Comparing mismatch strategies for patients being considered for ischemic stroke tenecteplase trials.

BACKGROUND: Currently there are multiple variations of imaging-based patient selection mismatch methods in ischemic stroke. In the present study, we sought to compare the two most common mismatch methods and identify if there were different effects on the outcome of a randomized clinical trial depending on the mismatch method used. AIMS: Investigate the effect of clinical and imaging-based mismatch criteria on patient outcomes of a pooled cohort from randomized trials of intravenous tenecteplase versus alteplase. METHODS: Baseline clinical and imaging scores were used to categorize patients as meeting either the DAWN mismatch (baseline NIHSS ≥ 10, and age cut-offs for ischemic core volume) or DEFUSE 2 mismatch criteria (mismatch volume > 15 mL, mismatch ratio > 1.8 and ischemic core < 70 mL). We then investigated whether tenecteplase-treated patients had favorable odds of less disability (on modified Rankin scale, mRS) compared to those treated with alteplase, for clinical and imaging mismatch, respectively. RESULTS: From 146 pooled patients, 71 received alteplase and 75 received tenecteplase. The overall pooled group did not show improved patient outcomes when treated with tenecteplase (mRS 0-1 OR 1.77, 95% CI 0.89-3.51, p = 0.102) compared with alteplase. A total of 39 (27%) patients met both clinical and imaging mismatch criteria, 25 (17%) patients met only imaging criteria, 36 (25%) met only clinical mismatch criteria and, finally, 46 (31%) did not meet either of imaging or mismatch criteria. Patients treated with tenecteplase had more favorable outcomes when they met either imaging mismatch (mRS 0-1, OR 2.33, 95% CI 1.13-5.94, p = 0.032) or clinical mismatch criteria (mRS 0-1, OR 2.15, 95% CI 1.142, 8.732, p = 0.027) but with differing proportions. CONCLUSION: Target mismatch selection was more inclusive and exhibited in a larger treatment effect between tenecteplase and alteplase.

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset.

BACKGROUND: Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase. METHODS: In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis). RESULTS: The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15). CONCLUSIONS: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).

Tenecteplase in ischemic stroke offers improved recanalization: Analysis of 2 trials.

OBJECTIVE: To test whether patients with complete vessel occlusion show greater recanalization at 24 hours and have improved clinical outcomes at 24 hours and 90 days when treated with tenecteplase compared to alteplase. METHODS: Pooled clinical and imaging data from 2 phase 2 randomized trials comparing tenecteplase with alteplase allowed CT angiography (CTA) scans to be assessed centrally for occlusion status at baseline and at 24 hours post thrombolysis using the modified thrombolysis in cerebral infarction (TICI) scale. Twenty-four-hour poststroke NIH Stroke Scale (NIHSS) and 90-day modified Rankin Scale (mRS) scores were also compared between treatment groups using linear regression to generate odds ratios (ORs). RESULTS: From 146 pooled patients, 69 had a TICI 0/1 occlusion overall at baseline. Tenecteplase-treated patients with a complete vessel occlusion had greater complete recanalization rates at 24 hours (71% for tenecteplase vs 43% for alteplase, p < 0.001). Patients with a TICI 0/1 occlusion who were treated with tenecteplase also showed greater early clinical improvement (median NIHSS change with tenecteplase was 9, interquartile range [IQR] 6, alteplase 1, IQR 1, p = 0.001) and higher rates of favorable 90-day outcomes (mRS 0-1 of tenecteplase compared with alteplase, OR 4.82, 95% confidence interval 1.02-7.84, p = 0.05). CONCLUSIONS: Tenecteplase may offer greater recanalization efficacy compared to alteplase, possibly exaggerated in patients with complete vessel occlusions on baseline CTA.

