Deflating balloon tamponade: Should we expand the use of stents for severe refractory esophageal variceal bleeding?
Authors: Loren Laine
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. See Article on Page 1957 Abbreviation EVB esophageal variceal bleeding Acute esophageal variceal bleeding (EVB) remains among the most serious emergencies managed by gastroenterologists and hepatologists. Most patients do well during the acute episode with current endoscopic and pharmacologic therapy. In this issue of hepatology, Escorsell and colleagues report a randomized trial comparing a very old and a very new intervention for the challenging minority of patients with refractory acute EVB.1 Acute EVB Current guidelines recommend endoscopic ligation and vasoactive medication for treatment of acute EVB, with consideration of transjugular intrahepatic portosystemic shunt in high‐risk patients.2 Randomized trials indicate that 2%‐13% of patients with acute EVB treated as recommended have persistent or recurrent bleeding over 5 days or during hospitalization.3 Consensus guidelines recommend transjugular intrahepatic portosystemic shunt for patients who have persistent bleeding despite initial endoscopic and medical therapy, while a second endoscopic treatment may be tried if bleeding recurs after initial hemostasis.2 Balloon tamponade is currently recommended only for refractory EVB as a temporary bridge to definitive therapy.2 However, randomized trials have not focused solely on patients with persistent active bleeding despite endoscopic and medical intervention, the high‐risk group in whom balloon tamponade may be considered. Balloon Tamponade Balloon tamponade is among the oldest therapies used for variceal bleeding. Case series suggest initial bleeding control in ∼90% of patients.5 Major complications, including esophageal rupture, airway obstruction, and aspiration pneumonia, occur in ∼12% of patients and may be lethal.5 Deaths attributed to use of balloon tamponade occurred in ∼6% of patients in these series.5 Randomized trials comparing tamponade to medical therapy with vasopressin, somatostatin, or terlipressin reveal no significant difference in initial control of bleeding or mortality. Randomized trials comparing tamponade to sclerotherapy for EVB show trends or significant benefit for sclerotherapy in initial hemostasis, and all indicate better sustained or definitive hemostasis with sclerotherapy.6 Thus, tamponade for acute EVB is not better than medical therapy, is less effective than endoscopic therapy, and not uncommonly causes serious and sometimes fatal complications. My view has been that the use of tamponade should be exceedingly rare: e.g., patients with persistent massive known EVB awaiting endoscopy or awaiting transjugular intrahepatic portosystemic shunt after unsuccessful endoscopic intervention. Self‐Expanding Metal Stents The removable covered self‐expanding metal stent used by Escorsell et al. was designed specifically to treat EVB and has been assessed previously only in case series.1 It can be placed without endoscopic or fluoroscopic guidance and is removed within ∼7‐14 days of placement. In the largest series, all 34 patients whose "bleeding could not be stopped using standard therapy" had successful placement with no rebleeding and one minor complication (an esophageal ulcer).9 Stent migration requiring endoscopic repositioning occurred in seven patients. Because observational studies are well known to overestimate the efficacy of interventions, a randomized trial is extremely important to define the utility of this device. Assessment of Study Methodology and Analyses Readers must carefully assess the methods and analyses of studies to develop their own conclusions rather than merely accepting the authors' conclusions. Two of this study's methodologic limitations bear special attention. Interim Analysis Interim analyses, in which a formal analysis is performed partway through a study, may be predefined for various reasons: e.g., to ensure the safety of participants; because assumptions about outcomes used in sample size determination are uncertain. If results at interim analysis are much different from the baseline assumptions for the study, in some cases modifications in the study may be made (adaptive design) or the study may be stopped for futility (no possibility the study can document a benefit) or efficacy (benefit in a clinically important primary outcome is dramatically better than expected). Formal stopping rules for efficacy generally require a very small P value for two reasons. First, a P < 0.05 is sometimes reached early in a study but no significance or even significance in the opposite direction is found at study completion. To better ensure a correct conclusion, a study should not be stopped unless very strong evidence of a difference is seen. Second, each time an analysis is performed some of the overall study P value of 0.05 is "used" (alpha spending). The larger the P value defined as the threshold for stopping a study at an interim analysis, the smaller (further below 0.05) the P value used to define significance at the end‐of‐study analysis. Examples of interim and end‐of‐study analysis P value thresholds might be 0.005 and 0.0048 for a more rigorous stopping rule and 0.012 and 0.044 for a less rigorous stopping rule.10 Escorsell et al. planned an interim analysis after 28 patients with a stopping rule for efficacy of P < 0.020.1 Their interim analysis after reaching 28 patients did not achieve P < 0.020. However, they stopped the study prematurely anyway—apparently because recruitment was slower than anticipated and funding ran out. Comparison of Proportions Statistical comparison of two proportions, using chi‐squared or Fisher's exact test, are among the most common analyses performed in randomized trials. Fisher's exact test is recommended with small sample sizes, as in the current study, because the chi‐squared test is less accurate in such cases. Escorsell et al. appropriately indicate that they used Fisher's exact test.1 However, calculation of their primary outcome measure with a Fisher's exact test reveals a P = 0.051, a chi‐squared with Yates correction P = 0.063, and a chi‐squared without correction P = 0.025 (the P value they report). Furthermore, the difference in their primary endpoint was not significant when using time‐to‐event analysis (log rank P = 0.056). Finally, when analyses are done of their secondary endpoints using Fisher's exact test, the differences in favor of stents for absence of bleeding and device‐related serious adverse events are no longer significant at the P = 0.05 level. Interpretation of the Study Results We are faced with a small randomized trial that was terminated prematurely and did not show statistical significance for its primary endpoint or key secondary endpoints. Although such results generally would not allow a new drug or device to be approved by the Food and Drug Administration, they potentially provide useful evidence for assessing the potential role of stents in clinical practice—especially in the absence of additional higher‐quality data. The morbidity and mortality of EVB refractory to endoscopic and medical therapy are high, treatment is difficult, and balloon tamponade is of unclear efficacy and causes serious and even fatal adverse events. Escorsell et al. show trends to benefit across several outcomes, with P values ≤0.056 for success of therapy.1 The definition of significance as P < 0.05 is merely a convention that indicates we are willing to accept a difference is "real" if the probability the result occurred by chance is less than 5 in 100. Thus, this threshold is a product of accepted practice rather than a physical law, and no appreciable difference exists between P = 0.051 and P = 0.049. Performing a randomized trial in patients with refractory EVB is difficult, as shown by the very slow recruitment in this study; and we may not have additional high‐quality evidence for refractory EVB in the near future. Although this study has important limitations, the totality of evidence on tamponade and stenting from this and other studies leads me to conclude that I would use stenting rather than tamponade in the rare patient with severe refractory EVB. Recent international guidelines similarly concluded that stenting may be a safer option than tamponade for refractory EVB.2 However, the stent studied by Escorsell et al. and others,1 which was specifically designed for EVB, is not available in a number of countries, including the United States; and no information allows us to determine if results with this stent can be generalized to other covered self‐expanding metal stents.