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Stroke. 1999;30:1326-1332

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(Stroke. 1999;30:1326-1332.)
© 1999 American Heart Association, Inc.

Original Contributions

Hemorrhagic Transformation in Acute Ischemic Stroke

The MAST-E Study

Assia Jaillard, MD; Catherine Cornu, MD; Anne Durieux, MD; Thierry Moulin, MD; Florent Boutitie, PhD; Kennedy R. Lees, MD; Marc Hommel, MD on behalf of the MAST-E Group

From the Department of Clinical and Biological Neurosciences, Stroke Unit, INSERM U 438, University Hospital, Grenoble, France (A.J., M.H.); Service de Pharmacologie, Clinique EA 643, Claude Bernard University, Lyon, France (C.C., F.B.); Service de Neurologie, University Hospital, Clermont-Ferrand, France (A.D.); Service de Neurologie, University Hospital, Besançon, France (T.M.); and the Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, UK (K.R.L.).

Correspondence to Assia Jaillard, Service de Neurologie–Unité d'Urgences Cérébrovasculaires, Centre Hospitalier Universitaire de Grenoble, BP 217-38043 Grenoble Cedex, France. E-mail Assia.Jaillard{at}ujf-grenoble.fr


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose—Hemorrhagic transformation (HT) is the most critical complication of thrombolytics in clinical trials in acute stroke. The aim of this study was to determine the rates and the predictors of HT in the Multicenter Acute Stroke Trial–Europe (MAST-E) study.

Methods—We performed a post hoc analysis of MAST-E data designed to assess the safety and efficacy of streptokinase administered intravenously within 6 hours of stroke onset. HT included all intracerebral hemorrhages and symptomatic hemorrhages (SHT) associated with clinical worsening. The predictors of HT and SHT were determined using multivariate modeling.

Results—Among the 310 patients included, 159 patients had HT and 37 SHT (97 and 33 in the streptokinase group and 62 and 4 in the placebo group, respectively). Patients with SHT had significantly more atrial fibrillation, diabetes mellitus, no heparin use, streptokinase treatment, and early CT signs. In the multivariate analysis, HT was predicted by early CT signs and streptokinase treatment. SHT was predicted by diabetes mellitus, early CT signs, streptokinase treatment, and the interaction between streptokinase treatment and decreased level of consciousness. Among the streptokinase-treated patients, the same predictors remained.

Conclusions—The relative risks of HT after streptokinase were in the same range in MAST-E as in other streptokinase and tPA trials. Early CT signs were strong predictors of both HT and SHT, stressing that these patients are at high risk of bleeding. In our study, the predictors of HT and SHT were similar to those of tPA trials in acute stroke.


Key Words: cerebral hemorrhage • clinical trials • streptokinase • stroke, acute


*    Introduction
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 up arrowAbstract
 *Introduction
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Until recently, the incidence of intracranial bleeding after acute ischemic stroke was not well known. It could vary between 18% and 71%,1 2 3 4 according to whether the information was from autopsy or CT scan studies. Hemorrhagic transformation (HT), either in control groups or after thrombolytic treatment, has been assessed in recent large clinical trials in acute stroke, with systematic admission and control CT scan assessment. HT includes symptomatic hemorrhages (SHT) that are associated with clinical worsening and those that are asymptomatic.5 6 7 8 9 The risk of bleeding is present for both streptokinase and tPA, because cerebral HT accounts for a major cause of early hazard in acute-stroke patients, ranging from 26 to 154 extra deaths for each 1000 patients treated in the recent studies.5 6 8 9 10 Predictors of HT have been evidenced in 2 tPA clinical trials11 12 but have not yet been reported in a streptokinase trial. Streptokinase is widely used in the treatment of myocardial infarction (MI), and cerebral infarction is one of the major complications after MI. Because the major risk carried by a thrombolytic agent, either in stroke or MI, is cerebral bleeding, to delineate the profile of patients having a high risk of bleeding and to identify predictors of HT remains a major issue. We performed a post hoc analysis of the Multicenter Acute Stroke Trial–Europe (MAST-E) data to study the occurrence and the predictors of cerebral HT in both the streptokinase and placebo groups.


