Factors Predicting Survival after Transjugular Intrahepatic Portosystemic Shunt Creation: 15 Years Experience from a Single Tertiary Medical Center

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1 Factors Predicting Survival after Transjugular Intrahepatic Portosystemic Shunt Creation: 15 Years Experience from a Single Tertiary Medical Center Jen-Jung Pan, MD, PhD, Chaoru Chen, PhD, James G. Caridi, MD, Brian Geller, MD, Roberto Firpi, MD, Victor I. Machicao, MD, Irvin F. Hawkins, Jr, MD, Consuelo Soldevila-Pico, MD, David R. Nelson, MD, and Giuseppe Morelli, MD PURPOSE: This retrospective analysis was conducted to identify factors predictive of survival after transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS: Patients who underwent TIPS creation between January 1991 and December 2005 at a tertiary-care center were identified. Log-rank tests were used to compare the cumulative survival functions among groups of patients who underwent TIPS creation for various indications. Thirty-day mortality after TIPS creation was examined by logistic regression. Cox proportional-hazards analyses were performed to analyze the cumulative 90-day and 1-year survival. Selected variables such as creatinine, bilirubin, and International Normalized Ratio (INR) were assessed with respect to survival. RESULTS: The study included 352 patients, of whom 229 (65.1%) were male. The mean age at the time of TIPS creation was 53.6 years (range, y). A Model for End-stage Liver Disease (MELD) score greater than 15 was significantly associated with poor survival (P <.05) at 30 days, 90 days, and 1 year after TIPS creation. Independently, a serum total bilirubin level greater than 2.5 mg/dl, an INR greater than 1.4 (P <.05), and a serum creatinine level greater than 1.2 mg/dl were predictive of poor survival. Finally, age greater than 70 years was associated with poor survival at 90 days and 1 year after TIPS creation (P <.05). CONCLUSION: The choice to create a TIPS in individuals whose MELD score is greater than 15 and/or whose age is greater than 70 years should involve a careful consideration of risk/benefit ratio, taking into account the finding that such patients have significantly poorer survival after TIPS creation. J Vasc Interv Radiol 2008; 19: Abbreviations: INR International Normalized Ratio, MELD Model for End-stage Liver Disease, TIPS shunt FOR more than a decade, the transjugular intrahepatic portosystemic From the Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine (J.J.P., C.C., R.F., V.I.M., C.S.P., D.R.N., G.M.) and Department of Radiology (J.G.C., B.G., I.F.H.), University of Florida, 1600 Southwest Archer Road, Room M-440, Gainesville, FL Received November 12, 2007; final revision received July 15, 2008; accepted July 21, Address correspondence to G.M.; morelgj@medicine.ufl.edu None of the authors have identified a conflict of interest. SIR, 2008 DOI: /j.jvir shunt (TIPS) has been used for the treatment of portal hypertension and its sequelae. Specifically, acute and recurrent intractable variceal bleeding (1 6) and refractory ascites (7 12) have been the primary indications. However, the overall clinical utility has been debatable. Although TIPS creation has clearly shown a benefit in reducing the volume and risk of recurrent bleeding from portal hypertension, it has not demonstrated an increased survival benefit compared with endoscopic banding and surgical shunt therapy (1,3). Regarding refractory ascites, the literature has been diverse, with some prospective studies describing a survival advantage whereas others report none (8,11,12). TIPS creation is infrequently associated with several potential complications. Serious complications have been reported to occur in approximately 2% of TIPS procedures (13,14). From a clinical standpoint, the most serious complications relate to the diversion of blood flow away from the liver parenchyma, resulting in synthetic dysfunction and new onset or exacerbation of hepatic encephalopathy (15). As clinicians balance the potential risks and benefits associated with TIPS creation, it is imperative that indicators of survival be included in the 1576

