Can Anticoagulation Enhance TIPS Patency?

Acute TIPS Thrombosis. Thrombosis of the TIPS usuallySEE ARTICLE ON PAGE 1433 develops acutely either at the time the stent is being deployed

or within several days of its placement. Fortunately, thisseems to be an uncommon problem, reported to occur in onlyThe transjugular intrahepatic portosystemic shunt (TIPS)3% to 10% of patients in several large series.1,2,14-18 It hasis now well accepted as an important tool in the managementbeen suggested that this process may be more common inof patients who have developed severe and life-threateningpatients with Child’s class A and B cirrhosis, who have acomplications of portal hypertension. The placement of annormal prothrombin time and platelet count.1 However,intrahepatic stent between the hepatic and portal veins isthrombosis of the TIPS has also been observed in patientsassociated with an immediate decline in the hepatic venouswith advanced Child class C liver disease who are both coagu-pressure gradient.1-4 This enables TIPS to be an extremelylopathic and thrombocytopenic.17 Three distinct processeseffective treatment for patients experiencing hemorrhageseem to be responsible for acute thrombosis. The advance-from esophageal varices that are refractory to pharmacologi-ment of guidewires into the portal vein during the TIPS pro-cal and/or sclerotherapy.3,4 In a recent study by Sanyal etcedure can tear the vascular endothelium, which in turnal.,3 the use of TIPS in this setting was associated with astimulates the clotting cascade.17,18 Thrombosis of the TIPSsurvival rate of approximately 50% compared with only 5%may also result when self-expanding stents, such as thein the pre-TIPS era. TIPS also seems to be a promising ther-Wallstent (Schneider, Minneapolis, MN), shorten and retractapy for the treatment of refractory ascites,5-7 although moreout of the hepatic and/or portal veins soon after they aredata regarding the long-term efficacy of TIPS for this indica-deployed.18 More recently, biliary fistulae have also been im-tion is required.4plicated as a cause for acute stent thrombosis. Bile ducts areSoon after its introduction to clinical practice, there wascommonly transected during the creation of the intrahepaticwidespread enthusiasm that TIPS could replace both chronictract, and communication between bile ducts and the stentsclerotherapy and shunt surgery as a means of preventinglumen in patients who have developed thrombosis has re-recurrent variceal hemorrhage following an index bleedingcently been demonstrated.18-20 It is hypothesized that theevent (secondary prophylaxis). Within the past several years,leakage of bile into the vascular lumen via these biliary fis-several centers have embarked upon clinical trials comparingtula may stimulate the clotting process.the efficacy of TIPS for secondary prophylaxis with chronic

Chronic TIPS Stenosis. As opposed to thrombosis, stenosissclerotherapy,8-11 a combination of sclerotherapy and b-block-of the TIPS is a chronic process which results from eitherers,12 and variceal band ligation.13 Preliminary results froman ingrowth of collagen through the wire mesh stent, whichmany of these trials have been presented only in abstractgradually fills the lumen and reduces its diameter, or fromform. At the time of this writing only one study had beenthe growth of collagen over the hepatic venous end of thepublished in a peer-reviewed journal,9 but a second had beendevice.15,18,21 This is a much more common problem thanaccepted for publication and is due shortly.8 Although one ofthrombosis and has been observed in 33% of patients withinthese trials demonstrated that patients who underwent TIPS6 months, 66% within 12 months, and up to 80% of patientshad a higher incidence of rebleeding,8 the others have demon-24 months following initial TIPS placement.1,2,14,15,18,21 A pre-strated no significant differences in rebleeding betweenliminary report by Sanyal et al.22 utilized immunohistochemi-TIPS-treated and endoscopically treated patients. A potentialcal techniques to demonstrate that this process results fromconcern is that several of these reports raise the possibilitysmooth muscle cells growing into the lumen and at the he-that mortality following TIPS may be higher than withpatic venous end of the stent. These smooth muscle cells neo-chronic sclerotherapy.8-13 A recent meta-analysis seems toarterialize the intraparenchymal tract by secreting a collagenconfirm this finding (N. Grace, personal communication,matrix, which is then covered by a vascular endothelium.June 1996). The reasons for this are unclear at this time andStent stenosis is the most common reason for rebleeding fol-will have to await the publication of these trials in peer-lowing TIPS placement, and this appears unrelated to Childreviewed journals.class, the presence of a coagulopathy or thrombocytopenia.Although TIPS is very effective in reducing portal pressure,

