Distal spleno-renal shunt versus endoscopic sclerotherapy in the prevention of variceal rebleeding

338

Journal of Hepatology. 1992; 16:338-345 © 1992 Elsevier Scientific Publishers Ireland Ltd, All rights reserved. 0168-8278/92/$05.00

HEPAT 01273

Distal spleno-renal shunt versus endoscopic sclerotherapy in the prevention of variceal rebleeding A meta-analysis of 4 randomized clinical trials Gian Paolo Spina a, J. Michael Henderson b, Layton F. Rikkers c, Josep Teres a, Andrew K. Burroughs e, Harold O. Conn f, Luigi Pagliaro g and Roberto Santambrogio a

Other participants Antonio Ascione h, Josep M. Bordas a, W. Scott Brooks b, Kenneth M. Buchi c, David A. Burnett c, Robert A. Cormier ~, John T. Galambos b, Michael H. Kutner b, William J. Millikan b, Enrico Opocher ~, Andrea Pisani ~, Stanley P. Riepe b, Josep Visa a and W. Dean Warren b ~Istituto di Scienze Biomediche S. Paolo. Universitd di Milano. Milan. Italy; bEmory University Hospital, Atlanta, GA, United States of America; cUniversity of Nebraska Medical Center, Omaha, N B, United States of America; dHospital Clinic i Provincial, Barcelona, Spain; "Royal Free Hospital School of Medicine. London. United Kingdom; f Yale University. New Haven, CT, United States of America; BClinica Medica R. Universitd di Palermo, Italy: and hOspedale Cardare/li, Servizio di Epatologia Epatica. Unitd Fegato, Naples. Italy {Received 15 September 19911

Meta-analysis was used to evaluate 4 clinical trials comparing distal spleno-renal shunt (DSRS) with endoscopic sclerotherapy (EVS) in the prevention of variceal rebleeding: the interval between bleeding and therapy ranges from < 14 days to > 100 days. A questionnaire was sent to each author of the published trials concerning methods, definitions and results of the trials in order to obtain more detailed and uprto-date information. The selected end-points for the meta-analysis were: rebleeding, mortality and chronic encephalopathy. Analysis of the results in the questionnaires was made using the method proposed by Collins. The pooled relative risk (i.e. the combined Odds ratio of each trial as an estimate of overall efficacy) of rebleeding was statistically reduced by DSRS (0.16; 95% confidence interval 0.100.27). Despite this, the overall risk of death following DSRS was only marginally decreased (0.78; 95% confidence interval 0.47-1.29); the lack of homogeneity in the results does not permit any significant conclusions on this endpoint. However, in non-alcoholic patients, the decrease in risk of death was greater, and this without heterogeneity, following DSRS than EVS (0.59; 95% confidence interval 0.23-1.50). The overall risk of chronic encephalopathy was slightly increased after DSRS (I.86; 95% confidence interval 0.90-3.86). In conclusion, DSRS significantly reduced the risk of rebleeding compared to EVS without increasing the risk of chronic hepatic encephalopathy. However, DSRS did not significantly affect the overall death risk. Only in non-alcoholic disease did it seem to show an advantage over EVS.

Key words." Portal hypertension; Distal splenorenal shunt; Endoscopic sclerotherapy; Meta-analysis

Randomized clinical trials (RCTs) of treatments for the prevention of variceal rebleeding in patients with cirrhosis have produced contrasting results. This has made questionable whether any of the therapies used in these trials should be administered to individual patients. Above all, two forms of treatment have been evaluated in recent years: selective distal spleno-renal shunt (DSRS)

(i) and endoscopic variceal sclerotherapy (EVS) (2). Four RCTs comparing these two treatments have recently been published (3-6). When considered individually, the results of 3 studies showed no difference between therapies as regards survival. One study (3) showed improved survival in the group randomized to EVS. In this paper we have applied meta-analysis (7,8) to

Correspondence to." Prof. Gian Paolo Spina. Semeiotica Chirurgica. Istituto di Scienze Biomediche San Paolo, Via A. di Rudini 8, 20142 Milan. Italy.

SCLEROTHERAPYVS. DISTALSPLENO-RENALSHUNT combine the findings from the 4 studies in an attempt to draw overall conclusions. In order to maximize the validity of the meta-analysis we have sought to overcome the lack of information in published studies by collecting the data directly from the authors.

Methods The meta-analysis used in this study conforms to recognized standards (9-11). All the authors agreed on the methodology and reached consensus on the interpretation of results.

