An Exploratory Study of Effectiveness and Safety of Rivaroxaban in Patients With Left Ventricular Thrombus
Phase: NA
Conditions: Ventricular Mural Thrombosis
Sponsor: China National Center for Cardiovascular Diseases

 
 
 
 
 
 
An Exploratory Study of Effectiveness and Safety of Rivaroxaban in 
Patients With Left Ventricular Thrombus 
 
Study Protocol and Statistical Analysis Plan 
(Sep 10, 2020) 
 
 
 
Trial registration This study was registered at ClinicalTrials.gov as NCT 04970381. 
 
 
 
 
 
 
 
 
 
 

Study Protocol 
Study design 
This study was a prospective, single-center, open, single-arm observational clinical 
study.  
Ethics approval 
For the study, documented approval from the appropriate independent ethics 
committees/institutional review boards was obtained for the participating center before 
the start of the study according to good clinical practice and local laws, regulations, and 
organizations. 
Patient population 
Consecutive patients aged 18–75 years with left ventricular (LV) thrombus confirmed 
by surface ultrasound within three months were eligible for study participation. Major 
exclusion criteria were contraindications to anticoagulation and current anticoagulant 
therapy. Complete inclusion and exclusion criteria were listed in Table 1. 
 
 
 

Table 1 Inclusion and exclusion criteria 
Inclusion criteria 
Exclusion criteria 
Age ≥18 years old 
LV thrombus exists > 3 months (old thrombus) 
Newly found LV thrombus ≤ 3 months by surface 
ultrasound before enrollment, and the underlying 
disease was not limited 
Has contraindications to anticoagulant therapy with rivaroxaban 
The standard anticoagulation treatment < 4 weeks 
before enrollment, with no antiplatelet drugs or only a 
single antiplatelet drug 
A history of acute pulmonary embolism or deep vein thrombosis within 3 weeks, 
requiring intensive anticoagulation therapy 
Patients voluntarily join the study and sign the 
informed consent form of the study. 
A history of hemorrhagic stroke within 4 weeks; -Malignant and benign heart tumors 
Dual antiplatelet therapy such as aspirin and P2Y12 receptor antagonist or other 
antiplatelet agents must be retained 
Severe liver and kidney dysfunction, alanine aminotransferase > 3 times the upper limit 
and total bilirubin > 2 times the upper limit, creatinine clearance rate < 15ml/min/1.73m2 
A history of major bleeding, intracranial hemorrhage, or active bleeding within 1 month 
Hematological diseases, hemoglobin < 100g/L, platelets < 880×109/L 
Pregnancy status, planned pregnancy, and lactating women 
Life expectancy was less than 1 year 
Has been included in other clinical studies 
Other situations which were not suitable for participation considered by investigators 
Note: In patients with LV thrombus complicated with hemorrhagic stroke ≥ 4 weeks or recent ischemic stroke/transient ischemic attack, the 
investigators decided whether anticoagulation therapy can be given according to the specific situation.  

Study treatments 
The enrolled patients were assigned to a standard dose of rivaroxaban 20 mg qd (it can 
be reduced to 10-15 mg qd depending on the patient's condition and renal function) 
after the confirmation of LV thrombus by contrast-enhanced echocardiography. 
Study endpoints 
The primary endpoint of this study was the LV thrombus resolution rate at 12 weeks 
confirmed on contrast-enhanced echocardiography. 
The secondary endpoint events: 
1) the LV thrombus resolution rate at 6 weeks, the LV thrombus resolution or reducing 
rate at 6 weeks, the LV thrombus unchanging or increasing rate at 6 weeks, the LV 
thrombus resolution or reducing rate at 12 weeks, and the LV thrombus unchanging or 
increasing rate at 12 weeks. (disappearance of thrombus as an indicator of resolution 
rate, >15% reduction in thrombus length or thickness measured by ultrasonography as 
an indicator of reduction rate, ≤15% variation in length or thickness as an indicator 
of unchanged rate, and >15% increase in length or thickness as an indicator of 
increasing rate) 
2) incidence of the composite of stroke, systemic embolism, myocardial infarction,and  
cardiovascular death during follow-up 
3) major bleeding according to the International Society on Thrombosis and 
Haemostasis [ISTH] criteria and clinically related non-major hemorrhage events during 
follow-up. 
An adverse event was any adverse medical event, including an exacerbation of a pre-
existing condition or abnormal laboratory findings on clinical examination of a subject 
on medication, which was not necessarily related to such treatment. A serious adverse 
event can be fatal, life-threatening, requiring hospitalization or prolongation of an 
ongoing hospital stay, resulting in persistent or significant disability/incapacity, and it 
was any adverse medical event that represents a significant risk of congenital 

anomalies/birth defects and/or other clinically significant serious events. 
Study procedures 
First of all, for patients with LV thrombus (regardless of the type of fundamental disease) 
confirmed by surface ultrasound within three months, who met the inclusion criteria 
and did not meet the exclusion criteria, informed consent was signed. Blood routine, 
biochemical and coagulation tests were required to complete, and baseline contrast-
enhanced echocardiography was evaluated. Secondly, a standard dose of rivaroxaban 
20 mg qd (it can be reduced to 10-15 mg qd depending on the patient's condition and 
renal function) was administered to the enrolled patients. Then, at 6 and 12 weeks, 
hematological parameters such as routine blood tests, liver and kidney function, 
coagulation, and other hematological parameters were re-examined. At the same time, 
contrast-enhanced echocardiography was also performed and thrombus size, 
anticoagulant use, and endpoint events were documented as well. After 12 weeks, the 
investigator decided on the follow-up treatment plan according to the patient's condition. 
Clinic or telephone follow-up visits were conducted at 6 months to collect events and 
anticoagulant use. During the entire study, patients were educated about anticoagulation 
and bleeding observation, informed about the importance of maintaining treatment 
compliance and notified about the management of bleeding in the presence of bleeding 
according to the EHRA 2018 NOACs clinical guidelines.  
 
 

Statistics Analysis Plan 
Patients who received at least one dose of rivaroxaban were included in the safety set 
population. Patients who completed treatment and follow-up visits were included in the 
primary analysis set which was used for evaluating efficacy outcomes.  
Normally distributed continuous data were presented as mean and standard deviation 
(SD) while non-normally distributed continuous data by the median and interquartile 
range (IQR), and the dichotomous data were computed using frequency and percentage. 
The rates and their 95% confidence intervals (CIs) were calculated for the primary 
endpoint and the secondary endpoints. The hazard ratio (HR)was estimated with or 
without adjustment for covariates using Cox regression models. Significant variables 
in the univariate analysis and other variables of interest were included in the subgroups 
to investigate the potential influences on the resolution of the thrombus, where 
continuous variables were dichotomized based on the median value. A forest plot was 
created to display subgroup analysis. To test for changes in diffusion data across 
different time points of thrombus resolved vs. thrombus unresolved (including reduced, 
unchanged, and enlarged thrombus), linear mixed models were tested using the lme 
function in R. To investigate any significant interactions in more detail, we then ran 
corresponding pairwise comparisons using the emmeans function in R. Comparisons 
were regarded as two-sided, and statistical significance was determined by the P value 
of 0.05. All analyses were scheduled for completion with R version 3.5.1 (The R Project 
for Statistical Computing, Vienna, Austria).