1
INTRODUCTION
1. BACKGROUND
Stroke is the third leading cause of death after cardiovascular
disease and cancer, and is also the leading cause of disability in
developed countries. The burden of strokes has increased steadily,
mainly in developing countries, with deaths accounting for 75.2% of
the world, including Vietnam. Therefore, the goal of reducing the
mortality and morbidity due to stroke is constantly urgent and
challenging.
Up to now, the strategy of recanalision treatment with the
intravenous thrombolysis by Alteplase remains the cornerstone in
the emergent management of acute ischemic stroke within 4.5 hour
from symptom onset. The recommendations of up-to-date
international guidelines show that the thrombolytic treatment as a
standard option, in a maximum time window of 4.5 hours, with the
highest level of evidence.
Studies in Asia had demonstrated the outcomes of low-dose
administration was noninferior to those with standard dose
thrombolytic trials in the United States and Europe, while the
complications are much lower, especially intracranial hemorrhage.
Domestic and international studies had indicated that the
treatment of low-dose Alteplase within 3 hours after stroke onset
had high rate of patients with favorable outcome at 3 months.
ENCHANTED, a international randomised control trial was
conducted to compare the results of low-dose and standard-dose
intravenous Alteplase in acute ischemic stroke within 4.5 hours after
the onset, did not show the noninferiority of low-dose alteplase to
standard-dose alteplase with respect to death and disability at 90
days However, symptomatic intracranial hemorrhage was
significantly higher in the standard dose group (2.1% vs 1.0%). In

2
addition, when analyzing the subgroup of 3 to 4.5 hours treatment,
the outcome in both groups were similar (51.1% versus 50.1%).
To date, there have not been any study specifically mentioned
the treatment of intravenous low dose Alteplase between 3 to 4.5hour after onset. Therefore, we conducted the study: "The treatment
outcome of acute ischemic stroke between 3 to 4.5 hours with low
dose Alteplase thrombolysis", with objectives as follow:
1. To describe the clinical features and brain CT scans
presentation of ischemic stroke patients between 3 to 4.5
hours after symptom onset.
2. To evaluate the outcome of acute ischemic stroke treating
with low dose Alteplase thrombolysis (0.6 mg / kg) between
3 to 4.5 hours after symptom onset, during hospital stay
period , at 3 months and adverse events.
3. To find out the predictive factors for neurological recovery
at 3 months.
3. THE LAYOUT OF THESIS:
There are pages, including: Introduction (3 pages); Chapter 1.
Overview (43 pages); Chapter 2. Objectives and methods (22
pages); Chapter 3. Results (40 pages); Chapter 4. Discussion (40
pages); Conclusion (2 pages) ; Recommendtion (1 page) ;
Limitation ( 1 page). There are also 170 references section,
appendices, tables, charts, illustrations.
2. NEW CONTRIBUTIONS
The thesis assessed the outcome and adverse events of
treatment for acute ischemic stroke patients at window time from 3
to 4.5 hours with low dose Alteplase (0.6 mg/kg) during inpatient
period and at 3 months. This publication does not overlap with those

of other studies in and out of the country.
The thesis identified independent outcome predictors and the role of
prognostic scores for unfavorable neurological recovery at 3
months. The study has simultaneously applied multiple score


3
(ASPECT, NIHSS, DRAGON, ASTRAL, HAT), which other studies
have not mentioned simultaneously.
CHAPTER 1: OVERVIEW
1.1.1. Cerebral autoregulation during ischemic stroke
Cerebral autoregulation is impaired during some disease
conditions, including ischemic stroke. As cerebral perfusion
pressure falls, cerebral blood vessels dilate to increase cerebral
blood flow. A decrease in perfusion pressure beyond the ability of
the brain to compensate results in a reduction in cerebral blood flow.
Initially, the oxygen extraction fraction is increased in order to
maintain levels of oxygen delivery to the brain. As the cerebral
blood flow continues to fall, other mechanisms come into play.
Neuronal electrical failure occurs at 16 to 18 mL/100 g per minute,
and failure of membrane ion homeostasis occurs at 10 to
12 mL/100 g per minute. This level typically marks the threshold for
the development of infarct
1.1.2. Ischemic penumbra
Ischemic penumbra is a localized ischemic area with
impaired function and at risk of infarction, but it is likely to be saved
by reperfusion or other strategies. If not, the ischemic zone would be
progressively infarcted until it reaches its maximum volume, that
was the original volume of risk.
1.1.3. Mechanism of ischemic stroke

