Form JTP/KKM-3ver1

NO DOKUMEN: KKMOH-AG2-AK2

ARAHAN KERJA: PERMOHONAN PERUNTUKAN PENYELIDIKAN KAJIAN

TANGGUNGJAWAB TINDAKAN

1. Pastikan permohonan pendaftaran kajian epidemiologi dipohon

melalui National Medical Research Registry di www.nmrr.gov.my iaitu
‘NIH GUIDELINES FOR CONDUCTING RESEARCH IN THE MOH
INSTITUTIONS AND FACILITIES’

TPKPE/KPPE 2. Isi Borang JTP /KKM/-3ver1 untuk permohonan peruntukan

penyelidikan kajian (borang seperti di bawah)

3. Buat 20 salinan Borang JTP/KKM-3ver1 yang lengkap dan hantar ke

Sekretariat NIH.

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Form JTP/KKM-3ver1

I. Project Identification

A. Project code (Please leave blank - code will be assigned by the NIH Secretariat)

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B. Type of Grant (Please tick one only. Small research grants are for amounts not exceeding RM
10,000 each)

√ Major Research Grant Small Research Grant

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C. Project Title (Please indicate the title of the project; the title should be short and concise)

TRANEXAMIC ACID AS ANTI-FIBRINOLYTIC AGENT IN NON-TRAUMATIC INTRACEREBRAL

HEMORRHAGE (TANICH II)

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D. Principal Investigator
(Please indicate the name and identification card number of the principal investigator)

NAME : MR ANANDA ARUMUGAM

I/C : 740618-08-6031

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E. Department (Please indicate the name, address, telephone number and fax number of the
Department in which the principal investigator is based. Where available, indicate the e-mail
address of the principal investigator too)

NEUROSURGERY DEPARTMENT
HOSPITAL QUEEN ELIZABETH / HOSPITAL LIKAS, KOTA KINABALU
HOSPITAL TEL. NO. 088-324600 / 088-522600
HOSPITAL FAX NO. 088-237532
ananda_arumugam@yahoo.com

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F. Key words (Please provide a maximum of 5 key words that describes the research project.
These key words shall be used in a database on research in the Ministry of Health)

TRANEXAMIC ACID
NON-TRAUMATIC
INTRACEREBRAL HEMORRHAGE

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Form JTP/KKM-3ver1

II. Objectives of the Project

A. Objectives of the project (Please describe the measurable general and specific objectives of
the project and define the expected results. Use results-oriented wording with verbs such as
‘to define …’, ‘to determine …’, ‘to develop …..’ )

To assess the efficacy of Tranexamic Acid (TXA) in different dosage of total 3g and 2g; as compared
to Placebo with respect to prevention of hematoma expansion in subjects with non-traumatic
intracerebral hemorrhage.

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B. Research background of the project (Please indicate if the project is new, modification, or
extension. Give a summary of your literature review and related research to indicate
originality and feasibility of proposed research. If modification, indicate why modification is
required. If extension, indicate findings of previous research project and why extension is
required).

 Project Status (Please tick one) New Modification Extension √

of previous of previous
project project

 Summary of literature review and related research (PLACE INFORMATION IN APPENDIX A)

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C. Type of Research (Please tick one only)
 Scientific (basic) research
o Technology development (applied research)
o Prototype development (design and engineering)
o Social / policy research

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D. Field of Research (Please tick one only)

o Biomedical
 Clinical
o Public health
o Epidemiological
o Health systems
o Health economics
o Behavioral
o Others, please specify ………………………………………

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Ministry of Health 9MP Health Research Priority Areas being addressed (Please refer to the Ministry
of Health Research Priorities for the 9th Malaysia Plan as in www.nih.gov.my)

According to 10th MP
Chapter 6. Burden of Disease
5.4 Adult Health

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Form JTP/KKM-3ver1

III. Benefits of the Project

A. Direct customers / beneficiaries of the project (Please identify clearly, the potential
customers / beneficiaries of the research findings and provide details of their relevance to
the health services. If this is a directed / requested research, please name the health service
provider involved)

Efficacy of tranexamic acid (TXA), an anti-fibrinolytic agent, in reducing hematoma growth is

now being studied worldwide, with promising results. It is easy to administer, readily
available, inexpensive, and effective in other haemorrhagic conditions.

The purpose of this study is to further establish the potential of different doses of injection
TXA ie recommended dose (1g bolus loading, then 1g over 8 hours infusion) and high dose
(1g bolus loading , then 2g over 8 hours infusion), together with strict BP control, in reducing
the growth of haematomas in patients with spontaneous (non-trauma) ICH.

We hope that the study can contribute in establishing a guideline for future acute ICH
management in Malaysia. Successful prevention of hematoma expansion may be helpful in
improving the outcome of ICH.