Use of Anticoagulation to Prevent Thrombosis and Steno-the main limitation of this procedure appears to be main-sis. The paper by Sauer et al.23 in the current edition of HEPA-taining the long-term patency of the stent.1,2,4,14 The TIPSTOLOGY has investigated the possibility that short-term anti-device may occlude acutely after its deployment, typically thecoagulation may prevent either TIPS thrombosis and/orresult of thrombosis. Alternatively, stenosis of the stent is astenosis. A total of 49 consecutive patients with Child’s classchronic process that evolves over several months to severalA or B cirrhosis who underwent TIPS placement with theyears. Either of these events result in the recurrence of portalPalmaz stent for variceal hemorrhage were randomized intohypertension, which is the major cause for rebleeding follow-this study. Patients with Child class C cirrhosis were ex-ing TIPS placement in all previous studies.1,2,8-13 However, itcluded from participating. All patients were treated with in-is important to make a distinction between acute thrombosistravenous heparin during the first 3 days following TIPSand TIPS stenosis as the pathogenesis for these two processesplacement. At that point, the patients were randomized toare quite different.receive either phenprocoumon to maintain the prothrombintime at an international normalization ratio of 1.5-2.1 for 3months or no additional anticoagulation (control group). All

Abbreviation: TIPS, intrahepatic portosystemic shunt.patients underwent duplex ultrasonography and portographyFrom the Hepatology Section, Medical College of Virginia, Virginia Commonwealth Uni-to assess shunt patency either at the time of rebleeding orversity, Richmond, VA.

Received August 13, 1996; accepted September 10, 1996. at 3-month intervals for 1 year.Address reprint requests to: Mitchell L. Shiffman, M.D., Hepatology Section, Medical The two groups were well matched for age, sex, cause of

College of Virginia/VCU, Box 980341, Richmond, VA 23298.liver disease, and Child’s class. In addition, no significantCopyright q 1996 by the American Association for the Study of Liver Diseases.

0270-9139/96/2406-0037$3.00/0 differences were noted between the hepatic-portal venous

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1534 SHIFFMAN HEPATOLOGY December 1996

pressure gradient either prior to or following TIPS place- rate of thrombosis observed in this study was use of the Pal-maz stent. Turbulent blood flow has been implicated as ament, prothrombin time, and/or platelet count. Two patients

from each group were dropped from the trial at 3 months; cause for stent thrombosis in high-flow arterial systems24,25

and in animal models,26 and anticoagulation seems to havethree of these patients refused to undergo repeat portogra-phy, and the third had inadvertently stopped anticoagula- limited this complication in these studies. Turbulence may

be more common with the Palmaz stent, because several oftion. It is important to note that thrombosis of the TIPS wasfound in this later patient 3 months after its placement. In these short-stiff stents must be placed in series to bridge

the parenchymal tract between the hepatic and portal veins,the remaining 45 patients undergoing a 3-month evaluation,narrowing of the stent lumen (stenosis) with recurrence of creating an irregular vascular channel. Although a recent

retrospective analysis found no major differences betweenportal hypertension was observed in 11 of 22 patients (50%)who received anticoagulation compared with 7 of 23 patients the Palmaz and Wallstent stents,27 this issue requires further

study.(30%) in the control group. In contrast, complete occlusion ofthe TIPS with thrombus was observed in 5 of 23 patients An important observation in the present study is that acute

thrombosis was not observed in any of the patients more than(22%) in the control group but in none of the anticoagulatedpatients. Thrombectomy was successful in 2 of these 5 pa- 3 months following the placement of the original TIPS. This