*    Subjects and Methods
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 up arrowAbstract
 up arrowIntroduction
 *Subjects and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
MAST-E was a multicenter, double-blind, controlled clinical trial designed to assess the safety and the efficacy of streptokinase in acute cerebral ischemia. The design and the results of the study have been reported elsewhere.7 13 Briefly, patients were eligible if they presented with clinical signs attributed to ischemia in the middle cerebral artery (MCA) territory. Either 1 500 000 U of streptokinase or placebo were administered intravenously after a CT scan within a maximum of 6 hours after the onset of symptoms. Patients with signs of hemorrhagic stroke on prerandomization CT were excluded. Efficacy was evaluated on a binary criterion combining mortality and severe disability at 6 months. Safety was evaluated on the mortality at 10 days, and symptomatic intracerebral hemorrhage and clinically silent intracerebral hemorrhage were assessed by control CT on day 5, or earlier in the event of clinical deterioration. These events were validated and adjudicated by the Critical Events Reviewing Committee, which was blinded to the treatment assignment. All CT scans were reviewed independently by 3 trained neurologists who were unaware of patient treatment assignment. CT scan imaging was scored with the use of a standard questionnaire, including previous lesions of stroke, cerebral atrophy, leukoaraiosis, and early signs of stroke.14 CT findings considered to be early CT scan signs of brain ischemia included loss of the density contrast of the lentiform nucleus,15 loss of the density contrast of the insular ribbon,16 and hemispheric sulcus effacement, either alone or in association with a hyperdense MCA sign.17

Cerebral HT, assessed either on CT scans by the Neuroradiologic Reviewing Committee or by autopsy, was considered to be both the symptomatic and asymptomatic cerebral HT. SHT were defined as clinical deterioration temporally related to HT documented by CT scan or autopsy, as adjudicated independently by the Critical Events Reviewing Committee.

Demographic characteristics, medical history, vascular risk factors, baseline clinical characteristics and neurological state (MAST-E score, the items and the sum) were collected. Administration of anticoagulants or antiplatelets agents during hospitalization was allowed to give the placebo group patients access to the best treatment available in the investigators' opinion. Use of heparin or antiplatelets agents during hospitalization was recorded.

Statistical Analysis
We analyzed HT and SHT using the {chi}2 test, Student t test, or the Fisher's exact test, as appropriate. Subgroup analyses were performed according to the following variables: age; sex; body weight; atrial fibrillation; history of hypertension, diabetes mellitus, previous stroke, or transient ischemic attack of the brain; systolic blood pressure and diastolic blood pressure; MAST-E score18 ; hand, arm, and leg paresias; level of consciousness at admission; side of the ischemia; cerebral atrophy; early CT signs of lentiform nucleus attenuation, insular ribbon contrast attenuation, hemispheric sulcus effacement, and hyperdense MCA; streptokinase treatment allocation; antithrombotic-associated treatment (heparin, antiplatelet agents); and delay from stroke onset to treatment.

A logistic forward stepwise regression model was used to define predictors of HT after adjustment for the effect of confounding variables.19 We chose to include in the initial model all variables associated with hemorrhage in univariate analysis with a value of P<0.2. We also included all variables reported to be related to cerebral hemorrhages in other studies: age, sex, weight, hypertension, previous stroke or transient ischemic attack, atrial fibrillation, systolic and diastolic blood pressures, and severity at admission.12 20 21 Because of the small number of patients, logistic regression was performed on symptomatic cerebral hemorrhages both in the total population and in the streptokinase group, which included most SHT. We tested the interactions among the selected variables and refit the model. We chose a value of P=0.05 as a level of statistical significance and did not correct for multiple comparisons. We assessed the sensivity, specificity, positive and negative predictive values, and efficiency of each mutivariate model for HT and SHT.


*    Results
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 *Results
down arrowDiscussion
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Among the 310 patients included (156 in the streptokinase group and 154 in the placebo group), 157 patients had an HT, 96 (61%) in the streptokinase group and 61 (31%) in the placebo group. The mean delay of CT from the onset of stroke was 150 minutes (first and third quartiles, 123 and 223 minutes). Control CT scan data were missing for 33 patients, because of either early death (12 patients in the streptokinase group and 4 in the placebo group), discharge before the second CT scan was performed (1 in each group), poor quality of the CT scan (3 in the streptokinase group and 8 in the placebo group), or the second CT scan being performed >10 days after stroke (1 in the streptokinase group and 3 in the placebo group). Among the 16 patients who died without CT scan control, 3 had autopsy. Thus, the analysis included 280 patients for HT and 310 for SHT.

