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Survival benefit of TIPS versus serial paracentesis in patients with refractory ascites: a single institution case-control propensity score analysis
Clinical Radiology 70 (2015) e51ee57
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Survival benefit of TIPS versus serial paracentesis in patients with refractory ascites: a single institution case-control propensity score analysis R.C. Gaba a, *, A. Parvinian b, L.C. Casadaban b, P.M. Couture b, S.P. Zivin a, J. Lakhoo b, J. Minocha a, C.E. Ray Jr. a, M.G. Knuttinen a, J.T. Bui a a
Department of Radiology, Division of Interventional Radiology, USA University of Illinois College of Medicine, University of Illinois Hospital and Health Sciences System, 1740 West Taylor Street, MC 931, Chicago, IL 60612, USA b
art icl e i nformat ion Article history: Received 29 September 2014 Received in revised form 28 January 2015 Accepted 2 February 2015
AIM: To compare the impact of covered stent-graft transjugular intrahepatic portosystemic shunt (TIPS) versus serial paracentesis on survival of patients with medically refractory ascites. MATERIALS AND METHODS: In this retrospective study, cirrhotic patients who underwent covered stent-graft TIPS for refractory ascites from 2003e2013 were compared with similar patients who underwent serial paracentesis during 2009e2013. Demographic and liver disease data, Model for End-Stage Liver Disease (MELD) scores, and survival outcomes were obtained from hospital electronic medical records and the social security death index. After propensity score weighting to match study group characteristics, survival outcomes were compared using KaplaneMeier statistics with log-rank analysis. RESULTS: Seventy TIPS (70% men, mean age 55.7 years, mean MELD 15.1) and 80 paracentesis (58% men, mean age 53.5 years, mean MELD 22.5) patients were compared. The TIPS haemodynamic success rate was 100% (mean portosystemic pressure gradient reduction 13 mmHg). Paracentesis patients underwent a mean of 7.9 procedures. After propensity score weighting to balance group features, TIPS patients showed a trend toward enhanced survival compared with paracentesis patients (median survival 1037 versus 262 days, p ¼ 0.074). TIPS conferred a significant increase or trend toward improved survival compared with paracentesis at 1 (66% versus 44%, p ¼ 0.018), 2 (56% versus 38%, p ¼ 0.057), and 3 year (49% versus 32%, p ¼ 0.077) time points. Thirty and 90 day mortality rates were not statistically increased by TIPS. CONCLUSION: Covered stent-graft TIPS improves intermediate- to long-term survival without significantly increasing short-term mortality of ascites patients, and suggests a greater potential role for TIPS in properly selected ascitic patients when medical management fails. Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction * Guarantor and correspondent: R.C. Gaba, Department of Radiology, Division of Interventional Radiology, University of Illinois Hospital and Health Sciences System, 1740 West Taylor Street, MC 931, Chicago, IL 60612, USA. Tel.: þ1 312 996 0242; fax: þ1 312 355 2857. E-mail address: [email protected] (R.C. Gaba).
Ascites is a leading cause of morbidity and mortality among cirrhotic patients. Abdominal fluid accumulation occurs in 50% of individuals within 10 years of liver disease diagnosis and becomes medically refractory in 5e10% of
http://dx.doi.org/10.1016/j.crad.2015.02.002 0009-9260/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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cases, which entails a 1 year mortality rate of up to 50%.1,2 Transjugular intrahepatic portosystemic shunt (TIPS) creation has been validated as an effective and safe treatment for ascites secondary to portal hypertension.2 Although the benefits of this procedure, including ascites control in most patients,3e9 reduced portal hypertensive complications,9 and improved quality of life,10 are well documented, data regarding the effect of TIPS on patient survival remain unproven. To this end, a 2006 Cochrane Collaboration review evaluated five randomized studies of TIPS versus serial paracentesis procedures for ascites treatment,3e7 and concluded that there was no significant difference in mortality between these therapies, although TIPS was more effective at improving ascites.11 However, all of these studies employed bare-metal stents for TIPS creation, a technology that has been widely supplanted in modern clinical practice by covered stent-grafts, which afford enhanced shunt patency and function.12,13 Given the persistent gap in knowledge regarding the relative impact of the TIPS versus paracentesis treatment approaches on clinical outcomes, as well as the paucity of comparative data involving covered stent-graft TIPS, the present caseecontrol investigation was undertaken with the purpose of comparing the influence of TIPS creation using covered stent-grafts versus serial paracentesis on overall survival in patients with medically refractory ascites.
Materials and methods The institutional review board at the University of Illinois Hospital granted approval for this study with waiver of consent for inclusion. All patients provided written informed consent for TIPS and paracentesis procedures.
Clinical setting and patient selection In this single institution, retrospective, caseecontrol study, consecutive patients with alcoholic or viral cirrhosis who underwent technically successful elective covered stent-graft TIPS creation as treatment for medically refractory ascites between August 2003 and December 2013 at a single tertiary care, academic university-affiliated hospital were identified and selected for retrospective comparison to a control cohort of alcoholic or viral cirrhosis patients with refractory ascites who were treated with serial paracentesis procedures at the same hospital between January 2009 and December 2013. TIPS patients were identified through review of the 296-patient Division of Interventional Radiology (IR) TIPS registry, while the control cohort was selected from 2610 paracentesis procedures documented in the Division of IR ultrasound procedure log. Patients in both groups had failed conventional therapy, including dietary sodium restriction, fluid restriction, and diuretic therapy, and thus required interventional treatment of ascites. Patients with a history of hepatobiliary cancer, human immunodeficiency virus (HIV) infection, or liver transplantation during the study period were excluded from analysis in order to minimize the effect of these medical comorbidities or interventions on patient survival.
Patients who underwent bare-metal stent TIPS were also excluded. The resulting cohorts comprised 70 and 80 patients in the TIPS and paracentesis groups, respectively.
