Conditions: Left Ventricular Thrombosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the novel oral anticoagulant apixaban with the standard therapy of warfarin on the size reduction or resolution of left ventricular thrombus over 3 months.

Detailed description:
Current treatment for left ventricular thrombus is anti-coagulant or blood thinning agent known as warfarin. Recently at least three novel oral anticoagulant agents were used in the treatment of atrial fibrillation, pulmonary embolism and deep vein thrombosis (DVT).

Novel oral anticoagulant drugs will require no blood taking for INR monitoring, hence less visit and more convenience to patients. Latest studies also showed lesser rate of bleeding as compared to warfarin and hence relatively safer.

Arms:
arm 1: warfarin daily, dosage according to INR monitor. Aim INR 2-3 arm 2: Apixaban 5 MG Oral Tablet \[ELIQUIS\] will be given for randomly selected patients for 3 months.

Interventions: intervention 1: Apixaban 5 MG Oral Tablet [ELIQUIS] intervention 2: Warfarin Sodium
Intervention descriptions: intervention 1: Apixaban is licensed for treatment of deep vein thrombosis and pulmonary embolism. Hence, a good study drug for left ventricular thrombosis for possibility of a new indication. intervention 2: as controlled arm since warfarin is the standard therapy for LV thrombus

Protocol document:
Prot_SAP_ICF_000.pdf: 
 
 
 
Apixaban Versus Warfarin in Patients With Left Ventricular 
Thrombus: A Prospective Randomized Outcome Blinded 
Study on the Size Reduction or Resolution of Left 
Ventricular Thrombus 
 
 
 
NCT02982590 
 
 
 
December 12, 2015 


- 1 - 
 
STUDY PROTOCOL 
Title 
Apixaban versus warfarin in left ventricular thrombus: A prospective randomized outcome blinded 
study on the size reduction or resolution of left ventricular thrombus. 
 
Introduction 
Left Ventricular Thrombus (LVT) is a blood clot in the left ventricle (LV) of the heart. It is a well-
recognized complication of acute myocardial infarction (AMI) and congestive heart failure (CHF) 
due to severely impaired LV systolic function. Previously, the incidence of LVT was reported to 
be as high as 30%-40% in patients with an anterior AMI. For patients with a non-anterior AMI, 
the risk of LVT was lower (<5%) (Asinger et al., 1981). Although controversial, in the 
contemporary era of routine early revascularization and more aggressive anticoagulation, the 
incidence of LVT complicating an anterior AMI is likely reduced and is currently estimated at 5% 
to 15% (Kalra et al., 2000; Greaves et al., 1997; Nayak et al., 2004). In patients with dilated 
cardiomyopathy and CHF, the reported frequency of LVT varies from 10%-30%, depending on 
the series (Ciaccheri et al., 1989; Gottdiener et al., 1983). Hence in certain parts of the world where 
there was delay to revascularization due to logistical and financial reasons the rate of incidence is 
presumably higher. Then the choice of anticoagulation is vital for lower risk of bleeding and 
complications in patients with multiple co-morbidities. 
 
 
 


- 2 - 
 
The pathophysiologic mechanisms for LV thrombus formation is the so-called “Virchow’s triad” 
that commonly exists in patients after AMI or in those with dilated cardiomyopathy and congestive 
heart failure. The triad consists of stasis of blood, endothelial injury or dysfunction and  
hypercoagulable state. In general, LVT can occur within 24 hour but commonly within the first 1-
2 weeks after an AMI (Nayak et al., 2004; Visser et al., 1983). Late occurrence of LVT is usually 
associated with adverse chamber remodelling, dilatation, reduced global function, and aneurysm 
formation. Factors associated with a higher risk of developing LVT have been well-studied, 
particularly in the post-MI setting. There are few high risk echocardiographic features for 
development of LVT such as large infarct size and extent, anterior more common than inferior, 
severe global and regional LV systolic dysfunction with presence of congestive heart failure, 
elevated LV end systolic volume with LV dilatation, spontaneous echo contrast, abnormal flow 
pattern within LV, apical rotating flow and vortex ring formation (Van Dantzig et al., 1995; 
Neskovic et al., 1998). 
 
The main complication of LVT remains systemic embolization, particularly in cerebral circulation. 
In a meta-analysis of studies performed in patients after anterior MI, the estimated odds ratio (OR) 
for increased risk of emboli in the presence of echocardiographically demonstrated LVT (11 
studies, 856 patients) was 5.45 (95% confidence interval (CI), 3.02 –9.83) (Vaitkus et al., 1993). 
The clinical features have not been found to be predictive of risk but the following 
echocardiographic characteristics of LVT are associated with a higher risk of embolization when 
the thrombus is mobile, protruding with presence of central echolucency (Haugland et al., 1984; 
Visser et al., 1985).  
 


- 3 - 
 
LVT remains an important complication in patients with ischemic heart disease after anterior AMI 
and in those with dilated cardiomyopathy and systolic heart failure. The diagnosis of LVT remains 
important, since anticoagulation will reduce the risk of systemic embolization and stroke. Despite 
advances in other imaging modalities, namely the cardiac computerized tomography (CT) and 
magnetic resonance imaging (MRI), echocardiography still remains the most important tool for 
diagnosis and risk stratification in patients predisposed to developing LVT. Largely due to cost 
and availability of the echocardiography. The transthoracic echocardiography (TTE) remains the 
most common imaging modality to use. When images are technically adequate coupled with 
competent operator, TTE has a sensitivity of 90%-95% and a specificity of 85%-90% for detection 
of LVT in studies where the presence of thrombi was confirmed at surgery or autopsy (Visser et 
al., 1983; Cacciapuoti et al., 1986).  
 