Embolic Mechanism: Embolism refers to clot or other material
formed elsewhere within the vascular system that travels from the
site of formation and lodges in distal vessels causing blockage of
those vessel and ischemia. The heart is a common source of this
material, although other arteries may also be sources of this embolic
material (artery to artery embolism). In the heart, clots may form on
valves or chambers. Tumors, venous clots, septic emboli, air, and fat
can also embolize and cause stroke. Embolic strokes tend to be


4
cortical and are more likely to undergo hemorrhagic transformation,
probably due to vessel damage caused by the embolus.
Hemodynamic Mechanism: Thrombosis refers to obstruction of a
blood vessel due to a localized occlusive process within a blood
vessel. The obstruction may occur acutely or gradually. In many
cases, underlying pathology such as atherosclerosis may cause
narrowing of the diseased vessel. This may lead to restriction of
blood flow gradually, or in some cases, platelets may adhere to the
atherosclerotic plaque forming a clot leading to acute occlusion of
the vessel. Atherosclerosis usually affects larger extracranial and
intracranial vessels. In some cases, acute occlusion of a vessel
unaffected by atherosclerosis may occur because of a
hypercoagulable state.
1.1.4. Etiologic classification of ischemic stroke
Acute ischemic stroke subtypes are often classified in clinical
studies using a system developed by investigators of the TOAST
trial, based upon the underlying cause. Under this system, strokes
are classified into the following categories: Large artery
atherosclerosis; Cardioembolism; Small vessel occlusion; Stroke of

other, unusual, determined etiology; Stroke of undetermined etiolog.
1.2. Mechanisms of Thrombus Formation and the impact of the
tissue plasminogen activator on thromboembolism
1.2.1. Mechanisms of Thrombus Formation
The main cause of clot formation for ischemic stroke is
endothelial cell injury of atherosclerotic plaque and it can also be
established from the heart chambers. In addition, the composition of
the thrombus may depend on a number of factors, including the
extent of blood vessel damage, intravascular pressure, and the
presence of thrombotic agents.


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1.2.2. Thrombolysis
Plasmin formation plays a central role in thrombolytic
processes. Endogenous fibrinolytic system includes plasminogen,
plasminogen activator, and fibrinolytic inhibitory factor. Fibrin
degradation requires plasmin activation. Plasminogen, its activating
factor, and fibrinolytic suppression factor contribute to the balance
between hemorrhaging and thrombosis.
1.2.3. The impact of the tissue plasminogen activator on
thromboembolism (Alteplase)
Alteplase is a specialized plasminogen activator with fibrin,
which has a good thrombolytic activity, does not reduce systemic
clotting factors, and has a short half-life. This is a remarkable
advantage of Alteplase compared with non-specific plasminogen
activators with fibrin.
1.3. The roles of neuroimaging in acute ischemic stroke
1.3.1. Computed tomography (CT)
Computed tomography plays a very important role in acute

ischemic stroke. The main advantage of computed tomography in
comparison with MRI is the availability and the technique could be
done quickly, cost-effectively. For hyperacute stroke, computed
tomography without contrast is often indicated for the exclusion or
identification of intracranial hemorrhage. Non-contrast CT should
be performed as soon as possible in order to initiate the thrombolytic
therapy in the best way.
The early signs of ischemic stroke on noncontrast computed
tomography: In hyperacute phase, early ischemic signs on CT
scans would hardly be found on noncontrast CT. The sensitivity of
standard noncontrast CT for cerebral infarction increases over time,
particularly after 24 hours.
ASPECT score in assessing early ischemic changes on head CT
scan: ASPECT score (the Alberta stroke program early CT score) is