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B. Outputs expected from the project (Please refer to the outputs in the Guidelines and give
further details. Your actual outputs at the completion of the project shall be compared with
the outputs listed here. Any unjustified shortfall may be detrimental to your future
application)

 assess efficacy of Tranexamic acid in preventing hematoma expansion

 study effect of strict BP control in prevention of hematoma expansion
 assess safety of TXA in primary intracerebral hemorrhage
 study the correlation of Total White Cell Count and volume of hematoma
 Glasgow Outcome Scale assessment at day 30

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Form JTP/KKM-3ver1

IV. Project Structure (Optional for Small Research Grants)

A. Departments and research organizations involved in the project (Please identify all MOH
Departments and other research organizations collaborating in the project and describe
briefly the role / contribution to the project)

NEUROSURGERY DEPARTMENT : Assess and recruit study subjects

: Administer treatment drug
: Monitor and follow-up study subjects

RADIOLOGY DEPARTMENT : Performing CT scan

: Calculation of hematoma volume

EMERGENCY DEPARTMENT : Detection of patients and referral to Neurosurgery Team

PHARMACY : Provide information on study drug

CLINCIAL RESEARCH CENTRE : Provide guidance and monitor study process

B. Project team
Name Department/ Organization Estimated days on
project
Principal Investigator :

MR ANANDA ARUMUGAM NEUROSURGERY 2 years

Co-investigators :

DR TAN SHZE EE NEUROSURGERY 2 years

DR JONATHAN JOSEPH NEUROSURGERY
PHARMACIST TAN SZE LING NEUROSURGERY

Support staff :

DR WAN NAJWA ZAINI RADIOLOGY 2 years

DR LIM CHENG KOOI RADIOLOGY
DR HAFIDAHWATI HAMAD EMERGENCY
DR AHMAD HASHIM EMERGENCY
DR MICHAL CHRISTINA CRC QEH

Contract staff : (Indicate numbers)

Total : 2 years
1 month = 20 days of 8 hrs

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Form JTP/KKM-3ver1

V. Research Approach

A. Research methodology (Please describe the research methodology to be used. Identify

specialized equipment, facilities and infrastructure which are required and which are
available)

This is a single-blinded, randomised controlled trial. Upon consent, eligible patients will be recruited
and randomly assigned to receive either Placebo, 2g TXA Treatment (1g slow bolus over 10 minutes
then followed by 1 g over 8 hours) or 3g TXA Treatment (1g slow bolus over 10 minutes then
followed by 2g over 8 hours). Randomization will be done by blinded patients or family members
choosing an envelope from a box, in which treatment option will be stated in the envelope. All
patients will need strict blood pressure control (systolic blood pressure < 140-160mmHg) using
Labetalol infusion; or other options of anti-hypertensives; if indicated.

B. Project Activities (Please list and describe the main project activities. The timing and duration
of these activities are to be shown in the Gantt chart in Section VI)

I. Writing of study proposal

II. Study initiation and training
III. Screening and enrolment of study subjects
IV. Baseline assessment
V. Randomization and allocation of study groups
VI. Administration of study drugs
VII. Monitoring in ward
VIII. CT Brain scan at 24 hours of treatment
IX. Hematoma evaluation
X. Data entry and cleaning
XI. Data analysis
XII. Report writing

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C. Key milestones (Please list and describe the principal milestones of the project. The timing of
milestones is to be shown in the Gantt chart in Section VI. A key milestone is reached when a
significant phase in the project is completed.)

Study proposal writing : 2 months (April – May 2016)

Study initiation and training : 2 months (June – July 2016)
Data collection : 2 years (October 2016 – October 2018)
Data entry and cleaning : 2 months (November – December 2018)
Data analysis and report writing : 3 months (January – March 2019)

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Form JTP/KKM-3ver1

D. Risks of the project (Please describe the factors that may cause delays in, or prevent
implementation, of the project as proposed above; estimate the degree of risk)

Factors:
Low Medium High
 Technical risk: /
/
 Timing risk: /

 Budget risk: /

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E. Duration (Indicate the planned starting date of the project and the elapsed time, in months, to
complete the project. Do not include time for preparation of publication)

Planned starting date : October 2016

Data collection duration : 2 years (October 2016 – October 2018)
Data entry : 2 months (November – December 2018)
Data analysis : 1 month (January 2019)
Report writing : 2 months (February – March 2019)

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Form JTP/KKM-3ver1
VI. Project Schedule
(Please prepare additional pages if necessary)

2016 2017 2018

Project Activities
A S O N D J F M A M J J A S O N D J F M A M J J A S O N D

Planned Starting Date ●

Data Collection ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

Data Entry ● ●

Use () to indicate planned milestones.

