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Address for correspondence:
Dr. Keun-Sik Hong,
Departments of Neurology and Clinical
Research Centre, Ilsan Paik Hospital,
Inje University College of Medicine,
2240 Daehwa-dong, Ilsanseo-gu,
Goyang, South Korea.
E-mail: nrhks@paik.ac.kr
Received : 09-07-2012
Review completed : 17-07-2012
Accepted : 29-07-2012
Effcacy and safety of thrombolysis in
patients aged 80 years or above with
major acute ischemic stroke
Sang-Chul Kim
1
, Keun-Sik Hong
1,2
, Yong-Jin Cho
1,2
, Joong-Yang Cho
1
, Hee-Kyung Park
1
, Pamela Song
1

1
Departments of Neurology,
2
Stroke Centre, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, South Korea
Abstract
Background: Elderly patients with major ischemic strokes may remain severely disabled or
dead. However, efficacy and safety of thrombolysis in this have not been fully explored.
Materials and Methods: Data from the case records of patients aged >80 years with
acute ischemic stroke with admission National Institute of Health Stroke Scale (NIHSS)
score 10 admitted between April 2009 and May 2011 were retrieved. Outcomes in
patients treated with thrombolysis and control subjects were compared. Primary outcome
was 3-month modified Rankin Scale (mRS) score 0-2. Secondary outcomes were 3-month
mRS score 0-3, mRS score 5-6, mortality, and improvement NIHHS score at discharge.
Safety outcome was hemorrhagic transformation. Results: Study subjects included
22 patients treated with thrombolysis and 23 controls not treated with thrombolysis.
Age, stroke severity, and proportion of identified major vessel occlusions were the
variables for comparison between the two groups. More patients in the thrombolyzed
group had mRS 0-2 outcome than in non-thrombolyzed group (18.2% vs. 0%; P =
0.049). Proportion of patients with mRS 0-3 outcome was also higher in thrombolyzed
group than in non-thrombolyzed group (22.7% vs. 0%; P = 0.022). Patients in the
thrombolyzed group had higher mortality, non-significant when compared to patients in
the non-thrombolyzed group (18.2% vs. 8.7%; P = 0.414). However, lesser number of
patients in the thrombolyzed group had mRS 5-6 outcome (35% vs. 65%; P = 0.075).
Median improvement in NIHSS score at discharge also showed a more favorable trend
in thrombolyzed group (10 vs. 2; P = 0.082). Rates of symptomatic and asymptomatic
hemorrhagic transformations in thrombolyzed group were 4.5% and 27.3% respectively.
Conclusion: For elderly patients with major ischemic strokes, thrombolysis offers a greater
chance of functional independence.
Key words: 80 years, elderly, major ischemic stroke, thrombolysis
Original Article
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***
DOI:
10.4103/0028-3886.100719
Introduction
Despite the proven effcacy of intravenous thrombolysis
within a 4.5-hour window
[1-3]
randomized controlled
trial data in patients aged 80 years are limited. Only
the National Institute of Neurological Disorders and
Stroke Tissue Plasminogen Activator (NINDS-TPA)
trials enrolled patients aged >80 years,
[1]
European
Cooperative Acute Stroke Study (ECASS) I, II, III and
Alteplase Thrombolysis for Acute Non-interventional
Therapy in Ischemic Stroke (ATLANTIS) trials excluded
patients in this age group.
[3-6]
As the data regarding safety
and effcacy of intravenous tPA in this age group has
been limited, intravenous tPA has not been formally
approved in this age group in some countries including
Kim, et al.: Thrombolysis in elderly major strokes
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Neurology India | Jul-Aug 2012 | Vol 60 | Issue 4
Univariate analyses were performed to compare the
outcomes between the two groups. To avoid a model
over ftting for this small sample and outcome numbers,
multivariable analyses were not considered unless
there was a signifcant imbalance in well-recognized
prognostic variables of age and initial NIHSS score
between the two groups. From the NINDS-TPA trials
database, outcomes of patients aged 80 years with a
baseline NIHSS 10 were extracted and numerically
compared with the outcomes of our patients.