2 Volume 19 Number 11 Pan et al 1577 equation. Although the specific numbers vary, previously reported indicators of decreased survival include hyperbilirubinemia, renal insufficiency, coagulopathy, and increased Model for End-stage Liver Disease (MELD) score (16 26). MELD score was initially created to predict survival after elective creation of a TIPS (23). The model was subsequently validated as a predictor of survival in several cohorts of patients with varying levels of liver disease. In a retrospective analysis of our 15-year TIPS experience, we evaluated these and other variables to determine which factors predicted diminished survival after TIPS creation. MATERIALS AND METHODS Study Population From January 1991 to December 2005, 364 patients referred for TIPS creation at a single institution were identified. Of this population, 352 (96.7%) had successful creation of a TIPS. The remaining 12 patients had vascular anatomy abnormalities that precluded TIPS creation. In this institutional review board approved study, we used the Social Security Death Index to confirm the date of death, in addition to inhospital records for those who died while in the hospital. In regard to endpoints, in patients who received a liver transplant, the date of transplantation was established as an endpoint to the follow-up of TIPS creation. Thirty-seven patients who underwent TIPS creation (11%) were lost to clinical follow-up. The last available date documenting a patent TIPS was used to calculate duration of TIPS patency in these 37 patients. Social Security death records were used to calculate survival after the TIPS procedure in 23 of the 37 patients. In the 14 patients who were still alive, contact was established by phone. However, documentation regarding whether the TIPS was still patent was not available. Date of contact with the patient was used as an endpoint for TIPS follow-up. Criteria for performing a TIPS procedure at our center included acute variceal bleeding not amenable to endoscopic therapy or recurrent variceal bleeding that could not be controlled by endoscopic/medical therapy. TIPS procedures were also undertaken for refractory ascites, which was defined as ascites requiring large-volume paracentesis at least every other week that could not be controlled well with maximumdose diuretics (spironolactone 400 mg/d and furosemide 160 mg/d), and in patients who were intolerant to high-dose diuretics as a result of side effects. Of the 352 patients studied, 229 (65.1%) were male (Table 1). The mean age at the time of TIPS creation was 53.6 years (range, y). Alcoholic liver disease was the most common underlying liver disease, followed by chronic hepatitis C and cryptogenic liver disease. The leading indication for TIPS creation in our group over time was variceal bleeding, followed by refractory ascites. Most subjects in our population (78.7%) received an uncovered Wallstent (Boston Scientific, Maple Grove, Minnesota); the others (21.3%) received a covered Viatorr stent (W.L. Gore & Associates, Flagstaff, Arizona). The mean duration of follow-up for our study population was 24.1 months. Laboratory Baseline laboratory data collected before TIPS creation and analyzed included prothrombin time, International Normalized Ratio (INR), serum creatinine, total bilirubin, and platelet count. MELD score was calculated for each subject based on laboratory values obtained the day of the TIPS procedure. The formula for calculating MELD score has been published previously (27). TIPS Procedure and Follow-up Details related to the performance of the actual TIPS procedure have been previously published (15). Doppler ultrasonography (US) was performed to assess shunt patency before hospital discharge in any patient who received a Wallstent. For those who received a polytetrafluoroethylenecovered Viatorr stent, follow-up evaluation of the TIPS was performed 2 3 weeks after the procedure. Viatorr stents were first introduced at our institution in Long-term Doppler Table 1 Selected Demographic, Clinical, and Laboratory Characteristics (N 352) Characteristic Value Age (y) Male sex 229 (65.1) Admission time period (22.4) (32.1) (45.5) Total bilirubin (mg/dl) Creatinine (mg/dl) Platelets (count per L) INR MELD score Underlying liver disease Alcohol 129 (36.6) Hepatitis C 79 (22.4) Cryptogenic 62 (17.6) Other* 82 (23.3) Type of stent Wallstent 277 (78.7) Viatorr 75 (21.3) Follow-up time (months) Variceal bleeding 194 (55.1) Refractory ascites 128 (36.4) Other 30 (8.4) Outcome Alive 90 (25.6) Transplant 91 (25.8) Death 171 (48.6) Mortality 30 days 42 (11.9) 90 days 60 (17.0) 1 year 102 (29.0) Overall 171 (48.6) Note. Values presented as means SE where applicable. Values in parentheses are percentages. * Hepatitis B, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, cystic fibrosis, venoocclusive disease. Variceal bleeding and refractory ascites. US studies were performed at 4-month intervals or whenever shunt dysfunction was clinically suspected based on recurrent ascites or bleeding. Shunt dysfunction was suspected on Doppler US if the calculated peak velocity in the shunt was less than 90 cm/sec or greater than 190 cm/sec and/or the change in peak shunt velocity decreased by more than 40 cm/sec or increased by more than 60 cm/sec from baseline measurements. A decrease in portal vein velocity of more

