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CADTH Health Technology Review
Authors; Nazia Darvesh, and Robyn Butcher.
An ischemic stroke is caused by decreased or blocked blood flow to the brain, which can lead to tissue damage or loss of brain function.1,2 Stroke affects thousands of individuals in Canada each year, and the number who had an ischemic stroke in 2019 was 524,129.3 To treat acute ischemic stroke (AIS), alteplase, a tissue plasminogen activator (tPA), is administered as the first line of therapy to dissolve blood clots.4,5 Alteplase (Activase, Cathflo Activase, and Actilyse6,7) is a tPA like tenecteplase, reteplase, and duteplase8,9; however, it is the only tPA approved for systemic thrombolysis for AIS patients in Canada.10
The Canadian Stroke Best Practice Recommendations for acute stroke management10 published in 2018 recommend providing alteplase within 4.5 hours of stroke; this guidance applies to acute stroke treatment prehospital and in the emergency department and acute inpatient stroke care settings. In the US, clinical policy by the American College of Emergency Physicians11 published in 2015 provides recommendations for physicians who work in the emergency department. This guidance11 recommends that select patients may be administered alteplase within 3 hours after stroke onset, although there is the potential for increased risk of hemorrhage. Further, this guidance recommends that carefully selected patients may be administered alteplase between 3 hours and 4.5 hours of stroke onset despite the known risk of hemorrhage and unknown degree of functional outcome benefit.11 Guidelines from the American Heart Association and American Stroke Association12 published in 2019 for prehospital care providers, allied health professionals, physicians, and hospital administrators recommend that selected patients may be treated within 3 hours and between 3 hours and 4.5 hours of stroke onset and provide different patient criteria for each time window. For example, for the within 3-hour window, alteplase is “recommended” for mild disabling stroke; for the 3-hour to 4.5-hour window, alteplase “may be reasonable” for mild disabling stroke.12
A Cochrane systematic review (SR) published in 201413 was used as 1 source of evidence for the previously mentioned guidelines. This SR included a summary of the literature on thrombolysis for AIS; earlier stroke trials were found to have imbalances in baseline patient characteristics between study groups, whereas later trials used modern randomization methods to better balance patient characteristics between treatment arms. The imbalance in baseline patient characteristics in these trials prompted the re-analyses of the findings of some trials. In 2020, Alper et al.14 published an article that re-analyzed the results from 1 trial. In the same year, the Canadian Journal of Emergency Medicine published a debate series that presented 2 perspectives regarding the use of alteplase for AIS.15 Because the Canadian and American guidelines were published between 2015 and 2019, they do not include any evidence on alteplase used for AIS made available since the guidelines were published.
The purpose of this Rapid Review is to summarize the evidence regarding the safety and effectiveness of alteplase administered within 3 hours and alteplase administered between 3 hours and 4.5 hours in adult patients with AIS.
A limited literature search was conducted by an information specialist on key resources including MEDLINE, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were alteplase and ischemic stroke. CADTH-developed search filters were applied to limit retrieval to health technology assessments, SRs, meta-analyses (MAs), or network meta-analyses (NMAs), or randomized controlled trials (RCTs) or controlled clinical trials. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2014, and January 19, 2022.
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. Primary studies or trials that were captured in eligible SRs were summarized based on the information available in the SR(s).
Selection Criteria.
Articles were excluded if they did not meet the selection criteria outlined in Table 1 or were duplicate publications. Studies were also excluded if they were about other recombinant tPAs that were not alteplase, compared different doses of alteplase, compared alteplase administered at different times, gave treatment to patients with unknown timing of stroke onset, or were about the effectiveness of co-therapies included with alteplase.
Systematic reviews in which all relevant studies were captured in other more recent or more comprehensive SRs were excluded. Primary studies retrieved by the search were excluded if they were captured in 1 or more included SRs.
The methodological quality of included publications was critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)16 for SRs, and the Downs and Black checklist17 for RCTs. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
A total of 737 citations were identified in the literature search. Following screening of titles and abstracts, 674 citations were excluded and 63 potentially relevant reports from the electronic search were retrieved for full-text review. Zero potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 55 publications were excluded for various reasons, and 8 publications met the inclusion criteria and were included in this report. These comprised 3 SRs13,18,19 and 3 RCTs; 1 of these RCTs was reported in 3 publications.14,20-23 Appendix 1 presents the PRISMA24 flow chart of the study selection.
Additional references of potential interest are provided in Appendix 6.
The scope of all 3 SRs13,18,19 was broader than the topic of the current review. All SRs included primary studies in which alteplase treatment was administered within 3 hours, between 3 hours and 4.5 hours, and after 4.5 hours (this time point was outside the scope of the current review). One Cochrane SR by Wardlaw et al.13 also included studies of different thrombolytic drugs administered at different doses. Only the characteristics and results of the subset of relevant studies will be described in this report.
