Clinical trial NCT03155256: Treatment of Gastric Varices Using EUS Guided Techniques
Official title: Comparative EUS Guided Techniques in Treatment of Gastric Varice: a Prospective, Ranzomized Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Gastric Varix
Keywords: EUS, cyanoacrylate, coils, gastric varices
Lead sponsor: Instituto Ecuatoriano de Enfermedades Digestivas
Sponsor class: OTHER
First posted: 2017-05-16
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Bleeding from gastric varices (GV) is associated with high mortality. Injection of cyanoacrylate (CYA) using standard gastroscopes has demonstrated higher hemostasis and lower rebleeding rates compared to band ligation or sclerotherapy. Nevertheless CYA treatment is known to be associated with significant adverse events. Pulmonary embolism due to CYA injection is a serious and sometimes fatal complication of this therapy. Romero-Garcia et al. recently showed that, even these patients usually have respiratory symptom, this complication can be present in asymptomatic patients and with only CT pathological images showing it. On the other hand, risk of glue embolism, has been described to be dependent on the volume of CYA injected, being significantly greater with high volume. Other complications related to CYA injection are, hemorrhage from post injection ulcers, fever, peritonitis, needle impaction, and even death. Also the injection material can cause serious damage to the endoscope.

Currently endoscopic treatments are CYA injection under direct visualization using a standard gastroscope and treatment under EUS guidance with injection of CYA, coils or both. However, to date, it is unknown whether one of these techniques is technically more feasible or causes less adverse events than the other.

Treatment under EUS guidance may improve results because of precise targeting of the varix lumen or afferent feeding veins. This allows the vein to be obstructed with a small amount of CYA, less than used for the "blind" injection of GV with standard endoscopic technique and may reduce the risk of glue embolism. EUS can confirm varix obliteration by using Doppler. Also visualization of GV by using EUS is not impaired by blood or food in the stomach and thus can be performed in the setting of active hemorrhage.

Detailed description: Coils that are currently used for intravascular embolization treatments can be delivered under EUS guidance offering a new treatment approach. Romero-Castro et al. previously reported a case series by using up to 20 coils to eradicate gastric fundic varices (GFV) in 4 patients, with a 75% success rate. More recently this author compared in a multicenter study the treatment of GFV using EUS guide injection of N-butyl cyanocryloate with Lipiodol vs. EUS guide injection of coils alone. Both techniques had excellent results with GFV obliteration rate of 94.7% and 90.9% respectively. However 47.4% of the patients in the CYA group required more than one session and 36.4% in the coil group either required additional coil or CYA placement. There was a significant difference in the overall adverse event rate between CYA group (57.9%) and coil group (9.1%), due to glue pulmonary embolism.

Coils in conjunction with CYA injection may reduce or eliminate the risk of glue embolization. Coils with attached synthetic fibers ("wool coils") may function as a scaffold to retain CYA within the varix and may decrease the amount of glue injection needed to achieve obliteration. Binmoeller et al. described them 6 years experience in 152 patients with GFV treated with 2-octyl cyanocrylate plus coils. Patients had active hemorrhage (5%), recent bleeding (69%) or were treated for primary prophylaxis (26%). Treatment was technically successful in 151 patients (\>99%), with mean number of coils of 1.4 and mean volume of CYA of 2 ml. Follow-up was possible in 125/151 patients (100 using EUS examinations and 25 with clinical and/or EGD follow-up). Complete obliteration was confirmed with EUS-Doppler image in 93/100 (93%). Post-treatment bleeding occurred in 20 of 125 patients (16%) and only 10 (50%) where GFV related bleeding. Mild post procedure abdominal pain occurred in 4 of 125 patients (3%), and clinical signs of pulmonary embolization were seen in 1 patient (1%). Another 4 of 125 patients (3%) presented with minor delayed upper GI bleeding from coil/glue extrusion.

The aim of this study is to describe and compared efficacy and safety two different EUS guided techniques for GFV treatment (Coils + CYA vs. Coils alone). Efficacy will be measure by technical success defined as successful technique performance and functional success defined as complete obliteration of the varix and absence of Doppler flow on EUS. Safety will be determinated by measure of adverse events related to the procedure or gastric varices within and after 30 days of the procedure.

METHODS Setting: Instituto Ecuatoriano de Enfermedades Digestivas (IECED), OmniHospital Academic Tertiary Center. Patients will be included from March 2016 to June 2017. The study protocol and consent form has been approved by the Institutional Review Board and will be conducted according to the declaration of Helsinki. Patients will sign an informed consent.

All procedures will be performed in a hospital-based interventional endoscopy suite, where fluoroscopy is available, by one endoscopist (C.R.M). Procedures will be performed under general anesthesia and under antibiotics prophylactic. After the procedure, patients will be observed for 2 hours in the recovery room before being discharged. Follow up will be performed by standard endoscopy and EUS at 3 and 6 months post procedure. Hemostasis, early post treatment bleeding and late post treatment bleeding will be considered according Baveno VI concensus. Complete obliteration of the varix will be defined as absence of Doppler flow on EUS.

