Trials of endovascular therapy for ischemic stroke have produced variable results. We conducted this study to test whether more advanced imaging selection, recently developed devices, and earlier intervention improve outcomes.
We randomly assigned patients with ischemic stroke who were receiving 0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. The coprimary outcomes were reperfusion at 24 hours and early neurologic improvement (≥8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3). Secondary outcomes included the functional score on the modified Rankin scale at 90 days.
The trial was stopped early because of efficacy after 70 patients had undergone randomization (35 patients in each group). The percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular-therapy group than in the alteplase-only group (median, 100% vs. 37%; P<0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P=0.002) and improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified Rankin scale, 71% vs. 40%; P=0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage.
In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome. (Funded by the Australian National Health and Medical Research Council and others; EXTEND-IA ClinicalTrials.gov number, NCT01492725, and Australian New Zealand Clinical Trials Registry number, ACTRN12611000969965.)
The results of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trial,1 which showed reduced disability among patients with ischemic stroke who were treated with endovascular thrombectomy in addition to standard care, represent an advance in stroke care. The MR CLEAN study followed several trials that had neutral findings with respect to the use of endovascular thrombectomy.2-4 In the largest of these trials, the Interventional Management of Stroke 3 (IMS-3) study, investigators compared the administration of 0.9 mg of alteplase per kilogram of body weight to a bridging strategy of the use of alteplase (at a dose of 0.6 mg per kilogram for most of the trial) followed by endovascular therapy. The IMS-3 trial was halted for futility after 656 patients had been enrolled.2
Potential contributors to the neutral results of previous studies include relatively low rates of angiographic reperfusion, delays in achieving reperfusion, and the lack of patient selection with the use of advanced imaging to ensure the presence of vessel occlusion and salvageable brain tissue. None of the previous studies raised any safety concerns, with rates of symptomatic hemorrhage of approximately 6% in both the alteplase group and the endovascular-therapy group. More recent advances in device technology have significantly improved the speed and efficacy of recanalization.5-7
Computed tomographic (CT) perfusion imaging can indicate the extent of irreversibly injured brain in the ischemic core and potentially salvageable but hypoperfused ischemic penumbra.8-11 Furthermore, CT perfusion imaging has evolved, and fully automated, standardized volumetric processing can now be rapidly performed in the context of a multicenter clinical trial.12,13
In the Extending the Time for Thrombolysis in Emergency Neurological Deficits — Intra-Arterial (EXTEND-IA) trial, we sought to test the hypothesis that patients with anterior circulation ischemic stroke who are selected with a dual target of vessel occlusion and evidence of salvageable tissue on perfusion imaging within 4.5 hours after the onset of stroke will have improved reperfusion and early neurologic improvement when treated with early endovascular thrombectomy with the use of the Solitaire FR (Flow Restoration) stent retriever after intravenous administration of alteplase, as compared with the use of alteplase alone. The release of the MR CLEAN trial results prompted the data and safety monitoring board for our study to review the data, and the trial was stopped early because efficacy was clearly shown.
Trial Design and Oversight
The EXTEND-IA trial was an investigator-initiated, multicenter, prospective, randomized, open-label, blinded-end-point study involving patients with ischemic stroke who were receiving intravenous alteplase within 4.5 hours after stroke onset. Details of the methods used in the trial have been published previously.14 The study protocol is available with the full text of this article at NEJM.org.
The design, analysis, and data collection for the trial were performed by members of the executive committee and investigators at the study sites (see the Supplementary Appendix, available at NEJM.org). The first author wrote the first draft of the manuscript. All the investigators vouch for the accuracy and completeness of the presented data and fidelity of the report to the study protocol. Covidien supplied the Solitaire FR device and an unrestricted grant to support trial infrastructure, but the company was not involved in the study design or conduct or in the preparation of the manuscript, except to review the protocol to ensure that the specified use of devices in the study followed the approved instructions for use.
