Significant differences were identified between treatment arms for 24-hour recanalization in proximal occlusions, with carotid T- and L-type and tandem internal carotid artery and M1 occlusions showing greater recanalization and a trend toward better outcome with endovascular treatment.
Abstract
Purpose
To use baseline computed tomographic (CT) angiography to analyze imaging and clinical end points in an Interventional Management of Stroke III cohort to identify patients who would benefit from endovascular stroke therapy.
Materials and Methods
The primary clinical end point was 90-day dichotomized modified Rankin Scale (mRS) score. Secondary end points were 90-day mRS score distribution and 24-hour recanalization. Prespecified subgroup was baseline proximal occlusions (internal carotid, M1, or basilar arteries). Exploratory analyses were subsets with any occlusion and specific sites of occlusion (two-sided α = .01).
Results
Of 656 subjects, 306 (47%) underwent baseline CT angiography or magnetic resonance angiography. Of 306, 282 (92%) had arterial occlusions. At baseline CT angiography, proximal occlusions (n = 220) demonstrated no difference in primary outcome (41.3% [62 of 150] endovascular vs 38% [27 of 70] intravenous [IV] tissue-plasminogen activator [tPA]; relative risk, 1.07 [99% confidence interval: 0.67, 1.70]; P = .70); however, 24-hour recanalization rate was higher for endovascular treatment (n = 167; 84.3% [97 of 115] endovascular vs 56% [29 of 52] IV tPA; P < .001). Exploratory subgroup analysis for any occlusion at baseline CT angiography did not demonstrate significant differences between endovascular and IV tPA arms for primary outcome (44.7% [85 of 190] vs 38% [35 of 92], P = .29), although ordinal shift analysis of full mRS distribution demonstrated a trend toward more favorable outcome (P = .011). Carotid T- or L-type occlusion (terminal internal carotid artery [ICA] with M1 middle cerebral artery and/or A1 anterior cerebral artery involvement) or tandem (extracranial or intracranial) ICA and M1 occlusion subgroup also showed a trend favoring endovascular treatment over IV tPA alone for primary outcome (26% [12 of 46] vs 4% [one of 23], P = .047).
Conclusion
Significant differences were identified between treatment arms for 24-hour recanalization in proximal occlusions; carotid T- or L-type and tandem ICA and M1 occlusions showed greater recanalization and a trend toward better outcome with endovascular treatment. Vascular imaging should be mandated in future endovascular trials to identify such occlusions.
© RSNA, 2014
Introduction
In the Interventional Management of Stroke (IMS) III trial, the approach of combining intravenous (IV) tissue-plasminogen activator (tPA) with endovascular therapies was tested in an attempt to improve revascularization and clinical outcomes compared with IV tPA alone in the setting of moderate to severe acute ischemic stroke. The overall results were neutral, with no significant improvement in clinical outcome with the endovascular approach added to IV tPA compared with IV tPA alone (1). Vascular imaging was not mandated for trial enrollment but was performed at a number of centers routinely as part of standard clinical care. Subjects with lower baseline National Institutes of Health Stroke Scale (NIHSS) scores (scores 8–9) were also eligible for the trial if a proximal occlusion was identified at baseline vascular imaging after protocol amendment 3 was implemented in January 2009. At centers where baseline computed tomographic (CT) angiography was performed routinely, the absence of a visible intracranial occlusion served as an exclusion from eligibility after amendment 5 was enacted in June 2011.
The subgroup of IMS III subjects for whom baseline CT angiography or magnetic resonance (MR) angiography was performed may provide valuable insight into which subgroups of patients with moderate or severe acute ischemic stroke may benefit from endovascular therapy versus IV tPA alone. The trial mandated follow-up (24-hour) CT angiography or MR angiography to evaluate recanalization rates for all subjects in both treatment arms. We present analyses to evaluate this baseline (pre–IV tPA) CT angiography and MR angiography information within the IMS III trial as a predictor of both the imaging end point of 24-hour recanalization and 90-day modified Rankin Scale (mRS) score for the two treatment groups.