6
a simple and reliable method for assessing ischemic cerebral lesions
on CT scans. Currently, the score is applied in specialized
neurodiagnostic units and plays an important role in thrombolytic
treatment and endovascular interventions for stroke patients.
CT angiography (CTA): CTA is considered as a standard practice
in managing acute ischemic stroke. The CTA evaluation of cerebral
blood vessels has high reliability. In addition, it is possible to do
multiphase CT and CT perfusion.
1.3.2. Magnetic Resonance Imaging (MRI)
MRI characteristics of early changes in acute ischemic stroke
including increased (hyperintense) DWI signal, hypointense signal
on ADC maps and increased signals on FLAIR.
Diffusion-weighted imaging (DWI): This technique can detect

ischemic abnormalities within 3 to 30 minutes after stroke onset,
meanwhile CT and standard MRI are not sensitive enough to expose
the lesion. MRI can be a good alternative for CT or in some cases,
the combination of both models is the best option.
Magnetic Resonance Imaging (MRI): A magnetic resonance
imaging (MRI) scan for narrowing or embolism is commonly
performed as part of pulse trainings for patients with acute cerebral
infarction.
MR angiography (MRA): MRA to detect vascular stenosis or
occlusion is routinely done as part of a fast MRI protocol for acute
ischemic stroke.
1.4. Studies of intravenous Alteplase treatment
International trials: An important breakthrough appeared in 1995,
the National Institute of Neurological Disorders and
strokepublicized NINDS trial . It showed that the intravenous use of
tissue plasminogen activator recombinant (rtPA) improve
neurological function in patients with ischemic stroke after three


7
months. In 2008, the ECASS 3 trial in Europe demonstrated the
safety and efficacy of Alteplase when given at 3 to 4.5 hours after
the onset of stroke. Since then, treatment window has been accepted
from 0 to 4.5 hours. In Asia, Japan routinely uses low doses after
approval by the Ministry of Health in 2006. By 2016, the
ENCHANTED trial compared the outcome of standard dose and
low-dose Alteplase within treatment window 4.5 hours. The results
shows that low doses (0.6mg/kg) was safer than the standard dose
(0.9 mg/kg) with significantly fewer symptomatic intracerebral
hemorrhages. And in the low dose group, favorable outcome at 3

months was equivalent to standard dose at the treatment window
from 3 to 4.5 hours. However, the study did not show the
noninferiority of low-dose alteplase to standard-dose alteplase with
respect to death and disability at 90 days.
By now, many efforts have been made to develop a more efective
drugs than Alteplase, but there is still not enough evidence.
Alteplase studies in Vietnam: The first case of intravenous rtPA
treatment for acute ischemic stroke patients were reported by Phan
Cong Tan from 2005. In 2006, the first study to evaluated the safety
and efficacy of rtPA was done in three facilities: 115 People's
hospital, Gia Dinh People's hospital and An Binh hospital. At three
months, the rate of good clinical outcome (modified Rankin 0-1)
was 43%, symptomatic intracranial hemorrhage was 4%, mortality
was 8%. In 2013, Nguyen Huy Thang published the results of 152
patients treated with intravenous standard dose alteplase within 3
hours after onset in 115 People's Hospital. Good outcome
rate(modified Rankin 0-1) at 90 days was 45%. Symptomatic
intracranial hemorrhage(sICH) was 4.6%. The risk of death due to
sICH was 71.4%. Mortality rate at three months was 11.8%. A
research of Mai Duy Ton (2013), assessed the safety and
effectiveness of treatment for acute ischemic stroke by intravenous
low dose alteplase within 3 hours window in 66 patients, at Bach


8
Mai hospital, Hanoi. The rate of good clinical outcome (Rankin 0-1)
was 51.51% at 90 days; symptomatic brain hemorrhage was 1.52%;
mortality was 3:03%. This result showed that low dose Alteplase
was safe and could be as efective as the standard dose regimen.
Currently, Alteplase remains the standard therapy for acute ischemic

stroke for up to 4.5 hours after symptom onset. Thrombolytic trials
are ongoing to increase benefits, reduce risk and widen treatment
windows to increase the number of patients using tPA.
1.5. Predictive factors and scores
1.5.1. Predictive factors: To date, many studies have shown that
factors that may be associated with prognosis include: Age, sex,
treatment windows, blood glucose, history of diabetes mellitus,
occlusion sites and causes of stroke.
1.5.2. Predictive Scores: Neurologists and radiologysts have
recently developed several diagnostic and prognostic scores for
better dicision in stroke treatment. Scores can be integrated multiple
symptoms and signs, both clinical presentation and neuroimaging
including, most importantly, ASPECT scores (CT), DRAGON, HAT
(Clinical and CT combination), ASTRAL, NIHSS (Clinical only) ...
CHAPTER 2: METHODS
2.1. Subjects
Patients who admitted to Emergency department, Bach Mai
hospital, diagnosis of acute ischemic stroke within 4.5 hours after
the symptom onset, eligible individuals was to participate in the
study, in the period from 20th of November 2014 to 1st of October
2017. The follow up ended in 02/2018.
All patients who were eligible for the thrombolytic treatment
by Alteplase generally had done urgent medical treatment on a rule
of "time is brain" . In cases the treatment indicated within 3 hours
after symptom onset, it was not allowed to delay Alteplase
administration. Only patients with objective, unforeseeable causes
leading to the time of Alteplase injection have fallen into the