We planned to enroll 100 patients at 14 centers in Australia and New Zealand. Patients were eligible if they could receive intravenous alteplase within 4.5 hours after the onset of anterior circulation ischemic stroke and had occlusion of the internal carotid artery or of the first or second segment of the middle cerebral artery, as seen on CT angiography. In addition, CT perfusion imaging, which was processed with the use of fully automated software (RAPID, noncommercial research version, Stanford University),12,13 was used to identify potentially salvageable brain tissue. Brain tissue at risk for infarction (“ischemic penumbra”) was distinguished from minimally hypoperfused tissue if the time to maximum (Tmax) delay was more than 6 seconds.15 Irreversibly injured brain (“ischemic core”) was diagnosed if the relative cerebral blood flow was less than 30% of that in normal tissue.10
Endovascular therapy had to be initiated (groin puncture) within 6 hours after stroke onset and completed within 8 hours after onset. There were no restrictions on age or clinical severity, as assessed according to the score on the National Institutes of Health Stroke Scale (NIHSS), which ranges from 0 (normal) to 42 (death). However, patients were required to have functional independence before the stroke episode, which was defined as a score of less than 2 on the modified Rankin Scale, which ranges from 0 (normal) to 6 (death).
The study was approved by the institutional ethics committee at each study site. Written informed consent was obtained from patients or a legal representative before enrollment. Detailed inclusion and exclusion criteria are provided in the Supplementary Appendix.
All patients received alteplase at a dose of 0.9 mg per kilogram as standard care. Patients were randomly assigned in a 1:1 ratio to receive either alteplase plus endovascular therapy (endovascular-therapy group) or no further therapy (alteplase-only group) by means of a centralized website and stratified according to the site of arterial occlusion: the internal carotid artery or the first or second segment of the middle cerebral artery.
The use of conscious sedation or general anesthesia for endovascular treatment was at the discretion of the neurointerventionist. The site of vessel occlusion was confirmed with the use of digital subtraction angiography. If there was no lesion amenable to thrombectomy, the procedure was terminated. The Solitaire FR retrievable stent (Covidien) was deployed at the site of intracranial-vessel occlusion and then removed under negative-pressure aspiration. Control angiography was performed at the conclusion of the procedure and centrally graded for angiographic revascularization, with the use of the modified Treatment in Cerebral Ischemia classification, on a scale ranging from 0 (no flow) to 3 (normal flow),16 and any embolization of thrombus into previously uninvolved vascular territories.
The coprimary outcomes were reperfusion (which was defined as the percentage reduction in the perfusion-lesion volume between initial imaging and imaging at 24 hours, which can be negative if hypoperfusion worsens) and early neurologic improvement (which was defined as a reduction of 8 points or more on the NIHSS or a score of 0 or 1 at 3 days). Secondary outcomes were the score on the modified Rankin scale at 90 days, death due to any cause, and symptomatic intracranial hemorrhage, including any subarachnoid hemorrhage associated with clinical symptoms and symptomatic intracerebral hemorrhage, which was defined as parenchymal hematoma type 2 within 36 hours after treatment combined with an increase on the NIHSS of at least 4 points from baseline.17 Further details are provided in the Methods section in the Supplementary Appendix.
After the release of the results of the MR CLEAN study, recruitment into the trial was suspended on October 31, 2014, and the data and safety monitoring board reviewed data for the 70 enrolled patients. A prespecified Haybittle–Peto stopping boundary was applied to the coprimary outcome in the intention-to-treat population with the use of Holm's step-down procedure,18 so that one coprimary outcome was tested at a z value of more than 3.29 and the other at a z value of more than 3. The data and safety monitoring board stopped the trial for efficacy after this analysis.
For the intention-to-treat analysis of the coprimary outcome, we compared the median percentage reperfusion between the endovascular-therapy group and the alteplase-only group after adjustment for baseline arterial occlusion strata using the van Elteren test, a stratified version of the Wilcoxon rank-sum test. We used logistic regression to compare the between-group difference in the proportion of patients with early neurologic recovery, as indicated by a reduction of 8 or more points on the NIHSS or a score of 0 or 1 at 3 days, after adjustment for age and baseline NIHSS score.
Although results are reported with and without adjustment for baseline covariates, the analysis with adjustment was prespecified as the primary analysis. The results are also reported for the target group who underwent endovascular thrombectomy according to the protocol, as compared with the alteplase-only group, to adjust for effects such as recanalization before cerebral angiography was performed and any off-protocol interventions.
