Andrew Bivard

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.).

Perfusion CT in acute stroke: a comprehensive analysis of infarct and penumbra.

PURPOSE To perform a large-scale systematic comparison of the accuracy of all commonly used perfusion computed tomography (CT) data postprocessing methods in the definition of infarct core and penumbra in acute stroke. MATERIALS AND METHODS The collection of data for this study was approved by the institutional ethics committee, and all patients gave informed consent. Three hundred fourteen patients with hemispheric ischemia underwent perfusion CT within 6 hours of stroke symptom onset and magnetic resonance (MR) imaging at 24 hours. CT perfusion maps were generated by using six different postprocessing methods. Pixel-based analysis was used to calculate sensitivity and specificity of different perfusion CT thresholds for the penumbra and infarct core with each postprocessing method, and receiver operator characteristic (ROC) curves were plotted. Area under the ROC curve (AUC) analysis was used to define the optimum threshold. RESULTS Delay-corrected singular value deconvolution (SVD) with a delay time of more than 2 seconds most accurately defined the penumbra (AUC = 0.86, P = .046, mean volume difference between acute perfusion CT and 24-hour diffusion-weighted MR imaging = 1.7 mL). A double core threshold with a delay time of more than 2 seconds and cerebral blood flow less than 40% provided the most accurate definition of the infarct core (AUC = 0.86, P = .038). The other SVD measures (block circulant, nondelay corrected) were more accurate than non-SVD methods. CONCLUSION This study has shown that there is marked variability in penumbra and infarct prediction among various deconvolution techniques and highlights the need for standardization of perfusion CT in stroke. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120971/-/DC1.

Defining the Extent of Irreversible Brain Ischemia Using Perfusion Computed Tomography

Background: Perfusion computed tomography (PCT) shows promise in acute stroke assessment. However, the accuracy of CT perfusion thresholds in defining the acute infarct core remains uncertain. Method: Concurrent PCT and MRI-DWI performed 3–6 h after symptoms onset were assessed in 57 ischemic stroke patients. PCT was compared to DWI images to define the infarct core using a pixel-based receiver operating characteristic curve analysis to calculate the area under the curve (AUC) for thresholds from PCT maps that were coregistered with the DWI slice location. Results: A relative cerebral blood flow (CBF) of 45% of the contralateral hemisphere was found to be the most accurate threshold for describing the infarct core (AUC 0.788), and it was also by far the most frequent threshold with the highest AUC across patients. Conclusion: CBF thresholds on PCT define the acute infarct core more accurately than do other PCT thresholds, including a cerebral blood volume of 2 ml/100 g.

Assessment of leptomeningeal collaterals using dynamic CT angiography in patients with acute ischemic stroke

Whole-brain dynamic time-resolved computed tomography angiography (CTA) is a technique developed on the new 320-detector row CT scanner capable of generating time-resolved cerebral angiograms from skull base to vertex. Unlike a conventional cerebral angiogram, this technique visualizes pial arterial filling in all vascular territories, thereby providing additional hemodynamic information. Ours was a retrospective study of consecutive patients with ischemic stroke and M1 middle cerebral artery +/– intracranial internal carotid artery occlusions presenting to our center from June 2010 and undergoing dynamic time-resolved CTA and perfusion CT within 6 hours of symptom onset. Leptomeningeal collateral status was assessed by determining relative prominence of pial arteries in the ischemic region, rate and extent of retrograde flow, and various topographical patterns of pial arterial filling. Twenty-five patients were included in the study. We demonstrate the existence of the following novel properties of leptomeningeal collaterals in humans: (a) posterior (posterior cerebral artery (PCA)–MCA) dominant collateralization, (b) intra-territorial ‘within MCA region’ leptomeningeal collaterals, and (c) significant variability in size, extent, and retrograde filling time in pial arteries. We also describe a simple and reliable collateral grading template that, for the first time on dynamic CTA, incorporates back-filling time as well as size and extent of collateral filling.

Perfusion computed tomography to assist decision making for stroke thrombolysis

The use of perfusion imaging to guide selection of ischaemic stroke patients for thrombolytic therapy remains controversial. Using two large independent cohorts, Bivard et al. demonstrate that perfusion imaging is able to identify patients who will benefit from treatment and that these patients are not readily identifiable using clinical assessments.

Review of Stroke Thrombolytics

The cornerstone of acute ischemic stroke treatment relies on rapid clearance of an offending thrombus in the cerebrovascular system. There are various drugs and different methods of assessment to select patients more likely to respond to treatment. Current clinical guidelines recommend the administration of intravenous alteplase (following a brain noncontract CT to exclude hemorrhage) within 4.5 hours of stroke onset. Because of the short therapeutic time window, the risk of hemorrhage, and relatively limited efficacy of alteplase for large clot burden, research is ongoing to find more effective and safer reperfusion therapy, as well as focussing on refinement of patient selection for acute reperfusion treatment. Studies using advanced imaging (incorporating perfusion CT or diffusion/perfusion MRI) may allow us to use thrombolytics, or possibly endovascular therapy, in an extended time window. Recent clinical trials have suggested that Tenecteplase, used in conjunction with advanced imaging selection, resulted in more effective reperfusion than alteplase, which translated into increased clinical benefit. Studies using Desmoteplase have suggested its potential benefit in a sub-group of patients with large artery occlusion and salveageable tissue, in an extended time window. Other ways to improve acute reperfusion approaches are being actively explored, including endovascular therapy, and the enhancement of thrombolysis by ultrasound insonation of the clot (sono-thrombolysis).

