Christopher Levi

Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial

BACKGROUND Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3-6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). METHODS We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3-6 h after onset of ischaemic stroke. PWI and DWI were done before and 3-5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537. FINDINGS We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71.6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1.24 with alteplase and 1.78 with placebo (ratio 0.69, 95% CI 0.38-1.28; Students t test p=0.239); the median relative infarct growth was 1.18 with alteplase and 1.79 with placebo (ratio 0.66, 0.36-0.92; Wilcoxons test p=0.054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than was no reperfusion. INTERPRETATION Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted.

A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke

BACKGROUND Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, is an alternative thrombolytic agent. METHODS In this phase 2B trial, we randomly assigned 75 patients to receive alteplase (0.9 mg per kilogram of body weight) or tenecteplase (0.1 mg per kilogram or 0.25 mg per kilogram) less than 6 hours after the onset of ischemic stroke. To favor the selection of patients most likely to benefit from thrombolytic therapy, the eligibility criteria were a perfusion lesion at least 20% greater than the infarct core on computed tomographic (CT) perfusion imaging at baseline and an associated vessel occlusion on CT angiography. The coprimary end points were the proportion of the perfusion lesion that was reperfused at 24 hours on perfusion-weighted magnetic resonance imaging and the extent of clinical improvement at 24 hours as assessed on the National Institutes of Health Stroke Scale (NIHSS, a 42-point scale on which higher scores indicate more severe neurologic deficits). RESULTS The three treatment groups each comprised 25 patients. The mean (±SD) NIHSS score at baseline for all patients was 14.4±2.6, and the time to treatment was 2.9±0.8 hours. Together, the two tenecteplase groups had greater reperfusion (P=0.004) and clinical improvement (P<0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg per kilogram) was superior to the lower dose and to alteplase for all efficacy outcomes, including absence of serious disability at 90 days (in 72% of patients, vs. 40% with alteplase; P=0.02). CONCLUSIONS Tenecteplase was associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging. (Funded by the Australian National Health and Medical Research Council; Australia New Zealand Clinical Trials Registry number, ACTRN12608000466347.).

Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.

Summary Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. Methods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. Findings We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10−16) and ZFHX3 (p=2·28×10−8), and for large-vessel stroke at a 9p21 locus (p=3·32×10−5) and HDAC9 (p=2·03×10−12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10−6. However, we were unable to replicate any of these novel associations in the replication cohort. Interpretation Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes. Funding Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10−11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28–1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

Knowledge of Stroke Risk Factors, Warning Symptoms, and Treatment Among an Australian Urban Population

Background and Purpose— Reduction in the risk of stroke and increase in the speed of hospital presentation after the onset of stroke both depend on the level of knowledge of stroke in the general population. The aim of the present study was to assess baseline knowledge regarding stroke risk factors, symptoms, treatment, and information resources. Methods— A community-based telephone interview survey was conducted in the Newcastle urban area in Australia. A total of 1278 potential participants between the ages of 18 to 80 were selected at random from an electronic telephone directory. A trained telephone interviewer conducted a telephone survey using the Computer-Assisted Telephone Interviewing (CATI) program. Results— A total of 822 participants completed the telephone interview. Six hundred three participants (73.4%) correctly identified the brain as the affected organ in stroke. The most common risk factors for stroke identified by respondents were smoking (identified by 324 [39.4%]) and stress (identified by 277 [33.7%]). The most common warning sign of stroke described by respondents was “blurred and double vision or loss of vision in an eye,” listed by 198 (24.1%). A total of 626 (76.2%) respondents correctly listed ≥1 established stroke risk factor, but only 409 (49.8%) respondents correctly listed ≥1 warning sign. Conclusions— The level of knowledge in the community of established stroke risk factors, warning signs, and treatment as indicated by this survey suggests that a community-based education program to increase public knowledge of stroke may contribute to reducing the risk of stroke and to increasing the speed of hospital presentation after the onset of stroke.

Refining the Perfusion–Diffusion Mismatch Hypothesis

Background and Purpose— The Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) tests the hypothesis that perfusion-weighted imaging (PWI)–diffusion-weighted imaging (DWI) mismatch predicts the response to thrombolysis. There is no accepted standardized definition of PWI-DWI mismatch. We compared common mismatch definitions in the initial 40 EPITHET patients. Methods— Raw perfusion images were used to generate maps of time to peak (TTP), mean transit time (MTT), time to peak of the impulse response (Tmax) and first moment transit time (FMT). DWI, apparent diffusion coefficient (ADC), and PWI volumes were measured with planimetric and thresholding techniques. Correlations between mismatch volume (PWIvol-DWIvol) and DWI expansion (T2Day 90-vol-DWIAcute-vol) were also assessed. Results— Mean age was 68±11, time to MRI 4.5±0.7 hours, and median National Institutes of Health Stroke Scale (NIHSS) score 11 (range 4 to 23). Tmax and MTT hypoperfusion volumes were significantly lower than those calculated with TTP and FMT maps (P<0.001). Mismatch ≥20% was observed in 89% (Tmax) to 92% (TTP/FMT/MTT) of patients. Application of a +4s (relative to the contralateral hemisphere) PWI threshold reduced the frequency of positive mismatch volumes (TTP 73%/FMT 68%/Tmax 54%/MTT 43%). Mismatch was not significantly different when assessed with ADC maps. Mismatch volume, calculated with all parameters and thresholds, was not significantly correlated with DWI expansion. In contrast, reperfusion was correlated inversely with infarct growth (R=−0.51; P=0.009). Conclusions— Deconvolution and application of PWI thresholds provide more conservative estimates of tissue at risk and decrease the frequency of mismatch accordingly. The precise definition may not be critical; however, because reperfusion alters tissue fate irrespective of mismatch.