As prespecified in the protocol, the initial analysis of the secondary outcome for the score on the modified Rankin scale was designed to be an assumption-free ordinal analysis19,20 that uses the Wilcoxon–Mann–Whitney generalized odds ratio across the full range of the modified Rankin scale (from 0 to 6). Then, we used a logistic-regression model to compare the proportions of patients with scores of 0 or 1 (defined as an excellent outcome) and those with scores of 0 to 2 (defined as a functionally independent outcome) in the two study groups after adjustment for age and baseline NIHSS score.
Characteristics of the Patients
From August 2012 through October 2014, a total of 70 patients underwent randomization (35 to the endovascular-therapy group and 35 to the alteplase-only group) at 10 study centers (9 in Australia and 1 in New Zealand) (Fig. S1 in the Supplementary Appendix). Baseline characteristics of the patients are provided in Table 1, and procedural characteristics in Table 2.
Approximately 25% of clinically eligible patients with vessel occlusion were excluded on the basis of perfusion-imaging criteria (Fig. S2 in the Supplementary Appendix). The majority of the thrombus had been lysed before angiography in 4 of 35 patients (11%) in the endovascular-therapy group. Four other patients in the endovascular-therapy group did not undergo thrombectomy because they had either major clinical deterioration or major clinical improvement, stenting of the extracranial internal carotid artery to obtain access achieved a flow with a rating of 2b on the modified Treatment in Cerebral Ischemia classification without requiring thrombectomy, or the procedure was terminated before deployment of the Solitaire FR stent retriever owing to vessel perforation caused by microcatheter manipulation.
Patients in the endovascular-therapy group had significant improvements in both coprimary end points, as compared with the alteplase-only group (Table 3). Endovascular therapy resulted in increased reperfusion at 24 hours (P<0.001) (Figure 1A) and a probability of reperfusion of more than 90% without symptomatic intracerebral hemorrhage, as compared with the alteplase-only group (89% vs. 34%, P<0.001). The improvement in reperfusion remained highly significant in a sensitivity analysis in which 100% reperfusion was imputed for the three patients in the alteplase-only group who had missing data owing to poor clinical status.
Endovascular therapy led to greater early neurologic recovery at 3 days (P=0.002) (Figure 1B) and improved functional outcome in an ordinal analysis of the score on the modified Rankin scale at 90 days (generalized odds ratio, 2.0; 95% confidence interval [CI], 1.2 to 3.8; P=0.006) (Figure 2). We determined that 2.8 patients would need to be treated with endovascular therapy to achieve improvement of at least 1 point on the functional score, as compared with the use of alteplase alone. Patients in the endovascular-therapy group were also more likely to be independent (functional score, 0 to 2) at day 90 (71% vs. 40%, P=0.01); we determined that 3.2 patients would need to be treated to achieve an independent outcome, as compared with alteplase alone. The median number of days spent at home (as compared with in the hospital or other inpatient facility) in the first 90 days after stroke22 was 64 days greater in the endovascular-therapy group than in the alteplase-only group (P=0.001).
Consistent results were seen across the range of tertiary clinical and imaging end points (Table 3, and Table S3 in the Supplementary Appendix) and the target-group analysis (Table S5 in the Supplementary Appendix). Patients with reperfusion of 90% or more in the affected vascular territory, as compared with those with reperfusion of less than 90%, had improved functional outcome on the ordinal modified Rankin scale at 90 days (generalized odds ratio, 4.5; 95% CI, 2.2 to 9.0; P<0.001) and had increased independence (score, 0 to 2; 72% vs. 30%; P<0.001) and an excellent outcome (score of 0 or 1, 58% vs. 11%; P<0.001).
Symptomatic intracerebral hemorrhage occurred in two patients in the alteplase-only group (both with fatal results) and in none of the patients in the endovascular-therapy group. However, a large parenchymal hematoma developed in two patients in the endovascular-therapy group without causing major clinical deterioration; in one patient, the bleeding was caused by perforation by a wire during angiography and before deployment of the Solitaire FR stent retriever. Both patients survived, with scores of 3 and 4 on the modified Rankin scale at day 90. Embolization into a different vascular territory occurred in 2 of 35 patients (6%) in the endovascular-therapy group but did not cause clinical symptoms. There was no significant difference in mortality between the two groups, although two of the three patients in the endovascular-therapy group who died had a deterioration in their condition during the initial alteplase infusion before angiography because of a second cerebral embolism. The other adverse procedural event was a groin hematoma requiring transfusion in the endovascular-therapy group. Details regarding adverse events are provided in Table S4 in the Supplementary Appendix.