The 2004 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines 
for the Management of Patients with ST-elevation (STE) MI, (Antman et al., 2004)  recommended 
the use of oral anticoagulation, targeted to an international normalized ratio (INR) of 2.0-3.0, for 
at least 3 months (Class I, Level of Evidence B) and perhaps, indefinitely in patients without an 
increased risk of bleeding (Class I, Level of Evidence C) in post-STEMI patients with documented 
LVT (Antman et al., 2004). This recommendation is based primarily on observational studies 
demonstrating that patients with LVT treated with heparin and warfarin had better outcomes and 
fewer cerebral emboli. In a meta-analysis of published studies in patients with LVT post-MI,( 
Vaitkus et al., 1993) the odds ratio (OR) of anticoagulation versus no anticoagulation in preventing 
embolization (7 studies, 270 patients) was 0.14 (95% CI, 0.04 - 0.52). Additional therapeutic 
interventions, such as thrombolysis or surgery, are rarely needed. In clinical practice, 


- 4 - 
 
echocardiographic imaging is routinely used to follow patients being treated for LVT. Repeated 
imaging of the left ventricle after 3 months of therapy may allow discontinuation of 
anticoagulation earlier than 6 months, if evidence of thrombus is no longer present, particularly if 
there is recovery of apical wall motion (Steg PG et al., 2012). 
 
Based on ESC  guidelines for STEMI 2012, anticoagulation should be considered in patients with 
extensive anterior infract leading to large anterior wall motion abnormalities involving apical 
segments. Especially, if they are at low risk of bleeding, to prevent the development of thrombi. 
For patients with confirmed mural thrombi, the consensus is that they require oral anticoagulant 
therapy with vitamin K antagonists for up to 6 months (Steg PG et al., 2012). However, this has 
not been revisited in the era of stenting and double antiplatelet. Combining oral anticoagulation 
and double antiplatelet into a triple therapy increases bleeding risks. The optimal duration of such 
triple antithrombotic therapy is unknown and should take into account the relative risks of bleeding 
and stent thrombosis. Repeated imaging of the left ventricle after 3 months of therapy may allow 
discontinuation of anticoagulation earlier than 6 months, if evidence of thrombus is no longer 
present, particularly if there is recovery of apical wall motion (Steg PG et al., 2012). 
 
Rationale 
 
Recently, novel oral anticoagulants (NOACs) have emerged as alternative to VKA for 
thromboembolism in patients with non-valvular atrial fibrillation. The indication of NOACs was 
then expanded to cover the treatment of DVT and pulmonary embolism following non-inferiority 
trials with VKA (Buller HR et al., 2012; Agnelli et al., 2013). However, the effect of NOACs on 


- 5 - 
 
left ventricular thrombus has not yet been studied in a prospective randomized trial. Only recently 
one study looked at left atrial thrombus. “XTRA” a study on the usage of rivaroxaban in patients 
with non valvular atrial fibrillation with left atrial appendage thrombus has been initiated in 2013 
in Europe. This was an open label single group interventional phase III trial and the result is still 
pending (Lip GY et al., 2015).   
 
In the Malaysian population, due to the lower rate of primary angioplasty, we are seeing more 
ischeamic induced left ventricular failure and hence higher prevalence of left ventricular thrombus 
(LVT) as opposed to Western population. We believe similar scenario might be happening in other 
developing countries as well as poorer nations. Hence the treatment was always with VKA – 
warfarin coupled with IV heparin in the beginning and resulting in longer stay in the hospital in 
order to achieve the targeted INR. The emergence of NOACs is an ideal alternative with lesser 
bleeding rate and no monitoring needed leading to shorter length of hospital stay. Available 
literatures consisting of case reports have shown favourable outcomes with the use of NOACs in 
left ventricle thrombus especially apixaban (Tohru et al., 2013; Mano et al., 2014; Atakan et al., 
2015; Nakasuka et al., 2014). The use of apixaban in LVT will be beneficial for patients who are 
most of the time at increased risk of bleeding due to the concurrent use of antiplatelet, elderly age 
and presence of renal and/or liver impairment. The study will add another indication for NOACs 
specifically apixaban. 
 
 
 


- 6 - 
 
The purpose of the study is to assess the size reduction and resolution of LVT. This study will give 
a preliminary data for further studies in the future. Specifically on the usage of the novel oral 
anticoagulant apixaban on LVT patients in order to prevent catastrophic morbidity and mortality 
from cardiac thromboembolic event.  
 
Objectives 
To compare the novel oral anticoagulant apixaban with the standard therapy of warfarin on the 
size reduction or resolution of left ventricular thrombus over 3 months. 
 
Research hypothesis 
The resolution of LVT in patients with apixaban was equal or better compared to warfarin based 
on LVT size reduction in cm2 or total resolution over 3 months  
 
Methodology and Material  
Definition of LV thrombus patients 
Patients with symptoms of heart failure or recently acquired acute coronary syndrome (ACS) who 
developed LV thrombus and highly visible spontaneous echo contrast (grade 4) confirmed on 2-D 
echocardiography by two operators. 
 
Study Design 
This is a two arms open label interventional and prospective randomized controlled outcome 
blinded endpoint (PROBE) study 
 


- 7 - 
 
Study flow chart 
 
Figure 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Apixaban  5mg BD 
Warfarin titrated as per INR of 2-3  
Visit wk: 1,2,3,6,9 and 12 for INR 
monitoring  
Data analysis 
All patients with heart 
failure symptoms and/or 
ACS presenting to HUSM 
Echocardiography on wk 0 – confirmed LV thrombus 
Inclusion/exclusion criteria fulfilled: Then randomization by stratified permuted block 
Conclusion 
Visit wk: 1,2,3,6,9 and 12 for 
adverse effects monitoring 
Echocardiography on  
wk 6  
Echocardiography on wk 12 


- 8 - 
 
Study Period 
October 2016 to October 2018 
 
Reference and study population 
Reference population are all patients with left ventricular thrombus with history of left ventricular 
failure from any causes and with/without prior stroke event.  
Study populations are patient who presented to the study centres with acute coronary syndrome 
(ACS) and/or heart failure with or without prior stroke. They will have 2D echocardiography from 
October 2016 till October 2018. 
 
Sampling Method 
o 
LVT patients fulfilling the inclusion and exclusion criteria were selected by convenience 
sampling 
o 
And treatment allocation will be decided by randomized stratified permuated block sampling 
using computer software: block stratified randomization windows version 6.0. The computer 
program used to generate these sheets makes block stratified assignments with user selected 
block size. The pseudorandom number generator is a linear congruential algorithm of Park 
and Miller with Bays-Durham shuffling. It has a period of over 2 billion. (Reference: Press 
WH et al. Numerical Recipes in C. Cambridge University Press, 1992, p 280.) 
o 
Strata decided are age 55 years old above and presence of diabetes mellitus. 
 
