BRIEF REPORT

Should Transjugular Intrahepatic Portosystemic Shunt Stent Grafts Be Underdilated? Ron C. Gaba, MD, Ahmad Parvinian, BS, Jeet Minocha, MD, Leigh C. Casadaban, BS, M. Grace Knuttinen, MD, PhD, Charles E. Ray, Jr, MD, PhD, and James T. Bui, MD

ABSTRACT Although underdilation of transjugular intrahepatic portosystemic shunt (TIPS) stent grafts is commonly performed to limit complications arising from excessive portosystemic shunting, it is uncertain whether underdilated stents retain their smaller diameter indefinitely or eventually expand to nominal caliber. In this investigation, postprocedure computed tomography (CT) was used to compare diameters of underdilated TIPSs and TIPSs expanded to a nominal diameter of 10 mm in 61 cases. The groups had comparable shunt diameters on post-TIPS imaging (9.8 mm vs 9.9 mm; P ¼ .079), with similar incidences of hepatic encephalopathy (34% vs 20%; P ¼ .372), indicating stent self-expansion over time, and bringing into question the advantages of underdilation for customization of shunt caliber.

ABBREVIATIONS HE = hepatic encephalopathy, PSG = portosystemic pressure gradient, TIPS = transjugular intrahepatic portosystemic shunt

The expanded polytetrafluoroethylene–covered VIATORR stent graft (W.L. Gore and Associates, Flagstaff, Arizona) is widely used for transjugular intrahepatic portosystemic shunt (TIPS) creation. This device affords superior patency and a marked decrease in the incidence of shunt dysfunction compared with its bare metal precursors (1,2). In an effort to alleviate portal hypertensive complications while avoiding risk of adverse secondary side effects caused by excessive shunting— such as hepatic encephalopathy (HE) and deterioration of liver function (3)—underdilation of VIATORR stent grafts with a nominal diameter of 10 mm has been proposed (4), with further balloon expansion and portosystemic pressure gradient (PSG) reduction reserved for cases of insufficient clinical response. This method of initial underexpansion has been anecdotally adopted in many interventional radiology practices. If the constricting From the Department of Radiology and Division of Interventional Radiology (R.C.G., J.M., M.G.K., C.E.R., J.T.B.) and University of Illinois College of Medicine (A.P., L.C.C.), University of Illinois Hospital and Health Sciences System, 1740 W. Taylor St., MC 931, Chicago IL 60612. Received February 28, 2014; final revision received August 8, 2014; accepted August 10, 2014. Address correspondence to R.C.G.; E-mail: [email protected] None of the authors have identified a conflict of interest. & SIR, 2015 J Vasc Interv Radiol 2015; 26:382–387 http://dx.doi.org/10.1016/j.jvir.2014.08.012

effects of fibrotic, cirrhotic liver exceed the outward radial expansive force of the VIATORR device, it is plausible that the transparenchymal portion of the stent may maintain a reduced diameter over time. However, the permanence of the underdilated stent caliber has not been confirmed, and eventual device self-expansion— balanced against the natural occurrence of pseudointimal tissue coverage and stent luminal reduction— may contest the utility of this approach. With this in mind, we undertook the present study to evaluate whether underdilated VIATORR stent grafts used for TIPS creation expand to nominal diameter over time or durably retain the initial smaller stent caliber.

MATERIALS AND METHODS Institutional review board approval was granted for this study, with waiver of consent for inclusion. Patients provided written informed consent for TIPS procedures.