Selections of trials The search for papers was performed using the MEDLINE database in all languages. A manual search was also performed using references from review articles, from trial reports, from congress abstracts and from personal communications from investigators in the field. We predetermined that studies would be selected if patients included in trials had bled from varices before entry and the surgical treatment of choice was DSRS. Nine articles comparing shunt surgery with sclerotherapy were found. Four RCTs (12-15) were excluded because they employed total shunts, including two (13,14) which used emergency shunts. One other study (16) was excluded because treatment regimens were given in emergency and were not randomly allocated. Therefore, only 4 RCTs met our selection criteria (3-6).

Data abstraction The data were collected on the basis of published papers (3-6) and a questionnaire of study methodology, clinical characteristics and primary results sent to the 4 principal authors. They were asked to complete all sections updating the data on RCT. Three questionnaires reported new data I-one from an updated published paper (17) and two from recently published abstracts 118,19)-1, while the fourth questionnaire was completed on the basis of the data already published (4). The findings were then evaluated by 4 independent critical appraisers. Tabulations with the results of the selected end-points were sent back to the 4 principal authors, who were then asked to reach a consensus on the interpretation of the results.

End-points jbr analysis The main end-points were: rebleeding (defined as all digestive rebleeding related to portal hypertension viz. varices, esophageal ulceration due to sclerotherapy and

339 congestive gastropathy), mortality and chronic hepatic encephalopathy. Secondary end-points such as mortality in subgroups of patients, acute encephalopathy and esophageal stenosis were recorded, but they were not included in meta-analysis.

Characteristics of RCTs Possible clinical heterogeneity has been taken into account in a preliminary analysis. The 4 RCTs selected (3-6) (to simplify the numbering of references in the text, we refer to the first published paper by each study group) included a total of 292 patients. The patient groups in the RCTs had similar ages, but differed as to etiology of liver disease, interval between variceal bleeding and treatment, and severity of liver disease. Both therapies were carried out according to different schedules (Table ! ). The randomization method used was sealed envelopes in 2 RCTs (3,4), Efron's biased coin design in one (5) and a blinded, computerized, random number table in the other (6). The sample size was precalculated in 3 RCTs (4-6) and not evaluated in one (3).

Statistical technique The analysis was performed according to the MantelHaentzel-Peto O-E method as described by Collins (10). This provides an estimate of the relative risks for the occurrence of each outcome in treatment groups. These are then combined to provide an estimate of the pooled relative risk (PRR). The relative risks of each trial and PRR are accompanied by 95% confidence i'nterval and plot. In these plots, when the relative risk and its confidence interval do not cross the vertical axis, which represents the equivalent risk (relative risk= i), then there is a statistically significant difference between DSRS and EVS. The homogeneity of treatment effect across RCTs was assessed by chi-square test (10). For a graphic display of heterogeneity, we used L'Abb6 plots (7,1 l) with the event rate in the DSRS group plotted on the vertical axis and the event rate in the EVS group plotted on the horizontal axis. The diagonal line is the line of equivalence between treatments. Points above this line indicate that the event rate in the DSRS group is higher than in the EVS group, while points below the line indicate the contrary. A wide dispersion of points above and below the equivalence line indicates heterogeneity. If heterogeneity was demonstrated, we did not accept a change in PRR as evidence of benefit even when it reached statistical significance.

340

G. P. SPINA et al

TABLE 1 Characteristics of patients and modality of treatments in 4 RCTs comparing DSRS with EVS

First report Update Questionnaire No. of pts. DSRS EVS Recruitment time (mth) No. of pts. rejected Interval bleeding treatment b DSRS EVS Age (mean) DSRS EVS Sex M/F DSRS EVS Etiology (alc./non-alc.) DSRS EVS Child's: A/B/C c DSRS EVS Follow-up time (mth) ° DSRS EVS Surgery: DSRS DSRS+SPD DSRS (retrop.) Total shunt Sclerotherapy Sclerosant ml per session Schedule Endoscopic survey (mth) Eradication