Materials and Methods
The study was funded by the National Institutes of Health and the National Institute of Neurologic Diseases and Stroke (grant numbers UC U01NS052220, MUSC U01NS054630, and U01NS077304). Genentech supplied the drug used for intraarterial tPA in the endovascular group. EKOS, Concentric, and Cordis Neurovascular supplied the study catheters during the period when amendments 1–3 were in effect. In Europe, IMS III investigator meeting support was provided in part by Boehringer Ingelheim.
Patients and Procedures
Patient eligibility criteria and IMS III trial methods have been detailed previously (1,2). Subjects were recruited from August 25, 2005, to April 17, 2012. The identification of a proximal arterial occlusive lesion was centrally adjudicated by the CT Imaging Analysis Centre at the University of Calgary (the central core laboratory). Each CT angiography or MR angiography study was interpreted by a consensus panel of two readers (stroke neurologists A.M.D. and M.D.H. and neuroradiologist M.G., each with at least 10 years of stroke imaging experience) at each session. Guidance for 24-hour CT angiography imaging parameters was provided (see Appendix E1 [online]), but specific CT angiography or MR angiography protocols were not mandated. Each segment of the extracranial and intracranial arterial vasculature was assessed for the presence of contrast material within the lumen and was graded for any stenosis or occlusion. The grading of segments for stenosis and occlusion and occlusion site locations are described in Appendix E1 (online). Recanalization according to specific site of occlusion by comparing the baseline and follow-up CT angiography and MR angiography findings is defined in Appendix E1 (online).
The primary clinical end point was a functionally independent outcome as manifested by mRS score of 0–2 at 90 days. One of the secondary clinical end points was 90-day mRS score distribution. Recanalization was measured in those who demonstrated intracranial occlusion at baseline CT angiography and/or MR angiography. Successful recanalization was defined as grade 3–5 flow in previously occluded (grade 1–2) segments of symptomatic intracranial arteries at 24-hour CT angiography and/or MR angiography. Subjects without 24-hour CT angiography and/or MR angiography data were excluded from further recanalization analysis. The primary safety outcomes were mortality within 90 days and symptomatic intracerebral hemorrhage (SICH), defined as an intracranial hemorrhage temporally related to a decline in neurologic status, as well as new or worsening neurologic symptoms in the judgment of the clinical investigator that may warrant medical intervention within 30 hours of IV tPA initiation.
Statistical Analysis
The analysis of mRS scores 0–2 among subjects with internal carotid artery (ICA), M1, or basilar arterial occlusions was prespecified (1). Subjects with 90-day outcome missing or collected outside the prespecified window were assigned an mRS score higher than 2. Other subgroup analyses, according to presence or absence of any occlusion or various specific occlusion locations, were considered exploratory. Within each subgroup, treatment arms were compared with respect to both effectiveness (clinical and recanalization) and safety end points. The χ2 test, or Fisher exact test in the case of small cell counts, was used to compare the treatment arms with respect to binary end points. The effect of treatment on recanalization was further described via risk difference and corresponding 95% confidence intervals, derived according to the Newcombe score. The distribution of ordinal mRS scores was analyzed by using the generalized Wilcoxon test; subjects with mRS score missing or obtained outside of the prespecified window were excluded from this analysis, and mRS scores 5 and 6 were combined into one category.
For the specific sites of occlusion, baseline differences between treatment arms were tested (and considered significant if P was less than .01) for the following variables: age; sex; baseline NIHSS score; baseline Alberta Stroke Program Early CT Score, or ASPECTS; atrial fibrillation (according to electrocardiography findings or medical history); time from onset to IV tPA treatment time; and baseline glucose level. Given the exploratory nature of the various analyses described that were not prespecified for the different occlusion sites, as well as the number of analyses anticipated, significance required a P value less than .01 to minimize false-positive results that arose from multiple hypothesis testing.
Results
Of the 656 subjects enrolled in the IMS III trial, 306 (47%) underwent baseline vascular imaging, including 292 CT angiography examinations and 14 MR angiography examinations. Heretofore, subjects who underwent either baseline CT angiography or MR angiography are referred to as subjects who underwent baseline CT angiography. In 78% (45 of 58) of enrollment centers in the trial, at least one subject underwent baseline CT angiography. Of the 282 subjects with any occlusion at baseline CT angiography, 66 had no 24-hour CT angiography or MR angiography data, of whom nine died within 31 hours. The remaining 216 subjects had both baseline and 24-hour vascular imaging data that were used for analysis of 24-hour recanalization.