was true in persons who developed TIPS stenosis and re-tients. In the other two patients, a new parallel TIPS wascreated. All cases of TIPS stenosis from both groups under- quired dilatation, thrombosis, and underwent thrombectomy

with dilatation or in patients who had normal stent hemody-went successful balloon angioplasty. Rebleeding within thefirst 3 months following TIPS placement was observed in 1 namics at 3 months. This observation clearly demonstrates

that thrombosis is an acute problem only encountered in thepatient in the phenprocoumon group and in 2 patients in thecontrol group (both of whom had thrombosis). Anticoagula- first few weeks following the initial deployment of the stent

and supports what are currently thought to be the majortion was discontinued after 3 months. Follow-up of these pa-tients up to 1 year demonstrated restenosis in 28% of patients etiologic factors responsible for acute thrombosis: 1) damage

to vascular endothelium; 2) biliary fistula; and 3) turbulentin the phenprocoumon group and in 25% in the control group.However, no cases of repeated or new thrombosis were ob- blood flow. Soon after the TIPS is placed, smooth muscle

cells move into the parenchymal tract and secrete a collagenserved after the initial 3 months following TIPS placement.Is Anticoagulation Really Effective? It is quite clear from matrix that encases the wire stent and is then covered by

vascular endothelium.22 This process appears to take approx-this study that 3 months of anticoagulation has no effect onthe rate or natural history of TIPS stenosis. In contrast, it imately 2 to 4 weeks19; once complete, the bile fistula are

probably sealed and flow turbulence is reduced. Thus, if anti-remains unclear whether or not anticoagulation reduces theincidence of acute TIPS thrombosis. The major issue regard- coagulation is utilized, limiting this treatment to only the

first 4 weeks following placement of the stent may proveing this point centers around the single patient, randomizedto the phenprocoumon group, who developed thrombosis. The sufficient.

Color duplex ultrasonography remains the most popularauthors of this study felt justified to exclude this patient fromanalysis since he discontinued treatment. In doing so, the and least invasive method by which to screen individuals

for either stenosis or thrombosis of the TIPS.28 In our owndifference in the rate of thrombosis between the control (5 of23 patients) and treatment groups (0 of 22 patients) was experience at the Medical College of Virginia, finding the

absence of flow through the stent on the color duplex ultra-statistically significant (P Å .049). In contrast, if an intent-to-treat analysis was performed, the patient in the phenpro- sound examination, within 7 days following deployment, was

highly sensitive and specific for acute TIPS thrombosis.29 Be-coumon group who developed thrombosis would have beenincluded (a thrombosis rate of 1 of 22), and the difference in cause thrombosis is an acute process, screening for this com-

plication at regular intervals shortly after the stent is placedthe rate of thrombosis between these two groups would nothave been significant by the Fisher’s Exact test (P Å .19). As may result in the early recognition of thrombosis and may

allow for rapid correction before rebleeding occurs. Acutesuch, this study suffers from a b-statistical error, i.e., thesample size was insufficient to determine if anticoagulation thrombosis has not been observed at our center more than 4

weeks following TIPS placement, despite aggressive monitor-within the first 3 months did indeed reduce the rate of TIPSthrombosis. Given the rate at which thrombosis was observed ing of TIPS dysfunction. Similar results were observed in the

study by Lind et al.14 Although duplex ultrasonography wasin the control (20%) and treatment groups (1 of 22), a samplesize of 76 patients would have been required to disprove the performed in the study by Sauer et al.,23 this was not done

until 3 months later, and no correlation between these find-null hypothesis tested in this study (anticoagulation was ef-fective in preventing thrombosis of the TIPS). As a result, ings and portography was provided.

