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(Stroke. 1998;29:2529-2540.)
© 1998 American Heart Association, Inc.
Original Contributions |
Thrombolysis With Intravenous rtPA in a Series of 100 Cases of Acute Carotid Territory Stroke
Determination of Etiological, Topographic, and Radiological Outcome Factors
From the Cerebrovascular Unit and Ataxia Research Center, Hôpital Neurologique, Lyon, France (P.T., N.N., L.D., J.H., G.R., P.N., J.C.G., W.L.); the Biostatistical Unit of Claude Bernard University (P.A.); the Department of Neuroradiology, Hôpital Neurologique, Lyon, France (J.C.F., F.T., Y.B.); the Emergency Units of Lyon Hospitals (D.M., J.F.); the Emergency Unit of Moutiers Hospital (A.L.G., X.L.) Moutiers, France; and the Hematological and Coagulation Laboratory (P.F., M.D.), Hôpital Neurologique, Lyon, France.
Correspondence to P. Trouillas, Cerebrovascular Unit and Ataxia Research Center, Hôpital Neurologique, 59, boulevard Pinel, 69003 Lyon, France.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose—Although new, large, double-blind, randomized studies are needed to establish the efficiency of intravenous thrombolysis, open trials of sufficient size may also provide novel data concerning specific outcomes after thrombolysis.
Methods—An open study of intravenous rtPA in 100 patients with internal carotid artery (ICA) territory strokes between 20 and 81 years of age, with a baseline Scandinavian Stroke Scale (SSS) score of <48 at entry was conducted. Inclusion time was within 7 hours after stroke onset. rtPA (0.8 mg/kg) was infused for 90 minutes, with an initial 10% bolus. Heparin was given according to 3 consecutive protocols. The SSS evaluation was done on days 0, 1, 7, 30, and 90. CT scan was performed before treatment, on days 1 and 7. Etiological investigations included echocardiography and carotid Doppler sonography and/or angiography. Outcome at 1 year was documented by SSS score, the modified Rankin Scale (mRS) score, and a 10-point invalidity scale. Multivariate logistic regression was used to identify predictors of poor versus good outcome.
Results—At day 90, 45 patients (45%) had a good result, defined as complete regression or slight neurological sequelae (mRS score of 0–1), 18 patients had a moderate outcome (mRS 2–3), and 31 patients had serious neurological sequelae (mRS 4–5). Six patients died, 2 with intracerebral hematoma after immediate heparin. Five of 11 patients (45.5%) treated between 6 and 7 hours had a good result. The overall intracerebral hematoma rate was 7%. Higher values of fibrin degradation products at 2 hours were observed in the subgroup with intracerebral hematomas. Significant predictors of poor outcome on multivariate logistic regression analysis were baseline SSS score of <15 (odds ratio [OR], 3.38; 95% confidence interval [CI], 1.07 to 10.74; P=0.04), indistinction between white and gray matter on CT scan (OR, 6.59; 95% CI, 2.19 to 19.79; P=0.0008), and proximal internal carotid thrombosis (OR, 3.29; 95% CI, 0.99 to 10.95; P=0.05).
Conclusions—Our study confirms the safety of intravenous rtPA at a dose of 0.8 mg/kg and suggests efficacy for this drug even within 7 hours. Outcome and hematoma rates were at least as favorable as for trials of therapy with a 3-hour time window. Subgroups with a poor prognosis include low baseline neurological score, baseline CT changes, and proximal ICA thrombosis. However, approximately 30% of patients with each of these characteristics show a good outcome, so their inclusion in future routine rtPA protocols is still justified.
Key Words: proximal internal carotid thrombosis • heparin • mannitol • plasminogen activator, tissue type • tomography, emission computed • thrombolytic therapy
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Large, double-blind studies have established that intravenous streptokinase is inefficient and dangerous in humans with ischemic stroke.1 2 3 Conversely, intravenous rtPA is effective and safe when given at a dose of 0.9 mg/kg within 3 hours.4 The ECASS study,5 using rtPA at a dose of 1.1 mg/kg within 6 hours, also showed a favorable trend in the intent to treat analysis. More information is necessary, however, about several problems that have not yet been completely solved concerning rtPA thrombolysis of acute carotid territory strokes: the benefit-to-risk ratio of doses <0.9 mg/kg, the specific outcome of different topographical strokes and of different causative subgroups, the clinical severity of stroke, the acceptable time interval to treatment, the use of heparin therapy, the occurrence of early rethrombosis, the predictive value of early and postthrombolytic CT images, and the causes and possible prevention of hemorrhagic transformation of infarcts. Therefore, well-defined, open studies may still be useful to generate new hypotheses and prepare for new multicenter studies.