The Lorenzo et al.22 publication reported on the Thrombolysis in Elderly Stroke Patients in Italy (TESPI) trial results and included an MA that pooled effects from other stroke trials with TESPI trial results. However, because this MA was not based on a systematic search it was not eligible for this Rapid Review; the Lorenzo et al.22 citation is also included as a reference of potential interest in Appendix 6 with other MAs without systematic searches.
The 3 SRs13,18,19 were published between 2014 and 2020. The Cochrane SR by Wardlaw et al.13 included results from the following trials: Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) A, ATLANTIS B, the European Cooperative Acute Stroke Study (ECASS) II, ECASS III, and the National Institute of Neurological Disorders and Stroke (NINDS). The SR by Chen et al.18 included results from the ATLANTIS A, ECASS II, ECASS III, NINDS and WAKE-UP trials. The Lan et al. SR19 included results from the NINDS and the Potential of rtPA for Ischemic Strokes With Mild Symptoms (PRISMS) trials.
The Cochrane SR by Wardlaw et al.13 included literature published between 1966 and 2013, while the other 2 SRs18,19 did not specify search dates. One SR with MAs18 by Chen et al. included 12 RCTs comparing alteplase to placebo in patients treated with alteplase at different time points after stroke onset; 7 of these trials were relevant to this Rapid Review because they provided treatment within 3 hours or between 3 hours and 4.5 hours. The SR by Wardlaw et al.13 included 27 RCTs in which different tPAs (including alteplase), or placebo were administered after different stroke onset times; 5 trials within this SR were relevant to this Rapid Review because alteplase was provided within 3 hours or between 3 hours to 4.5 hours. The SR by Lan et al.19 included 7 non-randomized studies and 3 RCTs of which 2 RCTs were relevant to the current report because they compared alteplase to placebo administered within 3 hours or between 3 hours and 4.5 hours. Of the relevant studies included in the SRs, publication dates ranged from 1995 to 2019.
All 3 RCTs were multi-centre studies. One 2021 publication22 reported on the TESPI RCT.25 A 2020 publication14 was a re-analysis of data from the ECASS III RCT,26 which was conducted because of baseline differences between study groups in the original publication for the trial. This Rapid Review focuses on the re-analysis of the ECASS III trial14; however, some study characteristics were obtained from the original article for this trial26 if not available in the re-analysis report.
Three publications20,21,23 reported on an RCT, the third International Stroke Trial (IST-3),27-29 and were published between 2014 and 2016. One publication23 reported only on mortality at 18-month follow-up; another publication20 reported only on mortality at 3-year follow-up. A third publication21 reported on mortality and hemorrhage at 7-day follow-up and on functional outcomes at 6-month follow-up. Some study characteristics were obtained from 3 earlier articles on the IST-3 trial27-29 if these details were not available in the report of the re-analysis.
The country of origin of the first author was Scotland for 2 articles,13,23 China for 2 articles,18,19 Italy for 1 article,22 the US for 1 article,14 Norway for 1 article,20 and Australia for 1 article.21 The Chen et al. SR18 included relevant studies conducted in Australia, China, Europe, and the US. The Lan et al. SR19 included relevant studies conducted in Australia, Europe, and North America. The Wardlaw et al. Cochrane SR13 included relevant studies conducted in Australia, Europe, and the US.
The TESPI trial, reported in 1 publication,22 was conducted at multiple centres in Italy. Another publication14 reported re-analyzed results for the ECASS III trial,26 which was conducted at multiple centres across Europe including Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Slovakia, Spain, Sweden, Switzerland, and the UK. Three articles20,21,23 reported results from the IST-3 trial,27-29 which was conducted across the UK, Poland, Italy, Sweden, Norway, Australia, Portugal, Austria, Belgium, Switzerland, Canada, and Mexico. One20 of these articles only reported results for a subset of patients in the UK, Norway, and Sweden. The IST-3 trial was the only trial in this report that included patients from Canada.
All SRs included adult patients with AIS. In the relevant primary studies from 2 SRs,18,19 the number of patients ranged from 58 to 730 and their ages ranged from 60 years to 69 years. In the Cochrane SR by Wardlaw et al.,13 relevant primary studies included all adults or only adults aged 18 years to 80 years.
