Topical Application Effect of Tranexamic Acid in Postoperative Bleeding and Blood Products Transfusion After Cardiac Surgery
Phase: PHASE4
Conditions: Coronary Artery Disease, Valvular Heart Disease, Surgical Blood Loss
Sponsor: Indonesia University

 
 
 
 
 
 
 
TOPICAL APPLICATION EFFECT OF TRANEXAMIC ACID IN 
POSTOPERATIVE BLEEDING AND BLOOD PRODUCTS 
TRANSFUSION AFTER CARDIAC SURGERY 
 
Principal Investigator 
Dr. dr. Dudy Arman Hanafy, Sp.BTKV(K)-D, MARS 
 
Investigator 
dr. Sugisman, Sp.BTKV(K)-D 
dr. Rendy Agustian  
dr. Putu Lokita Pradnyana Putra  
dr. Bastian Parningotan Simorangkir 
 
 
FACULTY OF MEDICINE UNIVERSITY OF INDONESIA 
 DEPARTMENT OF CARDIOTHORACIC AND VASCULAR SURGERY 
JAKARTA 
SEPTEMBER 5TH 2022 
 

CHAPTER 1 
INTRODUCTION 
 
1.1. Background 
Coronary heart disease is the highest cause of mortality in the world, contributing to 
16.6% of deaths in 2016.1 In Indonesia, 35% of mortality is due to cardiovascular 
disease, including coronary heart disease.2 Coronary artery revascularization plays 
an essential role in managing coronary heart disease by improving antegrade blood 
flow to reduce chest pain (angina). Cardiopulmonary bypass machine (CPB) has 
been used in coronary artery bypass grafting (CABG) surgery for over three 
decades. CPB machines allow for an adequate operating field without being 
disturbed by cardiac motion when performing coronary artery anastomosis, making 
intracardiac and extracardiac procedures easier to perform and potentially 
improving cardiac surgical services.3 However, CPB machines have many 
pathological effects, including fluid retention, coagulopathy, the release of 
inflammatory mediators, pulmonary dysfunction, stroke, and neurocognitive 
changes. In 2020, coronary artery bypass surgery was one of the most frequently 
performed procedures at Harapan Kita Heart and Vascular Hospital, with 419 cases. 
However, some experienced several postoperative complications, such as 
postoperative bleeding requiring reoperation (24 cases), cardiac arrest (14 cases), 
atrial fibrillation (11 cases), and stroke within the first 72 hours (5 cases). 
 
The choice of CABG therapy is based on the patient's clinical characteristics, 
SYNTAX score and the complexity of the coronary anatomy.4 One of the CABG 
techniques, off-pump coronary artery bypass (OPCAB), was the first 
revascularisation procedure performed on a beating heart in 1960. The OPCAB 
technique was abandoned until the invention of stabilisation aids and positioning 
aids that facilitate anastomosis. The OPCAB technique when performed by highly 
skilled surgical specialists can result in complete revascularisation and better 
outcomes in patients at high risk, including the elderly, low ejection fraction, high 

neurological  risk, women, and end-stage organ failure.5  
 
The surgical technique with OPCAB can be considered in high risk patients to 
reduce perioperative transfusion requirements. This statement is supported by a 
randomised controlled trial ( RCT ) study in 2359 patients >75 years old at 12 
German institutions with funding from the German Off-Pump Coronary Artery 
Bypass Grafting in Elderly Patients (GOPCABE) which states that the OPCAB 
surgical technique significantly reduces blood transfusion requirements.3 OPCAB is 
not completely free from the risk of postoperative bleeding, as blood loss in the 
OPCAB technique can occur due to mechanisms of activation of the fibrinolysis 
pathway caused by sternotomy, pericardiotomy, excision of vein and artery grafts, 
residual heparin, platelet disorders and surgical bleeding.6  
 
Management of valvular heart disease includes non-surgical and surgical 
interventions. Both are classified as class II and III recommendations respectively 
based on the 2017 European Society of Cardiology guidelines due to the limited 
number of studies involving large numbers of subjects related to valvular heart 
disease.9,12 Surgical intervention is performed in severe, symptomatic cases, and or 
there is a decrease in left ventricular ejection fraction <50% which can be done 
openly or transcatheter.8 Harapan Kita Heart and Vascular Hospital in 2020 reported 
521 patients undergoing heart valve replacement surgery. A total of 158 patients 
experienced postoperative complications, with the most common complication 
being bleeding, which was 43 patients. 
 
Massive blood loss is the leading cause of death in cardiovascular surgery. Bleeding 
from cardiac surgery can be assessed by the volume of chest tube drainage bleeding 
and the need for transfusion of blood components. Based on the guidelines of the 
Society of Thoracic Surgeons (2011), the use of intravenous tranexamic acid is 
recommended in cardiac surgery as a strategy to reduce the risk of bleeding (class I 
recommendation).9 Tranexamic acid has an antifibrinolytic profile that could 

theoretically increase the risk of thromboembolic events such as early closure of 
coronary vessels, deep vein thrombosis, myocardial and cerebral infarction, and 
pulmonary embolism. In addition, several post-cardiac coronary artery bypass 
grafting seizures have been reported in patients receiving high doses of intravenous 
tranexamic acid.9,10 According to Pačarić et al., although not statistically significant, 
post-cardiac surgery adverse events practically impose a cost burden, prolong the 
hospital stay, and affect the overall quality of life of patients.11  
 
Topical application of tranexamic acid (intrapericardial in open heart surgery) is 
expected to work locally and minimize the systemic effects that occur.12 The use of 
tranexamic acid topically has been widely studied in other fields of surgery and is 
beneficial in reducing bleeding.13 However, studies studying topical tranexamic acid 
in cardiac surgery, are limited and generally show results that are not significantly 
different from intravenous administration, although there is a trend towards less 
postoperative bleeding in the group that received topical tranexamic acid.12,13 In 
addition, the existing studies also used subjects from overseas populations, and there 
has never been a similar study in Indonesia.  
 
1.2. Problem identification  
Topical administration of tranexamic acid in similar patients has been used in other 
surgical fields and is known to reduce bleeding and blood transfusion. However, 
similar studies in adult cardiac surgery are controversial, and its use in clinical 
practice has not been conducted in Indonesia.       
  
1.3. Research question 
1. What is the effect of topical tranexamic acid application on bleeding in patients 
undergoing coronary artery bypass surgery (CABG)?  
2. What is the effect of topical tranexamic acid application on bleeding in patients 
undergoing off-pump coronary artery bypass (OPCAB)?  
3. What is the effect of topical tranexamic acid application on bleeding in patients 

undergoing heart valve surgery?  
4. What is the effect of topical tranexamic acid application on postoperative blood 
transfusion requirements in patients undergoing coronary artery bypass surgery 
(CABG)?  
5. What is the effect of topical tranexamic acid application on postoperative blood 
transfusion requirements in patients undergoing off-pump coronary artery 
bypass (OPCAB)?  
6. What is the effect of topical tranexamic acid application on postoperative blood 
transfusion requirements in patients undergoing heart valve surgery? 
 
1.4. Hypothesis 
1. There was a difference in mean bleeding volume between patients given topical 
tranexamic acid versus placebo in patients after coronary artery bypass surgery 
(CABG). 
2. There was a difference in mean bleeding volume between patients given topical 
tranexamic acid versus placebo in patients after off-pump coronary artery 
bypass (OPCAB). 
3. There was a difference in mean bleeding volume between patients given topical 
tranexamic acid versus placebo in patients after heart valve surgery. 
4. There was a difference in mean blood product transfusion requirements between 
patients given topical tranexamic acid versus placebo in patients after coronary 
artery bypass surgery (CABG). 
5. There was a difference in mean blood product transfusion requirements between 
patients given topical tranexamic acid versus placebo in patients after off-pump 
coronary artery bypass (OPCAB). 
6. There was a difference in mean blood product transfusion requirements between 
patients given topical tranexamic acid versus placebo in patients after heart 
valve surgery. 
 
1.5. Research objectives 

1.5.1. General objectives 
The superiority of topical use of tranexamic acid in patients undergoing adult 
cardiac surgery was investigated. 
 
1.5.2. Specific objectives   
1. The amount of postoperative bleeding in patients undergoing adult 
cardiac surgery with topical tranexamic acid application was determined.  
2. Postoperative blood product transfusion requirements in patients 
undergoing adult cardiac surgery with topical tranexamic acid 
application were determined. 
 
1.6. Research benefits 
1.6.1. Benefits in the field of science/knowledge 
1. To provide a knowledge base regarding the effect of topical tranexamic 
acid application on post adult cardiac surgery outcomes, including the 
amount of bleeding and blood products transfusion after cardiac surgery. 
2. Encourage further studies on the effects of topical tranexamic acid 
application on a larger scale or other post adult cardiac surgery 
outcomes. 
3. Increase the number of studies on the effect of topical tranexamic acid 
application on adult cardiac surgery outcomes  
 
 

1.6.2. Benefits in the field of health services 
1. To inform the management of patients undergoing adult cardiac surgery 
to reduce postoperative bleeding. 
2. Reduce the cost burden and duration of hospitalization due to post-
surgical outcomes of adulut cardiac surgery related to post-surgical 
bleeding.   
3. To serve as a reference for future clinical trials on topical tranexamic 
acid administration. 
 
