Endoscopic sclerotherapy compared with no specific treatment for the primary prevention of bleeding from esophageal varices. A randomized controlled multicentre trial [ISRCTN03215899]

About one-third of patients with liver cirrhosis and varices are likely to undergo hemorrhage during their lifetime [1‐5]. The average mortality due to the first variceal bleeding has been estimated to be about 30–50% [1, 6, 7]. Variceal bleeding therefore represents a frequent cause of death and one might expect survival to improve if bleeding could be prevented.

The potential of primary prevention of variceal bleeding to improve prognosis is dependent on the severity of the underlying disease. There is a close relationship between (risk of) bleeding and degree of liver failure. Often bleeding precipitates or exacerbates liver failure, while deteriorating liver function frequently precedes variceal bleeding. Obviously, prevention of bleeding in end-stage disease is unlikely to affect prognosis. For patients with a relatively preserved liver function, however, prevention of bleeding might improve prognosis, by reducing mortality due to exsanguination as well as from the complications frequently encountered after variceal bleeding, including hepatorenal syndrome, infections and multi-organ failure.

The first type of primary prophylaxis evaluated was the portacaval shunt [3‐5]. Although shunt surgery reduced the frequency of bleeding, the rate of both mortality and encephalopathy was increased. Data on other prophylactic surgical procedures are limited and do not allow conclusions [8].

The first reports on the use of prophylactic sclerotherapy suggested that this procedure not only significantly reduced the incidence of variceal bleeding [9‐12] but also lowered overall mortality [10, 12]. However, the results of these trials were disputed, mainly because the reported bleeding risk for control patients in some studies was considered exceptionally high and treatment of acute variceal bleeding episodes was not the same for the two treatment groups [1, 13].

The aim of the present multicentre study was to evaluate the effect of endoscopic sclerotherapy for the primary prevention of variceal bleeding in an adequate number of patients with cirrhosis and esophageal varices, with uniform treatment of variceal bleeding in both groups.

Of the 166 patients enrolled in the study 84 were randomized to undergo ES and 82 to the control group (Figure 1). Patient characteristics of the two groups were comparable (table 1). Mean follow-up was 32 ± SD 25 (range 0.1 – 88.5) months; for the ES group 30 ± 23 months and for controls 34 ± 27 months. Follow-up was incomplete for 11 (ES group 7) patients due to removal, emigration or other reasons. For these cases data were censored at the time of the last visit. In all cases, however, efforts were undertaken to determine whether the patients were alive at the time of analysis and this information, including causes of death, was used for analysis.

In this randomized trial primary prevention of variceal bleeding using endoscopic sclerotherapy did not reduce the bleeding risk for patients with liver cirrhosis and esophageal varices. We found that prophylactic sclerotherapy lowered the risk of fatal variceal bleeding without affecting overall survival. Finally, complications and costs were more marked among patients receiving endoscopic prophylaxis.

Several factors could possibly explain why sclerotherapy was not found to reduce the risk of variceal bleeding in the current trial. We may have failed to detect a real treatment effect, a type II statistical error. Although the sample size of this study seemed adequate, a type II error remains a realistic possibility, in particular because nearly 20% (16/84) of patients did not undergo the assigned sclerotherapy treatment. Since the bleeding risk for this particular subgroup was high, this may have diluted the beneficial effects of endoscopic prophylaxis. Although per protocol analysis showed a trend in favor of this possibility, it was not significant. Another factor that could have obscured benefits of ES is an unexpected low bleeding rate for the control group. However, we found that the 3-year bleeding risk for control patients was very similar to the predicted 30%, and consequently that this factor does not seem of importance. Although this was a randomized trial, one can never guarantee similarity between groups as far as prognostic variables are concerned. Moreover, differences between groups in baseline bleeding risk could be a source of bias. The distribution of variables of prognostic significance in the two groups, particularly Child-Pugh scores, age and variceal size, however, make it unlikely that such a bias was important. Sclerotherapy could increase the initial risk of (variceal) bleeding but have a protective effect over time, eventually translating into an overall treatment benefit. We found some evidence to support this possibility since the majority of variceal bleeding episodes were observed before achieving variceal eradication, and bleeding after eradication was a rare event. It has been noted previously that the bleeding risk for patients recruited for trials of prophylactic therapy seems highest during the first months of follow-up and decreases to about 1/3 after one year [1, 3]. This may suggest that, in retrospect, our sclerotherapy protocol was not optimal and a more intensive regimen, resulting in more rapid eradication of varices [20], could have been more effective.

