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Special Report |
1 From the Departments of Radiology (A.L., R.L.G., M.M.) and Internal Medicine (G.D.) and the Institute of Internal Medicine and Pneumology (A.L., L.P.), University of Palermo, Ospedale V Cervello, Via Trabucco 180, 90146 Palermo, Italy, and the Institute of Medical Statistics and Biometry, University of Milan, Italy (A.M.). Received May 1, 1998; revision requested July 6; revision received August 26; accepted January 25, 1999. Address reprint requests to A.L.
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Abstract |
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 TOP Abstract IntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1References |
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MATERIALS AND METHODS: Data from 11 relevant studies were retrieved by means of computerized and manual search. The combinability of the studies was assessed in terms of clinical and statistical criteria. Data were extracted on the basis of the intention-to-treat principle, and treatment effects were measured as risk differences between TIPS creation and conventional treatment. Pooled estimates were computed according to a random-effects model.
RESULTS: A total of 750 patients were included in 11 trials. No significant heterogeneity was found for any of the outcomes. Pooled risk differences were recurrent bleeding, -31% (95% CI, -39%, -23%); encephalopathy, +16% (95% CI, +10%, +22%); death due to all causes, +2% (95% CI, -4%, +9%); and death due to bleeding, -5% (95% CI, -11%, +6%). Clinically important complications occurred in 22% of patients and were associated with both treatments. TIPS dysfunction occurred in 55% of patients.
CONCLUSION: TIPS creation markedly reduces risk of rebleeding but increases risk of encephalopathy without affecting survival. Therefore, TIPS creation may not be the best first-choice therapy for prevention of recurrent variceal bleeding. Criteria for selection of candidates for TIPS creation should be assessed in future prospective studies.
Index terms: Liver, cirrhosis, 761.794 • Liver, hemorrhage, 761.458. 761.75 • Liver, interventional procedures, 761.1299 • Radiology and radiologists, outcomes studies • Shunts, portosystemic, 95.1268 • Varices, 71.75
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Introduction |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1References |
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In an early randomized study (9), published in abstract form in 1994, TIPS creation was compared with endoscopic sclerotherapy for the prevention of recurrent variceal bleeding. The results of this study showed an increased mortality rate in patients treated with TIPS. In 1994, a consensus conference sponsored by the National Digestive Advisory Board (10) recommended guidelines for TIPS creation. It was recommended that until the role of TIPS has been identified in randomized clinical trials, the procedure should be clinically used only in patients with acute variceal bleeding that cannot be controlled with endoscopic and pharmacologic therapy and in patients with recurrent bleeding despite adequate treatment with ß-adrenergic blocking agents (hereafter, ß-blockers) and endoscopic therapy. Thus far, however, randomized clinical trials usually have included small sample sizes and have shown conflicting results, which hinder the drawing of conclusions for clinical practice.
The aim of this meta-analysis was to assess the effectiveness of TIPS as compared with sclerotherapy or banding ligation of esophageal varices, with or without administration of propranolol hydrochloride, for the prevention of recurrent bleeding. Because these endoscopic treatments and the use of propranolol are well established and widely used for the prevention of recurrent bleeding in patients with cirrhosis (11), they are referred to as conventional treatment throughout this article.
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MATERIALS AND METHODS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1References |
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Selection of the Trials
Studies that fulfilled the following criteria were included in the present meta-analysis: (a) TIPS was compared with endoscopic treatment (sclerotherapy or banding ligation) alone or with propranolol; (b) patients were randomly assigned to the treatment regimen, and prospective follow-up was included; (c) patients with cirrhosis and previous variceal bleeding were included; (d) two or more of the following outcomes were assessed: (i) recurrent bleeding, (ii) encephalopathy, and (iii) death; and (e) results were published in English as abstracts or full reports.
Study Identification
Pertinent studies were retrieved from the MEDLINE database (January 1991–February 1998) by using the search terms "TIPS," "sclerotherapy," "variceal band ligation," and "beta-blockers" and by limiting the search to reports of clinical trials and studies with human patients. In addition, a manual search was performed by checking the reference lists from articles or reviews to identify studies not yet included in the MEDLINE database (16). Finally, the abstracts from international congresses on liver diseases underwent peer review to identify trials still in progress. When the results of a single study were reported in more than one publication, only the most recent and complete data were included in the meta-analysis. Eleven randomized clinical trials that fulfilled the criteria were identified, seven published in full form (17–23) and four published in abstract form (24–27).