1.6.3. Benefits for research subjects 
Avoid the possibility of undesirable post-surgical outcomes in patients 
undergoing adult cardiac surgery. 
 
1.6.4. Patient benefits 
The improved general quality of life in patients undergoing adult cardiac 
surgery. 

CHAPTER 2 
LITERATURE REVIEW 
 
6.1. Coronary heart disease 
Coronary heart disease (CHD) is a narrowing of the coronary arteries caused by the 
thickening and reduced elasticity of the coronary artery walls (arteriosclerosis), 
which, if severe enough, will cause reduced blood flow to the myocardium. In the 
early stages, the disease will only reduce coronary blood flow reserve (the average 
increase in blood flow that follows an increase in myocardial oxygen demand), but 
in advanced stages, CHD can reduce blood flow in the coronary arteries at rest. In 
its most severe stage, atherosclerosis in CHD can block blood flow in the coronary 
arteries.14 
6.1.1. Management of coronary heart disease revascularization 
Intervention in the form of coronary vessel revascularization is currently 
agreed to be the definitive therapy for coronary heart disease in both acute 
and chronic coronary syndromes. Based on several studies, it is known that 
revascularization by percutaneous coronary intervention or coronary artery 
bypass surgery in patients with coronary heart disease effectively reduces 
angina and the use of antianginal drugs and improves physical capacity and 
quality of life compared to the use of medical therapy with short or long 
term control. However, revascularization is performed on indications that are 
divided according to clinical appearance and prognostic factors (Table 
2.1).21 
 
 

Table 2.1 Indications for revascularization in patients with coronary heart 
disease.16 
Parameters 
Recommended Class 
Level of 
Evidence 
 
Clinical 
appearance 
Hemodynamically significant 
coronary vessel stenosis with 
angina, inadequate response to 
optimal medical therapy 
I 
A 
Prognostic 
factors 
Stenosis >50% of the left main 
coronary vessel 
I 
A 
Stenosis >50% at proximal left 
anterior descending coronary 
artery (LAD) 
I 
A 
 
Stenosis >50% in two- or three-
vessel coronary disease with 
impaired left ventricular 
function (ejection fraction 
≤35%) 
I 
A 
 
The large area of ischemia 
(>10% left ventricle) 
I 
B 
 
Only one remaining patent 
coronary artery with >50% 
stenosis 
I 
C 
Description:  
Recommendation class: I = recommended.  
Level of evidence: A = meta-analysis and multiple randomized clinical trials, 
B = one randomized clinical trial or sizeable non-randomized study, C = 
registry, retrospective studies, and/or consensus of expert opinion. 
The choice of revascularization method with percutaneous coronary 
intervention or coronary artery bypass surgery is determined by considering 
some aspects, such as clinical characteristics, technical and anatomical 
aspects, and whether or not contemporary interventions are necessary (Table 
2.2).21 
 
 

Table 2.2 Considerations for choosing the method of coronary artery 
revascularization by percutaneous coronary intervention or coronary artery 
bypass surgery.21 
Aspects 
Percutaneous 
coronary intervention 
Coronary artery bypass 
surgery 
Clinical 
characteristics 
• Presence of severe 
comorbidities  
• Advanced age, 
vulnerability, or low 
life expectancy 
• Condition and 
mobility limitations 
that affect 
rehabilitation 
• Diabetes mellitus 
• Decreased 
left 
ventricular 
function 
(ejection fraction ≤35%) 
• Contraindications 
to 
dual antiplatelet therapy 
• Occurrence of post-stent 
restenosis 
Anatomical 
and technical 
aspects 
• Multiple vessel 
disease with 
SYNTAX score 0-22 
• Anatomy that allows 
inadequate 
revascularization by 
coronary artery 
bypass surgery 
(absence of 
pathways) 
• Severe chest 
deformity, scoliosis 
• Multiple vessel disease 
with SYNTAX score 
≥23 
• Anatomy that allows 
inadequate 
revascularization by 
percutaneous coronary 
intervention 
• A coronary artery with 
severe calcification 
Need for other 
interventions 
None 
• Pathology 
of 
the 
ascending 
aorta 
requiring surgery 
• Need for another heart 
surgery 
*SYNTAX score: Synergy between Percutaneous Coronary Intervention 
with TAXUS and Cardiac Surgery - to assess the complexity of CHD. 
 
6.2. Coronary artery bypass surgery 
Coronary artery bypass graft (CABG) surgery is an open-heart surgical procedure in 
which a segment of the blood vessel is grafted to create an anastomosis from the 
aorta to the coronary artery to bypass the blood flow to feed the heart in place of the 
blocked coronary vessel. This procedure became more feasible after the invention of 

the heart-lung machine to perform a heart-lung bypass during surgery. The first 
successful myocardial vascular graft procedure was performed in 1950 by Vineburg 
and Buller of McGill University, Canada using an implant from the left internal 
mammary artery.22,23 
 Subsequently, in 1955, Sidney Smith successfully performed a similar 
procedure using an implant from the saphenous vein.17 Both vessels are currently 
recommended as implants for coronary artery bypass surgery, with the internal 
mammary artery as the first choice due to the lower incidence of decreased lumen 
patency, embolization, and perforation post-surgery compared to the saphenous 
vein. Perforation compared to the saphenous vein. In addition, implants from the 
radial artery and gastroepiploic artery can also be used.21,22    
 
6.2.1. Outcomes after coronary artery bypass surgery 
Several complications may occur after coronary artery bypass surgery. The 
possible complications are not limited to the cardiovascular system but also 
involve other systems, including respiratory failure, stroke, urinary tract 
infection, renal impairment, coagulopathy, limb ischemia, failure of wound 
edge union, pleural effusion, and hematological abnormalities. Frequent 
postoperative complications include bleeding, infection, congestive heart 
failure, and chest discomfort.3,11 
 
1.1.1 Definition off-pump coronary artery bypass grafting  
Coronary bypass artery graft (CABG) surgery is the most effective standard 
treatment for coronary heart disease. Off-pump CABG (OPCAB) is one of the 
CABG surgical techniques performed on a beating heart without the aid of a 
cardiopulmonary bypass (CPB) device, requiring high skills to perform this 
technique so it is not practised as widely as conventional CABG techniques.54 In 
the OPCAB technique, the heart is still allowed to beat so stabilisation aids are 
required with octopus and suction aids starfish to facilitate position transfer during 
surgery. The OPCAB technique is an option because it can reduce the incidence of 

postoperative complications caused by the use of CPB machines, these 
complications occur due to the effects of systemic inflammation due to the 
interaction of blood components with foreign objects, namely the surface of the 
bypass circuit. Complications include post surgical haemorrhage, neurocognitive 
dysfunction, thromboembolism, fluid retention and organ dysfunction.7 In high 
risk patients OPCAB has lower morbidity and mortality rates, this is due to 
improved organ perfusion, protection of the myocardium due to minimal 
manipulation of the aorta, and avoidance of systemic inflammation due to the use 
of CPB.8 Various studies have shown the advantages of OPCAB in reducing 
transfusion requirements, shorter hospital stay, reduced ICU and ventilator 
requirements, and more affordable costs.55    
 
1.1.2 Indication and contraindication of off-pump coronary artery bypass grafting  
The OPCAB technique is recommended for the management of revascularisation 
surgery alternatif conventional CABG by various guidelines. Indications for 
revascularisation with CABG are based on the patient's clinical characteristics, 
SYNTAX score and coronary anatomy complexity. CABG is indicated in patients 
with 
diabetes, 
decreased 
left 
ventricular 
function 
(EF<30%), 
patients 
contraindicated with antithrombotic drugs, diffuse in-stent recurrent restenosis, 
three vessel lesions with SYNTAX score >23, risk of incomplete revascularisation 
with percutaneous coronary intervention (IKP), coronary artery lesions with severe 
calcification, indications of concomitant cardiac surgery.4 In the chest pain 
management guidelines issued by the American College of Cardiology/American 
Heart Association ( ACC/AHA) 2021, OPCAB performed by experienced surgical 
specialists is recommended as the surgical technique of choice for 
revascularisation in patients with severe pulmonary disease (class IIb, level B-R) 
and in patients with aortic calcification to reduce the incidence of perioperative 
stroke 
(Class 
IIa, 
Level 
B-R).56 The 
 
2018 
European 
Society 
of 
Cardiology/European Association of Cardio-Thoracic Surgery (ESC/EACT) 
coronary artery revascularisation guidelines recommend the use of the OPCAB 

technique by experienced surgeons in patients with a high-risk profile (Class IIA, 
Level B) and in patients with atherosclerosis of the ascending aorta (Class I, Level 
B). Patients at high risk are women, patients with left ventricular dysfunction, ST-
elevation myocardial infarct ( STEMI ) patients, patients with a history of stroke, 
old age, renal insufficiency, history of previous cardiac surgery, cirrhosis, extreme 
body mass index ( BMI ) ( <25 or >35) and patients with high-risk Society of 
Thoracic Surgeons ( STS ) scores. The guideline also recommends the routine use 
of intraoperative graft flow measurement devices in OPCAB technique procedures 
(Class IIa, Level C).21 The 2017 European Association for Cardio-Thoracic 
Surgery/European 
Association 
of 
Cardiothoracic 
Anaesthesiology 
(EACTS/EACTA) bleeding management guidelines for cardiac surgery 
recommend the OPCAB technique to reduce the need for blood transfusion in 
anemic patients with low body surface area, patients undergoing surgery with dual 
antiplatelet therapy (DAPT) treatment and in dialysis-dependent patients (Class 
IIb, Level B).56 (3) The main contraindications for OPCAB are performed by 
inexperienced cardiac surgeons, intracavitary thrombus such as a left ventricular 
clot, intramyocardial vasculature, malignant arrhythmias, combined valve or 
ventricular repair, very small (<1mm) or calcified coronary arteries, poor vascular 
channels, hemodynamically unstable and cardiogenic shock.55  
 