TIPS and paracentesis procedures The decision to undertake TIPS versus serial paracentesis therapy was primarily made by the patient’s hepatologist, with discussion of cases at a multidisciplinary liver meeting. TIPS creation was performed according to previously described methods14 using general anaesthesia in the IR suite. Baseline Model for End-Stage Liver Disease (MELD) scores were calculated at the time of TIPS creation. Right jugular venous access was followed by placement of a 10 F sheath with measurement of systemic venous pressure. Selection of the right hepatic vein proceeded free and wedged hepatic venography. Subsequently, a € scheUchida transjugular liver access set (Cook Medical, Ro Bloomington, IN, USA) was used to puncture the right portal vein. After catheterization, pressure measurement, and tract dilation, direct portography was performed. Next, a 10 mm Viatorr covered stent-graft (W.L. Gore & Associated, Flagstaff, AZ, USA) was deployed followed by balloon dilation to achieve a final portosystemic pressure gradient (PSG) of 12 mmHg or less.15 This was followed by final shunt venography. After TIPS procedures, patients underwent inpatient monitoring for at least 24 h. Following hospital discharge, patients were followed in an outpatient hepatology clinic, and underwent Doppler ultrasound surveillance of TIPS at 1, 3, and 6 month intervals post-procedure. Sonographic abnormalities, including absent colour Doppler flow, aphasic spectral waveforms, abnormally high (>190 cm/s) or low (<90 cm/s) velocity, abnormal change in velocity (increase or decrease >50 cm/s) compared with prior examination, and change in direction of shunt flow compared with prior examination16 were indications for further venographic interrogation of TIPS. Paracentesis procedures were performed using local anaesthesia in the ultrasound procedure suite. Baseline MELD scores were calculated at the time of the first paracentesis procedure. Ultrasound was used to identify an appropriate abdominal entry site. A 5 F One-Step catheter (Merit Medical Systems, South Jordan, UT, USA) was used to enter the peritoneal cavity using real-time sonographic guidance. Fluid was withdrawn using evacuated glass containers (Baxter Healthcare Corporation, Deerfield, IL, USA). Patients undergoing removal of more than 5000 ml fluid were typically repleted with albumin.17 After catheter removal, puncture site haemostasis was obtained with manual compression. Paracentesis procedures were repeated on a weekly, biweekly, or monthly schedule as clinically indicated by rapidity of abdominal fluid reaccumulation and degree of patient abdominal distension and/or discomfort.
Measured outcomes and statistical analysis The primary outcome measure of the study was overall survival, measured from the date of TIPS creation or the
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patient’s first paracentesis procedure until the date of patient death or the end of the study period on 1 January 2014. Statistical analyses were performed using SPSS version 21 (SPSS, Chicago, IL, USA) and STATA SE 12.0 (StataCorp LP, College Station, TX, USA). p-Values 0.05 were considered statistically significant. The demographic features of the study population and procedure outcomes were reported using descriptive statistics as number (percent) or mean standard deviation (SD). Comparisons for categorical data were performed using Pearson’s chi-squared test or Fisher’s exact test. Patient overall survival was assessed using KaplaneMeier statistics with log-rank comparison. Overall survivals at specific time points were compared using KaplaneMeier estimates and Pearson’s chi-squared test. To better compare the cohorts and minimize selection bias due to perceived confounders in this observational study, propensity score weighting was performed on the paracentesis group.18 The probability of receiving TIPS treatment based on a set of baseline variables was calculated using a logistic regression model, which generated propensity scores for each patient. Using these values, patients in the paracentesis arm were assigned weights between 0 and 1, such that their representation of baseline variables would match that of the TIPS group. This allowed for calculation of the average treatment effect (ATE)19 of TIPS compared to a group of paracentesis patients with similar baseline characteristics. This was performed according to established methods,19,20 in which the weight ¼ 1 for patients in the TIPS arm, and the weight ¼ p/ (1ep) for patients in the paracentesis arm, where p denotes the propensity score. The observed baseline variables deemed to most influence receipt of TIPS were patient age, gender, cause of liver disease, MELD score, and prior history of hepatic encephalopathy (HE). These five parameters were thus used to generate the propensity score. Survival outcomes between the TIPS and weighted paracentesis cohorts were compared using KaplaneMeier statistics with logrank comparison and Cox regression analysis.
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Table 1 Baseline study population characteristics. Measure
TIPS
Paracentesis
Patients Age (years) Gender (male %) Liver disease aetiology Alcohol (%) Viral (%) Prior HE (%) MELD score
70 55.7 6.9 70
80 53.5 9.5 58
59 41 62 15.1 5.3
62 38 53 22.5 8.9
p-Value 0.112 0.113 0.623
0.243 <0.001
TIPS, transjugular intrahepatic portosystemic shunt; HE, hepatic encephalopathy; MELD, Model for End-Stage Liver Disease.
clinically relevant, as decompensated cirrhotic patients with these scores would have nearly equivalent mortality risk stratification.21,22
TIPS and paracentesis procedures Haemodynamic success, defined by a final PSG of 12 mmHg or less, was achieved in 70/70 (100%) TIPS patients, with a mean PSG reduction of 13 5 mmHg (from 20 5 mmHg pre-TIPS to 7 2 mmHg post-TIPS). Only 5/70 (7%) TIPS patients required a subsequent revision procedure, consisting of shunt angioplasty or additional stent insertion. Procedure-related adverse events within 30 days included hepatic decompensation in 3/70 (4%) and bleeding in 2/70 (3%). Post-TIPS new or worsening HE occurred in 22/ 70 (31%) patients, two of which underwent shunt calibre reduction, which successfully addressed HE in both instances. The 80 paracentesis patients underwent a mean of 7.9 8.4 paracentesis procedures. There were no procedure-related adverse events in the paracentesis cohort. Specifically, there were no procedure-related infections, including peritonitis. New or worsening HE developed in 22/80 (28%) paracentesis patients, which was not statistically different to the TIPS group (p ¼ 0.720).
Patient overall survival
Results Baseline patient characteristics Unweighted patient demographics and liver disease characteristics of the study cohorts are summarized in Table 1. There was a statistically significant difference in mean baseline MELD score between the two groups (15.1 versus 22.5 in TIPS and paracentesis cohorts, respectively; p < 0.001), but no differences in age, gender, liver disease aetiology, or prior HE incidence. Patient demographics and liver disease characteristics of the study cohorts after propensity score weighting are displayed in Table 2. Propensity score weighting resulted in nearly identical baseline study population features. Only MELD score retained a statistically significant difference, although the small quantitative score difference between groups (15.1 versus 16.9 in TIPS and paracentesis cohorts, respectively) was not felt to be
At the end of the data collection period, 37/70 (53%) and 50/80 (63%) patients in the TIPS and paracentesis groups had died, respectively. The unweighted 30 day, 90 day, 1 year, 2 year, and 3 year survival probabilities were 86%, 78%, Table 2 Baseline study population features after propensity score weighting. Measure
TIPS
Paracentesis
Patients Age (years) Gender (male %) Liver disease aetiology Alcohol (%) Viral (%) Prior HE (%) MELD score
70 55.7 6.9 70
80 55.2 12.2 60
59 41 62 15.1 5.3
56 44 61 16.9 5.5
p-Value 0.771 0.244 0.766
0.900 0.043
TIPS, transjugular intrahepatic portosystemic shunt; HE, hepatic encephalopathy; MELD, Model for End-Stage Liver Disease.