The Impact of CT Perfusion Threshold on Predicted Viable and Nonviable Tissue Volumes in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Perfusion imaging is used for patient selection in clinical practice and trials. Postprocessing and definitions of tissue viability are nevertheless not standardized. We compared the lesion volumes generated with two well-recognized perfusion tissue definitions in a single-center phase 2 thrombolysis study. METHODS: We analyzed perfusion imaging data from the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST) study using two popular tissue viability thresholds (ischemic core definition: (1) cerebral blood volume < 2.0 mL/100 g-1 or (2) relative cerebral blood flow < 40% that of the contralesional hemisphere and relative delay time >2 seconds; penumbra definitions: (1) mean transit time > 145% of contralesional hemisphere or (2) relative delay time < 2 seconds). We compared volumes of core and penumbra, mismatch ratio, percentage, and volume of penumbra salvaged at 24 hours. RESULTS: We included 73 (tenecteplase = 36, alteplase = 37) patients who had analyzable perfusion lesions at baseline. Significant differences were found in core volumes using the two thresholds (33 ± 37 mL vs. 26 ± 32 mL, P < .001), as was mismatch ratio (2.5 ± .9 vs. 4.2 ± 3.7, P < 0.001). The volume of penumbra salvaged at 24 hours (30 ± 19 mL vs. 35 ± 26 mL, P = .043) differed significantly, although the percentages of penumbra salvaged did not (P = .2). No difference was found between the two thrombolytic agents in the percentages of penumbra salvaged using either threshold. CONCLUSION: Two commonly used tissue definitions generated significantly different lesion volumes and mismatch ratios. Threshold selection may have significant impact on patient selection for trials or reperfusion therapies.

Impact of Computed Tomography Perfusion Imaging on the Response to Tenecteplase in Ischemic Stroke: Analysis of 2 Randomized Controlled Trials.

BACKGROUND: We pooled 2 clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke, 1 that demonstrated superiority of tenecteplase and the other that showed no difference between the treatments in patient clinical outcomes. We tested the hypotheses that reperfusion therapy with tenecteplase would be superior to alteplase in improving functional outcomes in the group of patients with target mismatch as identified with advanced imaging. METHODS: We investigated whether tenecteplase-treated patients had a different 24-hour reduction in the National Institutes of Health Stroke Scale and a favorable odds ratio of a modified Rankin scale score of 0 to 1 versus 2 to 6 compared with alteplase-treated patients using linear regression to generate odds ratios. Imaging outcomes included rates of vessel recanalization and infarct growth at 24 hours and occurrence of large parenchymal hematoma. Baseline computed tomography perfusion was analyzed to assess whether patients met the target mismatch criteria (absolute mismatch volume >15 mL, mismatch ratio >1.8, baseline ischemic core <70 mL, and volume of severely hypoperfused tissue <100 mL). Patients meeting target mismatch criteria were analyzed as a subgroup to identify whether they had different treatment responses from the pooled group. RESULTS: Of 146 pooled patients, 71 received alteplase and 75 received tenecteplase. Tenecteplase-treated patients had greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 7; alteplase, 2; P=0.018) and less parenchymal hematoma (2 of 75 versus 10 of 71; P=0.02). The pooled group did not show improved patient outcomes when treated with tenecteplase (modified Rankin scale score 0-1: odds ratio, 1.77; 95% confidence interval, 0.89-3.51; P=0.102) compared with alteplase therapy. However, in patients with target mismatch (33 tenecteplase, 35 alteplase), treatment with tenecteplase was associated with greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 6; alteplase, 1; P<0.001) and better late independent recovery (modified Rankin scale score 0-1: odds ratio, 2.33; 95% confidence interval, 1.13-5.94; P=0.032) than those treated with alteplase. CONCLUSIONS: Tenecteplase may offer an improved efficacy and safety profile compared with alteplase, benefits possibly exaggerated in patients with baseline computed tomography perfusion-defined target mismatch. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01472926. URL: https://www.anzctr.org.au. Unique identifier: ACTRN12608000466347.

