Abstract
Purpose: To evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) combined with gastric coronary vein embolization (GCVE) for cirrhotic portal hypertensive variceal bleeding and compare outcomes of first-line with second-line treatment, coil with glue, and single-covered with double stents.
Methods: Fifteen patients received TIPS plus GCVE as the first-line treatment for secondary prophylaxis of variceal bleeding, and 45 received it as second-line treatment. Preoperative and postoperative quantitative variables were compared using a paired t test. The incidence of survival rate, re-bleeding, hepatic encephalopathy, and shunt dysfunction were analyzed using the Kaplan-Meier method.
Results: The portal venous pressure was significantly decreased from 39.0 ± 5.0 mm Hg to 22.5 ± 4.4 mm Hg (P≤0.001) after TIPS treatment. After 1, 3, 6, 12, 18, and 24 months re-bleeding rates were 1.6%, 3.3%, 6.6%, 13.3%, 0%, and 0%, respectively. Shunt dysfunction rates were 5%, 0%, 10%, 16.6%, 1.6%, and 5%, respectively. Hepatic encephalopathy rates were 3.3%, 1.6%, 3.3%, 6.6%, 0%, and 0%, respectively. And survival rates were 100%, 100%, 100%, 96.6%, 93.3%, and 88.3% respectively. In comparative analysis, statistically significant differences were seen in re-bleeding between the first-line and second-line treatment groups (26.6% vs 24.4%, log-rank P=0.012), and survival rates between single-covered and double stent (3.7% vs 16.1%, log-rang (P=0.043).
Conclusion: The results suggest that TIPS combined with GCVE is effective and safer in the treatment of cirrhotic portal hypertensive variceal bleeding. The use of TIP plus GCVE as first-line treatment, may be preferable for high-risk re-bleeding, and more than 25 mm Hg portal venous pressure with repeated variceal bleeding. However, the sample size was small. Therefore, large, randomized, controlled, multidisciplinary center studies are needed for further evaluation.
- Cirrhotic portal hypertension
- Esophageal Variceal bleeding
- Gastric coronary vein embolization
- Gastric Variceal bleeding
- Transjugular intrahepatic portosystemic shunt
Transjugular intrahepatic portosystemic shunt (TIPS) is an established and minimally invasive procedure for treatment of the complications of cirrhotic portal hypertension such as esophageal and gastric variceal bleeding and refractory ascites.1,2 TIPS significantly reduces portal venous pressure through the placement of an artificial stent from the portal vein to the hepatic vein. The patency of shunts has greatly improved since the adoption of dedicated polytetrafluoroethylene stents.3,4 The first case of a TIPS using a bare-metallic stent on a human was published in 1989 in a patient with Child-Pugh ‘C’ alcoholic cirrhosis with recurrent esophageal variceal bleeding.5 However, the bare stent has poor prognosis with high shunt dysfunction, pseudointimal hyperplasia, and leakage of the bile duct that transected into the lumen shunt.4,6
TIPS can significantly decrease the level of the portal pressure gradient (PPG), but it is only considered a treatment choice after failed first-line treatment.7,8 For those patients with a portal venous pressure ≥25 mmHg or at high-risk of the first-line treatment failure and mortality, the primary goal is to reduce the level of portal venous pressure, which indicate TIPS can be applied as a first-line treatment to prevent further life-threatening conditions.9,10 Previous studies have reported TIPS combined with variceal vein embolization is more effective for recurrent variceal bleeding and can improve liver function.11,12 Gastric coronary vein embolization (GCVE) has been approved as an effective and supportive method for control of esophageal and gastric variceal bleeding.13
Most studies have focused on the use of TIPS as a treatment for recurrent variceal bleeding when pharmacological and endoscopic treatment failed to prevent recurrent variceal bleeding.14,15 However, in this study, 15 cases (PPG ≥25 mmHg or at a high risk of re-bleeding, severe bleeding) were treated with TIPS and GCVE as the first-line treatment for variceal bleeding;10 45 cases were treated with TIPS plus GCVE as a secondary prophylaxis for recurrent bleeding after the primary treatment. The aim of this study was to evaluate the efficacy and safety of TIPS with GCVE in cirrhotic portal hypertensive variceal bleeding. Additionally, we compared outcomes of first-line with second-line treatment, spring coil with glue embolized of gastric coronary vein and between single covered stent and double stents respectively.
Materials and Methods
Patients
This study was approved by the Medical Ethics Committee of the First Affiliated Hospital (No. 2019-KY-397), and informed consent was waived. We conducted a retrospective study based on patients with cirrhotic portal hypertension accompanied with esophageal and gastric variceal bleeding who underwent TIPS plus GCVE treatment from January 2015 to August 2018 at the First Affiliated Hospital. The inclusion criteria were the chief complain of esophageal and gastric variceal bleeding caused by cirrhotic portal hypertension (based on clinical, radiological, endoscopic, liver function test, and histological findings), no contraindications for TIPS plus GCVE treatment, and variceal bleeding treated with embolic agents during the TIPS procedure in our department. Exclusion criteria were patients without variceal bleeding, portal vein thrombosis, Budd-Chiari syndrome, chronic renal failure, coagulation disorder, and variceal bleeding treated with embolic agents before or after TIPS procedure in our department or other departments. The final population for this study included 60 patients (41 males and 19 females, age 15–72 years; mean age of 52.7 ± 11.0 years). The basic clinical characteristics are presented in Table 1.
