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July2005 Vol.42 Issue:      2 Table of Contents
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Therapeutic Study of Ischaemic Stroke in Minoufiya Governorate

M. Okda1, M. Allam2, M. Elwan1, W. El-Shekh1, L. Soltan3, R. Alkapany1
Department of Neurology, Minoufiya1, Cairo2, Alexandria3 Universities

ABSTRACT

Stroke is a common disease leading to disabilities of varying degrees and many deaths. At present, there is no agreed beneficial treatment for the acute stroke patients. This work aimed to study the outcome of patients with acute ischaemic stroke in correlation with treatment with either low molecular weight heparin unfractionated heparin or aspirin & treatment with folic acid, vitamin B6 and vitamin B12. The study was carried out on 60 patients suffering from first ever acute ischaemic stroke within 48 hours of onset. The selected patients were divided into three groups that were matched for age, sex and different risk factors. Unfractionated heparin group (group I) composed of 20 patients. They were 13 males and 7 female, their mean age was 53.2±4.6. low molecular weight heparin group (group II) composed of 20 patients, they were 10 males and 10 females with mean age was 53±4.9 years. Aspirin group (group III) composed of 20 patients, they were 11 males and 9 females with mean age 52.6±5.2 years. At the start of treatment there was no significant difference between the three groups in the degree of neurological impairment regarding NIHSSS and SSSS, After 14 days and one month all patients showed improvement in the neurological impairment but the improvement in group I who were treated with unfractionated heparin was better than group II and group III regarding NIHSS and SSS scores and this difference in the mean scores was statistically significant. Addition of vitamins to the treatment did not give any improvement to the patients regarding the NIHSS or SSS scores and the difference between the treated and non-treated groups with vitamins was not statistically significance. Haemorrhagic transformation occurred in one patient/only in group I and another in II. We can conclude that, treatment of patients with acute ischaemic stroke with intravenous unfractionated heparin decreases the severity of disability and improve the outcome of the patients at one month better than low molecular weight heparin or aspirin, addition of vitamins to treatment did not provide more benefit to the patients in improving outcome or decreasing severity of disability.

(Egypt J. Neurol. Psychiat. Neurosurg., 2005, 42(2): 465-473).

 




INTRODUCTION

 

Stroke is the third most common cause of death in the world, after coronary heart disease and all cancers1.

Ischaemic stroke accounts for 70 - 85 % of stroke incidence2.

The most important outcomes after stroke include death, worsening, stroke recurrence and functional disability with alteration of the quality of life3.

There is now agreement that, the most important outcome to focus on is the independent survival, as death alone is insensitive to detect treatment effect4.

There is strong rationale for considering antithrombotic therapy for treatment of patients with acute ischaemic strokes5.

Because thrombosis plays an important role in the pathogenesis of ischaemic stroke, drugs which interfere with haemostasis and clot formation such as anticoagulants and platelet antiaggregants are used in the management of ischaemic stroke6.

Heparin may reduce the risk of deep venous thrombosis and pulmonary embolism in patients with stroke, but there is a significant risk of intracranial haemorrhage especially in old age and hypertensive patients5.

Low molecular weight heparin is associated with lower risks of haemorrhage and more powerful antithrombotic effects, but there is few reliable information on its effect on other important outcomes; including death and disability7.

Antiplatelet therapy started within the first 48 hours of an ischaemic stroke, improves the patient outcome in the short and long term8.

Treatment with combination of folic acid, vitamin 85 and vitamin Bu reduces plasma homocysteine level in most cases, restores endothelial function and regress the carotid plaque but there is no evidence that such treatment will reduce the clinical events9.

The present work aimed to study the outcome of patients with acute ischaemic stroke in correlation with: Treatment with either low molecular weight heparin, unfractionated heparin or aspirin & treatment with folic acid, vitamin B6 and vitamin B12.

 

PATIENTS AND METHODS

 

This study was carried out on sixty patients suffering from first-ever acute ischaemic cerebrovascular stroke within 48 hours of onset. All patients were  admitted to neurology department of Minoufiya University Hospitals.

 

Exclusion Criteria:

1-     Patient's age below 40 years old or more than 60 years old.

2-     Patients with known history of diabetes mellitus before the onset of stroke.

3-     Patients who had a known history of congenital heart disease.

4-     Patients with prior history of stroke or transient ischaemic attack.

