Intravenous Thrombolysis

in Thai Patients with AcuteIschemic Stroke: Role of Aging

Pornpatr A. Dharmasaroja, MD,* Sombat Muengtaweepongsa, MD,*

and Permphan Dharmasaroja, MD, PhD†

From the *Division of N

Faculty of Medicine, T

†Department of Anatom

Bangkok, Thailand.

Received May 6, 2011

August 4, 2011.

Address corresponden

sion of Neurology, Depar

icine, Thammasat Unive

12120, Thailand. E-mail:

1052-3057/$ - see front

Crown Copyright � 2

National Stroke Associat

doi:10.1016/j.jstrokece

Journal of Stroke and C

Background: Intravenous thrombolysis is a standard treatment in eligible acute

ischemic stroke (AIS) patients. However, the advisability of treating patients

.80 years of age is still debated. The aim of this study was to evaluate the role of

aging on the outcomes in Thai patients treated with intravenous thrombolysis.

Methods: Patients with AIS treated with intravenous recombinant tissue-

plasminogen activator (rtPA) between June 2007 andNovember 2010were included.

The demographics and measured outcome variables were compared between

patients #70 and .70 years of age. Patients were also classified into 4 subgroups

by the age ranges: #60 years, 61 to 70 years, 71 to 80 years, and $81 years of age.

Results: Two hundred sixty-one patients were included. Seventeen patients (6.5%)

were.80 years old. Higher mortality (20.2% vs 5.1%; P, .001) and symptomatic in-

tracerebral hemorrhage (7.7% vs 1.2%; P5.004) were found in the patients.70 years

of agewhen comparedwith younger patients, and the rate of favorable outcomewas

lower (38.1% vs 55.4%; P 5 .010). Higher mortality rates were seen with increasing

age: 3%, 8%, 20%, and 21% in patients aged #60, 61 to 70, 71 to 80, and $81 years

of age, respectively. Conclusions: Thai stroke patients .70 years of age may carry

a higher risk of mortality when treated with intravenous rtPA compared to patients

#70 years of age. Key Words: Aging—Asian—stroke—thrombolysis.

Crown Copyright � 2013 Published by Elsevier Inc. on behalf of National Stroke

Association. All rights reserved.

Intravenous thrombolysis has become a standard

treatment in eligible acute ischemic stroke (AIS) patients.

However, the advisability of treating patients .80 years

of age is still debated because there were only limited

numbers of patients in this particular age group in the

large trials. The National Institute of Neurological

eurology, Department of Internal Medicine,

hammasat University, Pathumthani; and

y, Faculty of Science, Mahidol University,

; revision received July 22, 2011; accepted

ce to: Pornpatr A. Dharmasaroja, MD, Divi-

tment of Internal Medicine, Faculty of Med-

rsity, Klong 1, Klong Luang, Pathumthani

pornpatr1@hotmail.com.

matter

013 Published by Elsevier Inc. on behalf of

ion. All rights reserved.

rebrovasdis.2011.08.001

erebrovascular Diseases, Vol. 22, No. 3 (April)

Disorders and Stroke (NINDS) included all age ranges of

patients, while the European Cooperative Acute Stroke

Study (ECASS) excluded patients .80 years of age.1-4

Many studies have reported higher mortality rates and

lower favorable outcome in patients .80 years of age.

The rate of symptomatic intracerebral hemorrhage (ICH)

was also higher in patients aged .80 years in some

studies and similar to younger patients in others.5-7 Most

of these data came from Western countries. To our

knowledge, there were as yet no data about thrombolysis

in Asian stroke patients .80 years of age. Thrombolytic

studies from Taiwan and Vietnam did not include

patients aged .80 years.8,9 The purpose of this study

was to evaluate the role of aging on the outcomes in Thai

patients treated with intravenous thrombolysis.

Methods

Patients with AIS who were treated with intravenous

recombinant tissue-plasminogen activator (IV rt-PA) at

, 2013: pp 227-231 227

P.A. DHARMASAROJA ET AL.228

Thammasat University Hospital, Pathumthani, Thailand

between June 2007 and November 2010 were included.

