Residual Vessel Length on Magnetic Resonance Angiography Identifies Poor Responders to Alteplase in Acute Middle Cerebral Artery Occlusion Patients
Exploratory Analysis of the Japan Alteplase Clinical Trial II
Background and Purpose—It remains unknown whether the effects of 0.6 mg/kg alteplase differ with occlusion site of the middle cerebral artery (MCA). We therefore evaluated the effects of 0.6 mg/kg intravenous alteplase in patients with different sites of MCA occlusion.
Methods—An exploratory analysis was made of 57 patients enrolled in the Japan Alteplase Clinical Trial II (J-ACT II), originally designed to evaluate 0.6 mg/kg alteplase in Japanese patients with unilateral occlusion of the MCA (M1 or M2 portion). The residual vessel length (in mm), determined by pretreatment magnetic resonance angiography, was used to reflect the occluded site. The proportions of patients with valid recanalization (modified Mori grade 2 to 3) at 6 and 24 hours and a modified Rankin Scale (mRS) score of 0 to 1 and of 0 to 2 at 3 months were compared between the groups dichotomized according to length of the residual vessel. Multiple logistic-regression models were generated to elucidate the predictors of valid recanalization, mRS 0 to 1, and mRS 0 to 2.
Results—Receiver operating characteristics analysis revealed that 5 mm was the practical cutoff length for dichotomization. In patients with an M1 length <5 mm (n=12), the frequencies of valid recanalization at 6 and 24 hours (16.7% and 25.0%) were significantly lower compared with those (62.1% and 82.8%, respectively) of the 45 patients with a residual M1 length ≥5 mm and an M2 occlusion (P=0.008 for 6 hours, P<0.001 for 24 hours). The proportions of patients who achieved an mRS of 0 to 1 and an mRS of 0 to 2 were also lower for those with an M1 length <5 mm (8.3% and 16.7%, respectively) compared with the other group (57.8% and 68.9%, respectively; P=0.003 for mRS 0 to 1, P=0.002 for mRS 0 to 2). In logistic-regression models, the site of MCA occlusion (<5 mm) was a significant predictor of valid recanalization at 6 and 24 hours and of an mRS of 0 to 1 and of mRS of 0 to 2.
Conclusions—In patients with acute MCA occlusion, a residual vessel length <5 mm on magnetic resonance angiography can identify poor responders to 0.6 mg/kg alteplase.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412867.
- acute ischemic stroke
- middle cerebral artery occlusion
- tissue plasminogen activator
- magnetic resonance angiography
Intravenous thrombolysis with recombinant tissue plasminogen activator is effective in carefully selected patients with acute ischemic stroke.1,2 Among patients treated with intravenous alteplase, stroke severity, systolic hypertension, early ischemic changes on computed tomography, persistent arterial occlusion, stroke subtype, and time to thrombolytic treatment have been repeatedly demonstrated as independent predictors of poor outcome.3–10 Furthermore, the Japan Alteplase Clinical Trial II (J-ACT II) clearly demonstrated that recanalization of the occluded artery represented the most powerful predictor of a favorable outcome at 3 months in selected patients with magnetic resonance angiography (MRA)–documented middle cerebral artery (MCA) occlusions.11 Information concerning early predictors of recanalization resistance may thus be useful for selecting patients to receive more aggressive reperfusion strategies.
Previous angiographic,12–14 transcranial Doppler,15 and MRA16–18 studies have demonstrated that more proximal occlusions, such as those of the internal carotid artery (ICA)14,17–20 or tandem ICA/MCA,21 carry a greater thrombus burden, whereas distal MCA occlusions are more likely to recanalize with systemic alteplase therapy. A meta-analysis revealed that recanalization, either spontaneous or related to thrombolytic or interventional therapies, is less likely with ICA occlusions.22 ICA occlusion has been shown to predict a poorer clinical outcome compared with MCA occlusion.14,17,19,20 However, little is yet known about the differences in recanalization rates and response to alteplase among patients with various sites of MCA occlusion. We therefore performed an exploratory analysis of patients with MCA occlusion enrolled in J-ACT II, giving special attention to the residual vessel length as documented on pretreatment MRA.