General Characteristics
After applying inclusion and exclusion criteria according to the study, 60 patients were enrolled, and they were assigned to two groups. One group (of 15 patients) had been treated with TIPS as first-line treatment, and had been admitted in our department after a first episode of variceal bleeding with >25 mmHg hepatic venous pressure gradient or active variceal bleeding with Child-Pugh B or C, or high-risk chance of treatment failure with pharmacological and endoscopic therapy.10 The other group (of 45 patients) had been treated with TIPS as a second-line treatment after failure of pharmacological or endoscopic therapy or both to control variceal re-bleeding.10 In this group, 31 patients had double stents, and 27 had single-covered stents; 39 patients had different size of coils, and 21 patients had glue embolic agent. The primary end point was survival rate at 1 and 2 years; re-bleeding, shunt dysfunctions, and hepatic encephalopathy at 2 years were the secondary end points.
Preoperative Management
Before undergoing TIPS plus GCVE, all patients obtained contrast enhancement multiphase computed tomography (CT), contrast enhancement magnetic resonance imaging, ultrasonography, liver function test, kidney function test, coagulation function test, routine blood test, history, and physical examination. We evaluated for adequate monitoring of records, history of hepatic encephalopathy, and history of blood loss. Abdominal three-dimensional angiograms reconstructed via CT were obtained to determine the anatomic position of hepatic and portal veins. Child-Pugh class/scores were calculated for cases with known severity of liver cirrhosis. All patients received intravenous prophylactic antibiotics 30 minutes before the start of the procedure.
TIPS plus GCVE Procedure
All patients underwent indirect portal vein angiography and TIPS plus GCVE under local anesthesia. The procedure of TIPS plus GCVE has been described previously,9,11,12 and indicated by TIPS practice criteria.2,16,17 All procedures were performed by two interventional radiologists. Simply, after routine disinfection with betadine solution (7.5% povidone-iodine) and local anesthesia (5ml lidocaine 2%) injected into the puncture site, the right femoral artery was punctured with 18 G needle (Seldinger technique), and a 5F vascular sheath was introduced through the sheath. A 0.035-inch hydrophilic membrane guide wire was introduced into the superior mesenteric artery for anteroposterior and lateral indirect portography to confirm the shape of the portal vein. The right internal jugular vein was then punctured by the same method as above, and a 0.035-inch hydrophilic membrane guide wire and Rosch-Uchida transjugular liver access set (RUPS-100) were introduced into the right hepatic vein or middle hepatic vein. The left portal vein or right portal vein was then punctured successfully after the angle of intrahepatic was adjusted.
Next, the puncture needle was withdrawn and catheter and guide wire were introduced into the distal or proximal end of the splenic vein through the outer sheath tube and then connected with high pressure syringe angiography to evaluate the gastric coronary vein and collateral veins. The angiography showed that the gastric coronary vein originated from the proximal or distal end of splenic vein or portal vein. The diameter of the collateral vein or variceal vein was obviously thickened or curved and extended into the fundus of the stomach or the esophagus. The pre-shunt as well as, right atrial and portal venous pressures were measured.
A 5F snake catheter was next applied for super selective angiography of gastric coronary vein and a Cook macro catheter was introduced through the catheter into the variceal vein for embolization with different sizes of spring coil or cyanoacrylate (glue) plus iodized oil. After embolizing the variceal vein, we confirmed the results by repeated angiography. An Amplatz guide wire was then introduced into parenchyma track and a 6mm to 8mm × 6cm to 8cm balloon catheter was introduced through guide wire to dilate the intrahepatic track. A 7mm to 9mm × 4cm to 10cm stent (Luminexx + Fluency, Fluency, Viatorr, Astron, BARD, and Bare) was placed successfully between the hepatic vein and the portal vein, and the intrahepatic shunt was dilated with a 4mm to 8mm × 4cm to 8cm balloon catheter. Stent position was confirmed by angiography, and contrast medium flowed back into the right atrium smoothly through the intrahepatic shunt. Post-shunt, atrial, and portal pressures were measured, and the instruments were then withdrawn, and the punctured site was blocked with Starclose or Exoseal or gauze pieces with compressed bandage.
Postoperative Management
All patients were hospitalized until they were stable after the TIPC plus GCVE procedure. Vital signs, abnormal pain, consciousness, and gastrointestinal bleeding were monitored, and routine laboratory work was performed. Patients were treated with analgesics, anti-coagulation drugs, and a liver-protective diet with strategies for prevention of hepatic encephalopathy.
Follow-up
All patients were informed and invited to enroll in the follow-up protocol with color doppler ultrasound, CT angiography, liver function test, renal function test, blood coagulation function test, and blood ammonia test at 1, 3, 6, and 12 months after the TIPS procedure and then every 6 months thereafter (Supplementary Table 1, available online). TIPS-related complications included re-bleeding, hepatic encephalopathy, and shunt dysfunction. Laboratory examinations, portal vein pressure, and death were recorded respectively. A digital subtraction angiography examination was performed with Doppler ultrasound when CT suggested stenosis or occlusion in stents, including in patients with chief complaint of re-bleeding. Shunt dysfunction was recovered with a balloon dilated for the shunt channel. Hepatic encephalopathy was prevented with oral lactulose (15-30 ml × 3 times a day).