Intravenous rt-PAwas prescribed for AIS patients within

3 hours of onset if there were no contraindications.

However, after the publication of the European Coopera-

tive Acute Stroke Study III (ECASS III) and the recom-

mendation about the expansion of the time window for

treatment of AIS with IV rt-PA from the American Heart

Association/American Stroke Association,4,10 we have

extended the time window of treatment with rt-PA up

to 4.5 hours. Most contraindications were the same as in

the guidelines for treatment of AIS from the American

Heart Association/American Stroke Association.10

However, older age (.80 years old) was not an exclusion

criterion. Patients with high blood pressure (systolic

blood pressure .185 mm Hg or diastolic blood pressure

.110 mm Hg) were not excluded if blood pressure could

be controlled by intravenous nicardipine (the target

systolic blood pressure ,185 mm Hg and diastolic blood

pressure ,110 mm Hg) before rt-PA administration.

Patients who were treated with IV rt-PA (0.9 mg/kg)

were admitted to an intensive care unit or stroke unit

for monitoring and tight controlling of blood pressure

with close clinical follow-up for the first 24 hours.

Another computed tomography (CT) scan of the brain

was performed within 36 hours after receiving thrombo-

lysis in all patients. Stroke severity was evaluated by the

National Institutes of Health Stroke Scale (NIHSS) by the

same doctors before and after receiving rt-PA. The modi-

fied Rankin scale (mRS) was used to assess the outcome of

the patients at 3 months after stroke onset. Symptomatic

ICH was defined by ECASS study criteria, which is hem-

orrhage associated with worsening of $4 points on the

NIHSS score.3 Symptomatic ICH was also classified by

the NINDS stroke rt-PA stroke study criteria, which is

hemorrhage associated with a worsening of $1 point(s)

on the NIHSS score.1 Measured outcome variables of

this study were symptomatic ICH, favorable outcome

(mRS score of 0 or 1), and death at 3 months.

Baseline characteristics of the patients, including age,

sex, cardiovascular risk factors, blood glucose at presenta-

tion, blood pressure level, platelet count, prothrombin

time, severity of stroke, and stroke subtype were studied.

Older age ($70 years old) was inversely associated with

early improvement from a previous study in Thai

patients.11 Demographic andmeasured outcome variables

were compared between patients #70 and .70 years of

age and also between patients aged #80 and .80 years

of age, using the independent-samples t test for continu-

ous variables and the Chi-square test for dichotomous var-

iables. Patients were classified into 4 subgroups by age:

#60, 61 to 70, 71 to 80, and $81 years. Data were

presented as a mean for continuous variables and percent-

age (number) for dichotomous variables. The study was

approved by the human ethics committee of Faculty of

Medicine, Thammasat University.

Results

There were 261 patients treated with IV thrombolysis

during the study period. Because older age (.80 years

old) was not an exclusion criterion from the beginning,

the rate of rt-PA treatment was 21.5% in our center. The

reasons for not treating patientswith rt-PAwere presented

in a previous study.12 The mean age of the patients in the

studywas 63 years. ThemeanNIHSS score was 12. Seven-

teen patients had no clinical data at 3 months because

10 patients missed their follow-up dates and 7 patients

were recently treated with rt-PA (,3 months from the

data analysis date). Higher mortality (20.2% vs 5.1%;

P , .001) and symptomatic ICH (7.7% vs 1.2%; P 5 .004)

were found in the patients .70 years of age when com-

paredwith younger patients, and the rate of favorable out-

come was lower (38.1% vs 55.4%; P 5 .010; Table 1).