Data Extraction
Data from each randomized clinical trial were extracted by two independent reviewers (A.L., G.D.). For each study and each type of treatment, the following data were extracted: number of patients, mean age, sex, prevalence of alcoholic cirrhosis, Child-Pugh score, presence of ascites, time between index bleeding and random assignment to treatment, type and modality of control treatment, rate of technical success of the procedures, portacaval pressure gradient before and after TIPS creation, mean length of follow-up, incidence of TIPS dysfunction, and definition and number of each outcome (Tables 1–4). Numeric discrepancies between the two independent data extractions were resolved after discussion.
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Any discrepancy in the qualitative assessment between the two observers was discussed, and a consensus was achieved. The total score of each trial also was expressed as a percentage of the maximum achievable score.
Statistical Methods
We assumed that variceal endoscopic sclerotherapy and banding ligation with or without the use of ß-blockers were equivalent control interventions. Although the results of previous meta-analyses (29,30) do not support this assumption, there were no significant differences between the control groups of the trials included in the present analysis in terms of the incidence of outcomes of interest during the study period (Table 3). Thus, in an attempt to improve the power of the meta-analysis, we considered the control treatments to be equivalent.
All comparisons were performed according to the randomly assigned treatment (intended-treatment analysis). Because of differing clinical characteristics among study groups, varying sample sizes, and different control treatments, we assumed that heterogeneity was present even when not statistically significant, and we decided to combine data by using a random-effects model (31) whenever the 
2 value (a measure of the between-study variability of the treatment effect) was greater than 0 (32,33), to achieve more conservative pooled estimates.
For all outcomes, the pooled risk difference was computed with the method of DerSimonian and Laird (31). Summary point estimates and 95% CIs, 
2 statistics for heterogeneity, and 2 values are reported. For statistically significant risk differences (that is, if the 95% CI of the summary risk difference did not include 0), the number needed to treat was calculated (34). The number needed to treat is the number of patients who must be treated to avoid one unfavorable event; it is calculated by using the reciprocal of the weighted difference in rates between treatment and control groups. The 95% CIs for number needed to treat also are reported.
To determine the consistency of results, two sensitivity analyses were performed according to type of publication (abstract or full article) and control treatment. The data were processed by using the META-ANALYST program (version 0.989; Lau J, Boston, Mass).
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RESULTS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1References |
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TIPS creation was compared with sclerotherapy in five trials (17,20,21,23,24), with sclerotherapy and propranolol administration in three trials (18,19,24), and with band ligation in three trials (22,26,27). In one trial (18), eventual embolization of the varices was performed in half the patients in the TIPS group. The mean follow-up was 15.9 months in the TIPS groups and 16.3 months in the conventional treatment groups.
Treatment for episodes of recurrent bleeding was reported to be the same in the two treatment groups in one trial (19). In two trials (20,22), emergency sclerotherapy was performed in both groups, and balloon dilatation and/or further stent placement were also performed in the TIPS group. In the other trials, no information about treatment for recurrent bleeding was reported. The definition of death due to recurrent bleeding was reported in only two trials (19,23), although the number of patients who died of recurrent bleeding was reported in six of the seven studies published as full articles. The definitions of the other three outcomes in this meta-analysis were fairly comparable across the trials described in full reports (Table 4).
The quality score for the seven trials published as full reports and assessed for methodological quality ranged from 51% to 88%, which was indicative of fair to good quality. Details on the single components of the quality score for each trial are reported in the Appendix.
No significant heterogeneity of treatment effect was found for any of the assessed outcomes (even when the analyses were repeated by using odds ratios [data not shown]), and the 2 value was greater than 0 in all analyses.
Technical Results and Complications of Treatment
TIPS creation was successful in 90%–100% (median, 98.5%) of patients. The reduction of the portosystemic pressure gradient ranged from 10.3 to 16.2 mm Hg (median, 13.0 mm Hg). At stent surveillance (Table 4), narrowing or occlusion of the stent lumen, defined as stent dysfunction (Table 4) and necessitating shunt revision, was found in 18%–76% (median, 55%) of patients (Table 2).
Endoscopic sclerotherapy or banding ligation of varices resulted in variceal obliteration in 51%–80% (median, 66%) of patients. Recurrence of varices in endoscopically treated patients was reported in three studies and was 28% (20), 32% (19), and 55% (17).
Complications of treatment published in the seven full reports are summarized in Table 5. After TIPS creation, 60 of 268 (22%) patients experienced complications, the most serious of which were hemorrhage in nine patients (intraperitoneal in three, intrahepatic in two, and hemobilia in four) and infections in 23 patients. Complications of endoscopic therapy occurred in 61 of 272 (22%) patients, including bleeding in 13 patients (due to esophageal ulcer in eight and immediately after a sclerotherapy session in five); infection in 20; and dysphagia in 14, nine of whom had esophageal stenosis necessitating dilation.