5-     Patients with serum cholesterol level >250 mg/dL.

6-     Patients with liver or renal impairment.

7-     Patients with haemorrhagic lesion in CT. scan of the brain.

 

The patients were divided into three groups:

Group I: Composed of 20 patients (13 males and 7 females) with mean age 53.2±4.6 years. They received treatment in the form of unfractionated heparin at a dose of 5000LU. intravenously every 6 hours for 14 days adjusted according to Partial Thromboplastin Time (PTT) (which was done every 12 hours) and followed by warfarin l-l0 mg per day orally to be adjusted by Prothrombin Time (PT) and International Normalized Ratio (INR) for 14 days.

Group II: Composed of 20 patients (10 males and 10 females) with mean age 53.0±4.9 years. They received treatment in the form of Low molecular weight heparin (nadroparin) at dose of 0.6 U. twice daily by subcutaneous injection, contained in ready to use pre-filled syringe, for 14 days. To be followed by aspirin at dose of 300 mg per day orally for another 14 days.

Group III: Composed of 20 patients (11 males and 9 females) with mean age 52.6±5.2 years. They received treatment in the form of aspirin at dose of 300 mg per day for one month.

Each of the three groups were divided into two subgroups, composed of 10 patients. One subgroup patients received vitamins in the form of vitamin B6 at dose of 2 mg/day, vitamin B12 at dose of 6 ug/day and Folic acid at dose of 400 ug/day taken orally, while the other subgroup didn't receive any vitamins.

 

All patients were subjected to the following:

1-             At the start of the study:

a.      Thorough history taking and complete neurological examination.

                b.             Laboratory investigations:

-             Random blood sugar.

-             Blood urea and creatinine.

-             Liver function tests.

-       Serum cholesterol and triglyceride levels.

-             Serum uric acid level.

c.    ECG and Echocardiography.

d.    Carotid duplex.

e.      Computerized tomography of the brain (CT) was done for all patients at the time of admission (and after 3 days if it was free) to. detect site and size of infarction and to exclude haemorrhage.

f.     Clinical (outcome) scales:

The clinical scales were used for scoring the clinical presentation of the patients and to assess the severity of the neurological deficit10.

The patient's condition was assessed using 2 clinical scales:

-        National Institute of Health Stroke Scale (NIHSS).

-        Scandinavian Stroke Scale (SSS).

2-             Follow up of the patients using:

-        Outcome scales: Done first after 14 days then after one month from stroke onset.

-        CT scan: was done after one month to detect:

                                -               Any haemorrhagic transformation.

-             Change in size of infarction.

-             Occurrence of another lesion.

 

Statistical analysis:

                Two types of statistics were done:

a.      Descriptive statistics: e.g. percentage (%), mean (X) and standard deviation (SD).

b.     Analytic statistics: e.g. Chi-square test, F­-test (ANOVA analysis) and t-test.

 

RESULTS

 

Clinical results:

This study was carried out on 60 patients. They were 34 males and 26 females. Their age ranged from 40 - 60 years.

Heparin group included 20 patients, 13 (65%) males and 7 (35%) female. Low molecular weight heparin group included 20 patients, they were 10 (50%) males and 10 (50%) females. Aspirin group included 20 patients. They were 11 (55%) males and 9 (45%) females.

Table (1) shows baseline characteristics of the studied patient groups. We found that there was no statistically significant difference between the three groups regarding demographic factors, different clinical presentations, clinical risk factors and biochemical data.

 

CT results:

                All patients had CT scan at the start of the study and after one month.

Table (2) shows CT findings of the studied patient groups, regarding site, side, size of infarction in CT. There were no statistically significant difference between the three groups. Haemorrhagic transformation occurred in one patient of group I II and none in group III with no statistically significant difference.

 

Assessment of the disability of the patients:

All patients were assessed using NIHSS and SSS. This was done at the start of the study, then after 14 days and one month.

The improvement in degree of neurological impairment in patients who were treated with intravenous unfractionated heparin after 14 days and after one month was better than patients treated by low molecular weight heparin or aspirin as shown by NIHSS scores and SSS scores and the difference in mean scores was statistically significant.

There was no statistically significant difference between low molecular weight heparin group and aspirin group after 14 days and one month, regarding both scores.