Henderson

Ter6s

Rikkers

Spina

Ann. Surg. 86 Ann. Int. Med. 90 yes

Hepatology 87

Ann. Surg. 90 Abs. 90 yes

yes

Ann. Surg. 87 Abs. 90 yes

35 37 54 348 92% < 14 d 8% <21 d N.R. N.R. 54 ± 11 53±12 22/13 22/15

57 (43)a 55 (51)a 44 87

30 30 69 90

34 32 61 173

33±17 d 23 ± 15 d 53.9 ± 11 54.1 ±11 41/16 44/11

21 d 20 d 54 +_12 56±10 24/6 23/7

3.6±2.5mth 2.8±2.5mth 48.2±8.6 53.3±8.1 23/11 27/5

20/15 23/14

29/28 43/12

25/5 27/3

9/25 21/11

10/10/15 1I/I0/16 61 (30 to 84) N.R. N.R. 28r 6

7.07±1.17 a 7.54 ± 1.38d

13/6/II 12/4/14

9•23•0

27.5 ± 15.6 26.6± 16.9

48 (14-84) 48 (29-80) 26

15/19/0 28.8 + 20 23.6+19.6 16 16

43 4 STD/SM N.R. dictated by response 6 no varices

EO 10-20 every wk per 4 wk 6 no varices type I var.

STD/SM < 20 every 4/6 d per 4 wk 6 no varices

P 10-90 dictated by response 6 no varices FI white var.

'Number of patients analyzed. blnterval bleeding-treatment: Henderson did not report (N.R.) mean value ___SD, Rikkers did not report _+SD. ¢Child's classification: Warren's modification (3), Campbell's modification (4,5), Pugh score (6). dOnly the Campbell score is reported. CFollow-up time (months): Henderson and Rikkers reported median value and range. tOne patient died before shunt surgery. STD = sodium tetradecyl sulfate; SM = sodium morruate; EO = ethanolamine oleate; P = polidocanol.

Results

Table 2 shows the rate of the outcome in the 4 RCTs of rebleeding, mortality, chronic encephalopathy, acute encephalopathy and esophageal stenosis.

Rebleeding The rebleeding rate from portal hypertension was significantly reduced in each RCT, ranging from 3% (3,6) to 17% (5) in the DSRS group and from 31% (6) to 60% (5) in the EVS group. Therefore, it has shown a highly statistically significant PRR in favor of DSRS (PRR 0.16; 95% CI 0.10-0.27). No statistical or graphic heterogeneity was detected for this outcome (chi-square 4.55) (Fig. 1).

TABLE 2 Incidence of events in 4 RCTs

Rebleeding DSRS EVS Death DSRS EVS Chronic encephalopathy DSRS EVS Acute encephalopathy DSRS EVS Esophageal stenosis N.R. = not reported.

Henderson

Ter6s

Rikkers

Spina

1/35 22/37

6/43 18/51

5/30 18/30

1/34 10/32

20/35 12/37

9/43 15/51

12/30 20/30

4/34 8/32

5/31 3/26

8/42 3/48

6/29 4/29

2/30 2/29

N.R. N.R. 0/36

2/42 1/48 3/48

0/29 2/29 2/29

5/30 3/29 4/29

SCLEROTHERAPY VS. DISTAL SPLENO-RENAL SHUNT

a)

341

b)

1 DSRS

j.i/lJj ~ "

0.75

0.5'

Hendors(~

Teres

I •

/

Rlkker8

/i

0.25 '

~

0

0

0

4z

i

0

3plna

0.25

0,75

0.5

E'VS o

,1 '! . .

0

Henderson

o

Tereo

POOLED ~

Rlkkor3

u

q~

.Shine

i

0

1,5

0.5

2

2.5

3

3.5

4

4,5

5

i

i

5.5

6

Fig. i. Meta-analysis of rebleeding in RCTs comparing DSRS with EVS. (a) L'Abb6 plot• Each dot represents the outcome rates in one RCT. (b) Graph of the rebleeding risk, with 95";~- confidence interval (I--I). "Pooled" represents the global rebleeding risk: it shows a significant decrease for the DSRS group. Heterogeneity test: chi-square 4.55: p>0.05.

Mortality The risk of death after DSRS was significantly increased in one RCT (3) and decreased in the 3 others (4-6). The PRR of death was not significantly reduced by DSRS (PRR 0.78; 95% CI 0.47-1.29)• The chi-square test for heterogeneity was statistically significant (chisquare 10.48, p<0.05) (Fig. 2). This heterogeneity was due to the Emory study in which the death rate was above the line of identity, while the other 3 RCTs were below the line in the L'Abb6 plot (Fig. 2).

CI 0.90-3.86). There was no statistical heterogeneity (chi-square 1.32) (Fig. 3). The rate of acute encephalopathy was not statistically different in each study between DSRS and EVS, but differed between the RCTs, ranging from 0% (5) to 17% (6), probably due to the different method of event registration. Esophageal stenosis was an infrequent complication in these studies (see Table 2).