Patients Two hundred nineteen patients who underwent 221 technically successful VIATORR TIPS procedures (two patients underwent parallel TIPS creation) between May 2003 and December 2013 at an academic tertiary care center were identified through review of our interventional radiology division TIPS registry, and were selected

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for possible retrospective study. Evaluation of stent-graft diameter after TIPS creation was performed via postprocedure computed tomography (CT) imaging. Of those patients identified, 159 (72%) were excluded as a result of a lack of post-TIPS CT (n ¼ 150; 68%) or clinical or sonographic evidence of shunt dysfunction requiring shunt revision with balloon dilation before CT (n ¼ 9; 4%). Sixty patients who underwent 61 successful VIATORR TIPS procedures (one patient underwent parallel TIPS creation) were therefore included in the final study group. Baseline features of the study cohort are summarized in the Table. Statistically significant differences in distributions of liver disease etiology (P o .001) and procedure indication (P ¼ .017) between study groups were not believed to be clinically relevant to the study objective. There was no statistically significant difference in degree of liver disease between study groups based on baseline Child–Pugh and Model for End-stage Liver Disease scores. Liver biopsy data were available in 22 of 61 cases (36%), for which fibrosis was classified according to the Meta-analysis of Histological Data in Viral Hepatitis system (5). Of these, fibrosis stage was predominantly grade 4 (n ¼ 17), indicating probable or definite cirrhosis. The remaining patients had stage 3 fibrosis (n ¼ 3), indicating bridging fibrosis with architectural distortion

but no obvious cirrhosis, or stage 2 fibrosis (n ¼ 2), indicating periportal fibrosis or portal-to-portal septa, without architectural distortion. Eighteen of 22 patients with biopsy data belonged to the underdilated TIPS group and four belonged to the group with a TIPS dilated to nominal diameter. Fibrosis stages included stage 4 (n ¼ 15), stage 3 (n ¼ 2), and stage 2 (n ¼ 1) in the underdilated group and stage 4 (n ¼ 2), stage 3 (n ¼ 1), and stage 2 (n ¼ 1) in the nominally dilated group. Although the analysis was limited by an incomplete data set, there was no statistically significant difference in the distribution of fibrosis stages between study groups (P ¼ .210).

TIPS Technique The method used for TIPS creation has been previously described in detail (6). Ten-millimeter VIATORR stent grafts were used in all cases, and stents were incrementally dilated after deployment. An 8-mm balloon was typically employed first, and a resultant PSG reduction to ≤ 12 mm Hg obviated further dilation. Shunts with a PSG greater than 12 mm Hg after 8-mm balloon dilation were expanded with the use of a 10-mm balloon. Of note, the hepatic parenchymal tract was occasionally predilated with the use of a 6–8-mm balloon before stent-graft deployment.

Table . Patient Demographics, Liver Disease Characteristics, and Clinical Presentation Measure Patients Age (y)

All TIPS 60 54 (26–81)

Nominally Dilated 20 (33) 51 (26–81)

Underdilated

P Value

40 (67) 55 (42–72)

– .176

Sex Male Female

.332 40 (67) 20 (33)

15 5

25 15

13 (22) 19 (32)

10 4

3 15

o .001

Liver disease etiology Alcohol HBV or HCV Alcohol and HBV or HCV

14 (23)

1

13

Other Procedure indication (n ¼ 61)

14 (23)

5

9

Variceal hemorrhage

29 (48)

15

14

Intractable ascites Hepatic hydrothorax

24 (39) 5 (8)

5 0

19 5

Portal vein thrombosis

3 (5)

0

3

Procedure urgency (n ¼ 61) Emergent

14 (23)

7

7

47 (77)

13

34

Nonemergent Previous liver transplantation Baseline Child–Pugh score (n ¼ 61)

.017

.118

6 (10) 9

1 9 (7–12)

5 9 (5–14)

Class A

2

0

2

Class B Class C

36 23

14 6

22 17

15.0 (7–31)

13.5 (9–28)

15.0 (7–31)

Baseline MELD score (n ¼ 61)

.654 .191

.650

Values in parentheses are percentages or ranges where appropriate. HBV ¼ hepatitis B virus, HCV ¼ hepatitis C virus, MELD ¼ Model for End-stage Liver Disease, TIPS ¼ transjugular intrahepatic portosystemic shunt.