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Form JTP/KKM-3ver1

2019 2020
Project Activities
J F M A M J J A S O N D J F M A M J J A S O N D

Data Analysis ●

Report Writing ● ●

Use () to indicate planned milestones.

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Form JTP/KKM-3ver1

VII. Project Funding

A. Direct project expenses (Please indicate the yearly costs for the project. The amounts
should only include costs, which are to be requested from the MOH Allocation on
Research Development. Use additional pages, if necessary. Details and justification
for each cost category should be prepared in the form shown in Appendix B. *Please
refer to your Department’s Financial Unit in stating the allocation as OS - Objek
Sebagai)

Cost category Total RM 2016 RM 2017 RM 2018 RM

OS21000 : Travel &
Transportation
4800.00 1200.00 2400.00 1200.00
(In Country)

OS24000 : Rentals
- - - -

OS25000 : Raw Materials

- - - -

OS27000 : Research materials

and Supplies 1340.00 365.00 430.00 545.00

OS29000 : Special services

5250.00 1750.00 1750.00 1750.00

OS29000 : Temporary &

contract personnel - - - -

OS35000 : Special equipment

and accessories 3000.00 3000.00 - -

TOTAL
14390.00 6315.00 4580.00 3495.00

B. Disbursement Schedule (Please indicate how the fund requested above in Section
VII. A, will be allocated)

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Form JTP/KKM-3ver1

Department/
Total RM 2016 RM 2017 RM 2018 RM
Organization

14390.00 6315.00 4580.00 3495.00

NEUROSURGERY

TOTAL 14390.00 6315.00 4580.00 3495.00

C. Funding Sources (Please indicate all sources of funding for the project)

Funding Sorces RM % of Total Funding

MOH Allocation on Research
Development
(this is the total amount
14390.00 100
requested for in Section VII.A
above)

Operating budget
(emoluments of staff) - -

Other sources (please specify)

- -

TOTAL 14390.00 100%

VIII. Contractual Matters

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Form JTP/KKM-3ver1

(For Small Research Grant application, submit only information for the Principal Investigator
and not collaborators)
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Principal Investigator

Name: MR ANANDA ARUMUGAM

Signature:

Date: 12.5.2016

Head of Department of Principal Investigator

Name: DATUK MR DR PULIVENDHAN SELLAMUTHU

Signature and Official Stamp:

Date: 12.5.2016

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Co-Investigator

Name: DR TAN SHZE EE

Signature:

Date: 12.5.2016

Head of Department of Co-Investigator

Name: DATUK MR DR PULIVENDHAN SELLAMUTHU

Signature and Official Stamp:

Date: 12.5.2016

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Form JTP/KKM-3ver1

Co-Investigator

Name: DR JONATHAN JOSEPH

Signature:

Date: 12.5.2016

Head of Department of Co-Investigator

Name: DATUK MR DR PULIVENDHAN SELLAMUTHU

Signature and Official Stamp:

Date: 12.5.2016

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Co-Investigator

Name: PHARMACIST TAN SZE LING

Signature:

Date: 12.5.2016

Head of Department of Co-Investigator

Name: DR LIAU SIOW YEN

Signature and Official Stamp:

Date: 12.5.2016

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Form JTP/KKM-3ver1

IX. CURRICULUM VITAE

(Please prepare and submit curriculum vitae of all key researchers for major research grant
application. For small research grant application submit only the curriculum vitae of the
principal investigator. The curriculum vitae should contain the following information below)

1. Name: MR ANANDA ARUMUGAM

2. I/C No. 740618-08-6031

3. Age: 42

4. Nationality: MALAYSIA

5. Name and address of Department / Institution:

NEUROSURGERY DEPARTMENT
HOSPITAL QUEEN ELIZABETH II
88300 KOTA KINABALU
SABAH

6. Title of Position currently held: NEUROSURGEON

7. Official telephone number: 012-5223696

8. Official fax number: 088-237532

9. Official e- mail: ananda_arumugam@yahoo.com

10. Academic and professional qualifications:

(List all qualifications in the following format: title, field, year, name and place of
institution)

MBBS (MANIPAL), 2004

MASTER OF SURGERY (NEUROSURGERY), USM, 2014

11. Number of years of experience in the field related to this project:

10 YEARS

12. List all major research projects completed or involved in which are in the field
related to this project (List the projects in the following format: title, year started,
year completed, position held in project, major findings and outputs)