3 1578 Factors Predicting Survival after TIPS Creation November 2008 JVIR Table 2 Predictors of 30-Day Survival after TIPS Creation (N 352) Variable OR 95% CI P Value OR 95% CI P Value OR 95% CI P Value Age 70 y Total bilirubin 2.5 mg/dl Creatinine level 1.2 mg/dl INR Platelet count 129,500/ L MELD score Refractory ascites Other Note. OR odds ratio. * Adjusted for serum bilirubin, serum creatinine, INR, and platelet levels. Adjusted for platelet count and MELD score. Variceal bleeding and refractory ascites. Univariate Multivariate* Multivariate than 30 cm/sec from the baseline measurement was also considered to be evidence of shunt dysfunction. Abnormal Doppler US findings were confirmed with venography. Stenosis was defined as significant if there was a 50% or greater narrowing of the lumen on venography or the portosystemic gradient was found to be greater than or equal to 12 mm Hg. All TIPS were kept patent during follow-up. Patients were followed in an outpatient liver clinic until they underwent liver transplantation or died. Statistical Analysis Data are presented as means SD for continuous variables and as frequencies for categoric variables. Kaplan- Meier curves were generated for cumulative survival rates by TIPS indication as well as by calculated MELD score before the procedure. The logrank test was used to compare cumulative survival functions among groups. Short-term mortality at 30 days after TIPS creation was examined by logistic regression. Cox proportional-hazards analyses were performed to analyze the cumulative 90-day and 1-year survival. Selected clinical variables were assessed on univariate analysis with respect to endpoints: age, total bilirubin level, creatinine level, INR, platelet count, MELD score, and indication for TIPS creation. Only variables that had a statistically significant effect at the.05 level on univariate analysis were then subjected to multivariate analysis. MELD score, total bilirubin level, creatinine level, and INR level were categorized according to percentile distribution ( second tertile vs second tertile). Platelet count was also categorized according to percentile distribution ( third quartile vs third quartile). All reported P values were two-sided, and a P value of less than.05 was considered to indicate statistical significance. All statistical analyses were performed with SPSS software (version 15.0; SPSS, Chicago, Illinois). RESULTS Factors Predictive of Early Mortality On univariate analysis, the following preoperative laboratory parameters were associated with higher overall 30-day mortality rates after TIPS creation: total bilirubin level greater than 2.5 mg/dl, creatinine level greater than 1.2 mg/dl, INR greater than 1.4, platelet count less than 129,500, and MELD score greater than 15 (Table 2). In multivariate analysis, only bilirubin level greater than 2.5 mg/dl and creatinine level greater than 1.2 mg/dl could predict early (ie, 30-d) mortality. Patients with MELD scores of or more than 20 had 4.9-fold and 18.2-fold increases in 30-day mortality, respectively, versus those with MELD scores of 15 or lower. Among the 42 subjects who were dead at 30 days after TIPS creation, 31 (73.8%) had MELD scores greater than 15 and 11 (26.2%) had MELD scores of 15 or lower. Factors Predictive of Intermediate Mortality On univariate analysis, age greater than 70 years, total bilirubin level greater than 2.5 mg/dl, creatinine level greater than 1.2 mg/dl, INR greater than 1.4, and MELD score greater than 15 were associated with higher mortality rates at 90 days after TIPS creation (Table 3). On multivariate analysis, all these factors remained strong predictors of poor survival at 90 days after TIPS creation. Patients with MELD scores of or more than 20 had threefold and 9.7-fold increases in 90-day mortality, respectively, versus those with MELD scores of 15 or lower. Among 60 subjects who were dead at 90 days after TIPS creation, 38 (63.3%) had MELD scores greater than 15 and 22 (36.7%) had MELD scores of 15 or lower. Factors Predictive of Long-term Survival On univariate analysis, age greater than 70 years, total bilirubin level greater than 2.5 mg/dl, creatinine level greater than 1.2 mg/dl, INR greater than 1.4, and MELD score

