Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection.

BACKGROUND: Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage. RESULTS: The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P = 0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively. CONCLUSIONS: Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by Genentech; TIMELESS ClinicalTrials.gov number, NCT03785678.).

A Phase III, prospective, double-blind, randomized, placebo-controlled trial of thrombolysis in imaging-eligible, late-window patients to assess the efficacy and safety of tenecteplase (TIMELESS): Rationale and design.

RATIONALE: While thrombolysis is standard of care for patients with acute ischemic stroke (AIS) within 4.5 h of symptom onset, the benefit of tenecteplase beyond this time window is less certain. AIM: The TIMELESS trial (NCT03785678) aims to determine if treatment with tenecteplase increases the proportion of good clinical outcomes among patients with stroke due to a large vessel occlusion who present beyond 4.5 h after symptom onset. SAMPLE SIZE ESTIMATES: A total of 456 patients will provide ⩾90% power to detect differences in the distribution of modified Rankin Scale scores at Day 90 at the two-sided 0.049 significance level. METHODS AND DESIGN: TIMELESS is a Phase III, double-blind, randomized, placebo-controlled trial of tenecteplase with or without endovascular thrombectomy in patients with AIS and evidence of salvageable tissue via imaging who present within the 4.5- to 24-h time window with an internal carotid artery (ICA) or middle cerebral artery (MCA) (M1/M2) occlusion. STUDY OUTCOMES: The primary efficacy objective of tenecteplase compared with placebo will be evaluated with ordinal modified Rankin Scale scores at Day 90. Safety will be evaluated via incidence of symptomatic intracranial hemorrhage, incidence and severity of adverse events, and mortality rate. DISCUSSION: Results from TIMELESS will contribute to understanding of the safety and efficacy of tenecteplase administered 4.5-24 h following symptom onset for patients with an ICA or MCA occlusion.

Choosing the Correct "-ase" in Acute Ischemic Stroke: Alteplase, Tenecteplase, and Reteplase.

Alteplase is a tissue plasminogen activator approved for treating acute ischemic stroke (AIS), acute myocardial infarction (AMI), and acute massive pulmonary embolism. Two additional tissue plasminogen activators, tenecteplase and reteplase, are also approved for AMI treatment. However, neither tenecteplase nor reteplase is approved for AIS treatment. The U.S. Food and Drug Administration has received reports of accidental administration of tenecteplase or reteplase instead of alteplase in patients with AIS, which can lead to potential overdose. Primary factors contributing to medication errors include use of the abbreviations "TPA," "tPA," or "TNK" in written or verbal orders and use of these agents in similar settings. Steps to reduce the likelihood of accidental substitution include use of full brand or generic names and inclusion of the indication in written and verbal orders, addition of alerts in automated dispensing machines and ordering systems, and use of stroke boxes containing alteplase and materials for administration.

Comparison of Quantitative and Qualitative Oxygen Extraction Fraction (OEF) in Acute Stroke Patients with Large Vessel Occlusion.

The superficial temporal artery-middle cerebral artery bypass (STA-MCA) bypass surgery developed by Donaghy and Yarsagil in 1967 provided relief for patients with acute stroke and large vessel occlusive vascular disease. Early reports showed low morbidity and good outcomes. However, a large clinical trial in 1985 reported a failure of extracranial-intracranial (EC/IC) bypass to show benefit in reducing the risk of stroke compared to best medical treatment. Problems with the study included cross overs to surgery from best medical treatment, patients unwilling to be randomized and chose EC/IC surgery, and loss of patients to follow-up. Most egregious is the fact that the study did not attempt to identify and select the patients at high risk for a second stroke. Based on these shortcomings of the EC/IC bypass study, a carotid occlusion surgery study (COSS) was proposed by Dr. William Powers and colleagues using qualitative hemispheric oxygen extraction fraction (OEF) by positron emission tomography (PET) between the contralateral and ipsilateral hemispheres with a ratio of 1.16 indicative of hemodynamic compromise. To increase patient enrollment, several compromises were made mid study. First. The ratio threshold was lowered to 1.12 and the level of occlusion in the carotid reduced from 70% to 60%. Despite these compromises the study was closed for futility, apparently because the stroke rate in the medically treated group was too low. Thus, the question as to the benefit of EC/IC bypass surgery remains unresolved. In our NIH funded study Quantitative Occlusive Vascular Disease Study (QUOVADIS), we used quantitative OEF to evaluate stroke risk and compared it to the qualitative count-rate ratio method used in the COSS study and found that these two methods did not identify the same patients at increased risk for stroke, which may explain the reason for the failure of the COSS study as our results show that qualitative OEF ratios do not identify the same patients as quantitative OEF.