Across all RCTs,14,20-23 patients were adults with AIS, and population sizes ranged from 191 to 1,177. The authors did not indicate whether gender or sex were recorded or whether nonbinary identification was recorded, so these results are summarized as reported by the authors of the included studies. In 1 publication22 with results from the TESPI trial, all patients were older than 80 years, had National Institutes of Health Stroke Scale (NIHSS) scores below 17, and 61.8% were women. In a publication14 with re-analyzed results from the ECASS III trial, the mean age in the alteplase group was 64.7 years and mean age in the placebo group was 65.6 years. There were 63.2% males in the alteplase group and 57.3% males in the placebo group. In the IST-3 trial,27-29 which was reported in 3 articles,20,21,23 of the total population that received treatment within 6 hours of stroke onset, there were 52% females in the alteplase group and 52% females in the standard care group. For those who received treatment within 3 hours, 79.2% were older than 80 years.21 People who were of child-bearing potential or were breastfeeding were excluded from the IST-3 trial.27
Across all studies, alteplase at a dose of 0.9 mg/kg was administered intravenously within 3 hours of stroke onset or between 3 hours and 4.5 hours of stroke onset. Most studies reported on alteplase administered within 3 hours. One SR,18 1 publication14 on the ECASS III trial, and 2 publications21,23 on the IST-3 trial reported results for alteplase administered between 3 hours and 4.5 hours. In the IST-3 trial, which was reported in 3 articles,20,21,23 alteplase was administered with standard medical care. Comparator groups of included studies were standard care alone (without alteplase) or placebo.
Effectiveness was measured using different definitions for functional outcomes. Six publications13,14,18,19,21,22 reported on functional outcomes. These outcomes were measured using the modified Rankin Scale (mRS), the Oxford Handicap Scale, the NIHSS, the Barthel Index, the Glasgow Outcome Scale, or a global outcome. The mRS is a single-item rating to measure functioning after stroke with 6 grades ranging from 0 to 5.30,31 Grades of 0 or 1 indicate no symptoms or no significant disability; higher grades indicate increasing severity in disability.30,31 The Oxford Handicap Scale is a derivative of the mRS that uses the same grading and scale but uses the term “disability” versus “handicap.”32 The NIHSS was reported in the results from 1 RCT14 using an original and modified version. Each version has 15 items with a total score out of 42 in the original version and 46 in the modified version.14 Each item assesses functioning and is scored 0, 1, 2, 3, or 4 depending on the item.14 Smaller numbers indicate normal functioning and higher numbers indicate impairment.14
The Barthel Index is a 10-item scale measuring a person’s ability to function independently.14,33 The scale ranges from 0 to 100 with higher numbers indicating more independence.14,33 The Glasgow Outcome Scale is a 5-point scale in which 5 indicates death, 3 indicates severe disability, and 1 indicates independence.14 The global outcome was reported in the results from 1 RCT14 as a composite of other individual scales entered into a statistical algorithm that indicated the probability of a favourable outcome.
Safety outcomes included death reported in all studies,14,18-23,29 adverse events (AEs) reported in 1 trial,22 and symptomatic intracranial hemorrhage (sICH) reported in all SRs and 2 RCTs.13,14,18,19,21,22 In publications on the TESPI and IST-3 trials,20-23 mortality was referred to as “overall mortality” or from all causes; in 1 publication for the ECASS III trial,14 it is unclear if mortality was from all causes. One publication from the TESPI trial22 reported AEs although the definition for general AEs was unclear; for serious AEs, the definition included sICH, cerebral edema, pneumonia, pleuritis, cardiovascular event, pulmonary edema, anemia, cerebrovascular ischemic event, dysphagia, agitation, acute cholecystitis, urinary sepsis, macroscopic hematuria, laterocervical hematoma, femoral fracture after fall, vocal string paralysis, allergic reaction, or fever.
sICH is bleeding inside the skull which affects an individual’s neurological state.13 Intracerebral hemorrhage is a subtype of intracranial hemorrhage in which bleeding occurs in the brain parenchyma.34 The definition of sICH varied across studies. In some cases, symptomatic intracerebral hemorrhage was also referred to as sICH. Within studies, the terms were also used interchangeably. The term sICH will be used in this report to include subtypes in addition to the broader term for all types of ICH that were reported in the included studies.
Definitions of sICH in the TESPI and ECASS III trials14,22 and in 1 SR18 were based on the NINDS trials, the ECASS II, or the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST). The NINDS definition was any previously unseen sICH with any suspicion of hemorrhage or decline in neurologic status.35 The ECASS II definition was any sICH in which stroke severity was a change equal to or greater than 4 on the NIHSS.35 The SITS-MOST definition of sICH was hemorrhage identified by images obtained 22 hours to 36 hours after treatment localized to parenchymal hematoma type 2 and in which stroke severity was equal to or greater than 4 on the NIHSS.35 Two SRs13,19 reported sICH as reported by the authors of included studies. For the IST-3 trial, the definition of sICH was new headache, neurologic deterioration, acute hypertension, vomiting, nausea, or decrease in consciousness.27
Additional details regarding the characteristics of the included publications are provided in Appendix 2.
