Clinical trial NCT04173429
Conditions: Liver Cirrhosis Portal Vein Thrombosis
Keywords: Portal vein thrombosis Nadroparin calcium Warfarin Anticoagulation
Sponsor: Qilu Hospital of Shandong University
Start date: 2017-01-01; Completion date: 2020-01-31
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is aimed at evaluating the efficacy and safety of anticoagulant therapy with nadroparin calcium and warfarin in patients with portal vein thrombosis (PVT).

Detailed description:
Portal vein thrombosis (PVT) is a frequent complication of liver cirrhosis, referred to partial or complete thrombosis formed in the lumen of portal vein or/and branches of it. Currently, clinical guidelines of PVT in cirrhotic patients has not been addressed, and anticoagulant therapy of PVT patients with cirrhosis remains controversial. Although numerable studies have reported that anticoagulation therapy is effective, while a majority of them were respective and a few took control into consideration. In addition, no agreement has reached about the safety of anticoagulation. So, the efficacy and safety of anticoagulant therapy needs more prospective randomized controlled trial to be investigated.

Arms: arm 1: nadroparin calcium every 12 hours for 1 month followed by an oral administration of warfarin for 5 months arm 2: No anticoagulation therapy.
Interventions: intervention 1: Nadroparin calcium, warfarin
Intervention descriptions: intervention 1: Nadroparin calcium subcutaneously every 12hs for 1 months followed by warfarin orally for 5 months. INR(international normalized ratio ) was detected every 3-4 days and adjusted carefully by 0.75mg dosage until achieve the target level of 2-3.

Protocol documents:
Prot_000.pdf: 
Title :Efficacy and Safety of Nadroparin Calcium-Warfarin Sequential 
Anticoagulation in Portal Vein Thrombosis in Cirrhotic Patients：A 
Randomized Controlled Trial 
NCT number: NCT04173429 
Date of the Document:2020-7-3 
 
 


Study Protocol 
All patients admitted at the Gastroenterology Department of the Qilu Hospital of 
Shandong University in China, who were diagnosed with PVT, were prospectively and 
consecutively evaluated in this study. The inclusion criteria were the following: age 
between 18 and 75 years, liver cirrhosis diagnosis based on clinical, laboratory and 
imaging studies, PVT diagnosed by abdominal contrast-enhanced computed 
tomography (CT), contrast-enhanced magnetic resonance imaging (MRI) or portal 
angiography. The exclusion criteria were the following: cavernous transformation of 
the portal vein, uncontrolled active bleeding, platelet count lower than 10*10^9/L, 
creatinine more than 170 mol/L, ongoing or received antithrombotic/thrombolytic 
treatment, primary thrombophilia, Budd-Chiari syndrome, pregnancy or breast-feeding 
period, severe cardiopulmonary diseases, severe systemic infection or sepsis, and 
inability to sign the informed consent.  
Eligible patients were randomly divided into two equal groups: NWS therapy 
group and control group. Randomization was performed using a computer-based 
random number table procedure. Randomly generated serial numbers were placed in 
opaque envelopes. Patients and clinicians carrying out the interventions were not 
blinded, while clinicians performing the imaging assessments and data analysis were 
blinded to the group allocation and patients’ coded data. 
Procedure 
The NWS therapy group received a subcutaneous injection of nadroparin calcium 
every 12 h for 1 month followed by an oral administration of warfarin for 5 months. 