Baseline CT Angiography versus No Baseline CT Angiography
The baseline demographics of subjects with baseline CT angiography data versus those without are shown in Table 1. Significantly (P < .01) less hyperlipidemia and shorter times from IV tPA bolus to groin puncture time and from groin puncture to start of endovascular therapy were observed in the CT angiography group. This could be explained by the high rate of direct to comprehensive stroke center enrollment in the baseline CT angiography population (95%) compared with only 77% in those where baseline CT angiography was not performed.
Table 1.
Baseline Characteristics: Baseline CT Angiography versus No Baseline CT Angiography Performed
Note.—Unless specified otherwise, numbers in parentheses are percentages. ASPECTS = Alberta Stroke Program Early CT Score.
Numbers in parentheses are ranges.
Data are mean ± standard deviation.
Differences were considered significant at the P < .01 level.
Among direct to comprehensive stroke center subjects, no differences were seen in the time from IV tPA bolus to groin puncture (P = .08); however, time from groin puncture to start of intraarterial therapy was still shorter in the CT angiography group (P = .002). Subjects who underwent CT angiography were more likely to have a favorable clinical outcome (mRS score of 0–2) versus those who did not (45.4% [139 of 306] vs 35.4% [124 of 350], P = .009). Related to safety, the mean baseline creatinine level was similar in both the baseline CT angiography and no CT angiography subgroups (92.4 μmol/L ± 29.9 and 94.4 μmol/L ± 34.3, respectively) and was not different on day 5 (or at discharge) (77.1 μmol/L ± 29.2 and 79.4 μmol/L ± 47.8, respectively). In the IV tPA treatment arm, no differences in favorable clinical outcome were observed in the study sample that underwent baseline CT angiography versus those that did not (39% [37 of 95] versus 38.6% [49 of 127], P = .956).
Baseline CT angiography demonstrated an occlusion in 282 of 306 subjects (92.2%). The occlusion sites were distributed as follows: two isolated extracranial ICA occlusions, four intracranial ICA occlusions only, 58 ICA T- or L-type occlusions, 11 tandem ICA and M1 occlusions, 60 proximal M1 occlusions without ICA involvement, 79 distal M1 occlusions without ICA involvement, 54 M2 occlusions with or without ICA involvement; five M3 and M4 occlusions, five basilar artery (with or without vertebral artery) occlusions, and four posterior cerebral artery occlusions.
Baseline CT Angiography Subgroups
The only prespecified baseline CT angiography analysis was a comparison of treatment arms in the subset of subjects with proximal occlusions (ICA, M1, or basilar arteries; n = 220) with regard to 90-day mRS score of 0–2 and 24-hour recanalization. No difference in the primary outcome was seen (41.3% [62 of 150] endovascular vs 38% [27 of 70] IV tPA; relative risk, 1.07 [99% confidence interval: 0.67, 1.70]). Figure 1 illustrates the 90-day mRS distribution of the two treatments for this prespecified subgroup (generalized Wilcoxon test, P = .11); eight subjects were excluded from this analysis because outcome data were missing or were obtained outside the 90-day assessment window. The rate of recanalization at 24 hours was better with endovascular therapy (84.3% [97 of 115] endovascular versus 56% [29 of 52] IV tPA, P < .001).
Figure 1:
Diagram shows prespecified baseline CT angiography distribution of proximal occlusions (ICA, M1, basilar artery). The mRS distribution was not significantly different (generalized Wilcoxon test, P = .1068).
Subsequent analyses were all performed post hoc. The baseline CT angiography population was divided into subjects with no baseline occlusion and those with a baseline occlusion for subsequent analyses. Among subjects with no occlusion, a 90-day mRS score of 0–2 occurred in 81% (17 of 21) in the endovascular arm versus 67% (two of three) in the IV tPA arm (P = .52). Only one of 89 subjects (1%) with baseline NIHSS score of at least 20 had no visible occlusion, and 23 of 217 subjects (10.6%) with baseline NIHSS score of 8–19 had no visible occlusion. Within the endovascular arm, there were three of 20 subjects without visible occlusion at CT angiography that had evidence of intracranial occlusion at conventional angiography (M2 middle cerebral artery in two subjects and M3 middle cerebral artery in one subject). Median 24-hour infarct volume was 0.3 mL (interquartile range, 0–5.0 mL) in this group, and 10 of 23 subjects with follow-up CT data had no visible infarct.
