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doi:10.1111/jgh.12725

H E PAT O L O G Y

Long-term clinical outcome of patients with cirrhosis and refractory ascites treated with transjugular intrahepatic portosystemic shunt insertion Hiang Keat Tan,* Paul Damien James,* Kenneth Wilfred Sniderman† and Florence Wong* *Division of Gastroenterology, Department of Medicine and †Department of Medical Imaging, Toronto General Hospital, Toronto, Ontario, Canada

Key words cirrhosis, portal hypertension, refractory ascites, transjugular intrahepatic portosystemic shunt. Accepted for publication 13 August 2014. Correspondence Dr Florence Wong, Toronto General Hospital, 9N/983, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada. Email: [email protected] Funding: None. Declaration of conflicts of interest: Florence Wong has been a consultant for W. L. Gore & Associates. All other authors have no conflict of interest to declare. Author contributions: Both Hiang Keat Tan and Paul Damien James are equal first authors. Hiang Keat Tan and Paul Damien James: data collection, data analysis, and drafting of manuscript; Florence Wong and Kenneth Sniderman: formulation of the research idea/protocol and writing of manuscript. All four authors read and approved the manuscript.

Abstract Background and Aim: Transjugular intrahepatic portosystemic shunt (TIPS) is indicated for the treatment of refractory ascites in cirrhosis. The long-term outcome of TIPS for refractory ascites is unknown. The aim of this study is to describe the natural history of patients with refractory ascites post-TIPS, and compare between polytetrafluoroethylene (PTFE)-covered versus bare stents. Methods: A retrospective chart review of patients who had TIPS for refractory ascites was conducted. Prospectively collected data include demographics, angiographic data, blood work, and urinary sodium excretion. Results: There were 136 patients who received TIPS (bare = 104, covered = 32) for over 22 years. Patients with PTFE stents had lower international normalized ratio and model for end-stage liver disease score. More patients with bare stents developed shunt dysfunction (74.0% vs 24.1%, P < 0.0001) and required more TIPS revisions (1.6 ± 0.2/patient vs 0.2 ± 0.1, P < 0.0001). Urinary sodium excretion increased significantly from first month and progressed to 98 ± 9 mmol/day at 12th month post-TIPS (P < 0.001 vs baseline), concurrent with improved renal function. Most patients (77.6%) completely cleared the ascites without diuretics, but many achieved this beyond 2 years. Number of TIPS revision was predictive of complete response at 12 months (odds ratio [OR] 0.7, 95% confidence interval [CI] 0.5–0.9, P < 0.05). Age (hazard ratio [HR] = 1.05 [95% CI 1.02–1.08], P < 0.01), complete response (HR = 0.22 [95% CI 0.12–0.40], P < 0.0001) and polytetrafluoroethylene stents (HR = 0.23 [95% CI 0.05–0.97], P < 0.05) were predictive of survival. Conclusion: TIPS is an effective treatment for cirrhotic refractory ascites. Ascites clearance is dependent on number of TIPS revision, whereas survival is predicted by younger age, complete response, and covered stent use, although era effect likely contributed to improved survival with covered stent use.

Introduction The development of refractory ascites in cirrhosis portends a poor prognosis with 2-year survival of 30%.1,2 Although large-volume paracentesis (LVP) provides symptomatic relief,3 it does not correct the underlying pathophysiology of ascites formation and therefore, recurrence of tense ascites is inevitable. Liver transplantation is the definitive treatment for refractory ascites,4 but the current system of organ allocation using the model for end-stage liver disease (MELD) score disadvantages patients, whose major problem is refractory ascites, as MELD score correlates poorly with severity of ascites5 and underestimates mortality in these patients.6 Transjugular intrahepatic portosystemic shunt (TIPS) is a prosthesis, inserted radiologically into the liver parenchyma, to

decompress the portal system. It is widely used to treat complications of portal hypertension including refractory ascites.3,7 The initial high rate of shunt dysfunction of > 50% with bare stents within the first year8 has been largely overcome after the introduction of polytetrafluoroethylene (PTFE) stents.9,10 Despite this reduction in shunt dysfunction, there have been concerns about the use of TIPS in patients with refractory ascites, especially with the high rate of hepatic encephalopathy after TIPS.3,7,8 Careful selection of patients with refractory ascites is essential to successful outcome post-TIPS.11 No study has evaluated the long-term outcome of patients receiving TIPS for this indication, especially with respect to bare versus PTFE stents. In addition, renal sodium handling and time required for complete clearance of ascites after TIPS are not well documented. Therefore, this study

Journal of Gastroenterology and Hepatology 30 (2015) 389–395 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

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aims to evaluate the renal function and clinical complications in patients who received a TIPS for refractory ascites, comparing between bare and PTFE TIPS.