Hemorrhagic Transformation
Comparisons of baseline characteristics, treatments received, and CT scan signs between patients with and without HT are reported in Tables 1Down and 2Down. Streptokinase treatment and early CT scan signs (Figure 1Down) differed significantly between the 2 groups and remained significantly linked with HT in the multivariate stepwise logistic regression (Table 3Down). Age, body weight, atrial fibrillation, systolic and diastolic blood pressures, the delay from stroke onset to treatment, and heparin and antiplatelet agent use were not kept in the multivariate model. The specificity of the model was 44.9% (95% CI, 39% to 51%), the sensitivity 80% (95% CI, 75% to 85%), the positive predictive value 66% (95% CI, 60% to 72%), the negative predictive value 63% (95% CI, 57% to 69%), and the global efficiency 65% (95% CI, 59% to 71%). When we selected the streptokinase group, early CT signs remained the sole predictors of HT (Table 3Down).


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  		Table 1. Clinical Characteristics and Treatments of Patients With HT


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  		Table 2. Baseline CT Scan Characteristics of Patients With HT and SHT



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  		Figure 1. A, Seventy-nine-year-old patient with 4 hours 30 minutes of new left dense hemiparesis. Early CT signs are observed in the right MCA. Note lentiform nucleus contrast attenuation insular zone contrast attenuation and hemispheric sulcus attenuation. B, The CT scan 5 days later showed hypodensity in the deep and superficial territories of the right MCA with HT.


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  		Table 3. Results of Logistic Regression Model for HT

Symptomatic Hemorrhages
Among the 157 patients with HT, 37 had SHT (33 in the streptokinase group and 4 in the placebo group). Comparisons of the baseline characteristics, treatments, and baseline CT scan signs in patients with and without SHT, are reported in Tables 1Up and 2Up. SHT was significantly more frequent in patients with atrial fibrillation, diabetes mellitus, no heparin use, streptokinase treatment, and early CT scan signs (hemispheric sulcus attenuation and insular zone contrast attenuation; Figure 2Down). The multivariate model included streptokinase treatment, diabetes mellitus, hemispheric sulcus attenuation, and the interaction between a decreased level of consciousness and streptokinase treatment (ie, the patients who had a decreased level of consciousness and were treated with streptokinase). Within the streptokinase group, diabetes mellitus, hemispheric sulcus attenuation, and decreased level of consciousness were kept in the final model (Table 4Down). The predictive model for SHT had 19% sensitivity (95% CI, 15% to 24%), 99% specificity (95% CI, 98% to 100%), 78% positive predictive value (95% CI, 73% to 83%), 89% negative predictive value (95% CI, 85% to 93%), and 89% efficiency (95% CI, 85% to 93%).



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  		Figure 2. A, Eighty-nine-year-old patient with 2 hours 20 minutes of new left dense hemiparesis and drowsiness. Early CT signs are observed in the right MCA. Note lentiform nucleus contrast attenuation insular zone contrast attenuation and hemispheric sulcus attenuation. B, The CT scan 1 day later showed symptomatic HT in the total territory of the right MCA with midline shift and contralateral ventricular mass effect.


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  		Table 4. Results of Multivariate Analyses in the Total Population and Restricted to Streptokinase-Treated Patients


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
Incidence of HT and SHT
The rate of spontaneous HT ranged from 38% to 71% in autopsy studies1 2 3 and from 13% to 43% in the recent CT studies.14 22 23 24 25 26 27 In controlled clinical trials28 29 of thrombolysis for acute MI, rates of 14 and 30% of HT have been reported in patients with ischemic stroke. Recent series30 31 32 of patients treated with tPA for acute ischemic stroke reported rates of HT from 10% to 30%. Recent controlled clinical trials in acute ischemic stroke reported rates of total HT over the first 5 days from 3.2% to 37% in the placebo group and from 10.6% to 44% in the thrombolyzed group (Table 5Down).