All 3 SRs13,18,19 stated the populations, interventions, comparators, and outcomes of interest for reviews, and performed an adequately comprehensive search using at least 2 databases. Two SRs18,19 did not establish a protocol beforehand; the Cochrane SR by Wardlaw et al.13 had a protocol but did not describe details sufficiently, thus there is a possibility of bias due to selective outcome reporting. In the Wardlaw et al. SR,13 study screening and extraction was performed in duplicate; however, in the other 2 SRs,18,19 data extraction was conducted in duplicate, but it is unclear whether screening was done by 2 reviewers so relevant studies may have been missed. Two SRs13,19 used a satisfactory technique for assessing risk of bias, although it is unclear whether the Chen et al. SR18 assessed all important items for risk of bias assessment such as confounding, selection bias, and bias in outcome measurement. If all risk of bias considerations were not made, it is unclear whether synthesized evidence may have been from biased studies or if the conclusions align with the quality of the included studies (e.g., it may be overstated). All SRs reported some but not all details about included studies. The Chen et al. SR18 described populations, interventions, and study designs in sufficient detail, however details about outcomes, follow-up, and sources of funding were not provided for each included study. The Wardlaw et al. SR13 described interventions, comparators, outcomes, and study designs in sufficient detail, but sources of funding and population sizes were not reported. The Lan et al. SR19 did not describe populations, comparators, or sources of funding in sufficient detail. This is a limitation since the comparability and applicability of included studies to other primary studies and to the Rapid Review overall was difficult to determine from SR publications alone.
In the Chen et al. SR18 that reported MA results, the authors used random effects models that incorporated the assumption that studies were measuring different but related intervention effects (i.e., clinical and methodological heterogeneity may exist). This is a strength because this method would have assumed that there was a range of true effects of the intervention.
Two SRs18,19 declared no conflicts of interest. The Wardlaw et al. Cochrane SR13 had several potential conflicts of interest including funding, equipment, or recognition from Boehringer Ingelheim, a pharmaceutical company that manufactures alteplase. Further, the authors of this SR were also involved in the conduct or reporting of the trials included in the review itself. It is unclear how this may have affected selection of trials in the SR and interpretation of findings.
The TESPI trial publication22 had clearly stated objectives, outcomes, patient characteristics, interventions, risk factors, and main findings. Patients were randomized to balance important factors between study groups, which may have influenced outcomes. However, the TESPI trial was open label with blinded assessment of some but not all outcomes. This is a limitation because knowledge of study assignment may have introduced performance bias (e.g., patients may have been treated differently if clinicians knew what treatment they received). Knowledge of study assignment may have also introduced detection bias, specifically with subjectively measured or self-reported outcomes that were recorded through a telephone interview in this trial.22,36 The sICH outcome was measured using a change in NIHSS score and imaging scans25; bias may have been introduced in the interpretation of these scans and of the NIHSS score because the trial was open label and clinicians interpreting scans were aware of study assignment. The TESPI trial was also terminated early since findings from another study showed that the intervention was favourable, and the authors believed that was no need to continue; the study therefore was underpowered to detect any significant effects since follow-up was not completed. The trial population also included patients older than 80 years with a NIHSS score greater than 17; therefore, results may not be generalizable to other populations.
In the re-analysis of the ECASS III trial publication,14 authors clearly stated objectives, outcomes, patient characteristics, interventions, risk factors, and main findings. The authors indicated that they specified their analyses beforehand to avoid selective analysis and reporting.14 Another strength was that the ECASS III trial was conducted across multiple centres, which may have increased generalizability to other populations. Although randomization was conducted in the ECASS III trial to balance important factors between study groups that may have influenced outcomes, the re-analysis was performed to account for baseline imbalance in prognostic variables that were not comparable in the original ECASS III analysis and may have caused selection bias in the original results. The trial26 was also described as “double blind” and reported blinding of investigators and examiners, although the publication did not specifically state that patients were blinded. It was also unclear whether outcomes were measured objectively or subjectively. Although the re-analysis attempted to correct for issues present in the original data analysis, the secondary investigation of the data may have been limited due to potential bias of the statistician(s)’ knowledge of issues in the data; it is unclear whether the re-analysis was conducted in a blinded manner. Further, the authors of the re-analysis publication stated that re-analyses in general cannot definitively create new conclusions and can only increase or decrease certainty in the unadjusted analysis of the original study.14
For the IST-3 trial27-29 reported in 3 publications in this report20,21,23 there were some strengths and several limitations. Authors of included publications20,21,23 clearly stated the objectives, main outcomes, patient characteristics, interventions, and main findings. Patients in the trial were randomized to balance important factors between study groups that may have influenced outcomes. Mortality was measured in most cases using complete central death registries for 3 of the countries participating in the study (the UK, Sweden, and Norway), and time was accounted for in survival analyses.