The baseline CT angiography occlusion subgroup includes all sites of occlusion detected. Baseline demographics were all similar in the two treatment arms (Table 2). The baseline CT angiography occlusion subgroup did not demonstrate significant differences between the endovascular and IV tPA (alone) arms for the primary effectiveness outcome (44.7% [85 of 190] vs 38% [35 of 92], P = .29) and safety end points (SICH, 7.9% [15 of 190] vs 6% [six of 92], P = .68; 90-day mortality, 14.7% [28 of 190] vs 26% [24 of 92], P = .021). The full mRS distribution is shown in Figure 2, with a direction of treatment effect favoring endovascular therapy (P = .011). This excludes eleven subjects without mRS information (missing or obtained outside the assessment window).
Table 2.
Baseline Characteristics: Population with Baseline Occlusions in the Two Treatment Arms
Note.—Unless specified otherwise, numbers in parentheses are percentages. ASPECTS = Alberta Stroke Program Early CT Score.
Numbers in parentheses are ranges.
Data are mean ± standard deviation.
Figure 2:
Diagram shows post hoc baseline CT angiography distribution of any visible occlusions. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .011).
Individual sites of occlusion were subdivided in an exploratory fashion to identify any potentially unique differences in clinical outcomes between treatment arms. The 24-hour recanalization rates according to specific site of occlusion are reported in Table 3.
Table 3.
24-Hour Recanalization Rates in Each Treatment Arm according to CT Angiography–based Site of Occlusion
Note.—Numbers in parentheses are 95% confidence intervals. NA = not applicable.
Two subjects with isolated extracranial ICA occlusions were excluded.
The carotid T- and L-type occlusions were combined with tandem ICA and M1 occlusions, as these occlusions represent the largest thrombus volumes. No significant baseline imbalances between treatment arms were present. In this subgroup, the direction of treatment effect was in favor of endovascular treatment compared with IV tPA alone for the primary effectiveness end point (26% [12 of 46] vs 4% [one of 23], P = .047). The safety end points (SICH, 11% [five of 46] vs 13% [three of 23], P > .99; 90-day mortality, 37% [17 of 46] vs 48% [11 of 23], P = .39) were not significantly different. The full mRS distribution is shown in Figure 3a, with a direction of treatment effect favoring endovascular therapy (P = .02).
Figure 3a:
Diagrams show distribution of findings at baseline CT angiography. (a) Carotid T- or L-type occlusions or tandem ICA and M1 occlusions. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .02). (b) Proximal M1 occlusions without ICA involvement. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .93). (c) Distal M1 occlusions without ICA involvement. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .48). (d) M2 occlusion with or without ICA involvement. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .14).
The proximal M1 involvement (but no ICA occlusion) subgroup showed no treatment effect between the endovascular (n = 41) and IV tPA (alone) (n = 19) arms for both primary effectiveness (46% [19 of 41] vs 42% [eight of 19], P = .76) and safety end points (SICH, 7% [three of 41] vs 5% [one of 19], P > .99; 90-day mortality, 17% [seven of 41] vs 16% [three of 19], P > .99). Analysis of the full mRS distribution (Fig 3b) was not significant (P = .93).
Figure 3b:
Diagrams show distribution of findings at baseline CT angiography. (a) Carotid T- or L-type occlusions or tandem ICA and M1 occlusions. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .02). (b) Proximal M1 occlusions without ICA involvement. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .93). (c) Distal M1 occlusions without ICA involvement. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .48). (d) M2 occlusion with or without ICA involvement. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .14).
The distal M1 involvement (but no ICA occlusion) subgroup showed no treatment effect between endovascular and IV tPA (alone) arms for both the primary effectiveness (50% [27 of 54] vs 64% [16 of 25], P = .25) and the safety end points (SICH, 7% [four of 54] vs 0% [zero of 25], P = .30; 90-day mortality, 2% [one of 54] vs 12% [three of 25], P = .09). Analysis of the full mRS distribution (Fig 3c) was also not significant (P = .47).
