Subscribe to RSS
DOI: 10.1055/s-2006-944566
An evaluation of emergency sclerotherapy of varices in randomized trials: looking the needle in the eye
A. K. Burroughs
Liver Transplantation and Hepatobiliary Medicine
Royal Free Hospital · Pond Street · London NW3 2QG · UK
Fax: +44-20-747-26226
Email: andrew.burroughs@royalfree.nhs.uk
Publication History
Submitted 15 October 2005
Accepted after revision 14 February 2006
Publication Date:
28 August 2006 (online)
Background: The role of sclerotherapy for acute variceal bleeding is challenged by vasoactive
drugs and by ligation.
Aim: A meta-analysis was performed to evaluate whether sclerotherapy remains a gold standard
in acute variceal bleeding.
Methods: Sclerotherapy was evaluated across four randomized trial groups: (a) combined with
vasoconstrictors vs. vasoconstrictors alone (five trials, with 400 patients); (b)
vs. vasoconstrictors alone (15 trials, with 1296 patients); (c) vs. combination of
vasoconstrictors and sclerotherapy (eight trials, with 1026 patients); (d) vs. ligation
(12 trials, with 1309 patients). We used the risk difference (absolute risk reduction)
as our main effect measure.
Results: The efficacy of acute sclerotherapy was highest vs. ligation at 95 %, with a small
advantage for ligation (an overtube was used in eight trials) of 2.5 % (95 % CI 0.4
% to 4.6 %) (P = 0.018), but no survival difference. Efficacy of sclerotherapy combined with vasoconstrictors
vs. vasoconstrictors alone was 86 %, whereas it was 83 % for sclerotherapy vs. vasoconstrictors
alone. In both these groups sclerotherapy was superior for control of bleeding at,
respectively, 16.3 % (95 % CI 8.7 % to 23.9 % (P = 0.0001) and 5.9 % (95 % CI, 1.5 % to 10.3 %) (P = 0.008), with increased survival in the latter. In the combination group of sclerotherapy
with vasoconstrictors, the efficacy of sclerotherapy alone was 69 %, with the combination
superior in controlling bleeding, at 13.2 % (95 % CI, 8.4 % to 18.1 %) (P < 0.0001) but with no survival difference.
Conclusion: This comparison of sclerotherapy across trials demonstrates a problem in defining
its real efficacy. The conclusive evidence for substituting banding ligation or the
combination of vasoconstrictors with sclerotherapy as better therapeutic approaches
has not been provided in randomized trials. Sclerotherapy can remain a gold standard
in variceal bleeding but there is scope for further studies of ligation and vasoactive
drugs.
Introduction
Acute variceal bleeding occurs in about 30 % of cirrhotic patients [1] [2]. The use of prophylactic antibiotics [3], which also reduce early rebleeding [4], has been associated with a major improvement in survival, supporting the hypothesis of infection as a trigger for variceal bleeding [5]. However endotherapy has also contributed to this reduced mortality.
The most robust evidence for the benefit of sclerotherapy [6] [7] comes from a single study comparing sclerotherapy with sham sclerotherapy, that showed reduction of bleeding and increased hospital survival [8]. Recently, the role of emergency sclerotherapy has been challenged by variceal ligation [9] and vasoactive drug therapy [10], the latter being recommended for first-line therapy. We have questioned this interpretation [11].
Therefore we have systematically reviewed the use of sclerotherapy for acute variceal bleeding. We have assessed this modality as follows: (a) sclerotherapy combined with vasoactive agents vs. vasoactive agents alone [12] [13] [14] [15] [16]; (b) sclerotherapy vs. vasoactive agents alone [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31]; (c) sclerotherapy vs. sclerotherapy combined with drugs [19] [32] [33] [34] [35] [36] [37] [38]; and (d) sclerotherapy vs. ligation [9] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49]. The latter comparison may not be applicable as commonly thought, as eight out of the 12 studies [9] [40] [41] [44] [45] [46] [48] [49] reported the use of an overtube with ligation, which is not usual practice in many centers.
The aim of our systematic review was to clarify whether, compared with the newer treatment strategies, sclerotherapy is still the gold standard for treatment of bleeding esophageal varices for both control of acute bleeding and prevention of early rebleeding.
#Methods
#Data identification
We searched Medline and Embase databases from January 1980 to May 2005, using the textwords ”varices”, ”sclerotherapy”, ”vasopressin”, ”glypressin”, ”terlipressin”, ”somatostatin”, ”octreotide”, ”ligation”, ”band”, and ”haemorrhage”. We manually searched (C. T., J. G., and A. B.) all review articles (English and non-English), and we retrieved original studies and all abstracts from the meetings, held between 1995 and May 2005, of the American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver, and those from the Digestive Diseases Weeks (American) and the United Gastroenterology Weeks (European). Authors were contacted personally if clarifications were needed concerning the conduct or data of the trial.
#Inclusion criteria
Studies included fulfilled the following criteria: (i) there was a published abstract or article; (ii) there was a randomized design; (iii) participants were cirrhotic patients with acute esophageal variceal bleeding; (iv) sclerotherapy was compared with vasoactive agents or variceal ligation; and (v) there were reported clinical end points, of death, and of failure to control bleeding and/or prevention of early rebleeding (within 5 - 7 days), as defined in each individual trial. The end points regarding bleeding, although not the same in every study, were always defined using accepted clinical criteria.
The decision to include or exclude a study was made before the meta-analysis was carried out.
Studies with 2 % or fewer noncirrhotic patients, were considered to have a solely cirrhotic population.
#Data extraction
Data were extracted independently by C. T., J. G., and A. B., using a predefined review form, and disagreement was resolved by consensus.
#End points for analysis
We performed four separate meta-analyses assessing the efficacy of sclerotherapy: (i) sclerotherapy combined with vasoactive agents and/or balloon tamponade vs. vasoactive agents and/or balloon tamponade alone (group A); (ii) sclerotherapy vs. vasoactive agents (group B); (iii) sclerotherapy vs. sclerotherapy combined with vasoactive agents (group C); and (iv) sclerotherapy vs. variceal ligation (group D).
The end points were: (a) failure to control bleeding, either during drug infusion, or initial hemostasis when sclerotherapy was compared with ligation; (b) short-term mortality (during hospitalization or within 4 - 6 weeks); and (c) complications.
However, no study had an a priori definition of how complications were to be reported, whether on a rate per patient basis, or according to the absolute numbers of complications, or with no reporting at all. No meta-analysis of complications was possible given this heterogeneity; only a descriptive evaluation was made. The efficacy of sclerotherapy was evaluated with respect to year of study publication and trial group. Transfusion requirements were evaluated descriptively as documentation was very variable.
#Assessment of methodological quality
Three authors (C.T., J.G., and A.B.) independently assigned a quality score [50] incorporating methodological quality only for peer-reviewed articles.
#Statistical analysis
We used risk difference (absolute risk reduction) as our main effect measure, to facilitate interpretation of comparisons across the groups, as it is the most relevant outcome statistic for our meta-analysis [51]. The underlying risk of an event (in the sclerotherapy arms of the four groups) was examined to clinically interpret any significant risk difference. Where statistical significance was present, we calculated the number of patients needing treatment to prevent one outcome event (NNT), and the ”publication bias assessment” (the minimum number of negative or null studies required to render the meta-analytical results statistically nonsignificant).
We assessed heterogeneity using the Q test (P < 0.05), evaluating whether the treatment effect variation within each trial group was greater than expected, reporting it only if it was significant. However taking into account the lack of statistical power for heterogeneity testing, for both detection and extent of clinically significant heterogeneity, we performed separate sensitivity analyses for the end points of failure to control bleeding and of death. These analyses were done according to: (i) the type of publication (two strata, i. e., full paper or abstract only); (ii) the type of vasoactive drug used; (iii) the duration of drug infusion; and (iv) the etiology of liver disease (two strata, i. e., cirrhosis alone or cirrhotic/noncirrhotic liver disease).
All statistical analyses and plots were carried out using a computer program devised by G. Leandro [52].
#Results
#Descriptive assessment
We found 321 articles, 40 of which met the inclusion criteria [9] [12] [13] [14] [15] [16] [17] [18] [19] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49]. A total of 13 studies were excluded because: (i) it was difficult to interpret end points as absolute numbers [53]; (ii) a vasoactive drug was not given to all patients in the medical treatment arm and there were no data for control of bleeding [54]; (iii) randomization took place on the third day or 24 hours after bleeding stopped [55] [56]; (iv) sclerotherapy was performed only when treatment failure occurred [57]; (v) control of bleeding was only assessed during sclerotherapy [58]; (vi) there was no information about type of endoscopic therapy [59]; and (vii) in some trials of long-term sclerotherapy vs. ligation, there was no documentation of failure to control acute bleeding or of when sclerotherapy alone was used for acute bleeding [60] [61] [62] [63] [64] [65].
The quality scores did not differ significantly across the different groups of studies.
The time interval for evaluating transfusion requirement varied, both before and after randomization, and means or medians were not consistently used, so transfusion requirements could not be evaluated statistically.
#Group A: sclerotherapy combined with vasoactive agents/balloon tamponade vs. vasoactive agents/balloon tamponade
The five trials [12] [13] [14] [15] [16] in this group included three papers [13] [15] [16] and two abstracts [12] [14], and involved 413 episodes in 400 patients (see Tables [e1] and [e2]).
In three trials, vasopressin was used [12] [13] [15]; in one somatostatin [14]; and in one, octreotide [16]. The time in which treatment effect was evaluated ranged from within 24 hours to up to 120 hours, except for one study [13] where evaluation was done within 2 weeks.
Specific definitions of failure to control bleeding were given in four studies [13] [14] [15] [16]. Only three [13] [15] [66] reported complications. Blood transfusion was reported in four [13] [14] [15] [16], with three [13] [15] [16] reporting less transfusion with sclerotherapy, and one showing no difference [14].
The median quality score was 58 (range 49 - 68.5).
#Meta-analysis of group A trials
Failure to control bleeding (Figure [1]). There were 214 episodes of variceal bleeding in the sclerotherapy combined with vasoactive drugs/balloon tamponade group, and 199 in the group receiving only vasoactive drugs/balloon tamponade. Failure to control bleeding was significantly more frequent without sclerotherapy, with the pooled difference being 16.3 % (95 % CI 8.7 % to 23.9 %) (P = 0.0001). The NNT was 6 (95 % CI 4 to 11). The publication bias assessment was 15 null or negative studies. The sensitivity analyses differed from the main meta-analysis in that abstracts alone showed no differences between trial groups. In only one study, octreotide added to sclerotherapy did not improve control of bleeding.