Characterizing Strokes and Stroke Mimics Transported by Helicopter Emergency Medical Services.

OBJECTIVE: Stroke is the leading cause of disability in the United States with most of these patients being transported by emergency medical services. These providers are the first medical point of contact and must be able to rapidly and accurately identify stroke and transport these patients to the appropriate facilities for treatment. There are many conditions that have similar presentations to stroke and can be mistakenly identified as potential strokes, thereby affecting the initial prehospital triage. METHODS: A retrospective observational study examined patients with suspected strokes transported to a single comprehensive stroke center (CSC) by a helicopter emergency medical service (HEMS) agency from 2007 through 2013. Final diagnosis was extracted from the Get with the Guidelines (GWTG) database and hospital discharge diagnosis for those not included in the database. Frequencies of discharge diagnosis were calculated and then stratified into interfacility vs. scene transfers. RESULTS: In this study 6,243 patients were transported: 3,376 patients were screened as potential strokes, of which 2,527 had a final diagnosis of stroke (2,242 ischemic stroke and 285 transient ischemic attack), 166 had intracranial hemorrhage, and 655 were stroke mimics. Stroke mimics were more common among scene transfers (223, 32%) than among interfacility transfers (432, 16%). CONCLUSIONS: In our study approximately 20% of potential stroke patients transported via HEMS were mimics. Identifying the need for CSC resources can be an important factor in creating a prehospital triage tool to facilitate patient transport to an appropriate health care facility.

Impact of telemedicine implementation in thrombolytic use for acute ischemic stroke: the University of Pittsburgh Medical Center telestroke network experience.

BACKGROUND: Intravenous thrombolysis is the only therapy for acute ischemic stroke that is approved by the US Food and Drug Association. The use of telemedicine in stroke makes it possible to bring the expertise of academic stroke centers to underserved areas, potentially increasing the quality of stroke care. METHODS: All consecutive admissions for stroke were reviewed for 1 year before telemedicine implementation and for variable periods thereafter. A retrospective review identified 2588 admissions for acute stroke between March 2005 and December 2008 at 12 hospitals participating in a telestroke network, including 919 patients before telemedicine was available and 1669 patients after telemedicine was available. The primary outcome measure was the rate of intravenous tissue plasminogen activator (IV tPA) use before and after telemedicine implementation. RESULTS: One hundred thirty-nine patients received IV tPA in both study phases, with 26 (2.8%) patients treated before starting telemedicine and 113 (6.8%) after starting telemedicine (P < .001). Incorrect treatment decisions occurred 7 times (0.39%), with 2 (0.2%) pretelemedicine and 5 (0.3%) posttelemedicine (P = .70). Arrivals within 3 hours from symptom onset were more frequent in the posttelemedicine compared to the pretelemedicine phases (55 [6%] vs 159 [9.5%]; P = .002). Among the patients treated with IV tPA, symptomatic intracranial hemorrhage occurred in 2 patients (1 [10.7%] pretelemedicine vs 1 [1.8%] posttelemedicine; P = .34). CONCLUSIONS: Telestroke implementation was associated with an increased rate of thrombolytic use in remote hospitals within the telemedicine network.

Telestroke-guided intravenous tissue-type plasminogen activator treatment achieves a similar clinical outcome as thrombolysis at a comprehensive stroke center.

BACKGROUND AND PURPOSE: Telestroke networks offer an opportunity to increase tissue-type plasminogen activator use in community hospitals. METHODS: We compared 83 patients treated with intravenous tissue-type plasminogen activator by telestroke to 59 patients treated after in-person evaluation by the same neurologists at a tertiary care stroke center. Onset and door-to-treatment times and functional outcome at 90 days were obtained prospectively. Favorable outcome was defined as modified Rankin Scale score ≤2. RESULTS: Favorable outcome rates were comparable between the groups (42.1% versus 37.5%, P=0.7). There was no significant difference in the rate of symptomatic hemorrhage. CONCLUSIONS: Telestroke is a viable alternative to in-person evaluation when stroke expertise is not readily available.