9

window period of 3 to 4.5 hours were eligible to included in this
study. Selection criteria were based on the sampling protocol of the
NINDS and ECASS 3 trials.
2.2. Methods
A longitudinal, prospective, descriptive study. The variables
and indexs were collected according to the purpose of study. Stroke
specialist and fellow had implemented the study. The fellow
collected data according to given medical record forms. Data
calculation and processing by STATA 14.0.
Sample size was calculated by formula:
Z21-α/2 p ( 1- p)
n
=

d2

In which: n was minimal sample size; Z 1-α/2 = 1,96, was level
of confidence; p = 52.4% was the rate of favorable outcome
( modified Rankin score ≤ 1) at 3 months (52.4%) in ECASS 3 trial
that has criteriors and subjects similar to the study. d was deviation
= 0.1. Replace to the formula above,:we had n = 1.96 x 1.96 x 0.524
x 0.476/ 0.1 x 0.1 = 95.8. So, minimal sample size was 96 patients.
2.3. Ethical issues in medicine
The treatment protocol has been approved by the Bach Mai
Hospital, the Ministry of Health and the Scientific Council. The
study did not alter the existing treatment regimens and procedures
and did not generate any costs or any disturbance for the patient.
Patients and relatives were explained about the purpose of the study,
the steps taken and their voluntary participation in the study.
Information regarding the patients was kept confidential.



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CHAPTER 3: RESULTS
3.1. Baseline clinical characteristics, CT scan presentations and
stroke classification
Table 3.1: Baseline clinical and CT characteristics
Age (yrs)
Mean
64.79 ± 9.75
Median
64
Male (%)
58.59
Time from onset to Alteplase treatment (mins)
Mean
207.87 ± 26.5
Median
195
NIHSS
Mean
11.93 ± 4.23
Median
11
DRAGON score
Mean
4.68 ± 1.68
Median
5
ASTRAL score

Mean
25.83 ± 5.45
Median
25
HAT score
Mean
1.24 ± 1.07
Median
1
Pretreatment blood pressure (mmHg)
Systolic
152.79 ± 21.73
Diastolic
84.65 ± 10.1
Neurologic clinical presentation (%)
Impared level of consciousness
22.22
Hemiparesis
92.93
Hemisensory deficit
64.65
Cranial nerve paresis
92.93


11
Language impairment/aphasia
Disarthria
Extinction and inattention


35.35
63.64
30.30

History of diseases (%)
Hypertension
Diabetes mellitus
Dislipidemia

Athorosclerosis
Atrial fibrillation

Stroke
Valvular heart diseases
Heart failure
Cigarette smoking
Concomitant diseases (%)
Mitral valve stenosis
Heart failure (EF < 55)
Mitral valve stenosis/ Heart failure

Left ventricle thickness
Baseline CT scan presentation
ASPECT score (63 pts)
Mean
Median
ASPECT = 10
ASPECT = 9
ASPECT = 8
ASPECT = 7

Early signs on CT (%)
Cortical sulcal effacement

Focal parenchymal attenuation
Loss of grey – white matter differentiation
Loss of the insular ribbon

78.79
19.19
72.73
60.60
22.22
6.07
6.07
8.08
24.24
6.06
8.08
4.04
77.77

8.6 ± 1.11
9 (7 – 10)
26.98 %
23.81 %
28.57 %
20.64 %
16.16
54.55
40.40

28.28


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MCA hyperdense sign - M1 segment
MCA dot sign - M2 segment
Normal CT
Abnormal CT
Occlusion positions (%)
Middle cerebral artery (MCA) - M1 segment
Middle cerebral artery (MCA) - M2 segment
Middle cerebral artery (MCA) - M1 plus M2
Intracranial carotid artery ( ICA) plus M1
Intracranial carotid artery ( ICA)
Anterior cerebral artery ( ACA)
Posterior cerebral artery ( PCA)
Basilar artery ( BA)
Small vessels
Total
Etiologic classification (%)
Large-artery atherosclerosis
Small-vessel occlusion
Cardioembolism
Undetermined etiology
Other determined etiology
Total (99 pts)
3.2. Treatment Results
Table 3.2: Treatment Results
NIHSS changes after Alteplase administration
NIHSS