J-ACT II is a prospective, single-dose, open-label, multicenter, phase IV trial, originally designed to evaluate 0.6 mg/kg alteplase in Japanese patients with unilateral occlusion of the MCA. Details of the trial have been published previously.11 In brief, 58 patients with ischemic stroke within 3 hours of onset whose arterial occlusion was identified in the M1 or M2 segment on standardized MRA were enrolled. The results showed that the rates of early and delayed recanalization and a favorable outcome elicited by 0.6 mg/kg alteplase were comparable to the previously reported findings for the regular dose of 0.9 mg/kg.
Site of MCA Occlusion
All baseline MRA data were re-evaluated centrally by 2 reviewers, 1 expert neurologist, and 1 expert neuroradiologist (the image-reading panel), all of whom were blinded to all clinical information except the affected side. For patients with M1 occlusions, the site of occlusion was determined in an anteroposterior view on 3-dimensional time-of-flight MRA as the horizontal distance from the ICA bifurcation to the distal end of the flow signal. The residual vessel length (in mm) was used to reflect the occluded site in the patients with M1 occlusions (Figure 1).
Evaluation of Recanalization
MRA was repeated at baseline, 6 hours, and 24 hours after symptom onset. The time allowance for the 6-hour MRA was between the end of alteplase infusion and 8 hours from symptom onset, and that for the 24-hour MRA was between 24 and 36 hours after symptom onset.
Recanalization was evaluated centrally by the image-reading panel according to the modified Mori grade: grade 0, no reperfusion; grade 1, movement of thrombus not associated with any flow improvement; grade 2, partial (branch) recanalization in <50% of the branches in the occluded arterial territory; and grade 3, nearly complete recanalization with reperfusion in ≥50% of the branches in the occluded arterial territory.11 The recanalization rate was estimated by regarding grades 2 and 3 as valid recanalization, corresponding to Thrombolysis in Myocardial Infarction grades 2 and 3.
Functional outcome after 3 months was assessed by the modified Rankin Scale (mRS) score. Patients with an mRS of 0 to 1 at 3 months were regarded as having a favorable outcome. In addition, an mRS of 0 to 2 was judged to be indicative of functional independence, that is, avoiding death or dependency.
The proportions of patients with valid recanalization at 6 and 24 hours after symptom onset, a favorable outcome (mRS 0 to 1), and functional independence (mRS 0 to 2) at 3 months were compared between the groups dichotomized according to length of residual vessel on MRA. Receiver operating characteristics curves were constructed for the patients with M1 occlusions to make comparisons between vessel length and clinical outcome.
The predictors of valid recanalization at 6 and 24 hours, mRS 0 to 1, and mRS 0 to 2 were assessed by multiple logistic-regression analysis. Knowledge of disease-related factors before alteplase administration, such as time from onset, presence of hypertension, diabetes mellitus, baseline National Institutes of Health Stroke Scale score, and Alberta Stroke Program Early Computed Tomography Score (ASPECTS),6 as well as MCA occlusion site, was included in a stepwise regression analysis, for which age and sex were forcibly entered into the model to adjust for their possible confounding effects.
To examine the possible interaction of MCA occlusion site with recanalization for the 3-month outcome, the following recanalization patterns were evaluated with the logistic model in addition to the disease-related factors: (1) model 1, in which recanalization on 6-hour MRA was entered; (2) model 2, in which recanalization on 24-hour MRA was entered; and (3) model 3, in which recanalization within 6 hours and delayed recanalization (that is, arterial occlusion unchanged on 6-hour MRA but recanalized on 24-hour MRA) were entered. Significance was set at P<0.05 in all models. The odds ratio (OR) and 95% CIs were also determined. SAS 9.1.3 was used for statistical analyses.
Of the 58 patients enrolled in the trial, 41 (70.7%) were evaluated as having an M1 occlusion. Their residual M1 length ranged from 0.0 (origin) to 17.7 mm (distal end), whereas the contralateral M1 length ranged from 19.5 to 32.1 mm (mean±SD, 26.1±3.1 mm). One patient was judged to have no occluded artery on baseline MRA by the image-reading panel and was therefore excluded from the present analysis. The remaining 16 patients (27.6%) were evaluated as having an M2 occlusion. Further analyses were therefore performed on 57 patients with MCA occlusion. Table 1 summarizes these patients’ characteristics.