TRANEXAMIC ACID AS ANTIFIBRINOLYTIC AGENT FOR NON TRAUMATIC

INTRACEREBRAL HEMORRHAGE
2012-2013
PUBLISHED IN MALAYSIAN JOURNAL OF MEDICAL SCIENCES (MJMS), 2015

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Form JTP/KKM-3ver1

IX. CURRICULUM VITAE

(Please prepare and submit curriculum vitae of all key researchers for major research grant
application. For small research grant application submit only the curriculum vitae of the
principal investigator. The curriculum vitae should contain the following information below)

1. Name: TAN SHZE EE

2. I/C No. 850321-10-5972

3. Age: 31

4. Nationality: MALAYSIA

5. Name and address of Department / Institution:

NEUROSURGERY DEPARTMENT
HOSPITAL QUEEN ELIZABETH II
88300 KOTA KINABALU
SABAH

6. Title of Position currently held: MEDICAL OFFICER UD 48

7. Official telephone number: 012-3565830

8. Official fax number: 088-237532

9. Official e- mail: shzeee@hotmail.com

10. Academic and professional qualifications:

(List all qualifications in the following format: title, field, year, name and place of
institution)

MBBS (IMU) 2010 INTERNATIONAL MEDICAL UNIVERSITY, MALAYSIA

11. Number of years of experience in the field related to this project:

3 YEARS

12. List all major research projects completed or involved in which are in the field
related to this project (List the projects in the following format: title, year started,
year completed, position held in project, major findings and outputs)

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Form JTP/KKM-3ver1

IX. CURRICULUM VITAE

(Please prepare and submit curriculum vitae of all key researchers for major research grant
application. For small research grant application submit only the curriculum vitae of the
principal investigator. The curriculum vitae should contain the following information below)

1. Name: JONATHAN JOSEPH

2. I/C No. 850709-12-5507

3. Age: 31

4. Nationality: MALAYSIA

5. Name and address of Department / Institution:

NEUROSURGERY DEPARTMENT
HOSPITAL QUEEN ELIZABETH II
88300 KOTA KINABALU
SABAH

6. Title of Position currently held: MEDICAL OFFICER UD 44

7. Official telephone number: 010-2329785

8. Official fax number: 088-237532

9. Official e- mail: jon_joseph1985@yahoo.com.sg

10. Academic and professional qualifications:

(List all qualifications in the following format: title, field, year, name and place of
institution)

MD (LVIV NATIONAL MEDICAL UNIVERSITY), 2010, UKRAINE

11. Number of years of experience in the field related to this project:

1 YEAR

12. List all major research projects completed or involved in which are in the field
related to this project (List the projects in the following format: title, year started,
year completed, position held in project, major findings and outputs)

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Form JTP/KKM-3ver1

IX. CURRICULUM VITAE

(Please prepare and submit curriculum vitae of all key researchers for major research grant
application. For small research grant application submit only the curriculum vitae of the
principal investigator. The curriculum vitae should contain the following information below)

1. Name: TAN SZE LING

2. I/C No. 880510-35-5070

3. Age: 28

4. Nationality: MALAYSIA

5. Name and address of Department / Institution:

PHARMACY DEPARTMENT
HOSPITAL QUEEN ELIZABETH II
88300 KOTA KINABALU
SABAH

6. Title of Position currently held: CLINICAL PHARMACIST

7. Official telephone number: 016-4634369

8. Official fax number: 088-237532

9. Official e- mail: szeling88@hotmail.com

10. Academic and professional qualifications:

(List all qualifications in the following format: title, field, year, name and place of
institution)

MASTER OF PHARMACY, 2010

INTERNATIONAL MEDICAL UNIVERSITY TWINNING WITH UNIVERSITY OF
STRATHCLYDE

11. Number of years of experience in the field related to this project:

3 YEARS

12. List all major research projects completed or involved in which are in the field
related to this project (List the projects in the following format: title, year started,
year completed, position held in project, major findings and outputs)

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Form JTP/KKM-3ver1

APPENDIX A

Summary of literature review and related research

Stroke remains a major health burden worldwide. The incidence and prevalence
rates of stroke are decreasing in developed countries; an opposite trend is taking
place in the Asia Pacific, where an increasing number of patients are being diagnosed
with acute stroke. A prospective nationwide hospital-based registry done from 2010-
2014 has shown that the incidence and prevalence of stroke in Malaysia increased
dramatically. Ischemic stroke incidence is estimated to increase annually by 29.5%
and haemorrhagic stroke by 18.7% 1.

Spontaneous intracerebral haemorrhages (ICH) results in high mortality and

morbidity in the population. Hematoma expansion after acute intracerebral
haemorrhage is common and is associated with early deterioration (END) and poor
clinical outcome2. Clinical and biologic markers of the inflammatory reaction on
admission are predictors of subsequent early neurological deterioration, whereas
early intracerebral hematoma growth, intraventricular bleeding, and high systolic
blood pressure within 48 hours are factors associated with END in patients with
spontaneous ICH 2.