Methods This retrospective study was approved by the Research Ethics Committee of the University Health Network, University of Toronto. The Toronto General Hospital, part of the University Health Network, maintains a prospective database of all patients who underwent TIPS insertion since the inception of the TIPS program in 1992. All cirrhotic patients who received a successful elective TIPS insertion for the treatment of refractory ascites from April 1992 to January 2014 were included. All patients were managed by a single hepatologist (F.W.) and followed a standard protocol for pre-TIPS evaluation and post-TIPS follow-up. Data including patient demographics, angiographic information, blood work results, ultrasound findings, and clinical outcome were collected prospectively. All patients fulfilled prevailing criteria for refractory ascites by the International Ascites Club.2,12 Prior to 1996, diagnosis of refractory ascites was based on our standardized critieria,13 which were very similar to those of International Ascites Club. Patients with alcoholic cirrhosis had to abstain from alcohol for ≥ 6 months. All patients had to have serum bilirubin < 85 μmol/L11, serum creatinine < 177 μmol/L11, INR (international normalized ratio) < 211, with Child–Pugh score ≤ 1114 and MELD score ≤ 1815, no previous spontaneous hepatic encephalopathy and absence of organic renal disease.11 Patients with provoked hepatic encephalopathy were eligible if they were free of encephalopathy for 6 months. Patency of portal and hepatic veins was confirmed on Doppler ultrasound, and the absence of hepatoma confirmed on two modality of imaging. Patients also had to have an ejection fraction of > 55%, absence of diastolic dysfunction, and normal right-sided cardiopulmonary pressures on echocardiography.11,16 All patients received dental clearance to exclude potential sources of occult oral infection that may lead to endotipsitis.17 All TIPS procedure was performed according to standard technique18 by a single interventional radiologist (K.S.) since 1992. We routinely used a 10-mm diameter stent, dilated initially to 8-mm diameter, with further dilatation up to 10 mm if necessary to achieve a portosystemic gradient (PSG) of < 8 mmHg.19 PostTIPS Doppler ultrasound confirmed shunt patency and appropriate shunt flow velocities. Patients with suspected shunt dysfunction received a repeat venogram. Any thrombosis within the TIPS in the immediate post-TIPS period was macerated, whereas TIPS stenosis during the follow-up period was dilated with angioplasty. At any TIPS revision, any kink at the portal venous or hepatic venous ends was treated with placement of a new balloon-expandable stent within the existing stent. All patients were started on prophylactic lactulose immediately post-TIPS and remained on a 44-mmol sodium/day diet with diuretics permanently discontinued post-TIPS. Twenty-four hour urinary sodium excretion, renal/liver functions, and Doppler ultrasound assessment of TIPS function were performed regularly until elimination of ascites. Complete response was defined by absence of clinically detectable ascites. Partial response was defined by 390

improvement without complete resolution of ascites and nonresponse was defined by persistence of tense ascites, irrespective of the need for paracentesis. Statistical analysis. Patients were divided into bare and PTFE stent groups. Continuous variables were expressed as means ± standard error or medians with interquartile range (IQR). Categorical variables were expressed as numbers and percentages. Differences between the categorical parameters were tested by χ2 tests. Independent t-tests were conducted for differences between groups for continuous variables. The Mann–Whitney U-test was used to evaluate non-normally distributed continuous data. Kaplan–Meyer curves were constructed and survival compared between bare and PTFE stent groups using log–rank test. A Cox proportional hazards model was constructed to assess the independent association of type of stent and survival after controlling for potentially confounding factors. The maximal partial likelihood method was used to compute the relative hazards for each variable and the 95% confidence interval (CI) around the estimate. A P value of < 0.05 was considered statistically significant. All calculations were performed using SAS version 9.3 (SAS Institute Inc., Cary, NC, USA).