Figure 3c:
Diagrams show distribution of findings at baseline CT angiography. (a) Carotid T- or L-type occlusions or tandem ICA and M1 occlusions. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .02). (b) Proximal M1 occlusions without ICA involvement. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .93). (c) Distal M1 occlusions without ICA involvement. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .48). (d) M2 occlusion with or without ICA involvement. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .14).
The M2 segment with or without ICA occlusion subgroup showed no treatment effect between the endovascular and IV tPA (alone) arms for both the primary effectiveness (50% [18 of 36] vs 44% [eight of 18], P = .70) and SICH end point (6% [two of 36] vs 11% [two of 18], P = .59). A trend in favor of endovascular treatment was seen for 90-day mortality (6% [two of 36] vs 33% [six of 18], P = .012). The analysis of the full mRS distribution (Fig 3d) was not significant (P = .14).
Figure 3d:
Diagrams show distribution of findings at baseline CT angiography. (a) Carotid T- or L-type occlusions or tandem ICA and M1 occlusions. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .02). (b) Proximal M1 occlusions without ICA involvement. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .93). (c) Distal M1 occlusions without ICA involvement. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .48). (d) M2 occlusion with or without ICA involvement. The mRS distribution was not significantly different (generalized Wilcoxon test, P = .14).
There were too few subjects in the subgroup with M3 and M4 involvement or anterior cerebral artery involvement with or without ICA occlusion (n = 5) and the subgroup with posterior circulation (basilar artery alone, vertebral artery and basilar artery, posterior cerebral artery) occlusion (n = 9) to make useful comparisons.
Discussion
This baseline CT angiography subgroup of the IMS III trial represents a large cohort of randomized subjects with prerandomization vascular imaging information. Few randomized acute stroke trials have served to capture baseline vascular imaging with standardized follow-up imaging, and none have involved comparison of IV tPA and IV tPA followed by endovascular therapy. This current analysis demonstrated no differences in the primary outcome measure for the prespecified subgroup of subjects with the proximal occlusion subgroup of ICA, M1, and basilar arteries as identified with baseline vascular imaging. However, in a post hoc analysis of the entire baseline CT angiography subgroup with an intracranial occlusion, a trend toward better outcomes with endovascular treatment versus IV tPA alone was observed. This effect was largely driven by the subpopulation of occlusions that involved the ICA (carotid T- and L-type or tandem ICA and M1 occlusions). In the subgroup of the trial with both baseline and 24-hour CT angiography information available, recanalization at 24 hours was significantly more frequent in the endovascular arm than the IV tPA arm. This difference was also most evident in subjects with ICA occlusions where a low rate of 24-hour recanalization was seen with IV tPA alone. The large differential recanalization and clinical treatment effects with endovascular treatment in tandem ICA and M1 occlusions or terminal ICA occlusions is the most important finding and implies that in future clinical trials, investigators should pay particular attention to this subgroup and perhaps even stratify enrollment on the basis of the presence of a carotid T- or L-type or tandem ICA and M1 occlusion (3).
Another important finding of this analysis was the safety (4) of baseline vascular imaging in reperfusion treatment trials of IV tPA versus combined therapy. No differences in clinical outcome were seen in the trial subgroup that received IV tPA alone and underwent CT angiography versus those that did not, suggesting no evidence for impaired thrombolytic effect of radiographic contrast material on tPA activity as postulated in the cardiac literature (5,6). Contrast material–induced nephropathy was not prominent, and no differences in creatinine levels were seen on day 5 or in discharge rates between those that underwent baseline CT angiography and those that did not.
A wide variability in the rate of recanalization and clinical outcome with IV tPA administration according to the specific site of occlusion has been reported previously in nonrandomized cohort studies (7–13). The IV tPA 1–2-hour recanalization rates for intracranial ICA occlusion have been reported as being very low (4%–8%) (7,10) with correspondingly low rates of 90-day good outcome (0%–29%) (3,12–15). Rates of recanalization for intracranial ICA occlusions exceed 50% after endovascular treatment (16). Good clinical outcome with endovascular treatment in ICA occlusions ranges from 10% to 56%. Cervical ICA occlusions are associated with better outcomes than terminal ICA occlusions (15). Isolated M1 occlusions fare much better with systemic thrombolysis alone, with 1–2-hour recanalization rates of 26%–32% (7,10) and good outcome in the 24%–67% range, depending on exact origin of occlusion within the M1 segment (13). Endovascular treatment has been associated with high rates of good clinical outcome in M1 occlusions (17,18). The differential effects of endovascular treatment according to the presence and site of occlusion are consistent with prior trials, such as the Echoplanar Imaging Thrombolytic Evaluation Trial, or EPITHET, where the ICA occlusion population had very poor outcomes despite undergoing IV tPA treatment (3). This analysis provides compelling data, from a randomized trial, that a treatment effect in favor of endovascular treatment over standard IV tPA may exist for ICA occlusions. The planned third International Stroke Trial, or IST-3, analysis of prerandomization vascular imaging data to compare IV tPA with placebo will provide an interesting set of data to compare with those in the IMS III (19).