Several studies have investigated hypertensive treatments as well as other

potential therapies for ICH; many of which were designed to identify and treat ICH
progression. Despite this, there is currently no approved, effective therapy 3.

The influence of blood pressure (BP) lowering

4
on intracerebral haemorrhage (ICH) patients is unclear . The Intensive Blood
Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT) study suggests
that early intensive blood pressure (BP) lowering can attenuate hematoma growth at
24 hours after intracerebral haemorrhage5. In the INTERACT 2 trial, intensive BP
lowering appears beneficial across a wide range of baseline SBP levels, and target
SBP level of 130-139 mm Hg is likely to provide maximum benefit in acute ICH 6. For
ICH patients presenting with systolic blood pressure (SBP) between 150 and 220
mm Hg and without contraindication to acute BP treatment, acute lowering of SBP to
140 mm Hg is safe (Class I; Level of Evidence A) and can be effective for improving
functional outcome (Class IIa; Level of Evidence B). For ICH patients presenting with
SBP >220 mm Hg, it may be reasonable to consider aggressive reduction of BP with a
continuous intravenous infusion and frequent BP monitoring (Class IIb; Level of
Evidence C).

There are no randomized trials of reversing agents for newer anticoagulants

among patients with ICH or other major bleeding complications, and because these
agents have only been available for a few years, experience with reversal is limited.
Currently available agents in the United States (dabigatran, rivaroxaban, and
apixaban) have relatively short half-lives ranging from 5 to 15 hours. Evaluation of the
activated partial thromboplastin time and prothrombin time and consultation with a
hematologist are reasonable to individualize care.

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Form JTP/KKM-3ver1

Potential reversal strategies using factor VIII inhibitor bypassing activity (FEIBA),
other prothrombin complex concentrates (PCC), or recombinant activated factor VIIIa
(rFVIIa) might be considered. FFP is of unclear utility, and vitamin K is not useful. It
has been suggested that FEIBA or rFVIIa may be better for the direct thrombin
inhibitor Dabigatran, whereas other PCCs may be better for the factor Xa inhibitors
rivaroxaban and apixaban, but these data are preliminary. Activated charcoal can be
used if the most recent dose of dabigatran, apixaban, or rivaroxaban was taken
within the previous couple of hours. Hemodialysis has been noted as an option for
dabigatran, but less so for rivaroxaban or apixaban because these are more highly
protein bound. Specific antidotes for these medications are in early clinical
development.

rFVIIa has also been tested in patients with non-oral anticoagulant drugs
(OAC) ICH. Although a phase 2 randomized trial showed that treatment with rFVIIa
within 4 hours after ICH onset limited hematoma growth and improved clinical
outcome relative to placebo, a subsequent phase 3 trial did not find clinical
benefit. Use of rFVIIa was associated with an increased frequency of
thromboembolic events compared with placebo (7% versus 2%) in the phase 2 trial
and significantly more arterial events in the phase 3 trial. It remains to be
determined whether rFVIIa might benefit a particular subset of patients with ICH, but
currently its benefits in ICH patients, whether or not they are taking an OAC, remain
unproven7.

Early hematoma expansion (EHE) in patients with intracerebral hematoma is a

promising treatment target. To date, the time course of EHE has remained poorly
described. In a study, 25 patients with intracerebral hematoma were included; mean
(SD) time from onset to CT was 108.6 (45.7) minutes. Ten (40%) patients had EHE. In
patients with a final clinically significant hematoma expansion >12.5 mL, all EHE
occurred within 6 hours after admission scan. EHE was reliably reflected by
transcranial B-mode ultrasound and mainly occurred within the first 7 to 8 hours
after symptom onset8.

Spontaneous intracerebral haemorrhage (ICH) can be devastating, particularly

if hematoma expansion (HE) occurs. Tranexamic acid (TA), an antifibrinolytic drug,
significantly reduced mortality in bleeding patients after trauma in the large CRASH-2
trial9. The CRASH-2 ICH sub study found that TA no significantly reduced mortality
and dependency in traumatic ICH. There were no significant differences in secondary
outcomes including adverse events, HE, death, and dependency. One patient in the
TA group had a deep vein thrombosis10.

Mortality and morbidity associated with intracerebral haemorrhage is still

high. Up to now, there are no evidence-based effective treatments for acute ICH. In a
study to assess the effect of tranexamic acid (TXA) on hematoma growth of patients
with spontaneous ICH compared to a placebo, showed significant hematoma growth
in control group after 24 hours when compared to baseline; whereas the treatment
group there is no significant hematoma size expansion between baseline and after 24
hours11.

