-rank P=0.024; hazard ratio, 0.51; 95% confidence interval, 0.28–0.93). Conclusions— Treatment with MLC601 was associated with reduced early vascular events among subjects in the CHIMES study. The mechanisms for this effect require further study. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00554723.

Treatment With B Vitamins and Incidence of Cancer in Patients With Previous Stroke or Transient Ischemic Attack Results of a Randomized Placebo-Controlled Trial

Background and Purpose— To determine the effect of B vitamin treatment on the incidence of cancer among patients with stroke or transient ischemic attack. Methods— A total of 8164 patients with recent stroke or transient ischemic attack were randomly allocated to double-blind treatment with 1 tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B6, 500 &mgr;g vitamin B12) and followed for a median of 3.4 years for any cancer as an adverse event. Results— There was no significant difference in the incidence of any cancer among participants assigned B vitamins compared with placebo (4.04% versus 4.59%; risk ratio, 0.86; 95% CI, 0.70–1.07) and no difference in cancer mortality (2.35% versus 2.09%; risk ratio, 1.09; 0.81–1.46). Among 1899 patients with diabetes, the incidence of cancer was higher among participants assigned B vitamins compared with placebo (5.35% versus 3.28%; adjusted risk ratio, 2.21; 1.31–3.73), whereas among 6168 patients without diabetes, the incidence of cancer was lower among participants assigned B vitamins compared with placebo (3.66% versus 5.03%; adjusted risk ratio, 0.67; 0.51–0.87; P for interaction=0.0001). Conclusions— Daily administration of folic acid, vitamin B6, and vitamin B12 to 8164 patients with recent stroke or transient ischemic attack for a median of 3.4 years had no significant effect, compared with placebo, on cancer incidence or mortality. However, a post hoc subgroup analysis raises the hypothesis that folic acid treatment may increase the incidence of cancer among diabetics and reduce the incidence of cancer among nondiabetics with a history of stroke or transient ischemic attack. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00097669. URL: www.controlled-trials.com. Unique identifier: ISRCTN74743444.

CHInese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study (CHIMES-E): A Multicenter Study of Long-Term Efficacy.

Background: The CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) study was an international randomized double-blind placebo-controlled trial of MLC601 (NeuroAiD) in subjects with cerebral infarction of intermediate severity within 72 h. CHIMES-E (Extension) aimed at evaluating the effects of the initial 3-month treatment with MLC601 on long-term outcome for up to 2 years. Methods: All subjects randomized in CHIMES were eligible for CHIMES-E. Inclusion criteria for CHIMES were age ≥18, baseline National Institute of Health Stroke Scale of 6-14, and pre-stroke modified Rankin Scale (mRS) ≤1. Initial CHIMES treatment allocation blinding was maintained, although no further study treatment was provided in CHIMES-E. Subjects received standard care and rehabilitation as prescribed by the treating physician. mRS, Barthel Index (BI), and occurrence of medical events were ascertained at months 6, 12, 18, and 24. The primary outcome was mRS at 24 months. Secondary outcomes were mRS and BI at other time points. Results: CHIMES-E included 880 subjects (mean age 61.8 ± 11.3; 36% women). Adjusted OR for mRS ordinal analysis was 1.08 (95% CI 0.85-1.37, p = 0.543) and mRS dichotomy ≤1 was 1.29 (95% CI 0.96-1.74, p = 0.093) at 24 months. However, the treatment effect was significantly in favor of MLC601 for mRS dichotomy ≤1 at 6 months (OR 1.49, 95% CI 1.11-2.01, p = 0.008), 12 months (OR 1.41, 95% CI 1.05-1.90, p = 0.023), and 18 months (OR 1.36, 95% CI 1.01-1.83, p = 0.045), and for BI dichotomy ≥95 at 6 months (OR 1.55, 95% CI 1.14-2.10, p = 0.005) but not at other time points. Subgroup analyses showed no treatment heterogeneity. Rates of death and occurrence of vascular and other medical events were similar between groups. Conclusions: While the benefits of a 3-month treatment with MLC601 did not reach statistical significance for the primary endpoint at 2 years, the odds of functional independence defined as mRS ≤1 was significantly increased at 6 months and persisted up to 18 months after a stroke.

