Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights.
Original Research n Vascular
Xuefeng Luo, MD Zhu Wang, MD Jiaywei Tsauo, MD Biao Zhou, MD Hailong Zhang, MD Xiao Li, MD
Purpose:
To compare transjugular intrahepatic portosystemic shunt (TIPS) placement with or without variceal embolization with endoscopic band ligation (EBL) plus propranolol in preventing recurrent esophageal variceal bleeding in patients with advanced cirrhosis and portal vein thrombosis.
Materials and Methods:
The present randomized controlled trial was approved by the ethics committee board of West China Hospital. Written informed consent was obtained from each patient. Between January 2010 and December 2012, 73 patients were randomly allocated to receive TIPS (n = 37) or EBL plus propranolol (n = 36). The comparisons of recurrent variceal bleeding, hepatic encephalopathy, and survival rates were based on the Kaplan-Meier method and were compared using the log-rank test.
Results:
The mean follow-up time was 22.8 months 6 7.7(standard deviation) in the TIPS group and 20.9 months 6 8.9 in the EBL group. The 2-year probability of remaining free of recurrent variceal bleeding was higher in the TIPS group (77.8%) than in the EBL group (42.9%) (P = .002). Overall recanalization was achieved in 24 (64.9%) patients from the TIPS group and seven (19.4%) patients from the EBL group. The hepatic encephalopathy rates exhibited no significant differences between the two groups (P = .53). The 1- and 2-year probability of survival was 86.5% and 72.9%, respectively, in the TIPS group and 83.3% and 57.2%, respectively, in the EBL group, with no significant difference (P = .23).
Conclusion:
TIPS was more effective than EBL plus propranolol in preventing recurrent esophageal variceal bleeding in patients with advanced cirrhosis and portal vein thrombosis and did not increase the incidence of hepatic encephalopathy. Survival was similar in both groups.
1
From the Center of Interventional Radiology and Department of Gastroenterology, West China Hospital, Sichuan University, 37 Guoxue Lane, 610041 Chengdu, Sichuan, China. Received July 18, 2014; revision requested September 15; final revision received December 3; accepted December 13; final version accepted December 18. Supported by the National Nature Science Foundation of China (grants 81371656 and 81171444). Address correspondence to X. Li (e-mail: [email protected]).
and Interventional Radiology
Advanced Cirrhosis Combined with Portal Vein Thrombosis: A Randomized Trial of TIPS versus Endoscopic Band Ligation Plus Propranolol for the Prevention of Recurrent Esophageal Variceal Bleeding1
RSNA, 2015
q
RSNA, 2015
q
Radiology: Volume 000: Number 0— 2015 n radiology.rsna.org
1
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
V
ariceal bleeding is a major cause of death in patients with advanced cirrhosis. Failure to control acute variceal bleeding, early recurrent bleeding, and marked elevations in portal pressure are associated with increased mortality (1–3). Given the high recurrence rate, patients who survive acute variceal hemorrhage should receive prophylactic therapy to prevent recurrence before they are discharged from the hospital (4). In recent decades, clinical trials and meta-analyses concluded that the combination of endoscopic band ligation (EBL) and nonselective b-blockers should be considered as a first-line therapy for the prevention of recurrent variceal bleeding, reserving transjugular intrahepatic portosystemic shunt (TIPS) for those who fail standard medical therapy due to the higher incidence of postprocedure hepatic encephalopathy and lack of improved survival (4,5). Recently, some authors reported that TIPS may be more effective than endoscopic therapy combined with propranolol in the prevention of recurrent variceal bleeding (1,6). However, the exact efficacy of this strategy remains unclear because prospectively randomized controlled studies are lacking. Nonneoplastic portal vein thrombosis (PVT) is a critical but frequent event in patients with advanced cirrhosis, with an incidence ranging from 1% to 36% (7–10). Although the impact of PVT on the natural prognosis
Advances in Knowledge nn The 2-year probability of remaining free of recurrent variceal bleeding was higher in the transjugular intrahepatic portosystemic shunt (TIPS) group (77.8%) than in the endoscopic band ligation (EBL) group (42.9%) (P = .002). nn The hepatic encephalopathy rates exhibited no significant differences between the TIPS group and the EBL group (16.7% vs 17.7% at 1-year follow-up and 38.5% vs 46.5% at 2-year follow-up) (P = .53). 2
of cirrhosis remains controversial, it might worsen liver function and aggravate portal hypertension, with increased risks of the rupture of varices and the development of ascites. In addition, the presence of PVT increases posttransplantation morbidity and mortality and might even contraindicate transplantation, especially in patients with PVT that extends to the confluence of the superior mesenteric vein and the splenic vein (7,11,12). Several retrospective uncontrolled studies have shown that TIPS decreases portal pressure, prevents the recurrence of variceal bleeding, and recanalizes the portal vein by restoring portal venous flow (13–17). However, there is no established management algorithm for the prevention of recurrent esophageal variceal bleeding in patients with cirrhosis and PVT due to limited data. In addition, to our knowledge, TIPS has not been compared with EBL with respect to the prevention of recurrent esophageal variceal bleeding in patients with cirrhosis and PVT after the first bleeding episode. Therefore, the purpose of this randomized controlled trial was to prospectively compare TIPS with EBL plus propranolol in preventing recurrent esophageal variceal bleeding in patients with cirrhosis and PVT after the first bleeding episode.
Luo et al
on the basis of clinical history, physical examination, laboratory and imaging findings, and liver biopsy. Forty-one patients with any of the following were excluded from the study: PVT of 25% or less within the vessel lumen (n = 11); limited thrombosis in the intrahepatic portal branch (n = 8); portal cavernoma (n = 5); gastric varices (n = 9); hepatocellular carcinoma (n = 2); previous endoscopic treatment of varices within 3 months (n = 2); and contradictions to TIPS, EBL, or propranolol (n = 4) (Fig 1). The remaining 73 patients were randomly assigned to the TIPS group (n = 37) or the EBL group (n = 36). This randomized controlled trial was approved by the ethics committee board of West China Hospital and was registered in the Chinese Clinical Trial Registry (ChiCTR-TRC-11001577). Written informed consent for inclusion in the clinical trial and the treatment was obtained from each patient. Eligible patients were assigned randomly to the TIPS or EBL group by using consecutive numbers generated by computerallocated random-digit numbers.
Treatments The TIPS procedure was performed by two experienced radiologists (X.F.L. and X.L. with 5 and 10 years of experience, respectively) with a standard technique described previously (18).
Materials and Methods Study Design Between January 2010 and December 2012, 114 patients with cirrhosis and PVT, aged 18–70 years, a previous episode of variceal bleeding, and a ChildPugh score of 7–13 were considered eligible for inclusion in this study. The diagnosis of liver cirrhosis was made Implication for Patient Care nn TIPS was superior to EBL plus propranolol in the prevention of recurrent variceal bleeding in patients with advanced cirrhosis and portal vein thrombosis without increasing the incidence of hepatic encephalopathy.