On the basis of prior literature, the two unexpected results of the study were the high rates of good outcome with IV tPA alone in M1 occlusions and the lack of relationship between higher 24-hour recanalization and better rates of good outcome. Twenty-four–hour recanalization rates of M1 occlusions were similar and were high in the two treatment arms. Distal M1 occlusions did particularly well with IV tPA treatment alone, perhaps owing to smaller clot length. Very early treatment and larger sample sizes are likely to be required in future trials when comparing newer endovascular technologies (ie, stentrievers or aspiration) to IV tPA alone in M1 occlusions. The proximal occlusion subgroup had a 25% higher rate of 24-hour recanalization with endovascular therapy, but this translated into only a 3% higher rate of favorable clinical outcome. Patient selection (20,21), use of general anesthesia (22), endovascular treatment delays (23), extent of reperfusion despite recanalization (24), and endovascular treatment-related adverse events are possible explanations that require further study. The 24-hour recanalization end point may also be too late and have less effect on clinical outcome than an early (1–2-hour posttreatment) recanalization or reperfusion end point.
This analysis of baseline CT angiography and recanalization has limitations. Only 47% of all enrolled subjects in the IMS III trial underwent baseline vascular imaging. Baseline CT angiography was performed in at least one subject at 78% of all enrollment sites in the trial. Although this subgroup may not fully represent the entire IMS III population, baseline characteristics were similar to those of the population who did not undergo baseline CT angiography, with the exception of shorter time to endovascular treatment. This reflects a bias that centers where baseline CT angiography is performed follow a direct to comprehensive stroke center model in which patients are transported directly to a hospital where they may undergo endovascular treatment. Pertaining to the 24-hour recanalization end point, some subjects did not undergo repeat CT angiography, potentially creating a bias toward those with higher recanalization rates and better outcomes among those well enough to undergo repeat imaging. Another limitation is the use of a nonstandardized assessment of CT angiography recanalization; no CT angiography–based recanalization scales have been published to date. We focused specifically on the proximal intracranial arterial occlusive lesion and not downstream lesions, which may have led to the overestimation of the degree of recanalization overall. We also cannot comment on tissue-based reperfusion because single-phase CT angiography is limited to a snapshot in time in the arterial or early venous phase of imaging. This is best accomplished with conventional angiography, time-resolved and/or multiphase CT angiography, or CT perfusion imaging.
We conclude from this analysis that no clear differences in outcome were identified in the population with proximal occlusion in the IMS III trial. A post hoc analysis of carotid T- or L-type occlusions and tandem ICA and M1 occlusions showed greater recanalization and a trend toward better outcomes with endovascular treatment compared with IV tPA alone. A pooled analysis of recently completed and current endovascular trials is needed to confirm this encouraging finding in favor of endovascular treatment. Future comparisons of endovascular and thrombolytic treatment with thrombolytic treatment alone should include baseline vascular imaging in trial design, given the safety of CT angiography and wide differences in clinical effects and recanalization according to occlusion site seen in the IMS III trial. In such trials, investigators could then stratify enrollment on the basis of the presence of a carotid T- or L-type occlusion or a tandem ICA and M1 occlusion.
Advances in Knowledge
■ In the prespecified analysis of subjects with proximal occlusion observed at baseline CT angiography, combined intravenous (IV) tissue-plasminogen activator (tPA) and endovascular treatment has higher 24-hour recanalization rates (84.3%) compared with standard IV tPA (56%) as identified with CT angiography and MR angiography (P < .0001).