Seventeen patients (6.5%) were .80 years of age. Com-

pared with patients #80 years of age, older patients

(.80 years of age) had significant shorter onset-to-needle

times (137 vs 161; P 5 .029) and less hypertension (35.3%

vs 63.5%; P 5 .021; Table 1). Despite nonsignificant differ-

ences, a less favorable outcome (42.9% vs 49.8%; P5 .615),

a slightly higher asymptomatic ICH rate (17.6% vs 15.3%;

P 5 .798), and higher mortality (21.4% vs 9.7%; P 5 .162)

were also found in the patients .80 years of age. Patients

$80 years of age were divided into 3 subgroups: (a) 80 to

84 years old (16 patients); (b) 85 to 89 years old (5 patients);

and (c) $90 years of age (2 patients). Favorable outcome

was found in 4 patients (31%), 2 patients (40%), and 0 pa-

tients in subgroups (a), (b), and (c), respectively. Mortality

rates at 3 months were 31% and 20% in subgroups (a) and

(b), respectively. However, the number of the patients in

each subgroup was too small to see any significant differ-

ences in the outcomes.

Baseline characteristics of the patients classified by age

group are presented in Table 2. There were some differ-

ences in baseline characteristics of the patients among

age groups. More severe stroke, a shorter onset-to- needle

time, more common atrial fibrillation, and large-artery

atherosclerosis/cardioembolism stroke subtypes were

found more frequently in older subgroups compared

with younger subgroups. Higher mortality rates were

seen with increasing age: 3%, 8%, 20%, and 21% in pa-

tients aged #60, 61 to 70, 71 to 80, and $81 years, respec-

tively. Four patients died after discharge because of

sepsis. Twenty-one patients died during hospitalization,

and the causes of death were severe brainstem infarction

(1 patient), brain herniation from malignant middle cere-

bral artery infarction (1 patient), symptomatic ICH (5 pa-

tients), sepsis (10 patients), arrhythmia (3 patients), and

myocardial infarction (1 patient). The rate of symptomatic

ICHmarkedly increased at the 71- to 80-year-old range. A

less favorable outcome was also seen with increasing age,

especially in patients.70 years of age. The rate of asymp-

tomatic ICH was similar among the subgroups. Patient

Table 1. Comparison of baseline characteristics of the patients classified by age groups

Baseline characteristics

Age #70 y

(N 5 166)

Age .70 y

(N 5 92) P value

Age #80 y

(N 5 241)

Age .80 y

(N 5 17) P value

Mean NIHSS 11.2 6 6.9 13.8 6 7.3 .007 11.9 6 6.9 15 6 8.9 .180

Mean blood sugar (mg/dL) 139 6 75.8 134.3 6 67.9 .612 137.2 6 72.8 137.1 6 76.4 .995

Mean prothrombin time (sec) 11.6 6 2 12.2 6 2.2 .099 11.7 6 2.1 12.6 6 1.5 .071

Mean systolic blood pressure (mm Hg) 159.5 6 33.8 166.5 6 29.6 .188 162.2 6 33.2 162.8 6 19.4 .918

Mean diastolic blood pressure (mm Hg) 89.5 6 18.5 87.6 6 16.4 .527 89.1 617.9 84.8 6 14.7 .356

Mean onset-to-needle time (min) 162.7 6 45 154.1 6 40 .122 161.2 6 43.4 137.1 6 39 .029

Female (%) 43.4 45.7 .724 43.6 52.9 .452

Hypertension (%) 57.2 69.6 .051 63.5 35.3 .021

Diabetes mellitus (%) 27.7 20.7 .211 25.7 17.6 .458

Hyperlipidemia (%) 28.3 30.4 .719 29.9 17.6 .283

Coronary artery disease (%) 11.4 12 .902 11.2 17.6 .423

Old ischemic stroke (%) 12.7 10.9 .673 12 11.8 .974

Transient ischemic stroke (%) 4.2 3.3 .703 4.1 0 .392

Atrial fibrillation (%) 18.1 38 ,.001 24.9 29.4 .679

Smoking (%) 25.3 18.5 .211 22.4 29.4 .506

Stroke subtype (%)

LAA 30 33 .061 30.6 37.5 .490

SAO 40 23.9 35.3 18.8

CE 28.1 40.9 31.9 43.8

UND 1.9 2.3 2.2 0

ICH type (%)

Asymptomatic ICH 15.2 15.4 .816 15.3 17.6 .798

Symptomatic ICH

NINDS 2.4 11 .004 7.8 0 .606

ECASS 1.2 7.7 3.8 0 .780

Marked clinical improvement at

24 hours (%)

50 29.3 .004 42.9 33.3 .517

Favorable outcome (%) 55.4 38.1 .010 49.8 42.9 .615

Mortality rate (%) 5.1 20.2 ,.001 9.7 21.4 .162

Abbreviations: CE, cardioembolism; ECASS, European Cooperative Acute Stroke Study; ICH, intracerebral hemorrhage; LAA, large-artery

atherosclerosis; NIHSS, National Institutes of Health Stroke Scale; NINDS, National Institute of Neurological Disorders and Stroke; SAO, small

artery occlusion; UND, undetermined etiology.