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Stent-Graft Imaging Evaluation Preliminary ex vivo imaging standardization of nominal VIATORR device caliber was initially pursued. MicroCT (measurement accuracy, ⫾20 mm; model 40; Scanco Medical, Bruttisellen, Switzerland) and conventional clinical CT (measurement accuracy, ⫾0.2 mm; LightSpeed VCT; GE Healthcare, Milwaukee, Wisconsin) of a completely deployed and nominally dilated 10-mm device were used to calibrate measurement of stent-graft diameter (Fig 1). Subsequently, a picture archiving and communication system workstation (Centricity; GE Healthcare) was used to identify the first clinical CT scan acquired after TIPS creation for each patient. Clinically indicated CT scans were performed by using a LightSpeed VCT scanner (GE Healthcare) with or without intravenous injection of 100–150 mL iohexol (Omnipaque-300; Amersham, Princeton New Jersey). Standard acquisition parameters included 35–50-cm display field of view, 2.5–5.0-mm reconstruction interval, and 0.9 mm/rotation pitch. The transverse crosssectional diameter of indwelling VIATORR stent grafts was measured for each patient in the axial plane along the straight transparenchymal segment of each shunt (Fig 2) at magnification of 5. For measurement, the distance measurement tool on picture archiving and communication system workstations (Centricity; GE Healthcare) was used to delineate the size of measured structures with output accuracy in the tenth of a millimeter range. In regard to measurement accuracy and margin of error, the upper limit of measurement error for caliper-based distance measurements is equal to the CT pixel width, defined as the CT display field of view divided by the matrix size. It should be emphasized that

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stent diameter—as opposed to shunt luminal diameter— was measured, as in-stent pseudointimal hyperplasia formation could not be accounted for on CT imaging. Independent measurements were made by two Certificate of Added Qualification–licensed interventional radiologists, and mean values were used for analysis.

Measured Outcomes The primary outcome measure of this study was VIATORR device diameter as measured on post-TIPS CT imaging. Diameters were compared between initially underdilated (8 mm) and initially nominally dilated (10 mm) devices. Of note, postdeployment and postdilation stent diameters on angiographic images at the time of the TIPS procedures were not assessed as a study outcome measure because of the lack of a consistent internal control measurement device (eg, marking catheter) for distance calibration on postdeployment angiographic images. Secondary outcome measures included PSG reduction, 30-day and cumulative HE incidence, and rate of worsened liver function in each study group. TIPS hemodynamic success was defined as PSG reduction to ≤ 12 mm Hg (7,8). Post-TIPS HE was defined by mental status changes, confusion, or alterations in level of consciousness graded according to the West Haven system (9). Worsened liver function was designated as hepatic functional impairment resulting in at least doubling of bilirubin values beyond 30 days after TIPS creation. Clinical and laboratory data points were collected by trained medical student research associates under direct supervision of an attending interventional radiology physician (R.C.G.) via review of the hospital electronic medical record system.

Figure 1. Cross-sectional imaging performed for stent measurement calibration. (a) Axial image from micro-CT of a nominally dilated 10-mm VIATORR device demonstrates 10-mm stent diameter extending from the midportion of the metal strut to a point interpolated between metal struts. Inset shows micro-CT scout image and slice position. (b) Despite lesser resolution, axial image from conventional CT of 10-mm VIATORR device delineates analogous diameter measurement. Again, caliper measurement extends from the midportion of the metal strut to a point interpolated between metal struts.

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Figure 2. Axial (a) and reconstructed coronal (b) CT images demonstrate standardized location of VIATORR device diameter measurement within a straight, vertically oriented (arrowhead) transparenchymal segment of stent.

Statistical Analysis Data normality and demographic features of the study population were assessed with descriptive statistics. Categoric data comparisons were performed by using the Pearson χ2 test or Fisher exact test. Continuous nonparametric nonpaired data sets were compared by Wilcoxon rank-sum test. Continuous nonparametric paired data sets were compared by Wilcoxon signedrank test. Interrater measurement reproducibility was assessed by using intraclass correlation analysis. Statistical analysis was performed with the use of SPSS software (version 21; SPSS, Chicago, Illinois). P values of .05 or lower were considered statistically significant.