1.2 
Heart valve surgery 
Heart valve surgery is an open-heart surgery that aims to replace the mitral valve or aortic 
valve that has abnormalities, either stenosis or regurgitation. Current heart valve surgery 
procedures are also associated with good short-term and long-term outcomes.58 In valve 
replacement surgery, the choice of valve replacement can come from bioprosthetics or 
mechanical prosthetics. The choice of prosthetic is based on the availability of the 
prosthetic, surgeon's expertise, preference, patient's age, presence of comorbidities, and 
contraindications to the use of anticoagulants. 59,60 
 

1.2.1 2.2.1 Procedure  
The initial stages of a heart valve surgery procedure are positioning, sternotomy, and 
insertion of a cardiopulmonary bypass (CPB) machine. The patient is positioned supine, 
then monitor leads such as radial artery or pulmonary artery catheters are placed and 
sedation is performed. The patient's chest, abdomen, perineum and extremities are 
prepared sterile, followed by sternotomy. The mediana sternotomy method is the classic 
way to access the heart, but minimally invasive strategies such as upper/lower 
hemisternotomy, minitoracotomy, and right parasternotomy can be performed in order to 
rotate the ventricles of the heart to access the aortic root. Heparinization is then 
administered and a heart-lung bypass machine is inserted, before which cardioplegia 
agents such as low-temperature blood (32o C) are administered anterograd (through the 
aortic root) and retrograd (through the sinus coronarius). 58,60   
 
Mitral valve surgery 
The initial step for mitral valve surgery starts with accessing the mitral valve site. The 
best approach to access the mitral valve is to perform a left lateral atriotomy just anterior 
to the pulmonary veins. Another approach to access the mitral valve is through an incision 
in the right atrial appendage near the inferior vena cava that continues up to the fossa 
ovalis on the inferior side. 58,59 
 
In mitral valve replacement with a prosthesis, partial excision of the native mitral valve is 
performed while retaining the part of the valve around the annulus and the part attached to 
the tendinea cord, then suturing with pledgeted horizontal mattress circumferentially 
around the annulus with a prosthetic valve. Care is taken not to injure structures such as 
the sinistra circumflex artery, sinus coronarius, left atrial appendage, atrioventricular 
node, and aortic valve, and not to interfere with the left ventricular outflow tract. After 
suturing is completed, re-warming and suturing of the access hole to the mitral valve can 
be performed.58,59 
 
After mitral valve replacement surgery is performed, anticoagulant therapy using warfarin 

is administered until the target international normalized ratio (INR) of 2.5 to 3.5 is 
reached if the patient has a mechanical prosthetic valve. The use of warfarin is 
controversial when the patient has a bioprosthetic replacement valve. Some suggest using 
it for three months postoperatively and some state that warfarin is given when there are 
indications such as atrial fibrillation, previous history of thromboembolism, left 
ventricular dysfunction and hypercoagulable conditions.59 
 
Aortic valve surgery 
The first step in aortic valve surgery is to perform an aortotomy. This procedure can be 
performed obliquely or near transection. The oblique aortotomy starts from the anterior 
side at the midline of the ascending aorta, then proceeds to the right inferoposterior side 
until it reaches the sinus coronarius. The near-transection aortotomy is performed 4-6 mm 
above the aortic valve and a circular incision is made that almost cuts the aorta. However, 
there is a risk of massive bleeding on the posterior side when a near-transection aortotomy 
is performed so an oblique aortotomy is generally preferred.58,60 
 
After aortotomy, inspection of the aortic valve and identification of the coronary ostium 
site is performed. The aortic valve is then excised starting at the ostium in the center, then 
moving through the commissure and valve leaflets and circumferentially. This procedure 
is done carefully so as not to injure the connection between the aortic valve and the mitral 
valve. Debridement of the calcific material and irrigation with cold saline solution may be 
performed during the valve excision. Next, suturing of the replacement prosthetic valve at 
the aortic valve site is performed. The suturing technique can be interrupted, noneverting 
mattressed pledgets, everting mattressed pledgets, or continuous. After suturing is 
completed, rewarming and closure of the aortotomy is performed using polypropylene 
sutures. 58,60 
 
After aortic valve replacement surgery is completed, hypertension is controlled if present 
(intravenous sodium nitropruside or nicardipine is usually used) and adequate filling 
pressures are maintained (central venous pressure 10 - 15 mmHg and pulmonary capillary 

pressure 15 - 18 mmHg). Temporary pacing is performed in patients with conduction 
block which usually resolves within one to two days. In addition, patients with mechanical 
prosthetic valves received oral warfarin anticoagulation and aspirin on postoperative day 2 
to maintain an INR of 2.0 to 2.5 to minimize long-term bleeding and thrombotic events. 
Patients with bioprosthetic valves can receive aspirin without warfarin.60 
 
1.2.2 2.2.2 Postoperative outcomes 
The postoperative outcomes of heart valve surgery that need to be considered are similar 
to those of open heart surgery in general. In-hospital morbidity and mortality in patients 
undergoing heart valve surgery depends on the patient's demographics, risk factors, 
previous cardiovascular history, preoperative condition, and operative status (first or 
reoperative). Causes of early postoperative mortality include bleeding (commonly 
associated with anticoagulation), stroke, myocardial infarction, respiratory failure, 
multiorgan failure and infection, while persistent heart failure may be a cause of late 
mortality.58,60 
 
In cases of mitral valve surgery, left ventricular rupture can be one of the fatal 
complications (occurring in approximately 0.8% of patients). Cerebral small vessel 
disease (SVD) can occur five years after surgery and the incidence increases significantly 
after ten years. Valve thrombosis in the absence of infection with obstruction of blood 
flow through the valve occurs in approximately 0.5% of patients. Patients undergoing 
mitral valve surgery are also at risk of prosthetic valve endocarditis, with a higher 
incidence in patients receiving mechanical prosthetic valves than bioprosthetics. The risk 
of endocarditis in the first year is 1% and the risk decreases to 0.2-0.35% per year. 
Bacteremia or contaminants causing endocarditis may be acquired intraoperatively or 
from the use of intravenous catheters, urinary catheters, and surgical wound 
infections.58,59  
 
In cases of aortic valve surgery, mediastinal and perivalvular bleeding requiring 
reoperation have been reported in 5% and 1-2% of cases, respectively. Cardiac conduction 

block is experienced in about 1-2% of patients, while atrial fibrillation is experienced in 
about one-third of patients with no previous history. In addition, there are some 
thromboembolic events such as strokes that account for 1-2% of the total cases. 58,60 
 
2.3. Tranexamic acid 
6.3.1. Tranexamic acid pharmacology 
Tranexamic acid is a synthetic compound derived from the amino acid lysine 
that is an analog of aminocaproic acid and acts as a fibrinolysis inhibitor. 
Tranexamic acid works by binding to the five binding sites of the amino acid 
lysine on plasminogen to inhibit its activation into plasmin which plays a 
role in fibrinolysis. To inhibit its activation into plasmin which plays a role 
in fibrinolysis. In addition, tranexamic acid also has an anti-inflammatory 
profile by inhibiting 
plasmin-mediated activation of complement, 
monocytes, and neutrophils. This drug has good absorption with oral 
administration, an initial dose of 15 mg/kg and a follow-up dose of 30 mg/kg 
every 6 hours, and is eliminated through the kidneys. Tranexamic acid can 
also be given intravenously at a dose of 0.5-1 gram three times per day with 
a dose restriction of 5-10 mg/kg in patients with renal failure.29 The 
minimum concentration required to inhibit fibrinolysis in vitro is 10 mcg/ml 
in adults.35 A meta-analysis conducted in 2020 said that tranexamic acid 
administration did not affect blood clotting time but significantly reduced 
post-surgical bleeding and transfusion requirements in patients with cardiac 
surgery.36  
 
This compound is widely used as a prophylactic and therapeutic agent for 
bleeding, for example, in surgical interventions and severe trauma, thus 
reducing the amount of perioperative bleeding and the blood products 
transfusion after cardiac surgery. Early administration of tranexamic acid, 
primarily via the intravenous route, is known to increase the chances of 
survival in emergency cases of massive bleeding. Due to its significant role, 

the World Health Organization (WHO) included tranexamic acid in the list 
of essential drugs.37 However, it is contraindicated in patients with 
disseminated intravascular coagulation and upper genitourinary tract 
bleeding (kidney and ureter) due to its potential to cause excessive blood clot 
formation.34 
 