Definitions
Re-bleeding was defined as any subsequent hematemesis or melena occurring after TIPS plus GCVE treatment. Shunt dysfunction was diagnosed with color Doppler ultrasound when the suspected flow velocity was < 50/sec or absence of blood flow in the intrahepatic shunt; this was confirmed by angiography. Hepatic encephalopathy included diagnosis of hepatic encephalopathy as defined according to 11th World Congress of Gastroenterology in Vienna18 and classified according to the West Haven criteria grades.
First-line treatment: First-line treatment was defined as variceal bleeding patients initially treated with TIPS plus GCVE without pharmacological therapy and endoscopic variceal ligation.
Second-line treatment: Second-line treatment was defined as variceal bleeding patients treated with TIPS plus GCVE after pharmacological therapy or endoscopic variceal ligation.
Double stent: Double stent was defined as used one single covered stent and one uncovered stent (Supplementary Table 2, available online).
Single covered stent: Single covered stent was defined as only used single covered stent.
Gastric coronary vein embolization (GSVE): All variceal bleeding patients were embolized with different size of coils or glue during the TIPS procedure (A 5F snake catheter was applied for super selective angiography of gastric coronary vein and a Cook macro catheter was introduced through the catheter into the variceal vein for embolization with different sizes of spring coils or cyanoacrylate (glue) plus iodized oil. After embolizing the variceal vein, we confirmed the results by repeated angiography) (Supplementary Table 2, available online).
Statistical Analysis
The measurement data were expressed as mean ± standard deviation. Preoperative and postoperative quantitative variables were compared using a paired t test. The incidence of survival rate, re-bleeding, hepatic encephalopathy, and shunt dysfunction were analyzed using Kaplan-Meier method. A P value of <0.05 indicated statistical significance. Data processing and analysis used R software-version 4.0.2 and SPSS version 16 (SPSS, Chicago, IL).
Results
General Characteristics
A total of 60 patients diagnosed with cirrhotic portal hypertensive variceal bleeding and treated with TIPS combined with GCVE under local anesthesia were enrolled. There were 41 males and 19 females (15-72 years of age; median age 52.7 ± 11.0 years). The general characteristics are presented in Table 1. The most common etiology of liver cirrhosis was hepatitis B virus (58.3%). Preoperative Child-Pugh class was more “B” class, and postoperative Child-Pugh class was more “A” class. After TIPS plus GCVE treatments, re-bleeding occurred in 15 (25%) patients, shunt dysfunction in 20 (33.3%), and hepatic encephalopathy in 9 (15.0%). The survival rates at 1 and 2 years were 96.6% and 89.7%, respectively. The basic outcome for the postoperative 60 TIPS plus GCVE patients with cirrhotic portal hypertension is summarized in Table 2. The portal vein pressure (PVP) before shunt implantation was > 12 mmHg in all patients. The mean PVP decreased from 39.0 ± 5.0 mmHg to 22.5 ± 4.4 mmHg (P = 0.001) after TIPS implantation. No significant difference was seen between preoperative and postoperative in albumin, alanine transaminase, hemoglobin, or platelet after TIPS implantation. However, there were significant differences in total bilirubin (P =0.004) and prothrombin time/international normalized ratio (P =0.006).
Comparison of hematology, bio-chemical and portal vein pressure
All patients underwent TIPS plus GCVE under local anesthesia (5ml lidocaine 2%). The left portal vein was punctured (90%), and then the right portal vein punctured (10%). A stent was placed between the right hepatic vein and left portal vein (48.3%), middle hepatic vein and left portal vein (36.6%), right hepatic vein to right portal vein (10%), inferior vena cava and left portal vein (3.3%), and left hepatic vein to left portal vein (1.6%). A single-covered stent (45%), double stent (51.1%), and bare were used (3.3 %). Patients were embolized with spring coils of different sizes (65%) and glue (35%) (Supplementary Table 2, available online).
Re-bleeding
After the TIPS plus GCVE procedure, esophageal and gastric variceal bleeding occurred in 15 patients (25%). The cumulative rate of re-bleeding at 1, 3, 6, 12, 18, and 24 months were 1.6%, 3.3%, 6.6%, 13.3%, 0%, and 0%, respectively. The Kaplan-Meier curve (KMC) of re-bleeding is presented in (Figure 1). In a comparative analysis of re-bleeding, four patients were in the first-line treatment group, and eleven patients were in the second-line treatment group (26.6% vs 24.4%, log-rank P=0.012). The KMC of re-bleeding between both groups is presented in (Figure 2). Furthermore, nine patients with re-bleeding were in the coil group, and six patients were in the glue group (23.07% vs 28.5%, log-range P=0.95). The KMC of re-bleeding in both groups is presented in (Supplementary Figure 1, available online). Eight patients with re-bleeding were in the single-covered stent group, and five were in the double stent group (29.6% vs 16.1%) log-rank P =0. 26); the KMC of re-bleeding in both groups is presented in (Supplementary Figure 2, available online).