Published online before print 10.1148/radiol.15141252 Content codes: Radiology 2015; 000:1–8 Abbreviations: EBL = endoscopic band ligation PVT = portal vein thrombosis TIPS = transjugular intrahepatic portosystemic shunt Author contributions: Guarantors of integrity of entire study, B.Z., H.Z., X. Li; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, Z.W., H.Z.; clinical studies, X. Luo, Z.W., B.Z., H.Z., X. Li; statistical analysis, Z.W., B.Z., H.Z., X. Li; and manuscript editing, Z.W., J.T., H.Z. Conflicts of interest are listed at the end of this article.
radiology.rsna.org n Radiology: Volume 000: Number 0— 2015
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
Contrast material–enhanced CT, CO2wedged hepatic venography, or superior mesenteric arteriography was utilized to assist intrahepatic portal vein catheterization (Fig 2). Once the portal vein was accessed, a hydrophilic guidewire (Radiofocus M, Terumo, Tokyo, Japan) was advanced gradually to cross the thrombosed section until it reached the patent portion of the main portal vein, splenic vein, or superior mesenteric vein. A portal venogram was obtained, and the portal systemic gradient was also measured. The intrahepatic tract was dilated by using an 8 3 60-mm angioplasty balloon catheter (Powerflex; Cordis, Roden, the Netherlands). Ten-millimeter expanded polytetrafluoroethylenecovered stents (Fluency; C.R. Bard, Murray Hill, NJ) were implanted, with their proximal end at the hepatocaval junction and their distal end in the patent portion of the main portal vein. Subsequently, the portal systemic gradient was re-measured, and the stents were dilated again if necessary. A second stent would be deployed coaxially if the first stent could not maintain sufficient intrastent flow. Embolization with coils (MReye; Cook, Bloomington, Ind) was performed when portosystemic collateral veins were observed at postprocedure portography. Intravenous heparin (3000 U) was administered to all the patients once the portal vein was entered. Low-molecular-weight heparin was prescribed for 3 days, and warfarin was continued for an additional 6 months after recanalization of the portal venous system, with a target international normalized ratio of 2–3. Each session of EBL was performed by the same experienced hepatologist. A multiband ligator (Wilson-Cook Medical, Winston-Salem, NC) was utilized. During each treatment session, 4–6 elastic bands were used to ligate the varices. EBL was performed every 4–6 weeks until the varices were eradicated. Patients in the EBL group underwent routine endoscopy every 3–6 months. The recurrence of varices was treated with further ligations. For patients in the EBL group, propranolol was initiated at a dose of 20
Luo et al
Figure 1
Figure 1: Flowchart of screening and randomization of patients. HCC = hepatocellular carcinoma.
Figure 2
Figure 2: A, B, Contrast-enhanced CT scans show severe thrombosis (arrowhead) in the intrahepatic portal branches (A) and the main portal vein (B). C, Direct portal venogram shows extensive thrombosis in the portal venous system, multiple collaterals (arrows), and hepatofugal flow. D, One covered stent was deployed after the competing collaterals were embolized. Fifteen months after TIPS placement, E, F, CT scans show complete recanalization of the portal vein.
mg/day. The dose was increased by 20–40 mg per/day, every week, either until a reduction of the resting heart
Radiology: Volume 000: Number 0— 2015 n radiology.rsna.org
rate of 25% was achieved or up to the maximum dose was tolerated. In general, the dose was increased if it 3
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
was clinically tolerated and if the systolic blood pressure was 90 mm Hg or higher, with a resting heart rate of 55 beats per minute or higher. Immediately after variceal eradication, warfarin was prescribed and continued for an additional 6 months after recanalization of the portal venous system, with a target international normalized ratio of 2–3.
Follow-up and End Points Patients in both groups were followed until liver transplantation, death, or lost to follow-up. In the TIPS group, patients were evaluated at 1, 3, and 6 months after discharge and every 6 months thereafter or whenever clinically necessary. In the EBL group, patients were evaluated every 4–6 weeks at the time of EBL and every 3–6 months after variceal eradication. The primary end point was the incidence of recurrent variceal bleeding. The secondary end points were incidence of TIPS dysfunction, recanalization of the portal venous system, occurrence of hepatic encephalopathy, or death for any reason. Sample Size and Statistical Analyses We hypothesized that the 1-year recurrent variceal bleeding rate was 15% in the TIPS group and 45% in the EBL group based on published reports (3,6,14,19). The sample size was calculated by using a two-sided test. Thirtysix patients in each group were considered to detect the above-mentioned differences with a of .05 and b of .20. The data are expressed as the means 6 standard deviation. Categorical data are expressed as percentages. The results of the study were analyzed by using Student test for continuous data and the x2 test for categorical outcomes. The comparisons of recurrent variceal bleeding, hepatic encephalopathy, and survival rates were based on the Kaplan-Meier method and were compared by using the log-rank test. All tests of significance were two sided, and a P value , .05 was considered to indicate a statistically significant difference. Data processing and statistical analyses were performed 4
with SPSS (SPSS, version 16.0; SPSS, Chicago, Ill).
Results Study Patients There were no significant differences in the baseline characteristics between the two groups (Table). Three patients (one in the TIPS group and two in the EBL group) were lost to follow-up after a mean of 7 months. The mean follow-up time was 22.8 months 6 7.7 in the TIPS group and 20.9 months 6 8.9 in the EBL group. Treatments In the TIPS group, technical success was achieved in all 37 patients (100%). The mean portal systemic gradient decreased from 27.5 mm Hg 6 7.5 to 10.4 mm Hg 6 3.1 after shunt creation (P , .001). Variceal embolization was performed in 21 patients. One patient did not undergo variceal embolization because the varices were too tortuous to be catheterized. Two patients developed hepatic encephalopathy (grade III) at 2 and 3 days after the procedure, and both were successfully treated with medical therapy. No other major procedural complications were observed following TIPS. In the EBL group, 21 patients (58.3%) achieved variceal eradication after a mean of 3.5 EBL sessions, including four patients after recurrent variceal bleeding. Two patients did not achieve variceal eradication even after seven and five EBL sessions. Eleven patients experienced transient retrosternal pain after EBL, and post-EBL ulcer bleeding occurred in two patients. All patients received propranolol, with a mean dose of 65.4 mg/day 6 26.7. The dose was reduced in one patient due to bradycardia. Recurrent Bleeding During the follow-up period, a total of 43 variceal bleeding episodes occurred in 31 patients: 12 episodes in 10 patients from the TIPS group and 31 episodes in 21 patients from the EBL group. Eight of nine patients in the TIPS group
Luo et al
who underwent direct portal venography exhibited dysfunctional TIPS, with complete stent occlusion in six patients and stent stenosis in two patients. The remaining one patient died of massive gastrointestinal bleeding before revision could be performed in a local hospital. Nine of 21 patients in the EBL group received additional ligations. Recurrent bleeding in another 12 patients was considered uncontrolled; nine patients were treated with TIPS, whereas three patients died before TIPS placement could be performed. The 1- and 2-year probability of remaining free of recurrent variceal bleeding was 89.2% and 77.8%, respectively, in the TIPS group and 58.2% and 42.9%, respectively, in the EBL group. The recurrent variceal bleeding rate was significantly lower in the TIPS group than in the EBL group (P = .002, Fig 3).
TIPS Dysfunction and Recanalization of the Portal Venous System TIPS dysfunction occurred in 12 patients during the follow-up period. Direct portography confirmed stent occlusion in seven cases and stenosis in four cases. The remaining one patient died at a local hospital due to massive recurrent variceal bleeding before portal angiography could be performed. TIPS revision was successfully performed in nine patients with additional stent placement, and two patients underwent parallel TIPS creation. The 1- and 2-year probability of TIPS patency was 91.7% and 71.3%, respectively. The portal venous system was recanalized in a total of 31 patients: 24 (64.9%) from the TIPS group and seven (19.4%) from the EBL group. Improvement of PVT was also observed in five patients in the TIPS group and in nine patients in the EBL group. Hepatic Encephalopathy Hepatic encephalopathy occurred in a total of 31 patients: 15 from the TIPS group and 16 from the EBL group. Refractory hepatic encephalopathy occurred in five patients (three in the TIPS group and two in the EBL group), including four patients who died of progressive hepatic failure. The 1- and
radiology.rsna.org n Radiology: Volume 000: Number 0— 2015
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
Luo et al
Figure 3 Baseline Characteristics of TIPS and EBL Groups Variable Age (y)* M/F Cause of cirrhosis Hepatitis B virus Hepatitis C virus Alcohol Other Child-Pugh class B Child-Pugh class C Child-Pugh score* MELD score* Bilirubin level (mmol/L)* Albumin level (g/L)* Blood urea nitrogen level (mmol/L)* Creatinine level (mmol/L)* Sodium level (mmol/L)* Prothrombin time (sec)* International normalized ratio* Hemoglobin level (g/L)* White blood cell count (3109/L)* Platelet count (3109/L)* Hepatic encephalopathy grade 0 1 2 3 4 Ascites grade 0 I II III PVT grade II (26%–50% within vessel lumen) III (51%–75% within vessel lumen) IV (76 within vessel lumen) No. of thrombosed vessels 1 2 3
TIPS (n = 37)
EBL (n = 36)
P Value
50.78 6 13.61 19/18
49.53 6 14.02 24/12
.699 .236† .412‡
27 3 2 5 25 12
24 2 4 6 24 12
8.76 6 1.70 14.2 6 6.5 29.84 6 24.95 29.44 6 4.80 6.94 6 4.10 73.02 6 19.09 138.13 6 5.98 16.97 6 5.91 1.52 6 3.45 80.86 6 20.31 5.07 6 3.76 114.03 6 124.47
8.89 6 1.77 15.9 6 5.7 28.98 6 17.10 30.36 6 5.39 5.74 6 2.67 72.17 6 19.08 136.58 6 3.85 16.63 6 3.12 1.43 6 0.34 81.08 6 26.12 5.78 6 3.99 105.78 6 78.59
35 1 1 0 0
33 0 3 0 0
17 15 3 2
16 10 9 1
.935‡ .746 .376 .866 .438 .140 .849 .195 .761 .176 .968 .433 .737 .597‡
.796‡ 9 15 13
11 12 13 .534‡
5 22 10
5 18 13
* Data are means 6 standard deviations. x2 test.