This series of 100 consecutive patients with all types of carotid territory strokes, treated with an 0.8-mg/kg dose of rtPA, is the continuation of the first series of 43 patients published previously in this journal.6
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients, Inclusion Criteria, and Clinical Assessment
Beginning January 1, 1994, we proposed an open protocol of intravenous rtPA to all patients with acute internal carotid artery (ICA) territory stroke, regardless of severity. Inclusion criteria were (1) informed consent given by patient or his/her relatives; (2) age between 20 and 81 years; (3) treatment started within 7 hours of stroke onset; (4) absence of hemorrhage on baseline CT scan; (5) permanent or ingravescent symptomatology since the onset of stroke; and (6) a baseline Scandinavian Stroke Scale (SSS)7 score of <48. Inclusion was also possible for patients with baseline CT changes, hypodensities involving more than one third of the MCA territory (classic or fine, according to von Kummer et al8 ) and/or mass effect. Exclusion criteria included (1) systolic hypertension of >250 mm Hg; (2) shock (hemodynamic failure); (3) possible pregnancy; (4) critical cardiac, pulmonary, renal, or hepatic conditions that obviously did not allow a follow-up of 3 months; and (5) classic contraindications to thrombolysis (recent surgical operation, recent history of gastrointestinal bleeding and known coagulopathies).
Treatments
Alteplase, predominantly single-chain rtPA (Actilyse,
Boehringer-Ingelheim), was used. The rtPA infusion was
administered immediately after CT at a dose of 0.8 mg/kg over 90
minutes at a constant infusion rate, with an initial bolus of 10% of
the total dose. Heparin was administered according to the following 3
consecutive protocols: (1) immediate postthrombolysis
efficient intravenous unfractionated heparin therapy, with
an initial dose of 300 U/kg, adjusted according to the
postthrombolysis fibrinogen value, and as soon as it
was normalized, raised to 1.5 times the activated partial
thromboplastin time; (2) delayed heparinization, at 24+6 hours,
immediately after day 1 CT; unfractionated heparin was given
intravenously according to the same schedule as protocol 1;
and (3) calcic nadroparin immediately after
thrombolysis, at a dose of 3075 antiXa units. The
remainder of the patients were excluded from the heparin protocols
because of various contraindications, including immediate
intracerebral hematoma, various systemic bleedings and
hemostatic disturbances, such as secondary decrease of
hematocrit or platelets and fibrinogen values <1 g/L. In patients
with stupor and conjugate eye deviation (SSS <6), a bolus of 100 mL
mannitol 20% was given at the time of thrombolysis and
every 2 hours for 8 hours. For patients with complete hemiplegia
without stupor (SSS <26), a bolus of 100 mL mannitol 10% was given
with the same pattern. All patients were treated and monitored in an
intensive neurological care unit for 1 week. All patients with clinical
and/or echographically identified cardiac source of emboli had oral
anticoagulant therapy after heparin, with an INR of between 2 and 3.
Patients with ICA stenosis of >70%9 and good
outcome (mR 0–1) had endarterectomy by a surgeon
with morbidity-mortality rate of <2%, immediately after
hospitalization for stroke, without discontinuation of heparin
treatment until the operation. All patients not receiving anticoagulant
therapy were discharged on antiplatelet agents.
Outcome Assessment
The SSS assessment was done at 3 hours and at days 1 (24±6
hours), 7, 30, and 90. The clinical regression of the clinical
presentation within the 3 hours after the beginning of
thrombolysis was documented. A recovery of SSS score to
48 was considered a major neurological improvement and defined "rapid
regressors." The same recovery at 24 hours was defined as "day 1
major neurological improvement." "Reinfarct syndrome" was defined
on the basis of a complete regression of motor and/or aphasic deficits
followed by a recurrence of the neurological deficit in the
same territory within 48 hours after onset, without evidence of
hemorrhagic transformation. Outcome was classified into the following 4
categories according to the modified Rankin Scale (mRS): (1) "Good
outcome" (mRS 0–1) included patients with our original description
of total recovery (6) and patients with mRS 1; (2) "moderate
outcome" (mRS 2–3) corresponded to a presentation with
objective neurological sequelae, but allowing walking, speech
communication, and social life; (3) "poor outcome" (mRS 4–5)
corresponded to persistence of the neurological signs or to severe
neurological sequelae, the patient being dependent for daily life; and
(4) "death" corresponded to neurological death due to the infarct
or hemorrhage. No other cause of death was observed. The mRS
assessment was done at day 90 and at 1 year. We also used at 1 year a
10-point invalidity score giving more details on the recovery of
previous activities, especially concerning patients' professional
activity (Table 1
). Hemorrhagic events
were classified as hemorrhagic infarcts, without clinical
deterioration, and parenchymal hematomas associated with
deterioration.10 Only the latter were recorded as
adverse hemorrhagic events and studied as outcome experiences. A
distinction was made between immediate hematomas, occurring during or
by the end of thrombolysis, and delayed hematomas,
occurring later.