Kaplan-Meier Curve of re-bleeding; the cumulative rate of re-bleeding at 1, 3, 6, 12, 18, and 24 months were 1.6%, 3.3%, 6.6%, 13.3%, 0%, and 0%.
Kaplan-Meier curve of re-bleeding between first-line treatment and second-line treatment group (26.6% vs 24.4%, log-rank P= 0.012).
Shunt Dysfunction
After TIPS plus GCVE, shunt dysfunction occurred in 20 patients (33.3%). The cumulative rate of shunt dysfunction at 1, 3, 6, 12, 18, and 24 months were 5%, 0%, 10%, 16.6%, 1.6%, and 5%, respectively. The KMC of shunt dysfunction is presented in (Figure 3). In a comparative analysis of shunt dysfunction, eight patients of shunt dysfunction were in the first-line treatment group, and twelve patients were in the second-line treatment group (53.3% vs 26.6.6%, log-rank P=0.4). The KMC of shunt dysfunction in both groups is presented in (Supplementary Figure 3, available online). Furthermore, nine patients with shunt dysfunction were in the single-covered stent, and nine patients were in the double stent group (33.3% vs 29.0%, log-rank P=0.29). Thirteen patients with shunt dysfunction were in the coil group, and seven patients were in the glue group (33.3% vs 33.3%, log-rank P =0.42).
Kaplan-Meier curve of shunt dysfunction; the cumulative rate of shunt dysfunction at 1, 3, 6, 12, 18, and 24 months were 5%, 0%, 10%, 16.6%, 1.6%, and 5%.
Hepatic Encephalopathy
After TIPS plus GCVE procedure, hepatic encephalopathy occurred in nine patients (15.0%). The cumulative rate of hepatic encephalopathy at 1, 3, 6, 12, 18, and 24 months were 3.3%, 1.6%, 3.3%, 6.6%, 0%, and 0%, respectively. The KMC of hepatic encephalopathy is presented in (Figure 4). In a comparative analysis of hepatic encephalopathy, four patients were in the first-line treatment group, and five patients were in the second-line treatment group (26.6% vs 11.11%, log-rank P=0.47). The KMC of hepatic encephalopathy in both groups is presented in (Supplementary Figure 4, available online). Furthermore, two patients with hepatic encephalopathy were in the single-covered stent group, and seven patients were in the double stent group (7.4% vs 22.5%, log-rank P=0.13). The KMC of hepatic encephalopathy in both groups is presented in (Supplementary Figure 5, available online). Four patients with hepatic encephalopathy were in the coil group, and five patients were in the glue group (10.2% vs 23.8%).
Kaplan-Meier curve of hepatic encephalopathy; the cumulative rate of hepatic encephalopathy at 1, 3, 6, 12, 18, and 24 months were 3.3%, 1.6%, 3.3%, 6.6%, 0%, and 0%.
Survival Rate
Seven patients (11.6%) died during the follow up period after the TIPS and GCVE procedure. The cumulative survival rate at 1, 3, 6, 12, 18, and 24 months were 100%, 100%, 100%, 96.6%, 93.3%, and 88.3%, respectively. The KMC of the survival rate is presented in Figure 5. In a comparative analysis of the survival rate, one patient died in the first-line treatment group, and six patients died in the second-line treatment group (6.6% vs 13.3%, log-rank P=0.65). The KMC of the survival rate in both groups is presented in Supplementary Figure 6 (available online). Furthermore, one patient died in the single-covered stent group, and five patients died in the double stent group (3.7% vs 16.1%, log-range P= 0.043). The KMC of survival rate in both groups is presented in Figure 6. Two patients died in the coil group, and five patients died in the glue group (5.1% vs 23.8%).
Kaplan-Meier curve of survival rate; the cumulative survival rate at 1, 3, 6, 12, 18, and 24 months were 100%, 100%, 100%, 96.6%, 93.3%, and 88.3%.
Kaplan-Meier curve of survival rate between single covered stent group and double covered stent, (3.7% vs 16.1%, log-rang P=0.043).
Discussion
This extensive study evaluated clinical outcomes of TIPS with GCVE for esophageal and gastric variceal bleeding secondary to cirrhotic portal hypertension and compared outcomes between coil with glue, single-covered stent with double stent, and first-line treatment with second-line treatment. Most of the previous studies have focused on the single TIPS treatment outcomes for management of variceal bleeding. Only a few of the previous studies have reported on a comparative outcome between coil and glue embolized with TIPS or single-covered stents with double stents or, even first-line treatment for variceal bleeding with cirrhotic portal hypertension.9,11,12,19,20 We comprehensively present all of these outcomes in a single study.