Mean
Alteplase Pretreatment
11.93 ± 4.23
One hour after Alteplase loading
8.38 ± 5.11
24 hours after Alteplase loading
7.64 ± 5.69
At discharge
7.21 ± 5.32
NIHSS changes after 24 hours
No. of Patients

18.18
22.22
28.28
71.72
25.25
34.34
2.02
2.02
2.02
3.03
2.02
1.01
28.28
100
36.37
28.28
22.22
13.13

0.00
100

Median
11
7
7
7
Rate (%)


13
NIHSS improvement ≥ 4 points
58
58.59
NIHSS worsening ≥ 4 points
3
3.03
NIHSS changes within 4 points
38
38.38
Total
99
100
Recanalisation rate at 24h according to MORI classification
Mori score
No. of Patients
Rate (%)
Grade 0
35

49.30
Grade 1
8
11.27
Grade 2
9
12.67
Grade 3
19
26.76
Tổng số
71
100.00
Clinical Outcome at 3 months
Modified Rankin Scale (mRS)
No. of Pts
Rate (%)
mRS 0 - 1
52
52.53
mRS 2 - 3
31
31.31
mRS 4 - 5
8
8.08
mRS = 6 (death)
8
8.08
Total

99
100.00
Barthel Index (BI) ≥ 95 points
53
53.54
GOS (Glasgow Outcome Scale) = 1
48
48.48
Adverse events
Symptomatic ICH
No. of pts
Rate(%)
According to ECASS 3 definition
3
3.03
According to NINDS definition
5
5.05
According to ECASS 2 definition
4
4.04
According to SITS - MOST
2
2.02
ICH subtype

Hemorrhagic infarction 1 - HI 1
Hemorrhagic infarction2 - HI 2
Parenchymal hematoma - PH 1
Parenchymal hematoma - PH 2


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2
1
2

10.10
2.02
1.01
2.02


14
Others
Reocclusion
Cardiac infartion
Pneumonia
Urinary tract infection
Skin and mucous bleeding
Ureter and bladder bleeding
Alteplase allergy
3.3. Predictive factors and scores

3
1
1
1
2
2
0


3.03
1.01
1.01
1.01
2.02
2.02
0.00

3.3.1. Prediction related factors and the role of predictive scores
Table 3.3: Univariate analysis of the relationship between factors
and predictive scores with clinical outcome at 3 months
Factors/predictive
scores

Modified Rankin
≤ 1, n (%)

> 1, n (%)

Male

31 (59.62)

27 (57.45)

Female

21 (40.38)


20 (42.55)

< 50

5 (9.62)

3 (6.38)

≥ 50

47 (90.38)

44 (93.62)

< 60

17 (32.69)

11 (23.40)

Genders

Ages (years)
≥ 60

35 (67.31)

36 (76.60)

< 70


34 (65.38)

29 (61.70)

≥ 70

18 (34.62)

18 (38.30)

OR

p

1.09

0.827

1.56

0.558

1.58

0.307

1.17

0.704



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Baseline
NIHSS

Time from
onset to
treatment
(mins)

Diabetes
mellitus
History of
hypertetion
Atrial
fibillation

< 16

48 (92.31)

32 (68.09)

≥ 16

4 (7.69)

15 (31.91)


< 210

31 (59.62)

25 (53.19)

≥ 210

21 (40.38)

22 (46.81)

< 240

39 (75)

39 (83.98)

≥ 240

13 (25)

8 (17.02)

No

51 (98.08)

28 (59.57)


Yes

1 (1.92)

19 (40.43)

No

9 (17.31)

6 (12.77)

Yes

43 (82.69)

41 (87.23)

No

45 (86.54)

32 (68.09)

Yes

7 (13.46)

15 (31.91)


No

9 (17.65)