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Radiological Assessment
Baseline CT
The symptomatology proposed by von Kummer et al8
for baseline CT scans was retrospectively and prospectively applied
after consensus sessions with this author. An intra-team agreement
among neurologists and neuroradiologists was sought afterward for each
CT for early baseline images, with the clinical data blinded.
Days 1 and 7 CT
These were reviewed in terms of structure and topography of the
images according to the methodology and criteria already used for the
first 43 cases.6 The definition of "normal" was
different, taking into account the rejection of fine hypodensities that
would previously have been overlooked.8 In some cases of
unstructured hypodensity, an early MRI analysis at day 3 or 4
was performed to seek the underlying mechanisms. The topographical
definitions were also those of the previous study, determined on the
day 7 CT scan.6 This classification allows comparisons
with classic MCA series.11 12 13 Cases with posterior
cerebral artery (PCA) involvement were registered. The CT template used
for vascular territories of the MCA and ACA was that of
Damasio14 and for the AChA that of Hupperts et
al.15 The description of structured and unstructured
images according to the different topographical territories is shown in
Figure 1.
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Etiologic Data
All patients surviving more than 1 week (n=95) had both
echocardiography (transthoracic in 94
cases and/or transoesophageal in 34) and neck
Doppler ultrasonography in 90 patients and/or 4-vessel angiography
in 36 patients. All patients with suspected proximal ICA
stenosis >70% or ICA dissection had angiography. The degree
of ICA stenosis was estimated according to the ECST
criteria.9
Biological Data
Coagulation tests were obtained before treatment and at 2 hours
and 24 hours after thrombolysis. They included
fibrinogen, fibrinogen degradation products, activated
partial thromboplastin time, euglobulin clot lysis time, and
prothrombin time (PT). Blood count was done at days 1 and 2.
Statistical Analysis
Concerning clinical and outcome data, all patients were
analyzed.
Univariate Analysis
The main comparison involved the group with good outcome (mR
0–1) and the group with bad outcome and death (mR 4–6). We also
compared this with the "ischemic bad outcome/death" group,
in which patients with bad outcome due to parenchymal hematomas were
subtracted. Only the unequivocally interpretable CT scans were taken
into account for radiological correlations. Therapeutic subgroups
defined by specific treatments (heparin protocols) or etiologic
subgroups were also compared between them for outcome at day 90. For
statistical analysis, the values were expressed as the
mean±SD, and differences between the groups were examined by the
2-sided Student t test for quantitative variables and
the Pearson or Fisher exact 
2 2-sided test for
qualitative variables.
Multivariate Analysis
Logistic regression analysis by stepwise backward
elimination method was performed to select minimum sets of baseline
variables (including the diagnosis of proximal ICA thrombosis by
neck ultrasonography, a potentially baseline variable), which
allowed the separation of patients with good outcome (mR 0–1) versus
those with bad outcome/death (mR 4,5,6). Based on this regression
model, the prognostic variables were selected and then used to
analyze and describe the additional prognostic effect of
ipsilateral proximal internal carotid thrombosis. SPSS Windows 95
(version 7.5) was used for all calculations.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Outcome
By October 30, 1996, we had studied 69 men and 31 women. The mean age at inclusion was 62.61±11.50 years. The mean interval to treatment was 236±80 minutes. Twenty patients were treated within 3 hours and 11 between 6 and 7 hours. Mean baseline SSS was 19.3. Table 2
gives the overall outcome observed in
these 100 patients at day 90. Forty-five patients had an excellent
result (mR 0–1). Eighteen patients had a moderate outcome. Thirty-one
patients had severe neurological sequelae, 28 with infarcts and 3 with
secondary parenchymal hematoma. Six patients died, 5 of them during the
first week, 3 of them with a parenchymal hematoma. Table 3 shows that early inclusion (<3 hours)
provided an identical good outcome rate (45%), whereas late inclusions
(between hours 6 and 7) maintained the rate of good results (45.5%).