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LITERATURE REVIEW OF TRANEXAMIC ACID

According to a Systematic review, people with haematological disorders are

frequently at risk of severe or life-threatening bleeding as a result of
thrombocytopenia (reduced platelet count). This is despite the routine use of
prophylactic platelet transfusions to prevent bleeding once the platelet count falls
below a certain threshold. Platelet transfusions are not without risk and adverse
events may be life-threatening. A possible adjunct to prophylactic platelet
transfusions is the use of antifibrinolytics, specifically the lysine
analogues tranexamic acid (TXA) and epsilon aminocaproic acid (EACA)12.

Beneficial effects of tranexamic acid (TA) have been established in surgery and
trauma. In a study of using TXA in primary total knee replacement, 62 patients
undergoing primary total knee replacement were enrolled in the study,and
randomized to receive a single dose of 2.5g of intravenous tranexamic acid (Group
TA) or saline (Group GP), 5min before opening the pneumatic tourniquet,
respectively. Hemoglobin, hematocrit, and blood loss were recorded 24h after
surgery. Deep vein thrombosis was investigated during patient's hospitalization and
15 and 30 days after surgery in review visits. Study result showed that Tranexamic
acid reduced postoperative bleeding without promoting thromboembolic events 13.

In a postpartum haemorrhage (PPH) related clinical trial , women with PPH

>800 ml after vaginal delivery were assigned to receive either TA (4 g over 1 h, then 1
g per h over six h) (TA) or not (H). A non-haemorrhagic group (NH), <800 ml blood
loss, was included as postpartum reference. This study provides biological evidence
of an early increase in D-dimers and plasmin-antiplasmin complexes associated with
active post-partum haemorrhage and its attenuation by the early use of a clinically
effective high dose of TA, opening the perspective of dose ranging studies to
determinate the optimal dose and timing in this setting 14. A multicenter, double-
blind, randomized controlled trial involving 4000 women in labour, treatment (either
TXA 1 g or placebo) was administered intravenously just after birth. A 30 % reduction
in the incidence of PPH, from 10.0 % to 7.0 %15.

Tranexamic acid also recommended as part of a blood conservation strategy

in high risk patients undergoing off-pump coronary artery bypass (OPCAB) surgery
(Class I, Level A)16. In the CRASH-2 trial, the effects of early administration of
tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma
patients with significant haemorrhage were assessed. Result showed that the
Tranexamic acid significantly reduced all-cause mortality. Recommendation were
given to administer Tranexamic acid as early as possible to bleeding trauma patients.
For trauma patients admitted late after injury, tranexamic acid is less effective and
could be harmful17.

The antifibrinolytic drug tranexamic acid (TXA) is effective in reducing blood

loss and transfusion requirements in other fields of elective surgery and its use is
emerging in a number of plastic surgical subspecialties.

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Form JTP/KKM-3ver1

This systematic review and meta-analysis evaluates the current evidence for the
efficacy and safety of TXA in craniomaxillofacial, head and neck, breast, aesthetic,
burns, and reconstructive microsurgery. Level-1 evidence supports the use of TXA in
craniofacial and orthognathic surgery18.

The optimal dose of tranexamic acid (TA) is still an issue. In a study on adults
undergoing cardiac surgery with cardiopulmonary bypass, the authors compared
two doses of TA during cardiac surgery in a multicentre, double-blinded, randomized
study. Patients were stratified according to transfusion risk, then randomized to two
TA doses: 10 mg/kg bolus followed by 1 mg/kg/h infusion (low dose) until the end of
surgery or 30 mg/kg bolus followed by 16 mg/kg/h infusion (high dose).A high dose
of TA does not reduce incidence of blood product transfusion up to day 7, but is
more effective than a low dose to decrease transfusion needs, blood loss, and repeat
surgery19.

Intravenous administration of tranexamic acid in primary total knee

replacement, has presented a non-auto transfusion or allo-transfusion rate of 100%,
with no increased incidence of thrombotic events. Thus, its use in this group of
patients is recommended20.Also in a meta-analysis, the authors suggests that the
administration of TXA significantly reduced blood loss and the need for allogeneic
blood transfusion, without apparent increased risk of DVT or PE thromboembolic
complications21.

The anti-fibrinolytic agent tranexamic acid (TXA) has demonstrated clinical

benefit in trauma patients with severe bleeding, but its effectiveness in patients with
traumatic brain injury (TBI) is unclear. From a systematic review and meta-analysis,
results from the 2 RCTs demonstrated statistically significant reduction in ICH
progression with TXA and a non-statistically significant improvement of clinical
outcomes in ED patients with TBI 22. Blood loss is often a major complication in
neurosurgery that requires transfusion of multiple units of blood. A study result
showed there is a significant reduction in the total amount of blood loss in TXA
group. However, there was no reduction in intraoperative transfusion requirement 23.