One limitation of the IST-3 trial was that it is unclear if important confounders such as smoking history were measured and thus balanced between study groups. Since the trial was conducted across multiple centres, this may have increased generalizability to other populations; however, because the trial excluded people of child-bearing potential or those who were actively breastfeeding, it is unclear whether results from this large study can be applied to these individuals. The IST-3 trial was open-label so all those involved were aware of study assignment, including outcome assessors. This may have introduced selection, performance, and detection biases. Outside of the UK, Sweden, and Norway, mortality was measured as death reported by physicians, hospital coordinators, or self-reported on questionnaires or in telephone interviews instead of central death registries. Functional outcomes were also measured through self-reported questionnaires or in telephone interviews. Because the trial was open label, reporting of these outcomes may have been biased. The sICH outcome was measured using a stroke scale or an imaging scale; if only the stroke scale was used, this may have been biased because it was measured using an unblinded outcome assessor’s judgment. Authors of the publications20,21,23 of the IST-3 trial also noted that there was not enough power to detect effects either in the IST-3 trial as a whole or in their individual analyses.
All trial publications14,20-23 included in this report had potential conflicts of interest. Individuals involved in the conduct of trials or authors of publications of included studies received funds, resources, or recognition from Boehringer Ingelheim, a pharmaceutical company that manufactures alteplase. In addition to this company, authors of IST-3 publications20,21,23 also received funds, resources, or recognition from various industry sources.
Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.
Appendix 4 presents the main study findings by time after stroke onset and by outcome, in Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, and Table 12. The findings summarized in this report are based on the way outcomes are reported in the included publications.
The narrative summaries in this report may contain some data from the same trials because there was overlap in some of trials included within the SRs and in trials between SRs and RCTs. All 3 SRs13,18,19 included results from the NINDS trials. Two SRs13,18 included results from the ATLANTIS A, ECASS II, and ECASS III trials. This overlap across SRs is presented in Appendix 5. One included primary study14 was a re-analysis of the ECASS III trial (conducted by the authors to account for baseline imbalances between study groups), and the findings from the original analysis of the ECASS III (without this adjustment) were included in 2 of the SRs13,18 summarized in this report.
Two SRs13,18 and 2 RCTs (IST-320,21,23 and TESPI trials22) reported findings for mortality in patients who received treatment within 3 hours of stroke onset. For death at 7-day follow-up, 1 publication of the open-label IST-3 trial21 reported little-to-no difference in the odds of death for the alteplase group compared with the usual care group, but the effect estimate was imprecise.
At 3-month follow-up, results from the open-label TESPI trial22 and MA results from the Chen et al. SR18 showed little-to-no difference in the risk or odds of death in the alteplase group compared with the control group; however, the effect estimates were imprecise.
At the 6-month follow-up, results from the open-label IST-3 trial23 suggested little-to-no change in mortality with treatment with alteplase compared with usual care, with substantial imprecision.
At the 18-month follow-up, results from the open-label IST-3 trial23 reported a reduction in mortality in the alteplase group compared with the usual care group; however, the magnitude of this reduction is uncertain due to imprecision in the results.
At 3-year follow-up, results from the open-label IST-3 trial20 showed little-to-no difference in mortality in the alteplase group compared with the usual care group; however, these findings were imprecise.
Individual studies in the Wardlaw et al. SR13 with unknown follow-up times had inconsistent findings. Three RCTs showed little-to-no difference between alteplase and control, but effect estimates were substantially imprecise. One RCT showed a higher odds of death in the alteplase group compared with the control group; however, the magnitude of this increase is uncertain due to the serious imprecision of the results.
Three SRs13,18,19 and 2 RCTs (IST-321 and TESPI trials22) investigated sICH in patients who received treatment within 3 hours of stroke onset. For sICH measured at 36-hour follow-up, MA results from the Chan et al. SR18 showed little-to-no difference in the odds of sICH in the alteplase group compared with the control group, with substantial imprecision.
For 7-day follow-up, results from the open-label IST-3 trial21 showed increased odds of sICH in the alteplase group compared with the standard care group; however, the magnitude of the effect is uncertain because of the large imprecision in the results.
For the 3-month follow-up, results from the open-label TESPI trial22 showed little-to-no difference between the alteplase and standard care groups; however, the findings were affected by serious imprecision.