The incidence of reinfarct was only 3%. In patients with low baseline
score, good outcomes were still observed: 27.7% for SSS <15 and
22.7% for SSS <6.
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The overall parenchymal hematoma rate was 7%. Two patients had
immediate hematomas. The remaining 5 patients had delayed hematomas,
all occurring within 24 hours; 3 of them had had a spectacular recovery
of stroke before the hematoma. The role of heparin protocols for the
delayed hematomas is analyzed in Table 4. The 3 groups were not significantly
different for age, gender, interval, and baseline SSS. No hematoma was
observed in protocol 2 with intravenous heparin given after
the 24 (+6)-hour CT scan (41 patients), whereas 2 deaths out of 3
hematomas were observed in protocol 1 (immediate heparin, n=31). In
protocol 3, with subcutaneous low-molecular-weight heparin (SCLMWH) (9
patients), 2 hematomas occurred (22.2%). Thus, 5 patients of 40
(12.5%) had delayed hematomas with immediate heparin
(intravenous or SCLMWH) versus none of 41 with heparin at
24 (+6) hours (0%) (P=0.03).
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Table 2
also shows the outcome of patients at 1 year. The overall good
result (mR 0–1) at 1 year was 40%, while the cumulative death rate
was 10%. Of 38 patients less than 61 years of age engaged in
professional activity, 11 (28.9%) had returned to full-time work
(10-point score 0), 4 (10.5%) to part-time work (10-point score 1),
and 1 changed his job (10-point score 2); the total return-to-work rate
was 42.1%.
Stroke Territories
Table 5 shows the distribution of
the territories affected according to the interpretable day 7 CT scans
among survivors. The proportion of good results was high in stroke
territories of the AChA (75%), localized superficial MCA (68.8%), and
basal ganglia MCA (48%). Conversely, it was low in strokes affecting
the complete MCA (28.6%) and MCA+ACA (10%). Other rarer topographic
formulas were observed: total MCA+AChA, 1 case, and total MCA+ACA+AChA,
3 cases; these large infarcts had bad outcome and additionally involved
the PCA in 2 cases (Figure 3, panel 3). The differences in outcome at
day 90 between the above-mentioned topographical subgroups were
statistically significant (P<0.00001). Reinfarcts were
observed in 2 cases involving AChA infarcts and in 1 case of a small
infarct of the deep lenticulostriate branch of the ACA.
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Radiological Data
Table 6 indicates the radiological
findings observed at baseline and on the day 1 and day 7 CT scans whose
quality allowed a relevant analysis. On baseline CT scan, the
most frequent early abnormalities were lenticular nucleus effacement
(54.6%) and indistinction of gray/white matter (45.4%). Only 1
patient had classic hypodensity of more than one third of the MCA
territory (MCAt). Table 6 shows that early CT scan findings were much
more frequent among the subgroup with bad outcome/death. Three early
features were significantly linked to bad outcome/death: indistinction
between white and gray matter (P<0.0005), lentiform nucleus
effacement (P=0.01), and isolated fine hypodensity of more
than one third of the MCAt8 (P=0.09;
P=0.05 when a comparison of good outcome versus bad
outcome/death was performed). No type of swelling indicated a
significant difference in prognosis, but the combination of swelling
and fine hypodensity of more than one third of the MCAt was significant
(P=0.03). However, patients with good prognosis also had
early CT scan signs: 27.3% of them had swelling or fine hypodensity of
more than one third of the MCAt, 22.7% had indistinction of the
white/gray matter, and 38.6% had effacement of the lentiform
nucleus.
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On day 1 CT scans, so-called structured hypodensities6
were observed in 49.5% and unstructured hypodensities in 47.4%. In
some cases of unstructured hypodensities, the term "fragmented"
hypodensity might be more appropriate (Figure 1, panels 4 and 5).
Preliminary early MRI analysis of some of these images showed
that they corresponded to T2-weighted fragmented hypersignals actually
concerning the MCA territory at risk (Figure 2, panel
3). Unstructured hypodensities were linked to good outcome
(P<0.0005), while structured hypodensities were linked to
bad outcome/death (P<0.0005). Data from the day 7 CT scan
(Table 6) disclosed the stability of the frequency of structured and
unstructured hypodensities. Normal CT scans were observed only in the
good outcome group.