Figure 1 Forrest plot of risk difference for control of bleeding in group A trials of sclerotherapy combined with vasoactive agents/balloon tamponade vs. vasoactive agents/balloon tamponade (D, drugs). The risk differences were calculated as follows. Taking the trial by Soderlund et al. as an example: there was failure to control bleeding in 8 out of 50 patients treated with drugs (16 %), and in 3 out of 57 patients treated with sclerotherapy + drugs (5 %), giving a risk difference of 11 %.
Mortality (Figure [2]). Fewer deaths occurred with sclerotherapy combined with drugs than with drugs/balloon tamponade alone (Q test, P = 1.0), with a 5.5 % difference (95 % CI - 1.8 % to 12.7 %) (P = 0.138), with no significant changes in the sensitivity analyses.
Figure 2 Forrest plot of risk difference for mortality in group A trials of sclerotherapy combined with vasoactive agents/balloon tamponade vs. vasoactive agents/balloon tamponade (D, drugs).
Complications. These were reported in three studies [13] [15] [16], two of which [13] [16] did not report per patient. A systematic evaluation was not possible.
#Group B: sclerotherapy vs. vasoactive agents
There were 15 studies, that is, 11 papers [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] and four abstracts [28] [29] [30] [31]), involving 1324 episodes in 1296 patients (see Tables [e3] and [e4]).
In one study vasopressin was used [26], in one terlipressin [18], in four somatostatin [21] [22] [23] [28], and in nine studies octreotide was used [17] [19] [20] [24] [25] [27] [29] [30] [31]. Treatment effect was evaluated at the end of drug infusion (12 h to 168 h).
The efficacy of sclerotherapy was a median of 83 % (57 % - 94 %) in studies where drug infusion lasted 12 - 48 h [19] [20] [21] [22] [24] [25] [26] [28] [29] [30] [31] and a median of 73 % (68 % - 83 %) in studies where infusion lasted 120 - 168 h [17] [18] [23]. All except three trials [19] [29] [30] reported on complications. One study reported less transfusion with sclerotherapy (mean 2.1 ± 0.41 units vs. mean 2.9 ± 0.79 units; P < 0.05) [29]; ten found no difference [17] [18] [19] [20] [21] [22] [23] [24] [25] [27]; one did not state whether there was any difference [31]; and three did not report on transfusion [26] [28] [30].
The median quality score was 60 (range 51 - 73).
#Meta-analysis of group B trials
Failure to control bleeding (Figure [3]). There was significant heterogeneity (P = 0.01), but only in the magnitude and not in the direction of treatment effect; in only two [20] [31] were drugs better than sclerotherapy, but this did not reach statistical significance.
Figure 3 Forrest plot of risk difference for control of bleeding in group B trials of sclerotherapy vs. vasoactive agents.
When abstracts were excluded, there was no heterogeneity (P = 0.4). Failure to control bleeding was less frequent with sclerotherapy with a difference of 3.4 % (95 % CI - 1.8 % to 8.5 %) (P = 0.2), with no change following sensitivity analyses.
If all papers were considered, then sclerotherapy was more effective with a 5.9 % difference (95 % CI 1.5 % to 10.3 %) (P = 0.008). The other sensitivity analyses showed that octreotide in nine studies (P = 0.04) and vasopressin (one study), as well as the combined group of somatostatin and octreotide, were significantly worse than sclerotherapy. In these trials, there were no differences between treatment groups when the following variables were considered: whether only patients with cirrhosis were involved; whether reports were full studies or abstracts; use or not of somatostatin; drug infusion of more or less than 120 h; and combination of vasopressin and terlipressin, or use of terlipressin alone.
Mortality (Figure [4]). There were fewer deaths with sclerotherapy, with a difference of 4.3 % (95 % CI 0.6 % to 8.1 %) (P = 0.02). The NNT was 23 (95 % CI 12 - 157). The effect was not robust, as the publication bias assessment showed four null or negative studies. Sensitivity analyses did not change the findings of the main meta-analysis.
Figure 4 Forrest plot of risk difference for mortality in group B trials of sclerotherapy vs. vasoactive agents.
Complications. In 12 studies [17] [18] [20] [21] [22] [23] [24] [25] [26] [27] [28] [31], complications showed significant heterogeneity (P = 0.0001), and were less frequent with any drug, with a difference of 8.8 % (95 % CI 0.2 % to 15.6 %) (P = 0.01).
#Group C: sclerotherapy vs. sclerotherapy combined with vasoactive agents
The eight trials included six papers [19] [32] [33] [34] [35] [36] and two abstracts [37] [38] (the first having two treatment arms), and involved 1026 patients (Tables [e5] and [e6]). Five studies were placebo-controlled [32] [33] [34] [36] [37]. Vasoactive drugs were administered for 120 h in six trials [32] [33] [34] [36] [37] [38] and for 48 h in two [19] [35].
The efficacy of sclerotherapy was a median of 82.5 % (81 % - 84 %) with 48-h drug administration and a median of 61.5 % (36 % - 77 %) with 120-h administration (not significant). In all studies but one [19], the average number of units transfused was significantly less with combination therapy.
The median quality score was 60 (range 49.5 - 75).
#Meta-analysis of group C trials
Failure to control bleeding (Figure [5]). This was less frequent with sclerotherapy combined with drugs, with a difference of 13.2 % (95 % CI 8.4 % to 18.1 %) (P < 0.0001). The NNT was 8 (95 % CI 5 to 15). The publication bias assessment was 47 null or negative studies, that is, the result was very robust.
Figure 5 Forrest plot of risk difference for control of bleeding in group C trials of sclerotherapy (S) vs. sclerotherapy combined with vasoactive agents (S+D).
In the sensitivity analyses, terlipressin was not shown to have an advantage; there was no advantage of any drug added to sclerotherapy for 48-h administration; and no advantage of combined therapy when no placebo drug was used.
Mortality (Figure [6]). The difference in mortality was 3.4 % (95 % CI - 0.4 % to 7.1 %) in favor of combined therapy (P = 0.08). Sensitivity analysis showed that in placebo-controlled trials in which a drug was given for 120 h, the difference was 1.3 % (95 % CI - 3.3 % to 5.8 %), strongly suggesting no benefit with regard to mortality, despite the benefit for control of bleeding.
Figure 6 Forrest plot of risk difference for mortality in group C trials of sclerotherapy (S) vs. sclerotherapy combined with vasoactive agents (S+D).
Complications. Five studies had data but only two reported complications per patient [32] [33], with no statistical differences.
#Group D: sclerotherapy vs. variceal ligation
There were 12 trials [9] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49], including eight papers [9] [40] [41] [44] [45] [46] [48] [49] and four abstracts [39] [42] [43] [47], that involved 1309 patients (Tables [e7] and [e8]). Seven of the trials included only patients with cirrhosis [9] [40] [41] [43] [44] [45] [46]. The same ligating device (Bard Interventional Products, Tewkesbury, Massachusetts, USA) with an overtube was used in eight trials [9] [40] [41] [44] [45] [48] [49]; in three trials, the device was not mentioned [39] [42] [43]; and in one used a ”six-shooter” was used [47]. A definition of failure to control bleeding was stated in five [9] [40] [41] [45] [46].
The efficacy of sclerotherapy for initial hemostasis at the end of endoscopy was a median of 95 % (76 % - 100 %) compared with a median of 97 % (86 % - 100 %) in the endoscopic band ligation group (P = 0.4). Transfusion requirements were stated in six trials [9] [42] [44] [45] [46] [49], and in only one [46] were they less in the ligation group (mean 4.5 ± 1.8 units (0 - 12) vs. mean 3.2 ± 1.2 units (0 - 6); P < 0.01); in others there was no difference.
The median quality score was 68.5 (range 50.5 - 79).
#Meta-analysis of group D trials
Failure to control bleeding (Figure [7]). There was a difference favoring ligation of 2.5 % (95 % CI 0.4 % to 4.6 %) (P = 0.018). Sensitivity analyses showed no differences from the main meta-analysis, including an evaluation defining failure in some articles vs. those articles in which it was not.
Figure 7 Forrest plot of risk difference for control of bleeding in group D trials of sclerotherapy vs. variceal ligation.
Mortality (Figure [8]). The percentage difference was 1.3 %, favoring ligation (95 % CI - 2.3 % to 4.9 %) (P = 0.46). Sensitivity analyses showed no differences from the main meta-analysis.
Figure 8 Forrest plot of risk difference for mortality in group D trials of sclerotherapy vs. variceal ligation.
Overall results
Figures [9] - [11] display the efficacy of sclerotherapy in the study groups described above, showing the worst performance for sclerotherapy compared with sclerotherapy combined with vasoactive drugs.
Figure 9 Control of variceal bleeding. The efficacy of emergency sclerotherapy alone, in groups of randomized trials, compared with other treatments (pts, patients). Group A: sclerotherapy combined with vasoactive agents/balloon tamponade vs. solely vasoactive agents/balloon tamponade. Group B: sclerotherapy vs. vasoactive agents. Group C: sclerotherapy alone vs. sclerotherapy combined with vasoactive agents. Group D: sclerotherapy vs. variceal ligation.
Figure 10 Control of variceal bleeding. The efficacy of emergency sclerotherapy alone in groups of randomized trials compared with other treatments, with respect to the interval over which efficacy was evaluated (the number of trials is reported in each column). Group A: sclerotherapy combined with vasoactive agents/balloon tamponade vs. solely vasoactive agents/balloon tamponade. Group B: sclerotherapy vs. vasoactive agents. Group C: sclerotherapy alone vs. sclerotherapy combined with vasoactive agents. Group D: sclerotherapy vs. variceal ligation.
Figure 11 The efficacy of emergency sclerotherapy alone in randomized trials compared with vasoactive drugs alone or a combination of sclerotherapy and vasoactive drugs, with respect to the year of publication of the trial (1989 - 2001):
Discussion
The purpose of our systematic review was to compare emergency sclerotherapy, which has been the standard treatment for bleeding esophageal varices, with vasoactive drug treatment and variceal ligation.