4 Volume 19 Number 11 Pan et al 1579 Table 3 Predictors of 3-Month Survival after TIPS Creation (N 352) Univariate Multivariate* Multivariate Variables RR 95% CI P Value RR 95% CI P Value RR 95% CI P Value Age 70 y Total bilirubin 2.5 mg/dl Creatinine 1.2 mg/dl INR Platelet count 129,500/ L MELD score Refractory ascites Note. RR relative risk. * Adjusted for age, serum bilirubin, serum creatinine, and INR. Adjusted for age and MELD score. Table 4 Predictors of 1-Year Survival after TIPS Creation (N 352) Variable RR 95% CI P Value RR 95% CI P Value RR 95% CI P Value Age 70 y Total bilirubin 2.5 mg/dl Creatinine 1.2 mg/dl INR Platelet count 129,500/ L MELD score Refractory ascites Note. RR relative risk. * Adjusted for age, serum bilirubin, serum creatinine, and INR. Adjusted for age and MELD score. Univariate Multivariate* Multivariate greater than 15 were associated with poor survival at 1 year after TIPS creation. On multivariate analysis, all these factors remained strong predictors of poor survival at 1 year after TIPS creation (Table 4). Although there was a trend for subjects with refractory ascites to have a higher mortality rate at 1 year after TIPS creation, it did not reach significance. Subjects with MELD scores of or more than 20 had 1.7-fold and 5.5-fold increases of 1-year mortality, respectively, versus those with MELD scores of 15 or lower. Among 102 subjects who were dead at 1 year after TIPS creation, 54 (52.9%) had MELD scores greater than 15 and 48 (47.1%) had MELD scores of 15 or lower. A MELD score greater than 15 was associated with significantly poorer survival after TIPS creation, especially at 30 days and 90 days. However, at the same cutoff value, MELD score became a less significant predictor for survival at 1 year (Fig). DISCUSSION Since its inception, TIPS creation has become a relatively safe and fairly routine procedure that is used principally for the treatment of intractable variceal bleeding and refractory ascites. Compared with its medical counterparts, TIPS therapy has been very successful for these indications (1 12). Unfortunately, until recently, there have been no data to indicate that TIPS affords any improvement in survival. In fact, many patients who present with the aforementioned indications present with a poor MELD score and poor longterm survival prognosis. As previously stated, the TIPS procedure is relatively safe, but it is not without potential complications. Therefore, it would be extremely helpful to predict which patients would truly benefit from a TIPS procedure while avoiding unnecessary risk to those who would not benefit. We evaluated our 15-year TIPS experience to elucidate the variables that

5 1580 Factors Predicting Survival after TIPS Creation November 2008 JVIR Kaplan-Meier analysis of patient survival after TIPS creation based on MELD score:, MELD score 15; -----, MELD score 16 20;,MELD score 20. predicted poor survival after TIPS creation. Our study confirmed several preprocedural indicators. For 30-day mortality, we found that a bilirubin level greater than 2.5 mg/dl and a creatinine level greater than 1.2 mg/ dl predicted diminished survival. Previously published data from retrospective series (16 26) showed that a total bilirubin level greater than 3.0 mg/dl and a creatinine level greater than 1.7 mg/dl were associated with poor 30-day survival. Montgomery et al (25) also reported similar findings: higher serum bilirubin levels (P.02) and higher serum creatinine levels (P.002) were associated with early (ie, 30-d) death after TIPS creation. There was no difference in INR between the survivors and early death groups in their report (25). Previous reports (19,20) have shown higher significant critical levels for creatinine, ranging from 1.7 mg/dl to 1.9 mg/dl. Our 30-day mortality rate of 11.9% is comparable to the published rates of 20% and 31.5% (19,20). Regarding coagulopathy, there was a positive trend, but our analysis did not show it to be a strong predictor of increased 30-day mortality as in previously published series (19). Potential explanations for the differences noted between our results and those of previous reports are the fact we had a larger population of TIPS recipients. Two retrospective series (19,20) analyzed 73 and 90 subjects, respectively, compared with 352 subjects in our series. The difference noted may also be a result of patient selection at the time of the TIPS procedures. Although this is merely speculation, patients with more severe illness