12 (25.53)

Dyslipidemia
Yes

42 (82.35)

35 (74.47)

No

29 (55.77)

10 (21.28)

Yes

23 (44.23)

37 (78.72)

Cardioembolic

No

45 (86.54)


32 (68.09)

stroke

Yes

7 (13.46)

15 (31.91)

Abnormal

No

26 (50)

2 (4.26)

MCA occlusion

5.63

0.004

1.3

0.520

1.625


0.335

34.61

0.001

1.43

0.530

3.01

0.031

1.6

0.344

4.67

0.001

3.01

0.031

22.5

0.001



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Brain CT scan
Yes

26 (50)

45 (95.74)

<8

1 (3.34)

12 (36.36)

≥8

29 (96.66)

21 (63.64)

ASPECT score

DRAGON
score

16.57
<3


12 (23.08)

0 (0.00)

≥3

40 (76.92)

47 (100)

<4

19 (36.54)

5 (10.64)

≥4

33 (63.46)

42(89.36)

< 20

8 (15.38)

2 (4.26)

≥ 20


44 (84.62)

45 (95.74)

< 25

39 (75)

8 (17.02)

≥ 25

13 (25)

39 (82.98)

0.001

1

-

4.84

0.004

4.09

0.085


14.63

0.000

ASTRAL score

So, the factors and scores associated with unfavorable
outcome at 3 months were : NIHSS ≥16 points, diabetes mellitus,
atrial fibrillation, cardioembolic stroke, MCA occlusion, abnormal
brain CT, ASPECT score < 8 points, DRAGON score ≥ 4 points,
ASTRAL score ≥ 25 points.
3.3.2. Independent predictors for clinical outcome at 3 months
Factors and scores related to prognosis were included in the
multivariate regression analysis for independent predictors. Based
on the results of the analysis, any variables with a p value of less
than 0.05 and the range of a 95% confidence interval without 1


17
were considered to be independent predictors. Patients who have a
modified Rankin score of 0 to 1 were considered a favorable
outcome. Patients with a modified Rankin score greater than 1 (2 to
6) were considered to be a poor outcome (unfavorable). The analytic
results were as follows:
Table 3.4: Multivariate logistic regression to find out the
independent predictors of clinical outcome at 3 months
Khoảng tin cậy
Factors/predictive scores
OR
p

95 % (CI)
< 16
Baseline NIHSS
1.25 0.811
0.21 – 7.47
≥ 16
Diabetes mellitus
Abnormal
Brain CT scan

No
Yes
No
Yes

DRAGON score

≥8
<8
No
Yes
No
Yes
<4
≥4

ASTRAL score

< 25
≥ 25


ASPECT score
MCA occlusion
Cardioembolic
stroke

35.44

0.003

3.42 – 367.35

6.84

0.043

1.06 – 44.04

15.94

0.013

1.79 – 141.96

2.16

0.307

0.49 – 9.43


0.98

0.977

0.21 – 4.54

0.42

0.013

0.003 – 0.51

13.65

0.01

1.85 – 100.51

So, the factors and scores could independently predict
unfavorable outcome at 3 months were : Diabetes mellitus,
abnormal brain CT, ASPECT score < 8 points, DRAGON score ≥ 4
points, ASTRAL score ≥ 25 points.


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3.3.3. HAT score to predict intracranial hemorrhages

Figure 3.1: The relationship between HAT scores and ICH
The higher the HAT score, the more likely intracranial
hemorrhage would develop. With the HAT score of 0, there

were no cases of intracranial hemorrhage. With HAT scores
of 4, the likelihood of complications of ICH was highest,
accounting for 66.66%.


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CHAPTER 4: DISCUSSION
4.1. Treatment results
4.1.1. Treatment results of inpatient care
NIHSS changes after 24 hours: The NIHSS score is an reliable,
effective tool for assessing patients. However, a decrease in NIHSS
score does not mean that clinical outcomes are always favorable at 3
months or long term responses. After treatment, many factors affect
the outcome, including adverse events.
In our study, the proportion of patients had NIHSS scores dropped 4
points or more was 58.59%. It suggests that somewhat these patients
had revascularization. The rate of patients showed improvement is
lower than that of Nguyen Huy Thang, Mai Duy Ton, with 60% and
72.73%, respectively. The posible reason was due to extending
treatment time beyond 3 hours.
Recanalization rate at 24 hours after Alteplase administration
on Mori grading scale: According to Mai Duy Ton, the rate of
patients had any reperfusion was 57.2%, in which , complete and
nearly complete revascularization was 45.3% for low-dose Alteplase
treatment in the first 3 hours after stroke onset. And as stated by
Mori et al., the proportion of complete and nearly complete MCA
revasculisation on MRI at 6 hours was 51.7% and at 24 hours was
69%. In our study, the rate of failed repefusion accounted for
49.3%, minimal, partial and complete recanalizatin was noted in
11.27%, 12.67%, and 26.76%, respectively. The recanalization rate