‡
Mann-Whitney U test.
Figure 4
.354‡
Note.—Unless otherwise indicated, data are the number of patients. †
Figure 3: Graph shows the probability of remaining free from recurrent variceal bleeding between the two groups.
2-year probability of hepatic encephalopathy occurrence was 16.2% and 38.5%, respectively, in the TIPS group and 17.7% and 46.5%, respectively, in the EBL group. The hepatic encephalopathy occurrence rates were not
significantly different between the two groups (P = .53, Fig 4).
Survival A total of 29 patients died during the follow-up period: 12 from the TIPS
Radiology: Volume 000: Number 0— 2015 n radiology.rsna.org
Figure 4: Graph shows the probability of hepatic encephalopathy between the two groups.
group and 17 from the EBL group. The 1- and 2-year probability of survival was 86.5% and 72.9%, respectively, in the TIPS group and 83.3% and 57.2%, respectively, in the EBL group, with no significant difference between the two groups (P = .23, Fig 5). Nine patients in the TIPS group and 10 in the EBL group died of hepatic failure. One patient in the TIPS group and three in the EBL group died due to uncontrolled gastrointestinal bleeding. Other causes of death included multiple organ dysfunction syndrome (one TIPS patient and two EBL patients), hepatocellular carcinoma (one patient in each group), and sepsis (one patient of the EBL group). 5
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
Figure 5
Figure 5: Graph shows the probability of survival between the two groups.
Discussion Our results demonstrated that TIPS was superior to EBL plus propranolol in the prevention of recurrent variceal bleeding in patients with advanced cirrhosis and PVT without increasing the incidence of hepatic encephalopathy. However, the survival rate was not influenced by either TIPS or EBL plus propranolol. Our data also indicated that TIPS may have some advantages over EBL plus propranolol as a first-line therapy to prevent recurrent variceal bleeding in patients with advanced cirrhosis and PVT. Recently, our understanding of coagulopathy in cirrhosis has changed, and patients with cirrhosis, especially in the advanced decompensated stage, are no longer considered to be in a hypocoagulable state (7–9). Moreover, patients with cirrhosis or noncirrhotic liver disease had a substantially increased risk of venous thromboembolism (20). The optimal treatment of PVT and related portal hypertensive complications in cirrhosis has not been addressed in any consensus publication, including the very recent practice guidelines (5,21). The safety and efficacy of anticoagulation in the treatment of PVT in cirrhosis have been reported in a few series, whereas TIPS is preserved as an alternative therapy when anticoagulation fails due to its inherent defects (12,22–24). Recently, two large 6
retrospective studies demonstrated that TIPS is a safe and feasible therapy for PVT in patients with decompensated cirrhosis, with the additional benefit of treating variceal bleeding (13,14). However, these published studies generally focused more on the outcome of PVT than on symptomatic portal hypertension. There have been no controlled studies of b-adrenergic blockers or endoscopic therapy in such patients. We found that the recurrent variceal bleeding rate in the EBL group was higher than that reported in several previous reports (2,19,25,26) and slighter lower than that in another study (3). This result may be explained by the characteristics of our patient selection (a Child-Pugh score of 7–13) and the presence of PVT, which aggravated portal hypertension. More importantly, recanalization of the portal venous system was realized in only seven patients (19.4%) in the EBL group. Our results confirm previous studies revealing that the recurrent variceal bleeding rate was much lower after TIPS than after endoscopic treatment (6,27). Given that the combination of EBL and propranolol is ineffective for eliminating thrombosis or rectifying the underlying coagulopathy in patients with cirrhosis, its ability to reduce variceal bleeding may be counteracted by deteriorated PVT in most cases. The treatment strategy for patients with cirrhosis with symptomatic portal hypertension and PVT should take into account the presence of PVT. Although hepatic encephalopathy remains a potential risk in patients treated with TIPS, there is no significant difference between the two groups with respect to the proportion of patients exhibiting clinical hepatic encephalopathy. In our study, hepatic encephalopathy occurred more frequently in the EBL group than in other studies (3,25), possibly due to the poor recanalization rate of the portal venous system and the high occurrence of variceal bleeding. In patients with advanced cirrhosis and more severe PVT, TIPS was not associated with an increase in hepatic encephalopathy compared with EBL plus propranolol.
Luo et al
Although the risk of recurrent variceal bleeding was significantly reduced in the TIPS group, there was no significant difference in the cumulative survival rates between the two groups. In our study, only one patient in the TIPS group died of variceal bleeding in a remote hospital without timely treatment, whereas three patients in the EBL group presented with massive uncontrolled gastrointestinal bleeding and died before TIPS could be accomplished. It should be noted that nine patients with recurrent variceal bleeding in the EBL group received rescue TIPS, which might have obscured a potential benefit of TIPS for survival. Another explanation may be related to the relatively short follow-up. The incidence of shunt dysfunction was similar to that in a previous study in which patients with cirrhosis and PVT were included (13) and was better than that in a very recent study (39.9% for the Viatorr stent at 2 years) (28). The possible explanations for these differences are as follows: First, during the TIPS placement procedure, we deployed the stent with great caution to ensure that the proximal end of the stent was at the hepatocaval junction and that the distal end was in a patent portion of the portal vein. A second stent, usually a bare stent, would be deployed coaxially to ensure adequate blood flow in the stent if necessary. Second, variceal embolization in patients with competing portosystemic collateral veins may reduce the risk of shunt dysfunction and recurrent variceal bleeding during the first 6 months after TIPS (29). Third, the addition of warfarin may help maintain the patency of the portal vein. The current management strategies for the prophylaxis of recurrent variceal bleeding are based on the results of several randomized clinical trials and meta-analyses in which patients with PVT were mostly excluded (2,3,25,26,30–33). A combination of EBL and nonselective b-blocker therapy is recommended as a firstline treatment for preventing variceal bleeding, although TIPS is considered in patients in whom endoscopic and
radiology.rsna.org n Radiology: Volume 000: Number 0— 2015
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
pharmacologic therapy have failed (4,5). To our knowledge, there has been no clinical study evaluating the true applicability of the present treatment options, including TIPS, endoscopic treatment, and nonselective b-blockers, in the prevention of recurrent variceal bleeding in patients with cirrhosis and PVT. The main limitation of our study was that anticoagulation with warfarin was not comparable between the two groups. Anticoagulation was not started until eradication in the EBL group, whereas the TIPS group took warfarin immediately after stent placement. Although retrospective multivariate analysis in previous studies demonstrated that anticoagulation therapy in noncirrhotic patients would not increase the risk of gastrointestinal bleeding, the safety in patients with cirrhosis, especially those at a decompensated stage, remains unknown. Our anticoagulation therapy strategy in the EBL group was similar to that in two very recent clinical studies (22,23). Moreover, warfarin is not the suitable drug for anticoagulation therapy in patients with decompensated cirrhosis, as international normalized ratio may not reflect the true level of anticoagulation achieved by vitamin K antagonists. In conclusion, although further studies are needed, our results suggest that TIPS may be more effective than EBL plus propranolol in preventing recurrent esophageal variceal bleeding in patients with advanced cirrhosis and PVT and does not increase the incidence of hepatic encephalopathy. During the limited follow-up, survival was similar in the two groups. Acknowledgment: The authors thank Professor Song Ho-Young for critically reviewing the manuscript. Disclosures of Conflicts of Interest: X. Luo disclosed no relevant relationships. Z.W. disclosed no relevant relationships. J.T. disclosed no relevant relationships. B.Z. disclosed no relevant relationships. H.Z. disclosed no relevant relationships. X. Li disclosed no relevant relationships.