6.3.2. Effect of tranexamic acid on post-open heart surgery outcomes  
Tranexamic acid has been widely used in open-heart surgery to reduce 
bleeding and the need for post-surgical blood transfusions. Guidelines from 
the Society of Thoracic Surgeons have recommended using tranexamic acid 
to reduce bleeding from cardiac surgery (class I recommendation).9 The anti-
inflammatory profile of tranexamic acid also plays a role in addressing the 
inflammatory response after cardiac surgery, especially for those using 
cardiopulmonary bypass. This is because cardiopulmonary bypass carries the 
risk of coagulopathy, including activation of intrinsic and extrinsic 
coagulation pathways, platelet dysfunction, and systemic inflammatory 
response.38 Studies show that low-dose tranexamic acid (10 mg/kg 
intravenously) is the optimal dose for cardiac surgery.39 
 
Despite its benefits in reducing bleeding and inflammation, several 
unexpected post-surgical side effects have been reported with tranexamic 
acid as surgical prophylaxis. The antifibrinolytic profile of tranexamic acid 
theoretically allows for an increased risk of thromboembolic events such as 
deep vein thrombosis, early occlusion of vascular implants, cerebral and 
myocardial infarction, and pulmonary embolism.9,10 This is in line with Ross 
and Salman's meta-analysis, which showed that some patients receiving 
tranexamic acid prophylaxis and aprotinin (a tranexamic acid analog) 
experienced thromboembolic events at 1.9% (95% confidence interval 1.1-
2.9) and 3.0% (95% confidence interval 1.8-4.6), respectively. However, 
these events occurred in patients undergoing surgery for subarachnoid 

hemorrhage.39 
 
Tranexamic acid can cross the blood-brain barrier, with cerebrospinal fluid 
concentrations reaching about 10% of plasma concentrations. A 
concentration of as much as 15 micrograms per milliliter has been said to be 
the threshold for potential excitation effects.35 There have been reported 
cases of patients experiencing seizures after open heart surgery, especially 
those receiving high doses of intravenous tranexamic acid.14 Study by 
Kalavrouziotis et al. showed that tranexamic acid at doses ≥100 mg/kg 
intravenously was associated with an increased risk of early postoperative 
seizures in patients undergoing cardiac surgery with cardiopulmonary 
bypass.40 Meta-analysis by Takagi et al. and Guo et al. also showed that adult 
patients who underwent cardiac surgery and received tranexamic acid 
therapy had a fourfold risk of seizures.41,42 This is thought to be because the 
molecular structure of tranexamic acid is similar to that of gamma-
aminobutyric acid (GABA), an inhibitory neurotransmitter, and thus has an 
antagonistic effect on its receptors in the central nervous system.9 
 
Nonetheless, other studies have looked at this issue and provided different 
results. Saracoglu et al. presented the results of a retrospective cohort study 
on 172 subjects who underwent open-heart surgery, received a regimen of 50 
mg/kg intravenous tranexamic acid as bleeding prophylaxis, and showed no 
cases of thrombosis, stroke, or seizure. The number of post-heart surgery 
reoperations was similar to the group that did not receive tranexamic acid 
prophylaxis. Reoperation was similar to the group that did not receive 
tranexamic acid prophylaxis (4.1%).44 In addition, a retrospective cohort 
study In addition, a retrospective cohort study conducted by Maeda et al. 
also explained that discontinuing tranexamic acid for cardiac surgery did not 
make a significant difference in the incidence of thromboembolism and 
postoperative mortality. However, there was a decrease in seizures and 

increased postoperative bleeding when tranexamic acid was not given.45 
 
Although studies to date have shown controversial results regarding the 
adverse effects of tranexamic acid post-open heart surgery, such outcomes 
clinically affect the cost and duration of hospitalization and the quality of life 
for patients who experience adverse events.11 As these events are primarily 
reported in patients receiving tranexamic acid intravenously, it was thought 
that the route of administration might influence the risk of postoperative 
adverse events. Topical administration (intrapericardial in cardiac surgery) is 
considered a safer alternative as it works locally but is still effective in 
reducing bleeding and inflammation.12 
 
Several studies have compared post-cardiac surgery outcomes on tranexamic 
acid administration via topical, intravenous, and/or placebo routes, albeit 
with differing results. Vanĕk and Straka's meta-analysis of four randomized 
controlled clinical trials comparing topical and placebo administration of 
tranexamic acid in cardiac surgery showed a trend towards decreased 
bleeding in the group receiving topical tranexamic acid, although not 
statistically significant.46 Randomized controlled clinical trials conducted by 
Hosseini et al., Shah et al., and Chaudhary et al. showed a statistically 
significant reduction in the amount of bleeding after open heart surgery in 
the group receiving topical tranexamic acid compared to placebo.47–49 Similar 
results were also obtained in the meta-analysis of Montroy et al. and Habbab 
et al., with no significant difference in the incidence of post-heart surgery 
seizures and thromboembolism between the topical tranexamic acid and 
placebo groups.13,50 Habbab et al. randomized controlled clinical trial was the 
first to compare post-cardiac surgery outcomes between topical and 
intravenous tranexamic acid groups, showing a trend toward decreased 
bleeding, blood products transfusion after cardiac surgery, reoperation, and 
incidence of post-surgical seizures in the topical tranexamic acid group.12     

  
6.3.3. Comparison of systemic and topical tranexamic acid 
Intravenous administration of tranexamic acid has been associated with an 
increased risk of thromboembolism and early graft closure in coronary artery 
bypass surgery. Reported cases of thromboembolism include cerebral, 
pulmonary, mesenteric, and retinal thromboembolism. Due to the significant 
systemic side effects of intravenous administration, topical administration of 
tranexamic acid has become increasingly popular. This is because the local 
antifibrinolytic effect facilitated by the topical application of tranexamic acid 
has proven effective in preventing bleeding in several other disease cases, 
such as post-oral surgery of patients with hemophilia, epistaxis, bladder 
surgery, and gynecological bleeding.51 
 
Topical administration can provide adequate concentrations at the wound 
site while providing low systemic concentrations.35 Other studies show that 
topical tranexamic acid in surgery can significantly reduce bleeding and 
transfusion requirements without increased side effects.52,53 This condition 
may be due to the shallow degree of systemic absorption after topical 
application compared to intravenous bolus administration. The study stated 
that topical application of tranexamic acid gave a mean peak serum 
concentration of 4.9 mcg/mL in the group treated with fluid bolus in the 
wound cavity and 5.2 mcg/mL in the group treated with moisturizing the 
wound surface. These levels are lower than the minimum levels required for 
systemic effects. In addition, at 5 mcg/mL, only 0.5 mcg/mL will cross the 
blood-brain barrier, making it very unlikely to cause seizures. In contrast, 
after administration of 1 g of intravenous tranexamic acid, the serum 
concentration is above 10 mcg/mL for about 2.5 hours.35 
 
Topical administration of tranexamic acid in surgery is generally given as a 
bolus to the cavity or added to irrigation fluid.35 In a study by De Bonis et al. 

100 mL of tranexamic acid solution (1 g in 100 mL of 0.9% NaCl) or room-
temperature placebo was poured into the pericardial cavity and mediastinal 
tissue of patients before sternal closure. The bleeding was measured every 
hour, every 24 hours, and before discharge. The results showed that 1% 
tranexamic acid solution applied topically into the pericardial cavity after 
coronary artery bypass surgery can significantly reduce bleeding in the first 
3 hours, with a reduction of 36% in the first 3 hours and 25% in the first 24 
hours when compared with placebo. In addition, the study also showed that 
tranexamic acid could not be detected in blood samples taken 2 hours after 
the chest tube was opened, indicating that topically applied tranexamic acid 
can have a topical impact on the pericardial cavity without causing systemic 
effects, thus preventing the occurrence of feared systemic side effects.51 
However, tranexamic acid should not be applied topically to the central 
nervous system as it may cause seizures. In addition, topical application of 
high doses of tranexamic acid may also inhibit glutamate receptors in 
various tissues. Prolonged exposure to high-dose topical tranexamic acid 
may prevent nontoxic epithelial reepithelialization and shed in vivo human 
skin wound models.52  
 
There is no literature stating the ideal minimum effective dose of tranexamic 
acid. However, a meta-analysis study from Ausen et al. explained that a 
tissue concentration of tranexamic acid of at least 10 μg/mL is required to 
inhibit fibrinolysis significantly. No study has yet described the topical effect 
of tranexamic acid determined by the concentration of the drug, the total 
dose, and/or the combination of concentration and contact time of 
tranexamic acid with the surrounding tissue.52 
  
 
 
 

6.4. Theoretical framework 
 
Figure 2.2. Theoretical framework 
 
 
6.5 Conceptual framework 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2.3. Conceptual framework 
 
Topical 
Tranexamic acid 
- Postoperative 
bleeding 
- Blood products 
transfusion 
Independent 
Bound  
- Gender 
- Age 
- Body Mass Index 
- Comorbidity 
- Duration of aortic 
cross clamp 
- Duration of 
Cardiopulmonary 
bypass machine 
Confounding  

CHAPTER 3 
RESEARCH METHODS 
 
3.1. Research design 
This study used a randomized clinical trial, placebo-controlled and double-blinded.  
 
3.2. Time and place of research 
This study occurred from October to December 2022 at the Division of Adult 
Cardiac Surgery, Harapan Kita National Heart Center Hospital (RSPJNHK). 
 