■ Terminal and tandem occlusions of the internal carotid artery (ICA) and M1 segment showed greater recanalization (83.3% vs 27.8%, P = .0001) and a trend toward better outcomes (26% vs 4%, P = .047) with endovascular treatment as compared with IV tPA alone in post hoc analysis.
■ Future endovascular and/or thrombolytic trial design should include baseline vascular imaging and focus on enrollment of patients with evidence of intracranial occlusion, particularly involving the ICA, given the wide differences in clinical effects and recanalization according to occlusion sites seen in the Interventional Management of Stroke III study.
Implications for Patient Care
■ Recanalization rates at 24 hours are higher for endovascular treatment compared with standard IV tPA.
■ Subjects with a large thrombus burden identified at CT angiography, involving the extracranial or intracranial ICA and M1 middle cerebral artery, are unlikely to achieve good outcomes with standard IV tPA.
APPENDIX
Acknowledgments
Acknowledgments
Genentech supplied the drug used for intraarterial tPA in the endovascular group. EKOS Concentric and Cordis Neurovascular supplied study catheters during the period when amendments 1–3 were in effect. In Europe, IMS III investigator meeting support was provided in part by Boehringer Ingelheim.
Received November 25, 2013; revision requested December 23; revision received March 17, 2014; accepted March 25; final version accepted April 11.
Funding: This research was supported by the National Institutes of Health (grants UC U01NS052220, MUSC U01NS054630, and U01NS077304).
Disclosures of Conflicts of Interest: A.M.D. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: institution has grant funding from Covidien for the ESCAPE trial, and author received payment from Covidien for lecturing. Other relationships: none to disclose. M.G. Financial activities related to the present article: institution received grant money for partial support of the ESCAPE trial. Financial activities not related to the present article: author received consulting fees or honorariums from Covidien and has stock and/or stock options in NONO and Calgary Scientific. Other relationships: none to disclose. S.D.Y. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: author received payment from Genentech for a consultancy. Other relationships: none to disclose. J.C. No relevant conflicts of interest to disclose. L.D.F. No relevant conflicts of interest to disclose. E.Q. No relevant conflicts of interest to disclose. M.D.H. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: author received payment for consultancies with Vernalis Group and Merck and payment for lectures from Hoffmann–La Roche Canada, Servier Canada, and BMS Canada; institution has grants or grants pending with Hoffmann–La Roche Canada and Covidien; author has stock and/or stock options in Calgary Scientific. Other relationships: none to disclose. T.G.J. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: author received payment for a consultancy with Silk Road; author has stock and/or stock options in Silk Road. Other relationships: none to disclose. M.R. No relevant conflicts of interest to disclose. B.Y. No relevant conflicts of interest to disclose. O.O.Z. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: author received payment from Covidien, Stryker, Penumbra, and Codman for consultancies and speaking. Other relationships: none to disclose. D.F. No relevant conflicts of interest to disclose. R.v.K. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: author received payment for consultancies with Lundbeck, Penumbra, Covidien, and Synarc. Other relationships: none to disclose. K.C. Financial activities related to the present article: author received payment from Covidien Neurovascular for consulting and proctoring. Financial activities not related to the present article: author received payment from Actuated Medical for consulting. Other relationships: none to disclose. P.K. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: institution has a grant or grant pending with Penumbra and Genentech. Other relationships: none to disclose. D.S.L. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: institution received payment for consultancies with Stryker and Covidien. Other relationships: none to disclose. T.A.T. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: author received a grant from Covidien. Other relationships: none to disclose. Y.Y.P. No relevant conflicts of interest to disclose. J.P.B. Financial activities related to the present article: Genentech provided the drug for the IMS III; EKOS and Concentric provided the catheters for the IMS III. Financial activities not related to the present article: Genentech provided the drug for the CLEARER trial; author received consulting fees from Pfizer and payment from Boehringer Ingelheim for meeting attendance and travel expenses. Other relationships: none to disclose.
Abbreviations:
- ICA
- internal carotid artery
- IMS
- Interventional Management of Stroke
- IV
- intravenous
- mRS
- modified Rankin Scale
- NIHSS
- National Institutes of Health Stroke Scale
- SICH
- symptomatic intracerebral hemorrhage
- tPA
- tissue-plasminogen activator
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