sis and variceal bleeding. N Engl J Med 2010;362(25):2370–2379.
Luo et al
intrahepatic portosystemic shunt on portal vein thrombosis in patients with cirrhosis. Gut 2011;60(6):846–852.
2. Sauer P, Theilmann L, Stremmel W, Benz C, Richter GM, Stiehl A. Transjugular intrahepatic portosystemic stent shunt versus sclerotherapy plus propranolol for variceal rebleeding. Gastroenterology 1997; 113(5):1623–1631.
14. Han G, Qi X, He C, et al. Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with symptomatic portal hypertension in liver cirrhosis. J Hepatol 2011;54(1):78–88.
3. Pomier-Layrargues G, Villeneuve JP, Deschênes M, et al. Transjugular intrahepatic portosystemic shunt (TIPS) versus endoscopic variceal ligation in the prevention of variceal rebleeding in patients with cirrhosis: a randomised trial. Gut 2001;48(3):390–396.
15. Senzolo M, Tibbals J, Cholongitas E, Tri antos CK, Burroughs AK, Patch D. Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with and without cavernous transformation. Aliment Pharmacol Ther 2006;23(6):767–775.
4. Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010;362(9):823–832. [Published correction appears in N Engl J Med 2011;364(5):490. Dosage error in article text.]
16. Perarnau JM, Baju A, D’alteroche L, Viguier J, Ayoub J. Feasibility and long-term evolution of TIPS in cirrhotic patients with portal thrombosis. Eur J Gastroenterol Hepatol 2010;22(9):1093–1098.
5. 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. 6. Zheng M, Chen Y, Bai J, et al. Transjugular intrahepatic portosystemic shunt versus endoscopic therapy in the secondary prophylaxis of variceal rebleeding in cirrhotic patients: meta-analysis update. J Clin Gastroenterol 2008;42(5):507–516. 7. Francoz C, Valla D, Durand F. Portal vein thrombosis, cirrhosis, and liver transplantation. J Hepatol 2012;57(1):203–212. 8. Tsochatzis EA, Senzolo M, Germani G, Gatt A, Burroughs AK. Systematic review: portal vein thrombosis in cirrhosis. Aliment Pharmacol Ther 2010;31(3):366–374. 9. Englesbe MJ, Kubus J, Muhammad W, et al. Portal vein thrombosis and survival in patients with cirrhosis. Liver Transpl 2010;16(1):83–90. 10. Tripodi A, Primignani M, Chantarangkul V, et al. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology 2009;137(6): 2105–2111. 11. Werner KT, Sando S, Carey EJ, et al. Portal vein thrombosis in patients with end stage liver disease awaiting liver transplantation: outcome of anticoagulation. Dig Dis Sci 2013; 58(6):1776–1780.
References
12. Francoz C, Belghiti J, Vilgrain V, et al. Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation. Gut 2005; 54(5):691–697.
1. García-Pagán JC, Caca K, Bureau C, et al. Early use of TIPS in patients with cirrho-
13. Luca A, Miraglia R, Caruso S, et al. Shortand long-term effects of the transjugular
Radiology: Volume 000: Number 0— 2015 n radiology.rsna.org
17. Van Ha TG, Hodge J, Funaki B, et al. Transjugular intrahepatic portosystemic shunt placement in patients with cirrhosis and concomitant portal vein thrombosis. Cardiovasc Intervent Radiol 2006;29(5):785–790. 18. Cejna M, Peck-Radosavljevic M, Thurnher SA, Hittmair K, Schoder M, Lammer J. Creation of transjugular intrahepatic portosystemic shunts with stent-grafts: initial experiences with a polytetrafluoroethylenecovered nitinol endoprosthesis. Radiology 2001;221(2):437–446. 19. Escorsell A, Bañares R, García-Pagán JC, et al. TIPS versus drug therapy in preventing variceal rebleeding in advanced cirrhosis: a randomized controlled trial. Hepatology 2002;35(2):385–392. 20. Søgaard KK, Horváth-Puhó E, Grønbaek H, Jepsen P, Vilstrup H, Sørensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study. Am J Gastroenterol 2009;104(1):96–101. 21. DeLeve LD, Valla DC, Garcia-Tsao G; American Association for the Study Liver Diseases. Vascular disorders of the liver. Hepatology 2009;49(5):1729–1764. 22. Delgado MG, Seijo S, Yepes I, et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol 2012;10(7):776–783. 23. Amitrano L, Guardascione MA, Menchise A, et al. Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis. J Clin Gastroenterol 2010;44(6):448–451. 24. Senzolo M, M Sartori T, Rossetto V, et al. Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal
7
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
vein thrombosis in cirrhosis. Liver Int 2012; 32(6):919–927. 25. Sauer P, Hansmann J, Richter GM, Stremmel W, Stiehl A. Endoscopic variceal ligation plus propranolol vs transjugular intrahepatic portosystemic stent shunt: a longterm randomized trial. Endoscopy 2002; 34(9):690–697. 26. García-Villarreal L, Martínez-Lagares F, Sierra A, et al. Transjugular intrahepatic portosystemic shunt versus endoscopic sclerotherapy for the prevention of variceal rebleeding after recent variceal hemorrhage. Hepatology 1999;29(1):27–32. 27. 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.
8
28. Perarnau JM, Le Gouge A, Nicolas C, et al. Covered vs uncovered stents for transjugular intrahepatic portosystemic shunt: a randomized controlled trial. J Hepatol 2014;60(5):962–968.
Luo et al
shunts compared with endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage: a randomized, controlled trial. Ann Intern Med 1997;126(11):849–857.
29. Chen S, Li X, Wei B, et al. 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.
32. Merli M, Salerno F, Riggio O, et al. Transjugular intrahepatic portosystemic shunt versus endoscopic sclerotherapy for the prevention of variceal bleeding in cirrhosis: a randomized multicenter trial. Gruppo Italiano Studio TIPS (G.I.S.T.). Hepatology 1998;27(1):48–53.
30. Cello JP, Ring EJ, Olcott EW, et al. Endoscopic sclerotherapy compared with percutaneous transjugular intrahepatic portosystemic shunt after initial sclerotherapy in patients with acute variceal hemorrhage: a randomized, controlled trial. Ann Intern Med 1997;126(11):858–865.
33. Tripathi D, Lui HF, Helmy A, et al. Ran domised controlled trial of long term portographic follow up versus variceal band ligation following transjugular intrahepatic portosystemic stent shunt for preventing oesophageal variceal rebleeding. Gut 2004; 53(3):431–437.