Results
Forty-fve patients were included in the current study:
22 patients in the thrombolyzed group (14 intravenous
tPA alone, 4 intra-arterial reperfusion therapy alone,
and 4 combined intravenous and intra-arterial therapy)
and 23 in non-thrombolyzed control group. Between the
treatment and control groups age (85.2 5.2 vs. 85.7 4.1,
P = 0.735) and initial NIHSS score (median [interquartile
range], 21 [16-23] vs. 20 [17-23], P = 0.707) were well-
balanced. Proportion of major vessel occlusions identifed
on computed tomography (CT), magnetic resonance
(MR), or conventional angiography was also comparable
(72.2% in treatment vs. 65.2% in control, P = 0.586). For
patients treated with thrombolysis, there were 7 internal
carotid artery (ICA), 7 M1 portion of middle cerebral
artery (MCA), 1 basilar artery (BA), and 1 P1 portion of
posterior cerebral artery (PCA) occlusions; whereas, for
control subjects there were 10 ICA, 4 M1 portion of MCA
and 1 BA occlusions. Other baseline characteristics except
for onset-to-admission were comparable between the two
groups [Table 1]. In patients treated by thrombolysis,
the average intervals for onset-to-treatment and door-
to-treatment were 146.2 73.3 and 61.6 43.1 minutes.
Outcomes
Pimary outcome
Of the 22 patients in the thrombolyzed group, 4 (18.2%)
patients had mRS 0-2 at 3 months as compared to
none (0%) in the control group, (P = 0.049) [Table 2].
Secondary outcome: Proportion of patients with mRS 0-3
at 3 months was also signifcantly higher in patients in
thrombolyzed group than in patients in the control group
(22.7% vs. 0%, P = 0.022). Of the 14 patients treated with
intravenous tPA alone, 2 (14.3%) patients had mRS 0-2,
and 3 (21.4%) had mRS 0-3 at 3 months. Of the 8 patients
treated with intra-arterial alone or combined therapy,
2 (25%) patients had mRS 0-2 (same for mRS 0-3) at 3
months. The proportion of patients with worst outcome,
mRS 5-6, was substantially lower in the thrombolyzed
group than the in the control group. However, this
difference had not reached statistical signifcance (35.0%
vs. 65.0%, P = 0.075). Functional outcomes in the control
group were mRS of 4-6, and 61% remained in an extreme
disability of mRS 5 [Figure 1]. NIHSS improvement at
Korea. Data in regard to intra-arterial (IA) reperfusion
therapy are far more limited since trials exclusively
enrolled patients under 75 or 85 years.
[7,8]
Most studies
comparing the outcomes of intravenous thrombolysis
in patients aged 80 and <80 years have reported that
elderly patients had a less favorable outcome than
younger patients.
[9-13]
However, these studies did not
compare with placebo and the fndings could not refute
the benefit of thrombolysis in the elderly. A study
analyzing a large number of patient data pooled in a
database of 21 acute stroke trials demonstrated that
the beneft of thrombolysis was maintained in the very
elderly despite their expected poorer outcomes than
younger patients.
[14]
Major stroke in the elderly carries
a substantial hemorrhagic risk with thrombolysis.
[1,2,15,16]

The effcacy and safety of reperfusion therapy in the
elderly have not been systematically explored. This study
was to assess the effcacy and safety of thrombolysis in
patients aged 80 or above with major ischemic strokes.
Materials and Methods
From a prospectively captured institute stroke registry,
we extracted data of patients aged 80 years with
admission NIHSS 10, admitted within 7 days from
stroke onset between April 2009 and May 2011. Patients
with a pre-stroke modifed Rankin Scale (mRS) 4 were
excluded. Patients were categorized into thrombolyzed
group (intravenous tPA alone, intra-arterial reperfusion
therapy alone or combined intravenous and intra-
arterial therapy) and non-thrombolyzed group (control).
Treating physicians decided the modality of reperfusion
therapy based on the clinical and imaging fndings. For
each patient demographic data, co-morbid conditions,
pre-stroke mRS, onset-to-admission, onset-to-treatment
for thrombolysis, initial NIHSS score, stroke subtype,
NIHSS score at discharge, and 3-month mRS were
prospectively captured using a structured protocol.