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Etiologic Data
Table 7 indicates the presumptive
stroke etiology in the 95 early survivors, in whom the etiological
screening had been performed. The cardioembolic subgroup (isolated)
appeared as the major group (29.5%), whereas isolated unequivocal
ipsilateral atheromatous ICA disease (thrombosis and
stenosis of >70%) represented 23.1%. Four
patients with ICA stenosis ipsilateral to the stroke and a good
postthrombolytic short-term outcome had
endarterectomy, without any
perioperative morbidity. There was no significant
difference of outcome at day 90 between these groups, although a
tendency to worsened outcome was observed in ICA atheroma
subgroups.
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However, when an isolated etiologic factor versus lack of it was taken
into account for outcome at day 90 (atrial fibrillation, valvulopathy,
minor cardioembolic source, ICA atheromatous plaque,
ICA atheromatous stenosis >70%, aortic arch
atheroma, and proximal ICA thrombosis), proximal ICA
thrombosis (all types) ipsilateral to the stroke was the only factor
significantly linked to bad outcome/death (P=0.03).
Atheromatous proximal ICA thrombosis, a part of this
subgroup, was also a significant factor (P=0.02), whereas
dissectional proximal ICA thrombosis was not (Table
8).
Proximal ICA thrombosis ipsilateral to the stroke was present
in 24.2% of patients of this series (16 atherothrombotic, 7
dissectional) and defined a subgroup with bad prognosis/death (52.2%
of the entire group; 68.75% of the atherothrombotic subgroup).
Proximal ICA thrombosis was statistically linked to the presence of
large infarcts (Pearson 2 test, P=0.02) and
the presence of structured hypodensity on the day 1 CT scan (Fisher
exact test, P=0.01). Radiological formulas involved large
MCA infarcts isolated (34.7%) or associated with other carotid artery
branches: MCA+ACA, 21.7%; MCA+AChA, 4.3%; MCA+ACA+AChA, 4.3%; and
MCA+ACA+AChA+PCA, 4.3% (Figure 3). Proximal ICA
thrombosis was also statistically linked to lack of major neurological
improvement at day 1 (Fisher exact test, P=0.03).
Coagulation Data
Prethrombolysis and
postthrombolysis analyses of coagulation values
(baseline versus 2 hours after onset of treatment) showed that the mean
fibrinogen value did not diminish significantly (3.5±1.1 versus
3.5+8.6 g/L), whereas FDP values increased significantly (46.1±135.8
versus 262.7±836 mg/L; P=0.04). At day 1, fibrinogen levels
diminished (2.7±0.9 g/L) while FDP returned to normal (31.1±46.2
mg/L). In the group of patients with parenchymal hematomas, extremely
high postthrombolytic (2 hours) FDP values were
observed in 3 patients (600, 500, and 200), with corresponding
fibrinogen values of 2.8, 1.9, and 0.7 g/L.
Correlations
Univariate Outcome Comparison Studies
The good outcome group was compared with the overall bad
outcome/death group (including the 7 hematomas) (Table 8, columns A, B
and AvsB; Table 6 for radiology) and showed several significant
differences: (1) higher baseline SSS median score (P=0.01);
(2) lower number of patients having had mannitol treatment
(P<0.005) and lower number of patients having SCLMWH
(P<0.002); (3) lower proportion of patients with specific
types of early CT scan changes (Table 6); (4) increased proportion of
3-hour (P=0.02) and 24-hour regressors
(P<0.00005); (5) improved neurological score (SSS) at day 1
(P<0.0005); (6) increased proportion of patients showing
unstructured hypodensities on the day 1 CT scan (P<0.0005)
(UH) and a lower proportion with structured hypodensities
(P<0.0005); (7) lower proportion of patients having
arteriopathy of the lower inferior limbs
(P=0.05); (8) different distribution of stroke
territories (overall analysis, P=0.0005), with a
higher proportion of strokes in the territories of AChA, MCA basal
ganglia territory, and MCA superficial territory, and a lower
proportion of large strokes (total MCA territory or MCA with other
territories); and (9) lower proportion of patients with
ipsilateral atheromatous ICA thrombosis (11.1% versus
34.4%; P=0.02) and ICA thrombosis in general (15.6% versus
37.5%, p=0.03). Conversely, no difference was detected for age,
gender, vascular risk factors, time interval to treatment, timing of
intravenous efficient heparin, proportion of isolated
cardiac embolic sources, proportion of patients with atrial
fibrillation, and coagulation parameters.
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The same pattern of significant differences was observed when the good
outcome group was compared with the ischemic bad outcome/death
group (hematomas excluded), including the significant linkage of SCLMWH
heparin with bad outcome (Table 8, columns B versus C).
When the subgroup with 7 parenchymal hematomas was compared with the nonhematoma group, a significantly higher median FDP value at hour 2 was found (400 versus 200 mg/L; Mann-Whitney test, P=0.04).