The Lan et al.19 and the Wardlaw et al.13 SRs reported sICH results; follow-up times were not specified in these SRs. Most results from the primary studies in these reviews showed little-to-no difference in sICH when alteplase was compared with control and 1 primary study reported in the Wardlaw et al. SR13 showed increased odds of sICH in the alteplase group. Results across both SRs13,19 had a very high level of imprecision.
Three SRs13,18,19 and 2 RCTs (IST-321 and TESPI22 trials) reported results for functional outcomes in patients who received treatment within 3 hours of stroke onset. For 7-day follow-up, the open-label TESPI trial22 showed that a statistically significantly higher percentage of patients in the alteplase group had neurologic improvement compared with the standard care group.
For 3-month follow-up, results from the open-label TESPI trial22 and primary study results from the Lan et al. SR19 showed little-to-no difference in being alive and independent; these findings were affected by substantial imprecision. The Chen et al. MA18 showed higher odds of having no symptoms or no significant disability in the alteplase group compared with the control group.
For 6-month follow-up, results from the open-label IST-3 trial21 showed higher odds of functioning (no symptoms, mild symptoms, or minor handicap) in the alteplase group compared with the standard care group.
For the Wardlaw et al. Cochrane SR,13 in which follow-up times were not specified, results across individual studies were inconsistent. Findings from 2 primary studies showed little-to-no difference in having favourable outcomes, with large imprecision. Two primary studies showed increased odds of favourable outcomes; these results had a high level of imprecision.
The open-label TESPI trial22 that reported results for patients who received treatment within 3 hours showed little-to-no difference between treatment with alteplase and standard care for incidence of AEs and serious AEs.
Two SRs18,19 and results from 2 RCTs (IST-3 trial21 and the re-analysis14 of ECASS III results) reported mortality findings in patients who received treatment between 3 hours and 4.5 hours of stroke onset. Seven-day follow-up results from the re-analysis of the ECASS III trial14 showed little-to-no difference in mortality between treatment with alteplase and placebo, whereas results from the IST-3 trial21 showed increased odds of death in the alteplase group compared with the standard care group. There was serious imprecision in these findings.
Three-month follow-up results from the Chen et al. MA18 (which included the original ECASS III trial) and results from the re-analysis of the ECASS III trial14 both showed little-to-no difference in incidence of death between the alteplase and control groups, but these findings were affected by serious imprecision.
For the Lan et al.19 SR with unknown follow-up time, results from 1 RCT showed little-to-no difference in incidence of death between the alteplase and control groups; these results had substantial imprecision.
One SR,18 results from the IST-3 trial,21 and re-analysis results from the ECASS III trial14 reported findings for sICH in patients who received treatment between 3 hours and 4.5 hours of stroke onset. Meta-analysis results from the Chen et al. SR18 showed little-to-no difference in sICH at 36-hour follow-up; these results had a high level of imprecision.
In the re-analysis of the ECASS trial,14 authors presented data using different definitions of sICH and different analysis adjustments (i.e., using multivariable effect estimates or stratified effect estimates). For 7-day follow-up, all variations in adjustments showed a higher risk of sICH in the alteplase group compared with the placebo group. Results from the open-label IST-3 trial showed higher odds of sICH in the alteplase group compared with the standard care group; the magnitude of the effect is uncertain because the results had a high level of imprecision.
One SR,18 results from the open-label IST-3 trial,21 and re-analysis results from the ECASS III trial14 reported findings for functional outcomes in patients who received treatment between 3 hours and 4.5 hours of stroke onset. For 3-month follow-up, re-analysis from the ECASS III trial14 showed little-to-no difference in all functional outcomes for independence and neurologic outcomes, whereas results from an MA by Chen et al.18 found higher odds of having no symptoms or no significant symptoms in the alteplase group compared with the control group.
For 6-month follow-up, results from the open-label IST-3 trial21 showed little-to-no difference in favourable outcomes (having no symptoms, minor symptoms, or minor handicap) in the alteplase group compared with the standard care group.
No evidence was found that reported on AEs other than death for treatment provided between 3 hours and 4.5 hours after stroke onset.
There are several limitations to the evidence that met the criteria for this Rapid Review. The overall quality of the findings was limited by several factors, including a lack of blinding,20-23 high imprecision of results, uncertainty in whether data were reported correctly based on the interpretation of the findings, differences in trial conduct and analysis among researchers and clinicians, and potential conflicts of interest. Only the IST-3 trial included patients living in Canada so it is unclear whether results from the other studies can be applied to Canada.