Warfarin was started at least 5 days before nadroparin calcium was stopped. 
International normalized ratio (INR) was monitored every 3-4 days and the daily dose 
of warfarin was carefully adjusted by the increase or decrease of 0.75 mg until the INR 
target level of 2-3 was achieved. Patients in the control group did not receive any 
anticoagulation treatment. 
All patients underwent gastroscope to evaluate the degree of varices and received 
endoscopic ligation or sclerotherapy if necessary. Patients in the NWS therapy group 
initiated the anticoagulation therapy after endoscopic therapy.  
Imaging studies 
PVT assessed by imaging examination appears as the absence of flow in part or 
all the lumen of the splenoportomesenteric axis, including portal vein trunk and 
branches, SV or SMV, with the presence of solid material in the vein. The degree 
(partial occlusion or complete occlusion) and extension (portal vein only or extension 
into the SV and/or SMV) of PVT were also evaluated in all the enrolled patients at 
admission by upper abdominal contrast-enhanced CT or MRI or portal angiography. 
The assessments of thrombosis were based on a published study(22). For each venous 
segment, the vein and residual patent lumen were outlined at the level of the maximum 
thrombosis. Total lumen area and patent lumen area were calculated with commercially 
available software. The degree of thrombus occlusion was estimated as a percentage by 
thrombosis area/total lumen area×100%(22). The extension of thrombosis was referred 
to the involved segments of the portal vein system, regardless of whether thrombosis 
was formed in the portal vein only or extended into the SMV and/or SV(23, 24). 


Complete and partial thrombosis were defined as equal or greater than 90% and less 
than 90% thrombotic material presence within vessels, respectively. Although the 
imaging assessments were performed by a single reader, the bias is minimized as the 
calculated assessments are objective. 
Follow-up 
Follow-up visits were scheduled at the 0th and 6th month, and included clinical, 
laboratory and imaging evaluation. The follow-up started at the diagnosis of PVT, 
defined as starting on the date of the first radiological imaging documenting PVT, and 
stopped in January 2020 or the day of death or the date of the last visit at 6th month. 
Liver function and cirrhosis severity were assessed by Child-Pugh score and the Model 
for end-stage liver disease (MELD) score respectively at the 0th and 6th month.  
Bleeding episodes were assessed every month by phone call. Once a severe 
bleeding episode occurred, the anticoagulation treatment was stopped immediately and 
endoscopic therapy was performed if necessary.  
Outcomes and definitions 
The primary outcome was the overall recanalization rate, both complete and partial. 
The secondary outcomes were bleeding rates, consisting of rates of hematemesis, 
melena, epistaxis, injection-site hemorrhage and other bleeding events.  
Portal vein recanalization was evaluated on the basis of imaging examination. 
Complete recanalization was referred to the complete disappearance of the thrombus in 
the portal vein trunk, at least one of the two intrahepatic portal vein branches, SMV and 
SV. Partial recanalization was defined as a more than 50% reduction of the thrombus, 


with the thrombus not extending to other veins. No response or stable thrombosis was 
defined when the thrombus maintained the same dimension, or achieved a less than 50% 
decrease or less than 30% increase on cross section. Progression was defined as more 
than 30% increase of the thrombus than before or thrombus extended to unaffected 
segments of the splenoportomesenteric axis (Fig. 1). 
Group size calculation 
The overall recanalization rate of the PVT at the 6th month was chosen as the 
primary outcome to calculate the size of the groups. Based on previous studies (25), 
assuming a 30% difference in the overall recanalization of PVT at 6th month between 
the anticoagulation (70%) and control group (40%), 5% α and 20% β error, 27 patients 
were needed in each group. Considering a 10% dropout rate, 30 patients should be 
included in each group. 
 

SAP_001.pdf: 
Title :Efficacy and Safety of Nadroparin Calcium-Warfarin Sequential 
Anticoagulation in Portal Vein Thrombosis in Cirrhotic Patients：A 
Randomized Controlled Trial 
NCT number: NCT04173429 
Date of the Document:2020-7-3 
 
 


Statistical Analysis Plan 
Statistical analysis was performed using the statistical software IBM SPSS 
Statistical 24.0. The analysis of the outcomes between NWS therapy group and control 
group was conducted by both intention-to-treat (ITT) and per-protocol (PP) analysis. 
All eligible patients were analyzed by ITT analysis, and patients who did not violate 
the protocol were analyzed by PP analysis. 
Quantitative variables were expressed as the mean ± standard deviation (SD), 
while qualitative variables were expressed as percentages. Quantitative variables were 
compared using Student’s t-test or Wilcoxon-rank sums test, and categorical variables 
were compared using chi-squares or Fisher’s exact test, as appropriate. Univariate and 
multivariate logistic regression analysis were performed to find significant end point 
predictors for recanalization. A two-tailed p-value <0.05 was considered statistically 
significant.