Multivariate Outcome Studies
There was a trend for immediate heparin (intravenous
immediate or immediate SCLMWH) to be a factor of bad prognosis/death
(odds ratio [OR], 2.33; 95% confidence interval [CI], 0.94 to
5.76; P=0.06).
A model of 6 baseline variables exhibiting significant predictive values of bad outcome/death compared with good outcome in univariate analysis was proposed. It included (1) baseline SSS <15 (P=0.013); (2) hypodensity more than one third of the MCAt on CT scan (P=0.05); (3) indistinction of white/gray matter on CT scan (P=0.0005); (4) hypodensity or swelling of more than one third of the MCAt on CT scan (P=0.013); (5) lenticular nucleus effacement on CT scan (P=0.004); and (6) a potential baseline variable: presence of ipsilateral proximal internal carotid thrombosis (neck Doppler sonography and/or angiography) (P=0.03). When logistic regression was applied to this model to identify patients with bad outcome/death (mR 4,5,6) versus those with good outcome (mR 0–1), it selected the 3 most significant variables: baseline SSS<15 (OR, 3.38; 95% CI, 1.07 to 10.74; P=0.04), indistinction white/gray matter on CT scan (OR, 6.59; 95% CI, 2.19 to 19.79; P=0.0008), and proximal internal carotid thrombosis (OR, 3.29; 95% CI, 0.99 to 10.95; P=0.05). Further analysis disclosed that these 3 factors were not linked, so that proximal internal carotid thrombosis provided its own independent factor of bad prognosis. In 2 other models, atherothrombotic and dissectional proximal internal carotid thrombosis were submitted separately with the 5 other variables to logistic regression: atheromatous proximal internal carotid thrombosis appeared also as a significant independent predictive factor of bad prognosis.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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General Background
Our statistical analysis was obtained from an open, nonrandomized study. Thus, the different issues discussed here are observational. Only double-blind placebo rtPA trials could confirm the recommendations proposed here.
General Clinical Data
This extension of our open study to 100 patients confirms several
results of the first 43 patients already published,6
especially the suggestion of the efficacy of rtPA
thrombolysis in ICA territory acute strokes, at a dose
of 0.8 mg/kg administered for 90 minutes, within 7 hours of stroke
onset. This study has many points in common with the NINDS rtPA
study.4 It shares the same dosage range (0.8 versus 0.9
mg/kg) and the absence of exclusion criteria concerning clinical
severity and CT baseline images. The differences lie in the time window
(7 hours versus 3 hours), the use of immediate intravenous
heparin in approximately one third of the patients, the exclusion of
vertebrobasilar infarcts, and a probably more serious baseline score
(the estimated baseline NIH score would be at least 18, instead of 14
in the NINDS rtPA group, part 2). The good outcome rate at day 90
(45%) is in the range of that of NINDS rtPA part 2 (39%), while the
parenchymal hematoma rate is identical (7%). While the baseline SSS
median score is more serious in this study than in the
ECASS-15 intention-to-treat rtPA group (19.1 versus 28),
the good outcome rate at day 90 is better (45% versus 35.7%) and the
hematoma rate is lower (7% versus 19.8%). This might suggest that a
dose of 0.8 to 0.9 mg/kg can induce a better benefit/hematoma risk
ratio in ischemic stroke compared with 1.1 mg/kg. Moreover, our
study suggests that the dose of rtPA can be lowered to 0.8 mg/kg
without diminishing the efficiency.
Our study also suggests that the extension of the therapeutic window to 7 hours does not lower this efficacy; moreover, the rescue rate is exactly identical (45%) in the patients at <3 hours and >3 hours. Human thrombolysis time windows may differ from experimental ones, especially the 3-hour window in the rabbit.16 It has been shown experimentally that parenchymal central nervous zones involved in ischemic penumbra may be rescued by restoration of blood flow until 6 hours17 in a baboon MCAO model. The hypothesis of a larger human reperfusion window, open until 24 hours, has been proposed.17 18 19 On the other hand, we have shown that delayed rtPA thrombolysis between 6 and 7 hours does not increase the risk of hematoma formation. This fact is in keeping with the lack of increased hemorrhagic risk observed in a rabbit model of embolic stroke, when rtPA was delayed 8 to 24 hours.20 Thus, while new double-blind studies should test the 7-hour window, we suggest the launching of open trials to explore specifically the intervals of 7 to 8 hours and 8 to 9 hours.