There were also differences between the included studies that limited the interpretation of the findings, such as differences in how outcome measures were measured and variations in statistical analyses. It is also unclear whether the evidence base is applicable to younger populations or those of child-bearing potential.
Studies differed in how outcomes were measured, which may make it difficult to compare results. Different definitions of sICH were used, based on previous stroke trials, and some studies reported multiple sICH outcomes based on different definitions. Most studies reported results for functional outcomes based on the mRS or the Oxford Handicap Scale, and the re-analysis of the ECASS III trial14 reported results based on 5 different scales. Studies also varied in what was considered a favourable outcome; some reported it as complete independence whereas others reported favourable outcome as having some disability but not being completely dependent on others.
Of the evidence that met the criteria for this report, 1 publication, the re-analysis of the ECASS III trial,14 focused on the safety and effectiveness of alteplase when administered between 3 hours and 4.5 hours of stroke onset. The other primary studies focused on the zero- to 3-hour window,20,22 or a window of 6 hours or more, and then conducted subgroup analyses for the zero- to 3-hour or the 3-hour to 4.5-hour windows.21,23 For the Chen et al. SR18 that conducted MAs and NMAs, the NMA results were not relevant because different time frames were compared to one another, rather than each time frame compared with a control. The Lan et al. SR19 combined studies with varying treatment windows; therefore, MA results were not relevant to this review. The Wardlaw et al. Cochrane SR13 conducted MAs; however, these pooled results could not be included in the current report because some studies in the MAs used a dose of alteplase that was not 0.9 mg/kg, included children, or administered a tPA that was not alteplase.
Another limitation of the SRs13,19 was that the follow-up times were not reported for some of the outcomes, thus these results could not contribute to the narrative summaries for specific follow-up times. Because some SRs did not adequately report details from the original trials, some findings from these trials may be missing in this report.
In addition to the limitations of the evidence on alteplase, there are also limitations within this report. There was overlap in the primary studies in the SRs included in the review which may have resulted in reporting of the results from the same trial in multiple sections of the report. For example, ECASS III trial results were included in the MA from the Chen et al. publication,18 and the re-analysis of the results from the ECASS III trial were reported in the Alper et al. publication.14 Furthermore, details from some of the primary studies were not reported in the SRs and thus are not captured in this report. For example, some outcome follow-up times were unclear.
A Rapid Review was conducted to determine the clinical effectiveness of alteplase for patients with AIS when administered within 3 hours of symptom onset, or between 3 hours and 4.5 hours of symptom onset. Three SRs13,18,19 and 5 publications14,20-23 reporting on 3 RCTs were found. Articles were published between 2014 and 2021 and reported effects on mortality, sICH, functional outcomes, or AEs. The SRs included studies in which alteplase was administered at several different time points after stroke onset and included findings from the ATLANTIS A, ATLANTIS B, ECASS II, ECASS III, NINDS, PRISMS, and WAKE-UP trials. One publication22 reported results from the TESPI trial, in which treatment was administered within 3 hours. Another publication14 was a re-analysis of results from the ECASS III trial in which treatment was administered between 3 hours and 4.5 hours. Three publications20,21,23 reported on the IST-3 trial in which treatment was administered within 6 hours; subgroup analyses were reported for the zero- to 3-hour or 3-hour to 4.5-hour windows.
When alteplase was administered within 3 hours of stroke onset, studies showed little-to-no difference on mortality at 7-day,21 3-month,18,22 6-month,23 and 3-year follow-ups20 compared with usual care. For 18-month follow-up, results from an open-label trial23 showed a reduction in death in the alteplase group compared with standard care. All findings were substantially imprecise, which reduces the overall confidence in the conclusions. Results from an open-label trial19,22 showed little-to-no difference between treatment with alteplase and standard of care in the incidence of AEs.
Compared with usual care, when alteplase was administered within 3 hours of stroke onset, there was little-to-no difference on sICH after 36 hours based on MA results18 or at 3 months based on an open-label trial; however, the findings were imprecise.22 In contrast, 7-day results from an open-label trial21 showed higher odds of sICH in the alteplase group; however, the magnitude of the effect is unclear due to the imprecision of the results.
When alteplase was administered within 3 hours of stroke onset, there were more neurologic improvements in this group after 7 days compared with standard care based on an open-label trial.22 After 3 months, findings were inconsistent; results from 3 trials reported in 2 publications19,22 showed little-to-no difference, whereas 1 MA18 showed an increase in favourable outcomes compared with the control group. Results from an open-label trial suggested higher odds for functioning for alteplase compared to standard care after 6 months.