Discussion

Chronic encephalopathy The risk of chronic encephalopathy after DSRS increased in 3 RCTs (3-5) and slightly decreased in one (6). PRR was not significantly increased (PRR 1.86; 95%,

a)

Meta-analysis has been used to evaluate the RCTs comparing DSRS with EVS for the prevention of rebleeding in patients with cirrhosis and esophageal

b) ),SRS

/.J

./

0.75

o

j./~

0.5"

Hendersor~

Teres

/

/• "

Rlkk~rs

I I

0.25 ' •

&olna

I I

0 0

0.5 EV3

0.25

o

Henderson

o

Teree

0.75 POOLED RIk kerS

a

;

I I i

Spln== 0

0.5

1,5

2

2,5

3

3.5

4

4.5

5

5,5

Fig, 2. Meta-analysis of death in RCTs comparing DSRS with EVS. (a) L'Abb6 plot. Each dot represents the outcome rates in one RCT. (b) Graph of the death risk, with 95% confidence interval (I--[). 'Pooled" represents the global death risk. Heterogeneity test: chi-square 10.48: p<0.05.

G. P. SPINA et al

342

a)

b)

jjJJ

~SRS

0.75 -

L°

H er~lers(~t

'

I ~Q

I

Tere8

,

.11-"/"

0.5

~e

J

Rlkk~ers

'

I

0.25 e~

~lna O,25

0.5

o

FQr~

!

0.75

I

POOLED

EVS o Henderson

I

a

Rlkker8

o Splna 0

0,5

1.5

2

2.6

~

~5

4

4,5

5

6,5

6

Fig. 3. Meta-analysis of chronic encephalopathy in RCTs comparing DSRS with EVS. (a) L'Abb6 plot. Each dot represents the outcome rates in one RCT. (bl Graph of the encephalopathy risk, wilh 95'~; confidence interval ( I--I)- "Pooled" represents the global encephalopathy risk: it shows a favourable trend for the EVS group. Heterogeneity test: chi-square 3.74; p > 0.05.

varices. When such an analysis is made retrospectively, it is assumed that not every trial was planned so as to collect precisely the same data from its initiation. We have tried to overcome this bias in order to make our evaluation more precise and valid using a dedicated questionnaire. The participants in these trials have endeavored to standardize and assure accurate information from their own trials. This questionnaire has been useful i'or: (a) completing data included in abstracts which contained insufficient information (18,19); (b) obtaining information on subgroups of patients to evaluate treatment effects on a sufficient number of such patients in each subgroup; (c) evaluating differences in definition of end-points and their effect on analysis to identify the sources of heterogeneity. The meta-analysis showed that DSRS virtually abolishes the risk of rebleeding as compared to EVS, thus confirming a high rate of success with this procedure. Mortality was slightly reduced after DSRS. However, the heterogeneity of these data between the different studies, does not permit any significant conclusions in this case and warrants further investigation. We have assessed some of the potential sources of heterogeneity or reasons for differences between the trials. There is an obvious difference in the inclusion criteria. Henderson (3) excluded 348 cases, primarily for geographic reasons or because they had already received EVS: Rikkers 15) rejected 90 patients before randomization, Ter~s (4) 87 cases and Spina (61 excluded 173 cases, primarily for liver failure or unwillingness to accept the randomized therapy. The interval to randomization was another source of heterogeneity. In Ter~s's study (4) the analysis of data

was performed on patients who received the treatment. These patients were randomized after the arrest of variceal bleeding, but before preoperative evaluation. This led to a post-randomization exclusion of 25% of patients assigned to DSRS and 7% of patients assigned to EVS. The other authors who used analysis by intention to treat had few patients who failed to received the assigned treatment: Henderson (3) had 1 patient who died due to severe hepatitis before shunt surgery and Rikkers (5) had I patient who did not receive the assigned treatment (refused shunt surgery). The variable time of entry to a study following admission for variceal bleeding is an important confounding variable when analyzing survival data (20,21). In these RCTs the time of entry ranged from <14 days (3) to > 3 months (6). This may have affected the differences in operative mortality [ranging from 0% (6) to I1% (3)3 and longterm mortality [ranging from 12% (6) to 57% (3)]. Age and sex did not show any great differences across the studies, with the exception of the study in Milan (6) in which the mean age of patients submitted to DSRS was slightly lower than the others - - a younger age favors a better survival rate (22). Differences in follow-up times were also present, ranging from 23.6 (mean value) (6) to 61 (median value) (3) months. The incidence of negative events for both therapies increased with increasing periods of observation. This emphasises a feature which undoubtedly contributes to heterogeneity. As regards Child's classification, two sources of heterogeneity can be shown: the types of classification and the outcome in the surgical group. Two studies /4,5) used Child-Campbell's score, one (3) a personal modification and one (6) used Pugh-Child's score [in the fourth study

