Endoscopy critics vs. Endoscopy enthusiasts for primary prophylaxis of variceal bleeding
Authors: Roberto de Franchis
Journal: Hepatology (2005)

The risk of variceal hemorrhage in untreated patients with cirrhosis and varices ranges between 8% and 35% at 2 years from diagnosis,1, 2 and despite recent progress, variceal bleeding still carries a mortality around 20%3-5 at 6 weeks. For these reasons, several treatments aimed at preventing the first variceal hemorrhage have been tested. Among these, surgical portacaval shunts and endoscopic sclerotherapy have been abandoned, while nonselective beta-blockers have become the mainstay of prophylaxis.6, 7 Unfortunately, effective protection from bleeding can only be achieved in a fraction of patients treated with beta-blockers.8 In addition, beta-blockers cause side effects in 16% to 20% of cases, which lead to discontinuation of treatment in 6% to 12% of patients.9-11 This fact has stimulated the search for alternative treatments: trials comparing prophylactic band ligation with no treatment have shown that ligation decreases the relative risk of first bleeding by 64% and mortality by 45%.12 Between 1998 and 2005, prophylactic band ligation has been compared with beta-blockers in thirteen trials,13-25 of which seven are published in full.14, 15, 19, 21-24 Close scrutiny of these studies reveals that while there was a relative homogeneity concerning the size of varices and the doses of beta-blockers, they differed markedly in other parameters such as sample size, proportion of patients with severe liver dysfunction and length of follow-up, which was less than 2 years in all studies but two.22, 24 In addition, they were all underpowered. Ten trials13, 15-19, 21, 22, 24, 25 showed no difference between treatments in prevention of first variceal bleeding, whereas in three14, 20, 23 band ligation was significantly better than beta-blockers. A modest difference in mortality in favor of band ligation was observed in one trial.23 Meta-analysis of these trials shows that there is no statistical heterogeneity in treatment effects26 and that band ligation reduces the incidence of first bleeding from 18 % to 12%, with a relative risk reduction (RRR) of 34% and an absolute risk reduction (ARR) of 6% (95% CI −11% to −1%; NNT = 17), whereas there is no difference in mortality (ARR −1.15%; 95% CI −7% to + 5%). These results do not change when only the fully published trials or only high-quality trials are analyzed.26 In making an overall judgment of utility of treatments with similar efficacy, other important issues such as adverse events, quality of life, and cost must be considered. In the seven fully published trials, adverse events of band ligation and beta-blocker treatment occurred in about 26% and 40% of cases, respectively. Severe adverse events related to band ligation occurred in nine patients (3.3%) with two fatal outcomes from ligation-induced esophageal ulcer bleeds. Severe adverse events of beta-blockers requiring discontinuation of treatment occurred in 36 patients (12.1%). Meta-analysis shows a barely significant difference in favor of band ligation (ARR −7.6%; 95% CI −14.9% to −0.3%). It may be argued that the occurrence of two fatal ligation-induced bleeds tilts the scale in favor of beta-blockers; however, 9 of 36 (25%) patients in whom beta-blockers were discontinued bled, with two fatal outcomes. In addition, the mortality rates in bleeders were similar (band ligation 14/35 = 40%; beta-blockers 21/56 = 37.5%, P = .812). Quality of life is important as it may influence compliance, which is crucial for both treatments. In fact, band ligation requires life-long endoscopic follow up to detect and treat variceal recurrence, whereas beta-blocker treatment must be continued indefinitely, as patients discontinuing treatment are no longer protected from bleeding.27 No formal evaluation of quality of life has been made in any of the trials. Patients' preference, which may be considered a surrogate to quality of life, was estimated in only one trial22; this trial showed a nonsignificant trend in favor of band ligation. As a consequence, this important issue remains unsettled. Cost is another important variable to consider: only one trial23 included a direct cost analysis, showing no significant difference between treatments. Among cost-effectiveness analyses for primary prophylaxis of bleeding based on the Markov model, only one28 focused on the setting of these trials (i.e., screening endoscopy followed by beta-blockers or band ligation for patients with high-risk varices) and showed a slight difference in the incremental cost-effectiveness ratio in favor of beta-blockers. These data are clearly insufficient to make a final judgment. In summary, band ligation is slightly better than beta-blockers for prevention of a first variceal bleed. However, mortality and severe adverse event rates are similar, while differences in quality of life and cost between the two treatments are poorly defined. For these reasons, at a recent consensus workshop on portal hypertension,29 these results were interpreted with caution, and the conclusion was that in patients with medium and large esophageal varices, band ligation is more effective than nonselective beta-blockers in preventing first variceal bleeding but does not improve survival. However, the long-term benefits of banding are uncertain because of the short duration of follow-up. The opinion of the experts, therefore, was