When alteplase was administered between 3 hours and 4.5 hours of stroke onset, a re-analysis of a double-blind trial14 showed little-to-no difference in mortality after 7 days when compared with placebo, whereas an open-label trial21 showed increased odds of death after 7 days compared with standard care. Results from 1 MA18 and a re-analysis of a double-blind trial14 showed little-to-no difference in mortality at 3 months between alteplase and control groups. The findings were substantially imprecise.
When alteplase was administered between 3 hours and 4.5 hours of stroke onset, 1 MA18 showed little-to-no difference in sICH between the alteplase and control groups after 36 hours. The findings on sICH for 7-day follow-up were mixed. The re-analysis of a double-blind trial14 showed little-to-no difference, whereas results from an open-label trial21 suggested increased risk of sICH with treatment with alteplase compared with standard care; however, the magnitude of the effect was unclear due to the imprecision of the result.
When alteplase was administered between 3 hours to 4.5 hours of stroke onset, 3-month follow-up results were inconsistent when compared with a control group. The re-analysis of a double-blind trial14 showed little-to-no difference in functional outcomes, whereas results from 1 MA18 suggested improved functional outcomes. When alteplase was administered between 3 hours and 4.5 hours of stroke onset, an open-label trial21 showed little-to-no difference in functional outcomes at 6-month follow-up.
There were methodological limitations identified, such as lack of blinding,20-23and inconsistencies in how outcomes (e.g., functional outcomes)13,14,18,19,21,22 were measured and reported. In addition, some authors of included studies declared receiving funds or resources from a pharmaceutical company that manufactures alteplase, were involved in multiple stroke trials, or were authors of review articles that included these trials. Although many analyses found little-to-no difference between groups for the outcomes evaluated, these findings often had substantial imprecision (i.e., wide confidence intervals), and it is possible that this could change with the addition of high-quality, adequately powered studies. Researchers and clinicians may consider investigating whether there is a need to re-analyze data from other trials as was done in 1 included article14 in which results from the ECASS III trial were re-analyzed due to imbalances across treatment groups. If further work is conducted, it may reduce potential biases that have been identified, such as consideration of potential conflicts of interest of study personnel. New studies could also be conducted in a way that minimizes potential bias by ensuring blinding of all patients and study personnel, investigating imbalances in study groups to increase internal validity, and including personnel and resources not affiliated with pharmaceutical companies. In addition, researchers and clinician groups can discuss how to consistently report on functional outcomes (e.g., what degree of independence is considered favourable) so that studies can be compared to one another. If a gold standard outcome for stroke trials exists, this should be used consistently in future work. If additional work is done in this area, MAs can include new publications to gain a clearer understanding of the role of alteplase in treating AIS.
Overall, the limitations of the literature included in this rapid review13,14,18-23 and the imprecision of results should be considered when interpreting the findings from this report.
adverse event
acute ischemic stroke
Third European Cooperative Acute Stroke Study
confidence interval
Third International Stroke Trial
meta-analysis
modified Rankin Scale
National Institutes of Health Stroke Scale
National Institute of Neurological Disorders and Stroke study
Potential of rtPA for Ischemic Strokes with Mild Symptoms
randomized controlled trial
symptomatic intracranial hemorrhage
Thrombolysis in Elderly Stroke Patients in Italy
tissue plasminogen activator
Acknowledgement: Michelle Gates, PhD, Scientific Advisor, CADTH
Selection of Included Studies.
Note that this appendix was not copy-edited.
Characteristics of Included Systematic Reviews.
Characteristics of Included Randomized Controlled Trials.
Strengths and Limitations of Systematic Reviews Using AMSTAR 216.
Strengths and Limitations of Randomized Controlled Trials Using the Downs and Black Checklist.
Note that this appendix was not copy-edited.
Summary of Findings for Alteplase Administered Within 3 Hours of Stroke — Mortality.
Summary of Findings for Alteplase Administered Within 3 Hours of Stroke — Symptomatic Intracranial Hemorrhage.
Summary of Findings for Alteplase Administered Within 3 Hours of Stroke — Functional Outcomes.
Summary of Findings for Alteplase Administered Within 3 Hours of Stroke — Adverse Events.
Summary of Findings for Alteplase Administered 3 Hours to 4.5 Hours After Stroke — Mortality.
Summary of Findings for Alteplase Administered 3 Hours to 4.5 Hours After Stroke — Symptomatic Intracranial Hemorrhage.
Summary of Findings for Alteplase Administered 3 Hours to 4.5 Hours After Stroke — Functional Outcomes.
Note that this appendix was not copy-edited.
Overlap in Relevant Primary Studies Between Included Systematic Reviews.
Note that this appendix was not copy-edited.
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This document was externally reviewed by a content expert who has granted permission to be cited.
Dr. Gary Hunter
Neurologist
University of Saskatchewan
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