 


- 9 - 
 
Inclusion Criteria 
1.   Age 18 – 80 years old 
1. Presence of LV thrombus or spontaneous echo contrast (SEC) grade 3 or 4 (Patel VG 1996), 
with regional wall motion abnormalities  
2. HASBLED score less than 3 
3. No episodes of major bleeding in the past 6 months  
a)  Major bleeding defined as  
 episodes of bleeding with significant drop in haemoglobin(Hb)level of at least 2gm/dL  - 
Includes upper and lower gastrointestinal bleed 
 The need for blood transfusion (pack cell) of at least 2 unit 
 Recent surgery with bleeding complications and lost of Hb as in (i) or (ii) 
 Any intracranial bleeds with neurological deficits 
 
Exclusion Criteria 
1. Patient with unstable arrhythmias and/or recurrent cardiogenic shock 
2. Patient with large ischemic stroke on recruitment-defined as involving >1/3 of cerebral 
hemisphere or deemed to have high chance of haemorrhagic transformation 
3. Patient with permanent pacemaker 
4. Patient who is post valve replacement therapy 
5. Patient who is pregnant.  
6. Patient with advanced kidney disease at stage V and not on dialysis (CrCl <15 mL/min) 
7. Patient with advanced liver disease with coagulopathy 
8. Patient with organized and old left ventricular thrombus  


- 10 - 
 
Study sites  
o This study will require multiple centres across Malaysia subjected to the relevant ethical 
committee approval. 
o The confirmed centres for now are : 
1. The Echocardiography Unit Hospital Universiti Sains Malaysia (HUSM), Kubang Kerian, 
Kelantan.  
- prevalence of LVT in USM is approximately 70 a year or 5 to 6 patients a month. (source: 
patients registration books, echocardiography unit, HUSM) 
2. National Heart Institute (IJN), Kuala Lumpur.  
- prevalence of LVT in IJN is approximately 5 to 10 patients a month. (source: Datuk Dr 
Ahmad Khairuddin B Mohamed Yusof, senior consultant cardiologist specialized in cardiac 
imaging, IJN) 
o 
Term of references will contain points as below.  
1. Data ownership belong to USM.  
2. Recruitment of patients is by competitive sampling. i.e. if USM had reached the targeted 
sample size, then other center will cease their recruitment and vice versa.  
3. Safety of the patients is the responsibility of each principle investigator and subjected to 
local ethical approval guidelines. 
4. Main author for publication will be from USM. 
5. Each principal investigator will be the co-author. 
6. Each center need to obtain their own source of fundings, in the absence of major grant.  
7. No insurance will be provided for the duration of the study.  


- 11 - 
 
8. Investigators will not be paid for the duration of the study and involvement will be voluntary 
with no honorarium payment.  
 
Study methodology 
o Patients who are diagnosed with left ventricular thrombus (LVT) by echocardiography will be 
selected and screen for inclusion and exclusion criteria (convenience sampling).  
o Screening will be done by the principal investigator/ co-investigators who must be physician 
and not involved in doing echocardiography.  
o Blood investigations for screening will be carried on, which include full blood count, liver and 
renal function test as well as coagulation profile.  
o Informed consent will be obtained preferably in the cardiology clinic/ day care after all 
screening results available. 
o Once consented, the patient would be randomized using stratified permuted block 
randomization for the treatment arm into two (2) groups.  
o The first group will be given the study drug which is apixaban at 2.5mg BD from day one 
onwards until wk 12. The dose of 2.5mg BD is chosen for wider safety profile as well as 
suitable for patients with the following characteristics: age ≥ 80 years, weight ≤ 60kg or serum 
creatinine ≥ 133 micromol/L.  
o While the second group will receive the standard therapy which consisted of heparin infusion 
overlapping with warfarin with the targeted INR of 2-3. 
o Patients will be discharged failure symptoms improved.  
 


- 12 - 
 
o In the presence of recent ACS and patients not yet undergone angioplasty, only a single 
antiplatelet will be used concurrently. 
o If patient had to go for early/emergency percutaneous coronary intervention with a coronary 
stent then the choice of stent will have to take consideration of the higher risk of bleeding on 
triple therapy. 
o Once a coronary stent inserted then patient will put on triple therapy (apixaban/ warfarin + 
dual anti platlet). There’s a recent study comparing bleeding risk between warfarin and NOAC 
in triple anticoagulant therapy, of which, the bleeding risks were significantly lower in NOAC 
with triple therapy compared to those of warfarin triple therapy. (Deepak et al., 2016) 
o The study will be assisted by 2 nurses with one will help in randomization, nursing 
support and documentation. While another nurse is a trained echo technician who will 
do serial echocardiography for the patients.  
o The echocardiography nurse will be doing the first echo scan at the designated weeks in a 
allocated room (room A) 
o The second echo will be done by a cardiologist at another allocated room (room B) on the same 
day with the first scan. 
o Both the second nurse(echo technician) and the cardiologist will not have access to the medical 
folder and the treatment strategy. They are only required to fill in the given echocardiography 
report form. See Patient Data Collection Form (3) and (4). 
o This blinding process will be monitored by the first study nurse while making all effort not to 
reveal any information to the echocardiography operators.  
o Only previous echocardiography report will be available for the operator reference if requested. 


- 13 - 
 
o The completed echocardiography data entry forms will be kept separately from other forms for 
outcome blinding purpose. 
o The study visits  are scheduled at week 0,1,2,3,6,9 and (not more than 15 weeks). Week 0, 6 
and 12 are for echocardiography and INR review while the rest are for outpatient visit which 
include INR monitoring and screening for any adverse events.  
o Patient Data Collection Form (1) is for the first visit while form number (2) is for subsequent 
visits.  
o Screening for adverse events include blood investigations for hemoglobin level, renal and liver 
function for both groups. 
o The INR would be monitored nine times including week 0 and week 1,2,3,6,9 and 12. 
o Achieved INR with TTR of more than 60% (Connolly S et al., 2008) is considered adequate 
anticoagulation in the warfarin group. In total 3 echocardiography will be done to each patient 
and LV thrombus size is charted in cm2.  
o The spontaneous echo contrast (SEC) would be quantify based on the score of 0-4 as reported 
by Patel VG 1996:- 
0 = None  
1 = Faint but definite contrast, more linear than curving in  
2 = Spontaneous contrast of intermediate intensity between  
3 = Easily observed spontaneous contrast, swirling in nature  
4 = Dense, rope-like spirals with a slow moving pattern with motion pattern within the LV 
grades 1 and 3 but not heavily dense or slow moving in the LV. 
 