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66%, 56%, and 49% in the TIPS group and 88%, 71%, 46%, 38%, and 32% in the paracentesis group. The median survival times were 1037 (95% CI: 146e1928) days and 262 (95% CI: 24e500) days in the TIPS and paracentesis cohorts, respectively. KaplaneMeier survival analysis of the unweighted study cohorts with log-rank comparison revealed a survival benefit favouring the TIPS group (Fig 1), which was further corroborated by a statistically significant reduction in mortality incidence in the TIPS group compared to the paracentesis group at intermediate- to long-term time points (Table 3). However, this result could be explained by baseline differences in MELD scores between study groups. After propensity score weightingdin which baseline study group characteristics were matcheddthere remained a statistical trend towards improved survival in the TIPS cohort over the paracentesis group (Fig 2), with median survival times of 1037 days and 262 days in the TIPS and paracentesis cohorts, respectively. This survival benefit was further substantiated by a statistically significant reduction or statistical trend towards reduced mortality incidence in the TIPS group compared to the paracentesis group at intermediate- to long-term time points (Table 4). Expectedly, TIPS was associated with a slightly greater early postprocedure mortality incidence at 30 days (15% versus 6%) and 90 days (22% versus 20%), but these differences were not statistically significant (p ¼ 0.135 and 0.824, respectively).
Discussion The present study assessed the impact of covered stentgraft TIPS compared to serial paracentesis on the overall survival of cirrhotic patients with medically refractory ascites. In utilizing propensity score weighting to eliminate
Table 3 Unweighted KaplaneMeier estimated mortality incidence at selected time points. Time
TIPS (%)
Paracentesis (%)
p-Value
30 day 90 day 1 year 2 year 3 year
14 22 34 44 51
12 29 54 62 68
0.750 0.307 0.015 0.034 0.057
TIPS, transjugular intrahepatic portosystemic shunt.
differing baseline characteristics between the TIPS and paracentesis cohorts, TIPS creation using covered stentgrafts was associated with a clinically meaningful increase in median overall survival compared with serial paracentesis (1100 versus 262 days) for the management of ascites. The survival benefit was largely realized in the intermediate- to long-term time frames, where TIPS was associated with an approximately 20% mortality reduction at 1, 2, and 3 years post-procedure. The trade-off for patients undergoing TIPS was a slight, but statistically not significant, increase in 30 and 90 day mortality, an expected result given the relative technical complexity, degree of invasiveness, and physiological impact of TIPS compared with paracentesis. Of note, there was no significant difference in HE rates between TIPS and paracentesis groups in the current series, and the rates seen in each respective group were in line with previous literature reported incidences.12,23e27 The marked survival benefit of TIPS is likely related to the fact that this procedure, unlike paracentesis, is designed to eliminate portal hypertension and its attendant complications rather than providing mere symptomatic relief. To this end, TIPS diminishes sinusoidal hypertension, which otherwise leads to ascites formation via systemic vasodilation, reduced splanchnic vascular resistance, and increased mesenteric capillary filtration.28
Figure 1 Unweighted KaplaneMeier overall survival curves of patients stratified into TIPS and paracentesis cohorts reveals statistically significant difference favouring the TIPS group (p ¼ 0.039).
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Figure 2 KaplaneMeier overall survival curves of patients stratified into TIPS and paracentesis cohorts after propensity score weighting demonstrates statistical trend towards improved survival in the TIPS group (p ¼ 0.074).
The impact of bare-metal stent TIPS versus paracentesis on the survival of patients with medically refractory ascites has been studied in several prior prospective randomized controlled trials (RCTs). In 1996, Lebrec et al.3 accrued 25 patients with refractory ascites, and randomized 13 patients to TIPS and 12 to paracentesis. The paracentesis group showed a significantly higher 2 year survival rate than the TIPS cohort (56% versus 29%, p < 0.05).3 In 2000, Rossle et al.4 randomized 60 patients to TIPS or large-volume paracentesis for ascites treatment. Among 29 TIPS and 31 paracentesis patients, there was a trend toward improved 1 and 2 year transplant-free survival in the TIPS group (69% and 58% versus 52% and 32%, p ¼ 0.11), and TIPS was found to be independently associated with survival on multivariate analysis (RR ¼ 0.44, 95% CI: 0.22e0.87; p ¼ 0.02).4 In 2002, Gines et al.5 followed 35 TIPS and 35 paracentesis patients, and found no statistically significant difference in 1 and 2 year survival (41% and 26% versus 35% and 30%, p ¼ 0.51) between study groups. In 2003, Sanyal et al.6 reported on 109 patients who underwent TIPS (n ¼ 52) or paracentesis (n ¼ 57) for refractory ascites, and found no significant difference in transplant free survival between study groups (19.6 versus 12.4 months, p ¼ 0.77). In 2004, Salerno et al.7 studied 66 refractory ascites patients Table 4 Propensity score weighted KaplaneMeier estimated mortality incidence at selected time points. Time
TIPS (%)
Paracentesis (%)
p-Value
30 day 90 day 1 year 2 year 3 year
15 22 34 44 51
6 20 56 62 68
0.135 0.824 0.018 0.057 0.077
TIPS, transjugular intrahepatic portosystemic shunt.
assigned to receive TIPS (n ¼ 33) or paracentesis (n ¼ 33). One- and 2 year transplant-free survival was increased in the TIPS group (77% and 59% versus 52% and 29%, p ¼ 0.021), and paracentesis treatment was independently associated with mortality on multivariate analysis (RR ¼ 2.95, 95% CI: 1.32e6.58; p ¼ 0.008).7 In 2011, Narahara et al.29 enrolled 60 patients with refractory ascites for study, and assigned 30 to receive TIPS and 30 to undergo large-volume paracentesis. Overall survival was enhanced in the TIPS group at 1 and 2 years post-procedure (80% and 64% versus 49% and 35%, p < 0.005).29 Bai et al.30 summarized the findings of these six RCTs in a recent meta-analysis, and concluded that TIPS conferred a significant benefit in terms of transplant-free survival compared to serial paracentesis procedures (HR ¼ 0.61, 95% CI: 0.46e0.82; p < 0.001),30 a finding corroborated herein. To this end, the 1 and 2 year survival incidence in the TIPS (66% and 56%) and paracentesis (44% and 38%) cohorts obtained in the current study are in line with rates identified in the described RCTs. Although the noted RCTs provide level 1 data on the relative impact of TIPS versus serial paracentesis on the survival of patients with medically refractory ascites, all are limited by the exclusive use of bare-metal stent technology for TIPS creation, and therefore, are not exactly translatable or generalizable to current clinical practice. Bare-metal stents, which are associated with higher rates of shunt dysfunction,31,32 are largely outdated in contemporary IR practice, and have been predominantly replaced in day-today clinical care by expanded polytetrafluoroethylene (ePTFE) covered stent-grafts, which confer improved patency.12,13 Although no studies have confirmed a survival benefit of covered stent-graft TIPS over bare-metal TIPS, one RCT has shown lower rates of ascites relapse favouring covered stent-grafts (6.5% versus 13%).33 It stands to reason that a reduced rate of ascites recurrence may translate into