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  		Table 5. Incidence and Risk of Cerebral HT According to Thrombolytic Therapy in Recent Controlled Clinical Trials

The rate of SHT has not been reported for all studies. After thrombolysis for MI, 5 of 27 patients (19%) suffering from an ischemic stroke developed SHT.28 In recent series of patients treated with t-PA for acute ischemic stroke, SHT occurred in 3.6% of 85 consecutive patients,27 9.6% of 104 patients,30 5% of 100 patients32 and 7% of 30 patients.31 In controlled clinical trials of thrombolysis for acute stroke, SHT ranged from 0.6% to 7% in the placebo group and from 6.4% to 20% in the thrombolyzed group (Table 5Up). In our study, the rates of total HT and SHT were 43.7% and 2.6%, respectively, in the placebo group compared with 67.8% and 21.2% in the streptokinase group. The rates in the placebo group are within the range of published rates of HT and SHT. In the streptokinase group the rates of HT and SHT are higher than those in the treatment groups of other acute stroke trials (Table 5Up). However, the rates of HT and SHT differed significantly from one study to another. Such heterogeneity between trials in the incidence of HT and SHT may result in part from sample fluctuations. In each trial, the proportion of HT and SHT is small, and thus populations of HT, and particularly SHT, are small. By chance, sample fluctuations may result in major differences in HT and SHT rates. Potential biases in the HT rate estimation also need to be addressed. First, a selection bias related to the baseline characteristics of the patients, such as geographic or ethnic factors, severity, mechanism (cardiac embolism versus in situ thrombosis), topography of stroke (ICA versus MCA), delay to inclusion, and time period over which the HT were evaluated could have selected groups of patients with very different bleeding risks. Second, biases in the care given to patients could have occurred; for example, associated treatments were different between studies. Third, classification biases such as the assessment of HT and SHT may have occurred, because there is no shared criteria for the assessment and classification of HT on CT. This is particularly true for petechial HT.33 The classification of hemorrhages as symptomatic or not may also be controversial, because neurological deterioration may or may not be due to HT. Using crude rates rather than relative risks to compare the incidence of HT and SHT between these trials may be misleading. After thrombolysis, the relative risks are ranged from 1.165 to 3.110 for HT and from 2.75 to 10.010 for SHT (Table 5Up). No significant difference between streptokinase and tPA in hemorrhagic risk can be evidenced. In controlled thrombolytic trials for acute MI, an excessive number of hemorrhagic strokes has been reported for tPA.34 Therefore, only a direct comparison of streptokinase and tPA in an acute ischemic stroke trial could permit to assess the difference in risk of bleeding between the 2 drugs.

Predictors of HT and SHT
In controlled thrombolysis trials for MI, risk factors for HT have been reported to be low body weight,29 35 elderly age,20 21 29 35 hypertension at admission,20 29 35 and thrombolytic treatment assignment.29 35 Data for acute ischemic stroke are available from trials and from clinical and autopsy series. In acute ischemic stroke trials, body weight and hypertension have not been evidenced as risk factors, but advanced age and tPA treatment were associated with increased risk of parenchymal hemorrhage in ECASS11 and of both SHT and total HT in the NINDS.12 Other risk factors for SHT in acute stroke thrombolytic studies include a cardioembolic mechanism of stroke,11 28 31 prior MI,32 stroke severity,12 size of infarct,22 and early CT signs.12 31 In autopsy studies1 3 and recent clinical series without thrombolysis, HT was associated with severity, cardioembolic mechanism of the stroke27 and early CT signs.26

In our study, HT was predicted by both early CT signs and streptokinase treatment, whereas SHT was predicted by diabetes mellitus, early CT signs, streptokinase treatment and the interaction between streptokinase treatment and a decreased level of consciousness. When we ran the model of SHT among the streptokinase-treated patients, the same predictors remained. This suggests that streptokinase increases the risk of SHT among patients who would have presented with asymptomatic hemorrhage had the treatment been the placebo. This is consistent with data from ECASS I and ECASS II, in which tPA treatment was associated with an increased risk of parenchymal hemorrhage but not of hemorrhagic infarction.11 However, SHT has not been assessed in ECASS I.

The presence of early CT signs predicted both HT and SHT in the multivariate analysis, which is in agreement with other thrombolytic studies.11 12 31 32 In MAST-E, early CT signs were present in 63% of the patients, the same order of magnitude as the Australian Streptokinase Trial (57.7%) but higher than in MAST-I (4.7%), ECASS (31%),11 and the NINDS study (5%).12 Early CT signs are reported from 31% to 92% in series focused on early CT signs among patients with MCA ischemia, according to the delay from onset to CT scan (4 to 8 hours).14 15 16 36 37 38 39 These discrepancies may be related to the patient selection and to CT sign measurement biases. There were differences in the severity of stroke, in the delay from stroke onset to CT scan, in the criteria used for early CT signs assessment, and also in the quality of CT scans. Actually, the absence of shared definition of early CT signs and the subtle brain appearance changes they characterize may be important contributors to the discrepancies between the rates reported. This is supported by the low intraobserver and interobserver concordance14 40 for early CT sign assessment. Although important metrological and teaching efforts could be done to reach a high level of reliability,41 this emphasizes that a treatment based on such subtle signs might be very difficult to introduce into routine practice.