Protocol adherence and safety of intravenous thrombolysis after telephone consultation with a stroke center.

Intravenous tissue plasminogen activator (tPA) for acute ischemic stroke must be provided in an appropriate setting. The best way to provide thrombolysis in small community hospitals remains uncertain. Medical records were reviewed of tPA treatments at a stroke center between January 2002 and October 2005. The stroke center provides phone consultation for acute stroke to smaller hospitals in the region. Subjects were classified into 3 groups: tPA started at referring hospitals before transfer (treat and transfer group), tPA started at the stroke center after transfer (transfer and treat group), and the control group of patients who presented directly to the stroke center and received tPA (stroke center group). We recorded the patient and treatment characteristics, protocol deviations, symptomatic intracranial hemorrhage (ICH), and in-hospital deaths. There were 133 patients in the treat and transfer group, 35 patients in the transfer and treat group, and 86 patients in the stroke center group. Time from onset to treatment was similar in the treat and transfer and the stroke center groups, but the door-to-needle time was shorter by 12 minutes in the latter (P=.02). Fifty-five protocol deviations occurred in 38% patients in the treat and transfer group, compared with 6% in the stroke center group (P<.001). The most common deviations were related to time window violations and incorrect tPA dosing. Symptomatic ICH occurred in 8.2%, with no significant difference between the groups. Neither community hospital treatment nor protocol deviation was a predictor of symptomatic ICH or in-hospital mortality. Our findings indicate the need for improved protocol adherence for stroke thrombolysis in patients presenting to small community hospitals.

Increased cerebral oxygen metabolism and ischemic stress in subjects with metabolic syndrome-associated risk factors: preliminary observations.

Hypertension, diabetes, obesity, and dyslipidemia are risk factors that characterize metabolic syndrome (MetS), which increases the risk for stroke by 40%. In a preliminary study, our aim was to evaluate cerebrovascular reactivity and oxygen metabolism in subjects free of vascular disease but with one or more of these risk factors. Volunteers (n=15) 59±15 (mean±SD)years of age clear of cerebrovascular disease by magnetic resonance angiography but with one or more risk factors were studied by quantitative positron emission tomography for measure ment of cerebral blood flow, oxygen consumption, oxygen extraction fraction (OEF), and acetazolamide cerebrovascular reactivity. Eight of ten subjects with MetS risk factors had OEF >50%. None of the five without risk factors had OEF >50%. The presence of MetS risk factors was highly correlated with OEF >50% by Fisher's exact test (p<0.007). The increase in OEF was significantly (P<0.001) correlated with cerebral metabolic rate for oxygen. Increased OEF was not associated with compromised acetazolamide cerebrovascular reactivity. Subjects with one or more MetS risk factors are characterized by increased cerebral oxygen consumption and ischemic stress, which may be related to increased risk of cerebrovascular disease and stroke.

Transient ischemic attack after tissue plasminogen activator: aborted stroke or unnecessary stroke therapy?

BACKGROUND: The frequency with which intravenous thrombolysis for acute ischemic stroke results in normal clinical and radiographic status is currently unknown. METHODS: Patients who received intravenous thrombolysis at community hospitals and a stroke center were retrospectively analyzed for occurrence of normal imaging after tissue plasminogen activator (tPA) treatment. The cases were classified as nonischemic process (stroke mimic), transient ischemic attack (TIA) or ischemic stroke. The occurrence rate and predictors of each condition were sought. RESULTS: Of 254 patients who received tPA, 9 (3.5%) had a nonischemic process, 23 (9.1%) had TIA, and 222 (87%) were diagnosed with ischemic stroke. Nonischemic process patients were younger and were more likely to have received tPA at a community hospital than those with TIA or stroke. TIA was associated with lower pretreatment serum glucose, prevalence of coronary artery disease and stroke severity but not to time to treatment. CONCLUSION: Over 10% of patients who receive tPA for cerebral ischemia do not develop ischemic injury. tPA use for a nonischemic process is infrequent but is associated with community hospital use.