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improved overall survival of refractory ascites patients, as seen in the current study, where all of the TIPS were performed using covered stent-grafts requiring shunt revision in only 7% of cases. Notably, high rates of early bare-metal shunt dysfunction complicated the RCT of Lebrec et al., and may have contributed to outlier findings of improved survival in paracentesis patients compared with TIPS patients. Regardless, the results obtained herein provide a basis and justification for future studies comparing covered stent-graft TIPS to serial paracentesis for treatment of refractory ascites. Although the results of the present investigation suggest a benefit favouring elective covered stent-graft TIPS compared to serial paracentesis in the clinical outcomes of medically refractory ascites patients, it is important to recognize cases in which this procedure may be contraindicated due to high risk. To this end, TIPS eligibility is typically diminished in cases of marked hepatic insufficiency,34 significant HE, right-sided heart failure with right atrial pressure exceeding 20 mmHg,35 pulmonary hypertension with mean pulmonary arterial pressure above 45 mmHg,15 uncontrolled infection or sepsis, biliary obstruction, polycystic liver disease, hepatic malignancy, and uncorrectable coagulopathy or thrombocytopenia. A MELD score exceeding 18 is another relative contraindication to TIPS given association with poorer clinical outcomes.36,37 In such instances, the potential risk of TIPS may justify consideration for use of serial paracentesis procedures for symptomatic relief or application of alternative therapies, such as peritoneovenous (Denver) shunt insertion.38 Obviously, liver transplantation serves as definitive therapy for medically refractory ascites, but is limited by lack of donor organs. Propensity score weighting was utilized in the current study to minimize selection bias due to perceived confounding baseline factors among the study groups. This statistical technique is a form of propensity score analysis (others include stratification and matching), which aims to reduce partiality in observational studies by accounting for differences in parameters involved in allocating treatment.18 In propensity score weighting, all identified study patients are preserved in the analysis, but the relative contribution of each individual patient is weighted according to propensity to receive treatment based on baseline characteristics, with values calculated using a logistic regression model. Although this approach compensates for imbalances in study groups, such an analysis may be limited by improper selection and/or exclusion of clinical variables used to generate the propensity score, which, in this manner, may maintain residual bias. There are limitations to this investigation. First, this study was retrospective and non-randomized in nature. Second, the investigation contains a modest sample size that may have limited statistical power. Third, minor technical differences in TIPS technique and progress in medical care during the decade-long study period may have contributed to differences in clinical outcomes over time. Along these lines, the TIPS and paracentesis patients were accrued over overlapping but non-identical time frames.
Fourth, patients in the paracentesis group may have been deemed unsuitable for TIPS creation due to medical comorbidities and could have confounded survival analysis, although an attempt was made to account for this through application of propensity score weighting. Nonetheless, it remains possible that there existed an inherent selection bias regarding allocation of patients to TIPS versus serial paracentesis, with fitter patients referred for TIPS. To this end, there remained a small quantitative MELD score difference between study groups after propensity score weighting. Fifth, only five baseline variablesdnamely patient age, gender, liver disease aetiology, MELD score, and HE historydwere used to generate propensity scores, and omission of other relevant parameters may contribute to bias among the study groups. However, these five factors were felt to represent the most clinical practical and common considerations for TIPS allocation. Sixth, ascites control was not assessed in the current investigation, although the institutional results, which include the patients presented herein, have been previously published and show high efficacy.14,39 Strengths of the present study include the unique focus on covered stent-graft technology (a technical element not previously addressed), mature and robust follow-up data, detailed clinical information, and consistent patient treatment by a single group of IRs. In conclusion, covered stent-graft TIPS appears to be beneficial in terms of improving intermediate- to long-term overall survival of cirrhotic patients with medically refractory ascites as compared to serial paracentesis procedures, without significantly worsening short-term mortality. This finding, in combination with the proven effectiveness of TIPS in controlling ascites,8 suggests an earlier potential role in the therapy in properly selected patients when conservative medical management fails. Additional prospective data further substantiating the survival benefit conferred by TIPS for recurrent ascitesdperhaps in the form of a multicentre registrydmay help change current practice guidelines, which recommend reservation of TIPS to patients who are intolerant of repeat large-volume paracentesis.15
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R.C. Gaba et al. / Clinical Radiology 70 (2015) e51ee57 7. Salerno F, Merli M, Riggio O, et al. Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites. Hepatology 2004;40:629e35. 8. Russo MW, Sood A, Jacobson IM, et al. Transjugular intrahepatic portosystemic shunt for refractory ascites: an analysis of the literature on efficacy, morbidity, and mortality. Am J Gastroenterol 2003;98:2521e7. 9. Salerno F, Camma C, Enea M, et al. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology 2007;133:825e34. 10. Gulberg V, Liss I, Bilzer M, et al. Improved quality of life in patients with refractory or recidivant ascites after insertion of transjugular intrahepatic portosystemic shunts. Digestion 2002;66:127e30. 11. Saab S, Nieto JM, Lewis SK, et al. TIPS versus paracentesis for cirrhotic patients with refractory ascites. Cochrane Database Syst Rev 2006 Oct 18;(4):CD004889. 12. Bureau C, Pagan JC, Layrargues GP, et al. Patency of stents covered with polytetrafluoroethylene in patients treated by transjugular intrahepatic portosystemic shunts: long-term results of a randomized multicentre study. Liver Int 2007;27:742e7. 13. Jung HS, Kalva SP, Greenfield AJ, et al. TIPS: comparison of shunt patency and clinical outcomes between bare stents and expanded polytetrafluoroethylene stent-grafts. J Vasc Interv Radiol 2009;20:180e5. 14. Parvinian A, Bui JT, Knuttinen MG, et al. Transjugular intrahepatic portosystemic shunt for the treatment of medically refractory ascites. Diagn Interv Radiol 2014;20:58e64. 15. Boyer TD, Haskal ZJ. American Association for the Study of Liver D. The role of Transjugular Intrahepatic Portosystemic Shunt (TIPS) in the management of portal hypertension: update 2009. Hepatology 2010;51:306. 16. McNaughton DA, Abu-Yousef MM. Doppler US of the liver made simple. RadioGraphics 2011;31:161e88. 17. Gines P, Tito L, Arroyo V, et al. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988;94:1493e502. 18. McDonald RJ, McDonald JS, Kallmes DF, et al. Behind the numbers: propensity score analysis-a primer for the diagnostic radiologist. Radiology 2013;269:640e5. 19. Imbens GW. Nonparametric estimation of average treatment effects under exogeneity: a review. Rev Econ Stat 2004;86:4e29. 20. Kurth T, Walker AM, Glynn RJ, et al. Results of multivariable logistic regression, propensity matching, propensity adjustment, and propensity-based weighting under conditions of nonuniform effect. Am J Epidemiol 2006;163:262e70. 21. Boin IF, Leonardi MI, Pinto AO, et al. Liver transplant recipients mortality on the waiting list: long-term comparison to ChildePugh classification and MELD. Transplant Proc 2004;36:920e2. 22. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44:217e31. 23. Peter P, Andrej Z, Katarina SP, et al. Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with recurrent variceal hemorrhage. Gastroenterol Res Pract 2013;2013:398172.