TIPS is used for control and prevention of variceal bleeding due to cirrhotic portal hypertension.2,7,10 Variceal vein embolization has been approved as an effective and supportive method to control variceal bleeding.13,21 Previous studies have reported that TIPS combined with variceal vein embolization is more effective for re-bleeding and improvement in liver function.11,12 It is still unclear how liver function changes after TIPS treatment. However, some studies suggest that liver function improved after TIPS treatment.22 Other studies suggested that the liver function was impaired after TIPS implantation.23,24 TIPS treatment can significantly reduce portal venous pressure, and it is a more effective treatment method for esophageal and gastric variceal bleeding and refectory ascites.25 Expended polyterafluoroethylene stent grafting is recommended by the recent criteria for TIPS treatment.2 The rate of re-intervention treatment can be reduced.26
Variceal bleeding is one of the major causes of death in patients with cirrhotic portal hypertension. After the first episode of esophageal or gastric variceal bleeding, there is a high risk of re-bleeding at 2 years, 50% to 80%.12 However, in this study we found the rate of re-bleeding was high within the first year after the first episode bleeding. Early re-bleeding was shown in one patient within 1 week, and 8 of the 15 patients had re-bleeding at 12 months of post TIPS plus GCVE. The incidence of re-bleeding rate was reported to range from 6.7% to 38% in post TIPS treatment.27,28 We found 25% of patients had re-bleeding during the 24 months of follow-up. Some previous studies reported lower rates than our results.9,12 Shunt dysfunction is a major cause of re-bleeding post TIPS. The randomized control clinical study reported the rate of recurrent variceal bleeding of TIPS with variceal vein embolization was 1.5-fold lower than those treated with only TIPS at 1 year.12
A previous study suggested that patients with > 25 mm Hg portal venous pressure or with severe variceal bleeding and repeated bleeding had a higher incidence rate of re-bleeding. Thus, we can apply TIPS as the first-line treatment to these patients.9 We found that re-bleeding, shunt dysfunction, and hepatic encephalopathy percentages were higher in the first-line treatment group compared to the second-line treatment group. However, the survival rate was high in first-line treatment group, and the event of re-bleeding in both groups was statistically significant (P = 0.012). The percentage of re-bleeding was higher with glue than spring coil, but both showed shunt dysfunction. Hepatic encephalopathy and death were higher in the glue group. The rate of re-bleeding was higher in single-covered stent, and the incidence of hepatic encephalopathy was higher with double stents. Previous studies reported a higher therapeutic efficacy with double stents than single-covered stents.20
Shunt dysfunction is a major disadvantage of TIPS treatment for variceal bleeding. Stent stenosis and occlusion are important causes of re-bleeding after TIPS. Early shunt dysfunction was shown in two patients within a week. In 10 patients, shunt dysfunction was identified at 12 months after TIPS plus GCVE. Only 6.6% of shunt dysfunction occurred after 1 to 2 years. Shunt patency were restored with re-intervention balloon dilatation. Previous studies have reported that shunt dysfunction occurs in 14% to 82% of patients at 1 year after TIPS treatment.29,30 In our study, shunt dysfunction occurred in 26.6% of patients one year after the TIPS plus GCVE. Routine examination, anti-coagulation drugs, and covered stents can improve the shunt patency rate after TIPS treatment.31,32 Shunt dysfunction was higher in single-covered than double stents. However, there were no significant differences seen in shunt dysfunction in either group.
TIPS treatment has been extensively used in the treatment of variceal bleeding for more than two decades; however, TIPS treatment increases the incidence of hepatic encephalopathy,33,34 which was reported as 16% to 31% in post-TIPS patients.35,36 Here, hepatic encephalopathy occurred in 15% of patients post TIPS plus GCVE. Our results were less than previously reported in other studies. No statistically significant difference was seen in hepatic encephalopathy between the first-line with second-line treatment group or single-covered and double stents groups. The hepatic encephalopathy risk was high as reported in > 60 years-of-age, a high child-Pugh score, or high shunt diameter.37 Hepatic encephalopathy was managed with oral lactulose and monitoring of blood ammonia tests after the TIPS plus GCVE treatment.
The survival rate suggests the effectiveness and safety of the treatment method. Previous survival rates are reported from 58% to 80% at 1 year as a function of the severity of disease.29,38 In our study, the survival rate at 1 and 2 years were 96.6% and 89.3%, respectively. Other studies reported lower values than our results.9,19,39 No statistically significant difference was observed in survival rate between first-line and second-line treatment groups. However, the survival rate was significantly different between single-covered stent with double stents (P = 0.043). The survival rate at 2 years with the double stents was higher than single-covered stents.20 During follow up, color Doppler ultrasound and CT-scans were performed to detect shunt patency. Angiography was performed when re-bleeding occurred and color Doppler ultrasound or CT suggested stent stenosis or occlusion. The shunt patency was recovered with balloon dilatation during the angiography. We found that complications occurred more within the first year of follow-up period after TIPS plus GCVE treatment than during the second year.
Recently, previous studies reported TIPS can be a first-line treatment to prevent re-bleeding and improve survival time, and it is recommended for wider range of clinical practice.9,40 We found the survival rate was higher in the first-line treatment group than the second-line treatment group, and the percentage of re-bleeding was almost similar in both groups. However, shunt dysfunction and hepatic encephalopathy percentages were higher in the first-line treatment group, but without statistical significance. Thus, our data also show that the first-line treatment had a better survival rate or prevented re-bleeding versus second-line treatment in cirrhotic portal hypertensive variceal bleeding.