3.3. Research population 
The target population in this study were: (1) patients with coronary heart disease 
who indicated coronary artery bypass surgery (CABG) and off pump coronary 
artery bypass (OPCAB), (2) patients who had heart valve disease indicated by open-
valve heart surgery. The target population was patients who underwent adult cardiac 
surgery at the Division of Adult Cardiac Surgery, RSPJNHK, from October to 
Desember 2022.    
 
3.4. Sample selection method 
Sampling in this study was conducted consecutively, including all patients who 
underwent cardiac surgery in the Division of Adult Cardiac Surgery, RSPJNHK, 
until reaching the target sample size.  
 
3.5. Inclusion, exclusion, and dropout criteria 
3.5.1. Inclusion criteria 
1. Adult patients aged ≥18 years  
2. Coronary heart disease patients indicated for coronary artery bypass 
surgery and off-pump coronary artery bypass (OPCAB) 
3. Patients with heart valve disease are indicated for aortic or mitral valve 
repair and replacement through open heart surgery. 

4. The patient underwent open heart valve surgery with tricuspid valve 
repair. 
5. Patients undergoing open heart surgery at the Adult Cardiac Surgery 
Division, RSPJNHK. 
 
3.7.1. Exclusion criteria 
1. Patients who expressed unwillingness to become research subjects. 
2. Patients who have an allergy to tranexamic acid. 
3. Patients were undergoing urgent/emergency surgery and minimally 
invasive surgery 
4. The patient underwent a double procedure of simultaneous aortic and 
mitral valve surgery. 
5. Patients with a history of bleeding disorders (coagulopathy) such as 
clotting factor deficiency and heparin-induced thrombocytopenia or use 
of intravenous anticoagulants other than heparin at the time of surgery. 
6. Patients with a history of thromboembolic disease. 
7. Patients with active Infective endocarditis 
8. Patients with a history of previous cardiac surgery 
9. Patients with a estimated glomerular filtration rate <30 mL/min or on 
dialysis 
10. Patients who receiving oral therapy with clopidogrel, aspirin, 
dabigatran, or rivaroxaban in the last five days 
11. Patients who receiving chronic warfarin therapy who have not stopped 
their medication and have an international normalized ratio (INR) >1.5 
before surgery 
12. Patients with pre-operative thrombocytopenia (<50,000 platelets per μL) 
13. Pregnancy or breast feeding patients 
14. Patients who refusal of blood products 
15. Patients with a pericarditis 
 

 
5.5.2. Dropout criteria 
1. 
Patients are discharged from the operating room with a heart-lung 
bypass machine or extracorporeal membrane oxygenation (ECMO). 
2. 
History of intraoperative internal or external heart-lung resuscitation. 
 
5.6. Estimated sample size 
The number of samples in this study was calculated twice because the dependent 
variables observed were the amount of bleeding and the need for postoperative 
blood transfusion, all of which were numerical variables. From the overall 
calculation results, the largest sample size for this study was taken, then 10% was 
added to accommodate the possibility of dropping out. The formula used in the 
sample calculation for both variables is the hypothesis test formula for the mean of 
two independent groups. The literature used as a reference for calculating the 
sample of this study is a study by Chaudhary et al. (2018).44 The following are the 
sample calculation results for each research variable. 
• 
 A variable amount of bleeding 
𝑛1 = 𝑛2 = 2 [
(𝑧𝛼+ 𝑧𝛽)𝑠
(𝑥1 −𝑥2) ]
2
 
𝑛1 = 𝑛2 = 2 [
(1,96 + 0,842)339,021
300
]
2
 
𝑛1 = 𝑛2 = 20,05 ~ 20 𝑠𝑎𝑚𝑝𝑙𝑒 
Description: 
 = normal standard deviation for type I error with α is 0.05 (1.96) 
 = normal standard deviation for type II error with β is 0.2 (0.842) 
 = standard deviation between placebo and treatment groups according to the 
study (placebo = 445.941 mL and treatment = 232.101 mL, so that the mean 
value taken = 339.021 mL)44 
 = expected clinical difference (taken 300 mL) 
 

 
• 
Variable blood transfusion needs 
𝑛1 = 𝑛2 = 2 [(𝑧𝛼+ 𝑧𝛽)𝑠
(𝑥1 −𝑥2) ]
2
 
𝑛1 = 𝑛2 = 2 [
(1,96 + 0,842)1,072
1
]
2
 
𝑛1 = 𝑛2 = 18,04 ~ 18 𝑠𝑎𝑚𝑝𝑙𝑒 
 
Description: 
 = average standard deviation for type I error with α is 0.05 (1.96) 
 = average standard deviation for type II error with β is 0.2 (0.842) 
 = standard deviation between placebo and treatment groups according to the 
study (placebo = 1.225 units and treatment = 0.918 units so that the mean 
value taken = 1.072 units)44 
 = expected clinical difference (taken as 1 unit) 
Based on the above calculation results, 20 patients were taken as the minimum 
sample size for each placebo and treatment group. With the addition of 10% to 
anticipate dropouts (2 patients per group), the total sample for each group was 22 
samples. The total sample for both groups was 44 patients. In this study, there are 
three arms group (CABG group, OPCAB group, and Valve Surgery group). The 
total sample for both arms group was 132 patients.  
 
5.7. Data collection and retrieval steps 
3.7.1. Before surgery 
Patients with coronary heart disease and heart valve disesase who were 
indicated for cardiac surgery were determined to be eligible for the study 
based on the inclusion and exclusion criteria through history taking, physical 
examination, 
and 
the 
results 
of 
supporting 
examinations 
(electrocardiography, cardiac enzymes, and laboratory) obtained from the 

patient's medical record at RSPJNHK. Furthermore, researchers conducted 
informed consent to patients who were eligible to become research subjects 
and asked for written consent from patients. Patients who agreed to the 
informed consent were randomized into treatment or control (placebo) 
groups. A research assistant carried out randomization using the 
"randomizer.org" site. The treatment group in this study received 5 g of 
tranexamic acid in 50 mL of 0.9% NaCl solution administered topically to 
the pericardial cavity after protamine administration and before sternotomy 
closure. In contrast, the control group (placebo) received 100 mL of 0.9% 
NaCl solution without tranexamic acid administered in the same way as the 
treatment group. The pharmacy department prepared the preparations in the 
study so that neither the researchers nor the patients were aware of the 
preparations used intraoperatively. 
 
3.7.2. Perioperative 
Patients who became research subjects underwent coronary artery bypass 
surgery according to standard operating procedures at RSPJNHK. After 
inducing anesthesia, undergoing sternotomy, and installing a heart-lung 
bypass machine (on-pump), the patient underwent the primary procedure. 
Then the research protocol was carried out with either treatment or control 
(placebo) after the heart-lung bypass machine stopped and before the 
sternum was closed by previously clamping the chest tube. After skin 
closure was completed, the chest tube clamps were reopened, and internal 
suction was performed, followed by connecting the chest tube with a water-
sealed drainage system to accommodate post-surgical intrathoracic 
bleeding. The sternal closure to skin suturing process is done within 30-45 
minutes.  
 
In OPCAB group, after the graft anastomosis with OPCAB technique was 
completed, before sternal closure, the patient was given an intervention in 

the form of topical tranexamic acid (5g/50mL) or placebo (50mL normal 
saline) dissolved in 100mL normal warm saline (37o C) which was inserted 
into the pericardial cavity including mediastinal tissue and allowed to stand 
for five minutes. It was then cleaned and sternal closure was performed. 
 
The study subjects then underwent heart valve surgery according to the 
standard operating procedures of RSJPDHK, which began with induction of 
anesthesia, sternotomy, and CPB insertion. After the heart-lung bypass 
machine stopped, the chest tube was installed and clamped, the Subject then 
received one of the placebo or treatment fluids which were divided into two 
administrations, 50 mL of the first liquid was given to the intrapericardium 
and 50 mL of the second liquid was given to the sternum. The sternum was 
closed to the skin with an estimated completion of 30-45 minutes. Chest tube 
clamps were opened and connected to a water-sealed drainage (WSD) 
system to remove residual bleeding in the thorax after surgery. 
 
3.7.3. Post-surgery 
Patients were intensively treated in the intensive care unit (ICU), 
intermediate room, and standard room according to clinical conditions. The 
researcher observed and recorded the amount of bleeding accumulated until 
chest tube removal and blood products transfusion units of blood 
components during treatment. Transfusion will be given when there is an 
indication for transfusion. The indication for packed red cell (PRC) 
transfusion was Hb <10 g/dL, with a target of Hb >10 g/dL. The indication 
for platelet transfusion was platelets <100,000 U/µL, with a target of 
platelets >100. The indication for fresh frozen plasma (FFP) transfusion is if 
APTT > 1.5 times the control, the transfusion target is activated partial 
thromboplastin clotting time (APTT) < 1.5 times the control. Cryoprecipitate 
was given if fibrinogen < 100 mg/dL, and the transfusion target was 
fibrinogen > 100 mg. Observation of bleeding was recorded from initial 

bleeding, 6 hours, 24 hours, and 48 hours, or until chest tube removal if the 
bleeding was <200 mL/24 hours.  
Bleeding management protocols were performed if there was excessive or 
massive bleeding post-surgery. A single researcher conducted all 
observations to maintain data reliability which was then recorded for further 
processing.    
 