There are some reported adverse event post TXA administrations. In a study,
TXA was found to statistically significantly increase the incidence of total DVT on
post-operative day 7 compared with the control group (24 (18.9%) and 12 (9.4%),
respectively; p < 0.05) but most cases of DVT were isolated distal DVT, with the
exception of one patient with proximal DVT in each group. One patient in the control
group developed a non-fatal symptomatic pulmonary embolism (PE). However, the
use of TXA did not appear to affect the prevalence of either proximal DVT or PE 24. In a
case report of a 30-year-old otherwise healthy woman, who had been treated with
TXA for up to six months, presented with fatal acute, massive PE and cardiac arrest,
which was treated with prompt resuscitation including thrombolysis with
recombinant tissue plasminogen activator and subsequent return of spontaneous
circulation25.

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In another case of a 56-year-old woman without any previous cardiac history

who was admitted to the hospital for an elective right hip arthroplasty and who
received 1 dose of 10 mg/kg of TA, her immediate postoperative course was
complicated by hypotension and chest pain, and an electrocardiogram showed ST
segment elevation in the inferior leads. Emergent coronary angiography showed
complete occlusion of the distal right coronary artery that was successfully treated
with thrombectomy and percutaneous coronary intervention. An extensive literature
search showed only 4 cases of myocardial infarction in the setting of TA
administration, all of which were outside the United States 26.

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REFERENCES

1. Aziz ZA, Lee YY, Ngah BA,et al. Acute Stroke Registry Malaysia, 2010-2014: Results
from the National Neurology Registry. J Stroke Cerebrovasc Dis. 2015 Dec.

2. Leira R, Dávalos A, Silva Y, et al. Early neurologic deterioration

in intracerebral haemorrhage: predictors and associated factors; Stroke Project,
Cerebrovascular Diseases Group of the Spanish Neurological Society. Neurology. 2004
Aug 10

3. Adrian V. Specogna, Tanvir C. Turin, Scott B. Patten, Michael D. Hill. Factors

Associated with Early Deterioration after Spontaneous Intracerebral Haemorrhage: A
Systematic Review and Meta-Analysis PLoS One. 2014 May 8.

4. Pan C, Hu Y, Liu N, et al. Aggressive Blood Pressure Lowing Therapy in Patients with
Acute Intracerebral Haemorrhage is Safe: A Systematic Review and Meta-analysis.
Chin Med J (Engl). 2015 Sep 20

5. Anderson CS, Huang Y, Arima H, et al. Effects of early intensive blood pressure-
lowering treatment on the growth of hematoma and perihematomal oedema in
acute intracerebral haemorrhage: the Intensive Blood Pressure Reduction in Acute
Cerebral Haemorrhage Trial (INTERACT). Stroke. 2010 Feb.

6. Arima H, Heeley E, Delcourt C, et al. Optimal achieved blood pressure in acute

intracerebral haemorrhage: INTERACT2.Neurology. 2015 Feb 3

7. Hemphill JC 3rd, Greenberg SM, Anderson CS,et al. Guidelines for the
Management of Spontaneous Intracerebral Haemorrhage: A Guideline for Healthcare
Professionals from the American Heart Association/American Stroke Association.
Stroke. 2015 Jul; 46.

8. Ovesen C, Christensen AF, Krieger DW, et al. Time course of early postadmission
hematoma expansion in spontaneous intracerebral haemorrhage. Stroke. 2014 Apr;
45

9. CRASH-2 Collaborators et al (Intracranial Bleeding Study). Effect of tranexamic acid

in traumatic brain injury: a nested randomised, placebo controlled trial (CRASH-2
Intracranial Bleeding Study). BMJ 2011;

10. Sprigg N, Renton CJ, Dineen RA, Kwong Y, Bath PM. Tranexamic acid for
spontaneous intracerebral haemorrhage: a randomized controlled pilot trial. J Stroke
Cerebrovasc Dis. 2014 Jul

11. Arumugam A, A Rahman NA, Theophilus SC, et al. Tranexamic Acid as

Antifibrinolytic Agent in Non-Traumatic Intracerebral Haemorrhages. Malays J Med
Sci. 2015 Dec

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12. Estcourt LJ, Desborough M, Brunskill SJ, et al. Antifibrinolytics (lysine analogues)
for the prevention of bleeding in people with haematological disorders. Cochrane
Database Syst Rev. 2016 Mar 15

13. Volquind D, Zardo RA, Winkler BC, at al. Use of tranexamic acid in primary total
knee replacement: effects on perioperative blood loss. Braz J Anesthesiol. 2016 May-
Jun.