Hepatic encephalopathy is a common problem in chronic liver cirrhosis patient, even in those without TIPS treatment. We can reduce hepatic encephalopathy in TIPS treatment with puncture of the left portal vein and by selecting the exact diameter of the stent.41 Shunt dysfunction is also a more common disadvantage of TIPS treatment, and it depends on the quality of the stent, blood coagulation disorders, and severity of cirrhosis. The patency of the shunt has been greatly improved with a dedicated polytetrafluoroethylene stent.3,4,42
TIPS is recommended as the second-line treatment option for cirrhotic portal hypertensive variceal bleeding based on hepatic encephalopathy, shunt dysfunction, and deterioration of liver function.43 It can only be considered a choice of treatment after failed non-selective beta blockers and endoscopy variceal ligation to prevent recurrent bleeding. However, these criteria do not seem to be useful when the patient presents with acute variceal bleeding, more than 25 mmHg portal venous pressure, gastric variceal bleeding, and severe bleeding with a higher chance of re-bleeding. It is well known that the TIPS procedure can significantly decrease the level of the portal pressure gradient. This inspires the use of TIPS as the first-line treatment to control variceal bleeding.
A previous study suggested the use of double-covered stents in TIPS for cirrhotic portal hypertensive variceal bleeding. They may be more effective and beneficial for survival time.20 Here, we found the percentages of re-bleeding and shunt dysfunction were higher in single-covered stent versus double stents, but there were no statistically significant differences between the two groups. Hepatic encephalopathy and death rates were higher in double stent than single covered stents. There was statistical significance in survival rates between single-covered and double stents.
A potential limitation of this study was the nonrandomized retrospective study experience of a single institution and the lack of a large sample treated with TIPS plus GCVE due to management of esophageal and gastric variceal bleeding by multidisciplinary departments (infection medicine, gastroenterology, hepatology, critical emergency department, and interventional radiologists).We only included variceal bleeding treated with embolic agents during the TIPS procedure in our department. Variceal bleeding treated with embolic agents before or after the TIPS procedure in our department or other departments was excluded. For first-line treatment, most variceal bleeding patients were admitted in our department for a history of re-bleeding within 1 week to 6 months after the primary treatment in a local hospital. We found the first-line treatment group with punctured left portal vein and double stents had more effectiveness and better survival than single-covered stent for variceal bleeding with cirrhotic portal hypertension. There were no complications related to treatment with embolic agents after embolization.
Conclusion
In conclusion, our results suggest that TIPS combined with GCVE is effective and safer in the treatment of cirrhotic portal hypertension induced esophageal and gastric variceal bleeding. TIPS plus GCVE may be preferable as a first-line treatment for high-risk re-bleeding and > 25 mm Hg portal venous pressure with repeated variceal bleeding; this strategy could improve the survival rate. The application of double stents in TIPS treatment is more effective and can improve survival time. However, the sample size was small; therefore, large, randomized, controlled, multidisciplinary center studies are needed for further evaluation.
Acknowledgements
The authors thank Wu Kunpeng and Li Jing for help in data information, and Hou Changlong, Cheng De-Lei and BI Yonghua for critical review manuscript with them valuable comments. The authors also thank American Manuscript Editors for review manuscript and professional English editor.
Footnotes
Author Contributions: XH is responsible for Conceptualization, Supervision, and reviewing manuscript. GM is responsible for data collection, review data, analyzed data, writing and reviewing manuscript and writing original draft. DJ, YB, GP, ZL, ZL and YH are responsible for contribute to data collection, reviewed and writing manuscript. All authors contributed to the article and approved manuscript for submitted version.
- Received August 31, 2022.
- Revision received March 13, 2023.
- Revision received May 29, 2023.
- Revision received July 27, 2023.
- Accepted August 1, 2023.
References
- 1.↵Rössle M. TIPS: 25years later. J Hepatol. 2013;59(5):1081-1093. doi:10.1016/j.jhep.2013.06.014.
- 2.↵Boyer TD, Haskal ZJ; American Association for the Study of Liver Diseases. The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: Update 2009. Hepatology. 2010;51(1):306. doi:10.1002/hep.23383.
- 3.↵Rossi P, Salvatori FM, Fanelli F, Polytetrafluoroethylene-covered nitinol stent-graft for transjugular intrahepatic portosystemic shunt creation: 3-year experience. Radiology. 2004;231(3):820-830. doi:10.1148/radiol.2313030349
- 4.↵Charon JP, Alaeddin FH, Pimpalwar SA, Results of a retrospective multicenter trial of the Viatorr expanded polytetrafluoroethylene-covered stent-graft for transjugular intrahepatic portosystemic shunt creation. J Vasc Interv Radiol. 2004;15(11):1219-1230. doi:10.1097/01.RVI.0000137434.19522.E5
- 5.↵Richter GM, Palmaz JC, Nöldge G, Der transjuguläre intrahepatische portosystemische Stent-Shunt (TIPSS). Eine neue nichtoperative, perkutane Methode [The transjugular intrahepatic portosystemic stent-shunt. A new nonsurgical percutaneous method]. Radiologe. 1989;29(8):406-411.
- 6.↵Barrio J, Ripoll C, Bañares R, Comparison of transjugular intrahepatic portosystemic shunt dysfunction in PTFE-covered stent-grafts versus bare stents. Eur J Radiol. 2005;55(1):120-124. doi:10.1016/j.ejrad.2004.10.007.