SCLEROTHERAPYVS. DISTALSPLENO-RENALSHUNT (6), there was a slightly greater number of Child A patients in the surgical group]. It is obvious that different modifications of Child and Turcotte's classification (23) are not directly comparable and these different classifications could influence the analysis of these subgroups (24). Two studies (3,5) included Child C patients and both showed a higher mortality to shunt surgery than EVS. The technical aspects of the treatment could be an important source of heterogeneity. The Emory study (3) included only 18% of the DSRS procedures with splenopancreatic disconnection, which seems to improve the results in alcoholic patients to a level previously achieved with the traditional DSRS in non-alcoholic cirrhosis (25-27). On the other hand, in the Milan study (6), started later in 1984, the authors performed splenopancreatic disconnection in about half the cases. Finally, Ter6s (4) performed DSRS using a retroperitoneal approach. This technical modification could be responsible for impairing post-operative portal perfusion and consequently in favoring liver failure (28-32). However, this hypothesis cannot be confirmed by this RCT because liver failure as a cause of death was not reported. Finally, Rikkers (5) and Spina (6) had 4 and 2 patients, respectively, submitted to total shunt. EVS was applied using different techniques in each study. There are already contrasting results in the literature in RCTs analyzing different techniques: different sclerosants (33-37), volumes of sclerosant injected (38), time schedules (39-41) and injection techniques (42-44). The widespread use of EVS is relatively recent. It should be performed using objective criteria that justify the selection of a particular technique, but such data do not exist at present. An important source of heterogeneity of data analysis could be the different strategy used by the Emory group (3,45,46). Although they showed a high incidence of rebleeding in the EVS group (22 pts., 59%), they observed a lower mortality rate due to rebleeding (1 pt., 8%). Is it due to the larger number of surgical rescues with good outcome (12 had a surgical rescue procedure after EVS had failed with a survival rate of 58%)? It is difficult to answer this question. In order to assess the influence of surgical procedures used to rescue patients after they had failed EVS, we have performed a sensitivity analysis. We assumed, on one hand, that if the patients had not had surgical rescue, they would have died, while, on the other hand, we assumed that if all the patients had been treated according to Henderson's strategy (i.e. shunt rescue after EVS failure), they would have shown an overall survival rate of 58%. These data are shown in Figure 4: while the Emory study shows a reduction of EVS advantage in the first analysis (Fig. 4a), the other 3 studies show only a

343 slight improvement in EVS advantage in the latter (Fig. 4b). These findings seem to confirm that surgical rescue is important, but not the primary source of heterogeneity. The positive results of this strategy may also be favored by an inclusion criterion defining geographic limits: in the Emory study (3), when the patients rebled during the course of sclerotherapy, most came back directly to Emory for further management rather than to less experienced referral hospitals. Finally, the etiology of liver disease seems to be of great importance (30,47): non-alcoholic cirrhotics had a similar outcome in all the studies (Fig. 5a). On the other hand, the Emory RCT (3) showed a poorer prognosis in alcoholic cirrhotic patients submitted to DSRS (Fig. 5b), who had an increased risk of losing portal perfusion associated with impaired cardiac hemodynamics and liver function. It is not clear if the liver was more susceptible to alcoholic injury after DSRS or if recurrent excessive drinking was more frequent in the surgical group or if it was due to the absence of spleno-pancreatic disconnection. The data in these clinical trials cannot answer this question, although the authors indicated that the number of deaths due to alcohol abuse in the DSRS group was higher than the EVS group. The end-point of chronic encephalopathy was slightly increased after DSRS. However, one study (6) showed a slight reduction in the risk of chronic encephalopathy after DSRS, but it could be due to the more favorable trend in prognostic factors for the DSRS group. The low encephalopathy rate in these RCTs after DSRS confirmed a smaller contribution of this surgical procedure in promoting the appearance of encephalopathy. Across the RCTs, the differences observed between the authors reflected the kind of shunt employed (see Tables 1 and 2). Spina (6), Henderson (3) and Rikkers (5) performed a selective shunt with disconnection, while Ter6s (4) used a modified selective shunt without disconnection. The risk of HE progressively increased from selective shunt to less selective shunt. This progression is a confirmation of the results of meta-analysis of randomized trials comparing DSRS with the porto-caval shunt (8).