EUS will be performed using a 3.8 mm working channel linear-array therapeutic echoendoscopes (EG 3870UTK; Pentax, Hamburg, Germany), attached to an US console (Avius Hitachi, Tokyo, Japan). Active flow within GFV will be confirmed by color Doppler before and after therapy.

Endoscopic Procedure: First a standard diagnostic upper endoscopy will be performed in order to classify the varices according to the classification of Sarin and Kumar. As mentioned before only GOV II and IGV I varices will be included. Once the patient is conceder a candidate will be randomized to be treated with Coils plus CYA (Group A) or only Coils (Group B). Then the echoendoscope will be positioned in the distal esophagus (anterograde trans-esophageal, transcrural approach) or in the gastric fundus (trans-gastric approach) to visualize the gastric fundus, intramural varices and feeder vessels. The trans-esophageal approach will be preferred between both approaches. Once positioned, water will be instilled in order to fill the gastric fundus, improved acoustic coupling and visualization of GFV. EUS color Doppler imaging will be used to allow direct visualization of the varices flow. Then a 19G EUS-FNA needle (Expect flexible; Boston Scientific, USA) will be used to puncture the vessel, the stylet will be withdrawn and a syringe with negative pressure will be used to evaluate blood return and therefore intravascular location. After this 1 ml of saline solution will be instilled to prevent blood clotting in the needle light and then 2 ml of water-soluble contrast (Ultravist, Bayer, Ecuador), under fluoroscopy evaluation, will be used in order to ensure intravascular location and varix flow direction (afferent or efferent). If the patient is on Group A coils and then 2-Octyl-CYA will be injected, and if it is on group B only coils will be injected into the varix. The coils used will be intravascular embolization coils (10-16 mm coiled diameter, 12-20 cm straight lengths, 0.035 inches in diameter, Nester Embolization Coil; Cook Medical) and will be delivered into the vessel through the FNA needle using a 0.035-inch hydrophilic guidewire as a pusher. Special attention will be paid to not place the needle tip at the counter wall because of the risk of perforation, bleed, coils extrusion and to allow enough space for the coil to curl. The 2-Octyl-CYA (Dermabond; Ethicon, Piscataway, NJ) will be injected using the same needle and then 1 mL of normal saline solution to flush the glue completely through the catheter. The diameter and number of coils (10 to 16 mm) and the volume of 2-Octyl-CYA injected will be calculated according to the diameter of the vessel measured on EUS. After 15 to 30 seconds once the CYA is solidified and the risk of bleeding by puncturing decreases, the needle will be withdrawn. Finally obliteration of the vessel will be evaluated using Doppler imaging 5 minutes later.

The 2-octyl-CYA compared to the N-butyl-CYA, for the treatment of GV, has demonstrated similar efficacy for hemostasis and prevention of recurrent bleeding. It has a longer polymerization time, thus it does not need to be diluted with Lipiodol (which is viscous and makes injection more difficult). Also allows a longer injection time and reduced risk of damage to the endoscope by glue impaction of the working channel. Lipiodol enable fluoroscopic visualization of the injected vessel and confirmation that the feeder vessel had been accurately targeted. Also it is useful to identify an asymptomatic pulmonary embolism on an X-ray. However it can be replaced with water-soluble contrast to evaluate the varix. On the other hand glue embolization has only been reported immediately after injection, so if there are any suspicion of embolism because a high dose injected of CYA, in a asymptomatic patient, a CT can be performed in order to confirm it.

Statistical analysis: Baseline characteristics will be compared between the two group using Chi-square o Fisher Test for categorical variable, and for continuing variables, we will use the Mann-Whitney Test. Diagnosis efficacy will be measured thought sensitive, specificity and accuracy. All the statistical analysis will be performed using SPSS software suite v.22.

Limitations: It is a simple blind study, performed in a single center by one endoscopist

Eligibility criteria: Inclusion Criteria:

* Above 18 years old patients
* Who agree to participate in the study
* Proven GV (GOV II or IGV I) on initial standard diagnostic upper endoscopy
* Active bleeding, history of previous bleeding (secondary prophylaxis) and primary prophylaxis
* Patient preference for EUS-guided therapy

Exclusion Criteria:

* Inability to provide informed consent for the procedure
* Concurrent hepato-renal syndrome and/or multi-organ failure
* Pregnancy
* Platelet count less than 50,000/ml or International Normalized Rate (INR) \>2
* Esophageal stricture
* Splenic or Portal vein thrombosis because an increase risk of failure

Primary outcomes:
measure: Efficacy of EUS guided techniques (Coils + CYA vs Coils alone) for GFV treatment
timeFrame: 12 month
Secondary outcomes:
measure: Safety of EUS guided techniques (Coils + CYA vs Coils alone) for GFV treatment
timeFrame: 12 month
Other outcomes:
Locations:
city: Guayaquil
country: Ecuador
facility: Ecuadorian Institute of Digestive Diseases, Omnihospital
state: Guayas
Study officials:
affiliation: Ecuadorian Institute of Digestive Diseases
name: Carlos A Robles-medranda, MD
role: PRINCIPAL_INVESTIGATOR
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