Trained physicians or research nurses assessed mRS
outcomes at 3-month from a direct or telephone
interview. For patients treated with thrombolysis,
recanalization was defned as having Thrombolysis In
Cerebral Infarction (TICI) grade 2b or 3.
[17]
Symptomatic
hemorrhagic transformation was determined according
to the ECASS III criteria.
[3]
For quality monitoring and
improvement of stroke care, data collection of all stroke
patients was approved by the Ethics Committee of our
institution. Primary outcome was mRS 0-2 at 3 months.
Secondary outcomes were mRS 0-3, and mRS 5-6 at
3 months and NIHSS score improvement at discharge.
Safety outcomes were symptomatic and asymptomatic
hemorrhagic transformations and 3-month mortality.
Statistical analysis
Categorical variables were compared with
2
test,
and continuous variables with Mann-Whitney U test.
Kim, et al.: Thrombolysis in elderly major strokes
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Neurology India | Jul-Aug 2012 | Vol 60 | Issue 4
patients achieved recanalization, and 6 (31.6%) had
persistent occlusions. In 4 (21.1%) patients recanalization
could not be evaluated because of serious neurological
conditions or refusal of surrogates. Of the 11 patients
who received intravenous tPA alone, recanalization
was observed in 3 (27.3%) patients within 24 hours and
of the 8 patients treated with intra-arterial reperfusion
therapy alone or combined therapy, 6 (75%) patients
achieved recanalization on immediate post-treatment
conventional angiography.
Mortality and hemorrhagic transformation
Mortality at 3-months was higher in the thrombolyzed
group than in control group, but the difference did not
reach a statistical signifcance (18.2% vs. 8.7%, P = 0.414)
discharge (median, [interquartile range]) was greater
in thrombolyzed group than in control group, but the
difference was not statistically signifcant (10 [-1, 14] vs.
2 [-2, 8], P = 0.082).
Recanalization
After excluding 3 patients in the thrombolyzed group
who had no major vessel occlusions on pretreatment
CT angiography, recanalization status was assessed in
the remaining 19 patients using CT or MR angiography
within 24 hours after treatment or immediate post
intra-arterial conventional angiography. Nine (47.4%)
Table 1: Baseline characteristics of patients
Thrombolyzed (n = 22) Non-thrombolyzed (n = 23) P value
Age (mean SD) 85.2 5.2 85.7 4.1 0.735
Female, n (%) 16 (72.7) 14 (60.9) 0.399
Initial NIHSS, median (IQR) 21 (16, 23) 20 (17, 23) 0.707
Major vessel occlusion, n (%) 0.586
Occlusion 16 (72.7) 15 (65.2)
No occlusion 3 (13.6) 8 (34.8)
Undetermined 3 (13.6) 0 (0)
Onset to door time (min, mean SD) 84.6 57.5 1870.4 2021.8 <0.001
door to treat time (min, mean SD) 61.6 43.1 NA NA
Previous stroke history, n (%) 4 (18.2) 5 (21.7) >0.99
Medical history, n (%)
Hypertension 17 (77.3) 15 (65.2) 0.372
Diabetes mellitus 3 (13.6) 5 (21.7) 0.699
Coronary heart disease 5 (22.7) 5 (21.7) 0.936
Atrial brillation 5 (22.7) 6 (26.1) 0.793
Hyperlipidemia 4 (18.2) 8 (34.8) 0.314
Current smoking, n (%) 1 (4.5) 1 (4.3) >0.99
Peripheral artery disease 0 (0) 1 (4.3) >0.99
Prestroke mRS, n (%) 0.936
0 11 (50) 11 (47.8)
1 2 (9.1) 1 (4.3)
2 4 (18.2) 4 (17.4)
3 5 (22.7) 7 (30.4)
Stroke subtype, n (%) 0.870
LAD 2 (9.1) 3 (13)
SVO 1 (4.5) 0 (0)
CE 12 (54.5) 14 (60.9)
Other determined 0 (0) 0 (0)
undetermined 7 (31.8) 6 (26.1)
Figure 1: 3-month mRS distribution
Table 2: Primary and secondary outcomes
Thrombolyzed
(n = 22)
Non-
thrombolyzed
(n = 23)
P value
Primary outcome
3-month mRS 0-2, n (%) 4 (18.2) 0 (0) 0.049
Secondary outcomes
3-month mRS 0-3, n (%) 5 (22.7) 0 (0) 0.022
3-month mRS 5-6, n (%) 9 (35.0) 13 (65.0) 0.075
3-month mortality, n (%) 4 (18.2) 2 (8.7) 0.414
NIHSS improvement,
median (IQR)
5 (-1, 4) 2 (-2, 8) 0.082
Kim, et al.: Thrombolysis in elderly major strokes