31. Sanyal AJ, Freedman AM, Luketic VA, et al. Transjugular intrahepatic portosystemic
radiology.rsna.org n Radiology: Volume 000: Number 0— 2015
Original Research n Vascular
Xuefeng Luo, MD Zhu Wang, MD Jiaywei Tsauo, MD Biao Zhou, MD Hailong Zhang, MD Xiao Li, MD
Purpose:
To compare transjugular intrahepatic portosystemic shunt (TIPS) placement with or without variceal embolization with endoscopic band ligation (EBL) plus propranolol in preventing recurrent esophageal variceal bleeding in patients with advanced cirrhosis and portal vein thrombosis.
Materials and Methods:
The present randomized controlled trial was approved by the ethics committee board of West China Hospital. Written informed consent was obtained from each patient. Between January 2010 and December 2012, 73 patients were randomly allocated to receive TIPS (n = 37) or EBL plus propranolol (n = 36). The comparisons of recurrent variceal bleeding, hepatic encephalopathy, and survival rates were based on the Kaplan-Meier method and were compared using the log-rank test.
Results:
The mean follow-up time was 22.8 months 6 7.7(standard deviation) in the TIPS group and 20.9 months 6 8.9 in the EBL group. The 2-year probability of remaining free of recurrent variceal bleeding was higher in the TIPS group (77.8%) than in the EBL group (42.9%) (P = .002). Overall recanalization was achieved in 24 (64.9%) patients from the TIPS group and seven (19.4%) patients from the EBL group. The hepatic encephalopathy rates exhibited no significant differences between the two groups (P = .53). The 1- and 2-year probability of survival was 86.5% and 72.9%, respectively, in the TIPS group and 83.3% and 57.2%, respectively, in the EBL group, with no significant difference (P = .23).
Conclusion:
TIPS was more effective than EBL plus propranolol in preventing recurrent esophageal variceal bleeding in patients with advanced cirrhosis and portal vein thrombosis and did not increase the incidence of hepatic encephalopathy. Survival was similar in both groups.
1
From the Center of Interventional Radiology and Department of Gastroenterology, West China Hospital, Sichuan University, 37 Guoxue Lane, 610041 Chengdu, Sichuan, China. Received July 18, 2014; revision requested September 15; final revision received December 3; accepted December 13; final version accepted December 18. Supported by the National Nature Science Foundation of China (grants 81371656 and 81171444). Address correspondence to X. Li (e-mail: [email protected]).
and Interventional Radiology
Advanced Cirrhosis Combined with Portal Vein Thrombosis: A Randomized Trial of TIPS versus Endoscopic Band Ligation Plus Propranolol for the Prevention of Recurrent Esophageal Variceal Bleeding1
RSNA, 2015
q
RSNA, 2015
q
Radiology: Volume 000: Number 0— 2015 n radiology.rsna.org
1
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
V
ariceal bleeding is a major cause of death in patients with advanced cirrhosis. Failure to control acute variceal bleeding, early recurrent bleeding, and marked elevations in portal pressure are associated with increased mortality (1–3). Given the high recurrence rate, patients who survive acute variceal hemorrhage should receive prophylactic therapy to prevent recurrence before they are discharged from the hospital (4). In recent decades, clinical trials and meta-analyses concluded that the combination of endoscopic band ligation (EBL) and nonselective b-blockers should be considered as a first-line therapy for the prevention of recurrent variceal bleeding, reserving transjugular intrahepatic portosystemic shunt (TIPS) for those who fail standard medical therapy due to the higher incidence of postprocedure hepatic encephalopathy and lack of improved survival (4,5). Recently, some authors reported that TIPS may be more effective than endoscopic therapy combined with propranolol in the prevention of recurrent variceal bleeding (1,6). However, the exact efficacy of this strategy remains unclear because prospectively randomized controlled studies are lacking. Nonneoplastic portal vein thrombosis (PVT) is a critical but frequent event in patients with advanced cirrhosis, with an incidence ranging from 1% to 36% (7–10). Although the impact of PVT on the natural prognosis
Advances in Knowledge nn The 2-year probability of remaining free of recurrent variceal bleeding was higher in the transjugular intrahepatic portosystemic shunt (TIPS) group (77.8%) than in the endoscopic band ligation (EBL) group (42.9%) (P = .002). nn The hepatic encephalopathy rates exhibited no significant differences between the TIPS group and the EBL group (16.7% vs 17.7% at 1-year follow-up and 38.5% vs 46.5% at 2-year follow-up) (P = .53). 2
of cirrhosis remains controversial, it might worsen liver function and aggravate portal hypertension, with increased risks of the rupture of varices and the development of ascites. In addition, the presence of PVT increases posttransplantation morbidity and mortality and might even contraindicate transplantation, especially in patients with PVT that extends to the confluence of the superior mesenteric vein and the splenic vein (7,11,12). Several retrospective uncontrolled studies have shown that TIPS decreases portal pressure, prevents the recurrence of variceal bleeding, and recanalizes the portal vein by restoring portal venous flow (13–17). However, there is no established management algorithm for the prevention of recurrent esophageal variceal bleeding in patients with cirrhosis and PVT due to limited data. In addition, to our knowledge, TIPS has not been compared with EBL with respect to the prevention of recurrent esophageal variceal bleeding in patients with cirrhosis and PVT after the first bleeding episode. Therefore, the purpose of this randomized controlled trial was to prospectively compare TIPS with EBL plus propranolol in preventing recurrent esophageal variceal bleeding in patients with cirrhosis and PVT after the first bleeding episode.
Luo et al
on the basis of clinical history, physical examination, laboratory and imaging findings, and liver biopsy. Forty-one patients with any of the following were excluded from the study: PVT of 25% or less within the vessel lumen (n = 11); limited thrombosis in the intrahepatic portal branch (n = 8); portal cavernoma (n = 5); gastric varices (n = 9); hepatocellular carcinoma (n = 2); previous endoscopic treatment of varices within 3 months (n = 2); and contradictions to TIPS, EBL, or propranolol (n = 4) (Fig 1). The remaining 73 patients were randomly assigned to the TIPS group (n = 37) or the EBL group (n = 36). This randomized controlled trial was approved by the ethics committee board of West China Hospital and was registered in the Chinese Clinical Trial Registry (ChiCTR-TRC-11001577). Written informed consent for inclusion in the clinical trial and the treatment was obtained from each patient. Eligible patients were assigned randomly to the TIPS or EBL group by using consecutive numbers generated by computerallocated random-digit numbers.
Treatments The TIPS procedure was performed by two experienced radiologists (X.F.L. and X.L. with 5 and 10 years of experience, respectively) with a standard technique described previously (18).
Materials and Methods Study Design Between January 2010 and December 2012, 114 patients with cirrhosis and PVT, aged 18–70 years, a previous episode of variceal bleeding, and a ChildPugh score of 7–13 were considered eligible for inclusion in this study. The diagnosis of liver cirrhosis was made Implication for Patient Care nn TIPS was superior to EBL plus propranolol in the prevention of recurrent variceal bleeding in patients with advanced cirrhosis and portal vein thrombosis without increasing the incidence of hepatic encephalopathy.