3.8. Instruments used 
This study used a form instrument to record the results of observations of research 
subjects. The form includes informed consent, preoperative assessment results 
(history taking, physical examination, supporting examination, and tolerance of the 
study subject's surgery), and postoperative observations (including the amount of 
bleeding and the blood products transfusion units).  
 
3.9. Research Variables 
Table 3.1 Variables in the study. 
Variable 
Type 
Variables 
Free 
Topical administration of tranexamic acid 
Bound 
● Number of postoperative hemorrhages 
o 
Initial bleeding 
o 
Bleeding 6 hours 
o 
24-hour bleeding 
o 
48-hour bleeding 
● Need for postoperative blood transfusion 
o 
Packed red cell (PRC) transfusion 
o 
Platelet transfusion 
o 
Transfusion of fresh frozen plasma (FFP) 
o 
Cryoprecipitate transfusion 
Confounding8 
● Gender 
● Age 
● Body mass index 
● Concomitant conditions (diabetes mellitus, 
hypertension) 
● Aortic cross-clamp 
● Heart-lung bypass machine 

3.10. Operational Definition 
Table 3.2 Operational definitions. 
Variables 
Definition 
Measurement 
Variable 
Scale 
Variable Value 
Administration of  
topical tranexamic acid 
Intrapericardial administration of 5 g 
tranexamic acid in 50 mL 0.9% NaCl 
after 
protamine 
administration 
and 
before sternotomy closure in cardiac 
surgery 
- 
Nominal 
• Treatment 
(tranexamic acid) 
• Control (NaCl 0.9%) 
Amount of bleeding 
Initial bleeding 
Amount of blood accumulated in the 
patient's water-sealed drainage (WSD) 
system shortly after cardiac surgery 
Observation of the volume 
of blood collected in the 
WSD system 
Numerical 
mL 
6-hour bleeding 
Amount of blood accumulated in the 
water-sealed drainage (WSD) system of 
a patient 6-hour post  cardiac surgery 
Observation of the volume 
of blood collected in the 
WSD system 
Numerical 
mL 
24-hour bleeding 
Amount of blood accumulated in the 
water-sealed drainage (WSD) system of 
a patient 24 hour-post  cardiac surgery 
Observation of the volume 
of blood collected in the 
WSD system 
Numerical 
mL 
48-hour bleeding 
Amount of blood accumulated in the 
water-sealed drainage (WSD) system of 
a patient 48 hours- post  cardiac surgery 
Observation of the volume 
of blood collected in the 
WSD system 
Numerical 
mL 
Blood Transfusion Requirements 
Packed red cell (PRC) 
transfusion 
Amount of PRC transfusions received in 
post cardiac surgery patients with Hb 
levels <10 g/dL to reach Hb levels >10 
g/dL before discharge. 
Observation of the volume 
of PRC received by the 
patient 
Numerical 
mL 
Platelet transfusion49 
Amount of blood platelet transfusions 
received in post cardiac surgery patients 
with platelets <100,000 U/µL to reach 
levels of 100,000 U/µL or in platelet 
dysfunction. 
Observation of the volume 
of Platelet transfusion 
received by the patient 
Numerical 
mL 
Fresh Frozen plasma 
(FFP)Transfusion49  
Amount of blood  FFP transfusions 
received by post cardiac surgery patients 
with international normalized ratio (INR) 
>1.5 to reach 1.5 
Observation of the volume 
of FFP received by the 
patient 
Numerical 
mL 

 
 
 
T
a
b
l
e
  
D
e
s
c
ription: 
WSD: water-sealed drainage 
PRC: packed red cell 
FFP: fresh frozen plasma 
INR: international normalized ratio 
BMI: Body Mass Index 
Variables 
Definition 
Measurement 
Variable 
Scale 
Variable Value 
Cryoprecipitate 
transfusion49 
Amount of cryoprecipitate transfusions 
received by post cardiac surgery patients 
with fibrinogen levels <100 mg/dL to 
reach levels of 100 mg/dL 
Observation of the volume 
of cryoprecipitate received 
by the patient 
Numerical 
mL 
Gender 
Patient gender 
Data obtained from patient 
medical records 
Nominal 
• 
Male (0) 
• 
Female (1) 
Age 
Age of the patient at the time of the 
procedure 
Data obtained from patient 
medical records 
Numerical 
year 
Aortic cross-clamp 
Length of use of aortic cross-clamp 
during surgery 
Data obtained from patient 
medical records 
Numerical 
minutes 
Cardiopulmonary 
Bypass machine (CPB) 
Length of time the CPB replaces the 
patient's circulation during surgery 
Data obtained from patient 
medical records 
Numerical 
minutes 
Body Mass Index 
(BMI) 
(Patient's weight in kilograms) squared 
divided by (Patient's height in meters) at 
the time of the procedure. 
Data obtained from patient 
medical records 
Numerical 
kg/m2 
Comorbidity 
Presence of hypertension and/or diabetes 
mellitus as comorbidities at the time of 
the procedure 
Data obtained from patient 
medical records 
Nominal 
• Hypertension (1) 
• Diabetes Mellitus (2) 
 

3.11. Research ethics 
The study was approved by the ethics committee at Harapan Kita National Heart 
Center Hospital, number LB.02.01/VII/040/KEP040/2022, and has received 
research permit approval with number LB.02.01/XX.2/8186/2022.  
 
3.12. Data processing flow 
The data of the research subjects collected using the forms were verified and 
compiled using SPSS software for Microsoft Windows version 20.0 in the form of 
descriptive tables. Data normality and statistical analysis for each variable were 
performed using the same software. The tests used to analyze the two dependent 
variables (amount of bleeding and blood products transfusion after cardiac surgery) 
were the independent T-test (for normal data distribution) and the Mann-Whitney 
test (for abnormal data distribution).  
 
3.13. Research flow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisasi sederhana 
oleh asisten penelitian 
dengan situs 
randomized.org  
Patients undergoing cardiac surgery 
Treatment: topical 
tranexamic acid 
(n=66) 
Placebo: Topical 
NaCl (n=66) 
Inclusion 
Exclusion 
Data collection and analysis 
Report writing 
Registration: 
-
Number of postoperative 
hemorrage 
-
Postoperative blood transfusion 
requirements 

Table 3.3 Research protocol 
TIME 
LOCATION 
ACTION 
D-1 
Preoperative 
1. Patient's informed consent, signature on a 
consent form 
2. Put a green research sticker on the patient's status 
3. Ensure STOP ACE inhibitors (Captopril, 
Ramipril, Lisinopril) and ARBs (Candesartan, 
Valsartan) 24 hours preoperatively. 
4. Make sure to STOP antiplatelet drugs 3-7 days 
preoperatively 
5. Make sure to STOP Warfarin 4-5 days 
preoperatively 
6. Ensure Heparin STOP 4-6 hours preoperatively 
7. Ensure STOP LMWH 12-48 hours 
preoperatively 
8. Record all required patient data on the 
questionnaire 
D+0 
Operating 
Room 
1. Induction, intubation 
2. Standard operating procedures 
3. The surgeon administers topical tranexamic acid 
(5 g in 50 mL NS) or placebo in 100 mL, 50 mL 
after protamine administration, and 50 mL before 
closing the sternum. 
4. Chest tube clamps should not be opened until the 
skin closure process is complete. 
D+0 
ICU 
1. Calculate the initial bleeding when the patient 
arrives at the intensive care unit 
2. Collect blood coagulation examination data 
(blood, hematocrit, PT/APTT, INR) 
3. Count the amount of bleeding from the chest 
tube in the first 6 hours and 24 hours 
4. Disconnect the chest tube if the amount of 
bleeding is <200 mL in 24 hours 
D+1 
ICU 
1. Count the amount of bleeding from the chest 
tube in the second 24 hours (if the chest tube is 
still in place) 
2. Chest tube removal when the amount of bleeding 
is <200 mL in the second 24 hours 

TIME 
LOCATION 
ACTION 
3. Calculate the use of blood component transfusion 
(PRC, FFP, TC, Cryoprecipitate) 
D+2 – 
hospital 
discharge 
ICU - 
Wardroom 
1. Record clinical output results according to the 
questionnaire (total amount of drain production 
and transfusion use of blood components) 
 
1.3 
Research schedule 
Activities 
2022 
October 
November 
Desember 
Submission of research 
ethics approval 
X 
 
 
Data collection and 
retrieval 
 
X 
 
Data processing and 
hypothesis testing 
 
 
X 
Preparation of research 
report 
 
 
X 
 
1.4 
Detailed cost plan 
Proposal drafting (printing and photocopying costs) 
Rp600.000,00 
Submission of ethics and research permits 
Rp900.000,00 
Data collection (observation, consumables) 
Rp15.000.000,00 
Preparation of research report (printing and photocopying costs) Rp1.500.000,00 
Journal publication 
Rp5.000.000,00     
Total 
Rp23.000.000,00 
 
 
 

1.5 
Dummy table  
Tabel Error! No text of specified style in document..1 Sample table of 
experimental and control group characteristics 
Variables 
Experimental 
Group 
Control Group 
(Placebo) 
P-value 
Age (years) 
Rerata ± SD 
Rerata ± SD 
 