The cumulative frequency of valid recanalization at 6 and 24 hours increased as the residual M1 length increased. No patient had recanalization on 6-hour MRA that subsequently disappeared on 24-hour MRA. Receiver operating characteristics analysis revealed that valid recanalization differed between the groups dichotomized by residual vessel length at both 6 (Az 0.701, P=0.027) and 24 (Az 0.817, P=0.001) hours. The optimal cutoff residual M1 lengths for predicting valid recanalization at 6 and 24 hours were the same, 5.3 mm. When the patients with M1 occlusions were divided into 2 groups (residual vessel length <5 mm or ≥5 mm), the frequency of valid recanalization was significantly lower in the patients with a residual M1 length <5 mm (n=12) compared with the combined group with an M1 length ≥5 mm (n=29) and those with M2 occlusions (n=16) (P=0.008 for 6 hours, P<0.001 for 24 hours; Fisher’s exact test; Figure 2). In logistic-regression models, the site of MCA occlusion (<5 mm) was the only significant predictor of valid recanalization at both 6 (OR=0.076; 95% CI, 0.010 to 0.573) and 24 (OR=0.023; 95% CI, 0.002 to 0.245) hours.
Similarly, receiver operating characteristics analysis demonstrated that the proportions of patients with a favorable outcome (mRS 0 to 1) and functional independence (mRS 0 to 2) were also different among patients with M1 occlusions, with an optimal cutoff length of 5.3 mm. The distribution of scores on the 3-month mRS was different among patients with M1 lengths <5 mm compared with those with an M1 length ≥5 mm and M2 occlusions (Figure 3). On logistic-regression analysis including the disease-related factors present before alteplase administration, a residual M1 length <5 mm was the only significant predictor of a favorable outcome (OR=0.082; 95% CI, 0.008 to 0.812; Table 2). A residual M1 length <5 mm (OR=0.125; 95% CI, 0.020 to 0.793), together with a high ASPECTS value (OR=2.121; 95% CI, 1.082 to 4.158), was significantly related to functional independence at 3 months (Table 2).
Possible interactions between the pretreatment residual vessel length and patterns of recanalization were evaluated by multiple logistic-regression analysis (Table 3). Among the models for favorable outcome, recanalization in model 1, recanalization and baseline National Institutes of Health Stroke Scale score in model 2, and 6-hour and delayed recanalization in model 3 were significant predictors. Among the models for functional independence, recanalization and ASPECTS score in model 1, recanalization and ASPECTS score in model 2, and 6-hour recanalization and ASPECTS score in model 3 were significant predictors.
In the present exploratory analysis of the J-ACT II cohort, we found that a residual M1 length <5 mm on MRA was a negative predictor of early and delayed recanalizations as well as for a favorable outcome and functional independence at 3 months. Patients with residual M1 lengths <5 mm are poor responders to 0.6 mg/kg alteplase. The site of vessel occlusion was a strong predictor of outcome before systemic alteplase administration.
In a previous magnetic resonance imaging–based, open-label, nonrandomized study, the German Stroke Excellence Network Initiative,16 the reported recanalization rate of proximal MCA occlusions was comparable with distal MCA and M2 occlusions (76.7% for the proximal MCA, 60.0% for the distal MCA, and 87.5% for M2) in the 76 patients treated with thrombolysis. On the other hand, the difference in recanalization rate was significant between an MCA origin and other sites of MCA occlusion in our study. In addition to the different alteplase doses between Europe and Japan, the lack of a clear definition of “proximal” and “distal” MCA might have led to this discrepancy. In our study, cumulative analysis followed by receiver operating characteristics analysis demonstrated that <5 mm was the practical cutoff length between proximal and distal sites within the M1 portion.
Our results paralleled those of Saqqur et al,15 who examined the effects of alteplase by transcranial Doppler. They showed that patients with distal MCA occlusions were more likely to recanalize and were twice as likely to achieve an mRS of 0 to 1 than were those with proximal MCA occlusions. Their transcranial Doppler–based definitions of the occluded site in the MCA and of complete recanalization differed from ours, however. The proportions of patients achieving an mRS of 0 to 1 decreased with more proximal occlusions: distal MCA, 52%; proximal MCA, 25%; tandem ICA/MCA, 21%; and terminal ICA, 18%.
