doi: 10.1161/hs1201.99821
(Stroke. 2001;32:2821.)
© 2001 American Heart Association, Inc.
Original Contributions |
Time Course of Tissue Plasminogen Activator–Induced Recanalization in Acute Cardioembolic Stroke
A Case-Control Study
From the Cerebrovascular Unit, Departments of Neurology (C.A.M., J.M., S.A., J.F.A., M.R., R.H., J.A.-S.) and Neuroradiology (F.R.), Hospital Vall d‘Hebrón, Barcelona, Spain.
Correspondence to Carlos A. Molina, MD, Cerebrovascular Unit, Department of Neurology, Hospital Vall d’Hebron, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain. E-mail carmolcate{at}demasiado.com
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose— The relationship between arterial recanalization, infarct size, and outcome in patients treated with intravenous thrombolytics remains unclear. Therefore, we aimed to determine the time course of recombinant tissue plasminogen activator (rtPA)-induced recanalization in patients with cardioembolic stroke treated <3 hours from symptom onset and to investigate the relationship between arterial recanalization, infarct volume, and outcome.
Methods— We prospectively studied 72 patients with an acute cardioembolic stroke in the middle cerebral artery territory: 24 treated with rtPA at <3 hours and 48 matched controls. Serial transcranial Doppler examinations were performed on admission and at 6,12, 24, and 48 hours. Infarct volume was measured by use of CT at day 5 to 7. Modified Rankin Scale score was used to assess outcome at 3 months.
Results— Rate of 6-hour recanalization was higher (P<0.001) in the rtPA group (66%) than in the control group (15%). Five (20.8%) rtPA patients and 15 (31.2%) controls recanalized between 6 and 12 hours, and 2 (8.3%) patients and 12 (25%) controls between 12 and 48 hours, respectively. At 48 hours, 75% of rtPA patients and 27% of controls had improved (P<0.001). Infarct volume was 50.2±40.3 cm3 in rtPA patients and 124.8±81.6 cm3 in controls (P<0.001). Moreover, infarct volume was associated strongly (P<0.001) with duration of middle cerebral artery occlusion. At 3 months, 14 (58%) rtPA patients and 11 (23%) controls (P=0.037) became functionally independent (modified Rankin Scale score 
2). A close relationship (P=0.002) existed between modified Rankin Scale score at 3 months and time to reperfusion. In addition, clinical outcome was associated strongly (P=0.001) with degree of 6-hour recanalization. Logistic regression analysis identified National Institutes of Health Stroke Scale score <17 (odds ratio 12.1, 95% confidence interval 2.8 to 68, P=0.001) and early recanalization (odds ratio 23.4, 95% confidence interval 5.4 to 96, P=0.001) as independent predictors of functional independence at 3 months.
Conclusions— Intravenous rtPA is associated with early recanalization, which leads to lower infarct size and better clinical outcome. Early recanalization is a powerful independent predictor of functional independence at 3 months.
Key Words: cardioembolic stroke • reperfusion • thrombolysis • ultrasonography
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The rationale for thrombolysis for acute ischemic stroke is recanalization of occluded arteries to reestablish brain function by saving tissue at risk. The National Institutes of Neurological Disorders (NINDS) trial1 clearly demonstrated a beneficial effect of intravenous recombinant tissue plasminogen activator (rtPA) when given <3 hours after symptom onset. However, the NINDS trial, like other clinical trials of intravenous thrombolysis,2–6 did not monitor presence and location of arterial occlusion and recanalization at different times after stroke.