Results During the study period, 136 patients had successful TIPS insertion for the treatment of refractory ascites. The initial 104 patients received bare stents (Wallstent [Boston Scientific, Natick, MA, USA] or Palmaz [Johnson & Johnson, Warren, NJ, USA]), whereas the remaining 32 received PTFE stents (Fluency [Bard Incorporation, Murray Hill, NJ, USA] or Viatorr [WL Gore, Flagstaff, AZ, USA). Patient characteristics and baseline laboratory investigations at TIPS insertion are summarized in Table 1. The majority were middle-aged (mean age 54 ± 1 years) men (78.1%) who were abstinent alcoholics (66.9%). MELD score was lower in the PTFE stent group because of a lower INR. Patients in the PTFE stent group also had a numerically lower serum creatinine, although the difference was not statistically significant, and a trend toward higher urinary sodium excretion. The median duration of follow-up for the entire cohort was 22.2 (IQR 8.1–42.6) months, with the bare stent group receiving a significantly longer follow-up compared with PTFE stent group (25.1 [IQR 8.6–52.7] vs 14.1 [IQR 5.1–26.7] months, P < 0.01). Angiographic parameters. All patients had severe sinusoidal portal hypertension, indicated by a pre-TIPS PSG of 18.3 ± 0.5 mmHg, with PTFE group having lower pre-TIPS PSG (P < 0.05 vs bare) (Table 2). Successful TIPS insertion significantly decreased PSG to 6.8 ± 0.9 mmHg (P < 0.0001 vs baseline). Patients in the PTFE group required fewer number of stents inserted initially (1.3 ± 0.1 vs 1.5 ± 0.1, P < 0.05). Similar initial success rates and reductions in PSG were observed in both groups (Table 2). More patients who received bare TIPS had shunt dysfunction (74.0% vs 25.0%, P < 0.0001), needed more shunt revisions per patient to maintain stent patency compared with patients with PTFE stents (1.6 ± 0.2 vs 0.2 ± 0.1, P < 0.0001), and these involve Journal of Gastroenterology and Hepatology 30 (2015) 389–395

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Table 1

Intrahepatic shunt & refractory ascites

Baseline characteristics and laboratory results in all patients

Characteristics

Bare stent (n = 104)

PTFE stent (n = 32)

Age (year) Gender (male), n (%) Aetiology, n (%) Alcohol Viral hepatitis Others Bilirubin (normal ≤ 22 μmol/L) Albumin (normal 38–50 g/L) ALT (normal ≤ 40 IU/L) AST (normal ≤ 34 IU/L) INR (normal 0.80–1.20) Creatinine (normal ≤ 110 μmol/L) Serum Na (normal 135–145 mmol/L) MELD score Child–Pugh score Urine Na (mmol/day)

54 ± 1 82 (78.8)

55 ± 1 24 (75.0)

70 (67.3) 25 (24.0) 9 (8.7) 34 ± 3 33 ± 1 30 ± 3 55 ± 4 1.46 ± 0.03 106 ± 9 132.8 ± 0.4 12.9 ± 0.5 8.7 ± 0.2 17 ± 3

21 (65.6) 6 (18.8) 5 (15.6) 29 ± 4 33 ± 1 25 ± 5 41 ± 5 1.33 ± 0.04 85 ± 5 133.7 ± 1.0 10.4 ± 0.8 8.2 ± 0.2 27 ± 5

P value 0.41 0.81 0.48

0.29 0.94 0.46 0.06 < 0.05 0.20 0.36 < 0.05 0.15 0.07

Values are expressed either as mean ± standard error, or actual numbers with percentages in parentheses. ALT, alanine aminotransferase; AST, aspartate aminotransferase, INR, international normalized ratio; MELD, model for end-stage liver disease; Na, sodium; PTFE, polytetrafluoroethylene.