Mortality at day 90 (6%) and at 1 year (10%) is low in this series. This may result from to the benefits of care in a dedicated stroke unit and the use of high doses of mannitol in patients with low SSS scores. The other previously mentioned adjuvant therapies may also have played a role.
Results of the Univariate Data
Hematoma, Coagulation, and Heparin
Our study shows that the parenchymal hematoma rate might be linked
to the FDP increase at 2 hours, ie, to the intensity of
thrombolysis. Such a relationship has been suggested in
myocardial infarcts with intracranial hemorrhage in the TAMI
study,21 on the basis of a decreased
postthrombolytic fibrinogen value in this subgroup.
While immediate hematomas are beyond prevention, our study suggests a
possible preventive monitoring of delayed hematomas. The suppression of
any immediate postthrombolytic heparinization during
the first 24 (+6) hours (intravenous efficient or
subcutaneous presumably not efficient) induces a decrease of the
occurrence of delayed hematomas. Double-blind studies are necessary to
address this heparin issue and confirm the potential danger of its use
during the first 24 hours after thrombolysis.
Topographical Data
We have observed remarkable regressions in AChA strokes, in MCA
basal ganglia isolated strokes, and in superficial MCA strokes
(localized or total). These data are in keeping with the results of the
NINDS study4 mentioning higher good outcome and response
rate in "small-vessel strokes." In AChA strokes, we emphasize the
rapid regression of hemiplegia at the end of
thrombolysis. Conversely, complete MCA strokes,
isolated or with ACA or with ACA+AChA, were clearly related to bad
outcome. Taken together, these data suggest an inverse relationship
between the size of the clot and the effect of rtPA, a fact
demonstrated in experimental rtPA trials, which show a limitation of
the effect of rtPA with large clots.22 23 However,
patients with potentially large infarcts have definitely been rescued,
as demonstrated in Table 5, while the existence of an "aborted"
complete MCA infarct has been demonstrated in 1 case with T2-weighted
MRI (Figure 2). Thus, it does seem wise to continue the inclusion of
potentially large infarcts in future routine protocols, though the
success rate might be lower.
Early CT Changes
Univariate analysis indicates that only 3
early CT changes have a significant predictive value of bad
outcome/death: indistinction of white/gray matter, lentiform nucleus
effacement, and fine hypodensity of more than one third of the MCAt. We
thus confirm the suggestions by Hacke et al5 and von
Kummer et al8 concerning the bad outcome predictive value
of early CT scan changes. However, patients with impressive baseline
hypodensities may still provide good therapeutic surprises with
clinical and anatomical rescues (Figure 2).
Signification of "Unstructured" Hypodensities
Our earlier allegations6 concerning the
relationship between unstructured hypodensities on the day 1 CT scan
and good outcome, suggesting recanalization and
reperfusion, are confirmed. Our hypothesis, proposing that this type of
hypodensity corresponds to rescue of affected territories by
reperfusion hyperemia24 25 and/or incomplete
ischemic damage, could be illustrated in some cases by MRI
(Figure 2). Such an rtPA rescue has been demonstrated with positron
emission tomography (PET) scan.26 In natural infarcts, a
relationship between reperfusion demonstrated by PET scan and good
outcome has been suggested.27
Multivariate Data, With Particular Reference to
Proximal ICA Thrombosis
Baseline Neurological Score
Initial grave presentation with SSS <15 appears as a
key clinical independent predictor of bad prognosis. Some trials
exclude patients with initial seriousness. However, according to our
data, 27.7% of patients with SSS <15 still show a good outcome, and
even 22.7% of patients with SSS <6 are rescued. This fact may justify
the inclusion of grave patients in thrombolytic
protocols.
Indistinction Between White and Gray Matter
This baseline CT change is the only one that behaves as an
independent predictive factor of bad prognosis in our study, whereas
hypodensity and effacement of lenticular nucleus do not hold up
against logistic regression. A relationship between
indistinction of gray/white matter and early deep ischemia
might be proposed. An important finding, however, is that 22.7% of
patients with this change show a good outcome. Thus, exclusion of
patients with baseline indistinction gray/white matter may not be
justified.