Interaction of Recanalization, Intracerebral Hemorrhage, and Cerebral Edema After Intravenous Thrombolysis.

BACKGROUND AND PURPOSE: Both intracerebral hemorrhage (ICH) and brain edema have been attributed to reperfusion after intravenous thrombolysis. We explored the interaction of recanalization and core size for imaging outcomes (ICH and vasogenic brain edema). METHODS: In patients with anterior circulation occlusion given intravenous thrombolysis <4.5 hours and imaged with computed tomographic (CT) perfusion and CT angiography, we defined volumes of core (relative delay time >2 s and relative cerebral blood flow <40%) and penumbra (relative delay time >2 s). CT and CT angiography at 24 hours were reviewed for ICH (European Cooperative Acute Stroke Study [ECASS]-2 definition), early vasogenic edema (third International Stroke Trial [IST-3] criteria), and recanalization (thrombolysis in myocardial infarction 2-3). Independent effects of recanalization, core volume and potential interactions on edema, ICH and day 90 outcomes were estimated by logistic regression. RESULTS: In 123 patients, there was a trend for recanalization to be associated with H1/2 ICH (odds ratio [OR], 2.3 [0.97-5.5]; P=0.06) but not with PH1/2 ICH (OR, 1.7 [0.33-8.8]; P=0.5), any edema, or significant brain edema (OR, 1.45 [0.4-4.9]; P=0.55). Ischemic core (>50 mL) was associated with any ICH (OR, 4.0 [1.6-9.5]; P=0.003), edema (OR, 5.4 [2-14]; P<0.01), and significant brain edema (OR, 17.4 [5.3-57]; P<0.01) but not with PH1/2 ICH (OR, 1.2 [0.23-6.5]; P=0.8), after controlling for recanalization. There was no significant interaction of recanalization and large core for any adverse outcomes. CONCLUSIONS: Large ischemic core was associated with poorer outcomes and both early vasogenic brain edema and ICH, but recanalization on 24-hour CT angiography was associated with clinically favorable outcome. There was no significant interaction of recanalization and large core volume for any outcomes. The association of hemorrhage or brain edema with post-thrombolysis reperfusion is unclear.

What is the relationship among penumbra volume, collaterals, and time since onset in the first 6 h after acute ischemic stroke?

BACKGROUND: The steep, time-dependent loss of benefit from reperfusion in clinical trials is consistent with loss of penumbra over the early hours of ischemia, as observed in animal models. Human imaging studies, however, show persistent penumbra for up to 48 h. We investigated core and penumbra volumes and collateral status in relation to time after stroke onset within the first 6 h. METHODS: Using data from three multimodal computer tomography-based studies in acute ischemic stroke patients <6 h after onset, we measured core and penumbra volumes, collateral status, and target mismatch (defined as core volume < 50 ml, perfusion lesion volume > 15 ml, mismatch ratio > 1.8). Patients were grouped by onset to imaging time (<3, 3-4.5, 4.5-6 h). We explored correlates of penumbra proportion by multivariable linear regression. RESULTS: Analysis included 144 subjects. Across time epochs, neither proportions of penumbra (59%, 64%, 75% at <3, 3-4.5, >4. 5 h, respectively, p = 0.4) nor poor collaterals (15/56 (27%), 14/47 (30%), 4/15 (27%) at <3, 3-4.5, >4.5 h, p = 0.9) differed significantly. Penumbra proportion was not clearly related to time to imaging (R(2) = 0.003; p = 0.5) but a trend for divergent effects by collateral status was seen (slight increase in penumbra over time with good collaterals versus reduced with poor, interaction = 0.08). The proportion of patients with target mismatch did not vary by time (56%, 74%, and 67% at <3, 3-4.5, >4.5 h, p = 0.09). CONCLUSIONS: In a cross-sectional sample imaged within 6 h, neither the proportions of penumbral tissue nor "target mismatch" varied by time from onset. A trend for reducing penumbra proportion only among those with poor collaterals may have pathophysiological and therapeutic importance.