The efficacy of sclerotherapy across different trial groups has not been compared in previous meta-analyses. Sclerotherapy with somatostatin or octreotide has been reported to be more efficacious than drugs alone [67]. In eight studies, the combination of vasoactive agents with sclerotherapy achieved better initial control of bleeding and prevention of early rebleeding at 5 days, yet failed to improve mortality compared with endoscopic therapy alone [68]. Ligation has been considered to be the endoscopic treatment of choice in preference to sclerotherapy [44]. Two meta-analyses [10] [67] led to the conclusion that drug therapy was equivalent to sclerotherapy. Thus these previous meta-analyses suggested that sclerotherapy could either be improved by adding drugs, or be replaced by vasoactive drugs or ligation. In order to verify this, we chose to evaluate all the emergency sclerotherapy trials using the same criteria.
#Group B trials: sclerotherapy vs. vasoactive drugs
The group of 15 studies were equivalence trials [69] in most of which the sample size calculations were inadequate in terms of this design [70]; hence, for individual studies, treatment differences of moderate size cannot be ruled out [71]. Meta-analysis, particularly in this case, gives a better estimate of the efficacy [72].
Our meta-analysis showed that emergency sclerotherapy significantly reduced mortality, with a strong trend to a reduced failure rate for control of bleeding. This is an important difference from the latest published meta-analysis [10], which we have challenged on several grounds [11]. One of these was the definition used for the control of bleeding, involving analysis of bleeding/rebleeding occurrences over three time periods, that is, at the initial bleed, before the start of long-term preventative therapy for rebleeding, and within 42 days; the latter two periods being beyond the time that a treatment effect might be expected for emergency sclerotherapy or vasoactive drugs. From the 15 trials, only four [19] [20] [22] [31] reported drugs to be better than sclerotherapy but in no study was this statistically significant.
Somatostatin and octreotide have been reported to be more effective than emergency sclerotherapy for the control of bleeding [10] [73]. However, our sensitivity analysis suggested that sclerotherapy was better than octreotide, a drug commonly used in North America, but similar to the somatostatin generally used in Europe.
In the interpretation of our meta-analysis, other points should be taken into account. First, these trials were conducted unblinded for both investigator and patient. This unavoidably weakens the objectivity in evaluating end points. This may not be an issue for mortality, but it could be for failure to control bleeding which is usually a composite end point [74]. Recent guidelines have listed factors such as hemodynamic instability and blood transfusion requirement [75], which define success of therapy as comprising a period of stability, but in clinical practice this is not as easy to apply as might be anticipated. Overestimation of failure has been shown [34]. Time to failure may be a valid end point in trials of acute variceal bleeding [34] [74] [76] [77]. This uncertainty, coupled with the fact that comparative studies using drugs were usually financially supported by the biomedical company marketing the drug, makes interpretation difficult [72].The promotional interest of drug companies can affect the scientific content of the trials [78].
Secondly, trials of bleeding would be expected to document precisely blood transfusion requirements, but these are not expressed per unit time, making evaluation even more imprecise. In addition the indications for transfusion are usually not stated, so that the clinical significance is difficult to evaluate; for example, transfusion may have been done to restore hemodynamic stability or as a ”top up” to correct anemia.
Thirdly, and the most important caveat, is the great variability in the efficacy of the reference therapy, i. e. sclerotherapy. There was great variability within each group of trials but also between groups. The median efficacies were: group A 86 % (71 % - 95 %); group B 83 % (57 % - 94 %); group C 69 % (36 % - 84 %); and group D 95 % (76 - 100 %) (Figures [9]- [11]).
Lastly, the evaluation of complications, which may help in the choice of therapy is very difficult. The lack of blinding, the differing definitions, and the absence of specified protocols for identifying complications resulted in a significant heterogeneity.
#Group C trials: sclerotherapy vs. sclerotherapy combined with vasoactive agents
In all the eight studies the combined therapy was better in reducing failure to control bleeding. Five studies (which encompassed most patients, i. e. 711 of 1026) were placebo-controlled, obviating some of the problems in unblinded studies that compare sclerotherapy with drugs. However there are other problems that raise questions about the validity of this therapeutic approach. First, the meta-analysis for mortality showed that there was no statistically significant difference between the two treatment strategies, and the difference was smaller in the placebo-controlled studies. One might have expected a trend for lower mortality in the combined treatment group, given the significant reduction in the failure to control bleeding, a very marked clinical difference, which was the largest of all the groups of trials evaluated in this report.
The reported efficacy of sclerotherapy is the lowest of the groups evaluated, with a median of 69 % which is lower than the bottom of the range in other groups, i. e. 86 %, 83 %, and 95 %. Given that endoscopic technique has not changed in recent years, and indeed may have improved because operators have gained more experience, it is clear that this difference is likely to be due to differences in the definition of end points [74] [77], and not a real, concrete difference. Thus the benefit of combined therapy may have been overestimated due to the much lower efficacy of sclerotherapy in these trials.
#Group D trials: sclerotherapy vs. variceal ligation
These included 12 studies [9] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49], but data were mostly derived from long-term comparisons in which definition of failure to control bleeding was often absent. There was a significant difference favoring ligation regarding control of bleeding, but this was only an average of 2.6 % and there was no difference in mortality. A single trial [46] reported a 97 % efficacy for variceal ligation during the first 72 h. It is noteworthy that another randomized trial performed in patients with similar etiologies from the same geographic region (with fewer than 50 % having active bleeding at endoscopy), reported a 62 % efficacy of ligation within 48 h [79]. Thus as with sclerotherapy there are large variations in reported efficacy rate which are likely to be due to different definitions.
There is a further issue, and this concerns the applicability of the endoscopic therapies [80] [81]. A diagnostic endoscopy has to be done first and varices may not be the source of bleeding. If they are, a double intubation is needed. Attaching the ligation device for diagnostic endoscopy even if varices are known to be present, limits visualization. Even if double intubation is accepted (placing the ligation device after diagnosis), this increases the risk of complications and lengthens the procedure.
Moreover it has been overlooked that an overtube was used for ligation, but not for sclerotherapy, in eight of 12 randomized studies comparing these two techniques, and in only one was it specifically stated that an overtube was not used. To our knowledge, very few centers employ overtubes; freehand injection and banding are usually used. In a further prospective trial to resolve whether variceal ligation is better than sclerotherapy, the number of intubations and their complications should be taken into account, and overtubes should not be used.
#Summary
The interpretation of our detailed evaluation, including the use of meta-analysis, of emergency sclerotherapy for acute variceal bleeding, suggests that emergency endoscopic treatment with sclerotherapy, at the time of the initial endoscopy when the source of bleeding is to be diagnosed, should remain as first-choice therapy. The use of an additional pharmacologic agent given as soon as possible after admission, before diagnostic endoscopy, should be further tested in randomized controlled trials. Further standardization of definitions is needed following the evolution of the Baveno criteria [75] and, in particular, a consensus is needed for the reporting of blood transfusion requirements.
| Study [reference] | Quality score | Treatment compared | Study duration, h | No. of patients | Child C, n (%) | Drug dose | Sclerosing agent | Injection site | |
| S + D | D | ||||||||