In this trial ES significantly reduced the mortality rate for variceal bleeding, a finding also reported by other groups [10, 20‐24]. In only a few studies, however, was this associated with a corresponding improvement in overall survival [10, 20, 21, 24]. In these studies variceal bleeding occurred in at least 50% of control patients and was the main cause of death, accounting for 65–80% of mortality. This suggests that the magnitude of the effect of prophylactic sclerotherapy on the risk for variceal bleeding, but also on mortality, is dependent on the baseline bleeding risk. This hypothesis was supported by D'Amico, who found a clear relationship between the effect of sclerotherapy on the incidence of bleeding and the base line bleeding risk as reported in a large number of randomized controlled trials [25]. We also analyzed the relationship between baseline risk and treatment effect using the method proposed by Arends et al. [19]. We found, in agreement with D'Amico's results, that a significant (p < 0.001) relationship exists between the baseline bleeding risk and the effect of treatment when analyzing the results of trials of prophylactic sclerotherapy (Figure 4 and 5), which cannot be attributed to 'regression to the mean'. Thus, endoscopic sclerotherapy is likely to reduce bleeding risk, and probably also mortality, only for patients with a particularly high risk of bleeding. Identification of such patients is possible using the NIEC, or comparable, indices [26, 27]. For patients with a low bleeding risk, the effect of sclerotherapy will be marginal or absent; sclerotherapy might even have a deleterious effect. The numerous trials on prophylactic sclerotherapy have been subjected to meta-analysis [28‐31]. All studies have produced a statistically significant pooled estimate of treatment effect on bleeding risk and mortality in favor of sclerotherapy. Like the results of the individual studies, the conclusions based upon these analyses have been diverse, varying from an undetermined effect of sclerotherapy [29, 30] to sclerotherapy being effective, particularly for high-risk patients [28, 31]. One meta-analysis [31] yielded a marked difference in the outcome of trials according to the type of sclerosant used, the results clearly favoring polidocanol. The general recommendation emerging from international consensus conferences [18, 32, 33] has been that sclerotherapy should not be used for primary prophylaxis of variceal bleeding, mainly because of the statistically significant heterogeneity of the treatment effects as observed in studies, and the availability of a non-invasive and cheap alternative (non selective β-blocker treatment).

When the trial was designed the possibility existed that, as a result of the pre-randomization method, not all patients would accept the assigned treatment. In practice, refusal proved to be a more frequent problem than expected, which complicated the interpretation of results. However, this problem is not unique to the pre-randomization method and similar difficulties can occur with conventional randomization [3, 5, 34‐36]. Otherwise, no problems were encountered and our general experience was that the method worked well. Unfortunately, our study design did not allow us to assess whether pre-randomization indeed resulted in increased patient recruitment. Pre-randomization has the potential advantage that, at least in theory, all eligible patients will be selected while the conventional method implies that only a selection of eligible patients will be entered. Consequently, the results of trials using this allocation method may have wider applicability.

The observed rate of complications of sclerotherapy in this study is in agreement with previously reported data. In some studies, however, complications were much more frequent [37, 38]. An explanation for these divergent results remains speculative. Variations in technique [31], technical skill and experience with endoscopic sclerotherapy could at least partially account for some of the reported differences.

Our estimation of costs was based on a proportion of patients and the results obviously are preliminary in nature. Nevertheless, our data suggest that prophylactic treatment was the more expensive option. Taking into account the other findings, the cost/benefit ratio of prophylactic sclerotherapy as applied in this study seems unfavorable.

The present results does not support the use of sclerotherapy for primary prevention of variceal bleeding when patients are selected according to the criteria we used. Nevertheless, according to cumulative data from a large number of trials, it can be concluded that endoscopic sclerotherapy can result in a significant decrease in the bleeding risk and, probably, also in bleeding-associated mortality, but only in selected cases with a high bleeding risk. On the basis of lower rates of rebleeding, mortality, complications and the need for fewer endoscopic treatments, variceal band ligation has been shown to be superior to sclerotherapy for secondary prophylaxis of variceal bleeding [39]. Several trials have now evaluated band ligation for primary prophylaxis of variceal bleeding. In most, but not all [40], studies band ligation significantly reduced the bleeding risk when compared to control patients [40‐42] or administration of propranolol [43], and in one study ligation was also found to improve survival [42]. Additional studies comparing band ligation and non-selective β-blockers are needed before the role of ligation for primary prevention of variceal bleeding can be defined more precisely. For the time being, β-blockers remain the principal option for primary prophylaxis of variceal bleeding. For patients with contraindications or intolerance for β-blockers and for those who are not compliant or do not respond to treatment, variceal band ligation rather than sclerotherapy may be considered for primary prophylaxis [44].