Influence of Admission Body Temperature on Stroke Mortality

BACKGROUND AND PURPOSE The influence of body temperature on stroke outcome remains uncertain. The aim of this study was to investigate the prognostic role of admission body temperature on short-term and long-term mortality in a retrospective cohort study of patients with acute stroke. METHODS A retrospective cohort of 509 patients with acute stroke, admitted to a tertiary hospital between July 1, 1995, and June 30, 1997, was studied. The relationship between admission body temperature and mortality both in-hospital and at 1-year mortality was evaluated. Body temperature on admission was classified as hypothermia (</=36.5 degrees C), normothermia (>36.5 degrees C and </=37.5 degrees C), and hyperthermia (>37.5 degrees C). Logistic regression and proportional hazards function analysis were performed after adjustment for clinical predictors of stroke outcome. RESULTS In ischemic stoke, mortality was lower among patients with hypothermia and higher among patients with hyperthermia. The odds ratio for in-hospital mortality in hypothermic versus normothermic patients was 0.1 (95% CI, 0.02 to 0.5). The relative risk for 1-year mortality of hyperthermic versus normothermic patients was 3.4 (95% CI, 1.6 to 7.3). A similar but nonsignificant trend for in-hospital mortality was seen among patients with hemorrhagic stroke. CONCLUSIONS An association between admission body temperature and stroke mortality was noted independent of clinical variables of stroke severity. Hyperthermia was associated with an increase in 1-year mortality. Hypothermia was associated with a reduction in in-hospital mortality.

Perfusion computed tomography: Prediction of final infarct extent and stroke outcome

The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) has not been previously applied to perfusion CT (CTP). Five raters assigned ASPECTS to baseline noncontrast CT (NCCT), CT angiography source images (CTA‐SI), CTP source images (CTP‐SI), and CTP maps of cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) from 37 consecutive patients with less than 6‐hour anterior circulation ischemic stroke. Major reperfusion was identified on follow‐up imaging. Mean baseline ASPECTS was compared with follow‐up imaging ASPECTS. Rates of favorable outcome were compared for dichotomized baseline ASPECTS. In patients with major reperfusion, mean CBV and CTP‐SI ASPECTS closely predicted final infarct ASPECTS. In patients without major reperfusion, mean CBF and MTT ASPECTS best predicted final infarct ASPECTS. There were significant increases in rates of favorable outcome for CTP‐SI and CBV ASPECTS of greater than 6, versus less than or equal to 6, but not for other baseline CT modalities. ASPECTS applied to CTP is more accurate at identifying the extent of reversible and irreversible ischemia and at predicting final clinical outcome than NCCTor CTA‐SI. Ann Neurol 2005;58:672–679

Cerebral Blood Flow Is the Optimal CT Perfusion Parameter for Assessing Infarct Core

Background and Purpose— CT perfusion (CTP) is widely and rapidly accessible for imaging acute ischemic stroke but has limited validation. Cerebral blood volume (CBV) has been proposed as the best predictor of infarct core. We tested CBV against other common CTP parameters using contemporaneous diffusion MRI. Methods— Patients with acute ischemic stroke <6 hours after onset had CTP and diffusion MRI <1 hour apart, before any reperfusion therapies. CTP maps of time to peak (TTP), absolute and relative CBV, cerebral blood flow (CBF), mean transit time (MTT), and time to peak of the deconvolved tissue residue function (Tmax) were generated. The diffusion lesion was manually outlined to its maximal visual extent. Receiver operating characteristic (ROC) analysis area under the curve (AUC) was used to quantify the correspondence of each perfusion parameter to the coregistered diffusion-weighted imaging lesion. Optimal thresholds were determined (Youden index). Results— In analysis of 98 CTP slabs (54 patients, median onset to CT 190 minutes, median CT to MR 30 minutes), relative CBF performed best (AUC, 0.79; 95% CI, 0.77–81), significantly better than absolute CBV (AUC, 0.74; 95% CI, 0.73–0.76). The optimal threshold was <31% of mean contralateral CBF. Specificity was reduced by low CBF/CBV in noninfarcted white matter in cases with reduced contrast bolus intensity and leukoaraiosis. Conclusions— In contrast to previous reports, CBF corresponded with the acute diffusion-weighted imaging lesion better than CBV, although no single threshold avoids detection of false-positive regions in unaffected white matter. This relates to low signal-to-noise ratio in CTP maps and emphasizes the need for optimized acquisition and postprocessing.

Shared Genetic Susceptibility to Ischemic Stroke and Coronary Artery Disease A Genome-Wide Analysis of Common Variants

Background and Purpose— Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Methods— Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. Results— Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10−8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10−7) and ABO (PIS=2.6×10−4), as well as at HDAC9 (PLAS=2.32×10−12), 9p21 (PLAS=3.70×10−6), RAI1-PEMT-RASD1 (PLAS=2.69×10−5), EDNRA (PLAS=7.29×10−4), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10−4). Conclusions— Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.