Table 2

Angiographic interventions for the study patients

Angiographic data

Bare stent (n = 104)

PTFE stent (n = 32)

P value

Pre-TIPS PSG (normal ≤ 5 mmHg) Post-TIPS PSG (normal ≤ 5 mmHg) Mean number of stents inserted per patient at initial intervention Number of patients with shunt dysfunction in the first 2 years, n (%) Mean total number of TIPS revision per patient Mean number of TIPS revisions involving angioplasty only Mean number of TIPS revisions involving additional stent(s) insertion 1-year shunt primary patency rate

18.8 ± 0.6 6.9 ± 0.3 1.5 ± 0.1 77 (74.0) 1.6 ± 0.2 0.8 ± 0.1 0.8 ± 0.1 23.1% (95% CI 14.4–32.3)

16.1 ± 0.9 6.3 ± 0.5 1.3 ± 0.1 8 (25.0) 0.2 ± 0.1 0.1 ± 0.1 0.2 ± 0.1 79.9% (95% CI 60.4–90.5)

< 0.05 0.35 < 0.05 < 0.0001 < 0.0001 < 0.01 < 0.0001 < 0.0001*

*Hazard ratio 0.23 (95% CI 0.20–0.54). Values are expressed either as mean ± standard error or actual numbers with percentages in parentheses. CI, confidence interval; PSG, portosystemic gradient; PTFE, polytetrafluoroethylene; TIPS, transjugular intrahepatic portosystemic shunt.

both dilatations and additional stents (Table 2). Therefore, the 1-year primary patency rate was significantly higher in the PTFE stent group (Table 2). Renal sodium handling. Urinary sodium excretion increased significantly in all patients at 1 month (47 ± 5 mmol/ day) post-TIPS compared with baseline (20 ± 2 mmol/day) (P < 0.001) and continued to increase in the following 12 months to 98 ± 9 mmol/day (P < 0.001 vs baseline) (Fig. 1a). Renal function also improved, with the serum creatinine decreasing from 102 ± 7 μmol/L at baseline to 77 ± 2 μmol/L at 1-month postTIPS (P < 0.001 vs baseline). Thereafter, serum creatinine remained significantly lower than baseline for at least 6 months (Fig. 1b). There was no difference in terms of urinary sodium excretion (Fig. 1c) or serum creatinine (Fig. 1d) between the two groups post-TIPS. Following TIPS insertion, all patients in both groups were no longer dependent on regular paracentesis. However, 14 patients

(13.3%) in the bare group and four (12.5%) in the PTFE group required a median of one paracentesis post-TIPS (bare vs PTFE, P = 0.89). Reduction in ascites following TIPS insertion was slow (Fig. 2a). The proportion of complete responders gradually increased over time, with complete response achieved eventually in 77.6% patients. A greater proportion of patients who received PTFE stents achieved complete clearance of ascites from the third month onward, but this was not statistically significant (Fig. 2b). On univariate analysis, only the number of TIPS revision was associated with complete response at 12 months (1.3 ± 0.2/patient in complete responders vs 2.1 ± 0.3/patient in partial/nonresponders, P < 0.05). On multivariate analysis, the number of TIPS revisions was predictive of response at 12 months (odds ratio [OR] 0.68 [95% CI 0.49–0.94], P < 0.05). The use of PTFE stents (OR 0.47 [95% CI 0.13–1.66], P = 0.24) and baseline INR (OR 0.20 [95% CI 0.04–1.15], P = 0.07) were also included in the multivariate logistic regression model, but were not found to be statistically significant.

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Figure 1 (a) Urinary sodium excretion (mmol/day) and (b) renal function measured by serum creatinine (μmol/L), at baseline and at 1, 3, 6, and 12 months after insertion of transjugular intrahepatic portosystemic shunt (TIPS) in all patients. Comparison of (c) urinary sodium excretion (mmol/day) and (d) renal function measured by serum creatinine (μmol/L), at baseline, and at 1, 3, 6, and 12 months of post-TIPS in patients who received bare and polytetrafluoroethylene (PTFE) , Bare; , PTFE. *P < 0.001 stents. versus baseline; **P < 0.01 versus baseline; ***P < 0.05 versus baseline. SEM, standard error of mean.