Comparison of Computed Tomographic and Magnetic Resonance Perfusion Measurements in Acute Ischemic Stroke Back-to-Back Quantitative Analysis

Background and Purpose— Magnetic resonance perfusion (MRP) and computed tomographic perfusion (CTP) are being increasingly applied in acute stroke trials and clinical practice, yet the comparability of their perfusion values is not well validated. The aim of this study was to validate the comparability of CTP and MRP measures. Methods— A 3-step approach was used. Step 1 was a derivation step, where we analyzed 45 patients with acute ischemic stroke who had both CTP and MRP performed within 2 hours of each other and within 9 hours of stroke onset. In this step, we derived the optimal perfusion map with the least difference between MRP and CTP. In step 2, the optimal map was validated on whole-brain perfusion data of 15 patients. Step 3 was to apply the optimal perfusion map to define cross-modality reperfusion from acute CTP to 24-hour MRP in 45 patients and, in turn, to assess how accurately this predicted 3-month clinical outcome. Results— Among 8 different perfusion maps included in this study, time to peak of the residual function (Tmax) was the only one with a nonsignificant difference between CTP and MRP in delineating perfusion defects. This was validated on whole-brain perfusion data, showing high concordance of Tmax between the 2 modalities (concordance correlation coefficient of Lin, >0.91); the best concordance was at 6 s. At Tmax>6 s threshold, MRP and CTP reached substantial agreement in mismatch classification (&kgr; >0.61). Cross-modality reperfusion calculated by Tmax>6 s strongly predicted good functional outcome at 3 months (area under the curve, 0.979; P<0.05). Conclusions— MRP and CTP can be used interchangeably if one uses Tmax measurement.

Acute Stroke Imaging Research Roadmap III Imaging Selection and Outcomes in Acute Stroke Reperfusion Clinical Trials: Consensus Recommendations and Further Research Priorities.

Background and Purpose— The Stroke Imaging Research (STIR) group, the Imaging Working Group of StrokeNet, the American Society of Neuroradiology, and the Foundation of the American Society of Neuroradiology sponsored an imaging session and workshop during the Stroke Treatment Academy Industry Roundtable (STAIR) IX on October 5 to 6, 2015 in Washington, DC. The purpose of this roadmap was to focus on the role of imaging in future research and clinical trials. Methods— This forum brought together stroke neurologists, neuroradiologists, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), industry representatives, and members of the US Food and Drug Administration to discuss STIR priorities in the light of an unprecedented series of positive acute stroke endovascular therapy clinical trials. Results— The imaging session summarized and compared the imaging components of the recent positive endovascular trials and proposed opportunities for pooled analyses. The imaging workshop developed consensus recommendations for optimal imaging methods for the acquisition and analysis of core, mismatch, and collaterals across multiple modalities, and also a standardized approach for measuring the final infarct volume in prospective clinical trials. Conclusions— Recent positive acute stroke endovascular clinical trials have demonstrated the added value of neurovascular imaging. The optimal imaging profile for endovascular treatment includes large vessel occlusion, smaller core, good collaterals, and large penumbra. However, equivalent definitions for the imaging profile parameters across modalities are needed, and a standardization effort is warranted, potentially leveraging the pooled data resulting from the recent positive endovascular trials.

Prediction of Poststroke Hemorrhagic Transformation Using Computed Tomography Perfusion

Background and Purpose— Intracerebral hemorrhage is a serious potential complication of stroke thrombolysis. We investigated the optimal computed tomography perfusion (CTP) parameter to predict cerebral parenchymal hematoma (PH) in acute ischemic stroke. Methods— Patients with hyperacute ischemic stroke had whole-brain CTP and follow-up computed tomography/MRI to identify hemorrhagic transformation. The association of the 3 parameters relative cerebral blood flow, relative cerebral blood volume, and time to maximum (Tmax) with PH was examined using receiver operating characteristic analysis and multivariate logistic regression. Results— Of 132 patients, 70 were treated with thrombolysis, and 14 (10.6%) developed PH on follow-up imaging. Baseline National Institutes of Health Stroke Scale score (P=0.033) and thrombolysis (P=0.003) were both predictive of PH. Receiver operating characteristic analysis revealed that Tmax>14 s (area under the curve=0.748; P=0.002) and relative cerebral blood flow <30% of contralateral mean (area under the curve=0.689, P=0.021) were the optimal thresholds, and the Bayesian information criterion (+2.6) indicated that Tmax was more strongly associated with PH than relative cerebral blood flow. Tmax >14 s volumes of >5 mL allowed prediction of PH with sensitivity of 79%, specificity of 68%, and negative likelihood ratio of 3.16. Tmax>14 s volume and thrombolysis were both independently predictive of PH in a multivariate logistic regression model (P<0.05). Conclusions— Tmax >14 s was the CTP parameter most strongly associated with PH. This outperformed relative cerebral blood flow <30%, which closely equates to CTP estimates of ischemic core volume. Although ischemic core volume on CTP is useful in the pretreatment prediction of PH, severe hypoperfusion on Tmax is more strongly associated and may allow better prediction of the likely anatomic location of hemorrhage.

Arterial spin labeling identifies tissue salvage and good clinical recovery after acute ischemic stroke.

Arterial spin labeling (ASL) is a relatively new MR perfusion technique that requires validation.