THROMBOLYSIS IN ELDERLY STROKE PATIENTS 229

outcome at 3 months as classified by the mRS score is

shown in Fig 1.

Discussion

A systemic review and meta-analysis included 13 stud-

ies comparing the outcomes after IV thrombolysis in

764 elderly patients ($80 years of age) and 2792 patients

,80 years of age. Elderly patients had a less favorable out-

come (odds ratio [OR] 0.49; 95% confidence interval [CI]

0.93-1.84) and a higher mortality rate (OR 2.77; 95% CI

2.25-3.40) but a nonsignificant higher symptomatic ICH

rate (OR 1.31; 95% CI 0.93-1.84) compared with patients

,80 years of age.13 Ford et al7 studied outcomes and

symptomatic ICH rates in 19,411 patients aged

#80 years and 1831 patients aged .80 years in the Safe

Implementation of Treatment in Stroke–International

Stroke Thrombolysis Register. The patients .80 years of

age had a higher mortality rate (30% vs 12%; OR 1.53;

95% CI 1.43-1.65) and less independence (35% vs 57%;

OR 0.73; 95% CI 0.68-0.78). There was a nonsignificant

increase in the symptomatic ICH rate, per NINDS criteria,

in the older subgroup (9.5% vs 7.8%; OR 0.96; 95% CI 0.87-

1.06). Our study revealed that patients .80 years of age

had a less favorable outcome (42.9% vs 49.8%; P 5 .615)

and a higher mortality rate (21.4% vs 9.7%; P5 .162) com-

paredwith the younger subgroups (#80 years of age). The

rate of asymptomatic ICH (17.6% vs 15.3%; P 5 .798) was

quite similar. There was no symptomatic ICH in patients

.80 years of age. However, the small number of elderly

patients (.80 years old) in our studymay explain the non-

significant differences in the rates of favorable outcome

and mortality.

There were some differences in baseline characteristics

of the patients.80 years of age treated with thrombolysis

compared to the younger patients. A higher proportion

of female patients (59% to 68%) was reported in several

studies.6,7,14,15 More severe stroke and higher atrial

fibrillation (29% to 45%) were also seen, which may

explain the less favorable outcome in the older group.6,7,14

Table 2. Baseline characteristics of the patients in the study divided by age

Baseline characteristics

Age, y (N)

#60 (N 5 108) 61-70 (N 5 61) 71-80 (N 5 75) $81 (N 5 17)

Mean NIHSS 10.9 6 6.8 11.7 6 7.1 13.5 6 6.9 15 6 8.9

mean blood sugar (mg/dL) 141.4 6 84.1 132.6 6 56.5 116.4 6 38.1 137.1 6 76.4

Mean prothrombin time (sec) 11.4 6 1.5 11.9 6 2.7 12 6 2.4 12.6 6 1.5

Mean systolic blood pressure (mm Hg) 161.2 6 34.2 157.3 6 33.2 167.5 6 31.9 162.8 6 19.4

Mean diastolic blood pressure (mm Hg) 91.9 618.8 85.1 6 16.8 88.4 6 16.9 84.8 6 14.7

Mean onset-to-needle time (minutes) 163.9 6 45.5 159.3 6 43.4 157.8 6 39.9 137.1 6 39.5

Female (%) 46 (43%) 26 (43%) 33 (44%) 9 (53%)

Hypertension (%) 53 (49%) 44 (72%) 58 (77%) 6 (35%)

Diabetes mellitus (%) 28 (26%) 18 (30%) 16 (21%) 3 (18%)