Figure 2 (a) Proportion of ( ) complete responders compared with ( ) partial and non-responders over time, following insertion of transjugular ) bare stents versus intrahepatic portosystemic shunt (TIPS). (b) Proportion of complete responders in patients who received ( ( ) polytetrafluoroethylene (PTFE) stents up to 12 months post-TIPS.

Clinical outcome. Table 3 summarizes the liver-related complications of patients after TIPS insertion. Similar proportions of patients in both the bare stent group (50.0%) and PTFE stent group (43.8%) were hospitalized for cirrhotic complications (P = 0.54). The most common complication was hepatic encephalopathy, occurring in 41 patients (30.1%), with the majority (65.9%) developing at least one episode severe enough to require hospitalization, but none was refractory to treatment. There was an average of two admissions per patient for hepatic encephalopathy in both groups. There was also no difference in other liver-related complications between the groups (Table 3).

Survival. Overall median survival was 49.6 months. The cumulative 2-year survival of patients in the PTFE stent group was 392

85.9% (95% CI 54.0–96.3) versus 69.5% (95% CI 59.3–77.6) in the bare stent group (hazard ratio [HR] = 0.25 [95% CI 0.17– 0.95], P < 0.05) (Fig. 3a). The unadjusted survival was also superior in complete responders when compared with partial or non-responders (P < 0.0001) (Fig. 3b). On multivariate analysis, age (HR = 1.05 [95% CI 1.02–1.08], P < 0.01), complete response (HR = 0.22 [95% CI 0.12–0.40], P < 0.0001) and PTFE stents (HR = 0.23 [95% CI 0.05–0.97], P < 0.05) were predictive of survival. Other variables included in the final Cox proportional hazards model were male gender (HR 0.80 [95% CI 0.40–1.58], P = 0.51), baseline MELD score (HR 1.05 [95% CI 0.99–1.11], P = 0.11), viral (HR 0.80 [95% CI 0.25–2.55], P = 0.70) or alcohol (HR 0.91 [95% CI 0.33–2.45], P = 0.84) as etiologies of liver disease and pre-TIPS PSG (HR 1.02 [95% CI 0.97–1.06], P = 0.42), but none emerged as significant predictors. Journal of Gastroenterology and Hepatology 30 (2015) 389–395

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Table 3

Intrahepatic shunt & refractory ascites

Complications during follow-up

Complications

Bare metal stent (n = 104)

PTFE stent (n = 32)

P value

Number of patients hospitalized for any liver-related complication(s), n (%) Mean number of hospitalizations per patient for any liver-related complication(s) Number of patients with any grade of HE, n (%) Number of patients with severe HE requiring hospitalization(s), n (%) Mean number of hospitalizations per patient for severe HE 1-year probability of remaining free of any HE Number of patients with HCC Number of patients with SBP, n (%) Mean number of episodes of SBP per patient 1-year probability of remaining free of SBP

52 (50.0) 2.2 ± 0.3

14 (43.8) 2.1 ± 0.4

0.54 0.95

29 (27.8) 19 (65.5) 2.0 ± 0.3 69.0% (95% CI 58.4–77.4) 15 (14.4) 13 (12.5) 1.2 ± 0.1 90.7.3% (95% CI 82.2–95.2)

12 (28.6) 8 (66.7) 2.0 ± 0.4 59.1% (95% CI 38.9–74.6) 2 (6.3) 2 (6.3) 1.0 ± 0.0 96.8% (95% CI 79.2–99.6)

0.30 0.94 0.90 0.28 0.27 0.35 0.48 0.57

Values are expressed either as mean ± standard error or actual numbers and percentages in parentheses. CI, confidence interval; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; PTFE, polytetrafluoroethylene; SBP, spontaneous bacterial peritonitis.