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24. Masson S, Mardini HA, Rose JD, et al. Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt insertion: a decade of experience. QJM 2008;101:493e501. 25. Riggio O, Angeloni S, Salvatori FM, et al. Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stent grafts. Am J Gastroenterol 2008;103:2738e46. 26. Tripathi D, Ferguson J, Barkell H, et al. Improved clinical outcome with transjugular intrahepatic portosystemic stent-shunt utilizing polytetrafluoroethylene-covered stents. Eur J Gastroenterol Hepatol 2006;18:225e32. 27. Romero-Gomez M, Boza F, Garcia-Valdecasas MS, et al. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 2001;96:2718e23. 28. Moller S, Henriksen JH, Bendtsen F. Ascites: pathogenesis and therapeutic principles. Scand J Gastroenterol 2009;44:902e11. 29. Narahara Y, Kanazawa H, Fukuda T, et al. Transjugular intrahepatic portosystemic shunt versus paracentesis plus albumin in patients with refractory ascites who have good hepatic and renal function: a prospective randomized trial. J Gastroenterol 2011;46:78e85. 30. Bai M, Qi XS, Yang ZP, et al. TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated metaanalysis. World J Gastroenterol 2014;20:2704e14. 31. Sommer CM, Gockner TL, Stampfl U, et al. Technical and clinical outcome of transjugular intrahepatic portosystemic stent shunt: bare metal stents (BMS) versus viatorr stent-grafts (VSG). Eur J Radiol 2012;81:2273e80. 32. Barrio J, Ripoll C, Banares R, et al. Comparison of transjugular intrahepatic portosystemic shunt dysfunction in PTFE-covered stent-grafts versus bare stents. Eur J Radiol 2005;55:120e4. 33. 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;60:962e8. 34. Rajan DK, Haskal ZJ, Clark TW. Serum bilirubin and early mortality after transjugular intrahepatic portosystemic shunts: results of a multivariate analysis. J Vasc Interv Radiol 2002;13:155e61. 35. Valji K. Hepatic, splenic, and portal vascular systems. In: Valji K, editor. Vascular and interventional radiology. 2nd ed. Philadelphia, PA: Elselvier; 2006. p. 269e319. 36. Ferral H, Patel NH. Selection criteria for patients undergoing transjugular intrahepatic portosystemic shunt procedures: current status. J Vasc Interv Radiol 2005;16:449e55. 37. Gaba RC, Couture PM, Bui JT, et al. Prognostic capability of different liver disease scoring systems for prediction of early mortality after transjugular intrahepatic portosystemic shunt creation. J Vasc Interv Radiol 2013;24:411e20. 420 e411-414; quiz 421. 38. Martin LG. Percutaneous placement and management of the Denver shunt for portal hypertensive ascites. AJR Am J Roentgenol 2012;199:W449e53. 39. Gaba RC, Parvinian A. How quickly does ascites respond to TIPS? Clinical follow-up of a cohort of eighty patients. Diagn Interv Radiol 2014;20:364.
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Survival benefit of TIPS versus serial paracentesis in patients with refractory ascites: a single institution case-control propensity score analysis R.C. Gaba a, *, A. Parvinian b, L.C. Casadaban b, P.M. Couture b, S.P. Zivin a, J. Lakhoo b, J. Minocha a, C.E. Ray Jr. a, M.G. Knuttinen a, J.T. Bui a a
Department of Radiology, Division of Interventional Radiology, USA University of Illinois College of Medicine, University of Illinois Hospital and Health Sciences System, 1740 West Taylor Street, MC 931, Chicago, IL 60612, USA b
art icl e i nformat ion Article history: Received 29 September 2014 Received in revised form 28 January 2015 Accepted 2 February 2015
AIM: To compare the impact of covered stent-graft transjugular intrahepatic portosystemic shunt (TIPS) versus serial paracentesis on survival of patients with medically refractory ascites. MATERIALS AND METHODS: In this retrospective study, cirrhotic patients who underwent covered stent-graft TIPS for refractory ascites from 2003e2013 were compared with similar patients who underwent serial paracentesis during 2009e2013. Demographic and liver disease data, Model for End-Stage Liver Disease (MELD) scores, and survival outcomes were obtained from hospital electronic medical records and the social security death index. After propensity score weighting to match study group characteristics, survival outcomes were compared using KaplaneMeier statistics with log-rank analysis. RESULTS: Seventy TIPS (70% men, mean age 55.7 years, mean MELD 15.1) and 80 paracentesis (58% men, mean age 53.5 years, mean MELD 22.5) patients were compared. The TIPS haemodynamic success rate was 100% (mean portosystemic pressure gradient reduction 13 mmHg). Paracentesis patients underwent a mean of 7.9 procedures. After propensity score weighting to balance group features, TIPS patients showed a trend toward enhanced survival compared with paracentesis patients (median survival 1037 versus 262 days, p ¼ 0.074). TIPS conferred a significant increase or trend toward improved survival compared with paracentesis at 1 (66% versus 44%, p ¼ 0.018), 2 (56% versus 38%, p ¼ 0.057), and 3 year (49% versus 32%, p ¼ 0.077) time points. Thirty and 90 day mortality rates were not statistically increased by TIPS. CONCLUSION: Covered stent-graft TIPS improves intermediate- to long-term survival without significantly increasing short-term mortality of ascites patients, and suggests a greater potential role for TIPS in properly selected ascitic patients when medical management fails. Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction * Guarantor and correspondent: R.C. Gaba, Department of Radiology, Division of Interventional Radiology, University of Illinois Hospital and Health Sciences System, 1740 West Taylor Street, MC 931, Chicago, IL 60612, USA. Tel.: þ1 312 996 0242; fax: þ1 312 355 2857. E-mail address: [email protected] (R.C. Gaba).
Ascites is a leading cause of morbidity and mortality among cirrhotic patients. Abdominal fluid accumulation occurs in 50% of individuals within 10 years of liver disease diagnosis and becomes medically refractory in 5e10% of
http://dx.doi.org/10.1016/j.crad.2015.02.002 0009-9260/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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cases, which entails a 1 year mortality rate of up to 50%.1,2 Transjugular intrahepatic portosystemic shunt (TIPS) creation has been validated as an effective and safe treatment for ascites secondary to portal hypertension.2 Although the benefits of this procedure, including ascites control in most patients,3e9 reduced portal hypertensive complications,9 and improved quality of life,10 are well documented, data regarding the effect of TIPS on patient survival remain unproven. To this end, a 2006 Cochrane Collaboration review evaluated five randomized studies of TIPS versus serial paracentesis procedures for ascites treatment,3e7 and concluded that there was no significant difference in mortality between these therapies, although TIPS was more effective at improving ascites.11 However, all of these studies employed bare-metal stents for TIPS creation, a technology that has been widely supplanted in modern clinical practice by covered stent-grafts, which afford enhanced shunt patency and function.12,13 Given the persistent gap in knowledge regarding the relative impact of the TIPS versus paracentesis treatment approaches on clinical outcomes, as well as the paucity of comparative data involving covered stent-graft TIPS, the present caseecontrol investigation was undertaken with the purpose of comparing the influence of TIPS creation using covered stent-grafts versus serial paracentesis on overall survival in patients with medically refractory ascites.