Effects of thrombolytic therapy may vary among different stroke subtypes in accordance with pathophysiological mechanism. Response to fibrinolysis may depend on location of arterial occlusion, clot characteristics, and, ultimately, embolic source. Cardioembolic stroke probably represents the stroke subtype that better resembles animal models of cerebral ischemia. In animal models of thromboembolic stroke, administration of rtPA has been shown to be closely associated with early recanalization, reduced infarct volume, and mortality.7–9
Rapid identification of stroke patients who will obtain more benefit from thrombolysis is a crucial goal. Criticism of the widespread use of rtPA is based on the lack of vascular imaging in the standard emergent evaluation of acute stroke.10 Rational selection of ideal candidates for thrombolytic therapy requires rapid detection of arterial occlusion. Transcranial Doppler (TCD) is the ideal noninvasive, real-time bedside tool for evaluation of cerebral vessels. TCD has proved reliable for assessment of recanalization in acute stroke, particularly in the setting of thrombolysis.11–14 Prior uncontrolled TCD studies13,14 monitored recanalization during the first few hours after rtPA administration. However, data on systematic assessment of rtPA-induced recanalization at different times after stroke are lacking. In addition, the relationship between arterial recanalization, infarct volume, and outcome in patients receiving intravenous rtPA remains unclear. Therefore, the aim of the present study was to determine timing of rtPA-induced recanalization in patients with acute cardioembolic stroke treated <3 hours of stroke onset and to investigate the relationship between arterial recanalization, infarct volume, and clinical outcome by use of a case-control approach.
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Subjects and Methods |
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Our target group consisted of patients who had had an acute ischemic stroke admitted within the first 3 hours after symptom onset. Stroke onset was defined as the last time the patient was known to be without any neurological deficit. A total of 146 consecutive patients were evaluated between March 2000 and April 2001. Of these, 138 (94.5%) underwent urgent carotid ultrasonography and TCD examinations. A total of 98 (66%) patients had a nonlacunar stroke that involved the vascular territory of the middle cerebral artery (MCA). Of these, 34 (23.2%) received rtPA in a standard 0.9-mg/kg dose (10% bolus, 90% continuous infusion during 1 hour) at <3 hours after symptom onset. We chose patients who were considered to have had a cardioembolic stroke: 19 (61.2%) had atrial fibrillation on admission, 3 had had a recent myocardial infarction, 2 had dilated myocardiopathy, and 2 had an atrioseptal aneurysm. We excluded 2 patients who had an inadequate temporal bone window. We included in the study 24 patients who had had an acute cardioembolic stroke in the MCA territory who received rtPA at <3 hours after symptom onset.
A control group was selected from consecutive patients with acute ischemic stroke admitted <3 hours after symptom onset who were evaluated before local approval of rtPA for treatment of acute stroke between September 1998 and February 2000. Most of these patients participated in a previous study aimed to determine the timing of spontaneous recanalization.15 Of 184 patients, 108 had atrial fibrillation and nonlacunar stroke in the MCA territory. Of these 108, 48 control subjects were chosen who were matched for age (±2 years), sex, and National Institutes of Health Scale (NIHSS) score (±1 point) on admission with patients who received rtPA. A statistician who was blinded to the TCD, CT, and outcome data conducted matching.
On arrival in the emergency room and before enrollment in the study, patients underwent standard neurological and cardiological examinations, ECG, blood chemistry assessment, and noncontrast CT. Most control subjects were included in clinical trials of neuroprotective drugs. In both patients and control subjects, anticoagulant therapy was started in the absence of hemorrhagic transformation (HT) on the second CT scan performed at 36 to 48 hours. Informed consent was obtained from all patients or next of kin. The local ethics committee approved the study protocol.
TCD Assessment
A standard TCD examination was performed in the emergency room on admission (<3 hours) and again to assess recanalization on follow-up at 6, 12, 24, and 48 hours after symptom onset. The same neurologist conducted baseline and follow-up studies. Systolic and diastolic blood pressures and heart rate were measured at time of each TCD recording. TCD examination was performed by use of MultidopX4 (DWL Elektroniche Systeme GmbH) equipment with a hand-held probe in a range-gated, pulsed-wave mode at a frequency of 2 MHz. Flow velocities of the MCAs, anterior cerebral arteries (ACAs), and posterior cerebral arteries (PCAs) were recorded bilaterally with the transtemporal approach. MCA was identified as having a flow signal directed toward the probe at an insonation depth of 55 mm and traced up and down to 35 and 65 mm, respectively. ACA was identified as having a flow signal directed away from the probe at a depth of 65 mm and traced to 80 mm. Flow signal from the PCA was detected at 65 mm as a signal directed toward the probe and traced from a depth of 60 to 70 mm. Doppler shifts from all arteries were recorded at each 2-mm step.