may have presented for TIPS creation in the other studies, thus accounting for the higher laboratory ranges for creatinine and bilirubin. We observed a trend for refractory ascites as the indication for TIPS to be an independent predictor of poor 1-year survival on univariate analysis. However, it did not reach significance. In our study, patients with refractory ascites were older than those with variceal bleeding. It is conceivable that age is a stronger predictive factor than TIPS indication. Patients whose indication for TIPS creation was refractory ascites had significantly higher creatinine levels (P.001) than patients whose indication was variceal bleeding. This is consistent with the findings reported by Membreno et al (22). The combination of poor renal function and refractory ascites could explain the poor 1-year survival noted in our patients with both conditions. Similar to our findings, on univariate analysis, the landmark article that described the MELD model (23) described patients with refractory ascites to have a 66% greater chance of dying after TIPS creation compared with patients who undergo TIPS creation for the prevention of variceal bleeding (P.01). However, refractory ascites was not an independent variable in multivariate analysis (23). The most significant finding in our analysis was that a MELD score greater than 15 was associated with decreased 30-day, 90-day, and 1-year survival. The MELD model was originally developed to assess the 3-month prognosis of patients with cirrhosis undergoing a TIPS procedure (23). We found that patients with MELD scores greater than 15 had a 5.1-fold increase in 30-day mortality rate and a 2.9-fold increase in 3-month mortality rate compared with those with MELD scores of 15 or lower. Even though a MELD score greater than 15 has less significant impact on patient survival at 1 year than at earlier time points after TIPS creation, patients with MELD scores greater than 15 still had a 1.7-fold higher 1-year mortality rate than those with scores of 15 or lower. Our MELD score cutoff of greater than 15 and its effect on short-term and long-term mortality differ from what has previously been reported. One retrospective series (24) showed lower 3-month survival rates after TIPS creation in patients with MELD scores greater than 18. Two other series (25,26) showed higher 30-day and 6-month mortality rates after TIPS in patients with MELD scores greater than 24. The differences in MELD scores noted between our results and those of other reported series may be a result of patient selection. Again, this may relate to the extent of disease at presentation. Nevertheless, our finding of a lower MELD score threshold is important, as we have identified an additional group of patients who may not benefit significantly from TIPS creation. As with all retrospective studies, our study is limited by the shortcomings that are involved in such analysis. It is also subject to the potential bias that might have been entered into the analysis. Thirty-seven patients were lost to follow-up. These patients were also lost to interventions for TIPS patency. Secondary interventions such as angioplasty were therefore not available to them. This subgroup might have been biased toward a higher mortality rate as a result of undetected TIPS occlusion. Nevertheless, this large sample size has allowed us to thoroughly evaluate the validity of clinical factors that have been previously reported. Our review has significantly influenced our evaluation of patients

6 Volume 19 Number 11 Pan et al 1581 who present with intractable variceal bleeding and especially refractory ascites. We evaluated the acuity and severity of the presentation along with serum bilirubin and creatinine levels, MELD score, and patient age to determine if TIPS will be truly beneficial for each individual patient. Use of these criteria will hopefully allow the avoidance of unnecessary morbidity and improve the quality of life for these patients. References 1. Coldwell DM, Ring EJ, Rees CR, et al. Multicenter investigation of the role of shunt in management of portal hypertension. Radiology 1995; 196: Papatheodoridis GV, Goulis J, Leandro G, et al. Transjugular intrahepatic portosystemic shunt compared with endoscopic treatment for prevention of variceal rebleeding: a meta-analysis. Hepatology 1999; 30: Luca A, D Amico G, La Galla R, et al. TIPS for prevention of recurrent bleeding in patients with cirrhosis: metaanalysis of randomized clinical trials. 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