Each group of patients was subdivided into 2 subgroups a and b, subgroup (a) who take vitamins and subgroup (b) who did not take vitamins and we found that, there was no statistically significant difference between both subgroups in each group of patients as regards NIHSS scores and SSS scores.


Table 1. Base line characteristics of the studied patient groups.

 

 

Group I

No. 20

Mean±SD

Group II

No. 20

Mean±SD

Group III

No. 20

Mean±SD

F-test

P-value

Sig.

Characteristics

 

 

 

 

 

 

Age (years)

53.2±4.6

53±4.9

52.6±5.2

0.66

>0.05

N.S

Sex (M/F)

13/7

10/10

11/9

0.96

>0.05

NS

Clinical date

 

 

 

 

 

 

Hemiplegia

16

17

19

2.02

>0.05

N.S

Hemiparesis

3

2

I

0.22

>0.05

N.S

Ataxia

I

1

0

1.03

>0.05

N.S

Hemiainaesthesia

6

8

4

2.937

>0.05

N.S

Aphasia

6

8

4

1.905

>0.05

N.S

Facial palsy

II

9

10

OAO

>0.05

N.S

Disturbed

 

 

 

 

 

 

Conscious level

4

3

3

0.24

>0.05

N.S

Hemianopia

2

2

I

OA4

>0.05

N.S

Dysphagia

1

I

0

1.03

>0.05

N.S

Risk factors

 

 

 

 

 

 

Hypertension

12

10

10

0.536

>0.05

N.S

Smoking

8

7

7

0.144

>0.05

N.S

Cardiac disease

7

7

5

0.619

>0.05

N.S

Biochemical study

 

 

 

 

 

 

Uric acid

6.6±2.09

6.6±1.65

8.6±1.5

0.173

>0.05

NS

RBS

116.9±15.2

110.5±20.65

110.4±27.3

1.537

>0.05

N.S

Triglyceride

123.5±35.02

120.7±30.1

126.3±32.8

0.28

>0.05

N.S

Cholesterol

179.4±39.1

182.85±45.3

188.7±47.1

0.231

>0.05

N.S

S. creatinine

0.96±0.23

0.9±0.26

1.07±0.35

1.8

>0.05

N.S

 

Table 2. CT findings of the studied patient groups.

 

CT findings

Group I

No. 20

Group II

No. 20

Group III

No. 20

X2

P value

Sig.

No

%

No

%

No

%

Side of Infarction:

 

 

 

 

 

 

 

 

 

Left

9

45

     12        60

     10        50

0.934

>0.05

N.S

Right

11

55

8

40

     10        50

Size of Infraction:

 

 

 

 

 

 

 

 

 

Small

9

45

8

40

8

40

 

>0.05

 

Medium

9

45

9

45

8

40

1.27

N.S

Large

2

10

3

15

4

20

 

 

 

Site of Infraction:

 

 

 

 

 

 

 

 

 

Parietal

7

35

7

35

6

30

 

 

 

Temporal

1

5

I

5

2

10

 

 

 

Tempro-parietal

4

20

2

10

1

5

 

 

 

Fronto-parietal

3

15

3

15

2

10

 

 

 

Parieto-occipital

0

0

2

10

2

10

 

 

 

Capsular and basal

 

 

 

 

 

 

14.56

>0.05

N.S

Ganglia

3

15

3

15

5

25

 

 

 

Cerebellar

1

5

I

5

0

0

 

 

 

Brain stem

1

5

0

0

0

0

 

 

 

Fronto-parieto-temporal

0

0

1

5

2

10

 

 

 

Follow up CT after one month:

Haemorrhagic transformation

1

5

1

5

0

0

1.55

>0.05

N.S

Table 3. NIHSS and SSS scores in group I and group II.

 

 

Group I

No = 20

Mean±SD

Group II

No = 20

Mean±SD

t-test

P-value

Sig.

NIHSSS scores:

 

 

 

 

 

At the start of the study

12.4±2.68

12.45±2.5

-0.061

>0.05

N.S

After 14 days

7.25±2.68

9.6±3.2

4.14

<0.05

Sig

After one month

6.2±4.76

8.7±2.84

2.02

<0.05

Sig

SSS scores:

 

 

 

 

 

At the start of the study

24.45±5.66

24.25±7.18

0.98

>0.05

N.S

After 14 days

40.05±5.66

34.7±7.12

2.14

<0.05

Sig

After one month

42.4±9.7

36.25±8.54

2.13

<0.05

Sig

 

 

Table 4. NIHSS and SSS scores in group I and group III.