on 24-hour MRA was 50.7%. This result was somewhat lower than
those from other studies, that can explain by the extension of the
treatment window.
4.1.2. Clinical outcome at 3 months (table 4.1)
The outcome we noted in the study was similar
to that of the standard dose Alteplase trial in ECASS 3
(52.4%) with the same protocol, and the low dose
treatment within 3-hour time window was found by


20
Mai Duy Ton (51.51%), but not equivalent to those of
Nguyen Huy Thang (56.3%, low dose, within 3 hours).
In comparison with other studies, the rate of good
clinical outcomes in our study were higher. In
comparative table above, the clinical outcomes were
heterogeneous. The difference may be due to a
number of important reasons. Rather, there could be
many
factors
that
influence
the
therapy
simultaneously and interactively.
Table 4.1: Comparision of clinical outcome at 3 months with
other studies accordinh to Modified Rankin Scale (%)
Authors/studies

0-1


2-3

4-5

6

ECASS 3, placebo, 3 - 4.5h

45.1

27.8

18.9

8.2

ECASS 3, standard dose, 3 - 4.5h

52.4

23.4

17.4

6.7

Our study, low dose, 3 - 4.5h

52.53


31.3
1

8.08

8.0
8

Le V. Thanh, standard dose , 0 - 3h

43

49

8

J – ACT, low dose , 0 – 3h

36.9

53.4

9.7

Mori et al, standard dose , 0 - 3h

46.6

51.7


1.7

Mai Duy Ton, low dose, 0 – 3 giờ

51.51

25.7
6

19.7

3.0
3

N. H.Thang, standard dose, 0 - 3h

45

27

16

12

Nguyen T.H, low dose, 0-3h

56.3

41.7


2.1

NINDS placebo

26

26

27

21

NINDS standard dose

39

21

23

17

48.9

25.4

15

10.


Enchanted, standard dose, < 4.5h


21
6
Enchanted, low dose , < 4.5h

46.8

SITS-MOST

38.9

28.7

15.8

49.8

8.7
11.3

Mortality rate at three months was 8.08% for all causes,
similar to 8.7% in ENCHANTED trial, Le Van Thanh (8%), and
lower than that in SITS. -MOST (11.3%), NINDS (17.3%), J-ACT
(9.7%) and others (Table 4.1). However, the mortality rate in our
study was higher than that reported by Mai Duy Ton (3.03%). There
are many possible explanations for this result as mentioned above.
But in general, the most common cause of fatalities was severe

stroke with high average NIHSS scores, of which the majority was
over 15 points. The related conditons were heart failure, mitral
stenosis, MCA occlusion, ICH, diabetes mellitus, and failed
revascularization.
4.1.3. Symptomatic intracranial hemorrhage (sICH)
Symptomatic intracranial hemorrhage is the most worrying
complication following thrombolytic treatment because of its high
mortality and disability. Our study included all 15 cases of
haemorrhage during hospitalization, essentially in the first 36 hours
after treatment. Asymptomatic intracranial hemorrhage (sICH) in
12 cases (12.12%), sICH occurred in 3 cases, accounting for 3.03%
as defined by ECASS III. According to the definition of NINDS,
ECASS II, SITS - MOST, sICH were 5.05%, 4.4% and 2.2%,
respectively. Thus, the proportion of sICH was higher than that in
the ECASS III, SITS-MOST, but lower than that in the NINDS and
ECASS II (Table 4.2).