- 7.↵García-Pagán JC, Caca K, Bureau C, Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010;362(25):2370-2379. doi:10.1056/NEJMoa0910102
- 8.↵Lv Y, Zuo L, Zhu X, Identifying optimal candidates for early TIPS among patients with cirrhosis and acute variceal bleeding: a multicentre observational study. Gut. 2019;68(7):1297-1310. doi:10.1136/gutjnl-2018-317057
- 9.↵Liu J, Shi Q, Xiao S, Using transjugular intrahepatic portosystemic shunt as the first-line therapy in secondary prophylaxis of variceal hemorrhage. J Gastroenterol Hepatol. 2020;35(2):278-283. doi:10.1111/jgh.14761.
- 10.↵de Franchis R; Baveno V Faculty. Revising consensus in portal hypertension: Report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2010;53(4):762-768. doi:10.1016/j.jhep.2010.06.004.
- 11.↵Tesdal IK, Filser T, Weiss C, Holm E, Dueber C, Jaschke W. Transjugular intrahepatic portosystemic shunts: adjunctive embolotherapy of gastroesophageal collateral vessels in the prevention of variceal rebleeding. Radiology. 2005;236(1):360-367. doi:10.1148/radiol.2361040530.
- 12.↵Chen S, Li X, Wei B, Recurrent variceal bleeding and shunt patency: prospective randomized controlled trial of transjugular intrahepatic portosystemic shunt alone or combined with coronary vein embolization. Radiology. 2013;268(3):900-906. doi:10.1148/radiol.13120800
- 13.↵Kwok ACH, Wang F, Maher R, The role of minimally invasive percutaneous embolisation technique in the management of bleeding stomal varices. J Gastrointest Surg. 2013;17(7):1327-1330. doi:10.1007/s11605-013-2180-y.
- 14.↵LaBerge JM, Ring EJ, Gordon RL, Creation of transjugular intrahepatic portosystemic shunts with the wallstent endoprosthesis: results in 100 patients. Radiology. 1993;187(2):413-420. doi:10.1148/radiology.187.2.8475283.
- 15.↵Sanyal AJ, Freedman AM, Luketic VA, The natural history of portal hypertension after transjugular intrahepatic portosystemic shunts. Gastroenterology. 1997;112(3):889-898. doi:10.1053/gast.1997.v112.pm9041251.
- 16.↵Krajina A, Hulek P, Fejfar T, Valek V. Quality Improvement Guidelines for Transjugular Intrahepatic Portosystemic Shunt (TIPS). Cardiovasc Intervent Radiol. 2012;35(6):1295-1300. doi:10.1007/s00270-012-0493-y.
- 17.↵Dariushnia SR, Haskal ZJ, Midia M, ; Society of Interventional Radiology Standards of Practice Committee. Quality Improvement Guidelines for Transjugular Intrahepatic Portosystemic Shunts. J Vasc Interv Radiol. 2016;27(1):1-7. doi:10.1016/j.jvir.2015.09.018.
- 18.↵Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy-Definition, nomenclature, diagnosis, and quantification: Final report of the Working Party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002;35(3):716-721. doi:10.1053/jhep.2002.31250.
- 19.↵Jiang Q, Wang MQ, Zhang GB, Wu Q, Xu JM, Kong DR. Transjugular intrahepatic portosystemic shunt combined with esophagogastric variceal embolization in the treatment of a large gastrorenal shunt. World J Hepatol. 2016;8(20):850-857. doi:10.4254/wjh.v8.i20.850.
- 20.↵Xu B, Liu J, Liu S, Xiang X, Lai L. Clinical effect of single covered stent and double covered stent on TIPS in the treatment of hemorrhage due to rupture of esophageal and gastric varices in cirrhosis and its influence on immune function. Exp Ther Med. 2019;18(6):4259-4264. doi:10.3892/etm.2019.8106.
- 21.↵Tajiri T, Yoshida H, Obara K, General rules for recording endoscopic findings of esophagogastric varices (2nd edition). Dig Endosc. 2010;22(1):1-9. doi:10.1111/j.1443-1661.2009.00929.x.
- 22.↵Salerno F, Merli M, Riggio O, Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites. Hepatology. 2004;40(3):629-635. doi:10.1002/hep.20364.
- 23.↵Bercu ZL, Fischman AM, Kim E, TIPS for refractory ascites: a 6-year single-center experience with expanded polytetrafluoroethylene-covered stent-grafts. AJR Am J Roentgenol. 2015;204(3):654-661. doi:10.2214/AJR.14.12885.
- 24.↵Tan HK, James PD, Sniderman KW, Wong F. Long-term clinical outcome of patients with cirrhosis and refractory ascites treated with transjugular intrahepatic portosystemic shunt insertion. J Gastroenterol Hepatol. 2015;30(2):389-395. doi:10.1111/jgh.12725.