Published online before print 10.1148/radiol.15141252 Content codes: Radiology 2015; 000:1–8 Abbreviations: EBL = endoscopic band ligation PVT = portal vein thrombosis TIPS = transjugular intrahepatic portosystemic shunt Author contributions: Guarantors of integrity of entire study, B.Z., H.Z., X. Li; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, Z.W., H.Z.; clinical studies, X. Luo, Z.W., B.Z., H.Z., X. Li; statistical analysis, Z.W., B.Z., H.Z., X. Li; and manuscript editing, Z.W., J.T., H.Z. Conflicts of interest are listed at the end of this article.
radiology.rsna.org n Radiology: Volume 000: Number 0— 2015
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
Contrast material–enhanced CT, CO2wedged hepatic venography, or superior mesenteric arteriography was utilized to assist intrahepatic portal vein catheterization (Fig 2). Once the portal vein was accessed, a hydrophilic guidewire (Radiofocus M, Terumo, Tokyo, Japan) was advanced gradually to cross the thrombosed section until it reached the patent portion of the main portal vein, splenic vein, or superior mesenteric vein. A portal venogram was obtained, and the portal systemic gradient was also measured. The intrahepatic tract was dilated by using an 8 3 60-mm angioplasty balloon catheter (Powerflex; Cordis, Roden, the Netherlands). Ten-millimeter expanded polytetrafluoroethylenecovered stents (Fluency; C.R. Bard, Murray Hill, NJ) were implanted, with their proximal end at the hepatocaval junction and their distal end in the patent portion of the main portal vein. Subsequently, the portal systemic gradient was re-measured, and the stents were dilated again if necessary. A second stent would be deployed coaxially if the first stent could not maintain sufficient intrastent flow. Embolization with coils (MReye; Cook, Bloomington, Ind) was performed when portosystemic collateral veins were observed at postprocedure portography. Intravenous heparin (3000 U) was administered to all the patients once the portal vein was entered. Low-molecular-weight heparin was prescribed for 3 days, and warfarin was continued for an additional 6 months after recanalization of the portal venous system, with a target international normalized ratio of 2–3. Each session of EBL was performed by the same experienced hepatologist. A multiband ligator (Wilson-Cook Medical, Winston-Salem, NC) was utilized. During each treatment session, 4–6 elastic bands were used to ligate the varices. EBL was performed every 4–6 weeks until the varices were eradicated. Patients in the EBL group underwent routine endoscopy every 3–6 months. The recurrence of varices was treated with further ligations. For patients in the EBL group, propranolol was initiated at a dose of 20
Luo et al
Figure 1
Figure 1: Flowchart of screening and randomization of patients. HCC = hepatocellular carcinoma.
Figure 2
Figure 2: A, B, Contrast-enhanced CT scans show severe thrombosis (arrowhead) in the intrahepatic portal branches (A) and the main portal vein (B). C, Direct portal venogram shows extensive thrombosis in the portal venous system, multiple collaterals (arrows), and hepatofugal flow. D, One covered stent was deployed after the competing collaterals were embolized. Fifteen months after TIPS placement, E, F, CT scans show complete recanalization of the portal vein.
mg/day. The dose was increased by 20–40 mg per/day, every week, either until a reduction of the resting heart
Radiology: Volume 000: Number 0— 2015 n radiology.rsna.org
rate of 25% was achieved or up to the maximum dose was tolerated. In general, the dose was increased if it 3
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
was clinically tolerated and if the systolic blood pressure was 90 mm Hg or higher, with a resting heart rate of 55 beats per minute or higher. Immediately after variceal eradication, warfarin was prescribed and continued for an additional 6 months after recanalization of the portal venous system, with a target international normalized ratio of 2–3.
Follow-up and End Points Patients in both groups were followed until liver transplantation, death, or lost to follow-up. In the TIPS group, patients were evaluated at 1, 3, and 6 months after discharge and every 6 months thereafter or whenever clinically necessary. In the EBL group, patients were evaluated every 4–6 weeks at the time of EBL and every 3–6 months after variceal eradication. The primary end point was the incidence of recurrent variceal bleeding. The secondary end points were incidence of TIPS dysfunction, recanalization of the portal venous system, occurrence of hepatic encephalopathy, or death for any reason. Sample Size and Statistical Analyses We hypothesized that the 1-year recurrent variceal bleeding rate was 15% in the TIPS group and 45% in the EBL group based on published reports (3,6,14,19). The sample size was calculated by using a two-sided test. Thirtysix patients in each group were considered to detect the above-mentioned differences with a of .05 and b of .20. The data are expressed as the means 6 standard deviation. Categorical data are expressed as percentages. The results of the study were analyzed by using Student test for continuous data and the x2 test for categorical outcomes. The comparisons of recurrent variceal bleeding, hepatic encephalopathy, and survival rates were based on the Kaplan-Meier method and were compared by using the log-rank test. All tests of significance were two sided, and a P value , .05 was considered to indicate a statistically significant difference. Data processing and statistical analyses were performed 4
with SPSS (SPSS, version 16.0; SPSS, Chicago, Ill).
Results Study Patients There were no significant differences in the baseline characteristics between the two groups (Table). Three patients (one in the TIPS group and two in the EBL group) were lost to follow-up after a mean of 7 months. The mean follow-up time was 22.8 months 6 7.7 in the TIPS group and 20.9 months 6 8.9 in the EBL group. Treatments In the TIPS group, technical success was achieved in all 37 patients (100%). The mean portal systemic gradient decreased from 27.5 mm Hg 6 7.5 to 10.4 mm Hg 6 3.1 after shunt creation (P , .001). Variceal embolization was performed in 21 patients. One patient did not undergo variceal embolization because the varices were too tortuous to be catheterized. Two patients developed hepatic encephalopathy (grade III) at 2 and 3 days after the procedure, and both were successfully treated with medical therapy. No other major procedural complications were observed following TIPS. In the EBL group, 21 patients (58.3%) achieved variceal eradication after a mean of 3.5 EBL sessions, including four patients after recurrent variceal bleeding. Two patients did not achieve variceal eradication even after seven and five EBL sessions. Eleven patients experienced transient retrosternal pain after EBL, and post-EBL ulcer bleeding occurred in two patients. All patients received propranolol, with a mean dose of 65.4 mg/day 6 26.7. The dose was reduced in one patient due to bradycardia. Recurrent Bleeding During the follow-up period, a total of 43 variceal bleeding episodes occurred in 31 patients: 12 episodes in 10 patients from the TIPS group and 31 episodes in 21 patients from the EBL group. Eight of nine patients in the TIPS group
Luo et al
who underwent direct portal venography exhibited dysfunctional TIPS, with complete stent occlusion in six patients and stent stenosis in two patients. The remaining one patient died of massive gastrointestinal bleeding before revision could be performed in a local hospital. Nine of 21 patients in the EBL group received additional ligations. Recurrent bleeding in another 12 patients was considered uncontrolled; nine patients were treated with TIPS, whereas three patients died before TIPS placement could be performed. The 1- and 2-year probability of remaining free of recurrent variceal bleeding was 89.2% and 77.8%, respectively, in the TIPS group and 58.2% and 42.9%, respectively, in the EBL group. The recurrent variceal bleeding rate was significantly lower in the TIPS group than in the EBL group (P = .002, Fig 3).
TIPS Dysfunction and Recanalization of the Portal Venous System TIPS dysfunction occurred in 12 patients during the follow-up period. Direct portography confirmed stent occlusion in seven cases and stenosis in four cases. The remaining one patient died at a local hospital due to massive recurrent variceal bleeding before portal angiography could be performed. TIPS revision was successfully performed in nine patients with additional stent placement, and two patients underwent parallel TIPS creation. The 1- and 2-year probability of TIPS patency was 91.7% and 71.3%, respectively. The portal venous system was recanalized in a total of 31 patients: 24 (64.9%) from the TIPS group and seven (19.4%) from the EBL group. Improvement of PVT was also observed in five patients in the TIPS group and in nine patients in the EBL group. Hepatic Encephalopathy Hepatic encephalopathy occurred in a total of 31 patients: 15 from the TIPS group and 16 from the EBL group. Refractory hepatic encephalopathy occurred in five patients (three in the TIPS group and two in the EBL group), including four patients who died of progressive hepatic failure. The 1- and
radiology.rsna.org n Radiology: Volume 000: Number 0— 2015
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
Luo et al
Figure 3 Baseline Characteristics of TIPS and EBL Groups Variable Age (y)* M/F Cause of cirrhosis Hepatitis B virus Hepatitis C virus Alcohol Other Child-Pugh class B Child-Pugh class C Child-Pugh score* MELD score* Bilirubin level (mmol/L)* Albumin level (g/L)* Blood urea nitrogen level (mmol/L)* Creatinine level (mmol/L)* Sodium level (mmol/L)* Prothrombin time (sec)* International normalized ratio* Hemoglobin level (g/L)* White blood cell count (3109/L)* Platelet count (3109/L)* Hepatic encephalopathy grade 0 1 2 3 4 Ascites grade 0 I II III PVT grade II (26%–50% within vessel lumen) III (51%–75% within vessel lumen) IV (76 within vessel lumen) No. of thrombosed vessels 1 2 3
TIPS (n = 37)
EBL (n = 36)
P Value
50.78 6 13.61 19/18
49.53 6 14.02 24/12
.699 .236† .412‡
27 3 2 5 25 12
24 2 4 6 24 12
8.76 6 1.70 14.2 6 6.5 29.84 6 24.95 29.44 6 4.80 6.94 6 4.10 73.02 6 19.09 138.13 6 5.98 16.97 6 5.91 1.52 6 3.45 80.86 6 20.31 5.07 6 3.76 114.03 6 124.47
8.89 6 1.77 15.9 6 5.7 28.98 6 17.10 30.36 6 5.39 5.74 6 2.67 72.17 6 19.08 136.58 6 3.85 16.63 6 3.12 1.43 6 0.34 81.08 6 26.12 5.78 6 3.99 105.78 6 78.59
35 1 1 0 0
33 0 3 0 0
17 15 3 2
16 10 9 1
.935‡ .746 .376 .866 .438 .140 .849 .195 .761 .176 .968 .433 .737 .597‡
.796‡ 9 15 13
11 12 13 .534‡
5 22 10
5 18 13
* Data are means 6 standard deviations. x2 test.