RESULTS TIPS Procedures and Adverse Events Forty-one of 61 TIPSs (67%) were initially underdilated to 8 mm, and 20 (33%) were initially expanded with a 10-mm balloon. TIPS hemodynamic success was achieved in all cases. There was no statistically significant difference in pre-TIPS PSG (20.5 mm Hg vs 20.0 mm Hg; P ¼ .926), post-TIPS PSG (8.0 mm Hg vs 7.0 mm Hg; P ¼ .160), or PSG reduction (13.5 mm Hg vs 13.0 mm Hg; P ¼ .829) between the underdilated and nominally dilated stent groups. The incidence of new or worsening postprocedure HE was similar among underdilated and nominally dilated TIPS study groups within 30 days after the procedure (13 of 41 [31%] vs four of 20 [20%]; P ¼ .382). The cumulative rates of new or worsening postprocedure HE also showed no difference (14 of 41 [34%] vs four of 20 [20%]; P ¼ .372). Moreover, there was no statistically significant difference in the fraction of HE cases in patients with preexisting HE among study groups (five of 41 [12%] vs one of 20 [5%]; P ¼ .653), the percentage of patients receiving empiric HE therapy (eg, lactulose, rifaximin, or metronidazole) before TIPS creation (23 of 41 [56%] vs nine of 20 [45%]; P ¼ .417), or time to HE development (18 d vs

34 d; P ¼ .442) among underdilated and nominally dilated TIPS study groups, respectively. Thirty-day HE grades included grades 1 (n ¼ 4), 2 (n ¼ 6), 3 (n ¼ 2), and 4 (n ¼ 1) in the underdilated group and grades 1 (n ¼ 3) and 3 (n ¼ 1) in the nominally dilated group. Rates of post-TIPS liver function impairment were similar between the underdilated and nominally dilated groups (three of 41 [7%] vs two of 20 [10%]; P 4 .999).

Stent Diameter Measurements The intraclass correlation coefficient for independent operators measuring stent caliber was 0.807 (95% confidence interval, 0.679–0.884), indicating excellent agreement. For the entire study group, the CT-measured median stent diameter was 9.8 mm (range, 8.4–10.5 mm) at a median of 76 days (range, 1–1,739 d) after TIPS creation. There was no statistically significant difference in the median stent diameter in the underdilated group (9.8 mm; range, 8.4–10.2 mm) versus the nominally dilated group (9.9 mm; range, 9.3–10.5 mm; P ¼ .079) at statistically similar follow-up time points after TIPS creation (median, 76 d; range, 1–1,739 d [underdilated group] vs median, 100 d; range, 1–969 d [nominally dilated group]; P ¼ .628). The final stent diameter in the underdilated group showed a statistically significant increase compared with the acknowledged 8.0-mm baseline diameter (9.8 mm vs 8.0 mm; P o .001). Regarding measurement accuracy, the upper limit for possible measurement error was ⫾0.795 mm for the entire study cohort, and there was no difference in possible measurement error between underdilated and nominally dilated TIPS groups (0.787 mm vs 0.810 mm; P ¼ .164). It should be noted that this upper limit for margin of measurement error affected underdilated and nominally dilated TIPS groups equally, and as such would not be expected to obscure any true differences in shunt diameter, if present. Thirty-eight of 41 underdilated VIATORR stent grafts (93%) expanded to 9.0 mm or greater at CT follow-up, and 30 of 41 (73%) expanded to 9.5 mm or

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greater. Fourteen of 41 (34%) expanded to 9.9 mm or greater (Fig 3). Only three cases in the underdilated TIPS group (7%) had a measured shunt diameter less than 9.0 mm at CT follow-up (Fig 3). Interestingly, these cases were all imaged at an early time point (2, 12, and 13 d after TIPS creation), suggesting that an underexpanded diameter may sporadically be retained during the early post-TIPS period.