Baseline characteristics and treatment response of patients from the Philippines in the CHIMES study.

Background The CHIMES Study compared MLC601 with placebo in patients with ischemic stroke of intermediate severity in the preceding 72 h. Sites from the Philippines randomized 504 of 1099 (46%) patients in the study. We aimed to define the patient characteristics and treatment responses in this subgroup to better plan future trials. Methods The CHIMES dataset was used to compare the baseline characteristics, time from stroke onset to study treatment initiation, and treatment responses to MLC601 between patients recruited from Philippines and the rest of the cohort. Treatment effect was analyzed using end-points at month 3 as described in the primary publication, that is, modified Rankin Score, National Institutes of Health Stroke Scale, and Barthel Index. Results The Philippine cohort was younger, had more women, worse baseline National Institutes of Health Stroke Scale, and longer time delay from stroke onset to study treatment compared with the rest of the cohort. Age (P = 0·003), baseline National Institutes of Health Stroke Scale (P < 0·001), and stroke onset to study treatment initiation (P = 0·016) were predictors of modified Rankin Score at three-months. Primary analysis of modified Rankin Score shift was in favor of MLC601 (adjusted odds ratio 1·41, 95% confidence interval 1·01–1·96). Secondary analyses were likewise in favor of MLC601 for modified Rankin Score dichotomy 0–1, improvement in National Institutes of Health Stroke Scale (total and motor scores), and Barthel Index. Conclusions The treatment effects in the Philippine cohort were in favor of MLC601. This may be due to inclusion of more patients with predictors of poorer outcome.

The Use of NeuroAiD (MLC601) in Postischemic Stroke Patients

Aim. We aimed to assess the efficacy of MLC601 on functional recovery in patients given MLC601 after an ischemic stroke. Methods. This is a retrospective cohort study comparing poststroke patients given open-label MLC601 (n = 30; 9 female) for three months and matching patients who did not receive MLC601 from our Stroke Data Bank. Outcome assessed was modified Rankin Scale (mRS) at three months and analyzed according to: (1) achieving a score of 0-2, (2) achieving a score of 0-1, and (3) mean change in scores from baseline. Results. At three months, 21 patients on MLC601 became independent as compared to 17 patients not on MLC601 (OR 1.79; 95% CI 0.62–5.2; P = 0.29). There were twice as many patients (n = 16) on MLC601 who attained mRS scores similar to their prestroke state than in the non-MLC601 group (n = 8) (OR 3.14; 95% CI 1.1–9.27; P = 0.038). Mean improvement in mRS from baseline was better in the MLC601 group than in the non-MLC601 group (−1.7 versus −0.9; mean difference −0.73; 95% CI −1.09 to −0.38; P < 0.001). Conclusion. MLC601 improves functional recovery at 3 months postischemic stroke. An ongoing large randomized control trial of MLC601 will help validate these results.

Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial

BACKGROUND The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients. METHODS In this randomised, controlled, 2 × 2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532. FINDINGS Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1·9 years (IQR 1·0-3·0), the incidence of composite vascular events was 4·27 per 100 person-years in patients who received cilostazol and 5·33 per 100 person-years in patients who received aspirin (HR 0·80, 95% CI 0·57-1·11; non-inferiority p=0·0077; superiority p=0·18). Incidence of cerebral haemorrhage was 0·61 per 100 person-years in patients who received cilostazol and 1·20 per 100 person-years in those who received aspirin (HR 0·51, 97·5% CI 0·20-1·27; superiority p=0·18). The incidence of vascular events was 3·91 per 100 person-years in the probucol group compared with 5·75 per 100 person-years in the non-probucol group (HR 0·69, 95% CI 0·50-0·97; superiority p=0·0316). The incidence of cerebral haemorrhage was 0·72 per 100 person-years in the probucol group and 1·11 per 100 person-years in the non-probucol group (HR 0·65, 97·5% CI 0·27-1·57; p=0·55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation. INTERPRETATION In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior to aspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events. FUNDING Korea Otsuka Pharmaceutical.

Stroke Epidemiology in South, East, and South-East Asia: A Review

[This corrects the article on p. 286 in vol. 19.].