Proximal Internal Carotid Artery Thrombosis
We have shown that proximal ICA thrombosis ipsilateral to stroke
is both a predictor and a powerful baseline independent factor of bad
outcome/death. To our knowledge, this fact has not been previously
demonstrated on a statistical basis in a series with
intravenous rtPA thrombolysis. We also have
shown that proximal ICA thrombosis, atherothrombotic and dissectional,
was an extremely important etiologic factor in our series, since it
represented 24.2% of the patients. The frequency of
extracranial ICA thrombosis in a series of patients at <6 hours has
been specifically addressed by other investigators.28 29 30
The respective frequencies found were the same as ours. These data
demonstrate that ICA thrombosis plays a major role in prognosis. For
instance, while the good outcome rate in the first 43 cases of this
series was 58.2% with a prevalence of proximal ICA thrombosis of
13.9%,6 it fell in the present completed cohort of
100 cases at 45% while the prevalence rose to 24.2%. If proximal ICA
thrombosis patients are excluded from this series, the good outcome
rate becomes 52.8%.
The question of proximal ICA thrombosis in rtPA
thrombolysis should be discussed from 2 different
points of view: that of outcome and that of response. In terms of
outcome, our open-label study shows a high proportion of bad outcome in
this group, especially in the atheromatous thrombosis
subgroup (68.75%). However, 31.25% still have a good prognosis (Table 7; see also Figure 3, panel 5). Only a double-blind study could give
information on the possible participation of this subgroup to the final
improvement of outcome. Our data show that its exclusion would remove a
possibility of good outcomes. Thus, in the routine of the
intravenous thrombolytic technique, these
patients should not a priori be excluded.
From a response point of view, only a double-blind study with etiological investigations could demonstrate that proximal ICA thrombosis strokes respond clinically at a lower rate to rtPA thrombolysis. In the present state of knowledge, no direct indications are available. However, indirect arguments can be provided. The angiographic response of ICA thrombosis stroke to intravenous rtPA has been shown to be low.28 The same phenomenon has been observed with intra-arterial thrombolysis at the contact of the neck "clot": recanalization of proximal ICA is rarely obtained,31 32 33 34 the exact rate with urokinase being 12.5%.35 This low rate of angiographic response is considered by some authors as a contraindication of the method.36 Moreover, in our series, we found a relationship between proximal ICA thrombosis and low rate of clinical response on day 1 and low rate of radiological response (presence of "unstructured" hypodensities) on day 1 CT. The outcome is also linked to the large size of structured hypodensities on day 1, itself correlated with the presence of proximal ICA thrombosis.
The explanation of this probable relative
"pharmaco-resistance" of strokes with proximal ICA thrombosis to
thrombolysis might take into account at least 3
factors: (1) the large volume of the clot provides a particularly
unfavorable ratio, volume of clot/rtPAemia, according to the
already-cited limitation of rtPA efficiency in experimental large-clot
models22 23 ; (2) an extracranial block of rtPA takes
place, impeding the thrombolytic agent from reaching at
sufficient dose a causative clot if this is located in an
intracerebral branch; and (3) the important early
global hemispheric ischemic area involves the total MCA
territory, often associated with ACA, AChA, and PCA territories.
Classic autopsy series37 38 39 have provided elements in
favor of the following specificities: block of the circle of Willis by
direct extension of the clot; massive soft emboli in the MCA, ACA,
AChA, and even PCA territories; and supplementary ongoing clotting in
the form of diffuse platelet aggregation in these large
arterial territories. The high frequency of large infarcts
(about two thirds of cases) in these series is in keeping with
the data of our CT scans at days 1 and 7, which also show in 69.6% of
the ICA thrombosis cases a complete MCA stroke or complete MCA
associated with ACA and/or AChA, and even PCA (Figure 3, panels
1–5).
These anatomic characteristics provide arguments in favor of the hypothesis of a "supplementary hemodynamic block" in proximal ICA thrombosis, the thrombolytics having difficulties in crossing the thrombosis barrier. The question of a specific treatment for these patients is thus raised. A possible solution is the perforation of the proximal ICA clot, permitting thrombolysis beyond and in the clot. Nesbit et al,40 in performing this pioneer method with the navigation of a microcatheter through the occluded ICA in 4 patients (in 1 case dissectional), obtained 2 dramatic improvements and achieved the recanalization of the ICA in 2 cases. Higashida et al41 also succeeded in one case and completed the recanalization with an angioplasty of the ICA.
In conclusion, our study confirms the safety of intravenous rtPA at a dose of 0.8 mg/kg and suggests efficacy for this drug up to within 7 hours. Outcome and hematoma rates were at least as favorable as for trials of therapy with a 3-hour time window. The suppression of heparin during the 24 first hours is linked to a decrease of delayed hematomas. Subgroups with a poor prognosis determined by multivariate analysis include low baseline neurological score, baseline CT changes, and proximal ICA thrombosis. However, approximately 30% of patients with each of these characteristics show a good outcome, so their inclusion in future routine rtPA protocols may be justified.
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