| Soderlund & Ihre 1985 [15] | 58 | Vasopressin ± tamponade | 48 | 57 | 50 | 70 (65 %) | Bolus 20 IU + 4 - 6 IU/h for 24 h | Polidocanol | Intravariceal |
| Larson et al. 1986 [13] | 49 | Vasopressin + tamponade | 72 | 44 | 38 | 47 (57 %) | NR | Sotradecol | Intravariceal |
| Alexandrino et al. 1990 [12]* | Vasopressin/nitroglycerin + tamponade | 24 | 41† | 42† | 41 (49 %) | NR | NR | NR | |
| Novella et al.* 1996 [14] | Octreotide | 120 | 22 | 19 | 7 (17 %) | 50 μg/h | Ethanolamine | Intravariceal | |
| Villanueva et al. 1999 [16] | 68.5 | Somatostatin | 120 | 50‡ | 50‡ | 25 (27 %) | 250 μg/h + bolus 250 μg/6 h | Ethanolamine | Intravariceal |
| NR, not reported. * Abstract; † 2 dropped out in each group; ‡ episodes. | |||||||||
| Study [reference] | No of patients | Active bleeding, n (%) | Efficacy of sclerotherapy, % | Definition of failure to control bleeding | Failure to control bleeding, n | Deaths, n | Complications, n | ||||
| S + D | D | S + D | D | S + D | D | S + D | D | ||||
| Soderlund & Ihre 1985 [15] | 57 | 50 | NR | 95 | Hematemesis/gastric aspiration + ↓Ht hemodynamic instability | 3 | 8 | 16 | 18 | 10 | 8 |
| Larson et al. 1986 [13] | 44 | 38 | 24 (22 %) | 77 | Hematemesis/gastric aspiration + ↓Ht > 6 % in 24 h, or Hemodynamic instability/↓Ht > 3 % after bleeding-free period of 48 h |
10* | 20* | 2 | 5 | 25† | 42† |
| Alexandrino et al. 1990 [12] | 41 | 42 | NR | 71 | NR | 12 | 12 | 16 | 17 | NR | |
| Novella et al. 1996 [14] | 22 | 19 | NR | 86 | Persistent bleeding (within 6 h after endoscopy), early rebleeding | 3 | 7 | 3 | 2 | NR | |
| Villanueva et al. 1999 [16] | 50‡ | 50‡ | NR | 86 | Hematemesis/gastric aspiration + hemodynamic instability/↓Hb ≥ 2 g/dl within less than 6-hour period | 7 | 21 | 7 | 10 | 12†
|
4† |
| NR, not reported; Ht, hematocrit. * Up to 2 weeks; † number of complications; ‡ episodes. | |||||||||||
| Study [reference] | Quality score | Treatment compared | Study duration, h | No. of patients | Child C, n (%) | Drug dose | Sclerosing agent | Injection site | |
| S + D | D | ||||||||
| Westaby et al. 1989 [26] | 61 | Vasopressin + nitroglycerin | 12 | 33 | 31 | 22 (34) | Bolus 20 IU followed by 0.4 IU/min + 40 - 400 μg/min | Ethanolamine | Intravariceal |
| Di Febo et al. 1990 [28]* | Somatostatin | 48 | 24 | 23 | 19 (40) | Bolus 250 μg + 250 μg/h | NR | NR | |
| Shields et al. 1992 [23] | 60 | Somatostatin | 120 | 41 | 39 | 42 (52.5) | Bolus 250 μg/d + 250 μg/h | Ethanolamine | Intravariceal |
| Sung et al. 1993 [25] | 63 | Octreotide | 48 | 49 | 49 | 43 (44) | Bolus: 50 μg + 50 μg/h | Sotradecol (sodium tetradecyl sulphate) | Intravariceal |
| Planas et al. 1994 [21] | 69 | Somatostatin | 48 | 35 | 35 | 24 (34) | Bolus: 250 μg/6 h + 250 μg/h | Polidocanol | Intravariceal/paravariceal |
| Poo et al. 1996 [31]* | Octreotide | 48 | 21 | 22 | 20 (47) | 50 μg/h | Polidocanol | Intravariceal | |
| Jenkins et al. 1997 [20] | 73 | Octreotide | 48 | 77 | 73 | 80 (53) | 50 μg/h | Ethanolamine | Intravariceal |
| El-Jackie et al. 1998 [29]* | Octreotide | 48 | 50 | 50 | 40 (40) | Bolus 50 μg + 50 μg/h for 48 h | Ethanolamine | NR | |
| Lopez et al. 1999 [30]* | Octreotide | 24 | 33 | 31 | NR | 50 μg/h | Polidocanol | NR | |
| Bildozola et al. 2000 [17] | 51 | Octreotide | 120 | 37 | 39 | 8 (11) | Bolus 100 μg + 50 μg/h for 48 h + 100 μg three times daily subcutaneously for 72 h | Polidocanol | Intravariceal/paravariceal |
| Escorsell et al. 2000 [18] | 63 | Terlipressin | 120 | 114 | 105 | 69 (32) | 1 - 2 mg/4 h | Ethanolamine/Polidocanol | Intravariceal/paravariceal |
| Freitas et al. 2000 [19] | 60 | Octreotide | 48 | 53 | 58 | 38 (34) | 25 μg/h | Ethanol | Intravariceal/paravariceal |
| Sivri et al. 2000 [24] | 56 | Octreotide | 12 | 36 | 30 | 28 (27) | Bolus 50 μg + 50 μg/h | Polidocanol | Intravariceal/paravariceal |
| Yousuf et al. 2000 [27] | 54 | Octreotide | NR | 48 | 48 | 16 (17) | 50 μg/6 h | Sodium tetradecyl sulphate | Intravariceal |
| Ramires et al. 2000 [22] | 52.5 | Somatostatin | 48 | 19 | 21 | 10 (25) | 250 μg/h for 48 h + 250 μg 6-hourly for the first 24 h | Ethanolamine | Intravariceal |
| NR, not reported. * Abstract. | |||||||||
| Study [reference] | No. of patients | Active bleeding, n (%) | Efficacy of sclerotherapy, % | Definition of failure or success to control bleeding | Failure to control bleeding, n | Deaths, n | Complications, n | ||||
| S | D | S | D | S | D | S | D | ||||
| Westaby et al. 1989 [26] | 33* | 31* | 64 (100) | 88 | Presence of active bleeding (at repeat endoscopy/aspiration) | 4 | 11 | 9 | 12 | 3 | 3 |
| Di Febo et al. 1990 [28] | 24 | 23 | 47 (100) | 92 | Hematemesis/melena or ↓Hb > 2 g/L or hemodynamic instability | 2 | 5 | 5 | 6 | 2 | 1 |
| Shields et al. 1992 [23] | 41 | 39 | 51 (64) | 83 | Cessation of bleeding (assessed endoscopically) 10 - 20 min after start of somatostatin
treatment or after sclerotherapy Hematemesis/melena, ↓Hb, hemodynamic instability |
7 | 9 | 8 | 12 | 12 | 5 |
| Sung et al. 1993 [25] | 49 | 49 | 43 (44) | 73 | Cessation of bleeding (assessed endoscopically) 10 - 20 min after start of octreotide
treatment or after sclerotherapy Hematemesis/melena, blood pressure < 90 mm Hg and pulse rate > 110, or transfusion of ≥ 66 U over 12 h |
13 | 15 | 20 | 14 | 18 | 5 |
| Planas et al. 1994 [21] | 35 | 35 | 35 (50) | 83 | Persistence of bleeding or hematemesis/melena + ↓blood pressure > 30 mm Hg and pulse rate > 120 or transfusion of ≥ 3 U | 6 | 7 | 8 | 10 | 10 | 5 |
| Poo et al. 1996 [31] |
21 | 22 | 13 (30) | 90 | Hematemesis/melena or transfusion of ≥ 3 U | 2 | 1 | 5 | 3 | 1 | 1 |
| Jenkins et al. 1997 [20] | 77 | 73 | 85 (57) | 57 | Hematemesis/melena + hemodynamic instability or ↓Hb requiring blood transfusion | 33 | 22 | 13 | 22 | 15 | 19 |
| El-Jackie et al. 1998 [29] | 50 | 50 | 100 (100) | 94 | NR | 3 | 21 | 2 | 5 | NR | NR |
| Lopez et al. 1999 [30] | 33 | 31 | NR | 88 | NR | 4 | 5 | 7 | 6 | 21 | NR |
| Bildozola et al. 2000 [17] | 37 | 39 | 33 (43) | 73 | Hematemesis and/or melena, hemodynamic instability and a decrease of 5 % in hematocrit after the initial control of bleeding | 10 | 17 | 3 | 8 | 4 | 0 |
| Escorsell et al. 2000 [18] |
114 | 105 | 86 (39) | 68 | Fresh blood in gastric aspirates during a period of at least 6 h, hypovolemia + endoscopy and/or fresh melena and/or fresh blood in the gastric aspirate, or hematemesis | 36 | 35 | 19 | 26 | 34 | 2 |
| Freitas et al. 2000 [19] | 53 | 58 | 41 (77) | 77 | (a) Hematemesis or aspiration of more than 100 ml of bright red blood; (b) emission of bright red blood per rectum; (c) ↓Hb more than 4 g/dl in 48 h; (d) shock and melena | 12 | 12 | 8 | 13 | NR | NR |
| Sivri et al. 2000 [24] | 36* | 30* | 36 (100) | 58 | Overt hemorrhage or aspiration of more than 100 ml of fresh blood; passage of fresh blood per rectum; ↓Hb of more than 4 g/dl within 72 h; shock (pulse rate > 100, systolic blood pressure < 100 mm Hg) in the presence of continuing melena | 15 | 13 | 1 | 1 | 5 | 1 |
| Yousuf et al. 2000 [27] | 48 | 48 | NR | 92 | Aspiration of fresh blood on gastric lavage at any time following initial control of bleeding, and unstable vital signs | 4 | 8 | 5 | 5 | 6 | 8 |
| Ramires et al. 2000 [22] | 19 | 21 | 10 (53) | 74 | Hematemesis/melena or pulse rate > 100, systolic blood pressure < 100 mm Hg | 5 | 5 | 6† | 6† | 1 | 0 |
| Hb, hemoglobin; NR, not reported. * Number of episodes; † 7-day mortality. | |||||||||||
| Study [reference] | Quality score | Drug in combination | Study duration, h | No. of patients | Child C, n (%) | Drug dose | Sclerosing agent | Injection site | |
| S | S+D | ||||||||
| Besson et al. 1995 [33]* | 75 | Octreotide | 120 | 101 | 98 | 73 (37) | 256 μg/h | Polidocanol | Intravariceal/paravariceal |
| Signorelli et al. 1996 [37]*† | Somatostatin | 120 | 30§ | 33§ | NR | 3.5 μg/kg/h | Polidocanol | NR | |
| Signorelli et al. 1996 [37]*† | Octreotide | 120 | 30§ | 31§ | NR | sc 0.1 mg every 8 h | Polidocanol | NR | |
| Signorelli et al. 1999 [38] † | Octreotide | 120 | 45 | 43 | NR | Bolus 50 μg + 50 μg/h |
Polidocanol | NR | |
| Avgerinos et al. 1997 [32] | 72 | Somatostatin | 120 | 75 | 77 | NR | Bolus 250 μg (up to 10 doses) + 250 μg/h | Ethanolamine & Aethoxysclerol | Intravariceal |
| Freitas et al. 2000 [19] | 60 | Octreotide | 48 | 42 | 44 | 86 (34) | 25 μg/h | Ethanol | Intravariceal/paravariceal |
| Farooqi et al. 2000 [35] | 49.5 | Octreotide | 48 | 69 | 72 | 38 (27) | 50 μg/h | Ethanolamine | NR |
| Zuberi & Baloch 2000 [36] | 53 | Octreotide | 120 | 35 | 35 | NR | 50 μg/h | Ethanolamine | Intravariceal |
| Cales et al. 2001 [34] | 60 | Vapreotide‡ | 120 | 98 | 98 | 80 (41) | Bolus 50 μg + 50 μg/h |
NR | NR |
| NR, not reported. * Placebo-controlled; † abstract; ‡ combined with sclerotherapy or ligation; § the numbers are used twice; cs = subcutaneous. | |||||||||
| Study [reference] | No. of patients | Active bleeding, n (%) | Efficacy of sclerotherapy, % | Definition of failure to control bleeding | Failure to control bleeding, n | Deaths, n | Complications, n | ||||