In patients with acute ischemic stroke with major vessel occlusion and salvageable tissue on CT perfusion imaging, early mechanical thrombectomy with the Solitaire FR stent retriever after the intravenous administration of alteplase was associated with faster and more complete reperfusion than the use of alteplase alone. The increase in reperfusion led to a reduction in infarct growth and substantial clinical benefit in early neurologic recovery and functional outcome at 3 months. This reduction in infarct growth is consistent with salvage of ischemic penumbra as the mechanism of underlying clinical benefit.23
The magnitude of the clinical benefit of endovascular thrombectomy in our study was larger than that in previous trials, despite similar clinical severities and demographic characteristics. The results of this trial were unequivocal, despite the small sample size. Key differences between our study and the previous trials include the use of CT perfusion imaging to select patients with the greatest potential to benefit from endovascular therapy, shorter time to the onset of treatment, and improved rates of angiographic revascularization.
A unique feature of our study was the use of standardized, universal CT perfusion-imaging selection to exclude patients with large ischemic cores and without evidence of clinically significant salvageable ischemic brain. Such patients have a low probability of a good outcome and have a higher risk of symptomatic hemorrhage and malignant edema.15,24 In the time window of less than 4.5 hours, patients with large ischemic cores comprise 10 to 15% of an unselected population,24 a rate that was generally consistent with the estimate of 25% of patients (95% CI, 11 to 45) who were excluded from our study on the basis of perfusion-imaging criteria. Such patients may not only undergo futile reperfusion but also have a reduced treatment effect if reperfusion leads to hemorrhage or malignant edema. This factor may be particularly relevant if the intervention has a higher reperfusion rate than that in controls, which was shown in our study to be applicable to endovascular therapy. CT perfusion imaging was also performed in about 65% of patients in the MR CLEAN trial (Majoie C: personal communication). Such imaging was not required according to the protocol for the MR CLEAN trial but may have influenced patient selection. Hence, positive results in the MR CLEAN trial may not be entirely attributable to imaging selection on the basis of vessel occlusion alone.
The interval between the initiation of alteplase and randomization was 30 minutes in our study, as compared with 100 minutes in the MR CLEAN trial, because of our approach of identifying patients with the greatest potential to benefit from reperfusion and then maximizing early reperfusion with the use of combined alteplase and endovascular therapy, rather than waiting to assess clinical response to alteplase. As a result, the time from stroke onset to the initiation of the endovascular procedure was a median of 50 minutes shorter than the similar interval in the MR CLEAN trial, which may also have contributed to the substantially higher proportion of patients with independent functional outcomes observed in our study. Only 11% of the patients in our study had no retrievable thrombus on initial angiography, which is consistent with results that have been reported previously25 and mitigates any concern regarding unnecessary angiography. As endovascular therapy becomes standard care, there is further potential to streamline the “door-to-puncture” process and perhaps achieve even greater clinical benefits.
The rate of successful revascularization immediately after the procedure (86% of patients had a restoration of flow to >50% of the stroke-affected territory) was higher in our study than in previous randomized trials but is consistent with registry studies in which the Solitaire FR stent retriever was used.5 This finding probably relates to the use of earlier-generation devices and techniques in the IMS-3 and the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trials. The reperfusion rate in our study was also higher than the 58% reported in MR CLEAN, in which stent retrievers were used in 81.5% of patients. There is some evidence that the success of recanalization is increased in patients with good collateral flow,26 which correlates strongly with the presence of a “mismatch” pattern on perfusion imaging between a small, irreversibly injured ischemic core and a larger perfusion lesion indicating the presence of salvageable ischemic penumbra.27 The imaging selection of patients may therefore have chosen patients with a better chance of recanalization.