14. Ducloy-Bouthors AS, Duhamel A, Kipnis E, et al. Postpartum haemorrhage related

early increase in D-dimers is inhibited bytranexamic acid: haemostasis parameters of
a randomized controlled open labelled trial. Br J Anaesth. 2016 May.
15. Sentilhes L, Daniel V, Darsonval A, et all. Study protocol. TRAAP - TRAnexamic
Acid for Preventing postpartum hemorrhage after vaginal delivery: a multicenter
randomized, double-blind, placebo-controlled trial. BMC Pregnancy Childbirth. 2015
Jun 14

16. Menkis AH, Martin J, Cheng DC,et al. Drug, devices, technologies, and techniques
for blood management in minimally invasive and conventional cardiothoracic
surgery: a consensus statement from the International Society for Minimally Invasive
Cardiothoracic Surgery (ISMICS) 2011. Innovations (Phila). 2012 Jul-Aug

17. CRASH-2 collaborators, Roberts I, Shakur H et al. The importance of early

treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis
of the CRASH-2 randomised controlled trial. Lancet.2011 Mar 26

18. Murphy GR, Glass GE, Jain A. The Efficacy and Safety of Tranexamic Acid in Cranio-
Maxillofacial and Plastic Surgery. J Craniofac Surg. 2016 Mar

19. Sigaut S, Tremey B, Ouattara A, et al. Comparison of two doses of tranexamic acid
in adults undergoing cardiac surgery with cardiopulmonary bypass. Anaesthesiology.
2014 Mar

20. Sanz-Reig J, Parra Ruiz B, Ferrández Martínez J, Martínez López JF.

Single intravenous tranexamic acid dose to reduce blood loss in primary total knee
replacement. Rev Esp Cir Ortop Traumatol. 2016 Mar-Apr

21. Wei Z, Liu M. The effectiveness and safety of tranexamic acid in total hip or knee
arthroplasty: a meta-analysis of 2720 cases. Transfus Med. 2015 Jun

22. Zehtabchi S, Abdel Baki SG, Falzon L, Nishijima DK. Tranexamic acid for traumatic
brain injury: a systematic review and meta-analysis. Am J Emerg Med. 2014 Dec

23. Vel R, Udupi BP, Satya Prakash MV,et al. Effect of low dose tranexamic acid on
intra-operative blood loss in neurosurgical patients. Saudi J Anaesth. 2015 Jan

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24. Nishihara S, Hamada M. Does tranexamic acid alter the risk of thromboembolism
after total hip arthroplasty in the absence of routine chemical thromboprophylaxis?
Bone Joint J. 2015 Apr

25. Gybel M, Kristensen K, Roseva-Nielsen N. Cardiac arrest caused by massive

pulmonary embolism during treatment with tranexamic acid. Ugeskr Laeger. 2013
May 13.

26. Garg J, Pinnamaneni S, Aronow WS, Ahmad H. ST elevation myocardial infarction

after tranexamic acid: first reported case in the United States. Am J Ther. 2014 Nov-
Dec

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Appendix B

(Please provide detailed breakdown and justifications for all project costs requested in
Section VII. A. Use additional pages if necessary)

Cost Category Total RM 2016 RM 2017 RM 2018 RM

OS21000 : Travel &

Transportation
(In Country)
1. Travelling between 2 study
4800.00 1200.00 2400.00 1200.00
sites for data collection (HQE to
(200 x 6) (200 x 12) (200 x 6)
HQE 2).
Petrol cost–RM 200/ month

OS24000 : Rentals - - - -
OS25000 : Raw Materials - - - -
OS27000 : Research Materials
and Supplies
200.00 200.00 200.00
1. A4 Paper –RM10 per ream
(20x10) (20 x 10) (20 x 10)

50.00
2. Ring Files – RM 10 each 1340.00
(10 x 5)

115.00 230.00 345.00

3. Tranexamic Acid Supply
(2g x 4.6 x 5) (2g x4.6 x10) (2gx4.6x15)
RM 4.60 each gram
(3g x 4.6 x 5) (3g x4.6 x10) (3gx4.6x15)

OS29000 : Special Services

1.Professional Indemnity from 5250.00 1750.00 1750.00 1750.00
MPS
OS29000 : Temporary &
- - - -
Contract Personnel
OS35000 : Special Equipment
and Accessories
1. Laptop (RM 1500)
1500.00
2. Printer & Ink (RM 1000)
1000.00
3. External Hard Disc
200.00
(RM 100 each)
3000.00 (100 x 2) - -
4. Pendrive (RM 50 each)
250.00
(50 x 5)
5. Rewritable CD (RM 0.50 each)
50.00
(0.50 x 100)
For data security and data entry

TOTAL 14390.00 6315.00 4580.00 3495.00

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