Figure 3 (a) Comparison of probability of survival between patients who received ( ) polytetrafluoroethylene (PTFE) and ( ) bare transjugular ) complete responders, intrahepatic portosystemic shunt (TIPS). (b) Probability of post-TIPS survival in all patients according to response: ( ) partial responders, and ( ) non-responders. (

Discussion This study represents the largest study of patients who received TIPS as treatment for refractory ascites and followed for the longest period of time, thereby allowing us to clarify many of the issues related to TIPS insertion for refractory ascites. Furthermore, we routinely discontinued diuretics in all patients post-TIPS and this gave us a unique opportunity to describe the true natural history of patients with cirrhosis whose refractory ascites had been treated with TIPS, in terms of natriuresis and ascites clearance. We also confirmed previous findings9,10,20 that TIPS is effective as treatment for cirrhotic refractory ascites and that PTFE stent has superior long-term shunt patency. This study highlights the natural history of sodium handling following TIPS insertion. Renal sodium excretion increased progressively after TIPS insertion without the use of diuretics, to 98 ± 9 mmol/day at 12 months post-TIPS. This suggests that patients had to be maintained on a low sodium diet to achieve a negative sodium balance until complete elimination of ascites. We

have previously shown that the onset of natriuresis after TIPS is related to the suppression of various vasoconstrictor systems including renin-angiotensin-aldosterone axis to below a threshold, following the transfer of splanchnic blood volume into the central blood volume after TIPS.21 Rössle, in his summary22 of previously published TIPS studies, confirmed that it takes somewhere between 6 and 12 months before the normalization of these vasoconstrictor hormones, thereby permitting natriuresis. Therefore, response to TIPS is slow and may take many months before the complete resolution of ascites. The use of diuretic may decrease central blood volume and therefore may delay the onset of natriuresis. The improvement in sodium handling is also partly related to the concomitant improvement in renal function, the result of improved renal perfusion from an increased central blood volume. The loss of portal hypertension with the TIPS insertion also eliminated the hepatorenal reflex,23 further improving renal function. Therefore, patients with more TIPS revisions, suggestive of recurrent portal hypertension, were more likely to have incomplete clearance of ascites at 12 months. Although patients with

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bare stents required more TIPS revision compared with those with PTFE stents in this study, the use of PTFE stents was not predictive of response. This suggests that it is the recurrence of portal hypertension, which delayed ascites mobilization and this confirms once again the importance of portal hypertension in the pathogenesis of ascites formation.8 In addition, patients with better liver function may respond better to TIPS, as suggested by a previous metaanalysis24 and our multivariate analysis where baseline INR was close to statistical significance as predictor of response. Previous studies also confirmed a correlation between the level of liver dysfunction and sodium retention in both animal models and human cirrhosis.25,26 Our current selection criteria of only inserting TIPS in patients with Child–Pugh score ≤ 11 and MELD score ≤ 18 may have helped to ensure adequate natriuresis and clearance of ascites in the majority of patients. The second issue relates to the development of hepatic encephalopathy post-TIPS. This occurred in approximately 30% of our patients, and this is consistent with the literature.3,7 None of our patients developed refractory hepatic encephalopathy requiring reduction in shunt diameter, as opposed to 8–10% commonly reported.27 This may be related to the careful patient selection, with the exclusion of patients with spontaneous and recent hepatic encephalopathy. We routinely prescribed lactulose to all patients post-TIPS, although this is controversial as the only one randomized controlled trial (RCT) comparing efficacy of various treatments for the prevention of post-TIPS encephalopathy showed that both lactitol and rifaximin were no better than placebo, at least within the first month post-TIPS.28 The use of smaller diameter TIPS stent has also been proposed to lower the risk of post-TIPS encephalopathy, but a recent RCT was terminated prematurely due to increased risk of treatment failure among patients treated with the smaller 8-mm stent.29 Therefore, although there is no published evidence that any intervention is effective in the prevention of post-TIPS encephalopathy, careful patient selection may mitigate this risk, although it is impossible to arrive at any conclusion with regard to the use of nonabsorbable disaccharides given the lack of a control group in our study. Although not statistically significant, the 1-year probability of remaining free of encephalopathy among patients treated with PTFE stents in our study was numerically lower than those with bare stents. Our finding is similar to another large study,30 which reported a 1-year probability of remaining free of hepatic encephalopathy post-PTFE TIPS of 53.8%. Therefore, post-TIPS encephalopathy continues to be a significant problem with the use of PTFE stents. The third issue relates to survival of patients post-TIPS. In collaboration with others, we have found in a meta-analysis24 of four out of five RCTs using individual patient data comparing TIPS versus LVP as treatment for refractory ascites that patients who had a reasonable post-TIPS survival of at least 50% at 2 years are those whose pre-TIPS parameters included age < 55 years, serum bilirubin < 35 μmol/L, and serum sodium > 135 mmol/L. This is not surprising as these patients have minimal liver dysfunction and hemodynamic disturbance. Although there was no comparison group treated with regular LVP in this study, the median survival of 49.6 months is clearly superior to the survival of patients treated with regular LVP reported in the literature.1,2 In patients with not-so-favorable prognosis, TIPS may be best served as a bridge to liver transplantation rather than a definite therapy for 394