Our study, which was conducted at multiple centers with varying levels of imaging expertise, shows the practicality and generalizability of fully automated image processing. The time that is required to acquire, process, and interpret images is largely a function of computer-network speed and processing power, and should be less than 15 minutes.12 Analysis of the CT perfusion images occurred in parallel with administration of alteplase so that there was no treatment delay.28
Strengths of our study include the selection of patients who were most likely to benefit from reperfusion, earlier intervention, and a standardized stent-retriever intervention with more complete revascularization. Also, the routine assessment of reperfusion at 24 hours has the advantage of being quantitative, blinded, and objective because of the automated software that was used. The 24-hour interval provides assurance that reocclusion after initial successful recanalization is uncommon in such patients. Previous studies have been restricted to assessing angiographic reperfusion rates in only the endovascular group or, in some cases, recanalization at 24 hours in a subgroup of patients.2
Limitations of the study include the inability to perform subgroup analyses, given the small number of patients. Such analyses will require individual patient meta-analysis of multiple trials. We cannot rule out the possibility that some of the patients who were excluded from the trial on the basis of a large ischemic core or absence of significant salvageable ischemic brain tissue might have benefited from endovascular therapy. Purely volume-based criteria do not account for the location of the core, which is also relevant to the clinical outcome.29 The early termination of the trial does create potential for overestimation of the effect size. However, the investigators believed that the new information from the MR CLEAN trial ethically mandated review by the independent data and safety monitoring board. The details of the statistical stopping rule were highly conservative and were agreed on between investigators and the data and safety monitoring board in advance of accessing the data.
In conclusion, we found that patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging had improved reperfusion, early neurologic recovery, and functional outcome if endovascular thrombectomy with the Solitaire FR stent retriever was performed without delay after the initiation of intravenous alteplase. Further studies will be needed to clarify remaining uncertainties regarding the benefit in patients with more distal occlusions, later time windows, and the influence of the type of device that is used and variability in the endovascular technique.
Funding and Disclosures
Supported by grants from the Australian National Health and Medical Research Council of Australia (1043242 and 1035688), Royal Australasian College of Physicians, Royal Melbourne Hospital Foundation, the National Heart Foundation of Australia, and the National Stroke Foundation of Australia; and by infrastructure funding from the state government of Victoria. The Solitaire FR device and trial infrastructure were provided under an unrestricted grant from Covidien.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on February 11, 2015, at NEJM.org.
We thank Gregory Albers, Roland Bammer, and staff members at the Stanford University Stroke Center for providing a research version of the RAPID software; Simon McBride, Christopher Stanbridge, and Karen Harrap of the Commonwealth Scientific and Industrial Research Organization for creating the electronic-case-record and Internet randomization; Gagan Sharma and Simon Salinas for imaging-data management; and Elise Cowley and Rachael McCoy of Neuroscience Trials Australia for study management.
The authors' affiliations are as follows: the Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital (B.C.V.C., N.Y., B.Y., T.J.O., T.Y.W., S.M.D.), Department of Radiology (P.J.M., R.J.D., P.M.D.), and Florey Institute of Neuroscience and Mental Health (L.C., T.J.O., H.M., G.A.D.), University of Melbourne, Parkville, VIC, Royal Adelaide Hospital, Adelaide, SA (T.J.K., R.S), Austin Health, Heidelberg, VIC (H.M.D., M. Brooks, M.A.S.), Priority Research Centre for Brain and Mental Health Research, John Hunter Hospital, University of Newcastle, Newcastle, NSW (M.W.P., F.M., C.R.L., T.A.), Department of Neurology, Royal North Shore Hospital and Kolling Institute, University of Sydney (M.K., M.P.), and Department of Radiology, Royal North Shore Hospital (F.M., T.J.H., K.C.F., B.S.S.), St. Leonards, NSW, Western Hospital, Footscray, VIC (T.W.), Monash Medical Centre, Monash University, Clayton, VIC (T.G.P., W.C., R.V.C., H.M.), Box Hill Hospital (C.F.B.), and Eastern Clinical School, Faculty of Medicine, Nursing and Health Sciences (H.M.D.), Monash University, Box Hill, VIC, and Gold Coast University Hospital, Southport, QLD (M. Badve, H.R., L.V.) — all in Australia; and Centre for Brain Research, University of Auckland, Auckland City Hospital (P.A.B.), and Auckland City Hospital (B.M.) — both in Auckland, New Zealand.
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- Table 1. Characteristics of the Patients at Baseline.
- Table 2. Characteristics of Endovascular Procedures.
- Table 3. Study Outcomes.
- Figure 1. Reperfusion and Functional Scores.
- Figure 2. Scores on the Modified Rankin Scale at 90 Days in the Intention-to-Treat Population.
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