How many stroke patients might be eligible for mechanical thrombectomy?

INTRODUCTION: Recent studies showed improved patient outcomes with endovascular treatment of acute stroke compared to medical care, including IV rtPA, alone. Seven trials have reported results, each using different clinical and imaging criteria for patient selection. We compared eligibility for different trial protocols to estimate the number of patients eligible for treatment. PATIENTS AND METHODS: Patient data were extracted from a single centre database that combined patients recruited to three clinical studies, each of which obtained both CTA and CTP within 6 h of stroke onset. The published inclusion and exclusion criteria of seven intervention trials (MR CLEAN, EXTEND-IA, ESCAPE, SWIFT-PRIME, REVASCAT, THERAPY and THRACE) were applied to determine the proportion that would be eligible for each of these studies. RESULTS: A total of 263 patients was included. Eligibility for IAT in individual trials ranged from 53% to 3% of patients; 17% were eligible for four trials and under 10% for two trials. Only three patients (1%) were eligible for all studies. The most common cause of exclusion was absence of large artery occlusion (LAO) on CTA. When applying simplified criteria requiring an ASPECT score > 6, 16% were eligible for IAT, but potentially 40% of these patients were excluded by perfusion criteria and more than half by common NIHSS thresholds. CONCLUSION: Around 15% of patients presenting within 6 h of stroke onset were potentially eligible for IAT, but clinical trial eligibility criteria have much more limited overlap than is commonly assumed and only 1% of patients fulfilled criteria for all recent trials.

Coagulation and Fibrinolytic Activity of Tenecteplase and Alteplase in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: We compared the fibrinolytic activity of tenecteplase and alteplase in patients with acute ischemic stroke, and explored the association between hypofibrinogenaemia and intracerebral hemorrhage. METHODS: Venous blood samples from a subgroup of participants in the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST) study were obtained at pretreatment, 3 to 12 hours, and 24±3 hours post-intravenous thrombolysis for analyses of plasminogen, plasminogen activator inhibitor-1, d-dimer, factor V, fibrinogen, and fibrin(ogen) degradation products, in addition to routine coagulation assays. Related sample Wilcoxon signed-rank tests were used to test the within-group changes, and independent Mann-Whitney tests for between-group differences. RESULTS: Thirty patients were included (alteplase=14 and tenecteplase=16) with similar baseline demographics. Compared with baseline, alteplase caused significant hypofibrinogenaemia (P=0.002), prolonged prothrombin time (P=0.011), hypoplasminogenaemia (P=0.001), and lower factor V (P=0.002) at 3 to 12 hours after administration with persistent hypofibrinogenaemia at 24 hours (P=0.011), whereas only minor hypoplasminogenaemia (P=0.029) was seen in the tenecteplase group. Tenecteplase consumed less plasminogen (P<0.001) and fibrinogen (P=0.002) compared with alteplase. CONCLUSIONS: In patients with acute ischemic stroke, alteplase 0.9 mg/kg caused significant disruption of the fibrinolytic system, whereas tenecteplase 0.25 mg/kg did not, consistent with the trend toward lower intracerebral hemorrhage incidence with tenecteplase in the ATTEST study. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01472926.

Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study.