Hyperlipidemia (%) 33 (31%) 15 (25%) 25 (33%) 3 (18%)

Coronary artery disease (%) 8 (7%) 12 (20%) 8 (11%) 3 (18%)

Old ischemic stroke (%) 14 (13%) 8 (13%) 8 (11%) 2 (12%)

Transient ischemic stroke (%) 5 (5%) 3 (5%) 3 (4%) —

Atrial fibrillation (%) 18 (17%) 12 (20%) 30 (40%) 5 (29%)

Smoking (%) 30 (28%) 13 (21%) 12 (16%) 5 (29%)

Valve prosthesis (%) 3 (3%) — 1 (1%) —

Stroke subtype (%)

LAA 31 (29%) 19 (31%) 24 (32%) 6 (35%)

SAO 48 (44%) 19 (31%) 19 (25%) 3 (18%)

CE 26 (24%) 22 (36%) 30 (40%) 7 (41%)

UND 3 (3%) 1 (2%) 2 (3%) 1 (6%)

ICH type (%)

Asymptomatic ICH 15 (14%) 11 (18%) 11 (15%) 3 (18%)

Symptomatic ICH

NINDS 3 (3%) 1 (2%) 10 (13%) —

ECASS 1 (0.9%) 1 (2%) 7 (9%) —

Favorable outcome (%) 59/100 (59%) 30/60 (50%) 26/70 (37%) 6/14 (43%)

Mortality rate (%) 3/100 (3%) 5/60 (8%) 14/70 (20%) 3/14 (21%)

Abbreviations: CE, cardioembolism; ECASS, European Cooperative Acute Stroke Study; ICH, intracerebral hemorrhage; LAA, large-artery

atherosclerosis; NIHSS, National Institutes of Health Stroke Scale; NINDS, National Institute of Neurological Disorders and Stroke; SAO, small

artery occlusion; UND, undetermined etiology.

Figure 1. Three-month outcome classified by age range: patients #60

years of age (A), patients 61 to 70 years of age (B), patients 71 to 80 years

of age (C), and patients $81 years of age (D).

P.A. DHARMASAROJA ET AL.230

Carlo et al16 studied the outcomes of stroke in very old

patients ($80years of age; 1358patients). In strokepatients

who were not treated with rt-PA, a significantly higher

mortality rate at 3 months (44.6% vs 21.1%; P , .001) was

also found compared with patients ,80 years of age

(3141 patients). Severe stroke symptoms and prestroke in-

stitutionalization strongly determined 3-month disability.

Comorbidity, cognitive impairment, marital status, the

absence of caregivers, and a lack of motivation that re-

duced the effectiveness of rehabilitation and negatively

influenced stroke recovery were potential contributors

to frailty in the elderly.16-19 Progressive reduction in

good outcomes with increasing age was found in stroke

patients either with or without rt-PA treatment. The

poor outcome in patients .80 years of age treated with

rt-PA did not mean than thrombolysis is ineffective. Early

changes in NIHSS evaluation were similar between pa-

tients .80 and #80 years of age after thrombolysis in

1 study.7 Kim et al20 reported a similar proportion of

patients .80 years of age who experienced successful

recanalization with intraarterial therapy compared to

younger patients.20 These data suggest that there was

no major difference in the recanalization rate. Additional

THROMBOLYSIS IN ELDERLY STROKE PATIENTS 231

studies are required to clarify the effectiveness of throm-

bolysis in very old patients.

Our study had a few limitations. This was an observa-

tional study. There might be some selection bias in the

group of very old patients, because a rather small number

of patients (6.3%) were dependent before treatment, and

the onset-to-needle time was shorter. Also, statistically,

the small number of very old (.80 years old) patients

might cause nonsignificant differences in the outcomes

of treatment.

In conclusion, Thai stroke patients .70 years of age

may carry a higher risk of mortality when treated with

intravenous rt-PA compared to patients #70 years of age.

Acknowledgments: This work was supported by the

National Research University Project of Thailand Office of

Higher Education Commission. We would like to thank

Urai Kummark for her help in data collection.

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