Evaluating TIPS trials: The devil is in the details?

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756–760].) The theoretical advantage of this agent is that it may be safer when used on multiple occasions. Another important aspect of the present study was that it randomized all patients into the different treatment arms, regardless of risk status. Finally, the efficacy of repeated treatments with FG (until certain objective endoscopic end points were achieved) was compared not only with that of a single session of endoscopic treatment (in this case, polidocanol) but also with a single session of FG alone. The rationale for inclusion of this third arm was to prove that any beneficial effect in the multiple-FG group was due to its repeated application and not to any intrinsic superiority of FG by itself. This was a well-designed and carefully conducted trial with an impressively large number of patients that adds to our understanding about bleeding peptic ulcer. The trial convincingly shows the benefits of multiple sessions (mean number of treatments, 1.7) with FG injections over a single treatment with either FG or polidocanol, with a nearly 50% reduction in both the endoscopic as well as the clinically relevant rebleeding rate. The rates of surgery in the three groups (#5%) were not significantly different, probably reflecting the successful use of alternative forms of therapy (thermocoagulation, clipping, or other means). Mortality was unaffected by any approach and was in the range of 4%–5% in all groups. Interestingly, the incidence of adverse effects, including perforation and necrosis, was comparable in all groups. Should we be repeating endoscopy in all patients with a bleeding ulcer who have been successfully treated endoscopically? Regardless of lingering questions about efficacy, the cost itself of such an approach may be prohibitive, with more than 150,000 hospitalizations per year in United States alone ( J Clin Gastroenterol 1988;10:259–680). Clearly, we need to better define what groups are most at risk for rebleeding after initial hemostasis and target this group specifically. Some work in this regard has already been reported (Gastrointest Endosc 1996;43:111–116, Am J Gastroenterol 1993;88:1842–1849). Validation of these risk models will allow for a more cost-effective and rational approach to these patients. What is the best method for retreatment? The experience of at least one other group suggests that thermal methods can be carried out safely at least once again within the first 24 hours of the initial treatment (Endoscopy 1996;28:288– 294). Should this technique be used prophylactically, i.e., regardless of the appearance of the posttreatment ulcer or only if certain stigmata are visible? The latter approach may minimize the risk of injury but requires an accurate method to predict risk based on posttreatment ulcer appearance, for which there is no consensus presently. In conclusion, this is a provocative study that should be followed up by others to define better the natural history of endoscopically treated bleeding ulcers. PANKAJ PASRICHA, M.D.

EVALUATING TIPS TRIALS: THE DEVIL IS IN THE DETAILS? Sanyal AJ, Freedman AM, Luketic VA, Purdum PP, Shiffman ML, Cole PE, Tisnado J, Simmons S (Department of Medicine, Medical College of Virginia, Richmond, Virginia). Transjugular intrahepatic portosystemic shunts compared with endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage. Ann Intern Med 1997;126:849–857. Sanyal et al. studied 100 cirrhotic patients with bleeding esophageal varices, 80 of whom were entered into the study.

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Patients who became hemodynamically stable with endoscopic therapy were then randomized within 72 hours to undergo transjugular intrahepatic portosystemic shunt (TIPS) or sclerotherapy. Approximately half the patients in each group had Child–Pugh class C disease, and 40% had alcoholic liver disease. Sclerotherapy was performed using 5% sodium morrhuate and 12–20 mL per session at 2–3-week intervals. Patients randomized to TIPS underwent duplex ultrasonography to assess shunt patency at day 1, week 1, months 1 and 3, and every 3 months thereafter. Coil embolization of varices was not routinely performed. b-Blocker therapy was discontinued in all patients. Median follow-up was approximately 2.6 years. Rebleeding was comparable in both TIPS and sclerotherapy groups (approximately 23% vs. 21%). However, mortality was significantly lower in the sclerotherapy group (approximately 10% vs. 28%). Rehospitalization rates were similar in the two groups; however, the reasons for rehospitalization differed between the two groups. Patients in the TIPS group were much more likely to be hospitalized for encephalopathy or sepsis than patients in the sclerotherapy group. Patients in the sclerotherapy group were much more likely to be hospitalized for ascites than patients in the TIPS group. The investigators concluded that sclerotherapy rather than TIPS is the preferred treatment for elective management of variceal bleeding in patients with cirrhosis. Cello JP, Ring EJ, Olcott EW, Koch J, Gordon R, Sandhu J, Morgan DR, Ostroff JW, Rockey DC, Bacchetti P, LaBerge J, Lake JR, Somberg K, Doherty C, Davila M, McQuaid K, Wall SD (Gastroenterology Division, San Francisco General Hospital, San Francisco, California). Endoscopic sclerotherapy compared with percutaneous transjugular intrahepatic portosystemic shunt after initial sclerotherapy in patients with acute variceal hemorrhage. Ann Intern Med 1997;126:858–865. Cello et al. published a second study in the same issue as Sanyal et al.; this group randomized 49 patients with acute bleeding from esophageal varices to either endoscopic sclerotherapy or TIPS. All patients were approached for consent and randomization within 24 hours of admission. Entry criteria included the presence of massive or submassive gastrointestinal bleeding (systolic blood pressure ,80 mm Hg or orthostasis). Patients with a prothrombin time prolonged .5 seconds, bilirubin .5 mg/dL, and creatinine .2.5 mg/dL were excluded. Both studies also excluded patients with alcoholic hepatitis. All patients were initially treated with sclerotherapy. Patients randomized to TIPS underwent the procedure within 48 hours. Coil embolization was performed for varices that opacified at portal venography after TIPS. Patients assigned to sclerotherapy underwent sclerotherapy with up to 30 mL of ethonalamine oleate every 2–7 days during the initial hospitalization and then weekly thereafter. A mean of three ultrasound Doppler examinations were performed in the patients undergoing TIPS. Rebleeding was lower in the TIPS group than the sclerotherapy group (13% vs. 48%; P 5 0.012); no difference in mortality was found (33% vs. 32%). There was no difference in the incidence of portosystemic encephalopathy in the two