We found an association between stroke severity (MAST score of <20, or low level of consciousness) and SHT in univariate analyses, although it did not reach a level of significance. In the multivariate model, decreased level of consciousness was a predictor of SHT only in patients assigned to streptokinase. Stroke severity has been demonstrated to be a predictor for SHT in NINDS12 and for HI in ECASS.11 This confirms that patients with such conditions should not receive thrombolytic treatment.

Our data indicate that diabetes mellitus is associated with SHT. Hyperglycemia at baseline was associated with an increased risk of SHT in the NINDS trial,10 and history of diabetes mellitus was associated with parenchymal hematoma in a stroke series.26 Both hyperglycemia and diabetes were predictors of HT and SHT in tPA-treated patients.42 However, although diabetes mellitus is a well-known risk factor for ischemic stroke, whether it is a risk factor for hemorrhage has yet to be determined.2

Our univariate analysis showed a possible association between atrial fibrillation and both HT (P=0.12) and SHT (P=0.05). A relation between cardioembolic strokes and HT has been reported in autopsy studies1 3 in thrombolysis series,31 in ECASS,11 and in trials in MI.28 The high rate of cardioembolic stroke in the MAST-E population (30%) may have promoted a high rate of HT.

The high crude rates of HT and SHT in our streptokinase group could be attributed to the heavy use of heparin or aspirin as associated treatment within the first 48 hours. However, both heparin and aspirin were associated with a low incidence of SHT (Table 3Up). Moreover, heparin administration appeared to be a predictor of low risk of SHT in our multivariate analysis, suggesting a paradoxical protective effect. Heparin appears to be an established risk factor for HT in acute stroke.43 44 45 However, some studies have not reported an increased risk of bleeding during heparin treatment, either in association with thrombolytics in a meta-analysis of trials for MI35 or alone.46 Because heparin was not used randomly in MAST-E, it is likely that early occurrence of HT prevented the investigator from using antithrombotic drugs within the first hours. Therefore, because we thought that including this variable in the model could be misleading, we did not keep heparin treatment in our multivariate models.

It has been suggested30 that a long delay from stroke onset to thrombolytic treatment is related to a high rate of SHT. We explored this hypothesis, but neither univariate nor multivariate analysis demonstrated any association between HT or SHT and a longer delay. These results are supported by findings from ECASS I and ECASS II, in which patients treated between 3 and 6 hours after stroke did not have a higher risk of parenchymal hemorrhage than those treated within the first 3 hours,11 and by the NINDS study,12 in which patients treated between 90 and 180 minutes did not have a higher risk of SHT than those treated within 90 minutes of onset.

To explore the dose effect in HT occurrence, because a fixed dose of streptokinase was used, we studied the relationship between HT and body weight. We found no relationship, but in a recent study fibrinolytic blood parameters were strongly correlated with the body mass index.47 These conflicting results suggest that the dose issue should be addressed further.

Conclusion
We report the post hoc analysis of a controlled clinical trial using streptokinase in acute ischemic stroke (MAST-E). In both the streptokinase and placebo groups, higher absolute rates of HT and SHT than in other studies were found, but the relative risks of streptokinase were in the same range as in other streptokinase and tPA trials. Only a direct comparison of streptokinase and tPA in acute ischemic stroke would allow assessment of the differential effects of the 2 drugs. In addition, the issue of the dose of streptokinase should be addressed before planning other trials with streptokinase in acute stroke.

Through use of logistic regression analysis, early CT signs were identified as a strong predictor of both HT and SHT, stressing that this group of patients has a peculiarly high risk of bleeding. The precise role of diabetes mellitus in the occurrence of SHT must be assessed. Our results indicate that a decreased level of consciousness was a predictor of SHT in streptokinase-treated patients. This is consistent with the lower rate of SHT in studies that excluded patients with coma or stupor.5 9 10


*    Acknowledgments
 
This study was sponsored financially with a grant from the French Ministry of Health (PHRC 1993).

Received February 16, 1999; accepted March 30, 1999.


*    References
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 up arrowAbstract
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 up arrowSubjects and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

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