- 14 - 
 
o The LV thrombus size in cm2 for percentage of reduction or total resolution during the first 3 
months confirmed by echocardiography are the primary endpoints. 
o When there is no contraindication, the apixaban/warfarin will be continued after total 
resolution of LVT till the next visit with echocardiography. This is to make sure the resolution 
is maintained on 2 echocardiography (6 weeks apart). 
o The investigators will not have access to the echocardiography data except when it is time to 
stop the oral anticoagulation following 6 weeks of total resolution. 
o Echocardiography report will be unblinded when major events such as stroke, major bleeding, 
new onset acute coronary syndrome with or without left ventricular failure or any other events 
that are life threatening. 
o After 3 months (up to 15 weeks) has elapsed then each patient will undergo the last 
echocardiography. The result will have three possibilities: 
1. 
Total resolution persisted 
2. 
Residual smaller thrombus 
3. 
Organized thrombus  
o Note: No universal definition available apart from experts’ opinions. It is described as fixed or 
flatter thrombus with area of calcifications, homogenous echogenicity with no area of 
echolucency and high acoustic impedance on the outer layer (Delewi R et al., 2012; Haugland 
et al., 1984; Ports TA et al., 1978) 
o A successful treatment defined as complete resolution or organized clot achieved at any time 
before 15 weeks without any thrombotic events.  
 


- 15 - 
 
o A failure of treatment is defined as less than 50% reduction over the same period or any 
thrombotic events regardless of the left ventricular size.  
o In the case of residual smaller thrombus all anticoagulant will be switched on warfarin as per 
local protocol after week 15. The decision for longer term anticoagulation after study ended 
will depend on the primary managing team based on available clinical and echocardiography 
findings. 
o Demographic and clinical data such as past medical history and echocardiography findings etc. 
will be obtained by the folder review. While body weight, blood pressure etc. would be 
documented as per visit. 
o After 15 weeks has elapsed, follow up will be done by clinic follow up every 2 months till the 
end of study duration of 24 months. 
o Any major cardiovascular events including bleeding, stroke and death from any cause will be 
recorded and analyzed. 
o Bleeding attributed to the effect of the anticoagulation is considered as the safety endpoint. 
o After an episode of major bleeding, an OGDS or CT scan brain depending on the site of 
bleeding will be done after 4-6 weeks time for reassessment. 
o The decision to continue warfarin/apixaban after 6 weeks will be based on the risk of stroke 
from residual thrombus against the risk of future bleeding. The next dose of warfarin/apixaban 
will be reduced to lowest possible therapeutic dose and INR of 1.7- 2.2 (Chung J et al. 2015) 
(29) when the managing physician decided to restart the anticoagulant. 
o All adverse events will be documented and serious adverse events (SAE) will be 
communicated to the related ethical committee within 24 hour. The echocardiography findings 
will be unblinded and patient will be withdrew from the study in the event of SAE.  


- 16 - 
 
o Any patients who withdraw their consent or has to be terminated early for any reasons, will be 
put on warfarin if they’re on the study drug and follow up as per local guidelines.   
Procedures and visits schedule 
Visit week 
0 
1 
2 
3 
6 
9 
12 
Procedures 
Informed consent 
/ 
 
 
 
 
 
 
Full clinical review 
/ 
 
 
/ 
 
/ 
 
ECHO 
/ 
 
 
 
/ 
 
/ 
A/E review 
 
/ 
/ 
/ 
/ 
/ 
/ 
ECG 
/ 
 
 
 
 
 
 
INR/APTT 
/ 
/* 
/* 
/* 
/* 
/* 
/* 
FBC 
/ 
/ 
/ 
/ 
/ 
/ 
/ 
RFT 
/ 
 
/ 
 
/ 
 
/ 
LFT 
/ 
 
/ 
 
/ 
 
/ 
Note: * For patients on warfarin only. 
 
 
 
 


- 17 - 
 
Sample size calculation 
o Based on the best number for a study- the minimum number per group is 12 “the rule of 12” 
Belle and Julious (Griffiths HR et al., 2014). 
o David Schoenfeld (David Schoenfeld et al., 1980) in his paper suggested that in most cases of  
studies, 25 subjects would be sufficient for a meaningful difference between the groups. 
o After considering the resources available and time constraint imposed. A total of 100 patients 
were decided (50 in each group) to prove our hypothesis 
 
Statistical Analysis  
o Statistical calculation will be based on intention to treat analysis. Sample size calculation as 
mentioned previously. The full analysis set will include patients who have received at least 1 
dose of medication or had 1 or more post randomization, follow-up evaluation. 
o For primary and secondary outcomes, descriptive statistics and 95% confidence intervals will 
be used to summarize the differences between groups.  
o All data will be entered in SPSS version 24. The descriptive statistics of variables is presented 
as mean (SD) for continuous variables and frequency (%) for categorical variables.  
o The comparison of LV thrombus size (cm2) between warfarin and apixaban groups is based on 
the 2 variables (categorical and repeated numerical data) and would be analysed using the 
model statistical analysis of general linear model with repeated measures ANCOVA.   
o Model assumptions for the Repeated Measures ANCOVA analysis are then checked for 
normality, homogeneity of variances and compound symmetry to check correlation across all 
measurements. Histogram and box and whisker plot will be used for testing the normality of 
the residuals from the repeated measurement of LVT area (cm2) and normality reported. 