‡
Mann-Whitney U test.
Figure 4
.354‡
Note.—Unless otherwise indicated, data are the number of patients. †
Figure 3: Graph shows the probability of remaining free from recurrent variceal bleeding between the two groups.
2-year probability of hepatic encephalopathy occurrence was 16.2% and 38.5%, respectively, in the TIPS group and 17.7% and 46.5%, respectively, in the EBL group. The hepatic encephalopathy occurrence rates were not
significantly different between the two groups (P = .53, Fig 4).
Survival A total of 29 patients died during the follow-up period: 12 from the TIPS
Radiology: Volume 000: Number 0— 2015 n radiology.rsna.org
Figure 4: Graph shows the probability of hepatic encephalopathy between the two groups.
group and 17 from the EBL group. The 1- and 2-year probability of survival was 86.5% and 72.9%, respectively, in the TIPS group and 83.3% and 57.2%, respectively, in the EBL group, with no significant difference between the two groups (P = .23, Fig 5). Nine patients in the TIPS group and 10 in the EBL group died of hepatic failure. One patient in the TIPS group and three in the EBL group died due to uncontrolled gastrointestinal bleeding. Other causes of death included multiple organ dysfunction syndrome (one TIPS patient and two EBL patients), hepatocellular carcinoma (one patient in each group), and sepsis (one patient of the EBL group). 5
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
Figure 5
Figure 5: Graph shows the probability of survival between the two groups.
Discussion Our results demonstrated that TIPS was superior to EBL plus propranolol in the prevention of recurrent variceal bleeding in patients with advanced cirrhosis and PVT without increasing the incidence of hepatic encephalopathy. However, the survival rate was not influenced by either TIPS or EBL plus propranolol. Our data also indicated that TIPS may have some advantages over EBL plus propranolol as a first-line therapy to prevent recurrent variceal bleeding in patients with advanced cirrhosis and PVT. Recently, our understanding of coagulopathy in cirrhosis has changed, and patients with cirrhosis, especially in the advanced decompensated stage, are no longer considered to be in a hypocoagulable state (7–9). Moreover, patients with cirrhosis or noncirrhotic liver disease had a substantially increased risk of venous thromboembolism (20). The optimal treatment of PVT and related portal hypertensive complications in cirrhosis has not been addressed in any consensus publication, including the very recent practice guidelines (5,21). The safety and efficacy of anticoagulation in the treatment of PVT in cirrhosis have been reported in a few series, whereas TIPS is preserved as an alternative therapy when anticoagulation fails due to its inherent defects (12,22–24). Recently, two large 6
retrospective studies demonstrated that TIPS is a safe and feasible therapy for PVT in patients with decompensated cirrhosis, with the additional benefit of treating variceal bleeding (13,14). However, these published studies generally focused more on the outcome of PVT than on symptomatic portal hypertension. There have been no controlled studies of b-adrenergic blockers or endoscopic therapy in such patients. We found that the recurrent variceal bleeding rate in the EBL group was higher than that reported in several previous reports (2,19,25,26) and slighter lower than that in another study (3). This result may be explained by the characteristics of our patient selection (a Child-Pugh score of 7–13) and the presence of PVT, which aggravated portal hypertension. More importantly, recanalization of the portal venous system was realized in only seven patients (19.4%) in the EBL group. Our results confirm previous studies revealing that the recurrent variceal bleeding rate was much lower after TIPS than after endoscopic treatment (6,27). Given that the combination of EBL and propranolol is ineffective for eliminating thrombosis or rectifying the underlying coagulopathy in patients with cirrhosis, its ability to reduce variceal bleeding may be counteracted by deteriorated PVT in most cases. The treatment strategy for patients with cirrhosis with symptomatic portal hypertension and PVT should take into account the presence of PVT. Although hepatic encephalopathy remains a potential risk in patients treated with TIPS, there is no significant difference between the two groups with respect to the proportion of patients exhibiting clinical hepatic encephalopathy. In our study, hepatic encephalopathy occurred more frequently in the EBL group than in other studies (3,25), possibly due to the poor recanalization rate of the portal venous system and the high occurrence of variceal bleeding. In patients with advanced cirrhosis and more severe PVT, TIPS was not associated with an increase in hepatic encephalopathy compared with EBL plus propranolol.
Luo et al
Although the risk of recurrent variceal bleeding was significantly reduced in the TIPS group, there was no significant difference in the cumulative survival rates between the two groups. In our study, only one patient in the TIPS group died of variceal bleeding in a remote hospital without timely treatment, whereas three patients in the EBL group presented with massive uncontrolled gastrointestinal bleeding and died before TIPS could be accomplished. It should be noted that nine patients with recurrent variceal bleeding in the EBL group received rescue TIPS, which might have obscured a potential benefit of TIPS for survival. Another explanation may be related to the relatively short follow-up. The incidence of shunt dysfunction was similar to that in a previous study in which patients with cirrhosis and PVT were included (13) and was better than that in a very recent study (39.9% for the Viatorr stent at 2 years) (28). The possible explanations for these differences are as follows: First, during the TIPS placement procedure, we deployed the stent with great caution to ensure that the proximal end of the stent was at the hepatocaval junction and that the distal end was in a patent portion of the portal vein. A second stent, usually a bare stent, would be deployed coaxially to ensure adequate blood flow in the stent if necessary. Second, variceal embolization in patients with competing portosystemic collateral veins may reduce the risk of shunt dysfunction and recurrent variceal bleeding during the first 6 months after TIPS (29). Third, the addition of warfarin may help maintain the patency of the portal vein. The current management strategies for the prophylaxis of recurrent variceal bleeding are based on the results of several randomized clinical trials and meta-analyses in which patients with PVT were mostly excluded (2,3,25,26,30–33). A combination of EBL and nonselective b-blocker therapy is recommended as a firstline treatment for preventing variceal bleeding, although TIPS is considered in patients in whom endoscopic and
radiology.rsna.org n Radiology: Volume 000: Number 0— 2015
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
pharmacologic therapy have failed (4,5). To our knowledge, there has been no clinical study evaluating the true applicability of the present treatment options, including TIPS, endoscopic treatment, and nonselective b-blockers, in the prevention of recurrent variceal bleeding in patients with cirrhosis and PVT. The main limitation of our study was that anticoagulation with warfarin was not comparable between the two groups. Anticoagulation was not started until eradication in the EBL group, whereas the TIPS group took warfarin immediately after stent placement. Although retrospective multivariate analysis in previous studies demonstrated that anticoagulation therapy in noncirrhotic patients would not increase the risk of gastrointestinal bleeding, the safety in patients with cirrhosis, especially those at a decompensated stage, remains unknown. Our anticoagulation therapy strategy in the EBL group was similar to that in two very recent clinical studies (22,23). Moreover, warfarin is not the suitable drug for anticoagulation therapy in patients with decompensated cirrhosis, as international normalized ratio may not reflect the true level of anticoagulation achieved by vitamin K antagonists. In conclusion, although further studies are needed, our results suggest that TIPS may be more effective than EBL plus propranolol in preventing recurrent esophageal variceal bleeding in patients with advanced cirrhosis and PVT and does not increase the incidence of hepatic encephalopathy. During the limited follow-up, survival was similar in the two groups. Acknowledgment: The authors thank Professor Song Ho-Young for critically reviewing the manuscript. Disclosures of Conflicts of Interest: X. Luo disclosed no relevant relationships. Z.W. disclosed no relevant relationships. J.T. disclosed no relevant relationships. B.Z. disclosed no relevant relationships. H.Z. disclosed no relevant relationships. X. Li disclosed no relevant relationships.
sis and variceal bleeding. N Engl J Med 2010;362(25):2370–2379.