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Neurology India | Jul-Aug 2012 | Vol 60 | Issue 4
[Table 2]. Of the 4 patients who died after thrombolysis,
2 had recanalization and the other 2 did not. Brief case
summaries of 4 these patients: (1) A patient with ICA
T-occlusion and admission NIHSS score of 19 had
TICI IIb recanalization with intra-arterial therapy, but
subsequently developed symptomatic hemorrhagic
transformation; (2) A patient with ICA T-occlusion and
admission NIHSS score of 25 received intravenous tPA
alone and follow-up MRI showed recanalization, but he
subsequently developed malignant MCA infarction; (3)
A patient with ICA T-occlusion and admission NIHSS
score of 23 failed to achieve recanalization with combined
therapy and subsequently developed malignant MCA
infarction; and (4) A patient with basilar artery occlusion
and NIHSS score of 40 was treated with intravenous tPA
alone, and follow-up MRA showed persistent occlusion
and infarctions in brainstem, bilateral cerebellum and
bilateral PCA territory. The cause of death in these
4 patients were symptomatic hemorrhagic transformation
in 1 and severe stroke in 3 patients. There were two deaths
in the control group, one patient had a basilar artery
occlusion with NIHSS score of 33, and the other patient
had proximal ICA occlusion with NIHSS score of 26.
Symptomati c hemorrhagi c transformati on of
parenchymal hematoma type 2 developed in one
patient treated with intra-arterial therapy, who died.
Asymptomatic hemorrhagic transformation was
observed in 5 (27.3%) patients: 3 hemorrhagic infarction
type 1 and 2 hemorrhagic infarction type 2.
Discussion
In this study, none of the elderly patients in the non-
thrombolyzed group functional independence. In
contrast, with thrombolytic therapy, 18% of patients could
achieve good functional independence and look after
their activities of daily living and 22% of patients were
able to walk unassisted. In addition to improvement in
global functional outcome, neurological improvement at
discharge showed a favorable trend with thrombolysis.
With regard to safety, the rates of fatal and asymptomatic
hemorrhagic transformation of less than 5% and 22% are
highly acceptable given that patients were very elderly
and had severe strokes. With thrombolysis therapy,
the mortality rate showed an absolute increase of 10%,
but absolute decrease in extreme disability of mRS 5
by 40%. As a result, the thrombolysis therapy had an
absolute 30% risk reduction for extreme disability or
death. Increase in the mortality rates and decrease in the
extreme disability rates in the elderly with thrombolysis
is a debatable aspect from ethical point of view. In this
situation, generally acceptable comparative values for
death and extreme disability would help to guide a
treatment decision. Most-widely employed methods of
weighting diverse health conditions are quality weight
and disability weight. Quality weight is derived from
patients or healthy individuals, and disability weight
is derived from experienced health professionals. In a
quality weight study asking persons with a high risk for
stroke, 45% of respondents considered major stroke to be a
worse outcome than death.
[18]
In a disability weight study
convening multinational stroke experts with diverse
cultural backgrounds, the generated disability weight
with achieving substantial consensus for mRS 5 was
0.944, which is almost identical to the disability weight
of 1.0 for death.
[19]
In addition, another study surveying
stroke experts attitude also demonstrated that more
than 80% of experts considered a transition from death to
mRS 5 clinically not meaningful,
[20]
and therefore, recent
major acute stroke trials considered mRS 5 and mRS 6
into a single worst-outcome category.