- 18 - 
 
Overall linearity assumptions are fulfilled when the scatter plot of the predicted values for the 
LVT area (cm2) are charted against the residual for the LVT area (cm2). Homogeneity testing 
is performed using Levene’s test, and the equal variances assumption is met (P > 0.05). Box 
test is applied to test covariance. Compound symmetry then checked for all of the 
measurements using Mauchly’s test of sphericity. The P value of <0.05 indicates that 
assumption of compound symmetry is not met. In that case, analysis will continue with 
multivariate test or univariate test with Epsilon correction. When the time and LVT area 
interaction is significant (P < 0.05) then further analysis will produce adjusted means with 
confidence interval. Analysis will be continued with adjusted confidence interval using the 
Bonferroni adjustment method.  
o Differences exhibiting P values below 0.05 were considered significant 
 
Ethical consideration 
The risks and safety precautions 
a) The study will require patients to take the standard anti-coagulant drug for atrial fibrillation 
and DVT/pulmonary embolus (apixaban) for an experimental benefit in left ventricular 
thrombus as opposed to the warfarin which is the standard treatment. The control group will 
be on warfarin. 
b) The risk of inadequate anticoagulant is thromboembolic stroke while the side effect will be 
bleeding. 
c) Enrolled patients will receive all necessary ACS and anti-failure medications on top of the 
study drug or warfarin. 


- 19 - 
 
d) In-patients are expected to be the main participants in this study. However in the event of an 
out patient coming in for an echocardiography who turned to be positive for LVT then he/she 
will be admitted for further management. Once informed consent obtained, he/she will be 
randomized on the choice of treatment arm. In this study no placebo is given. 
e) Full blood count and coagulation profile will be taken on each patient on every visit to monitor 
hemoglobin levels and exclude occult bleeding. 
f) Renal and liver function test will also be taken on every visit. Any derangement more than 
30% from baseline for renal function and 1.5x ULN of the liver enzymes or billirubin will be 
reported as adverse event. 
g) In the event of bleeding, patients and family members will be reminded to come to the 
emergency department as soon as possible and to skip the next dose of warfarin/apixaban. 
Warfarin induced major bleeding has a clear set of international guidelines on reversal of INR. 
The apixaban bleeding occurs at a lower rate and tend to be lesser in severity. However in the 
event of apixaban induced major bleeding then partial reversal of prothrombin time 
prolongation has been seen after administration of prothrombin complex concentrates (PCCs) 
in healthy volunteers. The use of other procoagulant reversal agents like activated prothrombin 
complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) may be utilized when 
available but has not been evaluated. Minor bleeding will be managed by close observation 
and supportive care after stopping the medication. 
h) Patients can walk in to the clinical trial unit or echocardiography unit on any suspected adverse 
events. The list of phone numbers of all investigators and study nurses will be made available 
to all patients. 


- 20 - 
 
i) CT scan brain will be done immediately on the discovery of new neurological deficits or in the 
likely event of stroke 
 
The benefits from this study 
a) This study would be the first in the world utilizing novel anticoagulant agent in left ventricular 
thrombus 
b) The use of apixaban in LVT will benefit patients greatly if its efficacy and lesser rate of 
bleeding proven against warfarin. Patients would benefit on the convenience and safety of 
apixaban over warfarin. 
c) On the contrary, a negative findings will guide the physician worldwide that not all 
anticoagulants is suitable for intracardiac thrombus and unnecessary risks will be avoided on 
many patients. 
d) The demographics and local data on LVT will be made available from this study that would 
be beneficial for further knowledge in LVT management and risk assessment. 


21 
 
Gantt Chart of Research Activities: Apixaban versus warfarin in left ventricular thrombus: A prospective randomized outcome 
blinded study using two dimensional transthoracic echocardiography by two operators 
 
 
Milestones
1. Patient recruitement: October 2016  July 2018 
2. Data collection: October 2016  October 2018 
3. Data analysis: June 2018  October 2018 
4. Presentation & submission of reports: October 2018  February 2019 
5. Report writing: October 2018  February 2019 
6. Submission of research papers: February 2019  April 2019 
 


22 
 
Patient information and consent form  
 
Patient Information Sheet 
TOPIC : Apixaban versus warfarin in left ventricular thrombus: A prospective 
randomized outcome blinded study on the size of left ventricular thrombus between 
apixaban and warfarin  
 
INVESTIGATOR      : Dr W Yus Haniff W.Isa, MMC No: 40454 
C0-INVESTIGATOR : Dr Niny Hwong Perng Ling, MMC No: 51933 
                                          Datuk Dr. Ahmad Khairuddin B Mohamed Yusof,  
                           MMC No: 30163 
                           Dr Ng Seng Loong, MMC No: 38133 
                           Prof. Dato’ Dr Zurkurnai Yusof, MMC No:  25765 
                           Prof. Syed Hatim Noor@Nyi Nyi Naing, MMC No: 33063 
                           Prof. Gregory Y.H. Lip, GMC No: 3272189 
1. 
Introduction 
You are invited to take part voluntarily in the study as above. For your information, 
left ventricular thrombus is a condition whereby there is a blood clot in one of the 
heart chamber. In this case the heart chamber involved is known as the left ventricle. 
When a patient developed diseases that weakened the force of the heart muscle 
contraction then the blood will be pumped out at lower energy resulting in slower 
blood out-flow from the left ventricle. Hence the blood stay in the left ventricle at 
longer time with slower flow predisposing to clot formation. The most common 
disease that cause left ventricular thrombus is ischaemic heart disease due to 
coronary artery obstruction. The reduced or sudden interruption of blood supply will 
lead to damaged or death to the heart muscle. Other diseases are dilated 
cardiomyopathy whereby the heart chambers become enlarged to the extent the 
muscle was stretched and loss its contractility. This disease can be  due to multiple 
causes such as valvular heart disease, stress induced, alcoholism, viral infection and  
hereditary. The thrombus or blood clot inside the heart will cause stroke if it dislodged 
from the heart muscle in the left ventricle and travel to the brain. In patients who 
just had a heart attack or heart failure symptoms, echocardiography will be done as 
early as possible to look for left ventricular thrombus or clot so that treatment with 
anticoagulants can be given urgently. 
2. 
Purpose of Study 
Current treatment for left ventricular thrombus is anti-coagulant or blood thinning 
agent known as warfarin. Recently at least three novel oral anticoagulant agents were 
introduced in the treatment of atrial fibrillation(irregular heart beats that predispose 
to stroke) and the later indication is for the treatment of pulmonary embolism and 