 

 

Group I

No = 20

Mean±SD

Group III

No = 20

Mean±SD

t-test

P-value

Sig.

NIHSSS scores:

 

 

 

 

 

At the start of the study

After 14 days

After one month

12.4±2.68

7.25±2.68

6.2±4.76

11.75±2.68

10.6±2.68

6.2±4.76

0.77

2.81

1.97

>0.05

<0.05

<0.05

N.S

Sig

Sig

SSS scores:

 

 

 

 

 

At the start of the study

After 14 days

After one month

24.45±5.66

40.05±5.66

42.4±9.7

24.25±5.66

33.6±8.59

37.4±9.7

0.00

2.6

2.04

>0.05

<0.05

<0.05

N.S

Sig

Sig

 

 

Table 5. NIHSS and SSS scores in group II and group III.

 

 

Group II

No = 20

Mean±SD

Group III

No = 20

Mean±SD

t-test

P-value

Sig.

NIHSSS scores:

 

 

 

 

 

At the start of the study

After 14 days

After one month

12.45±2.5

9.6±3.2

8.7±2.84

11.75±2.68

10.6±2.68

6.2±4.76

0.85

1.15

0.18

>0.05

>0.05

>0.05

N.S

N.S

N.S

SSS scores:

 

 

At the start of the study

After 14 days

After one month

24.25±7.18

34.7±7.12

36.25±8.54

24.25±5.66

33.6±8.59

37.4±9.7

-0.092

0.38

0.25

>0.05

>0.05

>0.05

N.S

NS

N.S

 

 

Table 6. NIHSS and SSS scores in subgroups of group I.

 

 

Group (Ia)

No = 10

Mean±SD

Group (Ib)

No = 10

Mean±SD

t-test

P-value

Sig.

NIHSSS scores:

 

 

 

 

 

At the start of the study

After 14 days

After one month

13.6±2.87

7.2±5.15

6.0±5.75

11.2±1.93

7.3±3.59

6.4±3.83

0.021

0.108

-0.05

>0.05

>0.05

>0.05

N.S

N.S

N.S

SSS scores:

 

 

 

 

 

At the start of the study

After 14 days

After one month

23.6±5.79

40.2±13.3

44.2±14.85

25.3±1.8

37.9±12.34

40.6±13.02

0.918

0.749

0.829

>0.05

>0.05

>0.05

N.S

N.S

N.S

 

 

 

Table 7. NIHSS and SSS scores in subgroups of group II.

 

 

Group (IIa)

No = 10

Mean±SD

Group (IIb)

No = 10

Mean±SD

t-test

P-value

Sig.

NIHSSS scores:

 

 

 

 

 

At the start of the study

After 14 days

After one month

11.6±2.45

7.9±3.07

7.3±3.19

13.3±2.35

9.3±3.56

8.1±2.5

0.945

0.554

0.272

>0.05

>0.05

>0.05

N.S

N.S

N.S

SSS scores:

 

 

 

 

 

At the start of the study

After 14 days

After one month

25.7±8.6

37.4±10.9

39.2±10.7

22.8±5.3

34.0±9.5

37.3±8.5

0.89

0.74

0.43

>0.05

>0.05

>0.05

N.S

N.S

N.S

 

 

 

Table 8. NIHSS and SSS scores in subgroups of group III.

 

 

Group (IIIa)

No = 10

Mean±SD

Group (IIIb)

No = 10

Mean±SD

t-test

P-value

Sig.

NIHSSS scores:

 

 

 

 

 

At the start of the study

After 14 days

After one month

10.9±2.33

7.9±2.37

7.0±1.94

12.6±2.7

9.3±3.7

8.1±2.8

0.259

0.527

0.388

>0.05

>0.05

>0.05

N.S

N.S

N.S

SSS scores:

 

 

 

 

 

At the start of the study

After 14 days

After one month

26.4±5.6

32.9±11.77

39.4±5.52

22.5±7.01

34.4±10.89

37.4±4.0

0.443

0.752

0.164

>0.05

>0.05

>0.05

N.S

N.S

N.S


DISCTSSION

 

Ischaemic stroke is a syndrome of multiple aetiologies and different clinical manifesta­tions11.