| S | S + D | S | S + D | S | S + D | S | S + D | ||||
| Besson et al. 1995 [33] | 101 | 98 | 89 (45) | 75 | ↓Blood pressure ≥ 20 mm Hg; Hb < 9 g/L; Ht < 30 %; transfusion of > 2 U in 2 h, or 4 U in 4 h | 25 | 11 | 12 | 12 | 33 | 34 |
| Signorelli et al. 1996 [37] | 30 | 33 | NR | 63 | NR | 11 | 6 | 5 | 4 | NR | NR |
| Signorelli et al. 1996 [37] | 30 | 31 | NR | 63 | NR | 11 | 8 | 5 | 5 | NR | NR |
| Signorelli et al. 1999 [38] | 45 | 43 | NR | 60 | NR | 18 | 8 | NR | NR | NR | NR |
| Avgerinos et al. 1997 [32] | 75 | 77 | 69 (45) | 36 | Transfusion of > 2 - 5 U (according to baseline Hb); hematemesis; hemodynamic instability; use of rescue therapy; death | 48 | 31 | 24 | 27 | 37 | 37 |
| Freitas et al. 2000 [19] | 42 | 44 | 86 (100) | 81 | (a) Hematemesis or aspiration of more than 100 ml of bright red blood; (b) emission of bright red blood per rectum; (c) ↓Hb more than 4 g/dl in 48 h; (d) shock and melena | 8 | 16 | 31 | 27 | NR | NR |
| Farooqi et al. 2000 [35] | 69 | 72 | NR | 84 | NR | 11 | 3 | 6 | 1 | 27 | 31 |
| Zuberi & Baloch 2000 [36] | 35 | 35 | NR | 77 | (a) Hematemesis and melena for 24 consecutive hours; (b) stable concentration and hemodynamic conditions for 24 consecutive hours without blood transfusions; (3) blood at control EGD | 8 | 2 | 1 | 1 | 14† | 16† |
| Cales et al. 2001 [34] | 98 | 98 | NR | 53 | ↓Blood pressure ≥ 20 mm Hg, an increase in heart rate 20 beats per minute compared with the average of the two preceding values, and a decrease in the Ht of at least 5 percentage points compared with the preceding value | 46* | 31* | 21 | 14 | 8† | 6† |
| Hb, hemoglobin; Ht, hematocrit; NR, not reported; EGD, esophagogastroduodenoscopy. * Derived from Table [2] in reference 34, taking the best hypothesis that those who died within 5 days did not die from rebleeding; † episodes of complications. | |||||||||||
| Study [reference] | Quality score | Etiology of liver disease | Sclerosing agent | Injection site | Ligation equipment |
| Stiegmann et al. 1992 [9] | 79 | Cirrhosis | Sotradecol | Intravariceal | Overtube |
| Laine et al. 1993 [44] | 68 | Cirrhosis | Sotradecol | Intravariceal | Overtube |
| Gimson et al. 1993 [40] | 58 | Cirrhosis | Ethanolamine | Intravariceal | Overtube |
| Jensen et al. 1993 [43]* | Cirrhosis | Sotradecol | Intravariceal | NR | |
| Lo et al. 1995 [45] | 69 | Cirrhosis | Sotradecol | Intravariceal | Overtube |
| Hou et al. 1995 [41] | 70 | Cirrhosis | Sotradecol | Intravariceal | Overtube |
| Jain et al. 1996 [42]* | NR | NR | NR | NR | |
| Lo et al. 1997 [46] | 73 | Cirrhosis | Sotradecol | Intravariceal | Overtube |
| Sarin et al. 1997 [48] | 50.5 | Cirrhosis/extrahepatic portal hypertension | Alcohol 100 % | Intravariceal | Overtube |
| Fakhry et al. 1997 [39]* | Cirrhosis/schistosomal hepatic fibrosis | Ethanolamine | NR | NR | |
| Shafqat et al. 1998 [49] | 58 | Cirrhosis/noncirrhotic portral hypertension | Alcohol 75 % | Intravariceal/paravariceal | Overtube |
| Salem & Shiha 1999 [47]* | Cirrhosis/schistosomal hepatic fibrosis | NR | NR | ”Six-shooter” | |
| NR, not reported. * Abstract. | |||||
| Study [reference] | Total no. of patients | Active bleeding | Efficacy of sclerotherapy (%) | Definition of failure or success to control bleeding | Failure to control bleeding | Death | ||||
| S | L | S | L | S | L | S | L | |||
| Stiegmann et al. 1992 [9] | 65 | 64 | 13 | 14 | 95 | Stable Ht and vital signs; no hematemesis for 8 h after treatment | 3 | 2 | 15* | 10* |
| Laine et al. 1993 [44] | 39 | 38 | 9 | 9 | 97 | NR | 1 | 1 | NR | NR |
| Gimson et al. 1993 [40] | 49 | 54 | 23 | 21 | 94 | Stable vital signs and packed-cell volume; no hematemesis for 12 h after treatment | 3 | 3 | NR | NR |
| Jensen et al. 1993 [43] | 18 | 14 | 16 | 13 | 100 | NR | 0 | 3 | 3† | 2† |
| Lo et al. 1995 [45] | 59 | 61 | 15 | 18 | 95 | No sign of rebleeding; stable vital signs for 72 h after treatment | 3 | 1 | NR | NR |
| Hou et al. 1995 [41] | 67 | 67 | 16 | 20 | 97 | No sign of rebleeding; stable vital signs for 24 h after treatment | 2 | 0 | NR | NR |
| Jain et al. 1996 [42] | 24 | 22 | NR | NR | 92 | NR | 2 | 3 | 2‡ | 3‡ |
| Lo et al. 1997 [46] | 34 | 37 | 34 | 37 | 76 | No sign of rebleeding; stable vital signs for 72 h after treatment | 8 | 1 | 12 | 7 |
| Sarin 1997 [48] | 48 | 47 | 7 | 5 | 98 | NR | 1 | 1 | 3 | 3 |
| Fakhry et al. 1997 [39] | 41 | 43 | 17 | 18 | 98 | NR | 1 | 1 | 1 | 1 |
| Shafqat et al. 1998 [49] | 30 | 28 | 28 | 24 | 80 | NR | 6 | 1 | NR | NR |
| Salem & Shiha 1999 [47] | 180 | 180 | 180 | 180 | 82 | NR | 32 | 16 | 16 | 14 |
| Ht, hematocrit; NR, not reported. * Derived from the statement that more than half the deaths in each group occurred within 30 days of a patient’s entry into the study; † 30 days; ‡ hospital stay. | ||||||||||
Tables cited with “e” can be seen online only, at www.thieme-connect.de/ejournals/abstract/endoscopy/doi/10.1055/s-2006-944566
Competing interests: None
#References
- 1 The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices . Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med. 1988; 319 983-989
- 2 McCormick P A, O’Keefe C. Improving prognosis following a first variceal haemorrhage over four decades. Gut. 2001; 49 682-685
- 3 Soares-Weiser K, Brezis M, Tur-Kaspa R. et al . Antibiotic prophylaxis for cirrhotic patients with gastrointestinal bleeding [review]. Cochrane Database Syst Rev. 2002; 2 CD002907
- 4 Hou M C, Lin H C, Liu T T. et al . Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology. 2004; 39 746-753
- 5 Goulis J, Patch D, Burroughs A K. Bacterial infection in the pathogenesis of variceal bleeding. Lancet. 1999; 353 139-142
- 6 Crafoord C, Frenckner P. New surgical treatment of varicose veins of the oesophagus. Acta Otolaryngol. 1939; 27 422-429
- 7 De Franchis R, Banares R, Silvain C. Emergency endoscopy strategies for improved outcomes. Scand J Gastroenterol (Suppl). 1998; 226 25-36
- 8 Hartigan P M, Gebhard R L, Gregory P B. Sclerotherapy for actively bleeding esophageal varices in male alcoholics with cirrhosis. Veterans Affairs Cooperative Variceal Sclerotherapy Group. Gastrointest Endosc. 1997; 46 1-7
- 9 Stiegmann G V, Goff J S, Michaletz-Onody P A. et al . Endoscopic sclerotherapy as compared with endoscopic ligation for bleeding esophageal varices. N Engl J Med. 1992; 326 1527-1532
- 10 D’Amico G, Pietrosi G, Tarantino I. et al . Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: a Cochrane meta-analysis. Gastroenterology. 2003; 124 1277-1291
- 11 Triantos C, Samonakis D, Patch D. et al . Sclerotherapy versus vasoactive drugs. Are all meta-analyses the same?. Gastroenterology. 2004; 127 358-359
- 12 Alexandrino P, Alves P, Fidalgo M. et al . Is sclerotherapy the first choice treatment for active oesophageal variceal bleeding in cirrhotic patients? Final report of a randomized controlled trial [abstract]. J Hepatol. 1990; 11 S1
- 13 Larson A W, Cohen H, Zweiban B. et al . Acute esophageal variceal sclerotherapy. Results of a prospective randomized controlled trial. JAMA. 1986; 255 497-500
- 14 Novella M, Villanueva C, Ortiz J. et al . Octreotide vs. sclerotherapy and octreotide for acute variceal bleeding. A pilot study [abstract]. Hepatology. 1996; 24 207A
- 15 Soderlund C, Ihre T. Endoscopic sclerotherapy v. conservative management of bleeding oesophageal varices. A 5-year prospective controlled trial of emergency and long-term treatment. Acta Chir Scand. 1985; 151 449-456
- 16 Villanueva C, Ortiz J, Sabat M. et al . Somatostatin alone or combined with emergency sclerotherapy in the treatment of acute esophageal variceal bleeding: a prospective randomized trial. Hepatology. 1999; 30 384-389
- 17 Bildozola M, Kravetz D, Argonz J. et al . Efficacy of octreotide and sclerotherapy in the treatment of acute variceal bleeding in cirrhotic patients. A prospective, multicentric, and randomized clinical trial. Scand J Gastroenterol. 2000; 35 419-425
- 18 Escorsell A, Del Arbol L R, Planas R. et al . Multicenter randomized controlled trial of terlipressin versus sclerotherapy in the treatment of acute variceal bleeding: the TEST study. Hepatology. 2000; 32 471-476
- 19 Freitas D S, Sofia C, Pontes J M. et al . Octreotide in acute bleeding esophageal varices: a prospective randomized study. Hepatogastroenterology. 2000; 47 1310-1314
- 20 Jenkins S A, Shields R, Davies M. et al . A multicentre randomised trial comparing octreotide and injection sclerotherapy in the management and outcome of acute variceal haemorrhage. Gut. 1997; 41 526-533
- 21 Planas R, Quer J C, Boix J. et al . A prospective randomized trial comparing somatostatin and sclerotherapy in the treatment of acute variceal bleeding. Hepatology. 1994; 20 370-375
- 22 Ramires R P, Zils C K, Mattos A A. Sclerotherapy versus somatostatin in the treatment of upper digestive hemorrhage caused by rupture of esophageal varices. Arq Gastroenterol. 2000; 37 148-154