Conclusions Meta-analysis provides a more precise assessment of the efficacy of a treatment than a narrative, unstructured overview. Some weaknesses of meta-analysis can be overcome by keeping strictly to published methods, by beginning with a clear plan of the question to be

344

G.P. SPINA et al

a)

b) DSRS

OSRS

0.75 •

0.75"

0.5

0.5"

0.25.

0.25"

0

0 0

0.25

0.5

0.75

0

0.26

o Henderson

o

Teres

0.75

0.5

EVS

EVS i

Rlkkera

o Spine

o Henderson

0

t

Tere6

Rlkk~a

o Spine

Fig. 4. Sensitivity analysis. (a) On the assumption that if the patients had not been submitted to surgical rescue, they would have died. (b) On the assumption that if all the patients had been treated according to Henderson's strategy, they would have shown a survival rate of 58'~.

a)

b) DSRS

OSRS

T

!

0.75

0.75 O

./.j

j

"

'~

0.5"

0.5"

0.25 -

(125"

O

i

0

0,25

0.5

O

0.75

0

0.25

0,5

EVS o Henderson

o

rerea

0.75

EVS ~ Rlkkers

o Spine

o Henaereon

•

Teree

•

Rlkkere

a Spine

Fig. 5. L'Abb6 plot. Graph of the death risk in non-alcoholic subgroup (a) and in alcoholic patients (b). Each dot represents the outcome rates in one RCT. a n s w e r e d a n d the m e t h o d s to be e m p l o y e d . In p a r t i c u l a r ,

t r e a t m e n t is to p e r f o r m w e l l - d e s i g n e d R C T s of a d e q u a t e

as insufficient i n f o r m a t i o n

is a

size. T h i s a n a l y s i s d e m o n s t r a t e s t h a t v a r i c e a l r e b l e e d i n g

in p u b l i s h e d

l i m i t i n g factor, the use of a s t r u c t u r e d

reports

questionnaire

is b e t t e r p r e v e n t e d by D S R S t h a n by EVS. In a d d i t i o n ,

m a k e s m o r e d a t a a v a i l a b l e o n the o u t c o m e in s u b g r o u p s

it s h o w s t h a t D S R S has a lesser r a t e of t h e r a p y failure

of p a t i e n t s with different p r o g n o s t i c variables. A l t h o u g h

a n d , finally, t h a t s u r v i v a l s h o w s a m o r e p o s i t i v e t r e n d

this m e t a - a n a l y s i s has p a r t i a l l y r e s o l v e d the u n c e r t a i n t y

in the D S R S g r o u p w i t h n o n - a l c o h o l i c cirrhosis, w i t h o u t

a b o u t the r e a s o n s for different o u t c o m e s in the R C T s

i n c r e a s i n g the risk o f e n c e p h a l o p a t h y .

comparing

are n e e d e d to d e t e r m i n e the role of surgical rescue w h e n

best

way

D S R S with EVS, we still believe t h a t the to a n s w e r

questions

on

the efficacy of a

References I Spina GP, Santambrogio R. Distal spleno-renal shunt: where are we now'? ltal J Gastroenterol 1989: 21: 71-6. 2 lnfante-Rivard C, Esnaola S, Villeneuve J-P. Role of endoscopic variceal sclerotherapy in the long-term management of variceal bleeding: a meta-analysis. Gastroenterology 1989; 96: 1087-92. 3 Warren WD; Henderson JM, Millikan WJ et al. Distal splenorenal shunt versus endoscopic sclerotherapy for long-term management of variceal bleeding. Preliminary report of a prospective, randomized trial. Ann Surg 1986; 203: 454-62.

F u r t h e r studies

E V S has failed.

4 Ter6s J, Bordas JM, Bravo D, et al. Sclerotherapy vs. distal splenorenal shunt in the elective treatment of variceal hemorrhage: a randomized controlled trial. Hepatology 1987; 7: 430-6. 5 Rikkers LF, Burnett DA, Volentine GD, Buchi KN, Cormier RA. Shunt surgery versus endoscopic sclerotherapy for long-term treatment of variceal bleeding. Early results of a randomized trial. Ann Surg 1987; 206: 261-71. 6 Spina GP, Santambrogio R, Opocher E, et al. Distal splenorenal shunt versus endoscopic sclerotherapy in the prevention of variceal rebleeding. First stage of a randomized controlled trial. Ann Surg 1990; 21 I: 178-86.