23 
 
deep vein thrombosis (DVT). They make the blood thin like warfarin by acting at 
different sites in the coagulation pathway. The drugs will require no blood taking for 
INR monitoring ( the measure of blood thinning level;it is compulsory when patients 
on warfarin), hence less visit and more convenience to patients. Latest studies also 
showed lesser rate of bleeding as compared to warfarin and hence relatively safer. 
One of these novel oral anticoagulant is apixaban. This study will compare apixaban 
with warfarin in terms of efficacy in reduction or resolution of left ventricle thrombus 
size as well as prevention of stroke and the side effect of bleeding.  
3. 
Qualification to Participate 
Before agreeing to participate in this study, please understand this information sheet 
carefully. Only adult patients (>18 y.o) with confirmed left ventricular thrombus by 
echocardiography will be included in the study. Then you will be assessed based on 
bleeding risk including any recent episodes of major bleeding in the last 6 months 
prior to this. If you are found to have very high bleeding risk then you will be excluded 
from this study.    
If you have had a recent coronary angioplasty with coronary stents inserted coupled 
with high bleeding risk then you are not eligible for this study. Futhermore, you are 
exluded if you just had a heart attack with unstable blood pressure and heart 
rhythym, recent large stroke, underlying advance kidney disease stage V or advance 
liver disease with tendency to bleed. Lastly, if you have had pacemaker inserted or 
prosthetic valve(s) inserted then you are also not eligible to participate.  
Information regarding this study will be given to you or your legal representative 
over telephone and written consent will be taken. 
4.     Study procedures 
Once the doctors discovered that you have blood clot in your heart by 
echocardiography you will be counseled on the need of urgent treatment in the 
hospital. You will be given either one of the treatment; warfarin or apixaban by 
random allocation. Once the drug is started you will be required to stay in the hospital 
until INR (2-3) is achieved if you are on warfarin but in case of you are put on 
apixaban then your length of stay in the hospital is according to the doctors that are 
treating you for the heart attack or failure. At the time of discharge you will be given 
a timetable on the return appointments for titrating warfarin dose as to maintain INR 
level of 2-3 and repeat echocardiography. There are 8 visits (week 1, 2, 3, 6, 9, 12, 
18, 24) in total in which week 6, 12 and 24 are for repeat echocardiography. You will 
have blood investigations taken on each visit for INR monitoring if you are on 
warfarin. On the hand, if you are on apixaban, the return visits are for screening of 
bleeding (hemoglobin level) as well as to check on kidney and liver function for any 
contraindications to the treatment. 


24 
 
The size of left ventricular thrombus will be measured on every echocardiography 
visit. In case of the total resolution of the thrombus happened on any of the visit, 
your drug will be continued until the next echocardiography appointment (another 6 
weeks). Maximum weeks on the drug will be 26 weeks. The duration of the study is 
24 months whereby after 24-26 weeks has elapsed, you will be followed up every 2 
months for general well being assessment. In a rare case of persistent mobile/soft 
thrombus after 26 weeks then you will be put on your current drug until the end of 
the study as long as no contraindications to it. Other medications for your current 
medical problems will be prescribed as usual for this study. Your medical records will 
be evaluated and information will be analyzed.  
5. 
Possible risks 
The risk of stroke with the use of apixaban in the left ventricular thrombus is unknown 
hence the need for this study. However based the data from atrial fibrillation 
(irregular heart beat that predispose to stroke) studies, apixaban has reduced the 
risk of stroke equal to therapeutic dose of warfarin. Patients on apixaban has lower 
risk of bleeding with the exception of the risk of gastrointestinal bleeding was 
reported slightly higher with apixaban in one study. This study will not provide you 
with an insurance cover. You will be however, closely monitored in this study as to 
lower the risk of stroke and bleeding. On every appointments you will be assessed 
by the doctors involved in this study for any medical problems and signs of bleeding 
from the gastrointestinal tract. Due to the close monitoring, blood investigations will 
be done on every visit and you will feel uncomfortable during blood taking procedure. 
Your immediate family members must be informed regarding your bleeding tendency. 
Hence, they must inform the doctors once any suspicious bleeding occurs.  
6.      Reporting Health Experiences 
If you have any injury, bad effect, or any other unusual health experience during this 
study, make sure that you immediately tell the nurse or Dr. W. Yus Haniff W. Isa 
[MMA Registration No.40454] at 097673985 ext. 6592 or 0199228373, or Dr Niny 
Hwong [No. MMC: 51933] at 09-7673000/ 012-8592892.  You can call at anytime, 
day or night, to report such health experiences. In the event of true or suspicious 
bleeding, you must stop the study drug/ warfarin and come to the cardiology clinic/ 
day care immediately during office hour if able, othewise, family members must bring 
you to the nearest hospital as soon as possible.  
7.        Participation in the study 
 
Your participation is voluntary. You may refuse to disclose any information or refuse 
to take part in this study without any penalty or loss of any benefits to which you are 
entitled for. The doctors will continue to look after your well being irrespective of your 
choice with regard to this study including if you withdraw your consent to participate 
later on. There will be no monetary rewards/ honorarium for participating in this 


25 
 
study. However all necessary requirements for procedures and transportation during 
the study duration will be provided. 
 
 
8. 
Possible benefits 
The possible benefits of this study are:- 
 
All the cost of the study drugs will be borned by the researchers. 
 
If additional investigations are required under the study, then researchers will 
assist in whatever way possible.  
 
You may be informed of all the clinical findings and investigations throughout 
this study  
 
The result of this study will hopefully benefit the future patients at large 
especially those with heart failure and left ventricular thrombus.  
 