that ligation should be primarily offered to patients with medium/large varices and contraindications or intolerance to beta-blockers. In this issue of HEPATOLOGY, two letters30, 31 challenge these conclusions from opposite points of view. These letters nicely highlight the dichotomy existing between endoscopy critics and endoscopy enthusiasts concerning primary prophylaxis of variceal bleeding. The argument of Triantos et al.30 is that band ligation might even be unsuitable to treat patients with large varices and intolerance or contraindications to beta-blockers. Their contention is largely based on the results of a study they recently published,32 in which patients with varices of any size and contraindications or intolerance to beta-blockers were randomized to band ligation or no treatment. The study was terminated after 52 of the planned 214 patients had been enrolled, due to excess bleeding in the ligation group. Unfortunately, the argument of Triantos et al. is seriously weakened by flaws in the design and conduct of their study: first, about 60% of the patients had small varices. By general consensus,7, 29 these patients, whose risk of bleeding is very low,2 should not receive prophylactic treatments, especially band ligation. Second, the study was stopped after 5 years, when less than one fourth of the planned patients had been enrolled, corresponding to roughly half the 100 patients needed to carry out the planned interim analysis. Nevertheless, an unplanned interim analysis was done, which showed no difference in bleeding rates (P = .18) nor in mortality rates (P = .49) between the treatment groups. It is generally accepted that, when an interim analysis is done, its results should lead to stopping the trial only when a difference in mortality or a strong (P < .01) difference in the primary outcome are observed. This was not the case in the Triantos et al. study, and yet the trial was stopped: as a consequence, an important opportunity of ascertaining whether band ligation is useful for patients with medium/large varices and intolerance or contraindications to beta-blockers was sadly missed. Therefore, we still need more trials evaluating the suitability of band ligation for these patients. Jensen's letter31 takes a completely opposite view, i.e., that band ligation is easier to apply, better tolerated, and potentially more effective than beta-blockers. His conclusions are based on the results of a trial recently published by his group (Jutabha et al.23), in which patients with medium/large varices were randomized to receive band ligation or beta-blockers. As the Triantos et al. study,32 the trial by Jutabha et al.23 was interrupted after 62 of the planned 104 patients had been enrolled, after an interim analysis showed that the occurrence of treatment failures was significantly higher (P = .0098) in the propranolol group. However, this result was mostly due to the fact that no bleeding occurred in patients receiving band ligation: if a single bleeding episode had occurred in the ligation group, statistical significance would have been lost. Jutabha's results are in contrast with what should have been expected based on the results of other similar studies, in which the bleeding rates ranged between 7% and 25%, with an average of 12%. Given the small size of the study, the authors should have continued the trial, considering that the 0% bleeding rate they observed was possibly a chance occurrence. This fact is nicely outlined in a recent meta-analysis33 showing that trials stopped early for benefit tend to show implausibly large treatment effects, especially when the number of events is small. In his letter,31 Jensen gives a series of reasons to explain the exceedingly good results of band ligation in the study. However, even if Jensen's explanations are taken for granted, they only mean that when band ligation is performed by highly motivated, highly trained experts, it can perform exceedingly well. However, when making recommendations for clinical practice, one should keep in mind that the effectiveness of a therapy (i.e., the results of the therapy when it is applied "in the field" by the average doctor) is generally lower than efficacy (i.e., the results of the same therapy under the best possible conditions, such as in a trial carried out by experts34). Therefore, Jutabha's results cannot be taken as a paradigm of prophylactic band ligation. What can be concluded from these trials? They were both terminated prematurely for opposite reasons, because the Authors jumped to conclusions that are not supported by their data. These trials outline the risks we run when a study cannot be done in a double blind fashion. In such a situation, the presence of an independent data monitoring committee is essential to avoid making decisions based on "gut feelings" or the personal biases of the investigators. Had such a committee been in operation in the two trials by Triantos and Jutabha, neither study would have been stopped prematurely. As a consequence, for the time being, the conclusions of the recent Baveno consensus workshop29 should apply, i.e., that nonselective beta-blockers are effective in preventing first bleeding and should be used as first-line treatment for their ease of use. Band ligation is also a good treatment option, and, owing to the lack of alternatives for patients with contraindications or intolerance to beta-blockers, it should be primarily used to treat this patient population.