Clinical trial NCT02504723
Conditions: Esophageal and Gastric Varices
Keywords: Gastric varices cyanoacrylate carvedilol
Sponsor: Kaohsiung Veterans General Hospital.
Start date: 2011-12-01; Completion date: 2017-02-01
Enrollment: 121 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Gastric variceal obturation is the current endoscopic therapy of choice for gastric variceal bleeding but is associated with a high rebleeding rate. Carvedilol is a potent non-selective β-blocker. The role of carvedilol in the prevention of recurrent gastric variceal bleeding is not studied. This study aimed at evaluating the efficacy of carvedilol as an adjunct to gastric variceal obturation in the secondary prophylaxis of gastric variceal bleeding.

Detailed description:
Gastric variceal bleeding is a lethal complication of portal hypertension. The rebleeding rate ranged between 30% to 50% in patients after initial hemostasis. Endoscopic cyanoacrylate injection is currently the choice of endoscopic therapy of acute gastric variceal bleeding and prevention of recurrent bleeding. However, the rebleeding rate is still high in the patients undergoing repeated endoscopic cyanoacrylate injection.

Non-selective β-blockers are frequently used for the secondary prophylaxis of variceal bleeding. In the case of esophageal varices, combination of non-selective β-blockers and endoscopic therapy significantly lowers the rebleeding rate compared with endoscopic therapy alone. However, propranolol failed to decrease the rebleeding rate as an adjunct to endoscopic cyanoacrylate injection and was associated with a higher incidence of adverse effects in gastric variceal bleeding patients. A more potent non-selective β-blocker than propranolol might further decrease portal pressure and decrease the rebleeding rate.

Carvedilol is a potent non-selective β-blocker with both beta and alpha-1 blocker effect. It significantly lowers portal pressure even in propranolol non-responders. However, it is unclear weather carvedilol will play a role in the prevention of recurrent gastric variceal bleeding. The investigators conducted a randomized controlled trial to compare the efficacy of carvedilol combined with endoscopic cyanoacrylate injection with endoscopic cyanoacrylate injection alone in secondary prophylaxis of gastric variceal bleeding.

Arms: arm 1: The patients undergo repeated endoscopic cyanoacrylate injection every 3-4 weeks until obturation of gastric varices. Oral carvedilol is administrated during the whole study period, starting at 6.25 mg daily and increased until the maximum tolerated dose. arm 2: The patients undergo repeated endoscopic cyanoacrylate injection every 3-4 weeks until obturation of gastric varices.
Interventions: intervention 1: carvedilol intervention 2: cyanoacrylate
Intervention descriptions: intervention 1: Oral carvedilol is started after randomization at an initial dose of 6.25 mg daily. Doses are increased every 3 days during the admission or every 7 days in the out-patient clinics until the maximum tolerated dose was achieved or up to 25 mg daily, aiming at reducing resting pulse rate by 25 percent but not below 55 beats per minute with systolic blood pressure \>90 mm Hg. intervention 2: The patients undergo repeated endoscopic cyanoacrylate injection every 3-4 weeks until obturation of gastric varices.

Protocol documents:
Prot_SAP_001.pdf: 
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Carvedilol as an adjunct to endoscopic cyanoacrylate injection for secondary 
prophylaxis of gastric variceal bleeding 
 
Protocol ID: VGHKS11-CT10-11 
ClinicalTrials.gov ID: NCT02504723 
 
Principle investigator: Wen-Chi Chen, MD 
Division of Gastroenterology and Hepatology, Department of Internal Medicine, 
Kaohsiung Veterans General Hospital, 
No. 386, Ta-Chung 1st. Rd., Kaohsiung City 813, Taiwan 
Tel: +886-7-3422121 ext. 2075; Fax: 886-7-3468237; Email: wcchen@vghks.gov.tw 
 
Document date: Dec. 12, 2011 


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Materials and methods 
Patients 
Cirrhotic patients presenting with acute GVB were evaluated for eligibility.  
The inclusion criteria were:  
(1) age of 20 to 80 years;  
(2) cirrhotic patients with acute GVB proven by endoscopy within 24 h of bleeding; 
(3) stable hemodynamic condition for at least 3 days after a cyanoacrylate injection. 
The exclusion criteria were:  
(1) previous treatment for gastric varices (GV), including endoscopic therapy, 
transjugular intrahepatic porto-systemic shunt (TIPSS), or shunt surgery;  
(2) contraindications to NSBBs or cyanoacrylate injection;  
(3) serum total bilirubin > 10 mg/dL;  
(4) grade III/IV hepatic encephalopathy;  
(5) hepatorenal syndrome;  
(6) severe heart failure (NYHA Fc III/IV);  
(7) chronic kidney disease under renal replacement therapy;  
(8) refractory ascites;  
(9) malignancy other than hepatocellular carcinoma;  
(10) pregnancy;  