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groups. The investigators concluded that sclerotherapy or TIPS are both acceptable for management of acute variceal bleeding. Comment. The TIPS was first created in the dog by Josef Rosch in 1969 (Radiology 1969;92:1112–1114). The procedure has proved an important therapy in the treatment of patients with variceal bleeding refractory to medical therapy given the significant risks associated with urgent portosystemic shunt surgery. Furthermore, a previous portacaval shunt may complicate future liver transplantation, a problem that can be avoided by use of TIPS. The relatively noninvasive nature of the procedure and the potential to correct elevated portal pressures and thus provide definitive therapy for variceal bleeding have made TIPS an attractive and widely used modality. However, a number of complications have been associated with this procedure, including hepatic capsular puncture, worsening liver function, pulmonary edema, or sepsis (Radiographics 1993;13:1185–1210). It is appropriate therefore to examine the role of TIPS as a therapeutic modality for variceal bleeding in the context of controlled trials. The studies by Sanyal et al. and Cello et al. obtained discordant results and therefore arrived at different conclusions. Sanyal et al. concluded that TIPS was associated with a higher mortality and was not superior to endoscopic therapy for prevention of variceal rebleeding. The rate of variceal rebleeding in the sclerotherapy group in the Sanyal study was significantly lower (26%) than that reported in most other studies (40%–50%) and therefore did not show a benefit for TIPS in prevention of rebleeding; it is the opinion of the authors that the low rebleeding rates in their study were possibly caused by use of smaller volumes of sclerosant and greater interval between sessions, thus resulting in less bleeding from sclerotherapy ulcers (Sanyal AJ, personal communication, September 1997). If this were the case, differences in rebleeding rates should have been more apparent early rather than late. Such a difference was not apparent from examination of the reported data. Furthermore, the risk of upper gastrointestinal bleeding from nonvariceal sources was not different between the TIPS and sclerotherapy groups in the study by Cello et al., suggesting that sclerotherapy ulcers were not a significant cause for rebleeding. Nevertheless, it remains a possibility based on the Sanyal study that technical factors in endoscopic management of varices may result in much lower rebleeding than has been historically observed. Although Sanyal et al. found a lower survival in the TIPS group, increased mortality could be directly linked to the TIPS in only 3 patients; variceal rebleeding occurred in 2 additional patients in the TIPS arm, and there was mortality due to hemoperitoneum. It is unlikely that sepsis, which occurred months after the procedure, was directly caused by TIPS, and the one hepatoma-related mortality is also unlikely to have been directly TIPS related. However, because a high percentage of patients had Child’s C cirrhosis, one must consider the possibility that TIPS in this group may worsen liver function. Sanyal et al. did not exclude patients with severely decompensated liver disease, as did Cello et al.; it is therefore possible that patient selection may have explained the survival difference between the two studies. Cello et al. reported a lower rebleeding rate with TIPS than sclerotherapy (48% vs. 12%), although there was no significant survival benefit or improvement in health care costs. However, a large percentage of the patients in their study had alcoholic liver disease. As has been pointed out by Conn, studies in which alcoholic liver disease is more common often report higher rebleeding rates (Ann Intern Med 1997;126:907–909); it is possible that ongoing alcohol use or greater noncompliance contributes to rebleeding. Such studies may possibly show a greater benefit for TIPS. Cello et al. also did not report a higher