SCLEROTHERAPY VS. DISTAL SPLENO-RENAL SHUNT 7 Pagliaro L, Burroughs AK, Sorensen TIA, et al. Therapeutic controversies and randomised controlled trial IRCTs): prevention of bleeding and rebleeding in cirrhosis. Gastroenterol. Int. 1989; 2: 71 - 84. 8 Spina GP, Santambrogio R, Opocher E, Macri M, Pisani A, Pezzuoli G. The distal spleno-renal shunt. In: Dianzani MU, Gentilini P, Eds. Chronic Liver Damage. Amsterdam: Elsevier Science Publishers BV, 1990: 273-88. 9 Sacks HS, Berrier J, Reitman D, Ancona-Berk VA, Chalmers T. Meta-analysis of randomized controlled trials. N Engl J Med 1987; 316: 450-5. 10 Collins R, Yusuf S, Peto R. Overview of randomized trials of diuretics in pregnancy. Br Med J 1985; 290:17 23. I L'Abb6 KA, Detsky AS, O'Rourke K. Meta-analysis in clinical research. Ann Intern Med 1987; 107: 224-33. 2 Korula J, Yellin A, Yamada S, Weiner J, Cohen H, Reynolds TB. A prospective randomized controlled comparison of chronic endoscopic variceal sclerotherapy and portal-systemic shunt for variceal hemorrhage in Child's class A cirrhotics: a preliminary report. Gastroenterology 1987; 92:1745 (Abstract). 3 Cello JP, Grendell JH, Crass RA, Weber TE, Trunkey DD. Endoscopic sclerotherapy versus portacaval shunt in patients with severe cirrhosis and acute variceal hemorrhage. Long-term followup. N Engl J Med 1987, 316: 11-15. 14 Ter6s J, Baroni R, Bordas JM, Visa J, Pera C, Rodes J. Randomized trial of portacaval shunt, stapling transection and endoscopic sclerotherapy in uncontrolled variceal bleeding. J Hepatol 1987, 4: 159-67. 5 Planas R, Boix J, Broggi M, et al. Portacaval shunt versus endoscopic sclerotherapy in the elective treatment of variceal hemorrhage. Gastroenterology 1991; 100: 1078-86. 6 Kitano S, Hashizume M, Yamaga H, Higashi H, Sugimachi K. Sclerotherapy superior to surgery for longer survival and less rebleeding in 103 cirrhotics with variceal bleeding, lnt Surg 1989: 74:162-6. 7 Henderson JM, Kutner MH, Millikan WJ, et al. Endoscopic variceal sclerosis compared with distal splenorenal shunt to prevent recurrent variceal bleeding in cirrhosis. A prospective, randomized trial. Ann Intern Med 1990; 112: 262-9. 8 Rikkers LF, Burnett DA, Buchl KN, and Cormier RA. Shunt surgery versus endoscopic sclerotherapy for variceal hemorrhage: late results of a controlled trial. Hepatology 1989: 10: 577. 9 Spina GP, Santambrogio R, Opocher E, el al. Randomized trial comparing distal spleno-renal shunt and sclerotherapy in the prevention of variceal rebleeding. HPB Surg 1990, 2 lSuppl.l: FP064. 20 Graham DY, Smith JL. The course of patients after variceal hemorrhage. Gastroenterology 1981, 80: 800-9. 21 Burroughs AK, Mezzanotte G, Phillips A, McCormick PA, Mclntyre N. Cirrhotics with variceal hemorrhage: the importance of the time interval between admission and the start of analysis for survival and rebleeding rates. Hepatology 1989; 9: 801-7. 22 Lacaine F, LaMuraglia GM, Malt RA. Prognostic factors in survival after portasystemic shunts. Multivariate analysis. Ann Surg 1985; 202: 729-34. 23 Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, ed. The Liver and Portal Hypertension, 3rd Edn. Philadelphia: W.B. Saunders Co., 1964: 50-1. 24 D'Heygere F, Burroughs AK. Classification of patients. In: Burroughs AK, ed. Methodology and Reviews of Clinical Trials in Portal Hypertension. Amsterdam: Excerpta Medica, 1987:41-51. 25 Warren WD, Millikan W J, Henderson JM, et al. Spleno-pancreatic disconnection. Improved selectivity of distal spleno-renal shunt. Ann Surg 1986, 204: 346-54. 26 Henderson JM, Warren WD, Millikan W J, Galloway JR, Kawasaki S, Kutner MH. Distal splenorenal shunt with spleno-