BACKGROUND: In most countries, alteplase given within 4·5 h of onset is the only approved medical treatment for acute ischaemic stroke. The newer thrombolytic drug tenecteplase has been investigated in one randomised trial up to 3 h after stroke and in another trial up to 6 h after stroke in patients selected by advanced neuroimaging. In the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST), we aimed to assess the efficacy and safety of tenecteplase versus alteplase within 4·5 h of stroke onset in a population not selected on the basis of advanced neuroimaging, and to use imaging biomarkers to inform the design of a definitive phase 3 clinical trial. METHODS: In this single-centre, phase 2, prospective, randomised, open-label, blinded end-point evaluation study, adults with supratentorial ischaemic stroke eligible for intravenous thrombolysis within 4·5 h of onset were recruited from The Institute of Neurological Sciences, Glasgow, Scotland. Patients were randomly assigned (1:1) to receive tenecteplase 0·25 mg/kg (maximum 25 mg) or alteplase 0·9 mg/kg (maximum 90 mg). Treatment allocation used a mixed randomisation and minimisation algorithm including age and National Institutes of Health Stroke Scale score, generated by an independent statistician. Patients were not informed of treatment allocation; treating clinicians were aware of allocation but those assessing the primary outcome were not. Imaging comprised baseline CT, CT perfusion, and CT angiography; and CT plus CT angiography at 24-48 h. The primary endpoint was percentage of penumbra salvaged (CT perfusion-defined penumbra volume at baseline minus CT infarct volume at 24-48 h). Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT01472926. FINDINGS: Between Jan 1, 2012, and Sept 7, 2013, 355 patients were screened, of whom 157 were eligible for intravenous thrombolysis, and 104 patients were enrolled. 52 were assigned to the alteplase group and 52 to tenecteplase. Of 71 patients (35 assigned tenecteplase and 36 assigned alteplase) contributing to the primary endpoint, no significant differences were noted for percentage of penumbral salvaged (68% [SD 28] for the tenecteplase group vs 68% [23] for the alteplase group; mean difference 1·3% [95% CI -9·6 to 12·1]; p=0·81). Neither incidence of symptomatic intracerebral haemorrhage (by SITS-MOST definition, 1/52 [2%] tenecteplase vs 2/51 [4%] alteplase, p=0·55; by ECASS II definition, 3/52 [6%] vs 4/51 [8%], p=0·59) nor total intracerebral haemorrhage events (8/52 [15%] vs 14/51 [29%], p=0·091) differed significantly. The incidence of serious adverse events did not differ between groups (32 in the tenecteplase group, three considered probably or definitely related to drug treatment; 16 in the alteplase group, five were considered drug-related). INTERPRETATION: Neurological and radiological outcomes did not differ between the tenecteplase and alteplase groups. Evaluation of tenecteplase in larger trials of patients with acute stroke seems warranted. FUNDING: The Stroke Association.

Differences in wake-up and unknown onset stroke examined in a stroke registry.

INTRODUCTION: Debate exists as to whether wake-up stroke (WUS) (i.e. symptoms first noted on waking) differs from stroke developing while awake [awake onset stroke (AOS)]. Unknown onset stroke (UOS) with unclear symptom onset time is infrequently studied. AIMS: This study aimed to examine differences in stroke characteristics and outcomes in these three groups. METHODS: The stroke registry database from Halifax Infirmary, Canada, was interrogated for hospitalised stroke patients between 1999-2011. Information was available on demographics, stroke characteristics, and functional status at discharge and six months (modified Rankin score [mRS]). RESULTS: Of 3890 patients, 65% had AOS, 21% WUS and 14% UOS. UOS patients were significantly older, more commonly female and living alone than AOS patients, with no difference between AOS and WUS. UOS rates increased from 10 to 16% of patients during the study period (P < 0.0001). UOS but not WUS had a higher stroke severity than AOS. Intracerebral hemorrhage was less common (9 vs. 13%) and lacunar stroke more common (23 vs. 19%) in WUS compared to AOS. In UOS left hemisphere location was more likely, and lacunar stroke less common. Excellent outcomes were slightly lower for WUS. UOS had significantly higher rates of in-hospital mortality (23 vs. 16%, P < 0.0001) and poorer functional outcome six months after stroke (mRS < 3 in 26% of UOS and 46% of AOS, P = 0.02). CONCLUSION: WUS has lower rates of ICH but similar stroke severity and outcomes to AOS. UOS prevalence appears to be increasing, with higher stroke severity and worse prognosis.