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rate of portosystemic encephalopathy in the TIPS group, in contrast to Sanyal et al. Exclusion of patients with more advanced liver disease in the Cello study may be responsible for this discrepancy. Other differences between these two studies with regard to patient selection and study design may account for some of the differences in findings. The Cello study included only patients with massive or ‘‘submassive’’ hemorrhage, characterized by hypotension or orthostasis; the Sanyal study included patients with hematemesis and a decrease in serum hemoglobin level of 2 g/dL. There may have been a selection bias toward patients with more severe bleeding in the Cello study. Variceal embolization was not routinely performed in the study by Sanyal et al., whereas this technique was used as part of the standard protocol in the study by Cello et al. Another important difference between the two studies is the time of randomization. Cello et al. randomized patients within 24 hours of admission, whereas Sanyal et al. randomized patients a mean of 10 days after the presentation with acute bleeding. Graham and Smith showed that the greatest risk of mortality in variceal bleeding is during the first week; therefore, it is possible that a selection bias toward patients with less severe bleeding and lower risk of rebleeding was present in the Sanyal study (Gastroenterology 1981;870:800–809). However, it must be remembered that the Graham study was conducted before the era of endoscopic sclerotherapy; the only treatments used were vasopressin alone, Sengstaken–Blakemore tubes, and portosystemic shunt surgery; their findings may not be applicable today. At least two other randomized studies of TIPS vs. endoscopic sclerotherapy for prevention of variceal rebleeding have been published (Lancet 1997;349:1043–1049, Gastroenterology 1996;110:832– 839). Rossle et al. conducted a study with 126 patients receiving either TIPS with or without variceal embolization or endoscopic therapy (banding and/or sclerotherapy) plus propranolol (Lancet 1997;349:1043–1049). The study population in this report was more similar to that in the study by Cello et al. than that studied by Sanyal et al., with a higher percentage of alcoholics and fewer patients with severe liver disease (Child’s C). There was significantly lower variceal rebleeding in the TIPS than endoscopic therapy group at 1 (15% and 41%) and 2 years (21% vs. 52%, respectively); encephalopathy was more frequent in the TIPS group (36% vs. 18%). Cabrera et al. studied 63 patients who had predominantly alcoholic liver disease (.65%) and Child’s class A or B liver disease (Gastroenterology 1996;110:832–839). The rebleeding rate at 1 year was significantly lower in the TIPS group than the sclerotherapy group (23% vs. 52%), and the frequency of encephalopathy was significantly higher in the TIPS group (33% vs. 13%). These later results are very similar to those of Rossle et al. and Cello et al. with regard to variceal rebleeding rates. Jalan et al. have just published a study of TIPS vs. endoscopic band ligation for patients presenting with a first variceal hemorrhage (Hepatology 1997;26:1115–1122). TIPS was associated with lower rebleeding (10% vs. 52%) over a 15-month follow-up period, although no difference in mortality was observed. How can the differences in the findings of Sanyal et al. and Cello et al. be reconciled? I believe these discrepancies can be explained by differences in patient selection and study design. The population studied by Sanyal et al. probably had more advanced liver disease, fewer patients with alcoholic liver disease, and less severe bleeding than that studied by Cello et al. Furthermore, the longer time interval between bleeding episode and randomization may have selected out those with the most severe bleeding and the greatest risk of rebleeding; this may explain the failure to show a benefit in the TIPS group. Another, although less likely, explanation is that the choice of endoscopic technique somehow improved the rebleeding rate. The

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poorer survival in the TIPS group as shown by Sanyal et al. has not been found by others; furthermore, proportional hazards analysis in the Sanyal study failed to demonstrate treatment modality or other relevant variables as independent predictors of survival. Based on these studies, what can be concluded about the role of TIPS with regard to management of variceal rebleeding? It seems reasonable to conclude that in patients with alcoholic liver disease who have Child’s class A or B liver disease and hemodynamically severe variceal bleeding, TIPS after initial stabilization may be comparable or even superior to endoscopic therapy in prevention of variceal rebleeding over 1–2 years of follow-up. TIPS may be particularly attractive in patients in whom compliance with follow-up endoscopy is in doubt. If TIPS is performed, the current data appear to favor routine variceal embolization as an adjunct therapy. However, one must accept an increased risk of hepatic encephalopathy with TIPS, which will occur in a third to 40% of patients. TIPS may be a less attractive therapy in patients with Child’s class C liver disease, particularly if associated with less severe bleeding, and should possibly be reserved for those in whom initial endoscopic therapy fails or who have recurrent bleeding during follow-up endoscopic therapy. However, the utility of the TIPS procedure as a long-term treatment for portal hypertension must ultimately be evaluated in the context of shunt stenosis, which is being increasingly recognized as a management problem in patients who have undergone this procedure. KRIS V. KOWDLEY, M.D.