- 25.↵Arroyo V, Ginès P, Gerbes AL, Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology. 1996;23(1):164-176. doi:10.1002/hep.510230122
- 26.↵Bureau C, Garcia-Pagan JC, Otal P, Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology. 2004;126(2):469-475. doi:10.1053/j.gastro.2003.11.016
- 27.↵Freedman AM, Sanyal AJ, Tisnado J, Complications of transjugular intrahepatic portosystemic shunt: a comprehensive review. Radiographics. 1993;13(6):1185-1210. doi:10.1148/radiographics.13.6.8290720.
- 28.↵Stanley AJ, Jalan R, Forrest EH, Redhead DN, Hayes PC. Longterm follow up of transjugular intrahepatic portosystemic stent shunt (TIPSS) for the treatment of portal hypertension: results in 130 patients. Gut. 1996;39(3):479-485. doi:10.1136/gut.39.3.479.
- 29.↵Garcia-Pagán JC, Barrufet M, Cardenas A, Escorsell À. Management of gastric varices. Clin Gastroenterol Hepatol. 2014;12(6):919-928.e1, quiz e51-e52. doi:10.1016/j.cgh.2013.07.015.
- 30.↵Chen L, Xiao T, Chen W, Outcomes of transjugular intrahepatic portosystemic shunt through the left branch vs. the right branch of the portal vein in advanced cirrhosis: a randomized trial. Liver Int. 2009;29(7):1101-1109. doi:10.1111/j.1478-3231.2009.02016.x.
- 31.↵Bai M, He CY, Qi XS, Shunting branch of portal vein and stent position predict survival after transjugular intrahepatic portosystemic shunt. World J Gastroenterol. 2014;20(3):774-785. doi:10.3748/wjg.v20.i3.774.
- 32.↵Yang Z, Han G, Wu Q, Patency and clinical outcomes of transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stents versus bare stents: A meta-analysis. J Gastroenterol Hepatol. 2010;25(11):1718-1725. doi:10.1111/j.1440-1746.2010.06400.x.
- 33.↵Berry K, Lerrigo R, Liou IW, Ioannou GN. Association Between Transjugular Intrahepatic Portosystemic Shunt and Survival in Patients With Cirrhosis. Clin Gastroenterol Hepatol. 2016;14(1):118-123. doi:10.1016/j.cgh.2015.06.042.
- 34.↵Khan S, Tudur Smith C, Williamson P, Sutton R. Portosystemic shunts versus endoscopic therapy for variceal rebleeding in patients with cirrhosis. Cochrane Database Syst Rev. 2006;2006(4):CD000553. Published 2006 Oct 18. doi:10.1002/14651858.CD000553.pub2
- 35.↵Riggio O, Ridola L, Lucidi C, Angeloni S. Emerging issues in the use of transjugular intrahepatic portosystemic shunt (TIPS) for management of portal hypertension: Time to update the guidelines? Dig Liver Dis. 2010;42(7):462-467. doi:10.1016/j.dld.2009.11.007.
- 36.↵Rowley MW, Choi M, Chen S, Hirsch K, Seetharam AB. Refractory Hepatic Encephalopathy After Elective Transjugular Intrahepatic Portosystemic Shunt: Risk Factors and Outcomes with Revision. Cardiovasc Intervent Radiol. 2018;41(11):1765-1772. doi:10.1007/s00270-018-1992-2.
- 37.↵Hauenstein KH, Haag K, Ochs A, Langer M, Rössle M. The reducing stent: treatment for transjugular intrahepatic portosystemic shunt-induced refractory hepatic encephalopathy and liver failure. Radiology. 1995;194(1):175-179. doi:10.1148/radiology.194.1.7997547.
- 38.↵Ryan BM, Stockbrugger RW, Ryan JM. A pathophysiologic, gastroenterologic, and radiologic approach to the management of gastric varices. Gastroenterology. 2004;126(4):1175-1189. doi:10.1053/j.gastro.2004.01.058.
- 39.↵Han SW, Joo YE, Kim HS, Clinical results of the transjugular intrahepatic portosystemic shunt (TIPS) for the treatment of variceal bleeding. Korean J Intern Med. 2000;15(3):179-186. doi:10.3904/kjim.2000.15.3.179
- 40.↵Maleux G, Nevens F, Wilmer A, Early and long-term clinical and radiological follow-up results of expanded-polytetrafluoroethylene-covered stent-grafts for transjugular intrahepatic portosystemic shunt procedures. Eur Radiol. 2004;14(10):1842-1850. doi:10.1007/s00330-004-2359-4.
- 41.↵Qi XS, Bai M, Yang ZP, Fan DM. Selection of a TIPS stent for management of portal hypertension in liver cirrhosis: An evidence-based review. World J Gastroenterol. 2014;20(21):6470-6480. doi:10.3748/wjg.v20.i21.6470.
- 42.↵Perarnau JM, Le Gouge A, Nicolas C, ; STIC-TIPS group. Covered vs. uncovered stents for transjugular intrahepatic portosystemic shunt: A randomized controlled trial. J Hepatol. 2014;60(5):962-968. doi:10.1016/j.jhep.2014.01.015.
- 43.↵Burroughs AK, Vangeli M. Transjugular intrahepatic portosystemic shunt versus endoscopic therapy: randomized trials for secondary prophylaxis of variceal bleeding: an updated meta-analysis. Scand J Gastroenterol. 2002;37(3):249-252. doi:10.1080/003655202317284138.