- 23 Shields R, Jenkins S A, Baxter J N. et al . A prospective randomised controlled trial comparing the efficacy of somatostatin with injection sclerotherapy in the control of bleeding oesophageal varices. J Hepatol. 1992; 16 128-137
- 24 Sivri B, Oksuzoglu G, Bayraktar Y. et al . A prospective randomized trial from Turkey comparing octreotide versus injection sclerotherapy in acute variceal bleeding. Hepatogastroenterology. 2000; 47 168-173
- 25 Sung J J, Chung S C, Lai C W. et al . Octreotide infusion or emergency sclerotherapy for variceal haemorrhage. Lancet. 1993; 342 637-641
- 26 Westaby D, Hayes P C, Gimson A E. et al . Controlled clinical trial of injection sclerotherapy for active variceal bleeding. Hepatology. 1989; 9 274-277
- 27 Yousuf M, Rauf A, Baig I. et al . Initial management of acute variceal haemorrhage. Comparison of octreotide and sclerotherapy. J Coll Phys Surg Pak. 2000; 10 95-97
- 28 Di Fedo G, Siringo S, Vacirca M. et al . Somatostatin (SMS) and urgent sclerotherapy (US) in active oesophageal variceal bleeding [abstract]. Gastroenterology. 1990; 98 583A
- 29 El-Jackie A, Rowaisha I, Waked I. et al . Octreotide vs. sclerotherapy in the control of acute variceal bleeding in schistosomal portal hypertension: a randomized trial [abstract]. Hepatology. 1998; 28 553
- 30 Lopez F, Vargas R, Margarita G. et al . Octreotide vs sclerotherapy in the treatment of acute variceal bleeding [abstract]. Hepatology. 1999; 30 574A
- 31 Poo J, Bosques S, Guarduno R. et al . Octreotide versus emergency sclerotherapy in acute variceal hemorrhage in liver cirrhosis. A randomized multicenter study [abstract]. Gastroenterology. 1996; 110 A1297
- 32 Avgerinos A, Nevens F, Raptis S. et al . Early administration of somatostatin and efficacy of sclerotherapy in acute oesophageal variceal bleeds: the European Acute Bleeding Oesophageal Variceal Episodes (ABOVE) randomised trial. Lancet. 1997; 350 1495-1499
- 33 Besson I, Ingrand P, Person B. et al . Sclerotherapy with or without octreotide for acute variceal bleeding. N Engl J Med. 1995; 333 555-560
- 34 Cales P, Masliah C, Bernard B. et al . Early administration of vapreotide for variceal bleeding in patients with cirrhosis. French Club for the Study of Portal Hypertension. N Engl J Med. 2001; 344 23-28
- 35 Farooqi J, Farooqi R, Haq N. et al . Treatment and outcome of variceal bleeding - A comparison of two methods. JCPSP. 2000; 10 131-133
- 36 Zuberi B F, Baloch Q. Comparison of endoscopic variceal sclerotherapy alone and in combination with octreotide in controlling acute variceal hemorrhage and early rebleeding in patients with low-risk cirrhosis. Am J Gastroenterol. 2000; 95 768-771
- 37 Signorelli S, Negrini F, Paris B. et al . Sclerotherapy with or without somatostatin or octreotide in the treatment of acute variceal haemorrhage: our experience. Gastroenterology. 1996; 110 1326A
- 38 Signorelli S, Paris B, Negrini F. et al . Octreotide and endoscopic variceal sclerotherapy in the management of acute variceal haemorrhage [abstract]. Endoscopy. 1999; 31 E66
- 39 Fakhry S, Omar M, Mustafa A. et al . Endoscopic sclerotherapy versus endoscopic variceal ligation in the management of bleeding esophageal varices: a final report of a prospective randomized study in schistosomal hepatic fibrosis [abstract]. Hepatology. 1997; 26 137A
- 40 Gimson A E, Ramage J K, Panos M Z. et al . Randomised trial of variceal banding ligation versus injection sclerotherapy for bleeding oesophageal varices. Lancet. 1993; 342 391-394
- 41 Hou M C, Lin H C, Kuo B I. et al . Comparison of endoscopic variceal injection sclerotherapy and ligation for the treatment of esophageal variceal hemorrhage: a prospective randomized trial. Hepatology. 1995; 21 1517-1522
- 42 Jain A K, Ray R P, Gupta J. Management of acute variceal bleed: randomized trial of variceal ligation and sclerotherapy [abstract]. Hepatology. 1996; 23 I-51
- 43 Jensen D, Kovacs T, Jutabha R. et al . Randomized, blinded prospective study of banding vs. sclerotherapy for preventing recurrent variceal hemorrhage for patients without active bleeding at endoscopy [abstract]. Gastrointest Endosc. 1993; 41 315A
- 44 Laine L, el Newihi H M, Migikovsky B. et al . Endoscopic ligation compared with sclerotherapy for the treatment of bleeding esophageal varices. Ann Intern Med. 1993; 119 1-7
- 45 Lo G H, Lai K H, Cheng J S. et al . A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices. Hepatology. 1995; 22 466-471
- 46 Lo G H, Lai K H, Cheng J S. et al . Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices. Hepatology. 1997; 25 1101-1104
- 47 Salem S, Shiha G. A prospective randomized trial of sclerotherapy versus saeed six-shooter multiband ligation in the control of acute bleeding from oesophageal varices [abstract]. Gut. 1999; 44 (Suppl 1) A19
- 48 Sarin S K, Govil A, Jain A K. et al . Prospective randomized trial of endoscopic sclerotherapy versus variceal band ligation for esophageal varices: influence on gastropathy, gastric varices and variceal recurrence. J Hepatol. 1997; 26 826-832
- 49 Shafqat F, Khan A A, Alam A. et al . Band ligation vs endoscopic sclerotherapy in esophageal varices: a prospective randomized comparison. J Pak Med Assoc. 1998; 48 192-196
- 50 Papatheodoridis G V, Goulis J, Leandro G. et al . Transjugular intrahepatic portosystemic shunt compared with endoscopic treatment for prevention of variceal rebleeding: a meta-analysis. Hepatology. 1999; 30 612-622
- 51 Laupacis A, Sackett D L, Roberts R S. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med. 1988; 318 1728-1733
- 52 Leandro G. Meta-analysis in medical research. Oxford; Blackwell Publishing Ltd 2004
- 53 The Copenhagen Esophageal Varices Sclerotherapy Project . Sclerotherapy after first variceal hemorrhage in cirrhosis. A randomized multicenter trial. N Engl J Med. 1984; 311 1594-1600
- 54 El Zayadi A, ElDin S S, Kabil S M. Endoscopic sclerotherapy versus medical treatment for bleeding esophageal varices in patients with schistosomal liver disease. Gastrointest Endosc. 1988; 34 314-317
- 55 Escorsell A, Bordas J M, del Arbol L R. et al . Randomized controlled trial of sclerotherapy versus somatostatin infusion in the prevention of early rebleeding following acute variceal hemorrhage in patients with cirrhosis. Variceal Bleeding Study Group. J Hepatol. 1998; 29 779-788
- 56 Primignani M, Andreoni B, Carpinelli L. et al . Sclerotherapy plus octreotide versus sclerotherapy alone in the prevention of early rebleeding from esophageal varices: a randomized, double-blind, placebo-controlled, multicenter trial. New Italian Endoscopic Club. Hepatology. 1995; 21 1322-1327
- 57 Burroughs A K. International Octreotide Varices Study Group. Double blind RCT of 5 day octreotide versus placebo, associated with sclerotherapy for trial failures [abstract]. Hepatology. 1996; 24 325A
- 58 Moreto M, Zaballa M, Ruiz-Rebollo L. et al . Somatostatin as an adjuvant to emergency sclerotherapy of bleeding esophageal varices [abstract]. Gut. 1994; 35 A178
- 59 Abd-Elrazec W, Omar N, Khalil M. et al . Urgent endoscopy vs. octreotide in the management of acute variceal bleeding in patients with advanced encephalopathy [abstract]. J Hepatol. 2005; 42 (Suppl) 87
- 60 Avgerinos A, Armonis A, Manolakopoulos S. et al . Endoscopic sclerotherapy versus variceal ligation in the long-term management of patients with cirrhosis after variceal bleeding. A prospective randomized study. J Hepatol. 1997; 26 1034-1041
- 61 Baroncini D, Milandri G L, Borioni D. et al . A prospective randomized trial of sclerotherapy versus ligation in the elective treatment of bleeding esophageal varices. Endoscopy. 1997; 29 235-240
- 62 Jensen D M, Kovacs T, Jutabha R. et al . Randomized, blinded prospective study of banding vs. sclerotherapy for preventing recurrent variceal hemorrhage for patients without active bleeding at endoscopy [abstract]. Gastrointest Endosc. 1995; 41 315A
- 63 Masci E, Norberto L, D’Imperio N. et al . Prospective multicentric randomized trial comparing banding ligation with sclerotherapy of esophageal varices. Gastrointest Endosc.. 1997; 45 847A
- 64 Mundo F, Mitrani C, Rodriguez G, Farca A. Endoscopic variceal treatment, is band ligation taking over sclerotherapy? [abstract]. Am J Gastroenterol. 1993; 88 1493A
- 65 Serwah A A, Habba M R, AbdelHamid A S. Endoscopic variceal ligation compared with endoscopic sclerotherapy for bleeding oesophageal varices: a randomised controlled trial [abstract]. J Hepatol. 2004; 40 (Suppl 1) 73
- 66 Villanueva C, Minana J, Ortiz J. et al . Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding. N Engl J Med. 2001; 345 647-655
- 67 De Franchis R. Somatostatin, somatostatin analogues and other vasoactive drugs in the treatment of bleeding oesophageal varices. Dig Liver Dis. 2004; 36 (Suppl 1) S93-S100
- 68 Banares R, Albillos A, Rincon D. et al . Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis. Hepatology. 2002; 35 609-615
- 69 Makuch R W, Pledger G, Hall D B. et al .