 
9. 
Enquiries 
If you have any further questions about this study, please contact Dr W. Yus Haniff, 
MMC no: 40454, (09-7673987) or Dr Niny Hwong, MMC no: 51933 (09-7673000), 
Medical Department, Hospital Universiti Sains Malaysia, 16150 Kubang Kerian, 
Kelantan. 
If you have any questions regarding the Ethical Approval, please contact; 
 
En. Mohd Bazlan Hafidz Mukrim 
Setiausaha Jawatankuasa Etika Penyelidikan (Manusia) USM 
Pusat Inisiatif Penyelidikan -Sains Klinikal & Kesihatan 
USM Kampus Kesihatan. 
No. Tel: 09-767 2354 / 09-767 2362 
Email : bazlan@usm.my/jepem@usm.my 
 
 
10. 
Confidentiality 
Any information acquired during this study whether medically related or not, is 
confidential and would not be made public unless required by law. Data obtained from 
the study does not identify you individually. However data from the study may be 
used in future for other medically or scientifically related reasons. 
Thank You 
 
 


26 
 
 
 
Patient  Consent Form (Signature Page) 
 
 
Research Title : Apixaban versus warfarin in left ventricular thrombus: A prospective randomized 
outcome blinded study on the size reduction or resolution of left ventricular 
thrombus  
 
Researcher’s Name : Dr W. Yus Haniff W. Isa 
 
Co – Researchers    : Dr Niny Hwong Perng Ling / Dr Ng Seng Loong/  Datuk Dr. Ahmad 
Khairuddin B Mohamed Yusof/ Prof. Dato Zurkurnai Yusof/ Prof. Syed 
Hatim Noor@Nyi Nyi Naing/ Prof. Gregory Y.H. Lip. 
 
To become a part this study, you or your legal representative must sign this page 
 
By signing this page, I am confirming the following: 
 
i. 
I have read all of the information in this Patient Information and Consent Form  including any 
information regarding the risk in this study and I have had time to think about it. 
ii. 
All of my questions have been answered to my satisfaction. 
iii. 
I voluntarily agree to be part of this research study, to follow the study procedures, and to provide 
necessary information to the doctor, nurses, or other staff members, as requested. 
iv. 
I may freely choose to stop being a part of this study at anytime. 
v. 
I have received a copy of this Patient Information and Consent Form to keep for myself. 
 
 
 
Patient Name (Print or type) 
 
 
                     Patient Initials and Patient Number 
 
 
 
Patient  I.C Number (new) 
 
 
 
          Patient I.C No. (old) 
 
 
 
Signature of patient or Legal Representative 
         
          Date (ddMMyy)   
                                                                                                     (add time of day if appropriate) 
 
 
 
Name & Signature of Individual Conductiong                         Date (ddMMyy) 
Informed Consent Discussion (Print or Type) 
 
 
Name & Signature of witness  
 
                     Date (ddMMyy) 
 
Notes: All subject/patient who involved in this study will not be covered by insurance 
     Attachement S 


27 
 
 
 
Note: Circle or tick all applicable box and sections. Write down all important details. 
 Folder RN : 
Subject No: 
 
 
 
 
 
 
 
0 
0 
0 
 
 
 
For investigator use: 
Sex: 
M = 1  
F= 2 
DOB:                         Age (yr): 
<34 
1 
35-44 
2 
45-54 
3 
55-64 
4 
65-74 
5 
75> 
6 
Malay   1 
Chinese  
2 
Indian  
3 
Siamese  
4 
Others  
5 
 
Address :  
Telephone No: 
Occupation :  
Clinical Data: 
Medical 
Problems:  
DM  
1 
HPT 
2 
IHD 
3 
CRHD 
4 
AF 
5 
CKD 
6 
HPL 
7 
Other Cardiomyopathy - Specify 
8 
 
Date of LVT diagnosis/Date of 1st follow up:  
     Day 
 
    Month 
 
   Year 
 
LVT cause: 
IHD/CAD 
1 
Cardiomyopathy  2 
Other:specify 
 
3 
Symptoms  prior to 1st ECHO 
 No symptoms = 0 
With symptoms = 1 
SOB 
1 
Chest pain 
2 
Weakness/stroke 
3 
Giddiness 
4 
lethargy 
5 
Palpitation 
6 
 
 
 
 
History of bleeding  
Y=1 
N=0 
Major bleeding-state site 
Minor bleeding-state site 
HASBLED SCORE:  
Circle that aply. Then total the score. 
Maximum is 8. 
HPT (SBP>160mmHg) 
1 
Labile INRs  
Or <60% TTR 
1 
Abnormal renal function 
Creatinine > 200 mmol/L 
1 
Elderly > 65 years old 
 
 
Abnormal Liver function 
Bilirubin >2xULN, 
AST/ALT/ALP >3xULN 
1 
Drugs predispose to 
bleeding (antiplatelet, 
NSAIDs, etc.) 
1 
Stroke/TIA 
1 
Alcohol usage  
1 
Bleeding 
History/Anaemia 
1 
Total score 
 
 
Patient Data Collection Form (1)-Visit 0 


28 
 
 
Note: Circle or tick all applicable box and sections. Write down all important details.
Folder RN :                                                                                                    Subject No: 
0 
0 
0 
 
 
 
Visit No: 
Date: 
 
Hospital admission (0 =N,  1 = Y ) 
Date: 
Define the 
cause 
 
 
 
Stroke ( 0=N  , 1 = Y ) 
If Yes 
          Ischaemic  = 0 
haemorrhagic   = 1 
Bleeding ep. 1 
 
No bruising 
No bleeding 
0 
Bruising 
1 
Minor bleeding 
2 
Major bleeding 
3 
Bleeding ep. 2 
  
No bruising 
No bleeding 
0 
Bruising 
1 
Minor bleeding 
2 
Major bleeding 
3 
Current Symptoms    0=No 
1=Yes 
 
SOB 
1 
Chest pain 
2 
Weakness
/stroke 
3 
Giddiness 
4 
lethargy 
5 
lethargy 
6 
Palpitation 
6 
 