Materials and methods The institutional review board at the University of Illinois Hospital granted approval for this study with waiver of consent for inclusion. All patients provided written informed consent for TIPS and paracentesis procedures.
Clinical setting and patient selection In this single institution, retrospective, caseecontrol study, consecutive patients with alcoholic or viral cirrhosis who underwent technically successful elective covered stent-graft TIPS creation as treatment for medically refractory ascites between August 2003 and December 2013 at a single tertiary care, academic university-affiliated hospital were identified and selected for retrospective comparison to a control cohort of alcoholic or viral cirrhosis patients with refractory ascites who were treated with serial paracentesis procedures at the same hospital between January 2009 and December 2013. TIPS patients were identified through review of the 296-patient Division of Interventional Radiology (IR) TIPS registry, while the control cohort was selected from 2610 paracentesis procedures documented in the Division of IR ultrasound procedure log. Patients in both groups had failed conventional therapy, including dietary sodium restriction, fluid restriction, and diuretic therapy, and thus required interventional treatment of ascites. Patients with a history of hepatobiliary cancer, human immunodeficiency virus (HIV) infection, or liver transplantation during the study period were excluded from analysis in order to minimize the effect of these medical comorbidities or interventions on patient survival.
Patients who underwent bare-metal stent TIPS were also excluded. The resulting cohorts comprised 70 and 80 patients in the TIPS and paracentesis groups, respectively.
TIPS and paracentesis procedures The decision to undertake TIPS versus serial paracentesis therapy was primarily made by the patient’s hepatologist, with discussion of cases at a multidisciplinary liver meeting. TIPS creation was performed according to previously described methods14 using general anaesthesia in the IR suite. Baseline Model for End-Stage Liver Disease (MELD) scores were calculated at the time of TIPS creation. Right jugular venous access was followed by placement of a 10 F sheath with measurement of systemic venous pressure. Selection of the right hepatic vein proceeded free and wedged hepatic venography. Subsequently, a € scheUchida transjugular liver access set (Cook Medical, Ro Bloomington, IN, USA) was used to puncture the right portal vein. After catheterization, pressure measurement, and tract dilation, direct portography was performed. Next, a 10 mm Viatorr covered stent-graft (W.L. Gore & Associated, Flagstaff, AZ, USA) was deployed followed by balloon dilation to achieve a final portosystemic pressure gradient (PSG) of 12 mmHg or less.15 This was followed by final shunt venography. After TIPS procedures, patients underwent inpatient monitoring for at least 24 h. Following hospital discharge, patients were followed in an outpatient hepatology clinic, and underwent Doppler ultrasound surveillance of TIPS at 1, 3, and 6 month intervals post-procedure. Sonographic abnormalities, including absent colour Doppler flow, aphasic spectral waveforms, abnormally high (>190 cm/s) or low (<90 cm/s) velocity, abnormal change in velocity (increase or decrease >50 cm/s) compared with prior examination, and change in direction of shunt flow compared with prior examination16 were indications for further venographic interrogation of TIPS. Paracentesis procedures were performed using local anaesthesia in the ultrasound procedure suite. Baseline MELD scores were calculated at the time of the first paracentesis procedure. Ultrasound was used to identify an appropriate abdominal entry site. A 5 F One-Step catheter (Merit Medical Systems, South Jordan, UT, USA) was used to enter the peritoneal cavity using real-time sonographic guidance. Fluid was withdrawn using evacuated glass containers (Baxter Healthcare Corporation, Deerfield, IL, USA). Patients undergoing removal of more than 5000 ml fluid were typically repleted with albumin.17 After catheter removal, puncture site haemostasis was obtained with manual compression. Paracentesis procedures were repeated on a weekly, biweekly, or monthly schedule as clinically indicated by rapidity of abdominal fluid reaccumulation and degree of patient abdominal distension and/or discomfort.
Measured outcomes and statistical analysis The primary outcome measure of the study was overall survival, measured from the date of TIPS creation or the
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patient’s first paracentesis procedure until the date of patient death or the end of the study period on 1 January 2014. Statistical analyses were performed using SPSS version 21 (SPSS, Chicago, IL, USA) and STATA SE 12.0 (StataCorp LP, College Station, TX, USA). p-Values 0.05 were considered statistically significant. The demographic features of the study population and procedure outcomes were reported using descriptive statistics as number (percent) or mean standard deviation (SD). Comparisons for categorical data were performed using Pearson’s chi-squared test or Fisher’s exact test. Patient overall survival was assessed using KaplaneMeier statistics with log-rank comparison. Overall survivals at specific time points were compared using KaplaneMeier estimates and Pearson’s chi-squared test. To better compare the cohorts and minimize selection bias due to perceived confounders in this observational study, propensity score weighting was performed on the paracentesis group.18 The probability of receiving TIPS treatment based on a set of baseline variables was calculated using a logistic regression model, which generated propensity scores for each patient. Using these values, patients in the paracentesis arm were assigned weights between 0 and 1, such that their representation of baseline variables would match that of the TIPS group. This allowed for calculation of the average treatment effect (ATE)19 of TIPS compared to a group of paracentesis patients with similar baseline characteristics. This was performed according to established methods,19,20 in which the weight ¼ 1 for patients in the TIPS arm, and the weight ¼ p/ (1ep) for patients in the paracentesis arm, where p denotes the propensity score. The observed baseline variables deemed to most influence receipt of TIPS were patient age, gender, cause of liver disease, MELD score, and prior history of hepatic encephalopathy (HE). These five parameters were thus used to generate the propensity score. Survival outcomes between the TIPS and weighted paracentesis cohorts were compared using KaplaneMeier statistics with logrank comparison and Cox regression analysis.