22
Table 4.2: The rate of ICH in comparison with other studies
Studies

ICH (%)
aICH

sICH

NINDS (n = 624)

4.2


6.4

ECASS II (n = 800)

37.8

8.9

ATLANTIS (n = 613)

11.3

6,7

Mai Duy Ton (n = 66)

1.52

1.52

N. H. Thang (n = 152)

2,6

4,6

Enchanted standard dose

-


1.0

Enchanted low dose

-

2.1

24.6

2.4

-

1.7

12.12

3.03

ECASS III
SITS – MOST
Our studies (n = 99)
4.2. Independent predictors

Our results showed that diabetes mellitus,
abnormal baseline head CT scans, ASPECT scores < 8,
DRAGON scores ≥ 4 and ASTRAL scores ≥ 25 were
independent predictors for unfavorable outcome at 3

months, corresponding to a modified Rankin score of 2
to 6, in stroke patients treated with low-dose
Alteplase. This finding was paralled with Demchuk's,
that suggesting diabetes mellitus and abnormalities
on baseline brain CT scans may be independent
predictors of unfavorable clinical outcomes. According
to Hill et al., Barber et al., ASPECT scores < 8 were


23
independent factors for bad neurological functional
recovery.
For the DRAGON score, Arthur Wang and his colleagues
studied the application of this score and pointed that the DRAGON
score correlated with the outcome tested by the modified Rankin
score, the higher the DRAGON score, the better the prognosis and
vice versa, and the DRAGON score > 6 was associated with higher
mRS and higher mortality (a significant increase in the patient's
poor outcome).
On the ASTRAL score, according to Cooray et al., The score
had good predictability and was easy to apply as it does not require
imaging parameters. Thus, the score was well suited for evaluating
prehospital patients. In agreement with Papavasileiou et al, the
ASTRAL score was very reliable in predicting 5-year outcomes for
patients with acute ischemic stroke. As reported by Gaifen Liu et al.,
ASTRAL scores > 25 predicted poor outcome of up to 50%. In our
study, ASTRAL scores > 25 significantly increased the probability
of poor outcomes, with odds ratios OR = 13.65, p = 0.001, and 95%
confidence intervals (CI) from 1.85 - 100.51 (did not contain 1).
CONCLUSION

1. Clinical charisteristics and signs of brain CT scans
Clinical presentation: Mean age was 64.79 ± 9.75, median age was 64;
male/female ratio was 1.41/1. Mean NIHSS was 11.93 ± 4.23 points,
median NIHSS was 11 points. Clinical presentation of acute ischemic
stroke was various. Most of patients acquired at least one risk factor. The

most common were hypertension (78.79%), dyslipidemia (72.73%),
atherosclerosis (60.6%). Diabetes mellitus and atrial fibrillation
were on the increasing, with rates of 22.22% and 19.19%,
respectively. Average treatment time was 207.87 ± 26.5 minutes.
Etiology of atherosclerotic disease of large vessels accounted for


24
the highest rate, followed by small blood vessel disease and
cardioembolic stroke . Approximately 13% of patients had not been
classified.
Imaging of head CT scans: There were 25.25% of patients with M1
segment MCA occlusion, 34.34% of M2 MCA and 28.28% of small
vessels. The incidence of early abnormal signs on CT was 71%.
Focal parenchymal attenuation (54.55%), loss of grey – white matter
differentiation (40.4%), loss of the insular ribbon (28.28%), MCA
dot signs of M2 segment (22.22%), hyperdense MCA signs of M1
segment (18.18%) and the rest were different signs. The mean
ASPECT score was 8.6 ± 1.11 points and the median score was 9
points.
2. Treatment results
Inpatient period: NIHSS scores dropped by ≥ 4 points 24-hour
after Alteplase administration of 58.59%. The revascularization rate
for large vessel occlusion was 50.7%, of which 26.76% was

complete, 12.67% was partial, and 11.27% was minimal.
Clinical functional outcome at 3 months: The rate of patients
achieving favorable outcome was 52.53% and the mortality rate was
8.08% at 3 months.
Adverse events: The rate of symptomatic intracranial hemorrhage
was 3.03%. Other adverse events had low proportion. There was no
cases of systemic bleeding or drug allergy.
3. Independent predictors for clinical outcome at 3 months.
There were many factors associated with prognosis, but only the
following factors could be independent predictors of poor clinical
outcome (Rankin modified points 2 to 6), including: the ASPECT
score < 8 points, DRAGON score ≥ 4 and ASTRAL score ≥ 25
points.