It affects large number of population and causes great morbidity and mortality with the accompanying psychological, social, economic problems and great health care cost12.

There is no agreed beneficial treatment for acute ischaemic stroke patients13.

For acute cerebral infarction patients who are not eligible for intravenous r-tpA, a variety of anti thrombotic agents can be considered and the rationale for the use of antithrombotic therapy for treatment of acute ischaemic stroke is based on 2 promises: (1) reduction of the risk of stroke progression or recurrent thromboembolism (2) prevention of venous thromboembolic complications such as deep venous thrombosis and pulmonary embolism11.

There was no significant difference between the three groups regarding initially important prognostic factors as: age, sex, risk factors (clinical and laboratory) as well as initial neurological deficits as measured by NIHSS and SSS scores. Therefore, the difference in outcome between the three groups would be attributed to the effect of treatment.

This study found that, patients who were treated with intravenous unfractionated heparin had better outcome after 14 days and one month and this. was in agreement with Chamorro14. He studied patients with atrial fibrillation and ischaemic stroke treated early with intravenous unfractionated heparin and found that, 28% of the patients had excellent outcome. The improved outcome was associated with younger age, normal baseline CT scan, lower ischaemic scores at the baseline and early heparinization, Albers et al.11, concluded that, treatment with unfractionated heparin intravenously should not be withheld in patients with stroke and non valvular atrial fibrillation.

This can be explained by presence of intravenous unfractionated heparin might have other properties aside from anticoagulation effects that could influence and improve the outcome after an ischaemic stroke14.

In disagreement with this study, Haley et al.16, found no evidence in patients with acute ischaemic stroke treated with intravenous unfractionated heparin to improve the outcome.

Roden Jullig and Britton16, found that, intravenous unfractionated heparin have unsatisfying effectiveness since it couldn't improve the outcome of the patients and one third of the patients continued to progress whitest on treatment.

This study found that, the mean scores of NIHSS and SSS were better after 14 days and after one month in group (I), meaning that, patients who were treated with intravenous unfractionated heparin had a significant improvement in the outcome more than patients who were treated with low molecular weight heparin and aspirin. Also there is no significant difference in rate of haemorrhagic transformation of cerebral infarction in the three groups, 5% of 1st group, 5% of second group and 0% of third group (P>0.05).

This is in disagreement with Moonis and Fischer17, who reported that, patients treated with low molecular weight heparin (enoxoparine) experienced less neurological worsening as compared with patients who were treated with intravenous unfractionated heparin.

And also in disagreement with Berge and Sandercock18 who concluded that, no evidence that unfractionated heparin was superior to aspirin in reducing death and dependency at long term follow up.

In this study, there was no statistically significant difference between patients who were treated with aspirin and LMW heparin in mean scores (P>0.05) of NIHSS and SSS.

These results were in agreement with Berge et al.8, who reported no superiority for LMWH (deltaparin given at dose of 100 Iu/kg subcutaneously twice daily) as compared with aspirin (at dose of 160 mg daily) in the treatment of patients with ischaemic stroke and atrial fibrillation. In preventing stroke recurrence (8.5% of deltaparin group had recurrence in first 14 days compared with 7.5% of aspirin group) or improving clinical outcome.

Bath et al.7, also found no significant difference in outcome in patients with ischaemic stroke who were treated with either LMWH (Tinzaparin) either at high or low dose and aspirin at dose of 300 mg daily. The rate of intracerebral haemorrhage was more in high dose group than low dose group or aspirin group. In this study, there was no significant improvement of the outcome with vitamin therapy after 14 days or one month.

In this study, there was no significant improvement of the outcome with vitamin therapy after 14 days or one month, and the ongoing trials are currently underway to prove that, lowering homocysteine level with vitamins actually improves mortality and morbidity from atherosclerotic disease19.

We can conclude that, treatment of patients with acute ischaemic cerebrovascular stroke (within 48 hours of onset) with intravenous un-fractionated heparin decreases the severity of disability and improve the outcome of the patients at one month. Intravenous unfractionated heparin has a preferable effect on the outcome of the patients more than treatment with either LMW heparin or aspirin. Haemorrhagic transformation of cerebral infarction occurred more in heparin and LMW heparin groups than aspirin group, but not statistically significant. Addition of vitamins to treatment didn't provide more benefit to the patients in improving outcome or decreasing severity of disability.

 

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