Active control equivalence studies. In: Peace K, editor Statistical issues in drug research and development. New York; Marcel Dekker 1990: 225-262 - 70 Jones B, Jarvis P, Lewis J A. et al . Trials to assess equivalence: the importance of rigorous methods. BMJ. 1996; 313 36-39
- 71 Altman D G. Octreotide infusion versus injection sclerotherapy. Lancet. 1993; 342 1486
- 72 Grace N D, Groszmann R J, Garcia-Tsao G. et al . Portal hypertension and variceal bleeding: an AASLD single topic symposium. Hepatology. 1998; 28 868-880
- 73 Chan L Y, Sung J J. Review article: the role of pharmaco-therapy for acute variceal haemorrhage in the era of endoscopic haemostasis. Aliment Pharmacol Ther. 1997; 11 45-50
- 74 Burroughs A K, Patch D. Therapeutic benefit of vaso-active drugs for acute variceal bleeding: a real pharmacological effect, or a side-effect of definitions in trials?. Hepatology. 1996; 24 737-739
- 75 De Franchis R. Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol. 2000; 33 846-852
- 76 Burroughs A K, McCormick P A, Hughes M D. et al . Randomized, double-blind, placebo-controlled trial of somatostatin for variceal bleeding. Emergency control and prevention of early variceal rebleeding. Gastroenterology. 1990; 99 1388-1395
- 77 Burroughs A K. Assessment of value of consensus definitions in acute variceal bleeding. Lancet. 2001; 357 1147-1148
- 78 Shimm D S, Spece R G Jr. Industry reimbursement for entering patients into clinical trials: legal and ethical issues. Ann Intern Med. 1991; 115 148-151
- 79 Sung J J, Chung S C, Yung M Y. et al . Prospective randomised study of effect of octreotide on rebleeding from oesophageal varices after endoscopic ligation. Lancet. 1995; 346 1666-1669
- 80 Laine L. Ligation: endoscopic treatment of choice for patients with bleeding esophageal varices?. Hepatology. 1995; 22 663-665
- 81 Sauerbruch T, Schepke M. Sclerotherapy is out - nearly. Endoscopy. 1997; 29 281-282
A. K. Burroughs
Liver Transplantation and Hepatobiliary Medicine
Royal Free Hospital · Pond Street · London NW3 2QG · UK
Fax: +44-20-747-26226
Email: andrew.burroughs@royalfree.nhs.uk
References
- 1 The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices . Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med. 1988; 319 983-989
- 2 McCormick P A, O’Keefe C. Improving prognosis following a first variceal haemorrhage over four decades. Gut. 2001; 49 682-685
- 3 Soares-Weiser K, Brezis M, Tur-Kaspa R. et al . Antibiotic prophylaxis for cirrhotic patients with gastrointestinal bleeding [review]. Cochrane Database Syst Rev. 2002; 2 CD002907
- 4 Hou M C, Lin H C, Liu T T. et al . Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology. 2004; 39 746-753
- 5 Goulis J, Patch D, Burroughs A K. Bacterial infection in the pathogenesis of variceal bleeding. Lancet. 1999; 353 139-142
- 6 Crafoord C, Frenckner P. New surgical treatment of varicose veins of the oesophagus. Acta Otolaryngol. 1939; 27 422-429
- 7 De Franchis R, Banares R, Silvain C. Emergency endoscopy strategies for improved outcomes. Scand J Gastroenterol (Suppl). 1998; 226 25-36
- 8 Hartigan P M, Gebhard R L, Gregory P B. Sclerotherapy for actively bleeding esophageal varices in male alcoholics with cirrhosis. Veterans Affairs Cooperative Variceal Sclerotherapy Group. Gastrointest Endosc. 1997; 46 1-7
- 9 Stiegmann G V, Goff J S, Michaletz-Onody P A. et al . Endoscopic sclerotherapy as compared with endoscopic ligation for bleeding esophageal varices. N Engl J Med. 1992; 326 1527-1532
- 10 D’Amico G, Pietrosi G, Tarantino I. et al . Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: a Cochrane meta-analysis. Gastroenterology. 2003; 124 1277-1291
- 11 Triantos C, Samonakis D, Patch D. et al . Sclerotherapy versus vasoactive drugs. Are all meta-analyses the same?. Gastroenterology. 2004; 127 358-359
- 12 Alexandrino P, Alves P, Fidalgo M. et al . Is sclerotherapy the first choice treatment for active oesophageal variceal bleeding in cirrhotic patients? Final report of a randomized controlled trial [abstract]. J Hepatol. 1990; 11 S1
- 13 Larson A W, Cohen H, Zweiban B. et al . Acute esophageal variceal sclerotherapy. Results of a prospective randomized controlled trial. JAMA. 1986; 255 497-500
- 14 Novella M, Villanueva C, Ortiz J. et al . Octreotide vs. sclerotherapy and octreotide for acute variceal bleeding. A pilot study [abstract]. Hepatology. 1996; 24 207A
- 15 Soderlund C, Ihre T. Endoscopic sclerotherapy v. conservative management of bleeding oesophageal varices. A 5-year prospective controlled trial of emergency and long-term treatment. Acta Chir Scand. 1985; 151 449-456
- 16 Villanueva C, Ortiz J, Sabat M. et al . Somatostatin alone or combined with emergency sclerotherapy in the treatment of acute esophageal variceal bleeding: a prospective randomized trial. Hepatology. 1999; 30 384-389
- 17 Bildozola M, Kravetz D, Argonz J. et al . Efficacy of octreotide and sclerotherapy in the treatment of acute variceal bleeding in cirrhotic patients. A prospective, multicentric, and randomized clinical trial. Scand J Gastroenterol. 2000; 35 419-425
- 18 Escorsell A, Del Arbol L R, Planas R. et al . Multicenter randomized controlled trial of terlipressin versus sclerotherapy in the treatment of acute variceal bleeding: the TEST study. Hepatology. 2000; 32 471-476
- 19 Freitas D S, Sofia C, Pontes J M. et al . Octreotide in acute bleeding esophageal varices: a prospective randomized study. Hepatogastroenterology. 2000; 47 1310-1314
- 20 Jenkins S A, Shields R, Davies M. et al . A multicentre randomised trial comparing octreotide and injection sclerotherapy in the management and outcome of acute variceal haemorrhage. Gut. 1997; 41 526-533
- 21 Planas R, Quer J C, Boix J. et al . A prospective randomized trial comparing somatostatin and sclerotherapy in the treatment of acute variceal bleeding. Hepatology. 1994; 20 370-375
- 22 Ramires R P, Zils C K, Mattos A A. Sclerotherapy versus somatostatin in the treatment of upper digestive hemorrhage caused by rupture of esophageal varices. Arq Gastroenterol. 2000; 37 148-154
- 23 Shields R, Jenkins S A, Baxter J N. et al . A prospective randomised controlled trial comparing the efficacy of somatostatin with injection sclerotherapy in the control of bleeding oesophageal varices. J Hepatol. 1992; 16 128-137
- 24 Sivri B, Oksuzoglu G, Bayraktar Y. et al . A prospective randomized trial from Turkey comparing octreotide versus injection sclerotherapy in acute variceal bleeding. Hepatogastroenterology. 2000; 47 168-173
- 25 Sung J J, Chung S C, Lai C W. et al . Octreotide infusion or emergency sclerotherapy for variceal haemorrhage. Lancet. 1993; 342 637-641
- 26 Westaby D, Hayes P C, Gimson A E. et al . Controlled clinical trial of injection sclerotherapy for active variceal bleeding. Hepatology. 1989; 9 274-277
- 27 Yousuf M, Rauf A, Baig I. et al . Initial management of acute variceal haemorrhage. Comparison of octreotide and sclerotherapy. J Coll Phys Surg Pak. 2000; 10 95-97
- 28 Di Fedo G, Siringo S, Vacirca M. et al . Somatostatin (SMS) and urgent sclerotherapy (US) in active oesophageal variceal bleeding [abstract]. Gastroenterology. 1990; 98 583A
- 29 El-Jackie A, Rowaisha I, Waked I. et al . Octreotide vs. sclerotherapy in the control of acute variceal bleeding in schistosomal portal hypertension: a randomized trial [abstract]. Hepatology. 1998; 28 553
- 30 Lopez F, Vargas R, Margarita G. et al . Octreotide vs sclerotherapy in the treatment of acute variceal bleeding [abstract]. Hepatology. 1999; 30 574A
- 31 Poo J, Bosques S, Guarduno R. et al . Octreotide versus emergency sclerotherapy in acute variceal hemorrhage in liver cirrhosis. A randomized multicenter study [abstract]. Gastroenterology. 1996; 110 A1297
- 32 Avgerinos A, Nevens F, Raptis S. et al . Early administration of somatostatin and efficacy of sclerotherapy in acute oesophageal variceal bleeds: the European Acute Bleeding Oesophageal Variceal Episodes (ABOVE) randomised trial. Lancet. 1997; 350 1495-1499
- 33 Besson I, Ingrand P, Person B. et al . Sclerotherapy with or without octreotide for acute variceal bleeding. N Engl J Med. 1995; 333 555-560
- 34 Cales P, Masliah C, Bernard B. et al . Early administration of vapreotide for variceal bleeding in patients with cirrhosis. French Club for the Study of Portal Hypertension. N Engl J Med. 2001; 344 23-28
- 35 Farooqi J, Farooqi R, Haq N. et al . Treatment and outcome of variceal bleeding - A comparison of two methods. JCPSP. 2000; 10 131-133
- 36 Zuberi B F, Baloch Q. Comparison of endoscopic variceal sclerotherapy alone and in combination with octreotide in controlling acute variceal hemorrhage and early rebleeding in patients with low-risk cirrhosis. Am J Gastroenterol. 2000; 95 768-771
- 37 Signorelli S, Negrini F, Paris B. et al . Sclerotherapy with or without somatostatin or octreotide in the treatment of acute variceal haemorrhage: our experience. Gastroenterology. 1996; 110 1326A
- 38 Signorelli S, Paris B, Negrini F. et al . Octreotide and endoscopic variceal sclerotherapy in the management of acute variceal haemorrhage [abstract]. Endoscopy. 1999; 31 E66
- 39 Fakhry S, Omar M, Mustafa A. et al . Endoscopic sclerotherapy versus endoscopic variceal ligation in the management of bleeding esophageal varices: a final report of a prospective randomized study in schistosomal hepatic fibrosis [abstract]. Hepatology. 1997; 26 137A
- 40 Gimson A E, Ramage J K, Panos M Z. et al . Randomised trial of variceal banding ligation versus injection sclerotherapy for bleeding oesophageal varices. Lancet. 1993; 342 391-394
- 41 Hou M C, Lin H C, Kuo B I. et al . Comparison of endoscopic variceal injection sclerotherapy and ligation for the treatment of esophageal variceal hemorrhage: a prospective randomized trial. Hepatology. 1995; 21 1517-1522
- 42 Jain A K, Ray R P, Gupta J. Management of acute variceal bleed: randomized trial of variceal ligation and sclerotherapy [abstract]. Hepatology. 1996; 23 I-51