Gender 
 
 
 
Male 
n (%) 
n (%) 
 
Women 
n (%) 
n (%) 
 
Body surface area (m2) 
Mean ± SD 
Mean ± SD 
 
Comorbidities 
 
 
 
Hypertension 
n (%) 
n (%) 
 
Diabetes mellitus 
n (%) 
n (%) 
 
Preoperative hemoglobin 
Mean ± SD 
Mean ± SD 
 
Preoperative hematocrit 
Mean ± SD 
Mean ± SD 
 
Preoperative APTT 
Mean ± SD 
Mean ± SD 
 
Preoperative INR 
Mean ± SD 
Mean ± SD 
 
Preoperative creatinine 
Mean ± SD 
Mean ± SD 
 
Postoperative hemoglobin 
Mean ± SD 
Mean ± SD 
 
Duration of aortic cross 
clamp 
Mean ± SD 
Mean ± SD 
 
Duration of use of heart-
lung machine 
Mean ± SD 
Mean ± SD 
 
 
Tabel Error! No text of specified style in document..2 Sample output table of 
CABG results in experimental and control groups 
Primary outcome output 
Control group 
(n=22) 
Experimental group 
with TXA (n = 22) 
P-value 
Volume of chest drain 
bleeding 
 
 
 
Initial bleeding (mL) 
Mean ± SD 
Mean ± SD 
 
6-hour bleeding (mL) 
Mean ± SD 
Mean ± SD 
 
24-hour bleeding (mL) 
Mean ± SD 
Mean ± SD 
 
48-hour bleeding (mL) 
Mean ± SD 
Mean ± SD 
 
Blood Transfusion 
 
 
 
PRC transfusion (mL) 
Mean ± SD 
Mean ± SD 
 
FFP transfusion (mL) 
Mean ± SD 
Mean ± SD 
 
TC transfusion (mL) 
Mean ± SD 
Mean ± SD 
 
Cryoprecipitate 
transfusion (mL) 
Mean ± SD 
Mean ± SD 
 
 

Tabel Error! No text of specified style in document..3 Sample output table of 
OPCAB results in experimental and control groups 
Primary outcome output 
Control group 
(n=22) 
Experimental group 
with TXA (n = 22) 
P-value 
Volume of chest drain 
bleeding 
 
 
 
Initial bleeding (mL) 
Mean ± SD 
Mean ± SD 
 
6-hour bleeding (mL) 
Mean ± SD 
Mean ± SD 
 
24-hour bleeding (mL) 
Mean ± SD 
Mean ± SD 
 
48-hour bleeding (mL) 
Mean ± SD 
Mean ± SD 
 
Blood Transfusion 
 
 
 
PRC transfusion (mL) 
Mean ± SD 
Mean ± SD 
 
FFP transfusion (mL) 
Mean ± SD 
Mean ± SD 
 
TC transfusion (mL) 
Mean ± SD 
Mean ± SD 
 
Cryoprecipitate 
transfusion (mL) 
Mean ± SD 
Mean ± SD 
 
 
Tabel Error! No text of specified style in document..4 Sample output table of 
valve surgery results in experimental and control groups 
Primary outcome output 
Control group 
(n=22) 
Experimental group 
with TXA (n = 22) 
P-value 
Volume of chest drain 
bleeding 
 
 
 
Initial bleeding (mL) 
Mean ± SD 
Mean ± SD 
 
6-hour bleeding (mL) 
Mean ± SD 
Mean ± SD 
 
24-hour bleeding (mL) 
Mean ± SD 
Mean ± SD 
 
48-hour bleeding (mL) 
Mean ± SD 
Mean ± SD 
 
Blood Transfusion 
 
 
 
PRC transfusion (mL) 
Mean ± SD 
Mean ± SD 
 
FFP transfusion (mL) 
Mean ± SD 
Mean ± SD 
 
TC transfusion (mL) 
Mean ± SD 
Mean ± SD 
 
Cryoprecipitate 
transfusion (mL) 
Mean ± SD 
Mean ± SD 
 
 
 
 
 
 
 
 
 

REFERENCE 
 
1. World Health Organization (WHO). Global health estimates 2016: deaths by cause, age, 
sex, by country and by region, 2000-2016 [Internet]. Geneva: World Health Organization; 
2018. Diunduh dari: www.who.int/healthinfo/global_burden_disease/estimates/en/   
2. World Health Organization (WHO). Noncommunicable diseases (NCD) country profiles – 
Indonesia. Geneva: World Health Organization; 2018.  
3. Montrief T, Koyfman A, Long B. Coronary artery bypass graft surgery complications: a 
review for emergency clinicians. Am J Emerg Med [Internet]. 2018;36(12):2289-97.  
4. Firman D, Oktavion YH, Yahya AF, et al. Pedoman nasional pelayanan kedokteran 
intervensi koroner perkutan. Perhimpunan Dokter Spesialis Kardiovaskular Indonesia 
2021; 40. 
5. Yanagawa 
B, 
Halkos 
ME, 
Puskas 
JD. 
Myocardial 
revascularization 
without 
cardiopulmonary bypass. In: Cohn LH, Adam DH (eds) Cardiac Surgery in the Adult. 
McGraw-Hill Education, 2018, pp. 519–37. 
6. Hosseini H, Rahimianfar AA, Abdollahi MH, et al. Evaluations of topical application of 
tranexamic acid on post-operative blood loss in off-pump coronary artery bypass surgery. 
Saudi J Anaesth 2014; 8: 224–8.  
7. Soesanto A. Penyakit jantung katup di Indonesia: masalah yang hampir terlupakan. J 
Kardiol Indones 2012;33:205–8. 
8. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of 
valvular heart disease. Eur Heart J 2017;38:2739–91. 
9. Gerstein NS, Deriy L, Patel PA. Tranexamic acid use in cardiac surgery: hemostasis, 
seizures, or a little of both. J Cardiothorac Vasc Anesth. 2018;32(4):1635-7. 
10. Myles PS, Smith JA, Forbes A, Silbert B, Jayarajah M, Painter T, et al. Tranexamic acid in 
patients undergoing coronary-artery surgery. N Engl J Med. 2017;376(2):136-48.  
11. Pačarić S, Turk T, Erić I, Orkić Ž, Erić PA, Milostić-Srb A, et al. Assessment of the quality 
of life in patients before and after coronary artery bypass grafting (CABG): a prospective 
study. Int J Environ Res Public Health. 2020;17(4):1417.  

12. Habbab LM, Hussain S, Power P, Bashir S, Gao P, Semelhago L, et al. Decreasing 
postoperative blood loss by topical vs. intravenous tranexamic acid in open cardiac surgery 
(DEPOSITION) study: results of a pilot study. J Card Surg. 2019;34(5):305-11.  
13. Montroy J, Hutton B, Moodley P, Fergusson NA, Cheng W, Tinmouth A, et al. The 
efficacy and safety of topical tranexamic acid: a systematic review and meta-analysis. 
Transfus Med Rev. 2018;S0887-7963(17)30151-7.  
14. Jensen RV, Hjortbak MV, Bøtker HE. Ischemic heart disease: an update. Semin Nucl Med. 
2020;50(3):195-207. 
15. Sherwood L. Human physiology from cells to systems. 9th ed. Boston: Cengage Learning; 
2016. h. 326-31. 
16. Bergheanu SC, Bodde MC, Jukema JW. Pathophysiology and treatment of atherosclerosis: 
current view and future perspective on lipoprotein modification treatment. Neth Heart J. 
2017 Apr;25(4):231-42.  
17. Rafieian-Kopaei M, Setorki M, Doudi M, Baradaran A, Nasri H. Atherosclerosis: process, 
indicators, risk factors and new hopes. Int J Prev Med. 2014;5(8):927-46.  
18. Lanza GA. Careri G, Crea F. Mechanisms of coronary artery spasm. Circulation. 
2011;124:1774-82.  
19. Song J. Coronary artery vasospasm. Korean Circ J. 2018;48(9):767-77. 
20. Taqueti VR, Carli MF. Coronary microvascular disease pathogenic mechanisms and 
therapeutic options: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72(21):2625-
41.  
21. Neumann F, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U. 2018 
ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2018;40(2):87-165. 
22. Diodato M, Chedrawy EG. Coronary artery bypass graft surgery: the past, present, and 
future of myocardial revascularisation. Surg Res Pract. 2014;2014:726158.  
23. Omer S, Cornwell LD, Bakaeen FG. Acquired heart disease: coronary insufficiency. In: 
Townsend CM, Evers BM, Beauchamp RD, Mattox KL, eds. Sabiston textbook of surgery: 
the biological basis of modern surgical practice. 20th ed. Philadelphia: Elsevier; 2017. h. 
1660, 1669-83. 