Proximal MCA occlusion was defined as absence of flow or presence of minimal flow signal throughout the MCA at an insonation depth between 45 and 65 mm accompanied by flow diversion in the ipsilateral ACA and PCA. Distal MCA occlusion was defined as diffuse dampening of mean flow velocity in the affected MCA >21% versus unaffected MCA.16 Recanalization on follow-up TCD recordings was diagnosed when dampened flow appeared in a previously demonstrated proximal MCA occlusion (partial recanalization) or when a previous absent, minimal, or dampened flow came within the normal range (complete recanalization).11,16 Appearance of a low-resistance stenotic signal on follow-up also was considered to be complete recanalization.11 Absence of change in the abnormal waveforms was taken to indicate that no recanalization had occurred.
CT Studies
On admission, all patients underwent a CT scan within the first 3 hours after stroke onset, which was repeated after 36 to 48 hours (or earlier when rapid neurological deterioration occurred) and again between days 5 and 7. Presence of hyperdense MCA sign, early focal hypodensity, or swelling due to developing infarction on baseline CT was assessed according to European Cooperative Acute Stroke Study (ECASS) criteria.2,17 Extent of hypodensity or swelling as a result of acute ischemic edema on baseline CT was categorized as normal, hypoattenuation <33% of the MCA territory, and hypoattenuation >33% of the MCA territory. Presence and type of HT on 36- to 48-hour CT scan were defined according to previously published criteria.2,18 Hemorrhagic infarction (HI1 and HI2) was defined as a petechial infarction without space-occupying effect, and parenchymal hematoma (PH1 and PH2) was defined as hemorrhage with mass effect. Total infarct volume was measured on CT at day 5 to 7. We measured the ischemic lesion with and without hemorrhagic transformation by use of the formula for irregular volumes. In patients who died before day 5 to 7, the last available CT was used for measurement of infarct volume. A neuroradiologist who had extensive experience in acute stroke and was blinded to the clinical and TCD details reviewed CT scans.
Clinical Assessment
We assessed clinical status at baseline and at 6,12, 24, and 48 hours after symptom onset by means of the NIHSS, which was conducted by a neurologist or a senior neurology resident who was video trained and certified for application of the NIHSS.19 Early neurological deterioration or improvement was defined as an increase or decrease of 
4 points on the NIHSS score at 48 hours after baseline assessment.1 Complete recovery was defined as a decrease in total NIHSS score to <3 at 48 hours.1,20 Modified Rankin scale21 (MRS) was used to assess clinical outcome at 90 days. We defined good outcome as MRS score 2.
Statistical Analysis
Analyses were performed with the use of SPSS 9.0 software (SPSS Inc). Statistical significance for intergroup differences was assessed by the 2-tailed Fisher’s Exact Test and 
2 test for categorical variables and by the Kruskal-Wallis and Student t test for continuous variables. Pearson’s 
coefficient was applied to verify correlation between examined variables. A receiver-operator characteristic curve was applied to determine a cut point of infarct volume that better distinguishes between favorable and unfavorable outcome. Probability of good outcome and independence at 3 months was assessed by forward stepwise logistic regression analysis based on maximum likelihood ratio. Variables with a value of P0.1 on univariate testing were included. A level of P<0.05 was accepted as statistically significant.
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Results |
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We included in the study 72 (30 men and 42 women) patients with an acute cardioembolic stroke in the MCA territory. Table 1shows demographic data, risk-factor profile, and baseline clinical findings. Mean age was 67.7±10.7 years (range 31 to 80 years). A total of 65% of patients were hypertensive, and 22% had a history of diabetes mellitus. NIHSS score of the series on admission was 17.31±4.6 (range 5 to 22). In the rtPA group, time elapsed between symptom onset and drug administration was 149±27.4 minutes (range 89 to 180 minutes). Door-to-needle time was 67.5±20.3 minutes (range 34 to 86 minutes).