DISCUSSION In the present study, we investigated the expansion of underdilated VIATORR stent grafts after TIPS creation. In comparing intentionally underdilated versus nominally dilated 10-mm VIATORR lined shunts, we found that the diameters of the underdilated devices enlarged over time, reaching a CT-measured caliber comparable to those of devices dilated to the nominal 10-mm diameter at the time of TIPS creation. The predominant expansion of nearly all underdilated VIATORR stents suggests that the outward radial force of this device exceeds the restrictive effects of most cirrhotic liver parenchyma within a short postprocedure time frame approximating weeks to months. The cumulative rates of HE and worsened liver function were similar among patients undergoing initial VIATORR underdilation versus nominal dilation. Although the development of post-TIPS HE is a multifactorial process dependent on numerous physiologic and hemodynamic factors (10,11), it is known that the volumetric flow through a 10-mm shunt is

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approximately 2.5-fold that through an 8-mm shunt (12), and that the use of larger-caliber shunts results in progressively increased HE rates (13). Admittedly, the relationship between shunt caliber and balloon size is complex, and factors such as the stiffness of fibrotic liver parenchyma, pseudointimal hyperplasia, stent recoil, and intraluminal flow dynamics were not accounted for in the present study. However, these factors would presumably impact underdilated and nominally dilated stents equally, and the comparable rates of adverse secondary side effects of portosystemic shunting in the present study groups indicate that shunt underdilation does not curtail HE or occurrence of worsened liver function compared with nominal dilation, presumably because of shunt expansion. Although it is possible that stent underdilation may lessen the abruptness of portal and systemic hemodynamic changes after TIPS creation, thereby facilitating gradual adaptation to these changes as the stent expands to its nominal diameter over time, operators who desire durably smaller stent calibers to limit portosystemic shunt complications may be better served by employing 8-mm stent grafts with the option for future parallel TIPS creation in case of insufficient shunting (12). However, at least one randomized trial (14) has shown no difference in HE incidence between 8mm and 10-mm TIPSs, but greater clinical failure of 8mm shunts; however, this investigation (14) was limited by diversity and disparity of TIPS indications among patient cohorts, as well as early study termination. There are limitations to the present investigation. First, the study was retrospective and nonrandomized

Figure 3. (a) Magnified axial CT image acquired 327 days after TIPS creation in a 52-year-old woman reveals nominal expansion of originally underdilated indwelling VIATORR stent (arrowhead), measuring 9.9 mm in diameter; note perfectly round shape of completely expanded stent. (b) Magnified axial CT image 2 days after TIPS creation in a 56-year-old woman shows incomplete expansion of initially underdilated indwelling VIATORR stent (arrowhead), measuring 8.4 mm in diameter; note flattened edges of moderately constrained stent.

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in nature, without standardization of the CT imaging time point; the time frame for achievement of nominal stent size is therefore not exactly known and may be different between individual patients. Second, imaging measurement may have been limited by CT resolution, although micro-CT imaging was used to calibrate stent diameter measurement. Third, only a single in-stent transverse measurement was obtained in each case, and actual luminal diameter was not reported; further, the stent diameter was not measured where it may be smallest, at the portal vein entry site. Moreover, projected intrashunt flow rate and/or volume were not assessed, and may have shown differences among study groups not identified by stent diameter measurement; to this end, computational modeling may have value for instent hemodynamic quantification (10). Fourth, this study did not evaluate 8-mm– or 12-mm–diameter VIATORR devices, and it is unknown whether our findings translate to these stents. However, despite these drawbacks, our data suggest that VIATORR stent grafts largely self-expand to nominal diameter when underdilated. Although a controlled ex vivo experiment studying stent expansion dynamics would provide the most firm evidence for temporal dilation, our clinical results suggest that the underdilation approach to customizing shunt diameter may not be durable.

ACKNOWLEDGMENTS The authors acknowledge the Rush University Micro-CT/ Histology Core for providing instrumentation and assistance in conducting micro-CT imaging for the study.

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Should transjugular intrahepatic portosystemic shunt stent grafts be underdilated?

Although underdilation of transjugular intrahepatic portosystemic shunt (TIPS) stent grafts is commonly performed to limit complications arising from ...
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