NYHA score 
 
 CCS score – if applicable 
 
EHRA score – if applicable 
 
Warfarin        ( 0=N,   1=Y )                     
Dos ____mg  OD 
INR-Achieved?         
( 0=N,       1=Y )  
INR on this visit : 
Current Medications: (Circle that apply and write dosage od/bd ) 
 B-blocker 
(0=N, 1=Y) 
Carvedilol    
(1) 
Metoprolol   
(2) 
Bisoprolol  
(3) 
Propanolol   
(4) 
_____mg OD/BD 
Digoxin  ( N = 0 ,  Y =  1) 
Amiodarone   ( N=0 , Y = 1) 
_____mg OD/BD/TDS 
CCB ( 0=N,  1=Y ) 
Diltiazem  (1) 
Verapamil  (2) 
_____mg OD/BD/TDS 
ACE            
(0=N,  1=Y) 
Ramipril (1) 
Enalapril  (2) Perindopril   (3) 
Captopril (4) 
_____mg OD/BD/TDS 
ARB 
(0=N,1=Y)  
Valsartan (1) 
Irbesartan 
(2) 
Losartan (3) 
Telmisartan (4) 
_____mg OD 
 
 
Patient Data Collection Form (2a)- NOT FOR ECHOCARDIOGRAPHER 


29 
 
Diuretic   
(0=N, 1=Y) 
Frusemide (1) 
Chlorothiazide (1) 
HCTZ   (3)        
_____mg OD/BD/TDS 
Spironolactone (4) 
 
 
Antidiabetic 
Gliclazide  
 
Metformin  
 
Short acting 
insulin 
Iong acting insulin 
Antidiabetic (fill 
in if applicable) 
 
 
 
 
Statin (0=N, 1=Y) 
 
Atorvastatin (1) 
Simvastatin (2) 
Pravastatin (3) 
_____mg OD 
Rosuvastatin (4) 
 
 
 
Anti Platlet ( 0=N, 1=Y) 
Aspirin   (1) Clopidogrel   (2) 
Ticagrelor  (3) 
_____mg OD 
Others (0=N, 1=Y) 
Isordil  (1) 
Vastarel  (2) 
Ivabradine     (3) 
_____mg OD/BD/TDS 
Others-Specify 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
BP (mmHg): 
Pulse : 
Pulse oximeter on R/A: 
Weight (kg): 
Height(cm): 
JVP raised (Y/N) 
 Lung Clear  
Crepitation level  ( R/L/Both ) 
LZ 
MZ 
UZ 
 CVS :  Gallop (Y/N) 
Abdomen :  
PR done    (Y/N)  
Malaena     (Y/N) 
Lower limbs oedema  
Y 
N 
Level of edema: 
ankle 
knee 
sacral 
Neurological examination 
Upper limbs 
normal (Y/N) 
If N specify 
Tone 
Power  
Reflex 
Coordination 
Sensation 
Lower limbs 
normal (Y/N) 
Tone 
Power  
Reflex 
Coordination 
Sensation 
If this is follow up of previous findings, please state 
whether it is improved, similar or worsening 
 
Name of physician 
 
Signature and stamp 
 
 
Patient Data Collection Form (2b)- NOT FOR ECHOCARDIOGRAPHER 


30 
 
 
Folder RN  :                                                                              Subject No: 
Visit week :  
Echo no     : 
0 
0 
0 
 
 
 
2D- TRANSTHORACIC ECHO – FIRST OPERATOR 
LVIDd (cm) 
 
LVIDs (cm) 
CO(L/min)= 
EF ( simpson method) 
 
SV(cc) = [LVOT(cm)]2 x 0.785= 
LV aneurysm 
( 0=N, 1=Y) 
LVOT Pg(mmHg)= 
RMWA   
( 0=N, 1=Y) 
TEI index= AVCO-LVET/LVET= 
Area of hypokinetic 
 
Pericardial effusion 
( 0=N, 1=Y) 
measurement 
 
A0: PA 
 
 
 
MR ( 0=N, 1=Y) 
 
TR ( 0=N, 1=Y) 
 
Max PG: 
AR ( 0=N, 1=Y) 
 
P1/2=  
AS ( 0=N, 1=Y) 
 
Mean PG: 
SEC ( 0=N, 1=Y) 
SEC score 
0     
1 
2 
3 
4 
Comments:  
LV Thrombus 
present 
( 0=N, 1=Y) 
Size in cm2 
 
Type of Thrombus 
Mural/sesile 
Protruding 
pedunculated 
Mobile  
( 0=N, 1=Y) 
 
 
Organized? 
( 0=N, 1=Y) 
Note: It is described as fixed or flatter thrombus with area of 
calcifications,  homogenous echogenicity with no area of 
echolucency and high acoustic impedance on the outer layer 
(Delewi R 2012; Haugland JM 1984; Ports TA 1978) 
Final impression: 
Name of operator:                                                                  
Signature: 
Official stamp: 
Patient Data Collection Form (3) - TTE 


31 
 
Folder RN  :                                                                              Subject 
No: 
Visit week :  
Echo no     : 
0 
0 
0 
 
 
 
2D- TRANSTHORACIC ECHO – SECOND OPERATOR 
LVIDd (cm) 
 
LVIDs (cm) 
CO(L/min)= 
EF ( simpson 
method) 
 
SV(cc) = [LVOT(cm)]2 x 0.785= 
LV aneurysm 
( 0=N, 1=Y) 
LVOT Pg(mmHg)= 
RMWA   
( 0=N, 1=Y) 
TEI index= AVCO-LVET/LVET= 
Area of hypokinetic 
 
Pericardial effusion 
( 0=N, 1=Y) 
measurement 
 
A0: PA 
 
 
 
MR ( 0=N, 1=Y) 
 
TR ( 0=N, 1=Y) 
 
Max PG: 
AR ( 0=N, 1=Y) 
 
P1/2=  
AS ( 0=N, 1=Y) 
 
Mean PG: 
SEC ( 0=N, 1=Y) 
SEC score 
0     
1 
2 
3 
4 
Comments:  
LV Thrombus 
present 
( 0=N, 1=Y) 
Size in cm2 
 
Type of Thrombus 
Mural/sesile 
Protruding 
pedunculated 
Mobile  
( 0=N, 1=Y) 
 
 
Organized? 
( 0=N, 1= 
Note: It is described as fixed or flatter thrombus with area of 
calcifications,  homogenous echogenicity with no area of 
echolucency and high acoustic impedance on the outer layer 
(Delewi R 2012; Haugland JM 1984; Ports TA 1978) 
Final impression: 
Name of operator:                                                                          
Signature: 
Official stamp: 


32