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Time interval between stroke onset and baseline TCD examination ranged from 43 to 177 minutes (mean 131.7±63.1 minutes). On baseline TCD assessment, proximal MCA occlusion was detected in 15 (63%) rtPA patients and 38 (79%) controls (P=0.12) and distal MCA occlusion in 9 (37%) rtPA patients and 9 (17.8%) controls (P=0.09). TCD examination was normal in 0 rtPA patients and in 1 (2%) control. Recanalization within 48 hours occurred in 22 (91.8%) rtPA patients and 34 (70.8%) controls (P=0.012). Figure 1 illustrates time course of recanalization during first 48 hours. Early recanalization (at 6 hours) was identified in 23 (31.9%) patients: 11 had proximal and 12 distal MCA occlusions. Early recanalization was significantly (P<0.001) higher in the rtPA group (n=16, 66%) than the control group (n=7,15%). Six-hour complete recanalization was achieved in 8 (33%) rtPA patients and 2 (4.1%) controls, and partial recanalization in 8 (33%) and 5 (10.9%) patients, respectively. Delayed recanalization (>6 hours) occurred in 33 (46%) patients: 27 with proximal and 6 with distal MCA occlusions. Five (20.8%) rtPA patients and 15 (31.2%) controls recanalized between 6 and 12 hours, and 2 (8.3%) and 12 (25%), respectively, between 12 and 48 hours after stroke onset. In addition, in 2 (8%) rtPA patients and 14 (29%) controls, MCA remained occluded at 48 hours (P=0.012).
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Clinical assessment revealed that 14 (19.4%) patients worsened, 31 (43%) improved, and 27 (37.5%) remained stable during the first 48 hours after admission. Neurological improvement was significantly (P<0.001) more frequent in the rtPA group (75%) than the control group (27%, Table 1). Figure 2 shows changes in NIHSS score at 48 hours according to time to reperfusion. Early recanalization (<6 hours) was associated significantly with a greater decrease (P=0.024, Kruskal-Wallis test) in NIHSS score compared with other time points of recanalization. Complete recovery at 48 hours was seen in 5 of 24 (20.8%) rtPA and 11 of 48 (22.9%) of control patients (P=0.51). Complete recovery was associated strongly (P<0.001) with early recanalization; 12 of 23 (52.1%) patients who recanalized at <6 hours completely recovered at 48 hours.
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HT on CT was detected in 9 (37.5%) rtPA patients and in 10 (20.8%) controls (P=0.12). HT was considered symptomatic in 2 patients: 1 rtPA (4.1%) patient and 1 (2%) control. Distribution of HT subtypes that occurred within the first 48 hours was as follows: HI1 was identified in 9 (47.3%) patients, HI2 in 5 (26.3%), PH1 in 3 (15.7%), PH2 in 2 (10.5%). HT was identified in 18 of 56 (32.1%) reperfused and 1 of 16 (6.3%) nonreperfused patients (P=0.031). Although in the control group HT was closely associated (P=0.004) with delayed recanalization (>6 hours), HT appeared unrelated to the time to reperfusion in patients receiving rtPA.
Mean infarct volume as measured on CT at day 5 to 7 was 98.5±83.3 cm3. Infarct volume was significantly (P<0.001) lower in patients receiving rtPA (50.2±40.3 cm3) versus controls (124.8±81.6 cm3). Good correlation was found between baseline NIHSS score and infarct volume in controls (r=0.69, P<0.001, Pearson’s coefficient) but not in patients receiving rtPA (r=0.03, P=0.81, Pearson’s coefficient). Infarct volume was 24±17.8 cm3 in patients who completely recanalized at 6 hours, 41.2±27.1 cm3 in those who partially recanalized, and 131.8±80.5 cm3 in patients with persistent MCA occlusion at 6 hours (P<0.001 by Kruskal-Wallis test). In addition, infarct volume was strongly (P<0.001 by Kruskal-Wallis test) associated with persistence of MCA occlusion during the first 48 hours (Figure 3).