portal hypertension. The most interesting finding of this study is that patients who received PTFE stents had better survival, after controlling for various factors including MELD score and preTIPS PSG. This is intriguing, especially with the lack of difference in terms of liver-related complications between the two groups. However, this should be interpreted with caution as there were clear differences between the groups despite multivariate analysis: better baseline liver and renal function, lower pre-TIPS portal pressure, and greater urinary sodium excretion in the PTFE group. We postulate that the improved survival is due to era effect rather than stent type per se, where better understanding of patient selection for TIPS insertion, better overall care of patients with decompensated cirrhosis, and improved procedural skills over time could account for superiority of covered stents as these factors are difficult to account for in statistical analysis. Furthermore, survival analysis was hampered by the small number of patients with PTFE stents beyond 12 months of follow-up. One other interesting finding of this study is the poor prognosis of patients who did not achieve complete response with total clearance of ascites. Therefore, early liver transplantation should be considered for both partial and non-responders. The final issue that does not cause much controversy is the superiority of PTFE stent in maintaining TIPS patency. Therefore, patients with a PTFE stent have less attendance at hospital and require less radiological interventions. However, patients with PTFE stents still have the same risks for other complications of cirrhosis as patients who received bare stents until total clearance of ascites. Close surveillance for shunt patency with Doppler ultrasound until elimination of ascites is mandatory as shunt dysfunction is associated with recurrence of ascites or other complications of portal hypertension as shown in our study and others.8 In summary, our study confirms the efficacy of TIPS as a treatment for refractory ascites in cirrhosis with PTFE stents showing superior patency rate and similar post-TIPS complications. The response to TIPS is slow and the patients need to remain on a sodium-restricted diet until elimination of ascites. Those who require fewer TIPS revision are more likely to clear their ascites. Older patients and those with persistent ascites have poorer prognosis. In patients who eliminate their ascites, the results can be gratifying with improvement in nutritional status31 and quality of life.32

Acknowledgment Guarantor of the article: Florence Wong will resume the role of guarantor for this paper.

References 1 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: 217–31. 2 Salerno F, Guevara M, Bernardi M et al. Refractory ascites: pathogenesis, definition and therapy of a severe complication in patients with cirrhosis. Liver Int. 2010; 30: 937–47. 3 Sanyal AJ, Genning C, Reddy KR et al. The North American study for the treatment of refractory ascites. Gastroenterology 2003; 124: 634–41.