345

27

28

29 30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45 46 47

pancreatic disconnection. A 4-year assessment. Ann Surg 1989: 210:332 9. Maffei-Faccioli A, Gerunda GE, Neri D, Merenda F, Zangrandi F, Meduri F. Selective variceal decompression and its role relative to other therapies. Am J Surg 1990, 160:60 6. Spina GP, Santambrogio R, Opocher E, et al. Early hemodynamic changes following selective distal splenorenal shunt for portal hypertension: comparison of surgical techniques. World J Surg 1990; 14: 115-22. Maillard JN, Flamant JM, Hay JM, Chandler JG. Selectivity of the distal splenorenal shunt. Surgery 1979, 86: 663-71. Henderson JM, Millikan WJ, Wright-Bacon L, Kutner MH, Warren WD. Hemodynamic differences between alcoholic and nonalcoholic cirrhotics following distal spleno-renal shunt. Effect on survival? Ann Surg 1983; 198: 325-34. Henderson JM, Gong-Liang J, Galloway J, Millikan WJ, Sones P J, Warren WD. Portaprival collaterals following distal splenorenal shunt. Incidence, magnitude and associated portal perfusion changes. J Hepatol 1985, I: 649-61. Rikkers LF, Cormier RA, Vo NM. Effects of altered portal hemodynamics after distal spleno-renal shunts. Am J Surg 1987, 153: 80-5. Sarin SK, Mishra SP, Sachdev GK, Thorat V, Dalai L, Broor SL. Ethanolamine oleate versus absolute alcohol as a variceal sclerosant: a prospective randomized, controlled trial. Am J Gastroenterol 1988; 83: 526-30. Lyons SD, Sugawa C, Geller ER, Vandenberg DM. Comparison of 1':~ sodium tetradecyl sulfate to a thrombogenic sclerosant cocktail for endoscopic sclerotherapy. Am Surg 1988: 54: 81-4. Kitano S, Iso Y, Yamaga H, Hashizume M, Higashi H, Sugimachi K. Trial of sclerosing agents in patients with oesophageal varices. Br J Surg 1988: 75:751 3. Kitano S, Hashizume M, Yamaga H, et al. Human thrombin plus 5 per cent ethanolamine oleate injected to sclerose oesophageal varices: a prospective randomized trial. Br J Surg. 1989: 76: 715-8. Balanzo J, Sainz S, Espinos JC, et al. Efficacy of ethanolamine and polidocanol in the eradication of esophageal varices. A prospective randomized trial. Endoscopy 1989: 21:251 3. Iso Y, Kitano S, lwanaga T, Koyanagi N, Sugimachi K. A prospective randomized study comparing the effects of large and small volumes of the sclerosant 5'3 ethanolamine oleate injected into esophageal varices. Endoscopy 1988: 20: 285-8. Westaby D, Melia WM, MacDougall BRD, Hegarty JE, Williams R. Injection sclerotherapy for oesophageal varices: a prospective randomised trial of different treatment schedules. Gut 1984: 25: 129-32. Sarin SK, Sachdev G, Nanda R, Batra SK. Anand BS. Comparison of the two time schedules for endoscopic sclerotherapy: a prospective randomised controlled study. Gut 1986; 27: 710-13. Higashi H, Kitano S, Hashizume M, Yamaga H, Sugimachi K. A prospective randomized trial of schedules for sclerosing esophageal varices. I- versus 2-week intervals. Hepatogastroenterology 1989: 36: 337-40. Westaby D, MacDougall BRD, Melia W, Theodossi A, Williams R. A prospective randomized study of two sclerotherapy techniques for esophageal varices. Hepatology 1983; 3: 681-4. Kitano S, Koyanagi N, lso Y, lwanaga T, Higashi H, Sugimachi K. Prospective randomized trial comparing two injection techniques for sclerosing oesophageal varicers: over-tube and free-hand. Br J Surg 1987: 74: 603-6. Sarin SK, Nanda R, Sachdev G, Chari S, Anand BS, Broor SL. Intravariceal versus paravariceal sclerotherapy: a prospective, controlled, randomised trial. Gut 1987: 28: 657-662. Conn HO. Endoscopic sclerotherapy with portal-systemic shunt rescue. Hepatology 1987; 7: 606-7. Grace ND. Prevention of recurrent variceal bleeding - - Is surgical rescue the answer'? Ann Intern Med 1990:112: 242-4. Zeppa R, Hensley GT, Levi JU, et al. The comparative survivals of alcoholics versus non-alcoholics after distal spleno-renal shunt. Ann Surg 1978; 187: 510-4.