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Table 1 Baseline study population characteristics. Measure
TIPS
Paracentesis
Patients Age (years) Gender (male %) Liver disease aetiology Alcohol (%) Viral (%) Prior HE (%) MELD score
70 55.7 6.9 70
80 53.5 9.5 58
59 41 62 15.1 5.3
62 38 53 22.5 8.9
p-Value 0.112 0.113 0.623
0.243 <0.001
TIPS, transjugular intrahepatic portosystemic shunt; HE, hepatic encephalopathy; MELD, Model for End-Stage Liver Disease.
clinically relevant, as decompensated cirrhotic patients with these scores would have nearly equivalent mortality risk stratification.21,22
TIPS and paracentesis procedures Haemodynamic success, defined by a final PSG of 12 mmHg or less, was achieved in 70/70 (100%) TIPS patients, with a mean PSG reduction of 13 5 mmHg (from 20 5 mmHg pre-TIPS to 7 2 mmHg post-TIPS). Only 5/70 (7%) TIPS patients required a subsequent revision procedure, consisting of shunt angioplasty or additional stent insertion. Procedure-related adverse events within 30 days included hepatic decompensation in 3/70 (4%) and bleeding in 2/70 (3%). Post-TIPS new or worsening HE occurred in 22/ 70 (31%) patients, two of which underwent shunt calibre reduction, which successfully addressed HE in both instances. The 80 paracentesis patients underwent a mean of 7.9 8.4 paracentesis procedures. There were no procedure-related adverse events in the paracentesis cohort. Specifically, there were no procedure-related infections, including peritonitis. New or worsening HE developed in 22/80 (28%) paracentesis patients, which was not statistically different to the TIPS group (p ¼ 0.720).
Patient overall survival
Results Baseline patient characteristics Unweighted patient demographics and liver disease characteristics of the study cohorts are summarized in Table 1. There was a statistically significant difference in mean baseline MELD score between the two groups (15.1 versus 22.5 in TIPS and paracentesis cohorts, respectively; p < 0.001), but no differences in age, gender, liver disease aetiology, or prior HE incidence. Patient demographics and liver disease characteristics of the study cohorts after propensity score weighting are displayed in Table 2. Propensity score weighting resulted in nearly identical baseline study population features. Only MELD score retained a statistically significant difference, although the small quantitative score difference between groups (15.1 versus 16.9 in TIPS and paracentesis cohorts, respectively) was not felt to be
At the end of the data collection period, 37/70 (53%) and 50/80 (63%) patients in the TIPS and paracentesis groups had died, respectively. The unweighted 30 day, 90 day, 1 year, 2 year, and 3 year survival probabilities were 86%, 78%, Table 2 Baseline study population features after propensity score weighting. Measure
TIPS
Paracentesis
Patients Age (years) Gender (male %) Liver disease aetiology Alcohol (%) Viral (%) Prior HE (%) MELD score
70 55.7 6.9 70
80 55.2 12.2 60
59 41 62 15.1 5.3
56 44 61 16.9 5.5
p-Value 0.771 0.244 0.766
0.900 0.043
TIPS, transjugular intrahepatic portosystemic shunt; HE, hepatic encephalopathy; MELD, Model for End-Stage Liver Disease.
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66%, 56%, and 49% in the TIPS group and 88%, 71%, 46%, 38%, and 32% in the paracentesis group. The median survival times were 1037 (95% CI: 146e1928) days and 262 (95% CI: 24e500) days in the TIPS and paracentesis cohorts, respectively. KaplaneMeier survival analysis of the unweighted study cohorts with log-rank comparison revealed a survival benefit favouring the TIPS group (Fig 1), which was further corroborated by a statistically significant reduction in mortality incidence in the TIPS group compared to the paracentesis group at intermediate- to long-term time points (Table 3). However, this result could be explained by baseline differences in MELD scores between study groups. After propensity score weightingdin which baseline study group characteristics were matcheddthere remained a statistical trend towards improved survival in the TIPS cohort over the paracentesis group (Fig 2), with median survival times of 1037 days and 262 days in the TIPS and paracentesis cohorts, respectively. This survival benefit was further substantiated by a statistically significant reduction or statistical trend towards reduced mortality incidence in the TIPS group compared to the paracentesis group at intermediate- to long-term time points (Table 4). Expectedly, TIPS was associated with a slightly greater early postprocedure mortality incidence at 30 days (15% versus 6%) and 90 days (22% versus 20%), but these differences were not statistically significant (p ¼ 0.135 and 0.824, respectively).
Discussion The present study assessed the impact of covered stentgraft TIPS compared to serial paracentesis on the overall survival of cirrhotic patients with medically refractory ascites. In utilizing propensity score weighting to eliminate
Table 3 Unweighted KaplaneMeier estimated mortality incidence at selected time points. Time
TIPS (%)
Paracentesis (%)
p-Value
30 day 90 day 1 year 2 year 3 year
14 22 34 44 51
12 29 54 62 68
0.750 0.307 0.015 0.034 0.057
TIPS, transjugular intrahepatic portosystemic shunt.
differing baseline characteristics between the TIPS and paracentesis cohorts, TIPS creation using covered stentgrafts was associated with a clinically meaningful increase in median overall survival compared with serial paracentesis (1100 versus 262 days) for the management of ascites. The survival benefit was largely realized in the intermediate- to long-term time frames, where TIPS was associated with an approximately 20% mortality reduction at 1, 2, and 3 years post-procedure. The trade-off for patients undergoing TIPS was a slight, but statistically not significant, increase in 30 and 90 day mortality, an expected result given the relative technical complexity, degree of invasiveness, and physiological impact of TIPS compared with paracentesis. Of note, there was no significant difference in HE rates between TIPS and paracentesis groups in the current series, and the rates seen in each respective group were in line with previous literature reported incidences.12,23e27 The marked survival benefit of TIPS is likely related to the fact that this procedure, unlike paracentesis, is designed to eliminate portal hypertension and its attendant complications rather than providing mere symptomatic relief. To this end, TIPS diminishes sinusoidal hypertension, which otherwise leads to ascites formation via systemic vasodilation, reduced splanchnic vascular resistance, and increased mesenteric capillary filtration.28
Figure 1 Unweighted KaplaneMeier overall survival curves of patients stratified into TIPS and paracentesis cohorts reveals statistically significant difference favouring the TIPS group (p ¼ 0.039).
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Figure 2 KaplaneMeier overall survival curves of patients stratified into TIPS and paracentesis cohorts after propensity score weighting demonstrates statistical trend towards improved survival in the TIPS group (p ¼ 0.074).
The impact of bare-metal stent TIPS versus paracentesis on the survival of patients with medically refractory ascites has been studied in several prior prospective randomized controlled trials (RCTs). In 1996, Lebrec et al.3 accrued 25 patients with refractory ascites, and randomized 13 patients to TIPS and 12 to paracentesis. The paracentesis group showed a significantly higher 2 year survival rate than the TIPS cohort (56% versus 29%, p < 0.05).3 In 2000, Rossle et al.4 randomized 60 patients to TIPS or large-volume paracentesis for ascites treatment. Among 29 TIPS and 31 paracentesis patients, there was a trend toward improved 1 and 2 year transplant-free survival in the TIPS group (69% and 58% versus 52% and 32%, p ¼ 0.11), and TIPS was found to be independently associated with survival on multivariate analysis (RR ¼ 0.44, 95% CI: 0.22e0.87; p ¼ 0.02).4 In 2002, Gines et al.5 followed 35 TIPS and 35 paracentesis patients, and found no statistically significant difference in 1 and 2 year survival (41% and 26% versus 35% and 30%, p ¼ 0.51) between study groups. In 2003, Sanyal et al.6 reported on 109 patients who underwent TIPS (n ¼ 52) or paracentesis (n ¼ 57) for refractory ascites, and found no significant difference in transplant free survival between study groups (19.6 versus 12.4 months, p ¼ 0.77). In 2004, Salerno et al.7 studied 66 refractory ascites patients Table 4 Propensity score weighted KaplaneMeier estimated mortality incidence at selected time points. Time
TIPS (%)
Paracentesis (%)
p-Value
30 day 90 day 1 year 2 year 3 year
15 22 34 44 51
6 20 56 62 68
0.135 0.824 0.018 0.057 0.077
TIPS, transjugular intrahepatic portosystemic shunt.