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4 Wong F, Blendis L. The pathophysiological basis for the treatment of cirrhotic ascites. Clin. Liver Dis. 2001; 5: 819–32. 5 Yoo HY, Edwin D, Thuluvath PJ. Relationship of the model for end-stage liver disease (MELD) scale to hepatic encephalopathy, as defined by electroencephalography and neuropsychometric testing, and ascites. Am. J. Gastroenterol. 2003; 98: 1395–9. 6 Heuman DM, Abou-Assi SG, Habib A et al. Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death. Hepatology 2004; 40: 802–10. 7 Cabrera J, Maynar M, Granados R et al. Transjugular intrahepatic portosystemic shunt versus sclerotherapy in the elective treatment of variceal hemorrhage. Gastroenterology 1996; 110: 832–9. 8 Sanyal AJ, Freedman AM, Luketic VA et al. The natural history of portal hypertension after transjugular intrahepatic portosystemic shunts. Gastroenterology 1997; 112: 889–98. 9 Bureau C, García-Pagán JC, Otal P et al. Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology 2004; 126: 469–75. 10 Perarnau JM, Le Gouge A, Nicolas C et al. Covered vs. uncovered stents for transjugular intrahepatic portosystemic shunt: a randomized trial. J. Hepatol. 2014; 60: 962–8. 11 Wong F. The use of TIPS in chronic liver disease. Ann. Hepatol. 2006; 5: 5–15. 12 Arroyo V, Ginès P, Gerbes AL et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996; 23: 164–76. 13 Wong F, Tobe S, Legault L, Logan AG, Skorecki K, Blendis LM. Refractory ascites in cirrhosis: roles of volume expansion and plasma atrial natriuretic factor level elevation. Hepatology 1993; 18: 519–28. 14 Angermayr B, Cejna M, Karnel F et al. Child–Pugh versus MELD score in predicting survival in patients undergoing transjugular intrahepatic portosystemic shunt. Gut 2003; 52: 879–85. 15 Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000; 31: 864–71. 16 Rabie RN, Cazzaniga M, Salerno F, Wong F. The use of E/A ratio as a predictor of outcome in cirrhotic patients treated with transjugular intrahepatic portosystemic shunt. Am. J. Gastroenterol. 2009; 104: 2458–66. 17 Sanyal AJ, Reddy KR. Vegetative infection of transjugular intrahepatic portosystemic shunts. Gastroenterology 1998; 115: 110–5. 18 Wong F, Sniderman KW, Liu P, Allidina Y, Sherman M, Blendis L. Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium homeostasis in cirrhosis and refractory ascites. Ann. Intern. Med. 1995; 122: 816–22.

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19 Morali GA, Sniderman KW, Deital KM et al. Is sinusoidal portal hypertension a necessary factor for the development of hepatic ascites? J. Hepatol. 1992; 16: 249–50. 20 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: 225–32. 21 Wong F, Sniderman K, Liu P, Blendis L. The mechanism of the initial natriuresis after transjugular intrahepatic portosystemic shunt. Gastroenterology 1997; 112: 899–907. 22 Rössle M. TIPS, 25 years on. J. Hepatol. 2013; 59: 1081–93. 23 Jalan R, Forrest EH, Redhead DN, Dillon JF, Hayes PC. Reduction in renal blood flow following acute increase in the portal pressure: evidence for the existence of a hepatorenal reflex in man? Gut 1997; 40: 664–70. 24 Salerno F, Cammà C, Enea M, Rössle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology 2007; 133: 825–34. 25 Wensing G, Lotterer E, Link I, Hanh EG, Fleig WE. Urinary sodium balance in patients with cirrhosis: relationship to quantitative parameters of liver function. Hepatology 1997; 26: 1149–55. 26 Wong F, Massie D, Hsu P, Dudley F. Renal response to a saline load in well-compensated alcoholic cirrhosis. Hepatology 1994; 20: 873–81. 27 Riggio O, Nardelli S, Moscucci F, Pasquale C, Ridola L, Merli M. Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Clin. Liver Dis. 2012; 16: 133–46. 28 Riggio O, Masini A, Efrati C et al. Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study. J. Hepatol. 2005; 42: 674–9. 29 Riggio O, Ridola L, Angeloni S et al. Clinical efficacy of transjugular intrahepatic portosystemic shunt created with covered stents with different diameters: results of a randomized controlled trial. J. Hepatol. 2010; 53: 267–72. 30 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: 2738–46. 31 Allard JP, Chau J, Sandokji K, Blendis LM, Wong F. Effects of ascites resolution after successful TIPS on nutrition in cirrhotic patients with refractory ascites. Am. J. Gastroenterol. 2001; 96: 2442–7. 32 Gülberg V, Liss I, Bilzer M, Waggershauser T, Reiser M, Gerbes AL. Improved quality of life in patients with refractory or recidivant ascites after insertion of transjugular intrahepatic portosystemic shunts. Digestion 2002; 66: 127–30.

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Long-term clinical outcome of patients with cirrhosis and refractory ascites treated with transjugular intrahepatic portosystemic shunt insertion.

Transjugular intrahepatic portosystemic shunt (TIPS) is indicated for the treatment of refractory ascites in cirrhosis. The long-term outcome of TIPS ...
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