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(11) the use of a pacemaker;  
(12) refusal to participate. 
Randomization was performed when the hemodynamic conditions were stable, 
usually 3 to 5 days after initial GVO for acute bleeding. A computer-generated 
randomization sequence in a 1:1 ratio was used for randomization. The randomization 
sequences were concealed until after the patients had given consent to participate in 
the study and the interventions had been assigned.  
The patients randomized to group A underwent repeated GVO until the varices 
were completely obturated. The patients randomized to group B received carvedilol in 
addition to repeated GVO. 
General management 
  Patients were resuscitated with red cells and crystalloid solution. Terlipressin 1 g 
q6h for 3 days was immediately started on arrival at the emergency room. 
Prophylactic antibiotics were administered for 5 days and were adjusted according to 
sensitivity tests in the patients proven to have an infection. After GVO, esomeprazole 
40 mg intravenous infusion twice daily was administrated for 2 days, and then shifted 
to oral esomeprazole 40 mg daily until the ulcers associated with GVO had 
completely healed. 
Endoscopic therapy 


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The patients underwent emergency GVO whenever possible, usually 4 to 12 hours 
after presentation. GVO was performed using an XQ-260 or H-260 endoscope 
(Olympus Optical Co. Ltd., Tokyo, Japan) and a 22-gauge disposable injection needle 
(EIS 01943, Top Co., Tokyo, Japan) with a mixture of N-butyl-2-cyanoacrylate 
(Histoacryl blue, Braun, Melsungen, Germany) and lipiodol (Guerbet Laboratory, 
Aulnay-Sous-Bris, France) in a 1:1 ratio. The maximum amount of 
N-butyl-2-cyanoacrylate injected was usually 2 mL per session. GVO was performed 
at 3- to 4-week intervals during follow-up endoscopy, with the aim of eradicating the 
GV. GV was considered to be complete obturated when a firm consistency of the 
injected GV was noted in probing with the tip of the injection needle. The patients 
then underwent endoscopic ultrasonography to evaluate the status of obturation if scar 
tissue could not be differentiated from patent GV as previously described.1 The total 
amount of N-butyl-2-cyanoacrylate and the number of treatment sessions required to 
obliterate the GV were recorded. The patients underwent follow-up endoscopy at 
6-month intervals after obturation of GV. GVO was performed if recurrent GVB was 
encountered or GV recurred. Banding ligation was performed using Saeed® 
multi-band ligators (Cook Medical, Bloomington, IN) or Speedband Superview Super 
7™ multiple band ligators (Boston Scientific, Marlborough, MA) for primary or 
secondary prophylaxis of EVB in patients with high-risk EV if they agreed. 


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Carvedilol administration 
Carvedilol was started immediately after randomization in the patients assigned to 
group B at a dose of 6.25 mg daily. Patients underwent dose escalation every 3 days 
during the admission or every 7 days in the out-patient clinics until the maximum 
tolerated dose was achieved or up to 25 mg daily, with the goal of reducing the resting 
pulse rate by 25% but not less than 55 bpm while the systolic blood pressure was 
greater than 90 mm Hg. Adherence to the regimen was carefully assessed at each 
follow-up visit by questioning the patient and his or her relatives and counting the 
tablets where possible. 
Management of rebleeding 
The patients with recurrent GVB underwent emergency GVO. Emergency 
banding ligation was performed in the patients with EVB. The patients with 
uncontrolled variceal bleeding underwent TIPSS unless otherwise contraindicated. 
 
Study end-points 
The primary end-point of this trial was the occurrence of recurrent GVB. The 
secondary end-points were recurrent upper gastrointestinal bleeding, mortality or liver 
transplantation, and adverse events associated with both therapies. 
 


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Statistical analysis 
The proposed sample size was 60 cases in each group. 
Demographic data were compared between both groups. Categorical data were 
compared using the chi-square test or Fisher’s exact test as appropriate. Continuous 
variables with normal distribution were compared using independent Student’s t-tests, 
and continuous variables without normal distribution were compared using the 
Mann-Whitney U test. Kaplan-Meier analysis was conducted to examine the time 
from enrollment to the recurrence of GVB, UGIB, and mortality. A log-rank test was 
used to examine variations between groups. Univariate and multi-variate analyses 
using Cox’s proportional hazards model were used to examine the risk factors 
associated with recurrent GVB, UGIB, and mortality. Significance was defined as 
p<0.05 for all two-tailed tests.  
 
 
 


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