[21,22]
Considering
the greater chances of gaining functional independence
and independent gait and reducing extreme disability
or death, thrombolysis therapy should be strongly
considered for and provided to patients aged 80 years
with major ischemic strokes. Our fndings are similar to
the fndings in a prior study that demonstrated a beneft
of intravenous tPA in elderly patients.
[14]
Our results are in
contrast to two earlier studies that failed to show a beneft
of intravenous tPA when compared to placebo or no
treatment in elderly patients.
[23,24]
However, those studies
included mild to moderate strokes as well as severe
stroke, and were not suffciently powered to detect the
treatment effect. Despite a small sample size, exclusively
enrolling severe strokes where treatment effect could be
more magnifed than in mild to moderate stroke might
attribute to our positive results.
It would be instructive to compare the recanalization rates
in the current and earlier studies. In a systematic review,
recanalization rates within 24 hours were 24.1% without
thrombolysis, 46.2% with intravenous fbrinolytic, 63.2%
with intra-arterial fbrinolytic, and 67.5% with combined
intravenous and intra-arterial therapies.
[25]
In the current
analysis excluding patients who showed no major vessel
occlusion on pre-treatment CTA, the recanalization rate
of 75.0% with intra-arterial therapy alone or combined
therapy was generally comparable to, but 27.3% with
intravenous tPA alone was less than those estimated in
the systematic review. However, since at least more than
70% of patients had major vessel occlusions, the current
recanalization rate with intravenous tPA is likely to be
concordant with earlier studies which demonstrated
recanalization rates with intravenous tPA of 10% in
ICA occlusions and less than 30% in proximal MCA
occlusions.
[26,27]
Accordingly, thrombolysis therapy even in
elderly patients could achieve a comparable recanalization
rate as in general ischemic stroke patients.
Kim, et al.: Thrombolysis in elderly major strokes
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Neurology India | Jul-Aug 2012 | Vol 60 | Issue 4
Since the current study differs with the NINDS-TPA
trials in proportion of major vessel occlusions, interval
of onset-to-treatment, and treatment modality, outcome
comparison of two studies should be cautious, but would
be informative [Figure 1]. In the NINDS-TPA trials,
patients aged 80 years and baseline NIHSS 10 were 31
in tPA group and 23 in placebo group. On pretreatment
CT, hyper dense MCA sign strongly suggesting a major
vessel occlusion was observed in 25.8% in patients treated
with tPA and 13.0% in the placebo group. As shown in
Figure 1, as compared to tPA-treated patients in NINDS-
TPA trials, the current thrombolyzed patients had
comparable proportions of mRS 0-2 and mRS 0-3, but were
less extremely disabled or dead. In contrast, our control
subjects were more severely disabled than placebo-treated
patients in NINDS-TPA trials.
This study has several limitations. This is not a
randomized study, and thus unable to remove selection
bias in treatment allocation. Since outcome assessors
were not blinded to treatment, outcome assessment
could be potentially biased. However, all the patients
in the control group had outcomes of mRS 4-, for which
outcomes assessment are highly consistent,
[28]
and
therefore unblended outcome assessment was less likely
to alter the current results. This study was performed
in acentre well-experienced with reperfusion therapies
and the reperfusion therapy was not unifed. Thus, our
fndings have a limitation for generalizability.
In conclusion, if not thrombolyzed, patients aged 80 years
with major ischemic stroke may remain in an extreme
disability or may die. Thrombolysis therapy can offer a
greater chance of gaining functional independence or
independent gait and reduce extreme disability or death
at a price of more mortality, so it should be strongly
considered for and provided to these patients.
Acknowledgments
This work was supported by a grant of Inje University in 2010
(K.-S.H.).
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How to cite this article: Kim S, Hong K, Cho Y, Cho J, Park H, Song P.
Effcacy and safety of thrombolysis in patients aged 80 years or
above with major acute ischemic stroke. Neurol India 2012;60:373-8.
Source of Support: This work was supported by a grant of Inje
University in 2010 (K.-S.H.). Confict of Interest: None declared.
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