What are the potential reasons for different outcomes between patients with residual M1 lengths <5 mm and others? In terms of thrombus size and the association of thrombi with atherosclerosis, clot size is bigger in patients with a residual M1 length <5 mm, and there may be differences in clot composition between proximal and distal M1 occlusions.23 Fibrin-rich clots have been shown to display a greater propensity for lysis by alteplase compared with platelet-rich clots.10 Relative to other stroke subtypes, the rate of complete recanalization has been reported to be higher in patients with cardioembolic stroke.10 Although there was no statistical difference, atherosclerotic occlusion was found more frequently in patients with proximal M1 occlusions (16.7% in M1 <5 mm; 6.7% in M1 ≥5 mm and M2, P=0.281).
Another possible explanation concerns the number of perforating arteries originating from the M1 portion. Patients with a residual M1 length <5 mm seldom spare perforators that allow a continuous blood stream. Effective delivery and distribution of alteplase into the clot may thus become severely disturbed. Experimental studies have demonstrated that the fibrinolytic rate is dependent on the pressure gradient to which the clot is exposed.24
In our first logistic-regression model including only pretreatment factors, the site of vessel occlusion (M1 <5 mm or other) was a strong predictor of 3-month outcome. Once important posttreatment factors, like early and/or delayed recanalization, were included in the second of the 3 different models, the site of vessel occlusion no longer remained as significant. This is reasonable, because the site of vessel occlusion before treatment with alteplase was strongly correlated to posttreatment recanalization. To achieve an mRS of 0 to 1, the key is recanalization immediately after thrombolysis, as repeatedly reported.25–29 Using the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Register database, Kharitonova et al30 also noted that disappearance of a hyperdense MCA signs, an indirect marker of recanalization on computed tomography, was significantly related to functional independence and survival.
On the other hand, an mRS of 0 to 2 might be achieved independently of recanalization if the patient has good collateral flow, indicated by a high ASPECTS value.31 Regarding the influence of pretreatment ASPECTS, the Pro-Urokinase for Acute Cerebral Thromboembolism II trial demonstrated that patients with ASPECTS scores >7 were 3 times more likely to achieve an mRS of 0 to 2.32
It might be reasonable to modify our treatment strategy according to the MRA information concerning the site of pretreatment vessel occlusion. We speculate that patients with M1-origin occlusions (residual vessel length <5 mm) as well as those with ICA occlusions may be potential candidates for rescue interventional therapies, such as intra-arterial thrombolysis and mechanical thrombectomy, should intravenous thrombolysis fail to achieve recanalization and reperfusion.
The present study has several limitations. First, the number of patients was relatively small because the target population was strictly limited to MRA-documented M1 or M2 occlusions. Second, we could not evaluate collateral status because MRA was the only required modality for imaging. Good collateral flow up to the distal end of the clot might have accelerated recanalization.33 Third, the alteplase dose was 0.6 mg/kg, which is the specified dose in the Japanese license.34 The recanalization rate in patients with a residual M1 length <5 mm could have been improved with the 0.9 mg/kg dose of alteplase, although J-ACT II demonstrated efficacy in terms of vascular and clinical outcomes.11
In conclusion, the effect of 0.6 mg/kg intravenous alteplase differs according to the MRA-documented site of MCA occlusion. In patients with acute MCA occlusions, a residual M1 length <5 mm on MRA can identify poor responders to 0.6 mg/kg alteplase.
Sources of Funding
This clinical trial was supported by Kyowa Hakko Kirin Co, Ltd, and Mitsubishi Tanabe Pharma Corporation.
Teruyuki Hirano has received honoraria from Mitsubishi Tanabe Pharma and Kyowa Hakko Kirin. Makoto Sasaki has received honoraria from Mitsubishi Tanabe Pharma, Kyowa Hakko Kirin, and Lundbeck. Etsuro Mori has received a research grant, honoraria, and consulting fees from Mitsubishi Tanabe Pharma; honoraria and consulting fees from Kyowa Hakko Kirin; and consulting fees from Lundbeck. Kazuo Minematsu has received a research grant and honoraria from Mitsubishi Tanabe Pharma and honoraria from Kyowa Hakko Kirin and Lundbeck. Jyoji Nakagawara has received honoraria from Mitsubishi Tanabe Pharma, Kyowa Hakko Kirin, and Lundbeck. Takenori Yamaguchi has received consulting fees from Mitsubishi Tanabe Pharma and research grants from Kyowa Hakko Kirin and Lundbeck.
- Received June 22, 2010.
- Accepted September 7, 2010.
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