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TIPS creation resulted in a significant reduction in the rate of recurrent bleeding in nine trials (17–19,21–23,25–27) and a nearly significant reduction in another (24) (Fig 1), whereas there was no effect in one trial (20). The overall weighted recurrent bleeding rate was 21% for TIPS creation and 52% for endoscopic treatment. The pooled risk difference was -31% (95% CI, -39%, -23%) (Fig 1). The 2 value for heterogeneity was 11.79 (df = 10, P > .25). The "number needed to treat" (ie, number of patients who need to be treated with TIPS to prevent one episode of recurrent bleeding) was 3.3 (95% CI, 2.6, 4.4), which indicates that, compared to conventional therapy, two to five patients needed to be treated with TIPS to prevent one recurrent bleeding episode.
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2 value for heterogeneity was 6.87 (df = 9, P > .5). The number needed to treat was 6.0 (95% CI, 4.5, 10.0), which indicates that for every four to 10 patients treated with TIPS, one more episode of encephalopathy occurs more than if they had been treated conventionally.
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2 value for heterogeneity was 9.53 (df = 10, P > .25). Causes of death are reported in Table 6.
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2 value for heterogeneity was 13.74 (df = 7, P > .05).
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Sensitivity Analyses
Sensitivity analyses showed consistency of results for type of publication (full report or abstract) and type of conventional treatment (sclerotherapy, sclerotherapy with propranolol administration, or endoscopic band ligation). However, the increased risk of encephalopathy after TIPS creation was not statistically significant in abstract reports and in trials in which banding ligation was the conventional therapy. Results of the sensitivity analyses are shown in Table 7.
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DISCUSSION |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1References |
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Although no significant heterogeneity was found for any of the assessed outcomes, differences in the ways in which the trials were conducted and in the methods used suggest that some caution is warranted as regards interpretation of the results of the pooled estimates. Although inclusion of data from trials published in abstract form (24–27) did not significantly affect the overall estimates of the effect of TIPS creation, the combinability of the included trials should be reassessed after full reports of all have been published.
The beneficial effect of TIPS creation on recurrent bleeding was observed in all but one of the trials. The average rate of recurrent bleeding was 20% in patients treated with TIPS creation, which suggests that this interventional radiologic procedure is highly effective for the prevention of recurrent bleeding. A comparably low frequency of recurrent bleeding was reported (35) only in trials where portosystemic shunts were surgically created. However, the comparability of the effect on recurrent bleeding rates associated with TIPS creation and that associated with surgical creation of other types of portosystemic shunt should be reassessed after longer follow-up in patients treated with TIPS creation.
Despite the low frequency of recurrent bleeding in patients treated with TIPS creation, the median rate of stent dysfunction reported in the seven full articles (17–23) was 55%. This finding suggests that other factors may contribute to the precipitation of recurrent bleeding. Of interest in this regard, Sanyal et al (4) recently reported that active alcoholism and high systemic venous pressure together with stent dysfunction are independent risk factors for recurrent bleeding in patients treated with TIPS creation. The wide variability in dysfunction rates across the studies is accounted for by the different definitions and surveillance modalities used, with higher rates found when dysfunction is defined on the basis of invasive hemodynamic measurements. A 2-year incidence of TIPS dysfunction of up to 90% has been reported (4) when invasive hemodynamic measurement was used. The best approach to monitoring of TIPS function in clinical practice is still unsettled, however, and further studies specifically designed for this aim are needed.
The most important side effect of TIPS creation is encephalopathy. Experience with the surgical creation of portosystemic shunts was predictive of this outcome (35). In fact, in hemodynamic terms, a TIPS behaves like a side-to-side portosystemic shunt: The greater the diversion of blood into the systemic circulation, the greater the reduction in portal venous pressure and, hence, the greater the protection against bleeding and the greater the risk of encephalopathy. For this reason, portosystemic shunt surgery, either total or selective, was almost completely abandoned in the past 2 decades. Other than ease of performance, TIPS creation has the advantage over shunt surgery of the ability to calibrate the shunt, which can be tailored in each patient to achieve the minimum portosystemic blood diversion with the optimal portal venous pressure reduction.