Luo et al
intrahepatic portosystemic shunt on portal vein thrombosis in patients with cirrhosis. Gut 2011;60(6):846–852.
2. Sauer P, Theilmann L, Stremmel W, Benz C, Richter GM, Stiehl A. Transjugular intrahepatic portosystemic stent shunt versus sclerotherapy plus propranolol for variceal rebleeding. Gastroenterology 1997; 113(5):1623–1631.
14. Han G, Qi X, He C, et al. Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with symptomatic portal hypertension in liver cirrhosis. J Hepatol 2011;54(1):78–88.
3. Pomier-Layrargues G, Villeneuve JP, Deschênes M, et al. Transjugular intrahepatic portosystemic shunt (TIPS) versus endoscopic variceal ligation in the prevention of variceal rebleeding in patients with cirrhosis: a randomised trial. Gut 2001;48(3):390–396.
15. Senzolo M, Tibbals J, Cholongitas E, Tri antos CK, Burroughs AK, Patch D. Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with and without cavernous transformation. Aliment Pharmacol Ther 2006;23(6):767–775.
4. Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010;362(9):823–832. [Published correction appears in N Engl J Med 2011;364(5):490. Dosage error in article text.]
16. Perarnau JM, Baju A, D’alteroche L, Viguier J, Ayoub J. Feasibility and long-term evolution of TIPS in cirrhotic patients with portal thrombosis. Eur J Gastroenterol Hepatol 2010;22(9):1093–1098.
5. 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. 6. Zheng M, Chen Y, Bai J, et al. Transjugular intrahepatic portosystemic shunt versus endoscopic therapy in the secondary prophylaxis of variceal rebleeding in cirrhotic patients: meta-analysis update. J Clin Gastroenterol 2008;42(5):507–516. 7. Francoz C, Valla D, Durand F. Portal vein thrombosis, cirrhosis, and liver transplantation. J Hepatol 2012;57(1):203–212. 8. Tsochatzis EA, Senzolo M, Germani G, Gatt A, Burroughs AK. Systematic review: portal vein thrombosis in cirrhosis. Aliment Pharmacol Ther 2010;31(3):366–374. 9. Englesbe MJ, Kubus J, Muhammad W, et al. Portal vein thrombosis and survival in patients with cirrhosis. Liver Transpl 2010;16(1):83–90. 10. Tripodi A, Primignani M, Chantarangkul V, et al. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology 2009;137(6): 2105–2111. 11. Werner KT, Sando S, Carey EJ, et al. Portal vein thrombosis in patients with end stage liver disease awaiting liver transplantation: outcome of anticoagulation. Dig Dis Sci 2013; 58(6):1776–1780.
References
12. Francoz C, Belghiti J, Vilgrain V, et al. Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation. Gut 2005; 54(5):691–697.
1. García-Pagán JC, Caca K, Bureau C, et al. Early use of TIPS in patients with cirrho-
13. Luca A, Miraglia R, Caruso S, et al. Shortand long-term effects of the transjugular
Radiology: Volume 000: Number 0— 2015 n radiology.rsna.org
17. Van Ha TG, Hodge J, Funaki B, et al. Transjugular intrahepatic portosystemic shunt placement in patients with cirrhosis and concomitant portal vein thrombosis. Cardiovasc Intervent Radiol 2006;29(5):785–790. 18. Cejna M, Peck-Radosavljevic M, Thurnher SA, Hittmair K, Schoder M, Lammer J. Creation of transjugular intrahepatic portosystemic shunts with stent-grafts: initial experiences with a polytetrafluoroethylenecovered nitinol endoprosthesis. Radiology 2001;221(2):437–446. 19. Escorsell A, Bañares R, García-Pagán JC, et al. TIPS versus drug therapy in preventing variceal rebleeding in advanced cirrhosis: a randomized controlled trial. Hepatology 2002;35(2):385–392. 20. Søgaard KK, Horváth-Puhó E, Grønbaek H, Jepsen P, Vilstrup H, Sørensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study. Am J Gastroenterol 2009;104(1):96–101. 21. DeLeve LD, Valla DC, Garcia-Tsao G; American Association for the Study Liver Diseases. Vascular disorders of the liver. Hepatology 2009;49(5):1729–1764. 22. Delgado MG, Seijo S, Yepes I, et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol 2012;10(7):776–783. 23. Amitrano L, Guardascione MA, Menchise A, et al. Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis. J Clin Gastroenterol 2010;44(6):448–451. 24. Senzolo M, M Sartori T, Rossetto V, et al. Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal
7
VASCULAR AND INTERVENTIONAL RADIOLOGY: Recurrent Variceal Bleeding: TIPS versus Endoscopic Band Ligation Plus Propranolol
vein thrombosis in cirrhosis. Liver Int 2012; 32(6):919–927. 25. Sauer P, Hansmann J, Richter GM, Stremmel W, Stiehl A. Endoscopic variceal ligation plus propranolol vs transjugular intrahepatic portosystemic stent shunt: a longterm randomized trial. Endoscopy 2002; 34(9):690–697. 26. García-Villarreal L, Martínez-Lagares F, Sierra A, et al. Transjugular intrahepatic portosystemic shunt versus endoscopic sclerotherapy for the prevention of variceal rebleeding after recent variceal hemorrhage. Hepatology 1999;29(1):27–32. 27. 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.
8
28. Perarnau JM, Le Gouge A, Nicolas C, et al. Covered vs uncovered stents for transjugular intrahepatic portosystemic shunt: a randomized controlled trial. J Hepatol 2014;60(5):962–968.
Luo et al
shunts compared with endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage: a randomized, controlled trial. Ann Intern Med 1997;126(11):849–857.
29. Chen S, Li X, Wei B, et al. 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.
32. Merli M, Salerno F, Riggio O, et al. Transjugular intrahepatic portosystemic shunt versus endoscopic sclerotherapy for the prevention of variceal bleeding in cirrhosis: a randomized multicenter trial. Gruppo Italiano Studio TIPS (G.I.S.T.). Hepatology 1998;27(1):48–53.
30. Cello JP, Ring EJ, Olcott EW, et al. Endoscopic sclerotherapy compared with percutaneous transjugular intrahepatic portosystemic shunt after initial sclerotherapy in patients with acute variceal hemorrhage: a randomized, controlled trial. Ann Intern Med 1997;126(11):858–865.
33. Tripathi D, Lui HF, Helmy A, et al. Ran domised controlled trial of long term portographic follow up versus variceal band ligation following transjugular intrahepatic portosystemic stent shunt for preventing oesophageal variceal rebleeding. Gut 2004; 53(3):431–437.
31. Sanyal AJ, Freedman AM, Luketic VA, et al. Transjugular intrahepatic portosystemic
radiology.rsna.org n Radiology: Volume 000: Number 0— 2015