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MRS score at 3 months was 2.88±1.91 and was significantly (P=0.012) lower in rtPA patients (2.12±1.62) than controls (3.27±1.9). Figure 4 illustrates differences in clinical outcome at 3 months between rtPA and control patients. A total of 14 (58%) rtPA patients became functionally independent (MRS score 2) at 3 months compared with 11 (23%) controls (P=0.037). In contrast, rate of severe disability and death (MRS score 5 to 6) at 3 months was significantly (P=0.029) higher in control subjects (21%) than patients treated with rtPA (9%). A close relationship existed (P=0.002) between MRS score at 3 months and time to reperfusion (Figure 5A). Moreover, clinical outcome was strongly associated (P=0.001) with degree of 6-hour recanalization on TCD (Figure 5B). In addition, a graded response was observed with reduced favorable outcome rates as time of MCA occlusion increases. A total of 19 of 23 (82.6%), 9 of 20 (45%), and 2 of 13 (15.3%) patients who recanalized at <6, 6 to 12, and 12 to 48 hours, respectively, were independent at 3 months. Furthermore, strong correlation was seen between infarct volume and MRS score at 3 months (r=0.88, P<0.001, Pearson’s coefficient). A receiver-operator characteristic curve provided a cut point of 38.6 cm3 (sensitivity 83%, specificity 73%) as value of infarct volume that better distinguishes between favorable and unfavorable outcome. Table 2 shows relative contribution of different variables for good outcome and independence at 3 months on univariate analysis. Female sex (P=0.049), baseline NIHSS score <17 (P<0.003), diastolic blood pressure <85 mm Hg on admission (P=0.038), treatment with rtPA (P<0.011), infarct volume <38 cm3 (P=0.009), distal MCA occlusion (P=0.019), and early (<6 hours) recanalization (P<0.001) were associated significantly with good outcome and independence. Of these, NIHSS score <17 (OR 12.1, 95% confidence interval [CI] 2.8 to 68, P=0.001) and early recanalization (OR 23.4, 95% CI 5.4 to 96, P=0.001) emerged as independent predictors of good outcome and independence at 3 months with the use of a multiple logistic regression model.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present study demonstrates that in patients with acute cardioembolic stroke, the time course of spontaneous or rtPA-induced MCA recanalization as determined by use of TCD strongly correlates with infarct volume and long-term prognosis. Treatment with intravenous rtPA within <3 hours of stroke onset is associated with early recanalization, which leads to neurological 2improvement, smaller infarct size, and better clinical outcome, than was seen in control subjects matched for demographic factors, time windows, and initial stroke severity.
General agreement exists that clinical benefit of rtPA in ischemic stroke is linked to accelerated clot lysis and early recanalization.22,23 However, intravenous rtPA trials1–6 did not evaluate whether clinical improvement depended on the presence of arterial occlusion with subsequent recanalization after thrombolytic therapy or rate of spontaneous recanalization in patients receiving placebo. Previous nonrandomized angiographic studies24–26 with intravenous rtPA have revealed a recanalization rate of 25% to 50%. A recent noncontrolled TCD study14 with intravenous rtPA given within <3 hours of stroke onset has shown a rate of complete and partial recanalization at 6 hours of 30% and 40%, respectively. However, the lack of a control group in that study did not allow the authors to conclude whether recanalization occurred spontaneously or as a result of rtPA therapy. Our present case-control TCD study demonstrates that intravenous rtPA increases 8-fold and 3-fold the rate of complete and partial recanalization at 6 hours, respectively.
Several experimental studies27–29 have demonstrated a correlation between duration of cerebral hypoperfusion and irreversibility of brain damage. In a primate model of cerebral ischemia,27 release of MCA occlusion at up to 3 hours yielded to clinical improvement. Clinical studies have demonstrated a direct correlation between recanalization and clinical outcome.30,31 Normal 6-hour TCD that suggests early complete recanalization has been shown to be an independent predictor of early neurological improvement.32 Moreover, a 300-minute window of recanalization on TCD has been shown to be associated with achievement of early complete recovery.14 However, the independent contribution of recanalization at <6 hours of stroke onset on long-term outcome has not been tested previously. Our present study demonstrates that early recanalization emerges as a robust independent predictor of good clinical outcome and independence at 3 months.