The 11 randomized clinical trials included in the present meta-analysis showed a significant increase in the frequency of encephalopathy in patients treated with TIPS creation. However, a conclusion on this crucial point is not possible for two important reasons. First, the optimal reduction in portal venous pressure still is undefined: A reduction below the threshold value of 12 mm Hg should represent maximal protection against the risk of bleeding (36). It has also been suggested (37) and prospectively validated (38) that a 20% reduction from baseline may be enough of a decrease; however, it is not known whether reductions of either more or less than 20% will provide better protection. In none of the 11 trials included in this meta-analysis was there an attempt to determine the optimal reduction in portal venous pressure, and the available data do not allow such an analysis.
The second reason we cannot draw conclusions about TIPS creation and encephalopathy is that encephalopathy was not blindly assessed in any of the studies included in this meta-analysis. Diagnostic bias, therefore, cannot be ruled out.
Thus, the frequency of encephalopathy after TIPS creation should probably be reassessed in further randomized clinical trials that have been more specifically designed to tailor portal venous pressure reduction to achieve the best decrease in the risk of bleeding with the lowest frequency of encephalopathy.
Until such studies are performed, it may be prudent to not perform TIPS creation or to use smaller-diameter stents in patients with known risk factors for encephalopathy, such as age older than 60 years, female sex, previous episodes of encephalopathy, nonalcoholic cause of cirrhosis, low albumin levels, and Child-Pugh class (6–8,17–19). Moreover, a portacaval pressure gradient of less than 10 mm Hg after TIPS creation is associated with a substantially higher risk of encephalopathy (8) and should be avoided. Finally, it is important to remark that in patients with severe and progressive encephalopathy, it is possible to reduce flow through the prosthesis by placing reducing stents or detachable balloons (39).
The overall incidence of complications that occurred during the reviewed trials was high and similar for the two types of treatment. Major complications were bleeding and sepsis for both, although bleeding was more frequent after endoscopic treatment, and sepsis was more frequent after TIPS creation. The available information does not allow assessment of whether the excess rate of encephalopathy after TIPS creation occurred in patients free of other complications. Thus, it is not possible to compare the numbers of patients without complications for each type of treatment.
The results of this meta-analysis showed that TIPS creation did not significantly affect survival, although the significant reduction in the rate of recurrent bleeding after TIPS creation was expected to result in a parallel reduction in deaths due to bleeding. In one study (25), a significant reduction in the risk of death was observed in patients treated with TIPS creation, but no data on cause of death are available because the study was reported in abstract form. In another study (20), a significant increase in the risk of death was reported; in this study, cumulative death proportions were compared by using the log rank test; however, the mortality rate related to recurrent bleeding after TIPS creation was unusually high (42% of all deaths). Overall, in patients who underwent TIPS creation, there was no significant trend toward a reduction in deaths due to bleeding, and there was an opposite trend toward an increase in deaths due to other causes. This combination of results seems to have balanced the overall mortality rate between the two treatment groups. The lack of a significant reduction in deaths caused by bleeding probably is due to type II error; also, the large number of patients who did not respond to conventional treatment and therefore crossed over to TIPS creation could have contributed to lessen this difference. However, whether TIPS creation has a substantial effect on cause of death should be reassessed when all the studies included in this meta-analysis have been published as full reports.
In conclusion, the results of this meta-analysis show that in patients with cirrhosis and previous variceal bleeding, TIPS creation is more effective than endoscopic therapy with or without propranolol administration for the prevention of recurrent bleeding but significantly increases the risk of encephalopathy and does not affect survival.
Because of the significant excess risk of encephalopathy, TIPS creation is far from the ideal therapy for prevention of recurrent bleeding and, in our opinion, cannot be considered a first-choice treatment. However, several considerations suggest that the efficiency of TIPS creation can probably be much improved. First, the optimal reduction in portal venous pressure to achieve the highest protection against bleeding and the lowest risk of encephalopathy still is unsettled. Second, there may be improvements in the selection criteria for patients at lower risk for encephalopathy who may benefit more from TIPS creation. Third, technical advances are expected to reduce the frequency of TIPS dysfunction. In some respects, further meta-analysis of the available trials, in which individual patient data are used, will be most helpful, and the authors who conduct such trials should be encouraged to combine their data.
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Appendix 1 |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1References |
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Acknowledgments |
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Footnotes |
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Author contributions: Guarantors of integrity of entire study, A.L., G.D.; study concepts, A.L., G.D., L.P.; study design, G.D.; definition of intellectual content, A.L., G.D., L.P.; literature research, R.L.G., M.M.; data acquisition, R.L.G., M.M.; data analysis, A.L., G.D.; statistical analysis, A.M., G.D.; manuscript preparation and editing, G.D., A.L.; manuscript review, G.D.
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References |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAppendix 1References |
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