assigned to receive TIPS (n ¼ 33) or paracentesis (n ¼ 33). One- and 2 year transplant-free survival was increased in the TIPS group (77% and 59% versus 52% and 29%, p ¼ 0.021), and paracentesis treatment was independently associated with mortality on multivariate analysis (RR ¼ 2.95, 95% CI: 1.32e6.58; p ¼ 0.008).7 In 2011, Narahara et al.29 enrolled 60 patients with refractory ascites for study, and assigned 30 to receive TIPS and 30 to undergo large-volume paracentesis. Overall survival was enhanced in the TIPS group at 1 and 2 years post-procedure (80% and 64% versus 49% and 35%, p < 0.005).29 Bai et al.30 summarized the findings of these six RCTs in a recent meta-analysis, and concluded that TIPS conferred a significant benefit in terms of transplant-free survival compared to serial paracentesis procedures (HR ¼ 0.61, 95% CI: 0.46e0.82; p < 0.001),30 a finding corroborated herein. To this end, the 1 and 2 year survival incidence in the TIPS (66% and 56%) and paracentesis (44% and 38%) cohorts obtained in the current study are in line with rates identified in the described RCTs. Although the noted RCTs provide level 1 data on the relative impact of TIPS versus serial paracentesis on the survival of patients with medically refractory ascites, all are limited by the exclusive use of bare-metal stent technology for TIPS creation, and therefore, are not exactly translatable or generalizable to current clinical practice. Bare-metal stents, which are associated with higher rates of shunt dysfunction,31,32 are largely outdated in contemporary IR practice, and have been predominantly replaced in day-today clinical care by expanded polytetrafluoroethylene (ePTFE) covered stent-grafts, which confer improved patency.12,13 Although no studies have confirmed a survival benefit of covered stent-graft TIPS over bare-metal TIPS, one RCT has shown lower rates of ascites relapse favouring covered stent-grafts (6.5% versus 13%).33 It stands to reason that a reduced rate of ascites recurrence may translate into
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improved overall survival of refractory ascites patients, as seen in the current study, where all of the TIPS were performed using covered stent-grafts requiring shunt revision in only 7% of cases. Notably, high rates of early bare-metal shunt dysfunction complicated the RCT of Lebrec et al., and may have contributed to outlier findings of improved survival in paracentesis patients compared with TIPS patients. Regardless, the results obtained herein provide a basis and justification for future studies comparing covered stent-graft TIPS to serial paracentesis for treatment of refractory ascites. Although the results of the present investigation suggest a benefit favouring elective covered stent-graft TIPS compared to serial paracentesis in the clinical outcomes of medically refractory ascites patients, it is important to recognize cases in which this procedure may be contraindicated due to high risk. To this end, TIPS eligibility is typically diminished in cases of marked hepatic insufficiency,34 significant HE, right-sided heart failure with right atrial pressure exceeding 20 mmHg,35 pulmonary hypertension with mean pulmonary arterial pressure above 45 mmHg,15 uncontrolled infection or sepsis, biliary obstruction, polycystic liver disease, hepatic malignancy, and uncorrectable coagulopathy or thrombocytopenia. A MELD score exceeding 18 is another relative contraindication to TIPS given association with poorer clinical outcomes.36,37 In such instances, the potential risk of TIPS may justify consideration for use of serial paracentesis procedures for symptomatic relief or application of alternative therapies, such as peritoneovenous (Denver) shunt insertion.38 Obviously, liver transplantation serves as definitive therapy for medically refractory ascites, but is limited by lack of donor organs. Propensity score weighting was utilized in the current study to minimize selection bias due to perceived confounding baseline factors among the study groups. This statistical technique is a form of propensity score analysis (others include stratification and matching), which aims to reduce partiality in observational studies by accounting for differences in parameters involved in allocating treatment.18 In propensity score weighting, all identified study patients are preserved in the analysis, but the relative contribution of each individual patient is weighted according to propensity to receive treatment based on baseline characteristics, with values calculated using a logistic regression model. Although this approach compensates for imbalances in study groups, such an analysis may be limited by improper selection and/or exclusion of clinical variables used to generate the propensity score, which, in this manner, may maintain residual bias. There are limitations to this investigation. First, this study was retrospective and non-randomized in nature. Second, the investigation contains a modest sample size that may have limited statistical power. Third, minor technical differences in TIPS technique and progress in medical care during the decade-long study period may have contributed to differences in clinical outcomes over time. Along these lines, the TIPS and paracentesis patients were accrued over overlapping but non-identical time frames.
Fourth, patients in the paracentesis group may have been deemed unsuitable for TIPS creation due to medical comorbidities and could have confounded survival analysis, although an attempt was made to account for this through application of propensity score weighting. Nonetheless, it remains possible that there existed an inherent selection bias regarding allocation of patients to TIPS versus serial paracentesis, with fitter patients referred for TIPS. To this end, there remained a small quantitative MELD score difference between study groups after propensity score weighting. Fifth, only five baseline variablesdnamely patient age, gender, liver disease aetiology, MELD score, and HE historydwere used to generate propensity scores, and omission of other relevant parameters may contribute to bias among the study groups. However, these five factors were felt to represent the most clinical practical and common considerations for TIPS allocation. Sixth, ascites control was not assessed in the current investigation, although the institutional results, which include the patients presented herein, have been previously published and show high efficacy.14,39 Strengths of the present study include the unique focus on covered stent-graft technology (a technical element not previously addressed), mature and robust follow-up data, detailed clinical information, and consistent patient treatment by a single group of IRs. In conclusion, covered stent-graft TIPS appears to be beneficial in terms of improving intermediate- to long-term overall survival of cirrhotic patients with medically refractory ascites as compared to serial paracentesis procedures, without significantly worsening short-term mortality. This finding, in combination with the proven effectiveness of TIPS in controlling ascites,8 suggests an earlier potential role in the therapy in properly selected patients when conservative medical management fails. Additional prospective data further substantiating the survival benefit conferred by TIPS for recurrent ascitesdperhaps in the form of a multicentre registrydmay help change current practice guidelines, which recommend reservation of TIPS to patients who are intolerant of repeat large-volume paracentesis.15
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