GASTROESOPHAGEAL REFLUX–INDUCED ASTHMA: NEW INSIGHTS Hamamoto J, Kohrogi H, Kawano O, Iwagoe H, Fujii K, Hirata N, Ando M (First Department of Internal Medicine and Department of Laboratory Medicine, Kumamoto University School of Medicine, Kumamoto, Japan). Esophageal stimulation by hydrochloric acid causes neurogenic inflammation in the airways of guinea pigs. J Appl Physiol 1997;82:738–745. Increasing evidence suggests an association between gastroesophageal reflux (GER) and asthma. On one hand, it has been proposed that asthma predisposes to GER via effects of antiasthmatic medications and increased intrathoracic pressure on the competency of the lower esophageal sphincter. On the other hand, it has been proposed that GER predisposes to asthma via microaspiration of gastric contents and activation of vagally mediated neural reflexes. Recently, attention has focused on the role of sensory neurons, particularly those containing tachykinins such as substance P, as mediators of airway hyperreactivity and inflammation. Substance P is present in esophageal and pulmonary mucosa and is capable of eliciting various effects that could contribute to the changes observed in asthmatic airways including bronchial secretion, smooth muscle contraction, increased vascular permeability, activation of mast cells and lymphocytes, and chemoattraction and adhesion of neutrophils (Eur Respir J 1994;7:1161–1171). The present study was designed to examine whether (1) esophageal stimulation by acid releases substance P from sensory neurons and (2) release of substance P is coupled to plasma extravasation in the airways. A catheter was placed in the midesophagus of guinea pigs.

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The upper and lower portions were ligated to prevent leakage into the airways and communication between the esophagus and stomach. The esophagus was stimulated for 1 minute by instillation of 0.4 mL of 1N HCl or 0.9% saline (pH 6.4). Airway plasma extravasation was measured by quantitating the leakage of intravenously administered Evans blue dye. All animals were pretreated with propranolol and atropine to block b-adrenergic and muscarinic pathways. To deplete sensory transmitters, some guinea pigs were pretreated systemically with the sensory toxin capsaicin. To assess the involvement of substance P, other guinea pigs were pretreated with the neutral endopeptidase inhibitor phosphoramidon, which inhibits the breakdown of substance P, or with a selective substance P receptor antagonist, FK-888. A further subgroup of animals was pretreated with bilateral cervical vagotomy. Intravenous substance P and intraesophageal HCl each significantly increased plasma extravasation into the airway. Extravasation induced by HCl was (1) potentiated by the peptidase inhibitor, phosphoramidon; (2) blocked, in a dosedependent manner, by the substance P receptor antagonist FK-888; and (3) abolished by pretreatment with the sensory toxin capsaicin, even in the presence of phosphoramidon. Vagotomy reduced, by approximately 50%, the plasma extravasation potentiated by phosphoramidon. The investigators concluded that intraesophageal acid releases tachykinins, probably substance P, from sensory neurons, resulting in plasma extravasation in the airways. The neural pathways appear to involve vagal pathways and local axon reflexes. Comment. Asthma is considered a chronic inflammatory disorder of the airways characterized by increased airway reactivity and outflow obstruction. Recent studies have implicated tachykinins, such as substance P, which are distributed within sensory neurons of the lung (Annu Rev Physiol 1987;49:557–572), in the pathogenesis of asthma. Substance P enhances methacholine-induced airway reactivity in asthmatics ( J Appl Physiol 1994;77:1325–1332) and elicits various effects that could contribute to the changes observed in asthmatic airways including smooth muscle contraction, submucosal gland secretion, vasodilation, increased vascular permeability, chemoattraction of eosinophils and neutrophils, enhanced adhesion of neutrophils, and stimulation of lymphocytes, macrophages, and mast cells (Eur Respir J 1994;7:1161–1171). In addition, (1) sputum levels of substance P are 23-fold higher in asthmatics than in controls and are inversely correlated to the decrease in forced expiratory volume in 1 second (FEV1) (Am J Resp Crit Care Med 1995;151:613–617), and (2) messenger RNA for the substance P–preferring NK1 receptor is increased by 50% in the lungs of asthmatics ( J Mol Endocrinol 1993;11:1–7). Several of the newer antiasthmatic medications are thought to act via inhibition of substance P release (e.g., nedocromil sodium and azelastine) (Clin Exp Allergy 1993;23:69–71, J Allergy Clin Immunol 1996;98:S112–S117) or blockade of its effect (e.g., FK-224 and FK-888) (Lancet 1992;340:1248–1251, Am J Respir Crit Care Med 1996;153:936–941). FK224, which blocks both NK1 (i.e., substance P) and NK2 (i.e., neurokinin A) receptors, was shown to inhibit bradykinin-induced bronchoconstriction and cough in a small group of asthmatics. FK-888, a selective NK1-receptor antagonist, decreased