In contrast, duplex ultrasonography appears less usefulthe best that we can conclude from this study is that anticoag-ulation may be helpful in reducing the rate of acute thrombo- when screening for stenosis of the TIPS. The most common

ultrasound findings associated with stenosis include an in-sis in certain patients undergoing TIPS. A larger study willbe necessary to determine if this proves to be correct. crease in intrastent flow velocity, a reversal of flow within

the stent lumen, or a shift in the direction of flow from theAnother important issue to be considered in this study isthe incidence of TIPS thrombosis. Twenty percent of patients stent toward the periphery of the liver.28-31 Although these

findings are highly specific for stenosis, their sensitivity hasin the control group developed thrombosis, a value two- tofourfold greater than observed in other larger series.1,2,17,18 A not been rigorously tested against angiography. Portography

remains the gold standard and only reliable way of definingpossible explanation for this finding was that patients withChild class C cirrhosis were excluded from entering this trial. TIPS stenosis at this time.

Although the risk of bleeding complications did not appearPrevious trials by this23 and another group1 have suggestedthat acute thrombosis is observed more frequently in patients to be increased by anticoagulation in this study, one of the

primary risk factors for rebleeding in a patient with alcoholicwith a normal prothrombin time and platelet count. However,this has not been the experience at all centers.4,16,17 Addi- cirrhosis, even after TIPS placement, is a return to alcohol

consumption. One must, therefore, question whether or nottional studies are therefore necessary to more clearly definea subgroup of patients at greatest risk for developing acute patients with alcoholic liver disease who do not maintain

abstinence following TIPS placement are at greater risk forthrombosis following TIPS placement before additional trialsof anticoagulation are performed. developing complications of anticoagulation compared with

the relatively low risk of thrombosis.Another factor which may have contributed to the high

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HEPATOLOGY Vol. 24, No. 6, 1996 SHIFFMAN 1535

preliminary results of a multicenter randomized trial [Abstract]. HEPATOL-And so the question remains: Should patients with pre-OGY 1995;22:297A.served hepatic function and who are undergoing elective 13. Jalan R, Forrest EH, Redhead DN, Dillon JF, Bzeizi KI, Finlayson NDC,

TIPS receive anticoagulation? Unfortunately, the present MacGilchrist AJ, et al. TIPSS vs variceal band ligation in the secondaryprevention of variceal haemorrhage in cirrhosis: preliminary results of astudy does not provide a definitive answer regarding thisrandomized controlled study [Abstract]. HEPATOLOGY 1995;22:251A.issue; however, it does demonstrate that anticoagulation is

14. Lind CD, Malisch TW, Chong WK, Richard WO, Pinson CW, Meranze SG,of no benefit to improving long-term TIPS patency from ste- Mazer M. Incidence of shunt occlusion or stenosis following transjugularnosis, the major leading factor to stent dysfunction. To be intrahepatic portosystemic shunt placement. Gastroenterology 1994;106:

1277-1283.convinced that anticoagulation reduces the incidence of acute15. Freedman AM, Sanyal AJ. Complications of transjugular intrahepatic por-TIPS thrombosis will require a more conclusive evaluation

tosystemic shunts. Seminars in Interventional Radiology 1994;11:161-177.and a better understanding of the factors which contribute 16. Freedman AM, Sanyal AJ, Tisnado J, Cole PE, Shiffman ML, Luketic VA,to this process. Purdum PP III, et al. Complications of transjugular intrahepatic portosys-

temic shunt: a comprehensive review. Radiographics 1993;13:1185-1210.17. Shiffman ML, Cole PE. Complications of implantation. In: Conn HO, Pal-MITCHELL L. SHIFFMAN, M.D. maz J, Rosch J, Rossle M, eds. TIPS: Transjugular Intrahepatic Portal-

Hepatology Section Systemic Stent-Shunts. New York: Igaku-Shoin Medical Publishers; 1996:249-266.Medical College of Virginia/VCU

18. Saxon RR, Barton RE, Keller FS, Rosch J. Stenosis and occlusion afterRichmond, VATIPS: prevention and correction. In: Conn HO, Palmaz J, Rosch J, RossleM, eds. TIPS: Transjugular Intrahepatic Portal-Systemic Stent-Shunts.

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