24. Afilalo J, Rasti M, Ohayon SM, Shimony A, Eisenberg MJ. Off-pump vs. on-pump 
coronary artery bypass surgery: an updated meta-analysis and meta-regression of 
randomized trials. Eur Heart J. 2012;33(10):1257-67. 
25. Forouzannia SK, Abdollahi MH, Mirhosseini SJ, Hosseini H, Moshtaghion SH, Golzar A, 
et al. Clinical outcome and cost in patients with off-pump vs. on-pump coronary artery 
bypass surgery. Acta Med Iran. 2011;49(7):414-9.  
26. Gaudino M, Benedetto U, Bakaeen F, Rahouma M, Tam DY, Abouarab A, et al. Off- 
versus on-pump coronary surgery and the effect of follow-up length and surgeons’ 
experience: a meta-analysis. J Am Heart Assoc. 2018;7(21):e010034.  
27. Urso S, Sadaba R, González JM, Nogales E, Pettinari M, Tena MA, et al. Total arterial 
revascularization strategies: a meta-analysis of propensity score-matched observational 
studies. J Card Surg. 2019;34(9):837-45. 
28. Rushing GD, Yuh DD. Primary coronary artery bypass surgery. In: Yuh DD, Vricella LA, 
Yang S, Doty JR, eds. Johns Hopkins textbook of cardiothoracic surgery. 2nd ed. New 
York: McGraw-Hill; 2014. h. 387-401.   
29. Leavitt BJ, Sheppard L, Maloney C, Clough RA, Braxton JH, Charlesworth DC, et al. 
Effect of diabetes and associated conditions on long-term survival after coronary artery 
bypass graft surgery. Circulation. 2004; 110(1) suppl 1: II-41-II-44 
30. Hoque A, Moinuddin S. Effect of arterial hypertension on postoperative mortality and 
morbidity after off-pump CABG surgery. Cardiovasc j. 2017;10(1):13-16 
31. Terada T, Johnson JA, Norris C, Padwal R, Qiu W, Sharma AM, et al. Severe obesity is 
associated with increased risk of early complications and extended length of stay following 
coronary artery bypass grafting surgery. J Am Heart Assoc. 2016; 5:e003282 
32. Lv M, Gao F, Liu B, Pandey P, Feng Y, Wang Y, et al. The effects of obesity on mortality 
following coronary artery bypass graft surgery: a retrospective study from a single center in 
China. Med Sci Monit. 2021; 27:e929912-1–10 
33. Zehnder JL. Drugs used in disorders of coagulation. In: Katzung BG, editor. Basic and 
clinical pharmacology. 14th ed. New York: McGraw-Hill; 2017. h. 623. 
34. Ausen K, Pleym H, Liu J, Hegstad S, Nordgård HB, Pavlovic I, et al. Serum concentrations 
and pharmacokinetics of tranexamic acid after two means of topical administration in 

massive weight loss skin-reducing surgery. Plastic and reconstructive surgery. 
2019;143(6):1169e-1178e 
35. Yao Y, He L, Tan J. The effect of tranexamic acid on the values of activated clotting time 
in patients undergoing cardiac surgery: a prisma-compliant systematic review and meta-
analysis. Journal of clinical anesthesia. 2020;67:110020 
36. Pabinger I, Fries D, Schöchl H, Streif W, Toller W. Tranexamic acid for treatment and 
prophylaxis of bleeding and hyperfibrinolysis. Wien Klin Wochenschr. 2017;129(9):303-
16.  
37. Alaifan T, Alenazy A, Wang DX, Fernando SM, Spence J, Belley-Cote E, et al. 
Tranexamic acid in cardiac surgery: a systematic review and meta-analysis (protocol). BMJ 
Open. 2019;9(9):e028585.  
38. Koster A, Börgermann J, Zittermann A, Lueth JU, Gillis-Januszewski T, Schirmer U. 
Moderate dosage of tranexamic acid during cardiac surgery with cardiopulmonary bypass 
and convulsive seizures: incidence and clinical outcome. Br J Anaesth. 2013;110(1):34-40. 
39. Ross J, Salman RA. The frequency of thrombotic events among adults given 
antifibrinolytic drugs for spontaneous bleeding: systematic review and meta-analysis of 
observational studies and randomized trials. Curr Drug Saf. 2012 Feb;7(1):44-54.  
40. Kalavrouziotis D, Voisine P, Mohammadi S, Dionne S, Dagenais F. High-dose tranexamic 
acid is an independent predictor of early seizure after cardiopulmonary bypass. Ann Thorac 
Surg. 2012;93(1):148-54. 
41. Takagi H, Ando T, Umemoto T. Seizures associated with tranexamic acid for cardiac 
surgery: a meta-analysis of randomized and non-randomized studies. J Cardiovasc Surg. 
2017;58(4):633-41. 
42. Guo J, Gao X, Ma Y, Lv H, Hu W, Zhang S, et al. Different dose regimes and 
administration methods of tranexamic acid in cardiac surgery: a meta-analysis of 
randomized trials. BMC Anesthesiol. 2019;19:129.  
43. Saracoglu A, Ezelsoy M, Saracoglu KT. Postoperative thrombotic effects of tranexamic 
acid in open heart surgery. Ir J Med Sci. 2019 Nov;188(4):1373-8.  

44. Maeda T, Ishihara T, Miyata S, Yamashita K, Sasaki H, Kobayashi J, et al. Evaluating the 
effect on mortality of a no-tranexamic acid (TXA) policy for cardiovascular surgery. J 
Cardiothorac Vasc Anesth. 2018;32(4):1627-34.  
45. Vanĕk T, Straka Z. Topical use of tranexamic acid in cardiac surgery-a review and meta-
analysis of four randomized controlled trials. Cor Vasa. 2013;55(2):e184-9. 
46. Hosseini H, Rahimianfar AA, Abdollahi MH, Moshtaghiyoon MH, Haddadzadeh M, Fekri 
A, et al. Evaluations of topical application of tranexamic acid on post-operative blood loss 
in off-pump coronary artery bypass surgery. Saudi J Anaesth. 2014;8(2):224-8. 
47. Shah MU, Asghar MI, Siddiqi R, Chaudhri MS, Janjua AM, Iqbal A. Topical application of 
tranexamic acid reduces postoperative bleeding in open-heart surgery: myth or fact? J Coll 
Physicians Surg Pak. 2015;25(3):161-5. 
48. Chaudhary FA, Pervaz Z, Ilyas S, Niaz MN. Topical use of tranexamic acid in open heart 
surgery. J Pak Med Assoc. 2018 Apr;68(4):538-42.  
49. Habbab LM, Semelhago L, Lamy A. Topical use of tranexamic acid in cardiac surgery: a 
meta-analysis. Thorac Cardiovasc Surg. 2020;68(3):212-8. 
50. De Bonis M, Cavaliere F, Alessandrini F, Lapenna E, Santarelli F, Moscato U, et al. 
Topical use of tranexamic acid in coronary artery bypass operations: a double-blind, 
prospective, randomized, plasebo-controlled study. The Journal of Thoracic and 
Cardiovascular Surgery. 2020;119(3):575-580 
51. Ausen K, Fossmark R, Spigset O, Pleym H. Safety and efficacy of local tranexamic acid for 
the prevention of surgical bleeding in soft-tissue surgery: a review of the literature and 
recommendations for plastic surgery. Plastic and Reconstructive Surgery. 2022;149(3):774-
787 
52. Ker K, Beecher D, Roberts I. Topical application of tranexamic acid for the reduction of 
bleeding. Cochrane Database of Systematic Review. 2013(7):CD010562 
53. Bojar RM. Mediastinal bleeding. In: Manual of perioperative care in adult cardiac surgery. 
6th ed. Hoboken: Wiley-Blackwell; 2020.h 419-455 
54. Yanagawa 
B, 
Halkos 
ME, 
Puskas 
JD. 
Myocardial 
revascularization 
without 
cardiopulmonary bypass. In: Cohn LH, Adam DH (eds) Cardiac Surgery in the Adult. 

McGraw-Hill Education, 2018, pp. 519–37.Arora D, Metha Y, Trehan N. OPCAB-is it the 
“best technique” for coronary revascularization? J Clin Priv Cardiol 2015; 4: 89–97. 
55. Arora D, Metha Y, Trehan N. OPCAB-is it the “best technique” for coronary 
revascularization? J Clin Priv Cardiol 2015; 4: 89–97. 
56. Gulati 
M, 
Levy 
PD, 
Mukherjee 
D, 
et 
al. 
2021 
AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis 
of chest pain: executive summary: a report of the american college of cardiology/american 
heart association joint committee on clinical practice guidelines. J Am Coll Cardiol 2021; 
78: 2218–61. 
57. (EACTA) TF on PBM for ACS of the EA for C-TS (EACTS) and the EA of CA, Boer C, 
Meesters MI, et al. 2017 EACTS/EACTA guidelines on patient blood management for 
adult cardiac surgery. J Cardiothorac Vasc Anesth 2017; 32: 88–120. 
58. Rosengart T, Anand J. Acquired Heart Disease. In: Townsend C, Evers B, Beauchamp R, et 
al. (eds) Sabiston textbook of surgery : the biological basis of modern surgical practice. 
Philadelphia: Elsevier, 2017, pp. 1691–1717. 
59. Huddleson S, Yuh D. Mitral Valve Replacement. In: Yuh D, Vricella L, Yang S, et al. (eds) 
Johns Hopkins textbook of Cardio thoracic surgery. New York: McGraw-Hill, 2014, pp. 
551–8. 
60. Yarbrough W, Ikonomidis J. Aortic Valve Replacement. In: Yuh D, Vricella L, Yang S, et 
al. (eds) Johns Hopkins textbook of cardiothoracic surgery. New York: McGraw-Hill, 
2014, pp. 502–20