- 43 Jensen D, Kovacs T, Jutabha R. et al . Randomized, blinded prospective study of banding vs. sclerotherapy for preventing recurrent variceal hemorrhage for patients without active bleeding at endoscopy [abstract]. Gastrointest Endosc. 1993; 41 315A
- 44 Laine L, el Newihi H M, Migikovsky B. et al . Endoscopic ligation compared with sclerotherapy for the treatment of bleeding esophageal varices. Ann Intern Med. 1993; 119 1-7
- 45 Lo G H, Lai K H, Cheng J S. et al . A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices. Hepatology. 1995; 22 466-471
- 46 Lo G H, Lai K H, Cheng J S. et al . Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices. Hepatology. 1997; 25 1101-1104
- 47 Salem S, Shiha G. A prospective randomized trial of sclerotherapy versus saeed six-shooter multiband ligation in the control of acute bleeding from oesophageal varices [abstract]. Gut. 1999; 44 (Suppl 1) A19
- 48 Sarin S K, Govil A, Jain A K. et al . Prospective randomized trial of endoscopic sclerotherapy versus variceal band ligation for esophageal varices: influence on gastropathy, gastric varices and variceal recurrence. J Hepatol. 1997; 26 826-832
- 49 Shafqat F, Khan A A, Alam A. et al . Band ligation vs endoscopic sclerotherapy in esophageal varices: a prospective randomized comparison. J Pak Med Assoc. 1998; 48 192-196
- 50 Papatheodoridis G V, Goulis J, Leandro G. et al . Transjugular intrahepatic portosystemic shunt compared with endoscopic treatment for prevention of variceal rebleeding: a meta-analysis. Hepatology. 1999; 30 612-622
- 51 Laupacis A, Sackett D L, Roberts R S. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med. 1988; 318 1728-1733
- 52 Leandro G. Meta-analysis in medical research. Oxford; Blackwell Publishing Ltd 2004
- 53 The Copenhagen Esophageal Varices Sclerotherapy Project . Sclerotherapy after first variceal hemorrhage in cirrhosis. A randomized multicenter trial. N Engl J Med. 1984; 311 1594-1600
- 54 El Zayadi A, ElDin S S, Kabil S M. Endoscopic sclerotherapy versus medical treatment for bleeding esophageal varices in patients with schistosomal liver disease. Gastrointest Endosc. 1988; 34 314-317
- 55 Escorsell A, Bordas J M, del Arbol L R. et al . Randomized controlled trial of sclerotherapy versus somatostatin infusion in the prevention of early rebleeding following acute variceal hemorrhage in patients with cirrhosis. Variceal Bleeding Study Group. J Hepatol. 1998; 29 779-788
- 56 Primignani M, Andreoni B, Carpinelli L. et al . Sclerotherapy plus octreotide versus sclerotherapy alone in the prevention of early rebleeding from esophageal varices: a randomized, double-blind, placebo-controlled, multicenter trial. New Italian Endoscopic Club. Hepatology. 1995; 21 1322-1327
- 57 Burroughs A K. International Octreotide Varices Study Group. Double blind RCT of 5 day octreotide versus placebo, associated with sclerotherapy for trial failures [abstract]. Hepatology. 1996; 24 325A
- 58 Moreto M, Zaballa M, Ruiz-Rebollo L. et al . Somatostatin as an adjuvant to emergency sclerotherapy of bleeding esophageal varices [abstract]. Gut. 1994; 35 A178
- 59 Abd-Elrazec W, Omar N, Khalil M. et al . Urgent endoscopy vs. octreotide in the management of acute variceal bleeding in patients with advanced encephalopathy [abstract]. J Hepatol. 2005; 42 (Suppl) 87
- 60 Avgerinos A, Armonis A, Manolakopoulos S. et al . Endoscopic sclerotherapy versus variceal ligation in the long-term management of patients with cirrhosis after variceal bleeding. A prospective randomized study. J Hepatol. 1997; 26 1034-1041
- 61 Baroncini D, Milandri G L, Borioni D. et al . A prospective randomized trial of sclerotherapy versus ligation in the elective treatment of bleeding esophageal varices. Endoscopy. 1997; 29 235-240
- 62 Jensen D M, Kovacs T, Jutabha R. et al . Randomized, blinded prospective study of banding vs. sclerotherapy for preventing recurrent variceal hemorrhage for patients without active bleeding at endoscopy [abstract]. Gastrointest Endosc. 1995; 41 315A
- 63 Masci E, Norberto L, D’Imperio N. et al . Prospective multicentric randomized trial comparing banding ligation with sclerotherapy of esophageal varices. Gastrointest Endosc.. 1997; 45 847A
- 64 Mundo F, Mitrani C, Rodriguez G, Farca A. Endoscopic variceal treatment, is band ligation taking over sclerotherapy? [abstract]. Am J Gastroenterol. 1993; 88 1493A
- 65 Serwah A A, Habba M R, AbdelHamid A S. Endoscopic variceal ligation compared with endoscopic sclerotherapy for bleeding oesophageal varices: a randomised controlled trial [abstract]. J Hepatol. 2004; 40 (Suppl 1) 73
- 66 Villanueva C, Minana J, Ortiz J. et al . Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding. N Engl J Med. 2001; 345 647-655
- 67 De Franchis R. Somatostatin, somatostatin analogues and other vasoactive drugs in the treatment of bleeding oesophageal varices. Dig Liver Dis. 2004; 36 (Suppl 1) S93-S100
- 68 Banares R, Albillos A, Rincon D. et al . Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis. Hepatology. 2002; 35 609-615
- 69 Makuch R W, Pledger G, Hall D B. et al .
Active control equivalence studies. In: Peace K, editor Statistical issues in drug research and development. New York; Marcel Dekker 1990: 225-262 - 70 Jones B, Jarvis P, Lewis J A. et al . Trials to assess equivalence: the importance of rigorous methods. BMJ. 1996; 313 36-39
- 71 Altman D G. Octreotide infusion versus injection sclerotherapy. Lancet. 1993; 342 1486
- 72 Grace N D, Groszmann R J, Garcia-Tsao G. et al . Portal hypertension and variceal bleeding: an AASLD single topic symposium. Hepatology. 1998; 28 868-880
- 73 Chan L Y, Sung J J. Review article: the role of pharmaco-therapy for acute variceal haemorrhage in the era of endoscopic haemostasis. Aliment Pharmacol Ther. 1997; 11 45-50
- 74 Burroughs A K, Patch D. Therapeutic benefit of vaso-active drugs for acute variceal bleeding: a real pharmacological effect, or a side-effect of definitions in trials?. Hepatology. 1996; 24 737-739
- 75 De Franchis R. Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol. 2000; 33 846-852
- 76 Burroughs A K, McCormick P A, Hughes M D. et al . Randomized, double-blind, placebo-controlled trial of somatostatin for variceal bleeding. Emergency control and prevention of early variceal rebleeding. Gastroenterology. 1990; 99 1388-1395
- 77 Burroughs A K. Assessment of value of consensus definitions in acute variceal bleeding. Lancet. 2001; 357 1147-1148
- 78 Shimm D S, Spece R G Jr. Industry reimbursement for entering patients into clinical trials: legal and ethical issues. Ann Intern Med. 1991; 115 148-151
- 79 Sung J J, Chung S C, Yung M Y. et al . Prospective randomised study of effect of octreotide on rebleeding from oesophageal varices after endoscopic ligation. Lancet. 1995; 346 1666-1669
- 80 Laine L. Ligation: endoscopic treatment of choice for patients with bleeding esophageal varices?. Hepatology. 1995; 22 663-665
- 81 Sauerbruch T, Schepke M. Sclerotherapy is out - nearly. Endoscopy. 1997; 29 281-282
A. K. Burroughs
Liver Transplantation and Hepatobiliary Medicine
Royal Free Hospital · Pond Street · London NW3 2QG · UK
Fax: +44-20-747-26226
Email: andrew.burroughs@royalfree.nhs.uk
Figure 1 Forrest plot of risk difference for control of bleeding in group A trials of sclerotherapy combined with vasoactive agents/balloon tamponade vs. vasoactive agents/balloon tamponade (D, drugs). The risk differences were calculated as follows. Taking the trial by Soderlund et al. as an example: there was failure to control bleeding in 8 out of 50 patients treated with drugs (16 %), and in 3 out of 57 patients treated with sclerotherapy + drugs (5 %), giving a risk difference of 11 %.
Figure 2 Forrest plot of risk difference for mortality in group A trials of sclerotherapy combined with vasoactive agents/balloon tamponade vs. vasoactive agents/balloon tamponade (D, drugs).
Figure 3 Forrest plot of risk difference for control of bleeding in group B trials of sclerotherapy vs. vasoactive agents.
Figure 4 Forrest plot of risk difference for mortality in group B trials of sclerotherapy vs. vasoactive agents.
Figure 5 Forrest plot of risk difference for control of bleeding in group C trials of sclerotherapy (S) vs. sclerotherapy combined with vasoactive agents (S+D).
Figure 6 Forrest plot of risk difference for mortality in group C trials of sclerotherapy (S) vs. sclerotherapy combined with vasoactive agents (S+D).
Figure 7 Forrest plot of risk difference for control of bleeding in group D trials of sclerotherapy vs. variceal ligation.
Figure 8 Forrest plot of risk difference for mortality in group D trials of sclerotherapy vs. variceal ligation.
Figure 9 Control of variceal bleeding. The efficacy of emergency sclerotherapy alone, in groups of randomized trials, compared with other treatments (pts, patients). Group A: sclerotherapy combined with vasoactive agents/balloon tamponade vs. solely vasoactive agents/balloon tamponade. Group B: sclerotherapy vs. vasoactive agents. Group C: sclerotherapy alone vs. sclerotherapy combined with vasoactive agents. Group D: sclerotherapy vs. variceal ligation.
Figure 10 Control of variceal bleeding. The efficacy of emergency sclerotherapy alone in groups of randomized trials compared with other treatments, with respect to the interval over which efficacy was evaluated (the number of trials is reported in each column). Group A: sclerotherapy combined with vasoactive agents/balloon tamponade vs. solely vasoactive agents/balloon tamponade. Group B: sclerotherapy vs. vasoactive agents. Group C: sclerotherapy alone vs. sclerotherapy combined with vasoactive agents. Group D: sclerotherapy vs. variceal ligation.
Figure 11 The efficacy of emergency sclerotherapy alone in randomized trials compared with vasoactive drugs alone or a combination of sclerotherapy and vasoactive drugs, with respect to the year of publication of the trial (1989 - 2001):