In contrast to the cumulative evidence that suggests that early successful recanalization leads to favorable outcome, whether delayed recanalization is beneficial or harmful is matter of discussion. Experimental studies in nonprimate animals33 have shown a detrimental effect of delayed reperfusion on ischemic brain tissue. However, these observations have not been replicated in primate models of MCA occlusion and reperfusion.34 Clinical studies of reperfusion with angiography,26 and single-photon35–37 and positron38,39 emission tomography have shown that even delayed reperfusion is associated with smaller infarct size and better clinical outcome. Our TCD study confirms these observations and adds that a graded response is seen in both infarct volume and long-term outcome in relation to time to artery reopening. Thus, our results did not support the concept of reperfusion injury. The largest infarct volume and the worst prognosis corresponded to patients who had persistent MCA occlusion on 48-hour TCD. These findings are consistent with a recent diffusion-weighted MR imaging study40 that showed a significant increase in diffusion lesion at day 5 in patients without recanalization at 48 hours, which indicates further infarct dynamics and progressive infarct growth even after several days in patients with persistent arterial occlusion.
Interestingly, 45% of patients who recanalized at 6 to 12 hours were functionally independent (MRS2) at 3 months. This observation is in line with previous positron emission tomography studies38,39 that suggest that in some patients the time window for reperfusion therapy should be expanded. Nevertheless, despite the capability of TCD for detection of the presence of vessel occlusion, this technique cannot identify potential candidates for thrombolysis beyond the 3-hour and even 6-hour time window. Selection of these patients requires accurate estimation of the extent of ischemic penumbra by means of diffusion and perfusion MRI.
In the present TCD study, we assess recanalization and not reperfusion itself. Other factors, such as capacity of collateral flow, may contribute to reperfusion of the ischemic area. Theoretically, this occurrence may result in smaller infarctions and favorable outcome in patients with a good collateral flow, despite persistent MCA occlusion. However, our findings support the notion that reperfusion, neurological recovery and ultimately good outcome mainly depend on early clot lysis and recanalization of a major cerebral artery and that other factors, such as collateral flow, may play a secondary role in nutritional reperfusion and improved prognosis in the absence of recanalization. On the other hand, the combination of functional (MR imaging or single-photon emission CT) and vascular (TCD, CT, or MR angiography) imaging, as part of the standard emergent evaluation of stroke patients, may improve the management of these patients by providing information on both recanalization and reperfusion.
Unlike spontaneous recanalization after cardioembolic stroke,15 we failed to demonstrate an association between delayed recanalization and HT risk in patients treated with rtPA at <3 hours. The dynamic of thrombolysis-induced recanalization may differ from that which occurs spontaneously.41 Sudden clot lysis with abrupt reperfusion may promote blood-brain barrier disruption and HT. In a recent study,12 50% of rtPA-related symptomatic HT occurred in patients with a normal TCD before treatment, which suggests a deleterious effect of rtPA in already-reperfused brain tissue. Moreover, administration of rtPA may increase HT risk by promoting matrix metalloproteinase overexpression. This observation is supported by the fact that inhibition of matrix metalloproteinase activity has been shown to attenuate rtPA-related hemorrhage effectively.42 Nevertheless, larger studies are required to elucidate the relationship between timing of rtPA-induced recanalization and risk of HT.
In conclusion, this case-control study demonstrates that in patients with acute cardioembolic stroke treatment with intravenous rtPA at <3 hours after symptom onset strongly associates with early recanalization, which leads to reduced infarct size and better clinical outcome. Early recanalization is a powerful independent predictor of functional independence at 3 months. Moreover, a graded response is seen in both infarct volume and long-term outcome in relation to time to artery reopening. Therefore, TCD monitoring of recanalization may provide valuable prognostic information in patients receiving thrombolytic therapy.
Received July 31, 2001; revision received August 31, 2001; accepted September 6, 2001.
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